**Autologous Stem Cell Transplantation for Acute Myeloid Leukemia**

[46] Mellqvist UH et al. Improved progression-free survival with bortezomib consolida‐ tion after high dose melphalan: results of a randomized phase III trial [abstract] .

[47] Nooka A et al. The Improved Efficacy of Bortezomib Containing Induction Regimens (BCIR) Versus Non-Bortezomib Containing Induction Regimens (NBCIR) in Trans‐ plant-Eligible Patients with Multiple Myeloma (MM): Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) . 53rd ASH Annual Meeting and Exposition

[48] Durie BGM et al. International uniform response criteria for multiple myeloma. Leu‐

[49] Rajkumar SV et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011;

[50] Paiva B et al. Multiparameter flow cytometric remission is the most relevant prog‐ nostic factor for multiple myeloma patients who undergo autologous stem cell trans‐

[51] Barlogie B,Tricot G. Complete response in myeloma: a Trojan horse? Blood 2006;

[52] Walker R et al. Magnetic resonance imaging in multiple myeloma: diagnostic and

[53] Moreau P et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood

[54] Dick LR,Fleming PE. Building on bortezomob: second-generation proteasome inhibi‐

[55] Sonneveld P et al. Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan (HDM) in new‐ ly diagnosed patients with multiple myeloma (MM): a trial of the European Myelo‐ ma Network EMN . Blood (ASH Annual Meeting abstracts) 2011; 118(21) 290

[56] Jakubowiak AJ et al. Final results of a frontline phase 1/2 study of carfilzomib, lenali‐ domide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). Blood

(ASH Annual Meeting abstracts) 2011; 118(12) 288-289 [abstract 631].

clinical implications. Journal of Clinical Oncology 2007; 25(9) 1121-1128.

tors as anti-cancer therapy. Drug Discovery Today 2010; 15(5-6) 243-249.

Haematologica 2011; 96(s1) S31 [abstract O-11].

2011; abstract 3994.

240 Innovations in Stem Cell Transplantation

117(18) 4691-4695.

108(7) 2134.

2012; 120(5) 947-959.

[abstract 633].

kemia 2006; 20(9) 1467-1473.

plantation. Blood 2008; 112(10) 4017-4023.

Pier Paolo Piccaluga, Stefania Paolini, Giovanna Meloni, Giuseppe Visani and Felicetto Ferrara

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54280

## **1. Introduction**

In the majority of patients, the therapy of acute myeloid leukemia (AML) has a curative in‐ tent and includes two phases, i.e. induction and consolidation. The former aims at complete remission (CR) achievement, the latter at the eradication of residual leukemic cells, which are undetectable at morphologic examination of bone marrow after induction therapy in pa‐ tients in CR. Current induction regimens, conventionally based on the combination of dau‐ norubicin and cytarabine result in CR rates of 60 – 70% of AML patients younger than 65 years; in order to improve both CR rate and quality, different studies tested alternative an‐ thracyclines [1]-[5], higher schedules of Ara-C[6]-[10], the addition of a third cytotoxic drug [11]-[16] and, more recently, the combination with new agents. Overall, results have been disappointing even though the addition of gemtuzumab ozogamycin (GO), an antiCD33 monoclonal antibody conjugated with the cytotoxic agents chalicheamycin, has been report‐ ed to confer a significant advantage in selected patients with AML [17]-[21]. Notwithstand‐ ing, in absence of intensive post-induction therapy virtually all patients will ultimately relapse, therefore consolidation therapy is strictly needed. At present, after CR achievement all patients receive a consolidation chemotherapy based on intermediate or high dose ARA-C and then in young adult patients three options can be considered, i.e. allogeneic stem cell transplantation (allo-SCT), autologous SCT (ASCT) or repetitive intensive consolidation che‐ motherapy cycles (ICC) with high or intermediate dose ARA-C [22]-[37], depending on age, disease risk and donor availability. In particular, it is widely accepted that ICC and ASCT would be limited to patients with favorable risk, such as AML with t(8;21), AML with inv(16) or t(16;16) and AML with normal karyotype with NPM1 mutation in absence of mu‐

© 2013 Piccaluga et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tations of FLT3/ITD gene [38], [39]. In the remaining patient population, allo-SCT must be considered when age and performance status result in an acceptable risk/benefit ratio. In this regard, it should be considered that in the last years morbidity and mortality from allo-SCT have been considerably reduced; in addition, the introduction into daily practice of re‐ duced intensity conditioning (RIC) has allowed to offer the procedure to selected old and/or previously not eligible patient population.

abine (HD-AC) and Amsacrine. Subsequently, patients with HLA identical donor were allo-transplanted, whereas patients without HLA identical donor were randomized to re‐ ceive ASCT or a second consolidation (ICC) with daunorubicine and HD-AC. The CR rate after induction therapy was 66%. The relapse rate were 40% in the two arms (ASCT) and 57% (ICC), respectively; DFS was longer for patients submitted to ASCT compared to patients submitted to ICC (48% vs 30%; p=0.05). However the OS was not significant‐ ly superior in the ASCT group, due to the greater ability of ASCT to rescue relapsed pa‐

Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

http://dx.doi.org/10.5772/54280

243

In 1997 Harousseau and Colleagues reported data on 517 eligible patients (15-50 years of age) affected by previously untreated AML. Patients received 3 - 4 courses of conventional induction treatment (Ara-C: 200 mg/sqm/day for 7 consecutive days with either idarubicin administered intravenously on days 1 - 5 at a daily dose of 8 mg/sqm or rubidazone admin‐ istered intravenously on days 1 - 4 at a daily dose of 200 mg/sqm). Patients aged 40 year or younger, in CR after induction therapy, were assigned to SCT if an HLA identical donor was available. All other patients received a first course of HD-Ara-C (3 gr/sqm) administered ev‐ ery 12 hours along 4 days (ICC) and then were randomized to receive either a second course of ICC or an ASCT. Eighty-eight patients out of 517 received an SCT, while 164 out of 517 were eligible for randomization (75 received ASCT, 71 received ICC). No differences in terms of OS and DFS were observed between the two arms: the 4 years DFS was 44 +/- 5.5% in ASCT group and 40.5 +/- 5.5% in ICC group (p value 0.41); the 4 years OS was 50 +/- 6% in ASCT group and 54.5 +/- 6% in ICC group (p value 0.72). The retrospective analysis of DFS and OS based on the cytogenetic risk could not detect any differences between the ASCT

In 1998 Cassileth et al. reported on 740 AML patients treated with standard 3/7 – 3/5 induc‐ tion – consolidation chemotherapy cycles. Patients without an HLA identical donor were randomized between ASCT and HD-AC. The overall CR rate was 70%; the 4-years-DFS was 35% in both groups; the 4 years OS was 43% in ASCT group and 52% in ICC group respec‐

The first report on the MRC AML 10 trial was published in 1998 [29]. Patients were firstly randomly assigned to different induction chemotherapy regimens (DAT vs. ADE); all pa‐ tients achieving CR after two induction courses received a third consolidation chemothera‐ py course (MACE). Patients who lacked an HLA-matched sibling donor were randomized to receive one more chemotherapy course (MidAC) followed by either ASCT or no further therapy; patients with an HLA-matched sibling donor were assigned to receive an SCT. Ba‐ sis on the intention to treat analysis the number of relapses was significantly lower in the ASCT group than in the group assigned no further treatment (37% vs. 58%; p= 0.0007), re‐ sulting in superior DFS at 7 years (53% vs. 40%; p=0.04). No difference in terms of OS was observed. Of note, however, in this trial only 38% of patients available for randomization

Tsimberidou et al. then reported data on 120 patients with de novo AML in 2003. All pa‐ tients were treated with standard 3/7 regimen (2 courses) and if in CR underwent a first HD-AC course. All patients aged less than 50 years and with an HLA compatible donor received

tients in the ICC arm [24].

group and the ICC group [28].

tively (p= 0.05) [25].

were randomized [29].

Currently, even in patients with favourable prognostic factors at diagnosis, the role of ASCT remains unclear although most studies that have compared ASCT with ICC demonstrated a significantly lower rate of relapse following ASCT (5,6). Results in terms of survival were, however, less encouraging because of transplant-related deaths and the low rate of second CR in patients who relapsed after ASCT, therefore in the last year ASCT has become less popular, mainly in USA. Notwithstanding, different considerations should be made: first, both the occurrence of toxicity and mortality related to ASCT have greatly decreased since use of peripheral-blood stem cells was introduced, even in older patients. Second, reduction of relapse rate would represent a main therapeutic objective in the therapy of AML, just as it is any malignant disorder. Finally, consolidation therapy based on repeated courses of highdose or intermediate-dose cytarabine is probably more toxic and costly than ASCT and is poorly feasible in patients aged over 55-60 years. In elderly patients, particularly, the dose intensification by either ASCT or ICC has failed so far to induce a significant benefit [40]- [42]. Therefore, novel more rational targeted agents are particularly warranted in this set‐ ting. On the other hand, two important conditions are necessary in order to perform ASCT: CR achievement and collection of an adequate number of CD34+ cells (> 2 x 106 /Kg). As the latter aspect is concerned, it should be mentioned that a previous history of myeloid disor‐ der (especially myelodysplastic syndrome), advanced age and the use of certain drugs dur‐ ing the induction and consolidation phases (e.g. fludarabine [43]) can significantly impair the possibility to collect an adequate number of cells.

Overall, data from the literature are controversial, but it has been definitively demonstrated that ASCT provides better results in patients with favorable risk diseases and low amount of minimal residual disease after induction/consolidation therapy. In the last years, a few com‐ plete meta-analyses and extensive reviews tried to draw some conclusions but were not able to indicate definite guidelines [44]-[46].

In this chapter, the authors review the current knowledge on the use of SCT in post-consoli‐ dation therapy of AML, based on their own experience and the most recent literature data, by mainly focusing on randomized clinical trials (RCT).

## **2. Randomized clinical trials comparing autologous stem cell transplantation and chemotherapy or no further therapy**

In 1995 Zittoun et al. for the EORTC-GIMEMA groups reported on 941 AML patients treated with one or two cycles of standard Daunorubicine/Cytarabine schedule (3/7). Pa‐ tients obtaining CR were submitted to one consolidation cycle including high-dose cytar‐ abine (HD-AC) and Amsacrine. Subsequently, patients with HLA identical donor were allo-transplanted, whereas patients without HLA identical donor were randomized to re‐ ceive ASCT or a second consolidation (ICC) with daunorubicine and HD-AC. The CR rate after induction therapy was 66%. The relapse rate were 40% in the two arms (ASCT) and 57% (ICC), respectively; DFS was longer for patients submitted to ASCT compared to patients submitted to ICC (48% vs 30%; p=0.05). However the OS was not significant‐ ly superior in the ASCT group, due to the greater ability of ASCT to rescue relapsed pa‐ tients in the ICC arm [24].

tations of FLT3/ITD gene [38], [39]. In the remaining patient population, allo-SCT must be considered when age and performance status result in an acceptable risk/benefit ratio. In this regard, it should be considered that in the last years morbidity and mortality from allo-SCT have been considerably reduced; in addition, the introduction into daily practice of re‐ duced intensity conditioning (RIC) has allowed to offer the procedure to selected old and/or

Currently, even in patients with favourable prognostic factors at diagnosis, the role of ASCT remains unclear although most studies that have compared ASCT with ICC demonstrated a significantly lower rate of relapse following ASCT (5,6). Results in terms of survival were, however, less encouraging because of transplant-related deaths and the low rate of second CR in patients who relapsed after ASCT, therefore in the last year ASCT has become less popular, mainly in USA. Notwithstanding, different considerations should be made: first, both the occurrence of toxicity and mortality related to ASCT have greatly decreased since use of peripheral-blood stem cells was introduced, even in older patients. Second, reduction of relapse rate would represent a main therapeutic objective in the therapy of AML, just as it is any malignant disorder. Finally, consolidation therapy based on repeated courses of highdose or intermediate-dose cytarabine is probably more toxic and costly than ASCT and is poorly feasible in patients aged over 55-60 years. In elderly patients, particularly, the dose intensification by either ASCT or ICC has failed so far to induce a significant benefit [40]- [42]. Therefore, novel more rational targeted agents are particularly warranted in this set‐ ting. On the other hand, two important conditions are necessary in order to perform ASCT:

latter aspect is concerned, it should be mentioned that a previous history of myeloid disor‐ der (especially myelodysplastic syndrome), advanced age and the use of certain drugs dur‐ ing the induction and consolidation phases (e.g. fludarabine [43]) can significantly impair

Overall, data from the literature are controversial, but it has been definitively demonstrated that ASCT provides better results in patients with favorable risk diseases and low amount of minimal residual disease after induction/consolidation therapy. In the last years, a few com‐ plete meta-analyses and extensive reviews tried to draw some conclusions but were not able

In this chapter, the authors review the current knowledge on the use of SCT in post-consoli‐ dation therapy of AML, based on their own experience and the most recent literature data,

In 1995 Zittoun et al. for the EORTC-GIMEMA groups reported on 941 AML patients treated with one or two cycles of standard Daunorubicine/Cytarabine schedule (3/7). Pa‐ tients obtaining CR were submitted to one consolidation cycle including high-dose cytar‐

**2. Randomized clinical trials comparing autologous stem cell**

**transplantation and chemotherapy or no further therapy**

cells (> 2 x 106

/Kg). As the

previously not eligible patient population.

242 Innovations in Stem Cell Transplantation

CR achievement and collection of an adequate number of CD34+

the possibility to collect an adequate number of cells.

by mainly focusing on randomized clinical trials (RCT).

to indicate definite guidelines [44]-[46].

In 1997 Harousseau and Colleagues reported data on 517 eligible patients (15-50 years of age) affected by previously untreated AML. Patients received 3 - 4 courses of conventional induction treatment (Ara-C: 200 mg/sqm/day for 7 consecutive days with either idarubicin administered intravenously on days 1 - 5 at a daily dose of 8 mg/sqm or rubidazone admin‐ istered intravenously on days 1 - 4 at a daily dose of 200 mg/sqm). Patients aged 40 year or younger, in CR after induction therapy, were assigned to SCT if an HLA identical donor was available. All other patients received a first course of HD-Ara-C (3 gr/sqm) administered ev‐ ery 12 hours along 4 days (ICC) and then were randomized to receive either a second course of ICC or an ASCT. Eighty-eight patients out of 517 received an SCT, while 164 out of 517 were eligible for randomization (75 received ASCT, 71 received ICC). No differences in terms of OS and DFS were observed between the two arms: the 4 years DFS was 44 +/- 5.5% in ASCT group and 40.5 +/- 5.5% in ICC group (p value 0.41); the 4 years OS was 50 +/- 6% in ASCT group and 54.5 +/- 6% in ICC group (p value 0.72). The retrospective analysis of DFS and OS based on the cytogenetic risk could not detect any differences between the ASCT group and the ICC group [28].

In 1998 Cassileth et al. reported on 740 AML patients treated with standard 3/7 – 3/5 induc‐ tion – consolidation chemotherapy cycles. Patients without an HLA identical donor were randomized between ASCT and HD-AC. The overall CR rate was 70%; the 4-years-DFS was 35% in both groups; the 4 years OS was 43% in ASCT group and 52% in ICC group respec‐ tively (p= 0.05) [25].

The first report on the MRC AML 10 trial was published in 1998 [29]. Patients were firstly randomly assigned to different induction chemotherapy regimens (DAT vs. ADE); all pa‐ tients achieving CR after two induction courses received a third consolidation chemothera‐ py course (MACE). Patients who lacked an HLA-matched sibling donor were randomized to receive one more chemotherapy course (MidAC) followed by either ASCT or no further therapy; patients with an HLA-matched sibling donor were assigned to receive an SCT. Ba‐ sis on the intention to treat analysis the number of relapses was significantly lower in the ASCT group than in the group assigned no further treatment (37% vs. 58%; p= 0.0007), re‐ sulting in superior DFS at 7 years (53% vs. 40%; p=0.04). No difference in terms of OS was observed. Of note, however, in this trial only 38% of patients available for randomization were randomized [29].

Tsimberidou et al. then reported data on 120 patients with de novo AML in 2003. All pa‐ tients were treated with standard 3/7 regimen (2 courses) and if in CR underwent a first HD-AC course. All patients aged less than 50 years and with an HLA compatible donor received an SCT; patient aged more than 50 years or without an HLA-matched sibling donor were randomly assigned to receive a second HD-Ara course or an ASCT. With a median followup of 43 months the 3-year failure free survival rates was 42% for patients receiving ASCT and 33% for patients receiving conventional chemotherapy [33].

ent overall survival. Thus, they did not recommend ASCT as routine options for AML pa‐ tients in first CR [45]. Thereafter, Visani and Colleagues, based on evidence based medicine (EBM) criteria, considered 6 RCT evaluating the role of ASCT and concluded that due to the heterogeneity of AML biology (i.e. molecular genetics), further studies specifically dedicated to the different entities were probably necessary to build robust recommendation according

Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

http://dx.doi.org/10.5772/54280

245

More recently, the HOVON Group reported the results of a prospective, randomized phase 3 trial evaluating ASCT vs. ICC in newly diagnosed AML patients in first CR (CR1) [48]. Pa‐ tients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligi‐ ble for allogeneic SCT were randomized between ICC (including etoposide and mitoxantrone) or ASCT (Bu/Cy). More than 90% of randomized patients received their as‐ signed treatment (ICC, n = 259; ASCT, n = 258),. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs. 70%, P = 0.02) and better relapse-free survival at 5 years (38% vs. 29%,P =0.065) with nonrelapse mortality of 4% vs. 1% in the chemotherapy arm (P =0.02). OS was similar (44% vs. 41% at 5 years, P =0.86), possibly because of more opportunities for salvage with second-line

Finally, Pfirman et al reported the results of the AML96 trial [49], aiming to differentiate groups of patients according to the treatments that would provide them optimum benefit. Five hundred eighty six AML patients (aged below 60 years) - excluding those with t(8;21) – in CR1 after double induction treatment were consolidated with SCT or ASCT, or ICC con‐ taining HD-AC, in a priority-based and risk-adapted manner. The association between po‐ tentially prognostic variables and OS was assessed and a post-remission treatment (PRT) score was developed in 452 patients with a complete dataset. This score was then validated in additional 407 patients from the AML2003 trial. Age, percentage of CD34-positive blasts, FLT3-ITD mutant-to-wild-type ratio, cytogenetic risk, and de-novo or secondary AML were identified as independent prognostic factors, and included in the PRT score. Accordingly, patients were separated into three groups: favorable (N=190; 3-year survival 68%), inter‐ mediate (N=198; 49%), and unfavorable (n=64; 20%). These results were confirmed in the AML2003 trial dataset: 3-year survival for the favorable group (n=265) was 69%, for the in‐ termediate group (n=114) it was 61%, and for the unfavorable group (n=28) it was 46%. Therefore, the 3 groups presented with significantly different survival probabilities (p=0.015). Additionally, the Authors found that in the favorable group, patients who re‐ ceived SCT (n=60) had higher survival probabilities (82%) than did those given chemothera‐ py (n=56, 55%; p=0.0012) or ASCT (n=74, 66%; p=0.044). In the intermediate PRT score group, patients receiving ASCT (n=69) had the best survival probabilities (62%) compared with

chemotherapy and SCT in patients relapsing on the chemotherapy arm. [48].

those given chemotherapy (n=72, 41%; p=0.0006) or SCT (n=57, 44%; p=0.0045).

Results of the above mentioned studies on ASCT are summarized in Table 1.

younger with an intermediate PRT score.

Overall, the study thus supported the use of autologous HSCT in patients aged 60 years or

to EBM rules [46].

Subsequently, Breems et al in 2005 reported data on 646 patients enrolled in the HOVO/ SAKK AML4 trial. After two cycle of induction therapy combining cytarabine with daunor‐ ubicine (first course) and amsacrine (second course), CR patients (75%) were addressed to a consolidation therapy with mitoxantrone and VP16. Eighty-one patients received SCT. Pa‐ tients non eligible for SCT were randomized between ASCT (66 patients) and no further therapy (46 patients). After a median follow up of 154 months, there were no statistically significant differences concerning DFS, OS and relapse rate within the two randomization arms. There was a trend towards a better OS of the non-autografted patients. This was asso‐ ciated with a higher, though non significant, incidence of death in CR within the auto-trans‐ planted group with respect to the no treatment group. The 5 years OS after relapse for patients previously auto-grafted was significantly shorter with respect to patients who re‐ ceived no further treatment [34].

A large European intergroup trial [47] later evaluated HD-AC induction and escalation of post-remission therapy in a 2-stage RCT. Patients under the age of 60 years were random‐ ized to 1 of 2 induction courses (double HD-AC vs. standard cytarabine/HD-AC). Patients in remission received a third cycle of chemotherapy followed by a second randomization to ASCT or maintenance chemotherapy. Fifty-one percent assigned to maintenance received the assigned therapy, while only 24% received the assigned ASCT. Three-year remission du‐ ration was 50% versus 44%, 3-year relapse-free survival was 48% versus 43% for mainte‐ nance and ASCT, respectively, and there was no significant difference between the 2 arms when stratified according to cytogenetic risk profile [47].

An update of the AML10 study was then reported in 2006 [35]. Briefly, The overall survival of patients allocated to autologous transplantation was better than for those in the no-fur‐ ther-therapy arm (53% vs. 45%) at 10 years, with 165 patients at risk at that time point. Of note, although this difference was not statistically significant on a log-rank analysis (P=.09), the Kaplan-Meier plots clearly diverged after the first 3 years, the difference becoming sig‐ nificant. This was related to a highly significant reduction in relapse risk in the autograft arm (40% vs. 58%; P=.0005), with consequent improved DFS in the ASCT arm (50% vs. 39%; P=.03), a data which was partially obscured by a higher risk of death in remission (16% vs. 6%; P=.02). Overall, the study suggested a survival benefit with ASCT in patients in the good- and standard-risk groups but not in the poor-risk group. Conversely, it was unclear if any specific age group benefited [35].

Based on these studies, a couple of systematic meta-analyses and reviews, tried to delineate some possible indications. However, many data were conflicting a definitive recommenda‐ tions appeared difficult. Particularly, Nathan and Colleagues performed a comprehensive meta-analysis on consolidation therapy for AML. In particular, they analyzed 6 studies in‐ cluding 1044 patients randomly assigned t receive ASCT vs. ICC (5 studies), or ASCT vs. no further treatment (1 study). Patients receiving ASCT had a better disease free but not differ‐ ent overall survival. Thus, they did not recommend ASCT as routine options for AML pa‐ tients in first CR [45]. Thereafter, Visani and Colleagues, based on evidence based medicine (EBM) criteria, considered 6 RCT evaluating the role of ASCT and concluded that due to the heterogeneity of AML biology (i.e. molecular genetics), further studies specifically dedicated to the different entities were probably necessary to build robust recommendation according to EBM rules [46].

an SCT; patient aged more than 50 years or without an HLA-matched sibling donor were randomly assigned to receive a second HD-Ara course or an ASCT. With a median followup of 43 months the 3-year failure free survival rates was 42% for patients receiving ASCT

Subsequently, Breems et al in 2005 reported data on 646 patients enrolled in the HOVO/ SAKK AML4 trial. After two cycle of induction therapy combining cytarabine with daunor‐ ubicine (first course) and amsacrine (second course), CR patients (75%) were addressed to a consolidation therapy with mitoxantrone and VP16. Eighty-one patients received SCT. Pa‐ tients non eligible for SCT were randomized between ASCT (66 patients) and no further therapy (46 patients). After a median follow up of 154 months, there were no statistically significant differences concerning DFS, OS and relapse rate within the two randomization arms. There was a trend towards a better OS of the non-autografted patients. This was asso‐ ciated with a higher, though non significant, incidence of death in CR within the auto-trans‐ planted group with respect to the no treatment group. The 5 years OS after relapse for patients previously auto-grafted was significantly shorter with respect to patients who re‐

A large European intergroup trial [47] later evaluated HD-AC induction and escalation of post-remission therapy in a 2-stage RCT. Patients under the age of 60 years were random‐ ized to 1 of 2 induction courses (double HD-AC vs. standard cytarabine/HD-AC). Patients in remission received a third cycle of chemotherapy followed by a second randomization to ASCT or maintenance chemotherapy. Fifty-one percent assigned to maintenance received the assigned therapy, while only 24% received the assigned ASCT. Three-year remission du‐ ration was 50% versus 44%, 3-year relapse-free survival was 48% versus 43% for mainte‐ nance and ASCT, respectively, and there was no significant difference between the 2 arms

An update of the AML10 study was then reported in 2006 [35]. Briefly, The overall survival of patients allocated to autologous transplantation was better than for those in the no-fur‐ ther-therapy arm (53% vs. 45%) at 10 years, with 165 patients at risk at that time point. Of note, although this difference was not statistically significant on a log-rank analysis (P=.09), the Kaplan-Meier plots clearly diverged after the first 3 years, the difference becoming sig‐ nificant. This was related to a highly significant reduction in relapse risk in the autograft arm (40% vs. 58%; P=.0005), with consequent improved DFS in the ASCT arm (50% vs. 39%; P=.03), a data which was partially obscured by a higher risk of death in remission (16% vs. 6%; P=.02). Overall, the study suggested a survival benefit with ASCT in patients in the good- and standard-risk groups but not in the poor-risk group. Conversely, it was unclear if

Based on these studies, a couple of systematic meta-analyses and reviews, tried to delineate some possible indications. However, many data were conflicting a definitive recommenda‐ tions appeared difficult. Particularly, Nathan and Colleagues performed a comprehensive meta-analysis on consolidation therapy for AML. In particular, they analyzed 6 studies in‐ cluding 1044 patients randomly assigned t receive ASCT vs. ICC (5 studies), or ASCT vs. no further treatment (1 study). Patients receiving ASCT had a better disease free but not differ‐

and 33% for patients receiving conventional chemotherapy [33].

when stratified according to cytogenetic risk profile [47].

ceived no further treatment [34].

244 Innovations in Stem Cell Transplantation

any specific age group benefited [35].

More recently, the HOVON Group reported the results of a prospective, randomized phase 3 trial evaluating ASCT vs. ICC in newly diagnosed AML patients in first CR (CR1) [48]. Pa‐ tients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligi‐ ble for allogeneic SCT were randomized between ICC (including etoposide and mitoxantrone) or ASCT (Bu/Cy). More than 90% of randomized patients received their as‐ signed treatment (ICC, n = 259; ASCT, n = 258),. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs. 70%, P = 0.02) and better relapse-free survival at 5 years (38% vs. 29%,P =0.065) with nonrelapse mortality of 4% vs. 1% in the chemotherapy arm (P =0.02). OS was similar (44% vs. 41% at 5 years, P =0.86), possibly because of more opportunities for salvage with second-line chemotherapy and SCT in patients relapsing on the chemotherapy arm. [48].

Finally, Pfirman et al reported the results of the AML96 trial [49], aiming to differentiate groups of patients according to the treatments that would provide them optimum benefit. Five hundred eighty six AML patients (aged below 60 years) - excluding those with t(8;21) – in CR1 after double induction treatment were consolidated with SCT or ASCT, or ICC con‐ taining HD-AC, in a priority-based and risk-adapted manner. The association between po‐ tentially prognostic variables and OS was assessed and a post-remission treatment (PRT) score was developed in 452 patients with a complete dataset. This score was then validated in additional 407 patients from the AML2003 trial. Age, percentage of CD34-positive blasts, FLT3-ITD mutant-to-wild-type ratio, cytogenetic risk, and de-novo or secondary AML were identified as independent prognostic factors, and included in the PRT score. Accordingly, patients were separated into three groups: favorable (N=190; 3-year survival 68%), inter‐ mediate (N=198; 49%), and unfavorable (n=64; 20%). These results were confirmed in the AML2003 trial dataset: 3-year survival for the favorable group (n=265) was 69%, for the in‐ termediate group (n=114) it was 61%, and for the unfavorable group (n=28) it was 46%. Therefore, the 3 groups presented with significantly different survival probabilities (p=0.015). Additionally, the Authors found that in the favorable group, patients who re‐ ceived SCT (n=60) had higher survival probabilities (82%) than did those given chemothera‐ py (n=56, 55%; p=0.0012) or ASCT (n=74, 66%; p=0.044). In the intermediate PRT score group, patients receiving ASCT (n=69) had the best survival probabilities (62%) compared with those given chemotherapy (n=72, 41%; p=0.0006) or SCT (n=57, 44%; p=0.0045).

Overall, the study thus supported the use of autologous HSCT in patients aged 60 years or younger with an intermediate PRT score.

Results of the above mentioned studies on ASCT are summarized in Table 1.


**Author Population – Study design Outcome** *Pvalues*

Induction: 2 cycles of idarubicine and cytarabine Consolidation: idarubicine and cytarabine - If CR and HLA compatible donor: allo-SCT (N=113) - If not HLA compatible donor: randomization au‐ to-SCT (N =116) vs. HD-Cytarabine (N = 117)

1509 previously untreated AML patients aged less

*Study design:* - 2 Induction: Daunorubicine, Cytarabine, Thio‐




646 previously untreated AML patients (< 60 years)


Burnett et al

Tsimberidou et al

Breems et al

**Auto-SCT Chemotherapy/no**

Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

than < 56 yrs 10 yrs DFS: 50% 10 yrs DFS: 39% 0.03

Relapse rate at 10 yrs: 40%

*Study design:* 3 yrs FFS: 42% 3 yrs FFS: 33% NS

5 yrs DFS: about 35%

guanine vs Daunorubicine, Cytarabine, VP-16 10 yrs OS: 53% 10 yrs OS : 45% 0.009

120 previously untreated AML patients (<60 yrs) 3 yrs OS: 58% 3 yrs OS: 46% NS

*Study design:* 5 yrs OS : about

**further therapy**

http://dx.doi.org/10.5772/54280

247

Relapse rate at 10 yrs: 58%

5 yrs DFS: about 37%

45% 5 yrs OS : about 55% NS

0.0005

NS


**Author Population – Study design Outcome** *Pvalues*

990 patients (< 59 y) previously untreated AML.




If CR, age <40 yrs and HLA compatible donor: allo-


(16-55 yrs)

Zittoun et al

246 Innovations in Stem Cell Transplantation

Harousseau et al

Cassileth et al

**Auto-SCT Chemotherapy/no**

(941 evaluable) 4 yrs DFS: 48 ± 5% 4 yrs DFS: 30 ± 5% 0.05

*Study design:* 4 yrs OS : 56 ± 5% 4 yrs OS : 56 ± 5% NS

517 previously untreated AML patients (15-50 yrs) 4 yrs DFS: 44 ± 5.5% 4 y DFS: 40.5 ± 5.5% NS

zone. If no CR: 2nd cycle *Low risk group*

*Study design:* 4 yrs OS: 50 ± 6% 4 y OS: 54.5 ± 6%

zone 4 yrs DFS: 50 ± 9% 4 yrs DFS : 56 ± 11% NS

SCT (N=88) 4 yrs OS: 59 ± 9% 4 yrs OS: 71 ± 8% NS




*Study design:* 4 yrs OS: 43±9 % 4 yrs OS: 52±9 % P=0.05

772 previously untreated AML patients 4 yrs DFS: 35±9 % 4 yrs DFS: 35±9 % NS

*Intermediate risk group*

*High risk group*





NS

NS

NS

**further therapy**



**3. Discussion and perspectives**

age and comorbidities [50].

[17], [19]-[21], [51]-[55].

therapy and ASCT.

Current intensive induction chemotherapy for patients with AML produces CR rates higher than 60-65 %; however, less than 30% of patients still survive for more 5 years free of disease. In this context, the aim of post-remission treatment is to eradicate clonogenic leukemic cells, which persists after induction and are ultimately able to induce disease relapse. Nonetheless, the optimal form of treatment is still under debate. As discussed, three main strategies are used to prevent relapse in patients with AML in first CR, including intensive chemotherapy based on intermediate-dose or high-dose cytarabine, and allogeneic and autologous hemopoietic stem cell transplantation. The choice among these approaches for an individual patient relies on two main factors, namely the expected risk of relapse as determined by biological features of leuke‐ mic cells and expected morbidity and mortality associated with a specific option, according to

Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

http://dx.doi.org/10.5772/54280

249

Intensive chemotherapy (ICC) proved to be useful for improving AML patients outcome

On the other hand, allogeneic SCT was demonstrated to be the most effective strategy to re‐ duce the relapse risk [24], [25], [28], [29]. However, it is associated with a high-risk of treat‐ ment-related morbidity and mortality (TRM), and it is conventionally offered to younger patients with a HLA-matched sibling or unrelated donor. Of note, in the last years several evidences emerged that allogeneic SCT should not be offered as first option to patients with relatively favorable biological characteristics. The latter include a few genetic abnormalities – t(8;21)(q23;q22), inv(16)(p13q22), and t(15;17)(q22;q21) – as well as the presence of somatic mutations of *NMP1* and/or *CEBPA* genes in absence of other abnormalities. Therefore, for these patients, with the exception of M3 patients that can benefit from specific targeted agents, once achieved CR, the most suitable therapeutic options remain intensive chemo‐

ASCT is an alternative approach to deliver an effective anti-leukemic myeloablative thera‐ py to AML patients in CR, when a donor is not available. It has been demonstrated that ASCT is feasible and effective in AML, provided that an adequate induction/consolida‐ tion treatment has previously determined an effective in vivo purging. In fact, the results obtained with ASCT can be significantly affected by other relevant factors, including in‐ tensity of induction and consolidation chemotherapy as well as conditioning regimens, which strongly influencing the MRD burden before the procedure is performed [50]. Bear‐ ing this in mind, it is not surprising that the several RCT trying to define the role of ASCT as post-remission therapy in AML ended up with discrepant result. In particular, the nine largest studies, though considering 2,894 patients assigned to either ASCT or che‐ motherapy/no further therapy (among more than 8,000 enrolled ones) did not reach defin‐ itive conclusions (Table 1). In fact, although a reduced relapse risk was often recorded, only one study provided evidences of survival advantages for patients receiving ASCT, considering the whole population [35], while one assessed a significant advantage only in

**Table 1.** Summary of the most relevant randomized clinical trials evaluating the role of ASCT in AML

## **3. Discussion and perspectives**

**Author Population – Study design Outcome** *Pvalues*




*Study design:* 1st Randomization at induction: TAM-HAM vs. HAM-HAM

TAD: thioguanine, cytarabine, and daunorubicin HAM: cytarabine and mitoxantrone Consolidation: TAD 2nd Randomization (auto-SCT, N=429 vs. mantei‐ nance, N = 411) If eligible and compatible donor : allo-SCT (N= 128)

2,017 AML patients (age ≤ 60 years) Induction 1: cytarabine and idarubicinInduction 2:

Randomization to ASCT (N=258) vs. Chemothera‐

Assigment to ASCT (N=191) vs. Chemotherapy

**Table 1.** Summary of the most relevant randomized clinical trials evaluating the role of ASCT in AML

Buchner et al.

248 Innovations in Stem Cell Transplantation

Vellenga 2011

Pfirman 2012

**Auto-SCT Chemotherapy/no**

within 9 months

5 yrs OS after re‐ lapse: about 5%

840 AML/high-risk MDS patients (age ≤ 60 years) 3 yrs DFS: 48% 3 yrs DFS: 46% 0.65

cytarabine and amsacrine 5 yrs DFS: 38% 5 yrs DFS: 29% 0.065

(N=223) 3 yrs OS: 66% 3 yrs OS : 55%

py (N=259) Relapse rate: 58% Relapse rate: 70% 0.02

Consolidation: etoposide and mitoxantrone 5 yrs OS: 44% 5 yrs OS : 41% 0.86

1,151 AML patients (age ≤ 60 years) *Favorable PRT:*

Assigment to SCT (N=172) *Intermediate PRT:*

**further therapy**

1 pts died in CR within 9 months

5 yrs OS after re‐ lapse: about 25%

3 yrs OS : 43% 3 yrs OS : 41% 0.52

3 yrs OS: 62% 3 yrs OS : 41% 0.0006

*Adverse PRT:* 3 yrs OS: 7% 3 yrs OS : 19% NS

0.003

Current intensive induction chemotherapy for patients with AML produces CR rates higher than 60-65 %; however, less than 30% of patients still survive for more 5 years free of disease. In this context, the aim of post-remission treatment is to eradicate clonogenic leukemic cells, which persists after induction and are ultimately able to induce disease relapse. Nonetheless, the optimal form of treatment is still under debate. As discussed, three main strategies are used to prevent relapse in patients with AML in first CR, including intensive chemotherapy based on intermediate-dose or high-dose cytarabine, and allogeneic and autologous hemopoietic stem cell transplantation. The choice among these approaches for an individual patient relies on two main factors, namely the expected risk of relapse as determined by biological features of leuke‐ mic cells and expected morbidity and mortality associated with a specific option, according to age and comorbidities [50].

Intensive chemotherapy (ICC) proved to be useful for improving AML patients outcome [17], [19]-[21], [51]-[55].

On the other hand, allogeneic SCT was demonstrated to be the most effective strategy to re‐ duce the relapse risk [24], [25], [28], [29]. However, it is associated with a high-risk of treat‐ ment-related morbidity and mortality (TRM), and it is conventionally offered to younger patients with a HLA-matched sibling or unrelated donor. Of note, in the last years several evidences emerged that allogeneic SCT should not be offered as first option to patients with relatively favorable biological characteristics. The latter include a few genetic abnormalities – t(8;21)(q23;q22), inv(16)(p13q22), and t(15;17)(q22;q21) – as well as the presence of somatic mutations of *NMP1* and/or *CEBPA* genes in absence of other abnormalities. Therefore, for these patients, with the exception of M3 patients that can benefit from specific targeted agents, once achieved CR, the most suitable therapeutic options remain intensive chemo‐ therapy and ASCT.

ASCT is an alternative approach to deliver an effective anti-leukemic myeloablative thera‐ py to AML patients in CR, when a donor is not available. It has been demonstrated that ASCT is feasible and effective in AML, provided that an adequate induction/consolida‐ tion treatment has previously determined an effective in vivo purging. In fact, the results obtained with ASCT can be significantly affected by other relevant factors, including in‐ tensity of induction and consolidation chemotherapy as well as conditioning regimens, which strongly influencing the MRD burden before the procedure is performed [50]. Bear‐ ing this in mind, it is not surprising that the several RCT trying to define the role of ASCT as post-remission therapy in AML ended up with discrepant result. In particular, the nine largest studies, though considering 2,894 patients assigned to either ASCT or che‐ motherapy/no further therapy (among more than 8,000 enrolled ones) did not reach defin‐ itive conclusions (Table 1). In fact, although a reduced relapse risk was often recorded, only one study provided evidences of survival advantages for patients receiving ASCT, considering the whole population [35], while one assessed a significant advantage only in patients with an intermediate prognostic score [49]. Indeed, in most instances, the re‐ duced leukemia recurrence was balanced by an increase TRM. In this regard, however, it should be mentioned that in the last years the mortality of ASCT has definitely declined, possibly challenging some of the results published so far. Moreover, reduction of the re‐ lapse rate is a pivotal objective in the treatment of AML, as the only way toward the cure. In addition, the continuous and very fast improvement in our knowledge of the biology of the disease on one hand clearly established that AML is not a unique disease, provid‐ ing the basis for future more rationale therapies based on the specific molecular features, while on the other hand made more difficult to be interpreted results from most clinical trials, that were initiated when a comprehensive molecular characterization was not avail‐ able. Accordingly, a modern view of the problem should consider these new elements and rather than debating whether ASCT is superior to SCT or ICC in AML, it would be more useful to identify those patients who would more benefit from the procedure.

**Author details**

Felicetto Ferrara4

ty, Rome, Italy

Pesaro, Italy

Naples, Italy

**References**

1982;60(2):454-62.

mia 1990;4(3):177-83.

Group. J Clin Oncol 1998;16(3):872-81.

Pier Paolo Piccaluga1\*, Stefania Paolini1

\*Address all correspondence to: pierpaolo.piccaluga@unibo.it

, Giovanna Meloni2

1 Hematopathology and Hematology Sections, Department of Hematology and Oncology

2 Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza Universi‐

3 Haematology and Haematopoietic Stem Cell Transplant Center - San Salvatore Hospital –

4 Division of Haematology and Stem Cell Transplantation Unit, Cardarelli General Hospital,

[1] Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood

[2] Arlin Z, Case DC, Jr., Moore J, et al. Randomized multicenter trial of cytosine arabi‐ noside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leuke‐

[3] Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a

[4] Lowenberg B, Suciu S, Archimbaud E, et al. Mitoxantrone versus daunorubicin in in‐ duction-consolidation chemotherapy--the value of low-dose cytarabine for mainte‐ nance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon

[5] Visani G, Bernasconi P, Boni M, et al. The prognostic value of cytogenetics is rein‐ forced by the kind of induction/consolidation therapy in influencing the outcome of

acute myeloid leukemia--analysis of 848 patients. Leukemia 2001;15(6):903-9.

Southeastern Cancer Study Group Study. J Clin Oncol 1992;10(7):1103-11.

"L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, University of Bologna, Italy

, Giuseppe Visani3

Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

and

http://dx.doi.org/10.5772/54280

251

Of note, one study (actually the most recently published) tried to identify the optimal postremission strategy according to both clinical and biological features of the single case, recog‐ nizing three different groups based on an original post-remission treatment (PRT) score. Indeed, ASCT turned out to be the treatment of choice for the intermediate class, the out‐ come being quite favourable (Table 1). Therefore, although the proposed scoring systems will be probably modified/updated in the future, following, for example, the knowledge de‐ rived fro the most recent massive parallel sequencing studies [56] and the introduction of novel anti-leukemic compounds, an interesting scenario has probably (re)opened for ASCT. Finally, future research should focus on designing better ways to do autografts rather than conducting more trials comparing chemotherapy with the same autograft procedures cur‐ rently in use, including the adoption of immunotherapy, the selection of patients based on the absence of a minimal residual disease [57] and/or of new biologic molecularly targeted compounds in the post-ASCT phase.

In conclusion, although evidence based indication cannot be offered for ASCT in AML, it is reasonable to consider it as a valid therapeutic option for AML patients at low-intermediate risk in CR1. Indeed, a main goal should be having optimal frontline genetic characterization, as well as MRD evaluation on the harvested cells. For high risk patients, unfortunately, SCT can be an option, if they achieve a good quality CR; otherwise, experimental procedures are mandatory.

## **Acknowledgements**

Supported by BolognAIL, AIRC (IG4987; 5xMille 10007; IG10519), RFO (Prof. Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006 (Prof. Piccaluga).

## **Author details**

patients with an intermediate prognostic score [49]. Indeed, in most instances, the re‐ duced leukemia recurrence was balanced by an increase TRM. In this regard, however, it should be mentioned that in the last years the mortality of ASCT has definitely declined, possibly challenging some of the results published so far. Moreover, reduction of the re‐ lapse rate is a pivotal objective in the treatment of AML, as the only way toward the cure. In addition, the continuous and very fast improvement in our knowledge of the biology of the disease on one hand clearly established that AML is not a unique disease, provid‐ ing the basis for future more rationale therapies based on the specific molecular features, while on the other hand made more difficult to be interpreted results from most clinical trials, that were initiated when a comprehensive molecular characterization was not avail‐ able. Accordingly, a modern view of the problem should consider these new elements and rather than debating whether ASCT is superior to SCT or ICC in AML, it would be more useful to identify those patients who would more benefit from the procedure.

Of note, one study (actually the most recently published) tried to identify the optimal postremission strategy according to both clinical and biological features of the single case, recog‐ nizing three different groups based on an original post-remission treatment (PRT) score. Indeed, ASCT turned out to be the treatment of choice for the intermediate class, the out‐ come being quite favourable (Table 1). Therefore, although the proposed scoring systems will be probably modified/updated in the future, following, for example, the knowledge de‐ rived fro the most recent massive parallel sequencing studies [56] and the introduction of novel anti-leukemic compounds, an interesting scenario has probably (re)opened for ASCT. Finally, future research should focus on designing better ways to do autografts rather than conducting more trials comparing chemotherapy with the same autograft procedures cur‐ rently in use, including the adoption of immunotherapy, the selection of patients based on the absence of a minimal residual disease [57] and/or of new biologic molecularly targeted

In conclusion, although evidence based indication cannot be offered for ASCT in AML, it is reasonable to consider it as a valid therapeutic option for AML patients at low-intermediate risk in CR1. Indeed, a main goal should be having optimal frontline genetic characterization, as well as MRD evaluation on the harvested cells. For high risk patients, unfortunately, SCT can be an option, if they achieve a good quality CR; otherwise, experimental procedures are

Supported by BolognAIL, AIRC (IG4987; 5xMille 10007; IG10519), RFO (Prof. Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna,

compounds in the post-ASCT phase.

250 Innovations in Stem Cell Transplantation

mandatory.

**Acknowledgements**

Progetto Strategico di Ateneo 2006 (Prof. Piccaluga).

Pier Paolo Piccaluga1\*, Stefania Paolini1 , Giovanna Meloni2 , Giuseppe Visani3 and Felicetto Ferrara4

\*Address all correspondence to: pierpaolo.piccaluga@unibo.it

1 Hematopathology and Hematology Sections, Department of Hematology and Oncology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, University of Bologna, Italy

2 Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza Universi‐ ty, Rome, Italy

3 Haematology and Haematopoietic Stem Cell Transplant Center - San Salvatore Hospital – Pesaro, Italy

4 Division of Haematology and Stem Cell Transplantation Unit, Cardarelli General Hospital, Naples, Italy

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of the EORTC/GIMEMAAML-10 trial. Blood 2003;102(4):1232-40.

leukemia. Cancer 2003;97(7):1721-31.

America 2011;25(6):1189-213.

2011;29(20):2758-65.

1998;351(9104):700-8.

254 Innovations in Stem Cell Transplantation

385-400.

59-65.


[52] Hann IM, Stevens RF, Goldstone AH, et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 1997;89(7):2311-8.

**Chapter 11**

**Tumorablative Allogeneic Hematopoietic Stem Cell**

**Transplantation in the Treatment of High-Risk and**

**Refractory Leukemia — New Concepts and Clinical**

The substance of bone marrow transplantation is the organ transplantation. Accurately, it is the grafting of hematopoietic and immunologic system. Comparing to the transplantation of solid organ, in the hematopoietic stem cell transplantation (HSCT), the ill organ, id est. hem‐ atopoietic and immunology system, is ablated by high-dose chemotherapy and total body irradiation(TBI) (conditioning regime). Thus, the normal hematopoietic stem cells could be engrafted and normal function of hematopoietic and immune system could be reconstituted. The standard myeloablative conditioning regimen would be reasonable or enough for the non-malignances of marrow, which needed by replacing therapy, such as marrow failure. However, for treatment of hematopoietic malignances, it maybe not cure the malignance diseases to ablate the normal hematopoietic, immune system and reconstitute the normal function of allogeneic hematopoietic and immune system of patients. Because the leukemic stem cells (LSC) are not only existence in the bone marrow, it might be occurrence in any site of body. For instance, the traditional myeloablative conditioning regimen to treat leuke‐ mia could have striking killing effects of leukemic cells, and residual leukemic cells further eradicated by effect of the graft versus leukemia (GVL), but the malignant cells are not al‐ ways removed at all in the all patients, therefore, relapse post transplantation could be oc‐ curred in the some patients. In fact, the traditional allogeneic myeloablative HSCT could cure or improve outcome of acute leukemic patients with standard risk, however, the dis‐ ease relapse after transplant for acute leukemia with high risk and refractory is 40% to 80% [1-4]. Moreover, the leukemic cells in the majority of relapsed cases originate from inceptive

> © 2013 Da and Da; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Practice**

Wan-ming Da and Yong Da

http://dx.doi.org/10.5772/53031

**1. Introduction**

Additional information is available at the end of the chapter


**Tumorablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of High-Risk and Refractory Leukemia — New Concepts and Clinical Practice**

Wan-ming Da and Yong Da

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53031

## **1. Introduction**

[52] Hann IM, Stevens RF, Goldstone AH, et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council.

[53] Mandelli F, Petti MC, Lo Coco F. Therapy of acute myeloid leukemia: towards a pa‐ tient-oriented, risk-adapted approach. Haematologica 1998;83(11):1015-23.

[54] Stein EM, Tallman MS. Remission induction in acute myeloid leukemia. International

[55] Candoni A, Martinelli G, Toffoletti E, et al. Gemtuzumab-ozogamicin in combination with fludarabine, cytarabine, idarubicin (FLAI-GO) as induction therapy in CD33 positive AML patients younger than 65 years. Leukemia research 2008;32(12):1800-8.

[56] Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. The New England journal of medicine

[57] Inaba H, Coustan-Smith E, Cao X, et al. Comparative Analysis of Different Ap‐ proaches to Measure Treatment Response in Acute Myeloid Leukemia. J Clin Oncol

Blood 1997;89(7):2311-8.

256 Innovations in Stem Cell Transplantation

2012;366(12):1079-89.

2012.

journal of hematology 2012;96(2):164-70.

The substance of bone marrow transplantation is the organ transplantation. Accurately, it is the grafting of hematopoietic and immunologic system. Comparing to the transplantation of solid organ, in the hematopoietic stem cell transplantation (HSCT), the ill organ, id est. hem‐ atopoietic and immunology system, is ablated by high-dose chemotherapy and total body irradiation(TBI) (conditioning regime). Thus, the normal hematopoietic stem cells could be engrafted and normal function of hematopoietic and immune system could be reconstituted. The standard myeloablative conditioning regimen would be reasonable or enough for the non-malignances of marrow, which needed by replacing therapy, such as marrow failure. However, for treatment of hematopoietic malignances, it maybe not cure the malignance diseases to ablate the normal hematopoietic, immune system and reconstitute the normal function of allogeneic hematopoietic and immune system of patients. Because the leukemic stem cells (LSC) are not only existence in the bone marrow, it might be occurrence in any site of body. For instance, the traditional myeloablative conditioning regimen to treat leuke‐ mia could have striking killing effects of leukemic cells, and residual leukemic cells further eradicated by effect of the graft versus leukemia (GVL), but the malignant cells are not al‐ ways removed at all in the all patients, therefore, relapse post transplantation could be oc‐ curred in the some patients. In fact, the traditional allogeneic myeloablative HSCT could cure or improve outcome of acute leukemic patients with standard risk, however, the dis‐ ease relapse after transplant for acute leukemia with high risk and refractory is 40% to 80% [1-4]. Moreover, the leukemic cells in the majority of relapsed cases originate from inceptive

© 2013 Da and Da; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

leukemic cells at initial diagnosis [5-7], which strongly indicated that the standard myeloa‐ blative conditioning regimen could remove the normal lymphohematopoietic system of the recipients and make grafts successfully ecize and proliferate, but could not always kill the residual leukemic stem cells in vivo, particularly the those in extramedullary sites. Those re‐ sidual leukemic stem cells are the crime for the disease recurrence. We pioneered the tumor‐ ablative allogeneic hematopoietic stem cell transplantation (TAHSCT) for treatment of those patients with high-risk, refractory, even advanced-stage acute leukemia. The TAHSCT in‐ volve all parts in procedure of transplantation, the principal contents include two elements that are using the individual tumorablative conditioning regimen and enhancing the immu‐ notherapy post-transplantation.

Although GVL effect after transplantation produces a marked effect, it is always later after transplant. Eventually, the residual leukemic stem cell could be proliferation and disease re‐

Tumorablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of High-Risk and Refractory...

http://dx.doi.org/10.5772/53031

259

The purpose of tumorablative tailored conditioning regimen is not only to suppress or de‐ stroy the immune and hematopoietic system to make space for engraftment, but also to ablate leukemic stem cell, especially the leukemic stem cells in the "asylum" of extramedul‐

Compared with myeloablative transplantation, besides removal of normal hematopoietic tis‐ sue, TAHSCT focuses more on killing residual tumor cells, especially elimination of extrame‐ dullary residual tumor cells. In the selection of drugs, it puts more emphasis on the killing intensity of drugs on leukemic cells, the maintenance effective concentration and enough time of killing effect, and reduction of post-transplant leukemia relapse to minimum [11]. Com‐ pared with non-myeloablative transplantation or reduced toxicity transplantation, the latter still retains hematopoietic stem cells of recipient, in some extent, for autologous hematopoiet‐ ic reconstruction, but also residue a certain amount of leukemic stem cells which might cause relapse, therefore the reconstructed mixed hematopoietic chimerism often requires donor lymphocyte infusion (DLI) to ensure the possibility of a successful engraftment, and the pre‐ vention and treatment of relapse are also dependent on DLI and subsequent immunotherapy

lary sites, and to induce or enhance the GVL effect as far as possible [11].

or targeted therapy[11]. Their comparison is showed in Figure 1.

**Figure 1.** Comparison of tumorablative to myeloablative and non-myeloablative transplantation

lapse occurrences [10].

#### **2. Indication of TAHSCT**

The indication of TAHSCT is the patients with high-risk, relapsed, refractory, even ad‐ vanced leukemia. On the one hand, the recurrence of disease post-transplantation in these patients is very high by standard myeloablative transplantation. In the recent years, with the development of immunosuppressant, antibiotic agents and effective supportive therapy, it makes significant improvement to reduce the morbidity and mortality of non-relapse, such as GVHD, infections and multiple organ failure, post allogeneic HSCT, how to prevention and treatment of relapse after allogeneic HSCT in these acute leukemia is the key point to increase the long-term survival. In a recent retrospective cohort from the Center for Interna‐ tional Blood and Marrow Transplant Research, the 3-year overall survival rate only was 16% in patients who underwent allo-HSCT in relapse or primary induction failure of acute lym‐ phoblastic leukemia (ALL) [4], for acute non-lymphoblastic leukemia (ANLL) with Highrisk, refractory and relapsed, it could be up to 20%-40%. On the other hand, we are faced with more and more of those patients in the clinical transplantation. It is necessary to im‐ prove and optimize traditional procedure of HSCT.

#### **3. Rationale of TAHSCT**

The leukemia is the malignant clone disease derived from hematopoietic cell. The leukemic stem cell is quite different from the normal hematopoietic stem cell in the biocharacteristics [8]. Comparing to the latter, the former has strong growth vigor and tolerance in some de‐ gree to chemotherapy or radiotherapy. Furthermore, the leukemic stem cell is not only in marrow, but also infiltrates to any sites or organs besides hematopoietic system, including some sites in which the anti-leukemia drugs could but achieved to the treating concentra‐ tion, such as central nerve system, skin and lung and so on. On account of the insight in bio‐ nomics of leukemic stem cell, and the results in clinical transplantation, it is demonstrated that standard myeloablative HSCT could not enough to root out of leukemic or leukemic stem cells, particularly the in extramedullary sites. Therefore, the myeloablative HSCT is not equal to TAHSCT, the residual leukemic or leukemic stem cell is the convict for relapse [9]. Although GVL effect after transplantation produces a marked effect, it is always later after transplant. Eventually, the residual leukemic stem cell could be proliferation and disease re‐ lapse occurrences [10].

leukemic cells at initial diagnosis [5-7], which strongly indicated that the standard myeloa‐ blative conditioning regimen could remove the normal lymphohematopoietic system of the recipients and make grafts successfully ecize and proliferate, but could not always kill the residual leukemic stem cells in vivo, particularly the those in extramedullary sites. Those re‐ sidual leukemic stem cells are the crime for the disease recurrence. We pioneered the tumor‐ ablative allogeneic hematopoietic stem cell transplantation (TAHSCT) for treatment of those patients with high-risk, refractory, even advanced-stage acute leukemia. The TAHSCT in‐ volve all parts in procedure of transplantation, the principal contents include two elements that are using the individual tumorablative conditioning regimen and enhancing the immu‐

The indication of TAHSCT is the patients with high-risk, relapsed, refractory, even ad‐ vanced leukemia. On the one hand, the recurrence of disease post-transplantation in these patients is very high by standard myeloablative transplantation. In the recent years, with the development of immunosuppressant, antibiotic agents and effective supportive therapy, it makes significant improvement to reduce the morbidity and mortality of non-relapse, such as GVHD, infections and multiple organ failure, post allogeneic HSCT, how to prevention and treatment of relapse after allogeneic HSCT in these acute leukemia is the key point to increase the long-term survival. In a recent retrospective cohort from the Center for Interna‐ tional Blood and Marrow Transplant Research, the 3-year overall survival rate only was 16% in patients who underwent allo-HSCT in relapse or primary induction failure of acute lym‐ phoblastic leukemia (ALL) [4], for acute non-lymphoblastic leukemia (ANLL) with Highrisk, refractory and relapsed, it could be up to 20%-40%. On the other hand, we are faced with more and more of those patients in the clinical transplantation. It is necessary to im‐

The leukemia is the malignant clone disease derived from hematopoietic cell. The leukemic stem cell is quite different from the normal hematopoietic stem cell in the biocharacteristics [8]. Comparing to the latter, the former has strong growth vigor and tolerance in some de‐ gree to chemotherapy or radiotherapy. Furthermore, the leukemic stem cell is not only in marrow, but also infiltrates to any sites or organs besides hematopoietic system, including some sites in which the anti-leukemia drugs could but achieved to the treating concentra‐ tion, such as central nerve system, skin and lung and so on. On account of the insight in bio‐ nomics of leukemic stem cell, and the results in clinical transplantation, it is demonstrated that standard myeloablative HSCT could not enough to root out of leukemic or leukemic stem cells, particularly the in extramedullary sites. Therefore, the myeloablative HSCT is not equal to TAHSCT, the residual leukemic or leukemic stem cell is the convict for relapse [9].

notherapy post-transplantation.

258 Innovations in Stem Cell Transplantation

**2. Indication of TAHSCT**

**3. Rationale of TAHSCT**

prove and optimize traditional procedure of HSCT.

The purpose of tumorablative tailored conditioning regimen is not only to suppress or de‐ stroy the immune and hematopoietic system to make space for engraftment, but also to ablate leukemic stem cell, especially the leukemic stem cells in the "asylum" of extramedul‐ lary sites, and to induce or enhance the GVL effect as far as possible [11].

Compared with myeloablative transplantation, besides removal of normal hematopoietic tis‐ sue, TAHSCT focuses more on killing residual tumor cells, especially elimination of extrame‐ dullary residual tumor cells. In the selection of drugs, it puts more emphasis on the killing intensity of drugs on leukemic cells, the maintenance effective concentration and enough time of killing effect, and reduction of post-transplant leukemia relapse to minimum [11]. Com‐ pared with non-myeloablative transplantation or reduced toxicity transplantation, the latter still retains hematopoietic stem cells of recipient, in some extent, for autologous hematopoiet‐ ic reconstruction, but also residue a certain amount of leukemic stem cells which might cause relapse, therefore the reconstructed mixed hematopoietic chimerism often requires donor lymphocyte infusion (DLI) to ensure the possibility of a successful engraftment, and the pre‐ vention and treatment of relapse are also dependent on DLI and subsequent immunotherapy or targeted therapy[11]. Their comparison is showed in Figure 1.

**Figure 1.** Comparison of tumorablative to myeloablative and non-myeloablative transplantation

## **4. Strategy for TAHSCT**

Based on the regularity and characteristics of disease relapse after transplantation, we pro‐ posed a preventive pathway for leukemic recurrence post-transplantation in the early of 2007 years [12]. They are general prophylaxis, early intervention and clinical therapy. The general prophylaxis means to avoid the selection of high risks (shown in table 1) during the grafting procedure, the key points in early intervention are to institute a reasonable individ‐ ual tumorablative conditioning regimen. The clinical therapy is to treat the leukemia in the early or frank relapse, including immunotherapy post transplantation. In the clinical prac‐ tice for 5 years, the relapse rate of 85 and 83 cases with high risk, refractory or relapse re‐ ceived TAHSCT in 2008 and 2009 year was 2.3% and 5%, respectively [11]. It was strikingly advance; however, the challenge is still presence. Obviously, among the risks associated to relapse, the conditioning regimen and immunotherapy are more important.

future. According to the clinical experiences for successful treatment of refractory or re‐ lapsed leukemia, and combining with standard myeloablative regimen, we selected some regimen with high effective and less toxicity, and establish a tumorablative conditioning

Tumorablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of High-Risk and Refractory...

High risk in CR

or leukopenia

ANLL

ALL

Remission or early relapse in high risk patients with bone marrow hypoplasia

http://dx.doi.org/10.5772/53031

261

Progressive or advanced patients with

Progressive or advanced patients with

**Regimen content indication**

Bu 1mg/kg.6hrs, -8d- -6d MCCNU 250mg/ m2 (ANLL) or Vm26 300mg/ m2 (ALL), -5d CY 50mg/kg.d IV, -3- -4d

G-CSF 5µg/kg.d sc, -12- -9d Ara-C 3 g/ m2 IV, -11d- -9d Bu 1mg/kg.6hrs, -8d- -6d MCCNU 250mg/ m2 (ANLL) or Vm26 300mg/ m2 (ALL), -5d CY 50mg/kg.d IV, -3- -4d

Ara-C 2 g/ m2.d CI, -13- -9d FDL 30mg/ m2.d IV, -13 --9d BSF 0.8mg/kg.6hr IV, -8 - -6d CY 50 mg/m2.d IV, -5 - -4d MCCNU 250mg/m2.d, -3d

Vm26 300 mg/m 2. IV, -10d G-CSF 5µg/kg.d sc, -10- -5d Ara-C 2 g/ m2.d CI, -9- -5d FDL 30mg/ m2.d, IV, -9 --5d CY 30 mg/kg.d IV, -4 - -3d

\* All regimens can be used in transplantation of HLA matched unrelated and halo-identical HSCT, but ATG must be added. ATG, antithymocyte globulin; Ara-C, cytarabine; Bu, busulfan; BSF, busulfex; Vm26, teniposide; CY, cyclophos‐ phamide; FDL, fludarabine; MCCNU, semustine; RIT, reduced intensive transplantation; TBI, total body irradiation.

regimens (shown in table 2).

G-CSF primed HDAra-C+Bu/Cy

HDAra-C+Bu/Cy Ara-C 2.5g/m2 IV, -11d- -9d

rest, -2 - -1d, HSCT d 0

Rest, -2 - -1d, HSCT d 0

Rest, -2 - -1d, HSCT d 0

Rest, -2 - -1d, HSCT d 0

FLAG/RIT G-CSF 5µg/kg.d sc, -14- -9d

TBI/FLAG/CY TBI 1.5 - 2 Gy, Bid, -13- -11d

**Table 2.** Some tumorablative conditioning regimen\*


**Table 1.** The risks associated to relapse in the transplantation

#### **5. Approach to tumorablative conditioning regimen**

Theoretically, the tumorablative conditioning regimen should contain drugs or TBI to ablate normal hematopoietic and immunologic tissue, also drugs or agents to get rid of leukemic or leukemic stem cell, particularly, those in the extramedullary sites. The ideal drugs should be high effective and targeted on the leukemic or leukemic stem cell, however, these special target agents have not been successfully used in clinical, and it should be exploited in the future. According to the clinical experiences for successful treatment of refractory or re‐ lapsed leukemia, and combining with standard myeloablative regimen, we selected some regimen with high effective and less toxicity, and establish a tumorablative conditioning regimens (shown in table 2).


\* All regimens can be used in transplantation of HLA matched unrelated and halo-identical HSCT, but ATG must be added. ATG, antithymocyte globulin; Ara-C, cytarabine; Bu, busulfan; BSF, busulfex; Vm26, teniposide; CY, cyclophos‐ phamide; FDL, fludarabine; MCCNU, semustine; RIT, reduced intensive transplantation; TBI, total body irradiation.

**Table 2.** Some tumorablative conditioning regimen\*

**4. Strategy for TAHSCT**

260 Innovations in Stem Cell Transplantation

Recipient

Grafts

tumor cell burden extramedullary disease unfavorable chromosome unfavorable molecule sensitive to chemotherapy performance status GVHD post grafting

peripheral stem cell vs marrow cell

number of grating cells T cell depleted

immunosuppressive agent interfere by immunotherapy

**Table 1.** The risks associated to relapse in the transplantation

**5. Approach to tumorablative conditioning regimen**

Grafting technique

Based on the regularity and characteristics of disease relapse after transplantation, we pro‐ posed a preventive pathway for leukemic recurrence post-transplantation in the early of 2007 years [12]. They are general prophylaxis, early intervention and clinical therapy. The general prophylaxis means to avoid the selection of high risks (shown in table 1) during the grafting procedure, the key points in early intervention are to institute a reasonable individ‐ ual tumorablative conditioning regimen. The clinical therapy is to treat the leukemia in the early or frank relapse, including immunotherapy post transplantation. In the clinical prac‐ tice for 5 years, the relapse rate of 85 and 83 cases with high risk, refractory or relapse re‐ ceived TAHSCT in 2008 and 2009 year was 2.3% and 5%, respectively [11]. It was strikingly advance; however, the challenge is still presence. Obviously, among the risks associated to

relapse, the conditioning regimen and immunotherapy are more important.

**Elements High risk for relapse Low risk for relapse**

high yes Yes yes insensitive worse no

low low yes

conditioning regimen non myeloablative myeloablative GVHD Prophylaxis strong fairly

Theoretically, the tumorablative conditioning regimen should contain drugs or TBI to ablate normal hematopoietic and immunologic tissue, also drugs or agents to get rid of leukemic or leukemic stem cell, particularly, those in the extramedullary sites. The ideal drugs should be high effective and targeted on the leukemic or leukemic stem cell, however, these special target agents have not been successfully used in clinical, and it should be exploited in the

low no no no sensitive good yes

high high no

yes

reduce or stop early

**FLAG/reduced intensive transplantation (FLAG/RIT regimen)** A large number of clinical practice confirmed that intravenous infusion of high-dose cytosine (Ara-C) was an effective rescue measure for the treatment of refractory or relapsed leukemia, about 40% refractory acute myeloid leukemia (AML) could achieve remission. Pharmacokinetic study on highdose Ara-C intravenous infusion revealed that intravenous infusion of Ara-C (1.8-32.0) g/m2 for 2 hours, every 12 hours, the plasma concentrations could reach (8-24) µg/ml, cerebrospi‐ nal fluid concentrations was about (10-15)% of plasma concentration. This high concentra‐ tion of this drug in blood and cerebrospinal fluid was thought to be the pharmacological basis of significantly increased efficacy [13-15]. Ara-C combined with anthracycline (uniqui‐ none) or acridines drugs could further improve the CR rate to 50 % [16, 17].

variant NKT (iNKT) cells, a marked increase of post-transplant cell mediated CD8+

improved the safety of transplantation and reduced the relapse [23].

toxicity, and enhancement of GVL effect [20]. Takahashi et al. had proved that application of G-CS together with conditioning regimen could reduce the post-transplantation relapse in refractory myeloid leukemia [21]. Ooi et al. used G-CSF + Ara-C or + total body irradiation and fludarabine as a conditioning regimen, and performed unrelated cord blood transplan‐ tation in adult AML patients, the results showed that 2-year disease-free survival was 76%[22]. Rational application of G-CSF in tumorablative conditioning regimen not only aug‐ mented anti-leukemia effect, but also separated GVHD and GVL effect to a certain degree,

Tumorablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of High-Risk and Refractory...

**Regimen containing high Ara-C** For the transplantation of ANLL with high risk in the com‐ plete remission, we used the regimen containing high Ara-C as tumorablative conditioning. As early as 2004, Lu DP et al. reported the application of GIAC protocol (Ara-C, busulfan, cyclophosphamide, MCCNU and G-CSF activated bone marrow and peripheral blood) in‐ cluding high-dose Ara-C, MCCNU and G-CSF for mobility of peripheral blood stem cells in donor-recipients HLA-unmatched or haploidentical hematopoietic stem cell transplantation. Post-transplant observation confirmed this protocol resulted in a higher disease-free surviv‐ al rate (70%) and lower relapse rate (13%), further suggesting the necessity of intensified

Based on the above theory and the specific situation of individual patient, we have modified GIAC protocol and designed the HDAra-C+Bu/Cy. Preliminary clinical attempts have yield‐

In clinical practice, about one-third of AML and more than half of ALL patients relapsed firstly manifested as extramedullary relapse, such as leukemic sarcoma or infiltration into the central nervous system. So that, drugs with good liposolubility and ability to penetrate blood-brain barrier, such as Carmustine (BCNU), methyl cyclohexyl nitrosourea (MCCNU), teniposide (VM26) as well as high-dose Ara-C or MTX, should be chosen as a part of tumor‐

Our tumorablative conditioning regimen possess following features: The first, it could en‐ hance the intensity of anti-leukemia chemotherapy. All regimens included continuous infu‐ sion of medium dose Ara-C for 72 hours, meanwhile drugs with good liposolubility were added such as MCCNU (acute myeloid leukemia) and teniposide (acute lymphocyte leuke‐ mia). The duration of the regimen extended to 11-14 days, which not only enhanced the antileukemia effects on leukemic (stem) cells in hematopoietic tissue, but also ensured a longer maintaining period of effective drug concentration in extramedullary tissue including cen‐ tral nervous system, and further depletion of leukemic (stem) cells in all tissues. Secondly, granulocyte-stimulating factor was added in some regimes. It not only recruited quiescent leukemic (stem) cells into proliferation cycle, increased the sensitivity to the killing effects of drugs, but also reduced or alleviates the incidence of post-transplant GVHD through regula‐ tion of immune cells, or might induce GVL effects. Third, the reduction of the dosage of al‐ kylating agent decreased or alleviated the toxic and side effects, under the circumstances of depletion of normal hematopoietic tissue and effective immunosuppressant. Fourth, indi‐ vidualization was emphasized. In clinical, application of these regimens should focus on in‐

measures with direct anti-leukemic cell effects in the conditioning regimen [24].

ed encouraging results (Table 2).

ablative regimen.

T cyto‐

263

http://dx.doi.org/10.5772/53031

FLAG protocol consisting of fludarabine combined with Ara-C plus recombinant human granulocyte-stimulating factor (G-CSF) is currently a potent and well-tolerated treatment for refractory and relapsed AML. Fludarabine is a nucleotide analogue, acts as a ribonucleic acid inhibitor by phosphorylation to active triphosphate form F-ara-ATP. As a substrate for DNA synthesis in leukemic cells, F-ara-ATP has anti-leukemia activity by inhibition of DNA polymerase and ribose reductase, especially has a strong effect on quiescent cells. In vitro and in vivo studies proved that addition of fludarabine before Ara-C administration might increase the intracellular concentration of Ara-CTP, enhance the cytotoxicity and clinical ef‐ ficacy of Ara-C, so that the CR rate of refractory and relapsed AML reaching 50% - 75%, CR period reaching 9 months and above [18]. Schmid et al [19] used combination chemotherapy with fludarabine and Ara-C for 4 days followed by reduced-toxicity allogeneic hematopoiet‐ ic cell transplantation and post-transplant donor lymphocyte infusion in 103 refractory acute myeloid leukemia patients, followed up for a median period of 25 months. It was found that 1, 2 and 4-year overall survival rates were 54%, 40% and 32%, respectively. Therefore, the FLAG/RIT regimen is mainly used in treatment of ANLL with progressive or advanced pa‐ tients with ANLL.

**TBI/FLAG/CY regimen** It consists of total body irradiation, FLAG and reduced cyclophos‐ phamide, and always utilized to treat ALL in progressive or advanced phase. Because, TBI was more effectiveness in allo-HSCT for ALL.

**G-CST priming regimen** It is usually to treat the ANLL at remission or early relapse in high risk with bone marrow hypoplasia or leucopenia. Granulocyte-stimulating factor can induce the proliferation of AML cells and increase the proportion of S phase cells in vitro or in vivo, thereby enhancing cell sensitivity to chemotherapeutic drugs. Reasonable and sequential ap‐ plication of G-CSF and chemotherapeutics is another effective option for the treatment of re‐ fractory AML, such as the above-mentioned FLAG protocol and CAG protocol composed of low-dose Ara-C (LD-Ara-C), aclacinomycin and G-CSF. In fact a large number of experi‐ mental and clinical studies confirmed that pre-transplant application of G-CSF not only pro‐ moted the differentiation of T cells to TH2 and enhanced the function of regulatory T cells, but also amplified immature antigen-presenting cells and plasmacytoid dendritic cells, which was beneficial for maintenance of post-transplant T cells function and reduction the incidence of GVHD. Morris ES, et al. also confirmed that through modification of pegylation and combination with Flt-3L, G-CS might lead to activation and amplification of donor in‐ variant NKT (iNKT) cells, a marked increase of post-transplant cell mediated CD8+ T cyto‐ toxicity, and enhancement of GVL effect [20]. Takahashi et al. had proved that application of G-CS together with conditioning regimen could reduce the post-transplantation relapse in refractory myeloid leukemia [21]. Ooi et al. used G-CSF + Ara-C or + total body irradiation and fludarabine as a conditioning regimen, and performed unrelated cord blood transplan‐ tation in adult AML patients, the results showed that 2-year disease-free survival was 76%[22]. Rational application of G-CSF in tumorablative conditioning regimen not only aug‐ mented anti-leukemia effect, but also separated GVHD and GVL effect to a certain degree, improved the safety of transplantation and reduced the relapse [23].

**FLAG/reduced intensive transplantation (FLAG/RIT regimen)** A large number of clinical practice confirmed that intravenous infusion of high-dose cytosine (Ara-C) was an effective rescue measure for the treatment of refractory or relapsed leukemia, about 40% refractory acute myeloid leukemia (AML) could achieve remission. Pharmacokinetic study on highdose Ara-C intravenous infusion revealed that intravenous infusion of Ara-C (1.8-32.0) g/m2 for 2 hours, every 12 hours, the plasma concentrations could reach (8-24) µg/ml, cerebrospi‐ nal fluid concentrations was about (10-15)% of plasma concentration. This high concentra‐ tion of this drug in blood and cerebrospinal fluid was thought to be the pharmacological basis of significantly increased efficacy [13-15]. Ara-C combined with anthracycline (uniqui‐

FLAG protocol consisting of fludarabine combined with Ara-C plus recombinant human granulocyte-stimulating factor (G-CSF) is currently a potent and well-tolerated treatment for refractory and relapsed AML. Fludarabine is a nucleotide analogue, acts as a ribonucleic acid inhibitor by phosphorylation to active triphosphate form F-ara-ATP. As a substrate for DNA synthesis in leukemic cells, F-ara-ATP has anti-leukemia activity by inhibition of DNA polymerase and ribose reductase, especially has a strong effect on quiescent cells. In vitro and in vivo studies proved that addition of fludarabine before Ara-C administration might increase the intracellular concentration of Ara-CTP, enhance the cytotoxicity and clinical ef‐ ficacy of Ara-C, so that the CR rate of refractory and relapsed AML reaching 50% - 75%, CR period reaching 9 months and above [18]. Schmid et al [19] used combination chemotherapy with fludarabine and Ara-C for 4 days followed by reduced-toxicity allogeneic hematopoiet‐ ic cell transplantation and post-transplant donor lymphocyte infusion in 103 refractory acute myeloid leukemia patients, followed up for a median period of 25 months. It was found that 1, 2 and 4-year overall survival rates were 54%, 40% and 32%, respectively. Therefore, the FLAG/RIT regimen is mainly used in treatment of ANLL with progressive or advanced pa‐

**TBI/FLAG/CY regimen** It consists of total body irradiation, FLAG and reduced cyclophos‐ phamide, and always utilized to treat ALL in progressive or advanced phase. Because, TBI

**G-CST priming regimen** It is usually to treat the ANLL at remission or early relapse in high risk with bone marrow hypoplasia or leucopenia. Granulocyte-stimulating factor can induce the proliferation of AML cells and increase the proportion of S phase cells in vitro or in vivo, thereby enhancing cell sensitivity to chemotherapeutic drugs. Reasonable and sequential ap‐ plication of G-CSF and chemotherapeutics is another effective option for the treatment of re‐ fractory AML, such as the above-mentioned FLAG protocol and CAG protocol composed of low-dose Ara-C (LD-Ara-C), aclacinomycin and G-CSF. In fact a large number of experi‐ mental and clinical studies confirmed that pre-transplant application of G-CSF not only pro‐ moted the differentiation of T cells to TH2 and enhanced the function of regulatory T cells, but also amplified immature antigen-presenting cells and plasmacytoid dendritic cells, which was beneficial for maintenance of post-transplant T cells function and reduction the incidence of GVHD. Morris ES, et al. also confirmed that through modification of pegylation and combination with Flt-3L, G-CS might lead to activation and amplification of donor in‐

none) or acridines drugs could further improve the CR rate to 50 % [16, 17].

tients with ANLL.

262 Innovations in Stem Cell Transplantation

was more effectiveness in allo-HSCT for ALL.

**Regimen containing high Ara-C** For the transplantation of ANLL with high risk in the com‐ plete remission, we used the regimen containing high Ara-C as tumorablative conditioning. As early as 2004, Lu DP et al. reported the application of GIAC protocol (Ara-C, busulfan, cyclophosphamide, MCCNU and G-CSF activated bone marrow and peripheral blood) in‐ cluding high-dose Ara-C, MCCNU and G-CSF for mobility of peripheral blood stem cells in donor-recipients HLA-unmatched or haploidentical hematopoietic stem cell transplantation. Post-transplant observation confirmed this protocol resulted in a higher disease-free surviv‐ al rate (70%) and lower relapse rate (13%), further suggesting the necessity of intensified measures with direct anti-leukemic cell effects in the conditioning regimen [24].

Based on the above theory and the specific situation of individual patient, we have modified GIAC protocol and designed the HDAra-C+Bu/Cy. Preliminary clinical attempts have yield‐ ed encouraging results (Table 2).

In clinical practice, about one-third of AML and more than half of ALL patients relapsed firstly manifested as extramedullary relapse, such as leukemic sarcoma or infiltration into the central nervous system. So that, drugs with good liposolubility and ability to penetrate blood-brain barrier, such as Carmustine (BCNU), methyl cyclohexyl nitrosourea (MCCNU), teniposide (VM26) as well as high-dose Ara-C or MTX, should be chosen as a part of tumor‐ ablative regimen.

Our tumorablative conditioning regimen possess following features: The first, it could en‐ hance the intensity of anti-leukemia chemotherapy. All regimens included continuous infu‐ sion of medium dose Ara-C for 72 hours, meanwhile drugs with good liposolubility were added such as MCCNU (acute myeloid leukemia) and teniposide (acute lymphocyte leuke‐ mia). The duration of the regimen extended to 11-14 days, which not only enhanced the antileukemia effects on leukemic (stem) cells in hematopoietic tissue, but also ensured a longer maintaining period of effective drug concentration in extramedullary tissue including cen‐ tral nervous system, and further depletion of leukemic (stem) cells in all tissues. Secondly, granulocyte-stimulating factor was added in some regimes. It not only recruited quiescent leukemic (stem) cells into proliferation cycle, increased the sensitivity to the killing effects of drugs, but also reduced or alleviates the incidence of post-transplant GVHD through regula‐ tion of immune cells, or might induce GVL effects. Third, the reduction of the dosage of al‐ kylating agent decreased or alleviated the toxic and side effects, under the circumstances of depletion of normal hematopoietic tissue and effective immunosuppressant. Fourth, indi‐ vidualization was emphasized. In clinical, application of these regimens should focus on in‐ dividualization, in view of the differences of cytogenetics and gene alterations in the pathogenesis of leukemic cell, clinical manifestations and prognosis, or pre-transplant dis‐ ease, performance status and drug tolerance of patients. In addition, the regimens should al‐ so be adjusted in accordance with the donor source, for example, the transplantation of unrelated or haploididential donor, anti-lymphocyte globulin (ATG) should be included in the corresponding conditioning regimen [25]. We met a case of AML-M5 with primary re‐ sistance to chemotherapy, the blasts remain more than 50% in marrow after induction by daunomycin plus Ara-C (DA), idarubicin plus Ara-C (IA), mitoxantrone plus Ara-C and eto‐ poside (MAE), CAG and FLAG regimen, but, after AE (amsacrine + Vm26) regimen, near CR was achieved. Then he received haplo-identical transplantation using TBI/FLAG/CY regi‐ men in February, 2012, in which amsacrine + Vm26 instead of FLAG, because his leukemic cell is sensitive to amsacrine and Vm26. After successful engraftment, he is still alive in con‐ tinual CR up to now.

or the systemic application of cytokine induced killer cells (CIK) for additional immunosti‐ mulation to increase GVL efficacy. In addition, infusion of allogeneic natural killer (NK) cells is also a promising innovative immunotherapy, being alloreactive NK cells reported to produce a strong GVL effect after haploidentical HSCT in patients with advanced AML, without causing GVHD [28]. In vitro studies have suggested the possibility to create specific antileukemic cytotoxicity by stimulation of donor lymphocytes using AML-derived dendrit‐ ic cells. Porter and colleagues reported encouraging results from a phase I trial using con‐ ventional DLI, followed by an additional infusion of ex vivo activated donor T cells. Therefore, we used DLC, DSI or CIK as maintenance therapy after HSCT for patients in re‐ mission or in a minimal residual disease situation in our program to exploit the GVL effica‐ cy, and got a ducky result. Recently, we treated 18 cases in relapse after allogeneic HSCT, including 11 of HLA matched sibling, 5 of haploidentical and 2 of matched unrelated donor by donor's dendritic cell-primed CIK (DC-CIK). After the median number of 3.6 X 109 DC-CIK infused, molecule complete remission was obtained in 12 cases (68%), and 11 of 12 cases are survival with a median follow-up of 12 (range 6-41) months, except 1 died of treatment related complication. It confirms that donor derived DC-CIK infusion is efficacious and safe‐ ty in this setting [29]. However, DLI or CIK infusion was often associated with a considera‐ ble risk of GVHD, and clinically, we should be careful to assay and prevent from GVHD.

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Along with screening and identification of new immunogenic tumor protein or peptides, an‐ ti-tumor specific functional T cells could be produced in vitro, the anti-leukemia specific im‐ munotherapy would have more definite position in treatment of relapse post transplantation. Further experimental and clinical research are required to overcome the ob‐ viously high burden of leukemia blasts to escape from an allogeneic immunereaction in re‐

In fact, the first TAHSCT with HLA identical donor we preformed was in 2007 for a 54 years old female with resistant relapse, She was diagnosed as AML in July 2004 and obtained CR after 3 courses of chemotherapy by daunomycin plus Ara-C (DA), idarubicin plus Ara-C (IA) and mitoxantrone plus Ara-C (MA), and then received 13 courses of intensive consoli‐ dation chemotherapy including high dose of Ara-C, and autologous CIK infusion for 3 times. Her leukemia relapsed in the end of Dec 2006, and could not response to the several courses of reinduction chemotherapy. Before she received tumorablative allo-HSCT, there were 27% of leukemic blasts in marrow. The FLAG/RIT regimen was conditioned for HLAidentical sibling HSCT on February 22nd 2007. Her neutrophil and platelet were successful‐ ly engraftment on +18 days, chimerism analyses shown that full donor chimerism achieved by +30 days. Assay of MRD periodically by FCM monitoring after TAHSCT was zero. Grade I aGVHD of intestinal tract and liver was happened on +51 days, and thereafter invasive fungal infections in sinusitis, lung, liver on right-sidedness (pathological culture supported mucor infection) were happened, The Aspergillus was detected in sputum culture. All the

lapsing patients after allogeneic HSCT for refractory acute leukemia.

**7. Clinical practice of TAHSCT**

## **6. Detection of minimal residual disease and immunotherapy post TAHSCT**

Detection of minimal residual disease (MRD) and immunotherapy post transplantation are very impotent principle in the TAHSCT [25]. Although it is almost specific method to detect the marrow morphology, clone culture, immunophenotype, and abnormal gene or protein of leukemic cell, clinically, the flow cytometry (FCM) and polymerase chain reaction (PCR) are the more convenience, fast and sensitive. It should be routinely done post transplanta‐ tion. In some patients, relapse proceeded in extramedullary sites, even sarcoma, especially, CNS, subperiosteum, skin, serous cavity, lung and intestinal tract, so image analysis also is necessity, such as, CT, MIR, PET or PET-CT. We had used a PET-CT to detect proceed re‐ lapse in extramedullary sites in an advanced case with ANLL after underwent unrelated HSCT, and successful pinpoint treated by the cyberknife.

With regard to immunotherapy, firstly, immunosuppressive agents should be decreased or even stopped as quickly as possible, when GVHD was strictly controlled. Then, if necessary, some immune modulators should be given, such as interferon, IL2 and thymopeptides. For the two latter, which should not use in T cell malignances. Finally, it is the cell therapy [25, 26].

Donor lymphocyte or G-CSF mobilized peripheral blood stem cell infusion (DLI/DSI) for treatment of leukemia relapse after allo-HSCT was introduced in early 1990s, being extreme‐ ly effective in chronic myeloid leukemia. The DLI for AML relapse post-transplant has been questioned in general. Recently, Schmid C, et al retrospectively analyzed the data of 399 pa‐ tients with AML in first hematological relapse after HSCT whose treatment did or did not include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. The results confirm a role for an allogene‐ ic GVL effect in AML [27]. Various modifications of DLI have been investigated. These in‐ cluded the systematical use of mobilized donor PBSC concentrates instead of lymphocytes, or the systemic application of cytokine induced killer cells (CIK) for additional immunosti‐ mulation to increase GVL efficacy. In addition, infusion of allogeneic natural killer (NK) cells is also a promising innovative immunotherapy, being alloreactive NK cells reported to produce a strong GVL effect after haploidentical HSCT in patients with advanced AML, without causing GVHD [28]. In vitro studies have suggested the possibility to create specific antileukemic cytotoxicity by stimulation of donor lymphocytes using AML-derived dendrit‐ ic cells. Porter and colleagues reported encouraging results from a phase I trial using con‐ ventional DLI, followed by an additional infusion of ex vivo activated donor T cells. Therefore, we used DLC, DSI or CIK as maintenance therapy after HSCT for patients in re‐ mission or in a minimal residual disease situation in our program to exploit the GVL effica‐ cy, and got a ducky result. Recently, we treated 18 cases in relapse after allogeneic HSCT, including 11 of HLA matched sibling, 5 of haploidentical and 2 of matched unrelated donor by donor's dendritic cell-primed CIK (DC-CIK). After the median number of 3.6 X 109 DC-CIK infused, molecule complete remission was obtained in 12 cases (68%), and 11 of 12 cases are survival with a median follow-up of 12 (range 6-41) months, except 1 died of treatment related complication. It confirms that donor derived DC-CIK infusion is efficacious and safe‐ ty in this setting [29]. However, DLI or CIK infusion was often associated with a considera‐ ble risk of GVHD, and clinically, we should be careful to assay and prevent from GVHD.

Along with screening and identification of new immunogenic tumor protein or peptides, an‐ ti-tumor specific functional T cells could be produced in vitro, the anti-leukemia specific im‐ munotherapy would have more definite position in treatment of relapse post transplantation. Further experimental and clinical research are required to overcome the ob‐ viously high burden of leukemia blasts to escape from an allogeneic immunereaction in re‐ lapsing patients after allogeneic HSCT for refractory acute leukemia.

## **7. Clinical practice of TAHSCT**

dividualization, in view of the differences of cytogenetics and gene alterations in the pathogenesis of leukemic cell, clinical manifestations and prognosis, or pre-transplant dis‐ ease, performance status and drug tolerance of patients. In addition, the regimens should al‐ so be adjusted in accordance with the donor source, for example, the transplantation of unrelated or haploididential donor, anti-lymphocyte globulin (ATG) should be included in the corresponding conditioning regimen [25]. We met a case of AML-M5 with primary re‐ sistance to chemotherapy, the blasts remain more than 50% in marrow after induction by daunomycin plus Ara-C (DA), idarubicin plus Ara-C (IA), mitoxantrone plus Ara-C and eto‐ poside (MAE), CAG and FLAG regimen, but, after AE (amsacrine + Vm26) regimen, near CR was achieved. Then he received haplo-identical transplantation using TBI/FLAG/CY regi‐ men in February, 2012, in which amsacrine + Vm26 instead of FLAG, because his leukemic cell is sensitive to amsacrine and Vm26. After successful engraftment, he is still alive in con‐

**6. Detection of minimal residual disease and immunotherapy post**

HSCT, and successful pinpoint treated by the cyberknife.

Detection of minimal residual disease (MRD) and immunotherapy post transplantation are very impotent principle in the TAHSCT [25]. Although it is almost specific method to detect the marrow morphology, clone culture, immunophenotype, and abnormal gene or protein of leukemic cell, clinically, the flow cytometry (FCM) and polymerase chain reaction (PCR) are the more convenience, fast and sensitive. It should be routinely done post transplanta‐ tion. In some patients, relapse proceeded in extramedullary sites, even sarcoma, especially, CNS, subperiosteum, skin, serous cavity, lung and intestinal tract, so image analysis also is necessity, such as, CT, MIR, PET or PET-CT. We had used a PET-CT to detect proceed re‐ lapse in extramedullary sites in an advanced case with ANLL after underwent unrelated

With regard to immunotherapy, firstly, immunosuppressive agents should be decreased or even stopped as quickly as possible, when GVHD was strictly controlled. Then, if necessary, some immune modulators should be given, such as interferon, IL2 and thymopeptides. For the two latter, which should not use in T cell malignances. Finally, it is the cell therapy [25, 26].

Donor lymphocyte or G-CSF mobilized peripheral blood stem cell infusion (DLI/DSI) for treatment of leukemia relapse after allo-HSCT was introduced in early 1990s, being extreme‐ ly effective in chronic myeloid leukemia. The DLI for AML relapse post-transplant has been questioned in general. Recently, Schmid C, et al retrospectively analyzed the data of 399 pa‐ tients with AML in first hematological relapse after HSCT whose treatment did or did not include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. The results confirm a role for an allogene‐ ic GVL effect in AML [27]. Various modifications of DLI have been investigated. These in‐ cluded the systematical use of mobilized donor PBSC concentrates instead of lymphocytes,

tinual CR up to now.

264 Innovations in Stem Cell Transplantation

**TAHSCT**

In fact, the first TAHSCT with HLA identical donor we preformed was in 2007 for a 54 years old female with resistant relapse, She was diagnosed as AML in July 2004 and obtained CR after 3 courses of chemotherapy by daunomycin plus Ara-C (DA), idarubicin plus Ara-C (IA) and mitoxantrone plus Ara-C (MA), and then received 13 courses of intensive consoli‐ dation chemotherapy including high dose of Ara-C, and autologous CIK infusion for 3 times. Her leukemia relapsed in the end of Dec 2006, and could not response to the several courses of reinduction chemotherapy. Before she received tumorablative allo-HSCT, there were 27% of leukemic blasts in marrow. The FLAG/RIT regimen was conditioned for HLAidentical sibling HSCT on February 22nd 2007. Her neutrophil and platelet were successful‐ ly engraftment on +18 days, chimerism analyses shown that full donor chimerism achieved by +30 days. Assay of MRD periodically by FCM monitoring after TAHSCT was zero. Grade I aGVHD of intestinal tract and liver was happened on +51 days, and thereafter invasive fungal infections in sinusitis, lung, liver on right-sidedness (pathological culture supported mucor infection) were happened, The Aspergillus was detected in sputum culture. All the complications above were controlled and cured after symptomatic treatment. She is still alive in continue complete remission up to now (more than 78 months).

AML and CML patients was 83.3%, which was significant higher than that in the ALL and NHL patients (40.0%, P<0.05) [32]. Our another 45 patients, form Beijing Dao-pei hospital, with refractory recurrent AML treated by TAHSCT [33]. The median blasts in marrow were 36% (20% to 92%) before transplantation, including 6 of HLA identical sibling, 9 of unrelated and 30 of haploindentical transplantation. All but 2 patients attained durable engraftment. The incidence of grade II to IV aGVHD and cGVHD were 34% and 59.1%, respectively. With median follow-up 30 (0.5 to 57) months, the relapse rate was 29.2%. Twenty nine (60.2%) pa‐ tients remained CR since transplantation. Three years DFS and Overall survival (OS) were 60.2% and 62.6%, respectively. These data confirmed that the individualized tumorablative allogeneic hematopoietic stem cell transplantation is a promising and safety choice for treat‐

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ment of high risk, refractory or relapse leukemia, even with high leukemia burden.

cal trials on a large population.

**8. Conclusion**

In the recent, these TAHSCT have being carried out in many hospitals in China. A total of 250 patients from 5 hospitals enrolled, the all patients with high-risk, resistant or relapse, even advanced hematological malignances, including leukemia and lymphoma [32,33-34]. The primary clinical observation revealed that the results are the similar to that above (data not published). Obviously, its efficacy must be confirmed by randomized, prospective clini‐

Actually, many investigators have being devoted to prevent from and treat recurrence post transplantation in refractory leukemia, including Schmid C, et al, who used a sequential treatment with chemotherapy and reduced-intensity conditioning for allogenic stem cell transplantation [19], and Takahashi S. et al, which used GCS-F combined regimen for alloge‐ neic bone marrow transplantation shown above [21]. Recently, Eom KS, et al. reported that FLANG salvage chemotherapy as a safe bridge to transplantation for patients with relapsed or refractory acute myeloid leukemia is an effective regimen [35]. Arita K, et al. described that a sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell trans‐ plantation for refractory acute lymphoblastic leukemia [36], and so on. All of them have ob‐ tained encouraging results. Comparing to them, our TAHSCT strategy emphasizes more

entirety, individual and tumorablative efficacy in the sitting of tolerated toxicity.

In summary, the TAHSCT strategy is a primary entirety approach for treatment of hemato‐ poietic malignances with high-risk, refractory or resistant relapse, based on the successful experiences either standard HSCT or chemotherapy for these patients. It is true, there were still some relapse post TAHSCT strategy, however, and it has reduced the relapse rate to about 20% in these patients, so it also highlights the need to improve. Theoretically, the re‐ sidual leukemic stem cell is the chief offender in relapse post transplantation. We can utilize the differences in the biocharacteristics between normal and leukemic stem cells, which re‐ sult of regulating disorder in proliferation, differentiation, apoptosis and ecize, signaling pathways, and so on [8,37,38], to exploit the targeted drugs with specific killing effects on LSC and niches for LSC, apoptosis-promoting and differentiation-inducing effects, such as

The first TAHSCT with haploidentical donor we did was in 2008. The case with 22 years old male was diagnosed as AML with t (8; 21), AML1/ETO positive in August 2005. He had re‐ ceived several courses of intensive consolidation, and maintenance chemotherapy including high dose Ara-C. Three years later, he had leukemia relapse, and not obtained CR again af‐ ter reinduction chemotherapy. Before transplantation, there were 75% of leukemic blasts in marrow. The patient received the FLAG/RIC/ATG conditioning regimen for HLA haploi‐ dentical TAHSCT from his sibling. On January 1st 2008, after TAHSCT, engraftment was durable with full donor chimerism, and detection of non MDR by FCM, chromosome, and realtime PCR for AML1/ETO fused gene monitoring. Limited cGVHD was controlled by CSA and prednisone in fewer months. The patient is still alive in disease-free survival (DFS) until now.

Between August 2006 and march 2007, a total of 57 patients with high risk/refractory leuke‐ mia were received tumorablative individualized conditioning regiments, included HDAra-C +Bu/Cy, G-CSF primed HDAra-C+Bu/Cy, and FLAG/RIT. Among 57, 20 patients of acute lymphoblast leukemia (ALL), 23 patients of acute myelogenous leukemia (AML), and 12 pa‐ tients of chronic myeloid leukemia (CML) in accelerate or blast crises phase, and 2 patients of myelodysplastic syndrome–refractory anemia with excess of blasts (MDS-RAEB). 28 pa‐ tients received haplo-identical transplantation, 17 patients HLA-identical unrelated donor transplantation and 12 patients HLA-identical sibling transplantation. The results showed that 56 patients, but one recovered with autologous hematopoiesis, attained durable engraft‐ ment. The median time to an absolute neutrophil count >0.5x109 /L was 16 (range: 12-21) days. The median time to a platelet count >20x109 /L was 18 (range: 12–32) days..With a me‐ dian follow-up of 17.5 (2-34)months, the probabilities of OS and DFS were (74.7±6.1) % and (62.4±6.7) %, respectively. The incidence rate of aGVHD in grades II-IV and III-IV were (19.3±5.2)% and (12.3±4.3)% respectively. Extensive chronic GVHD was observed in 36 (64.3%) patients. Cytomegaloviremia (CMV) was observed in 39 (68.42%) patients. Hemor‐ rhagic cystitis was observed in 13 (22.8%) patients. Fungous and bacterial infection occurred in 16 (28.07%) and 38 (66.67%) patients, respectively. The relapse in all patients occurred in 14 (24.6%). Among them, relapse rate in high risk and advanced group (blast cells were more than 20% in bone marrow) were 28.1% and 15.6%, respectively. 11 of 14 patients re‐ lapsed in marrow, 3 of 14 relapsed in extramedullary sites, 15 patients died (6 from hemato‐ logical relapse, 5 from infection of bacterial and fungous, 4 from chronic GVHD) after 100 days. The toxicity in this TAHSCT could be tolerance, and overcame [30,31].

Recently, we reported forty-nine patients, from first affiliated hospital, Chinese PLA General Hospital, of hematological malignancy with high risk or refractory, including 24 AML, 14 ALL, 9 non-Hodgkin lymphoma (NHL), and 2 CML in blast crisis. All patients received hap‐ loidentical TAHSCT, in which umbilical cord mesenchymal stem cells were added. All pa‐ tients achieved engraftment and complete remission after TAHSCT. Regimen-related toxicities were tolerable. Only five patients (10.2%) experienced relapse at a median time of 192 days after transplantation. The probability of 2 year leukemia free survival (LFS) in AML and CML patients was 83.3%, which was significant higher than that in the ALL and NHL patients (40.0%, P<0.05) [32]. Our another 45 patients, form Beijing Dao-pei hospital, with refractory recurrent AML treated by TAHSCT [33]. The median blasts in marrow were 36% (20% to 92%) before transplantation, including 6 of HLA identical sibling, 9 of unrelated and 30 of haploindentical transplantation. All but 2 patients attained durable engraftment. The incidence of grade II to IV aGVHD and cGVHD were 34% and 59.1%, respectively. With median follow-up 30 (0.5 to 57) months, the relapse rate was 29.2%. Twenty nine (60.2%) pa‐ tients remained CR since transplantation. Three years DFS and Overall survival (OS) were 60.2% and 62.6%, respectively. These data confirmed that the individualized tumorablative allogeneic hematopoietic stem cell transplantation is a promising and safety choice for treat‐ ment of high risk, refractory or relapse leukemia, even with high leukemia burden.

In the recent, these TAHSCT have being carried out in many hospitals in China. A total of 250 patients from 5 hospitals enrolled, the all patients with high-risk, resistant or relapse, even advanced hematological malignances, including leukemia and lymphoma [32,33-34]. The primary clinical observation revealed that the results are the similar to that above (data not published). Obviously, its efficacy must be confirmed by randomized, prospective clini‐ cal trials on a large population.

Actually, many investigators have being devoted to prevent from and treat recurrence post transplantation in refractory leukemia, including Schmid C, et al, who used a sequential treatment with chemotherapy and reduced-intensity conditioning for allogenic stem cell transplantation [19], and Takahashi S. et al, which used GCS-F combined regimen for alloge‐ neic bone marrow transplantation shown above [21]. Recently, Eom KS, et al. reported that FLANG salvage chemotherapy as a safe bridge to transplantation for patients with relapsed or refractory acute myeloid leukemia is an effective regimen [35]. Arita K, et al. described that a sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell trans‐ plantation for refractory acute lymphoblastic leukemia [36], and so on. All of them have ob‐ tained encouraging results. Comparing to them, our TAHSCT strategy emphasizes more entirety, individual and tumorablative efficacy in the sitting of tolerated toxicity.

## **8. Conclusion**

complications above were controlled and cured after symptomatic treatment. She is still

The first TAHSCT with haploidentical donor we did was in 2008. The case with 22 years old male was diagnosed as AML with t (8; 21), AML1/ETO positive in August 2005. He had re‐ ceived several courses of intensive consolidation, and maintenance chemotherapy including high dose Ara-C. Three years later, he had leukemia relapse, and not obtained CR again af‐ ter reinduction chemotherapy. Before transplantation, there were 75% of leukemic blasts in marrow. The patient received the FLAG/RIC/ATG conditioning regimen for HLA haploi‐ dentical TAHSCT from his sibling. On January 1st 2008, after TAHSCT, engraftment was durable with full donor chimerism, and detection of non MDR by FCM, chromosome, and realtime PCR for AML1/ETO fused gene monitoring. Limited cGVHD was controlled by CSA and prednisone in fewer months. The patient is still alive in disease-free survival (DFS)

Between August 2006 and march 2007, a total of 57 patients with high risk/refractory leuke‐ mia were received tumorablative individualized conditioning regiments, included HDAra-C +Bu/Cy, G-CSF primed HDAra-C+Bu/Cy, and FLAG/RIT. Among 57, 20 patients of acute lymphoblast leukemia (ALL), 23 patients of acute myelogenous leukemia (AML), and 12 pa‐ tients of chronic myeloid leukemia (CML) in accelerate or blast crises phase, and 2 patients of myelodysplastic syndrome–refractory anemia with excess of blasts (MDS-RAEB). 28 pa‐ tients received haplo-identical transplantation, 17 patients HLA-identical unrelated donor transplantation and 12 patients HLA-identical sibling transplantation. The results showed that 56 patients, but one recovered with autologous hematopoiesis, attained durable engraft‐

dian follow-up of 17.5 (2-34)months, the probabilities of OS and DFS were (74.7±6.1) % and (62.4±6.7) %, respectively. The incidence rate of aGVHD in grades II-IV and III-IV were (19.3±5.2)% and (12.3±4.3)% respectively. Extensive chronic GVHD was observed in 36 (64.3%) patients. Cytomegaloviremia (CMV) was observed in 39 (68.42%) patients. Hemor‐ rhagic cystitis was observed in 13 (22.8%) patients. Fungous and bacterial infection occurred in 16 (28.07%) and 38 (66.67%) patients, respectively. The relapse in all patients occurred in 14 (24.6%). Among them, relapse rate in high risk and advanced group (blast cells were more than 20% in bone marrow) were 28.1% and 15.6%, respectively. 11 of 14 patients re‐ lapsed in marrow, 3 of 14 relapsed in extramedullary sites, 15 patients died (6 from hemato‐ logical relapse, 5 from infection of bacterial and fungous, 4 from chronic GVHD) after 100

Recently, we reported forty-nine patients, from first affiliated hospital, Chinese PLA General Hospital, of hematological malignancy with high risk or refractory, including 24 AML, 14 ALL, 9 non-Hodgkin lymphoma (NHL), and 2 CML in blast crisis. All patients received hap‐ loidentical TAHSCT, in which umbilical cord mesenchymal stem cells were added. All pa‐ tients achieved engraftment and complete remission after TAHSCT. Regimen-related toxicities were tolerable. Only five patients (10.2%) experienced relapse at a median time of 192 days after transplantation. The probability of 2 year leukemia free survival (LFS) in

/L was 16 (range: 12-21)

/L was 18 (range: 12–32) days..With a me‐

alive in continue complete remission up to now (more than 78 months).

ment. The median time to an absolute neutrophil count >0.5x109

days. The toxicity in this TAHSCT could be tolerance, and overcame [30,31].

days. The median time to a platelet count >20x109

until now.

266 Innovations in Stem Cell Transplantation

In summary, the TAHSCT strategy is a primary entirety approach for treatment of hemato‐ poietic malignances with high-risk, refractory or resistant relapse, based on the successful experiences either standard HSCT or chemotherapy for these patients. It is true, there were still some relapse post TAHSCT strategy, however, and it has reduced the relapse rate to about 20% in these patients, so it also highlights the need to improve. Theoretically, the re‐ sidual leukemic stem cell is the chief offender in relapse post transplantation. We can utilize the differences in the biocharacteristics between normal and leukemic stem cells, which re‐ sult of regulating disorder in proliferation, differentiation, apoptosis and ecize, signaling pathways, and so on [8,37,38], to exploit the targeted drugs with specific killing effects on LSC and niches for LSC, apoptosis-promoting and differentiation-inducing effects, such as tyrosine kinase inhibitor, FLT3 inhibitor [39], hypomethylating agent, and so on, together with the specific functional T cell adoptive immunotherapy. It should provide a broad pros‐ pect for the prevention and radical cure of relapse after TAHSCT in patients with refractory and relapsed leukemia.

[5] Da Wan-ming, Wu Tong, Lu Dao-pei. Prevention and treatment of leukemia relapse after allogeneic hematopoietic stem cell transplantation for acute leukemias . Chin J

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[6] Flynn CM, Kaufman DS. Donor cell leukemia: insight into cancer stem cells and the

[7] Majhail NS. Old and new cancers after hematopoietic cell transplantation. Hematol

[8] Dick JE, Lapidor T. Biology of normal and acute myeloid leukemic stem cells. Int J

[9] Da WM. Strategies for prevention and management of leukemic relapse after alloge‐ neic hematopoietic cell transplantation. Chinese Blood and Marrow Transplantation Forum and Annual Scientific Meeting of Hong Kong Society of Haematology. 2010;

[10] Ringden O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoiet‐

[11] Da WM. Tumorablative allogeneic hematopoietc stem cell transplantation. In Da WM, Chen XQ (ed.) Hematology 2010. Beijing: Chinese Medical Multimedia Press.

[12] Da WM. Prevention and treatment for relapsed leukemia post allogeneic hemato‐ poietic cell transplantation. Beijing: Chinese Medical Multimedia Press. 2008. p22. [13] Breithaupt H, Pralle H, Eckhardt T, et al. Clinical results and pharmacokinetics of high-dose cytosine arabinoside(HD ARA-C) . Cancer. 1982, 50(7) 1248-1257.

[14] Capizzi RL, Poole M, Cooper MR, et al. Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase. Blood 1984; 63(3) 694-700.

[15] Xie Xiao-tian, Li Ben-shang, Li L, et al. Determination of plasma and cerebrospinal fluid drug concentrations during high-dose cytosine arabinoside treatment[J]. Shang‐

[16] Kern W, Aul C, Maschmyer G, et al. Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leuke‐ mia: results of an age -justed prospective randomized comparison. Leukemia 1998;

[17] Pastore D, Specchia G, Carluccio P, et al. FLAG-IDA in the treatment of refractory/ relapsed acute myeloid leukemia: single-center experience. Ann Hematol 2003; 82(4)

Hematol 2007; 28(12) 793-794.

Hematol 2008; 82(5) 389-396.

Beijing. 2010. p230-239.

12(7) 1049-1055.

231-235.

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37.

stem cell niche. Blood 2007; 109(7) 2688-2692.

Am Soc Hematol Educ Program 2008;142-149.

ic stem cell transplantation. Blood 2009;113(13) 3110-3118.

## **Acknowledgements**

I thank all members of hematology department, first affiliated hospital, Chinese PLA gener‐ al hospital, and Beijing Dao-pei Hospital for their dedicated works in these studies. Thank Dr Haiyan Zhu for preparation of this manuscript.

## **Author details**

Wan-ming Da1 and Yong Da2

\*Address all correspondence to: dwanming@medmail.com.cn, dayong2727@sohu.com

1 Department of Hematology, Unit of Bone Marrow Transplantation, and Department of Geriatric Hematology, Chinese PLA General Hospital & Chinese Medical College; The De‐ partment of Hematology, Unit of Bone Marrow Transplantation, First affiliated Hospital, Chinese PLA General Hospital & Chinese Medical College;, Beijing, China

2 The Affiliated Hospital of The Military Medical Science Academy of Chinese PLA, Beijing, China

## **References**


[5] Da Wan-ming, Wu Tong, Lu Dao-pei. Prevention and treatment of leukemia relapse after allogeneic hematopoietic stem cell transplantation for acute leukemias . Chin J Hematol 2007; 28(12) 793-794.

tyrosine kinase inhibitor, FLT3 inhibitor [39], hypomethylating agent, and so on, together with the specific functional T cell adoptive immunotherapy. It should provide a broad pros‐ pect for the prevention and radical cure of relapse after TAHSCT in patients with refractory

I thank all members of hematology department, first affiliated hospital, Chinese PLA gener‐ al hospital, and Beijing Dao-pei Hospital for their dedicated works in these studies. Thank

\*Address all correspondence to: dwanming@medmail.com.cn, dayong2727@sohu.com

Chinese PLA General Hospital & Chinese Medical College;, Beijing, China

John Wiley & Sons Ltd, Publication. p761-774.

1 Department of Hematology, Unit of Bone Marrow Transplantation, and Department of Geriatric Hematology, Chinese PLA General Hospital & Chinese Medical College; The De‐ partment of Hematology, Unit of Bone Marrow Transplantation, First affiliated Hospital,

2 The Affiliated Hospital of The Military Medical Science Academy of Chinese PLA, Beijing,

[1] Appelbaum FR. Hematopoietic cell transplantation for adult acute myeloid leuke‐ mia. In: Appelbaum FR, Forman SJ, Negrin RS, Blume KG.(ed.). Thoma's hemato‐ poietic cell transplantation: stem cell transplantation. 4th edition. Wiley–Blackwell, A

[2] Lu Dao-pei. The major developments in hematopoietic stem cell transplantation—be‐

[3] Da Wan-ming, Wu Tong, Lu Dao-pei. Unceasingly improving outcomes of allogeneic

[4] Duval M, Klein JP, He W,, et al. Hematopoietic stem cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28(23) 3730-3738.

fore 2003. J Peking University: Health Sciences 2003; 35(2) 113-114.

hematopoietic cell transplantation. Chin J Hematol 2006; 7(8) 505-506.

and relapsed leukemia.

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**Acknowledgements**

**Author details**

Wan-ming Da1

China

**References**

Dr Haiyan Zhu for preparation of this manuscript.

and Yong Da2


[18] Clavio M, Carrara P, Miglino M, et al. High efficacy of fludarabine-containing thera‐ py (flag-flang) in poor risk acute myeloid leukemia. Haematologica 1996; 81(6): 513-520.

[29] Wang JB, Wu T, Yang JF et al. Management of early leukemia relapse after allogeneic hematopoietic stem cell transplantation by donor's dendritic cell-primed cytokine-in‐ duced killer cells. Blood 2008; 112: 307 (2008 ASH Annual Meeting Abstracts 829). [30] Da WM, Wang JB, Zhang JP, et al. Tumorablative tailored allogeneic hematopoietic stem cell transplantation in treatment of high risk and reftractory leukemia. Chin J

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[31] Wang JB, Da WM, Zhang JP, et al. Successful treatment of high risk/refractory leuke‐ mia by tumor-ablative individualized conditioning allogeneic hematopoietic stem

[32] Wu YM, Wang ZH, Cao YB, et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a modified myeloablative regimen

for refractory/relapsed hematologic malignancy. Ann Hematol 2012 (in press). [33] Wang JB, Wu T, Da WM, et al. Salvaged allgeneic hematopoietic stem cell transplan‐ tation for refractory recurrent acute myeloid leukemia. Chin J Hematol 2012; 33(6)

[34] Wang ZH, Wu XX, Liu ZY, et al. Curative efficacy analysis of allo-HSCT using condi‐ tioning regimen of FLAG combined with modified BuCy for refractory and relapsed patients with hematologic malignancies. Chin J Experimental Hematol 2011; 19(1)

[35] Eom KS, Min WS, Kim HJ,et al. FLANG salvage chemotherapy is an effective regi‐ men that offers a safe bridge to transplantation for patients with relapsed or refracto‐

[36] Arita K, Kondo T, Sugita J, et al.Sequential chemotherapy and myeloablative alloge‐ neic hematopoietic stem cell transplantation for refractory acute lymphoblastic leu‐

[37] Miller JS, Warren EH, van den Brink MRM, et al. NCI first international workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: Report from the committee on the biology underlying recurrence of malignant disease following allogeneic HSCT: graft-versus-tumor/leukemia reac‐

[39] Sorà F, Chiusolo P, Metafuni E, et al. Sorafenib for refractory FMS-like tyrosine kin‐ ase receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogenic stem cell trans‐

ry acute myeloid leukemia. Med Oncol. 2011; 28 Suppl 1: S462–S470.

[38] Abboud CN. Another nail in the AML coffin. Blood 2009;113(24) 6045-6046.

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[18] Clavio M, Carrara P, Miglino M, et al. High efficacy of fludarabine-containing thera‐ py (flag-flang) in poor risk acute myeloid leukemia. Haematologica 1996; 81(6):

[19] Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108(3)

[20] Morris ES, MacDonald KP, Rowe V, et al. NKT cell- dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest 2005;

[21] Takahashi S, Okamoto SI, Shirafuji N, et al. Recombinant human glycosylated granu‐ locyte colony-stimulating factor (rhG-CSF) - combined regimen for allogeneic bone marrow transplantation in refractory acute myeloid leukemia. Bone Marrow Trans‐

[22] Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult pa‐

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[24] Lu DP, Dong L, Wu T, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplanta‐ tion can achieve comparable outcomes with HLA-identical sibling transplantation.

[25] Da WM. Allogeneic tumorablative hematopoietc stem cell transplantation. BME&

[26] Mackall C,Fry T,Gress1 R,et al. Background to hematopoietic cell transplanta‐ tion , including post transplant immune recovery. Bone Marrow Transplant

[27] Schmid C, Labopin M, Nagler A, et al. Donor Lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: A retrospective risk factors analysis and comparison with other strategies by the EBMT acute leukemia working party. J Clin Oncol 2007; 25(31)

[28] Nguyen S, Béziat V, Norol F, etal. Infusion of allogeneic natural killer cells in a pa‐ tient with acute myeloid leukemia in relapse after haploidentical hematopoietic stem

cell transplantation. Transpl Cellular Eng 2011;51(8) 1796-1778.

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4938-4945.


**Chapter 12**

**Stem Cell Transplantation in**

Anna Gazzola, Alessandro Broccoli,

http://dx.doi.org/10.5772/53085

world, with an incidence of 3–6/105

**1. Introduction**

Vittorio Stefoni and Pier Paolo Piccaluga

Additional information is available at the end of the chapter

gressive course and die within few years from diagnosis [3, 4].

*NOTCH1*, *SF3B1*, and *BIRC3* mutations [10-15].

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in Western

This disease is characterized by an extremely heterogeneous behavior, with the clinical course varying from patients who never require therapy to patients with a rapid disease progression and early resistance to treatment. In fact, about 20% of the patients show an ag‐

Molecular markers, such as cytogenetic alteration [5], immunoglobulin heavy chain (*IGH*) and *TP53* genes mutational status [6, 7], zeta associated protein 70 (ZAP70) expression [8] and CD38 expression [9], help to predict outcomes in CLL. However, their presence in the absence of clinical symptomatology is not a sufficient criterium to initiate therapy. Further, even in the absence of these factors, resistance to purine-analogue treatment can occur. This suggests that additional molecular mechanisms, which confer drug refractoriness in poorrisk CLL, do exist. In this regard, based on next generation sequencing studies, it was recent‐ ly shown that additional genetic events can predict CLL patients outcome, including

A major issue in CLL is the identification of the optimal timing and type of first-line treat‐ ment. In the current recommendation of International Workshop on CLL (IWCLL) updated guidelines for the diagnosis and treatment of CLL the therapy is reserved for advanced, symptomatic or progressive disease [16]. Numerous studies showed that, either as first-line therapy or in relapsed/refractory settings, treatment with new agents, such as alemuzumab, ofatumumab, lenalidomide, and flavoperidole [17-22] or combination of conventional che‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Gazzola et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

per year, that increase to 12.8/105 at the age of 65 [1-3].

**Chronic Lymphocytic Leukemia**

## **Chapter 12**

## **Stem Cell Transplantation in Chronic Lymphocytic Leukemia**

Anna Gazzola, Alessandro Broccoli, Vittorio Stefoni and Pier Paolo Piccaluga

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53085

## **1. Introduction**

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in Western world, with an incidence of 3–6/105 per year, that increase to 12.8/105 at the age of 65 [1-3]. This disease is characterized by an extremely heterogeneous behavior, with the clinical course varying from patients who never require therapy to patients with a rapid disease progression and early resistance to treatment. In fact, about 20% of the patients show an ag‐ gressive course and die within few years from diagnosis [3, 4].

Molecular markers, such as cytogenetic alteration [5], immunoglobulin heavy chain (*IGH*) and *TP53* genes mutational status [6, 7], zeta associated protein 70 (ZAP70) expression [8] and CD38 expression [9], help to predict outcomes in CLL. However, their presence in the absence of clinical symptomatology is not a sufficient criterium to initiate therapy. Further, even in the absence of these factors, resistance to purine-analogue treatment can occur. This suggests that additional molecular mechanisms, which confer drug refractoriness in poorrisk CLL, do exist. In this regard, based on next generation sequencing studies, it was recent‐ ly shown that additional genetic events can predict CLL patients outcome, including *NOTCH1*, *SF3B1*, and *BIRC3* mutations [10-15].

A major issue in CLL is the identification of the optimal timing and type of first-line treat‐ ment. In the current recommendation of International Workshop on CLL (IWCLL) updated guidelines for the diagnosis and treatment of CLL the therapy is reserved for advanced, symptomatic or progressive disease [16]. Numerous studies showed that, either as first-line therapy or in relapsed/refractory settings, treatment with new agents, such as alemuzumab, ofatumumab, lenalidomide, and flavoperidole [17-22] or combination of conventional che‐

© 2013 Gazzola et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

motherapy to target immunotherapy lead to a better response in these patients [23-29]. These approaches significantly reduce the tumor load in refractory patients, even if the ulti‐ mate cure of disease has not yet been achieved. Therefore, CLL remains incurable outside the setting of allogeneic stem cell transplant (allo-SCT). In fact, up to date this is the only therapeutical approach that can potentially offer a curable solution to this disease [9]. The indications for SCT in CLL were established by European Bone Marrow Transplant (EBMT) [30]. Specifically, based on the evidence of efficacy and potential toxicity of SCT in CLL, these procedure is designated for high-risk CLL patents. These include: a) patients with *TP53* abnormalities, who fail to achieve complete remission (CR) or who progress within 12 months after purine analogues, b) those who relapse within 24 months after having ach‐ ieved a response with purine-analogue-based combination therapy, c) those who relapsed after prior autologous SCT and d) patients who are fludarabine refractory [31, 32]. It should be noted that none of these categories requires assessment of biologic risk factors except cy‐ togenetic detection of *TP53* deletions. Ongoing prospective clinical studies will determine the impact of biomarkers such as *IGH* mutational status and other cytogenetic abnormalities in identification of patients at sufficiently high risk for allogeneic SCT use at first CR. Several groups agree that allogeneic transplant early in the disease course is the best strategy for pa‐ tients with high-risk or poor response to initial therapy. For those with durable first remis‐ sions, the timing of transplant is more controversial. The debate in "*when to proceed to a more aggressive treatment approach?*" in CLL is in part driven by the presence of new therapeutic strategies available for these patients. However, it is unknown how these therapies will change the indications for or the outcome following transplant in CLL. Nevertheless, these promising results have already started to impact the transplant recommendations in CLL patients in a similar manner to chronic myeloid leukemia (CML) patients in imatinib era.

the outcome of ASCT is strongly correlated with the status of the disease: patients transplant‐ ed in CR have a much better outcome than those transplanted with active disease [36]. There‐

Stem Cell Transplantation in Chronic Lymphocytic Leukemia

http://dx.doi.org/10.5772/53085

275

Other factors that negatively influence the transplantation outcome and correlate with early relapse are: the interval between the diagnosis and the transplant, the number of prior lines of therapy, the presence of adverse cytogenetic abnormalities and of unmutated *IGH* genes [36, 38]. In addition, the detection of MRD by either polymerase chain reaction (PCR) or

As mentioned above, different studies have investigated the role of ASCT in patients with CLL and the results were controversial. A retrospective matched-pair analysis suggested a survival advantage for ASCT in 66 patients who had undergone a uniform high dose thera‐ py and transplantation over conventional therapy in 291 patients. With an overall median follow-up time of 70 and 86 months, survival was significantly longer for the patients who had undergone ASCT compared with conventionally treated patients [41]. However, in 2011, several prospective studies have failed to confirm the survival advantage of ASCT in advanced CLL patients [42, 43]. Brion et al. [43] published the results of a prospective multi‐ center randomized trial on the benefit of ASCT using a cyclophosphamide/TBI preparative regimen in advanced clinical-stage untreated CLL compared to conventional treatment. The conventional treatment was represented by 6 cicles of miniCHOP; for the ASCT cohort the scheduled therapy consisted of 3 miniCHOP cicles followed by immediate ASCT for pa‐ tients with a very good partial remission (VGPR) or CR. This study highlights the absence of differences in median overall survival (OS) between the two groups thus denying the supe‐

The necessity of additional randomized studies to better clarify the role of ASCT in the man‐ agement of patients with CLL was further emphasized by a comparative study conducted by the EBMT group in which 621 autografted patients were compared to 630 non-autograft‐ ed patients. Patients autografted within 18 months of diagnosis had a better outcome that those treated with chemotherapy, but this was offset by an inferior outcome of patients au‐ tografted after 18 months [44]. In addition it was found a promising benefit by the T-cell mediated cytotoxicity via autologous transplantation in the high-risk CLL population.

Interestingly, Porter et al. [45] reported on the management of a chemo-refractory, CLL pa‐ tient with del(17p) treated with autologous T-cells genetically modified to express anti-CD19; although the long-term disease control and late toxicities are not yet known, the

Most of the studies published have relatively short follow up and therefore only focus on treatment related mortality (TRM) early after transplant, but the late consequences, particu‐ larly the development of secondary myelodysplasia and acute myeloid leukaemia (MDS/ AML), deserve some concern [37]. In fact, among 65 patients treated with fludarabine fol‐ lowed by ASCT, 8 developed MDS/ AML [37, 46]. Of note, in most studies, despite a high initial CR rate, relapse is common, suggesting that autologous transplant is unlikely to be curative in CLL [37]. However, based on the present literature, although ASCT cannot be

fore, optimal disease control prior to transplantation is mandatory [33, 34, 37].

flow cytometry after transplantation anticipates clinical relapse [39, 40].

riority of ASCT over conventional therapy.

patient was in remission [45].

In this chapter the Authors, based on their own experience as well as on the most updated literature, discuss the usage of autologous and allogeneic SCT in the clinical setting of CLL, also in the light of the novel biological prognostic indicators.

## **2. Autologous hematopoietic stem cell transplantation**

Autologous stem cell transplantation (ASCT) has been extensively investigated as a treat‐ ment option for CLL patients during the last years.

Evidences from clinical and minimal residual disease (MRD) studies have suggested that ASCT has curative potential in only few patients. Nevertheless, ASCT might be capable of prolonged disease control even in CLL with poor-risk features.

Autologous transplantation consists in the collection of stem cells from the patient's marrow or peripheral blood before high-dose irradiation or chemotherapy and their subsequent reinfu‐ sion to guarantee a new blood production. The main problems with this procedure are the risk of re-infusion of leukemic cells that could potentially contaminate the stem cell population and the difficulty in mobilizing progenitor cell in patients who have received multiple previous treatments [33, 34]; particularly if purine analogs, have been administrated [35]. In addition, the outcome of ASCT is strongly correlated with the status of the disease: patients transplant‐ ed in CR have a much better outcome than those transplanted with active disease [36]. There‐ fore, optimal disease control prior to transplantation is mandatory [33, 34, 37].

motherapy to target immunotherapy lead to a better response in these patients [23-29]. These approaches significantly reduce the tumor load in refractory patients, even if the ulti‐ mate cure of disease has not yet been achieved. Therefore, CLL remains incurable outside the setting of allogeneic stem cell transplant (allo-SCT). In fact, up to date this is the only therapeutical approach that can potentially offer a curable solution to this disease [9]. The indications for SCT in CLL were established by European Bone Marrow Transplant (EBMT) [30]. Specifically, based on the evidence of efficacy and potential toxicity of SCT in CLL, these procedure is designated for high-risk CLL patents. These include: a) patients with *TP53* abnormalities, who fail to achieve complete remission (CR) or who progress within 12 months after purine analogues, b) those who relapse within 24 months after having ach‐ ieved a response with purine-analogue-based combination therapy, c) those who relapsed after prior autologous SCT and d) patients who are fludarabine refractory [31, 32]. It should be noted that none of these categories requires assessment of biologic risk factors except cy‐ togenetic detection of *TP53* deletions. Ongoing prospective clinical studies will determine the impact of biomarkers such as *IGH* mutational status and other cytogenetic abnormalities in identification of patients at sufficiently high risk for allogeneic SCT use at first CR. Several groups agree that allogeneic transplant early in the disease course is the best strategy for pa‐ tients with high-risk or poor response to initial therapy. For those with durable first remis‐ sions, the timing of transplant is more controversial. The debate in "*when to proceed to a more aggressive treatment approach?*" in CLL is in part driven by the presence of new therapeutic strategies available for these patients. However, it is unknown how these therapies will change the indications for or the outcome following transplant in CLL. Nevertheless, these promising results have already started to impact the transplant recommendations in CLL patients in a similar manner to chronic myeloid leukemia (CML) patients in imatinib era.

In this chapter the Authors, based on their own experience as well as on the most updated literature, discuss the usage of autologous and allogeneic SCT in the clinical setting of CLL,

Autologous stem cell transplantation (ASCT) has been extensively investigated as a treat‐

Evidences from clinical and minimal residual disease (MRD) studies have suggested that ASCT has curative potential in only few patients. Nevertheless, ASCT might be capable of

Autologous transplantation consists in the collection of stem cells from the patient's marrow or peripheral blood before high-dose irradiation or chemotherapy and their subsequent reinfu‐ sion to guarantee a new blood production. The main problems with this procedure are the risk of re-infusion of leukemic cells that could potentially contaminate the stem cell population and the difficulty in mobilizing progenitor cell in patients who have received multiple previous treatments [33, 34]; particularly if purine analogs, have been administrated [35]. In addition,

also in the light of the novel biological prognostic indicators.

ment option for CLL patients during the last years.

274 Innovations in Stem Cell Transplantation

**2. Autologous hematopoietic stem cell transplantation**

prolonged disease control even in CLL with poor-risk features.

Other factors that negatively influence the transplantation outcome and correlate with early relapse are: the interval between the diagnosis and the transplant, the number of prior lines of therapy, the presence of adverse cytogenetic abnormalities and of unmutated *IGH* genes [36, 38]. In addition, the detection of MRD by either polymerase chain reaction (PCR) or flow cytometry after transplantation anticipates clinical relapse [39, 40].

As mentioned above, different studies have investigated the role of ASCT in patients with CLL and the results were controversial. A retrospective matched-pair analysis suggested a survival advantage for ASCT in 66 patients who had undergone a uniform high dose thera‐ py and transplantation over conventional therapy in 291 patients. With an overall median follow-up time of 70 and 86 months, survival was significantly longer for the patients who had undergone ASCT compared with conventionally treated patients [41]. However, in 2011, several prospective studies have failed to confirm the survival advantage of ASCT in advanced CLL patients [42, 43]. Brion et al. [43] published the results of a prospective multi‐ center randomized trial on the benefit of ASCT using a cyclophosphamide/TBI preparative regimen in advanced clinical-stage untreated CLL compared to conventional treatment. The conventional treatment was represented by 6 cicles of miniCHOP; for the ASCT cohort the scheduled therapy consisted of 3 miniCHOP cicles followed by immediate ASCT for pa‐ tients with a very good partial remission (VGPR) or CR. This study highlights the absence of differences in median overall survival (OS) between the two groups thus denying the supe‐ riority of ASCT over conventional therapy.

The necessity of additional randomized studies to better clarify the role of ASCT in the man‐ agement of patients with CLL was further emphasized by a comparative study conducted by the EBMT group in which 621 autografted patients were compared to 630 non-autograft‐ ed patients. Patients autografted within 18 months of diagnosis had a better outcome that those treated with chemotherapy, but this was offset by an inferior outcome of patients au‐ tografted after 18 months [44]. In addition it was found a promising benefit by the T-cell mediated cytotoxicity via autologous transplantation in the high-risk CLL population.

Interestingly, Porter et al. [45] reported on the management of a chemo-refractory, CLL pa‐ tient with del(17p) treated with autologous T-cells genetically modified to express anti-CD19; although the long-term disease control and late toxicities are not yet known, the patient was in remission [45].

Most of the studies published have relatively short follow up and therefore only focus on treatment related mortality (TRM) early after transplant, but the late consequences, particu‐ larly the development of secondary myelodysplasia and acute myeloid leukaemia (MDS/ AML), deserve some concern [37]. In fact, among 65 patients treated with fludarabine fol‐ lowed by ASCT, 8 developed MDS/ AML [37, 46]. Of note, in most studies, despite a high initial CR rate, relapse is common, suggesting that autologous transplant is unlikely to be curative in CLL [37]. However, based on the present literature, although ASCT cannot be considered as a standard treatment it should be considered in the context of clinical trials or as an innovative therapy to prolong survival in selected patients (i.e. those with chemosensi‐ tivity, absence of unfavorable factors, and transplanted early in the course of the disease).

cells by immune mechanisms c) better survival curves. In fact, studies from MD Anderson Cancer Center demonstrate improved outcome after allogeneic compared to ASCT [59] sug‐ gesting that myeloablative allo-SCT can induce durable remission even in patients with re‐ fractory disease. However, the major limitation of using myeloablative allo-SCT is the increased risk of transplant-associated morbidity and mortality, mostly from organ failure due to direct toxicity of the preparative regimen and/or development of GVHD [48, 60, 61]. Registry data from the International Bone Marrow Transplant Research (IBMTR) group and the EBMT group reported a transplant-related mortality (TRM) of 46% with mortality from GVHD of 20% [60]. These published data showed that approximately two-thirds of allo‐ transplanted CLL patients will succumb either to TRM or to recurrent disease, and approxi‐

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277

Active chronic GVHD is principal determinant of long-term morbidity and significantly re‐ duced long-term health status in patients allografted for various hematological malignancies [62]. Indeed, transplant-related long-term morbidity after allo-SCT for CLL can be signifi‐ cant but is mainly restricted to those patients who have ongoing active chronic GVHD. However, in the majority of affected patients clinical symptoms of chronic GVHD resolved over time, allowing discontinuation of systemic therapeutic immunosuppression after a me‐ dian of 25 months [63]. Further, a high graft rejection rates remain a relevant complication in myeloablative allo-SCT; a possible explanations could be the significant marrow infiltration in CLL patients at the time of transplantation, inversely correlated with outcome [64], and the role played by host dendritic cells, which are seriously defective in CLL patients [65]. Another problem is represented by the high infection rates, that correlated with preexisting immunosuppression. Infections are the cause of about 50% of all CLL-related deaths [62, 66] primarily in fludarabine and/or alemtuzumab-refractory patients [16, 67]. Moreover in re‐ cent reports the risk of infections has been clearly correlated with presence of GVHD [57, 63, 65, 68] and refractory disease [67, 69]. In addition, it is important to note that patients with chemosensitive disease have significantly better outcomes than patients with refractory dis‐ ease, suggesting that an earlier application of allo-SCT may further improve transplantation

In conclusion, allo-SCT is a therapy with curative potential in CLL and, in contrast to con‐ ventional treatment, with an high potential of providing long-term disease control even in patients with a very unfavorable biological and clinical risk profile. However, in addition to the disease risk, it is necessary to consider patient-related risk factors, such as age and co‐

Although myeloablative allo-SCT in CLL can result in durable remissions, rates of TRM are after unacceptably and greatly reduced its application, even in the most refractory and high-

**5. Reduced-intensity conditioning stem cell transplantation**

mately one-third will be cured of their disease [54, 60].

outcomes [60, 70, 71].

risk individuals.

morbidity, when allo-SCT is performed [63].

**(nonmyeloablative allo-SCT)**

## **3. Allogeneic hematopoietic stem cell transplantation**

In recent years, allogeneic hematopoietic stem cell transplant (allo-SCT) was visibly emerged as the favorite treatment option for patients with high-risk CLL. In fact, in contrast with ASCT, allo-SCT can induce durable responses even in patients refractory to therapy [47-49]. Studies on the outcomes post ASCT failed to show a plateau effect on survival curves and resulted in a remarkably high incidence of secondary myelodysplastic syn‐ dromes (9% to 12%) [50]. On the contrary, in most series where allo-SCT has been carried out, a plateau is observed, with 40–60% of the patients remaining alive and free of disease 5– 6 years after transplantation [39, 44, 46, 48, 49, 51-55]. Therefore, allo-SCT become, in the last two decades, the first treatment approach with curative potential in CLL.

The crucial anti-leukemic principle of allo-SCT in CLL appears to be the graft-versus-leuke‐ mia effect (GVL). The resultant GVL effect derived from alloreactive donor T cells is the key mechanism responsible for lowering relapse rates after allo-SCT. There is evidence that the GVL effect plays an essential role in controlling the disease and reverts poor prognostic bio‐ logical variables such as unmutated *IGH* genes [56, 57]. In addition, one of the most impor‐ tant advantage of allo-SCT includes infusion of tumor-free hematopoietic progenitor and effector cells from healthy donors. Of note, it is important to exclude the presence in donor peripheral blood of a monoclonal population immunophenotypically identical to that of pa‐ tients with CLL; in fact it was demonstrated that CLL clones were found in around 12% of the first-degree relatives of patients with CLL and in up to 3% of the general population [58]. Nevertheless, the use of allo-SCT is limited due to the advanced age of most patients with CLL and the high mortality associated with the procedure (in the range 24–47%), main caus‐ es for death being graft-vs host disease (GVHD) and infections.

At present, ongoing prospective clinical studies will determine the impact of biomarkers in‐ cluding *IGH* mutational status and other cytogenetic abnormalities in identification of pa‐ tients with sufficiently high risk to deserve use of allo-SCT in first CR.

## **4. Myeloablative allogeneic stem cell transplantation**

In myeloablative allo-SCT, patients are given extremely high doses of chemotherapy, with or without radiation, to wipe out, or "ablate," the marrow. Then they are given an infusion of donor stem cells to revive blood cell production and immunity.

Several theoretical advantages of myeloablative allo-SCT over ASCT are: a) none tumor con‐ tamination of the stem cell b) GVL effect to eliminate chemotherapy-resistant leukaemia cells by immune mechanisms c) better survival curves. In fact, studies from MD Anderson Cancer Center demonstrate improved outcome after allogeneic compared to ASCT [59] sug‐ gesting that myeloablative allo-SCT can induce durable remission even in patients with re‐ fractory disease. However, the major limitation of using myeloablative allo-SCT is the increased risk of transplant-associated morbidity and mortality, mostly from organ failure due to direct toxicity of the preparative regimen and/or development of GVHD [48, 60, 61].

considered as a standard treatment it should be considered in the context of clinical trials or as an innovative therapy to prolong survival in selected patients (i.e. those with chemosensi‐ tivity, absence of unfavorable factors, and transplanted early in the course of the disease).

In recent years, allogeneic hematopoietic stem cell transplant (allo-SCT) was visibly emerged as the favorite treatment option for patients with high-risk CLL. In fact, in contrast with ASCT, allo-SCT can induce durable responses even in patients refractory to therapy [47-49]. Studies on the outcomes post ASCT failed to show a plateau effect on survival curves and resulted in a remarkably high incidence of secondary myelodysplastic syn‐ dromes (9% to 12%) [50]. On the contrary, in most series where allo-SCT has been carried out, a plateau is observed, with 40–60% of the patients remaining alive and free of disease 5– 6 years after transplantation [39, 44, 46, 48, 49, 51-55]. Therefore, allo-SCT become, in the last

The crucial anti-leukemic principle of allo-SCT in CLL appears to be the graft-versus-leuke‐ mia effect (GVL). The resultant GVL effect derived from alloreactive donor T cells is the key mechanism responsible for lowering relapse rates after allo-SCT. There is evidence that the GVL effect plays an essential role in controlling the disease and reverts poor prognostic bio‐ logical variables such as unmutated *IGH* genes [56, 57]. In addition, one of the most impor‐ tant advantage of allo-SCT includes infusion of tumor-free hematopoietic progenitor and effector cells from healthy donors. Of note, it is important to exclude the presence in donor peripheral blood of a monoclonal population immunophenotypically identical to that of pa‐ tients with CLL; in fact it was demonstrated that CLL clones were found in around 12% of the first-degree relatives of patients with CLL and in up to 3% of the general population [58]. Nevertheless, the use of allo-SCT is limited due to the advanced age of most patients with CLL and the high mortality associated with the procedure (in the range 24–47%), main caus‐

At present, ongoing prospective clinical studies will determine the impact of biomarkers in‐ cluding *IGH* mutational status and other cytogenetic abnormalities in identification of pa‐

In myeloablative allo-SCT, patients are given extremely high doses of chemotherapy, with or without radiation, to wipe out, or "ablate," the marrow. Then they are given an infusion

Several theoretical advantages of myeloablative allo-SCT over ASCT are: a) none tumor con‐ tamination of the stem cell b) GVL effect to eliminate chemotherapy-resistant leukaemia

**3. Allogeneic hematopoietic stem cell transplantation**

276 Innovations in Stem Cell Transplantation

two decades, the first treatment approach with curative potential in CLL.

es for death being graft-vs host disease (GVHD) and infections.

tients with sufficiently high risk to deserve use of allo-SCT in first CR.

**4. Myeloablative allogeneic stem cell transplantation**

of donor stem cells to revive blood cell production and immunity.

Registry data from the International Bone Marrow Transplant Research (IBMTR) group and the EBMT group reported a transplant-related mortality (TRM) of 46% with mortality from GVHD of 20% [60]. These published data showed that approximately two-thirds of allo‐ transplanted CLL patients will succumb either to TRM or to recurrent disease, and approxi‐ mately one-third will be cured of their disease [54, 60].

Active chronic GVHD is principal determinant of long-term morbidity and significantly re‐ duced long-term health status in patients allografted for various hematological malignancies [62]. Indeed, transplant-related long-term morbidity after allo-SCT for CLL can be signifi‐ cant but is mainly restricted to those patients who have ongoing active chronic GVHD. However, in the majority of affected patients clinical symptoms of chronic GVHD resolved over time, allowing discontinuation of systemic therapeutic immunosuppression after a me‐ dian of 25 months [63]. Further, a high graft rejection rates remain a relevant complication in myeloablative allo-SCT; a possible explanations could be the significant marrow infiltration in CLL patients at the time of transplantation, inversely correlated with outcome [64], and the role played by host dendritic cells, which are seriously defective in CLL patients [65]. Another problem is represented by the high infection rates, that correlated with preexisting immunosuppression. Infections are the cause of about 50% of all CLL-related deaths [62, 66] primarily in fludarabine and/or alemtuzumab-refractory patients [16, 67]. Moreover in re‐ cent reports the risk of infections has been clearly correlated with presence of GVHD [57, 63, 65, 68] and refractory disease [67, 69]. In addition, it is important to note that patients with chemosensitive disease have significantly better outcomes than patients with refractory dis‐ ease, suggesting that an earlier application of allo-SCT may further improve transplantation outcomes [60, 70, 71].

In conclusion, allo-SCT is a therapy with curative potential in CLL and, in contrast to con‐ ventional treatment, with an high potential of providing long-term disease control even in patients with a very unfavorable biological and clinical risk profile. However, in addition to the disease risk, it is necessary to consider patient-related risk factors, such as age and co‐ morbidity, when allo-SCT is performed [63].

## **5. Reduced-intensity conditioning stem cell transplantation (nonmyeloablative allo-SCT)**

Although myeloablative allo-SCT in CLL can result in durable remissions, rates of TRM are after unacceptably and greatly reduced its application, even in the most refractory and highrisk individuals.

Reduced-intensity conditioning (RIC) regimens were introduced as a way to take advantage of GVL effect, reducing TRM and making transplant more approachable also in older or younger patients with comorbidities [72, 73]. These reduced regimens, are associated with improved TRM; in fact, in 2003, the EBMT reported outcomes of 77 CLL patients who re‐ ceived an allo-SCT [74]. The authors described an encouraging TRM rate of 18%, an impres‐ sive overall response rate of 91%, as well as a 69% complete response rate and a 22% partial response rate, associated with reduction in the ablative intensity of the preparative regimen. This lower TRM (18%), when compared with that linked to a myeloablative conditioning (46%), turned out to be extremely promising [74].

Quantitative MRD monitoring by RQ-PCR or flowcytometry is an essential tool to establish the clinical benefit of allo-SCT in CLL; in fact, the absence of detectable MRD, one year after allo-SCT, was strongly associated with a reduced risk of clinical relapse. In addition, there are evidences of a powerful correlation between MRD status and GVL activity, while its di‐ rect involvement for guiding GVL-inducing immunomodulation needs further evaluation [83]. Therefore quantitative MRD monitoring seems to be mandatory to assure safe and ef‐

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http://dx.doi.org/10.5772/53085

279

The best approach to post transplant immunotherapy in CLL includes monoclonal antibody (MoAbs). Some of them, although a still short follow-up, show very promising results and the use of MoAbs in the conditioning or just after transplant, could improve the results of allo-SCT. Initially, RIC allo-SCT was associated with the use of only fludarabine and cyclo‐ phosphamide. The CLL3X trial from the German CLL Study Group evaluated the long-term outcome of RIC allo-SCT in patients with poor-risk CLL who received allogeneic transplant following fludarabine and cyclophosphamide-based conditioning. The 4-year non relapse mortality (NRM), event-free survival (EFS), and OS were 23%, 42%, and 65%, respectively. To improve relapse-free survival following transplant and to modulate the impact of GVHD, MoAbs have been incorporated into transplant regimens [84]. Alemtuzumab, Ritux‐ imab are the most used MoAbs with recognized clinical activity in CLL. Alemtuzumab is a humanized anti-CD52 IgG1 MoAb with an activity in reducing the incidence of GVHD but, also, associated with an high risk of death from opportunistic infections [85]. Rituximab (an‐ ti-CD20 MoAb), instead, used in tandem with RIC preparative regimens, can induce re‐ sponse and help in disease control, decreasing the incidence of acute GVHD and modulating the GVL effect. [59]. However, there is no clear consensus concerning the opti‐ mal conditioning regimen to be used prior to allo-HCT. Using RIC regimens may reduce toxic deaths, but the success of non-myeloablative allo-SCT is highly dependent on the che‐

Despite much progress in its treatment, CLL continues to be an incurable disease with standard treatments. SCT cell transplantation has changed the management of CLL patients with refractory disease or younger patients with aggressive disease. In particular, ASCT has partially failed in the treatment of advanced CLL: it prolongs survival in selected patients, but unfortunately do not cure the disease. In addition, secondary MDS/AML is one of major

Allo-SCT, conversely, may be an acceptable option: myeloablative allo-SCT is an opportuni‐ ty for younger patients with bulky, refractory, or aggressive disease; RIC allo-SCT, instead,

Although allo-SCT appears to result in high response rates and eradication of PCR detectable MRD, the follow up of most clinical trials is too short to assess whether allo-SCT can cure CLL.

is an emerging curative possibility for older patients with high-risk disease.

fective immunotherapy in the context of allo-SCT [83].

mosensitivity of the disease.

**6. Conclusion and future directions**

complication in autografted patients.

On the contrary, there were no significant differences in terms of OS or progression free sur‐ vival (PFS) between these two groups [74]. In fact, although nonmyeloablative transplants may carry a stronger safety profile, the rate of relapse was higher than that associated with traditional myeloablative treatment [74]. Interestingly, instead, Sorror et al. have recently published data indicating that non-myeloablative transplants can provide a lower risk of re‐ lapse [63]. They reported encouraging long-term outcomes in 82 CLL patients who received RIC allo-SCT. In this study, at a median follow-up of 5 years, TRM, PFS, and OS were 23%, 39%, and 50%, respectively, suggesting a curative potential for RIC allo-SCT in patients with relapsed CLL, with a more favorable toxicity profile particularly in older patients who would not have been eligible to receive myeloablative conditioning regimens [63].

In contrast to ASCT where the efficacy relies exclusively on the cytotoxicity administered with the high-dose regimen, and in agreement to myeloablative allo-SCT, nonmyeloablative allo-SCT adds the immune-mediated anti-host activities conferred with the graft as a second fundamental principle of antileukemic efficacy: the GVL effect.

There is no doubt that the main therapeutic principle of allo-SCT in CLL is GVL activity and this evidence derives from some remarkable observations such as: 1) decreasing relapse inci‐ dence over time even in RIC allo-SCT, in contrast to ASCT or other intensive therapies [56, 60, 63, 70, 71, 75, 76], 2) durable clinical and molecular responses due to antitumor activity [77], 3) reduced relapse rates in patients with chronic GVHD [78], 4) increased relapse rates associated with T cell–depleted grafts [79, 80], 5) high efficacy of donor lymphocyte infu‐ sions (DLIs) in the post-transplant relapse [65, 80].

This finging supports alloreactivity as the principal mechanism responsible for GVL.

On the other hand, the most important cause of RIC allo-SCT failure in CLL patients is the disease relapse. Early relapses are correlated with chemorefractory disease at the time of transplantation, the most of time due to the unsuccessfulness of RIC regimens in controlling the disease before the GVL effect. The late relapse, instead, derives from different mecha‐ nism including: CLL clonal evolution, development of tolerance [80], presence of tumor cells in "GVCLL sanctuary sites"[63] and an insufficient GVL effect to produce a complete dis‐ ease eradication. Interestingly, an high percentage of these late relapses occurred in lymph nodes without bone marrow or peripheral blood involvement, or even in patients with MRD negative status [40, 53, 55, 81, 82].

Quantitative MRD monitoring by RQ-PCR or flowcytometry is an essential tool to establish the clinical benefit of allo-SCT in CLL; in fact, the absence of detectable MRD, one year after allo-SCT, was strongly associated with a reduced risk of clinical relapse. In addition, there are evidences of a powerful correlation between MRD status and GVL activity, while its di‐ rect involvement for guiding GVL-inducing immunomodulation needs further evaluation [83]. Therefore quantitative MRD monitoring seems to be mandatory to assure safe and ef‐ fective immunotherapy in the context of allo-SCT [83].

The best approach to post transplant immunotherapy in CLL includes monoclonal antibody (MoAbs). Some of them, although a still short follow-up, show very promising results and the use of MoAbs in the conditioning or just after transplant, could improve the results of allo-SCT. Initially, RIC allo-SCT was associated with the use of only fludarabine and cyclo‐ phosphamide. The CLL3X trial from the German CLL Study Group evaluated the long-term outcome of RIC allo-SCT in patients with poor-risk CLL who received allogeneic transplant following fludarabine and cyclophosphamide-based conditioning. The 4-year non relapse mortality (NRM), event-free survival (EFS), and OS were 23%, 42%, and 65%, respectively. To improve relapse-free survival following transplant and to modulate the impact of GVHD, MoAbs have been incorporated into transplant regimens [84]. Alemtuzumab, Ritux‐ imab are the most used MoAbs with recognized clinical activity in CLL. Alemtuzumab is a humanized anti-CD52 IgG1 MoAb with an activity in reducing the incidence of GVHD but, also, associated with an high risk of death from opportunistic infections [85]. Rituximab (an‐ ti-CD20 MoAb), instead, used in tandem with RIC preparative regimens, can induce re‐ sponse and help in disease control, decreasing the incidence of acute GVHD and modulating the GVL effect. [59]. However, there is no clear consensus concerning the opti‐ mal conditioning regimen to be used prior to allo-HCT. Using RIC regimens may reduce toxic deaths, but the success of non-myeloablative allo-SCT is highly dependent on the che‐ mosensitivity of the disease.

## **6. Conclusion and future directions**

Reduced-intensity conditioning (RIC) regimens were introduced as a way to take advantage of GVL effect, reducing TRM and making transplant more approachable also in older or younger patients with comorbidities [72, 73]. These reduced regimens, are associated with improved TRM; in fact, in 2003, the EBMT reported outcomes of 77 CLL patients who re‐ ceived an allo-SCT [74]. The authors described an encouraging TRM rate of 18%, an impres‐ sive overall response rate of 91%, as well as a 69% complete response rate and a 22% partial response rate, associated with reduction in the ablative intensity of the preparative regimen. This lower TRM (18%), when compared with that linked to a myeloablative conditioning

On the contrary, there were no significant differences in terms of OS or progression free sur‐ vival (PFS) between these two groups [74]. In fact, although nonmyeloablative transplants may carry a stronger safety profile, the rate of relapse was higher than that associated with traditional myeloablative treatment [74]. Interestingly, instead, Sorror et al. have recently published data indicating that non-myeloablative transplants can provide a lower risk of re‐ lapse [63]. They reported encouraging long-term outcomes in 82 CLL patients who received RIC allo-SCT. In this study, at a median follow-up of 5 years, TRM, PFS, and OS were 23%, 39%, and 50%, respectively, suggesting a curative potential for RIC allo-SCT in patients with relapsed CLL, with a more favorable toxicity profile particularly in older patients who

would not have been eligible to receive myeloablative conditioning regimens [63].

fundamental principle of antileukemic efficacy: the GVL effect.

sions (DLIs) in the post-transplant relapse [65, 80].

negative status [40, 53, 55, 81, 82].

In contrast to ASCT where the efficacy relies exclusively on the cytotoxicity administered with the high-dose regimen, and in agreement to myeloablative allo-SCT, nonmyeloablative allo-SCT adds the immune-mediated anti-host activities conferred with the graft as a second

There is no doubt that the main therapeutic principle of allo-SCT in CLL is GVL activity and this evidence derives from some remarkable observations such as: 1) decreasing relapse inci‐ dence over time even in RIC allo-SCT, in contrast to ASCT or other intensive therapies [56, 60, 63, 70, 71, 75, 76], 2) durable clinical and molecular responses due to antitumor activity [77], 3) reduced relapse rates in patients with chronic GVHD [78], 4) increased relapse rates associated with T cell–depleted grafts [79, 80], 5) high efficacy of donor lymphocyte infu‐

This finging supports alloreactivity as the principal mechanism responsible for GVL.

On the other hand, the most important cause of RIC allo-SCT failure in CLL patients is the disease relapse. Early relapses are correlated with chemorefractory disease at the time of transplantation, the most of time due to the unsuccessfulness of RIC regimens in controlling the disease before the GVL effect. The late relapse, instead, derives from different mecha‐ nism including: CLL clonal evolution, development of tolerance [80], presence of tumor cells in "GVCLL sanctuary sites"[63] and an insufficient GVL effect to produce a complete dis‐ ease eradication. Interestingly, an high percentage of these late relapses occurred in lymph nodes without bone marrow or peripheral blood involvement, or even in patients with MRD

(46%), turned out to be extremely promising [74].

278 Innovations in Stem Cell Transplantation

Despite much progress in its treatment, CLL continues to be an incurable disease with standard treatments. SCT cell transplantation has changed the management of CLL patients with refractory disease or younger patients with aggressive disease. In particular, ASCT has partially failed in the treatment of advanced CLL: it prolongs survival in selected patients, but unfortunately do not cure the disease. In addition, secondary MDS/AML is one of major complication in autografted patients.

Allo-SCT, conversely, may be an acceptable option: myeloablative allo-SCT is an opportuni‐ ty for younger patients with bulky, refractory, or aggressive disease; RIC allo-SCT, instead, is an emerging curative possibility for older patients with high-risk disease.

Although allo-SCT appears to result in high response rates and eradication of PCR detectable MRD, the follow up of most clinical trials is too short to assess whether allo-SCT can cure CLL.

Future approaches in menagment of CLL must take in consideration the balance between in‐ creased morbidity and mortality of SCT in CLL with the potentiality of new therapy in the setting of the improvements in outcome.

[8] Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavychain gene mutation status as a predictor of disease progression in chronic lympho‐

Stem Cell Transplantation in Chronic Lymphocytic Leukemia

http://dx.doi.org/10.5772/53085

281

[9] Rassenti LZ, Jain S, Keating MJ, et al. Relative value of ZAP-70, CD38, and immuno‐ globulin mutation status in predicting aggressive disease in chronic lymphocytic leu‐

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[11] Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. The Journal of experimental medi‐

[12] Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent muta‐ tions of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature ge‐

[13] Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chron‐ ic lymphocytic leukemia: association with progression and fludarabine-refractori‐

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In the absence of any other treatment modalities currently capable of improving outcome in CLL, SCT should be considered the main option for patients with high-risk, refractory to standard therapy or with relapsed after prior ASCT.

## **Author details**

Anna Gazzola, Alessandro Broccoli, Vittorio Stefoni and Pier Paolo Piccaluga

\*Address all correspondence to: pierpaolo.piccaluga@unibo.it

Hematopathology and Hematology Sections, Department of Hematology and Oncology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, University of Bologna, Italy

### **References**


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Future approaches in menagment of CLL must take in consideration the balance between in‐ creased morbidity and mortality of SCT in CLL with the potentiality of new therapy in the

In the absence of any other treatment modalities currently capable of improving outcome in CLL, SCT should be considered the main option for patients with high-risk, refractory to

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**Author details**

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**Chapter 13**

**Current Status of Hematopoietic Stem Cell**

**Hodgkin Lymphoma**

http://dx.doi.org/10.5772/55106

**relapse hodgkin lymphoma**

Taner Demirer

**1. Introduction**

Leylagül Kaynar, Mustafa Çetin, Ali Ünal and

Additional information is available at the end of the chapter

**Transplantation in Patients with Refractory or Relapse**

**1.1. Current status of hematopoietic stem cell transplantation in patients with refractory or**

Although the high response rates, approximately 10% of patients with early-stage Hodgkin Lymphoma (HL) and 20% with advanced disease will be refractory to initial treatment or relapse after a first complete response [1-3]. The strategy for management of relapsed or refractory disease is to deliver salvage chemotherapy, followed by high-dose chemotherapy

The use of autoSCT for HL in first remission was wondered. There are only a few prospective randomized clinical trials focusing in this issue. Although historically controlled studies are

The HD01 trial included 163 patients achieving complete remission (CR) or partial remission (PR) with advanced HL after four cycles of ABVD (ABVD; doxorubicin, bleomycin, vinblastine, and dacarbazine) or other doxorubicin-containing regimens who had an unfavorable risk profile (at least two factors: high lactate dehydrogenase level, large mediastinal mass, more

and reproduction in any medium, provided the original work is properly cited.

© 2013 Kaynar et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and autologous stem-cell transplantation (AutoSCT) in responding patients [4,5].

**2. Autologous stem cell transplantation for Hodgkin lymphoma**

**2.1. Autologous stem cell transplantation at first-line therapy**

promising, prospective controlled studies showed different results [6].
