**7. Allogeneic haematopoietic cell transplantation in older patients**

Allogeneic haematopoietic cell transplantation (HCT), as post-remission treatment, offers the highest potential for long-term survival and cure for patients with AML. For younger patients, the choice for consolidation with an allogeneic transplant is nuanced, as particular younger patients with high-risk disease, entailing high-risk mutations and presence of measurable residual disease after treatment, benefit post-remission treatment with an allogeneic HCT. As older patients generally have low chance for long-term survival, also if they have "goodrisk" cytogenetic abnormalities, allogeneic HCT should be considered in older (fit) AML patients [10, 70, 71]. Nevertheless, only a minority of older patients actually receives an allogeneic HCT [72, 73]. Allogeneic HCT in older patients is limited by concerns related to treatment-related mortality (TRM) (e.g. TRM is >40% in patients with a HCT-comorbidity score ≥ 3) [74]. However, the development of less toxic conditioning regimens (reduced intensity conditioning (RIC) and nonmyeloablative (NMA)), has been an important conceptual change that has created the opportunity for older patients with AML to receive an allogeneic HCT. These conditioning regimen are less dependent on cytotoxic effects of the conditioning regimen and more dependent on the graft-versus-leukaemia effect.

Several studies evaluating allogeneic HCT after RIC in older AML patients have shown promising results. A phase II study of 114 older patients receiving an allogeneic HCT after RIC with fludarabine and busalfan reported a 2-year OS of 48% with a non-relapse mortality (NRM) of 15%. However, cumulative incidence of relapse was 44% at 2 years [75]. A large retrospective study analysing the outcomes of 1080 AML patients who underwent allogeneic HCT after RIC found a 2-year OS of 36% in patients age ≥ 65 years, a NRM of 34%, and 2-year relapse probability of 33% [76]. This analysis included several age groups ranging from 40 to above 65 years and found no significant impact of age on NRM, relapse, diseasefree survival, or OS. In addition, studies comparing allogeneic HCT after RIC to conventional post-remission treatments have reported favourable outcomes with allogeneic HCT after RIC. A study comparing allogeneic HCT after RIC (n = 97), chemotherapy (n = 44), autologous transplantation (n = 23), and no further treatment (n = 336) as post-remission therapy reported a 5-year OS of 35% for patients receiving allogeneic HCT after RIC compared to 26% and 21% for chemotherapy/ autologous transplantation and no treatment, respectively [77]. Multivariate analysis

**175**

**Author details**

The Netherlands

Jacobien Hilberink and Gerwin Huls\*

\*Address all correspondence to: g.huls@umcg.nl

provided the original work is properly cited.

Universitair Medisch Centrum Groningen, University of Groningen,

© 2021 The Author(s). Licensee IntechOpen. 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,

*Treatment of AML in Older Patients*

*DOI: http://dx.doi.org/10.5772/intechopen.94979*

confirmed the beneficial effect allogeneic HCT after RIC on 5-year survival. A comparison between allogeneic HCT after RIC and chemotherapy in patients age 60–70 years showed that allogeneic HCT after RIC was associated with a lower risk of relapse at 3 years (32 vs. 81%) although NRM was increased (36% vs. 4%), leading to an OS of 37% vs. 25% at 3 years [78]. These studies underscore the delicate balance between sufficient antileukemic effect and treatment toxicity, which is

The efficacy and safety of NMA conditioning consisting of low-dose total body

evaluated in a prospective cohort of 372 patients aged 60 to 75 years. The OS at 5 years post-transplantation was 35% with an NRM of 27%. Relapse rate was 41% at 5 years indicating the need for further improvement [73]. Nevertheless, these data compare very favourably with historical data on long-term survival of about 10% after treatment of older AML patients with intensive chemotherapy without

Treatment of relapsed or refractory (R/R) AML, in general, has presented challenges for haematologists for decades. Despite numerous clinical studies, outcomes are consistently disappointing with 5-year OS rates of ∼10%. Allogeneic HCT at the time of second complete remission remains the only reliable option with curative potential. For older patients, treatment of R/R AML is even more difficult and outcomes poorer. However, the availability of new drugs, like venetoclax, gilteritinib, ivosidenib and enasidenib offer reasonable chances of temporally disease control with acceptable side effects. This implies the importance of detailed

molecular analysis, also in the R/R setting, as the R/R disease might contain different (targetable) mutations. Phase 1 studies are generally an option for those patients with a strong wish to receive treatment. Finally, only best supportive care

with antibiotics and transfusions can be a preferable option.

) in older patients was

challenging in post-remission treatment of older AML patients.

irradiation alone or combine with fludarabine (90 mg/m<sup>2</sup>

post-remission treatment with allogeneic HCT.

**8. Refractory/relapsed AML**

#### *Treatment of AML in Older Patients DOI: http://dx.doi.org/10.5772/intechopen.94979*

*Acute Leukemias*

to that of conventional chemotherapy.

treatment efficacy [67]. CPX-351 preferentially targets leukaemic cells to a greater degree than non-leukaemic cells in the bone marrow, leading to decreased cytotoxicity against normal haematopoietic cells [68]. A small study of CPX-351 as firstline therapy in 30 newly-diagnosed AML patients ≥65 years showed a promising remission rate of 53.2% with a median OS 14.5 months [68]. In a randomised phase II trial in older adults with untreated AML comparing CPX-351 and conventional '3 + 7' treatment a trend towards increased response rates was observed in the CPX-351 group, 66.7% vs. 51.2%. Survival was comparable between both treatment groups (14.7 vs. 12.9 for the CPX-351 and '3 + 7' group respectively). However, CPX-351 treatment was superior in the subset of secondary AML patients with a median OS of 12.1 months vs. 6.1 months in the '3 + 7' group [67]. Superiority of CPX-351 to conventional '3 + 7' chemotherapy in secondary AML, also including AML with MDS related changes, was confirmed in a phase III trial including 309 older AML patients. The observed remission rates were 47.7% vs. 33.3% and median OS was 9.6 vs. 6.0 months in favour of CPX-351 [69]. The safety profile of CPX-351 was similar

**7. Allogeneic haematopoietic cell transplantation in older patients**

regimen and more dependent on the graft-versus-leukaemia effect.

Several studies evaluating allogeneic HCT after RIC in older AML patients have shown promising results. A phase II study of 114 older patients receiving an allogeneic HCT after RIC with fludarabine and busalfan reported a 2-year OS of 48% with a non-relapse mortality (NRM) of 15%. However, cumulative incidence of relapse was 44% at 2 years [75]. A large retrospective study analysing the outcomes of 1080 AML patients who underwent allogeneic HCT after RIC found a 2-year OS of 36% in patients age ≥ 65 years, a NRM of 34%, and 2-year relapse probability of 33% [76]. This analysis included several age groups ranging from 40 to above 65 years and found no significant impact of age on NRM, relapse, diseasefree survival, or OS. In addition, studies comparing allogeneic HCT after RIC to conventional post-remission treatments have reported favourable outcomes with allogeneic HCT after RIC. A study comparing allogeneic HCT after RIC (n = 97), chemotherapy (n = 44), autologous transplantation (n = 23), and no further treatment (n = 336) as post-remission therapy reported a 5-year OS of 35% for patients receiving allogeneic HCT after RIC compared to 26% and 21% for chemotherapy/ autologous transplantation and no treatment, respectively [77]. Multivariate analysis

Allogeneic haematopoietic cell transplantation (HCT), as post-remission treatment, offers the highest potential for long-term survival and cure for patients with AML. For younger patients, the choice for consolidation with an allogeneic transplant is nuanced, as particular younger patients with high-risk disease, entailing high-risk mutations and presence of measurable residual disease after treatment, benefit post-remission treatment with an allogeneic HCT. As older patients generally have low chance for long-term survival, also if they have "goodrisk" cytogenetic abnormalities, allogeneic HCT should be considered in older (fit) AML patients [10, 70, 71]. Nevertheless, only a minority of older patients actually receives an allogeneic HCT [72, 73]. Allogeneic HCT in older patients is limited by concerns related to treatment-related mortality (TRM) (e.g. TRM is >40% in patients with a HCT-comorbidity score ≥ 3) [74]. However, the development of less toxic conditioning regimens (reduced intensity conditioning (RIC) and nonmyeloablative (NMA)), has been an important conceptual change that has created the opportunity for older patients with AML to receive an allogeneic HCT. These conditioning regimen are less dependent on cytotoxic effects of the conditioning

**174**

confirmed the beneficial effect allogeneic HCT after RIC on 5-year survival. A comparison between allogeneic HCT after RIC and chemotherapy in patients age 60–70 years showed that allogeneic HCT after RIC was associated with a lower risk of relapse at 3 years (32 vs. 81%) although NRM was increased (36% vs. 4%), leading to an OS of 37% vs. 25% at 3 years [78]. These studies underscore the delicate balance between sufficient antileukemic effect and treatment toxicity, which is challenging in post-remission treatment of older AML patients.

The efficacy and safety of NMA conditioning consisting of low-dose total body irradiation alone or combine with fludarabine (90 mg/m2 ) in older patients was evaluated in a prospective cohort of 372 patients aged 60 to 75 years. The OS at 5 years post-transplantation was 35% with an NRM of 27%. Relapse rate was 41% at 5 years indicating the need for further improvement [73]. Nevertheless, these data compare very favourably with historical data on long-term survival of about 10% after treatment of older AML patients with intensive chemotherapy without post-remission treatment with allogeneic HCT.
