**7. Prognostic factors in older ALL patients**

Now, we have a better understanding of the factors that determine survival, but these will require reexamination as we introduce novel therapies. Cytogenetic findings such as Philadelphia chromosome positivity, t (4; 11), complex cytogenetic abnormalities (more than five chromosomal changes), and low hypodiploidy/near triploidy result in inferior survival. Some of these changes are more common in older adults. Other conventional factors such as increasing age, high white blood cell count, and B-cell disease (rather than T-cell disease) still hold true and predict higher failure rates with standard chemotherapy. However, many of these factors are also associated with a higher relapse rate after allografting, and it is not necessarily the case that bone marrow transplantation (BMT) is the solution for patients with adverse prognostic features. Combining these factors may allow individualization of therapy, a prospect not previously possible in this rare condition. As well as undertreating patients with ALL with chemotherapy that is likely to fail, prognostic factors should be used to avoid over treating better prognosis patients with allogeneic transplants that have a high upfront risk and may result in chronic graft-versus host disease (GVHD), infertility, and secondary malignancy. Chemotherapy and transplant have complementary roles in ALL management, and a pragmatic approach is required to deliver the best outcomes. The role of BMT is likely to increase, especially with the promising results of reduced-intensity allografting, but conversely, the use of BMT should be reduced if advances in nontransplant therapy improve cure rates [11, 17, 20, 23].

Increasing age itself is one of the most relevant prognostic factors for outcome of ALL from childhood to old age. Since older patients show opposite problems, namely higher mortality and relapse rates, prognostic factors for both have to be analyzed. Prognostic factors for relapse risk in younger ALL patients are probably also valid in older patients, such as early and mature T-ALL, pro-B ALL, elevated white blood cell count, and Ph+ ALL; however, their predictive value is somewhat diluted by mortality risks. Evaluation of minimal residual disease (MRD) has demonstrated that persistence of MRD is associated with a relapse rate above 90% in younger patients despite continued intensive chemotherapy. Few data on the prognostic impact of MRD are available in older patients. In one study, only 11% of the older patients with molecular failure after first consolidation remained in complete response (CR) compared with 68% of those with molecular remission. In older patients with less intensive therapy, a higher rate of MRD persistence and an even poorer outcome can be expected. Therefore, prospective evaluation of MRD in older patients is essential to identify those who could benefit from alternative experimental treatments, if they were available [18–20, 24].

Some poor prognosis factor applicable to young patients can also be in elderly patients, which tells us of the profound impact they have on the biology of the disease: the T lineage and the positive Phi chromosome are a pair of these. The persistence of positive minimal residual disease is directly related to an increased frequency of relapse after remission; it is estimated that young patients with positive MRD will relapse up to 90% despite receiving intensive CT. We do not have

such exact estimates of how much the likelihood of relapse increases when this phenomenon occurs in older patients, but it has been estimated in some studies that only 11% of these who presented with MRD positive remain in response to the disease. Prospective studies that answer these questions are required; however, it is necessary to determine MRD in elderly patients as part of the management and surveillance protocols [18–20, 23].

In the GMALL study for older patients, we identified comorbidity score, age, and performance status before onset of leukemia as prognostic factors with significant impact on early mortality. Interestingly, Eastern Cooperative Oncology Group (ECOG) status of 2 or more was documented in 7% of the patients before onset of leukemia-associated symptoms, but in 38% after onset. The strong correlation of performance status with mortality was confirmed by others.

For assessing prognosis in an older ALL patient, it is essential to identify features suitable for predicting high risk of early mortality resulting from complications. These features can help determine whether a patient has any chance of benefiting from intensive treatment. For this purpose, I would consider performance status before onset of leukemia, comorbidities, and geriatric assessment and would not rely on scores, which are calculated on the basis of historical patient cohorts.

In addition, prognostic factors for response to antileukemic treatment and relapse risk must be considered. Because of the lack of confirmed prognostic factors for older ALL patients, my approach would be to take known prognostic factors for younger patients into consideration, but to focus on MRD evaluation as an individual prognostic feature that can cover the impact of biologic factors and also treatment intensity, compliance, and other unknown features [21, 26].

In the case of patients with characteristics that could increase the risk of early mortality when starting treatment, we must be careful in how to approach this last parameter. Several groups dedicated to the analysis of prognostic factors in special groups of patients have determined a series of variants and elements that could guide the clinic when defining the risk of death of his patient. The GMALL group determined, in a prospective analysis, that the low physical status (ECOG status of 2 or more) prior to the onset of leukemia symptoms correlates with earlier mortality and in those patients who already have a diagnosis, this score is seen duplicated at the beginning of the symptomatology. To be able to carry out a complete evaluation of elderly patients, it is necessary to apply tools that are useful in most clinical scenarios and that confer a high degree of reliability with respect to their predictive power of prognosis. It is therefore necessary to apply validated geriatric scores and specific scores of the patient for known morbidities in order to achieve the most complete vision possible before the diagnosis, in order to guide the treatment and its intensity [21].

In addition to this, we must define what prognostic factors for relapse should be applied to these patients after treatment is initiated. Although several of them already known with importance in young group can also be applied to elderly patients, it should be determined which are more specific for this last group [26].

#### **7.1 Philadelphia ALL**

One-quarter of all adults have Philadelphia chromosome, and the incidence increases with age. Until the results of recent studies in older patients became available, most patients with Philadelphia ALL were managed with intensive chemotherapy and a tyrosine kinase inhibitor (TKI). Imatinib has improved the CR rate in a number of trials to 90% and makes more patients eligible for transplant. Imatinibresistant mutations are increasingly reported, and these should be sought in relapsed and refractory patients. Dasatinib, which inhibits tyrosine and src kinases, holds considerable promise. It may also be effective in CNS disease. There are no

**147**

**7.2 Therapy**

*Overview and Current News in Acute Lymphoblastic Leukemia*

randomized comparisons with imatinib, although it is a more potent inhibitor of tyrosine kinase in vitro. Recent studies from Italy and France with dasatinib alone in older patients have achieved very high remission rates with encouraging short-term survival. Good minimal residual disease (MRD) responses correlated with outcome. Data regarding the combination of dasatinib and intensive chemotherapy are lacking. It is possible that less conventional induction therapy may be required and that allogeneic stem cell transplantation (SCT) may not be mandatory. The remarkable effectiveness of TKI therapy, in some studies without chemotherapy or allografting, has made us consider de-escalation of therapy, but the long-term results of these less intensive approaches are unknown, and allografting is the only known cure.

The effect of pretransplant MRD status on outcome is unclear [27, 28].

A study of 267 patients (prior to the TKI era) showed allogeneic transplant to be superior to chemotherapy, with 44 and 36% surviving 5 years after sibling and unrelated donor SCT, respectively. However, only 28% of patients proceeded to a CR1 allograft, reducing its impact, and making it important that we improve no transplant therapy (and improve access to transplant). The Minneapolis group reported 50% survival in 14 patients who received reduced-intensity conditioning (RIC) allografts from cord or sibling donors. TKIs were used only for morphologic or molecular relapse posttransplant. Studies of TKI posttransplant that examine dose, duration, and molecular response are urgently required; this is the subject of studies from the German and UK groups that are soon to be reported [28, 29].

The goal of remission induction therapy is to achieve remission without undue toxicity with a hematologic recovery that permits further therapy to be promptly given. Most regimens use prednisolone or dexamethasone, vincristine, daunorubicin, and asparaginase, with later exposure to cyclophosphamide and Ara-C (cytosine arabinoside or cytarabine). Hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD), which does not contain L-asparaginase, achieves high complete remission (CR) rates in newly diagnosed patients and is a reasonable alternative for induction therapy, but has not been shown to be superior to more traditional induction protocols. Dexamethasone is preferred to prednisolone because of superior lymphocytotoxicity, better central nervous system (CNS) penetration, and fewer thromboembolic events; these data are derived from pediatric studies. Poly(ethylene glycol)-asparaginase may be associated with more effective asparagine depletion, and this in turn may lead to better outcomes. But this requires a randomized comparison. The safety and optimum dose of this drug

Population-based study registries give an impression on the overall outcome of unselected older ALL patients. Survival rates in patients aged 60 years were 12% at 5 years in Northern England. For those aged between 65 and 74 years, survival was 25% in Sweden where outcome further decreased to 10% in patients aged 74 years. Five-year OS in patients aged 60–69 years increased from 8% in the years 1992– 2001 to 20% in the years 2002–2011, whereas only marginal improvements from 5 to 10% were observed for patients aged 70 years. Palliative treatment: some 30–70% of the older patients are allocated to palliative therapy mainly due to poor performance status at diagnosis. Most studies have shown an advantage of more intensive therapy such as higher CR rate, lower early death, better remission duration, and median survival compared with palliative treatment according to protocols for adult ALL patients. The majority of published data are based on results reported for the subgroup of older patients treated within protocols designed for adult ALL in general. One large data set confirmed considerable mortality of 18%. The conclusion

*DOI: http://dx.doi.org/10.5772/intechopen.86662*

require further study in adults [25, 26, 30].

*Overview and Current News in Acute Lymphoblastic Leukemia DOI: http://dx.doi.org/10.5772/intechopen.86662*

randomized comparisons with imatinib, although it is a more potent inhibitor of tyrosine kinase in vitro. Recent studies from Italy and France with dasatinib alone in older patients have achieved very high remission rates with encouraging short-term survival. Good minimal residual disease (MRD) responses correlated with outcome. Data regarding the combination of dasatinib and intensive chemotherapy are lacking. It is possible that less conventional induction therapy may be required and that allogeneic stem cell transplantation (SCT) may not be mandatory. The remarkable effectiveness of TKI therapy, in some studies without chemotherapy or allografting, has made us consider de-escalation of therapy, but the long-term results of these less intensive approaches are unknown, and allografting is the only known cure. The effect of pretransplant MRD status on outcome is unclear [27, 28].

A study of 267 patients (prior to the TKI era) showed allogeneic transplant to be superior to chemotherapy, with 44 and 36% surviving 5 years after sibling and unrelated donor SCT, respectively. However, only 28% of patients proceeded to a CR1 allograft, reducing its impact, and making it important that we improve no transplant therapy (and improve access to transplant). The Minneapolis group reported 50% survival in 14 patients who received reduced-intensity conditioning (RIC) allografts from cord or sibling donors. TKIs were used only for morphologic or molecular relapse posttransplant. Studies of TKI posttransplant that examine dose, duration, and molecular response are urgently required; this is the subject of studies from the German and UK groups that are soon to be reported [28, 29].

#### **7.2 Therapy**

*Geriatric Medicine and Gerontology*

surveillance protocols [18–20, 23].

such exact estimates of how much the likelihood of relapse increases when this phenomenon occurs in older patients, but it has been estimated in some studies that only 11% of these who presented with MRD positive remain in response to the disease. Prospective studies that answer these questions are required; however, it is necessary to determine MRD in elderly patients as part of the management and

In the GMALL study for older patients, we identified comorbidity score, age, and performance status before onset of leukemia as prognostic factors with significant impact on early mortality. Interestingly, Eastern Cooperative Oncology Group (ECOG) status of 2 or more was documented in 7% of the patients before onset of leukemia-associated symptoms, but in 38% after onset. The strong correlation of

For assessing prognosis in an older ALL patient, it is essential to identify features suitable for predicting high risk of early mortality resulting from complications. These features can help determine whether a patient has any chance of benefiting from intensive treatment. For this purpose, I would consider performance status before onset of leukemia, comorbidities, and geriatric assessment and would not rely on scores, which are calculated on the basis of historical patient cohorts. In addition, prognostic factors for response to antileukemic treatment and relapse risk must be considered. Because of the lack of confirmed prognostic factors for older ALL patients, my approach would be to take known prognostic factors for younger patients into consideration, but to focus on MRD evaluation as an individual prognostic feature that can cover the impact of biologic factors and also

performance status with mortality was confirmed by others.

treatment intensity, compliance, and other unknown features [21, 26].

before the diagnosis, in order to guide the treatment and its intensity [21].

In addition to this, we must define what prognostic factors for relapse should be applied to these patients after treatment is initiated. Although several of them already known with importance in young group can also be applied to elderly patients, it should be determined which are more specific for this last group [26].

One-quarter of all adults have Philadelphia chromosome, and the incidence increases with age. Until the results of recent studies in older patients became available, most patients with Philadelphia ALL were managed with intensive chemotherapy and a tyrosine kinase inhibitor (TKI). Imatinib has improved the CR rate in a number of trials to 90% and makes more patients eligible for transplant. Imatinib-

relapsed and refractory patients. Dasatinib, which inhibits tyrosine and src kinases, holds considerable promise. It may also be effective in CNS disease. There are no

resistant mutations are increasingly reported, and these should be sought in

In the case of patients with characteristics that could increase the risk of early mortality when starting treatment, we must be careful in how to approach this last parameter. Several groups dedicated to the analysis of prognostic factors in special groups of patients have determined a series of variants and elements that could guide the clinic when defining the risk of death of his patient. The GMALL group determined, in a prospective analysis, that the low physical status (ECOG status of 2 or more) prior to the onset of leukemia symptoms correlates with earlier mortality and in those patients who already have a diagnosis, this score is seen duplicated at the beginning of the symptomatology. To be able to carry out a complete evaluation of elderly patients, it is necessary to apply tools that are useful in most clinical scenarios and that confer a high degree of reliability with respect to their predictive power of prognosis. It is therefore necessary to apply validated geriatric scores and specific scores of the patient for known morbidities in order to achieve the most complete vision possible

**146**

**7.1 Philadelphia ALL**

The goal of remission induction therapy is to achieve remission without undue toxicity with a hematologic recovery that permits further therapy to be promptly given. Most regimens use prednisolone or dexamethasone, vincristine, daunorubicin, and asparaginase, with later exposure to cyclophosphamide and Ara-C (cytosine arabinoside or cytarabine). Hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD), which does not contain L-asparaginase, achieves high complete remission (CR) rates in newly diagnosed patients and is a reasonable alternative for induction therapy, but has not been shown to be superior to more traditional induction protocols. Dexamethasone is preferred to prednisolone because of superior lymphocytotoxicity, better central nervous system (CNS) penetration, and fewer thromboembolic events; these data are derived from pediatric studies. Poly(ethylene glycol)-asparaginase may be associated with more effective asparagine depletion, and this in turn may lead to better outcomes. But this requires a randomized comparison. The safety and optimum dose of this drug require further study in adults [25, 26, 30].

Population-based study registries give an impression on the overall outcome of unselected older ALL patients. Survival rates in patients aged 60 years were 12% at 5 years in Northern England. For those aged between 65 and 74 years, survival was 25% in Sweden where outcome further decreased to 10% in patients aged 74 years. Five-year OS in patients aged 60–69 years increased from 8% in the years 1992– 2001 to 20% in the years 2002–2011, whereas only marginal improvements from 5 to 10% were observed for patients aged 70 years. Palliative treatment: some 30–70% of the older patients are allocated to palliative therapy mainly due to poor performance status at diagnosis. Most studies have shown an advantage of more intensive therapy such as higher CR rate, lower early death, better remission duration, and median survival compared with palliative treatment according to protocols for adult ALL patients. The majority of published data are based on results reported for the subgroup of older patients treated within protocols designed for adult ALL in general. One large data set confirmed considerable mortality of 18%. The conclusion

that induction therapy designed for younger patients may be too intensive for older patients. Patients may acquire severe infections, nonpredefined treatment modifications occur frequently, and treatments may be interrupted or even stopped due to severe complications. Overall, potential conclusions from these studies are very limited. Prospective studies of protocols for older ALL patients specifically designed for older ALL patients have the theoretical aim to provide a chance of cure on the one hand and to limit toxicity, early mortality, and hospitalization duration on the other hand, and the therapy maintains as much quality of life as possible. One central question is whether and/or which anthracycline has to be included in induction regimens for older patients, because these drugs contribute considerably to bone marrow toxicity [5, 6, 15, 31]. One approach is the use of idarubicin in induction, based on a potentially lower cardiac and hepatic toxicity. The results of liposomal anthracyclines in elderly ALL are not convincing so far. Asparaginase is an essential compound in the treatment of ALL. The PETHEMA group reported the results of an intensive induction regimen, including asparaginase for older ALL patients. The early death rate, mainly due to infection, was rather high (36%) and was reduced after omission of asparaginase and cyclophosphamide. A high early mortality rate (29%) and a number of complications including infections (71%), cardiac toxicity (18%), and hyperglycemia (24%) were also observed in another trial utilizing asparaginase during induction therapy. Furthermore, a pediatric-based regimen using pegylated asparaginase during induction in older patients revealed grade 3–4 bilirubin increases in 33% of the patients. Thrombosis and pancreatitis are other relevant toxicities of asparaginase. Altogether, there is some evidence that the use of asparaginase during induction therapy may be associated with increased risks in older patients. Therefore, it would be advisable to start asparaginase in older patients later during consolidation. The majority of complications in older ALL patients is observed during induction; thus, there is still space for intensification of consolidation therapy [14, 23, 32]. Based on this assumption, a consensus treatment protocol for older patients with ALL was defined by the European Working Group for Adult ALL (EWALL). The 4-week, pediatric-based induction comprises dexamethasone, vincristine, and idarubicin in phase 1 and cyclophosphamide and cytarabine in phase 2. Consolidation consists of six alternating cycles with intermediate-dose methotrexate combined with asparaginase and high-dose cytarabine, followed by maintenance. The median age at enrollment was 66 (56–73) years with 22% at 70 years. The incidence of grade 3–4 cytopenias was 90%, and infections during phases 1 and 2 of induction occurred in 16 and 25% of the patients, respectively. Toxicities were less pronounced during consolidation, and asparaginase was well tolerated. CR, survival, and continuous CR rates after 1 year were 85, 61, and 49%, respectively. Another report based on the same backbone showed CR rates of 74% and an OS of 30% at 2 years [18, 20, 33]. The authors also observed grade 3–4 infections in 62% of the patients during induction therapy with a median duration of neutropenia of 24 days, whereas consolidation was far better tolerated even when including the use of asparaginase [18, 20, 23, 34]. The GMALL has conducted thus far the largest prospective trial specifically designed for older patients with Ph/BCR–ABL-negative ALL. Pediatric (Berlin-Frankfurt Munster)-based, dosereduced induction therapy with idarubicin, dexamethasone, vincristine, cyclophosphamide, and cytarabine was followed by alternating consolidation cycles for 1 year and maintenance. Patients with CD201 ALL received rituximab in combination with chemotherapy. The median age of this cohort was 67 (55–85) years. In 268 patients, the CR rate was 76%, early death rate 14%, mortality in CR 6%, continuous remission 32%, and survival 23% at 5 years. Patients aged 75 years with an Eastern Cooperative Oncology Group performance status below 2 had an 86% CR rate, 10% early death, and 36% survival at 3 years. Interestingly, the replacement

**149**

pies [23, 36, 37].

*Overview and Current News in Acute Lymphoblastic Leukemia*

of triple intrathecal therapy during induction resulted in a reduced early mortality. Moderate intensification of consolidation as in the EWALL regimen, with inclusion of high-dose cytarabine and intermediate-dose methotrexate and native *Escherichia* 

Overall, mortality in CR was 6% only. Overall, pediatric-based regimens in ALL are undoubtedly successful and should be scheduled with prospectively defined adaptations with respect to tolerability in older patients. The most important modification of induction therapy in older patients is probably the omission of asparaginase, and the flexible, reduced dose of anthracyclines. In consolidation, intensified treatment should be attempted, and during this treatment phase, even asparaginase may be surprisingly well tolerated at moderate doses [29, 34]. In this treatment, patients aged 55–70 years and 70–75 years tolerated pegylated asparaginase at dose levels of 1000 and 500 U/m2

respectively, as single-drug interim therapy during consolidation. Combination with high-dose methotrexate will be further explored and careful use is recommended in patients with preexisting liver disease. [23, 24, 26, 30, 35]. Nowadays, older patients with Ph+ ALL may have a better chance to achieve a CR than patients with Ph+ ALL. The use of TKIs upfront is most promising. The GMALL conducted a first randomized study to evaluate the efficacy of imatinib single-drug induction compared with chemotherapy. The remission rates were 96 and 50%, respectively. Only 11% of the patients achieved a molecular remission. A follow-up including nonrandomized data yielded a CR rate of 88% in 121 patients, together with a 22% 5-year survival rate. The Gruppo Italiano Malattie Ematologiche dell'Adulto trial used imatinib (800 mg) with prednisone for induction, followed by imatinib single-drug treatment. The CR rate, survival, and disease-free survival were 100, 74, and 48%, respectively, after 1 year. A subsequent trial with dasatinib (140 mg) and prednisone, followed by dasatinib singledrug treatment, was not specifically designed for older patients (range, 24–76 years). The CR rate was 92% and survival was 69% at 20 months. Postremission therapy was at the discretion of the treating physician and 14 of 19 patients with TKI monotherapy relapsed with a high frequency of T315I mutations [31, 33, 35]. Another trial was based on a rotating schedule with 6 weeks of nilotinib treatment alternating with imatinib treatment. In 39 patients, the CR rate was 94% and the OS at 1 year was 79%. Nearly, all relapsed patients in this trial showed mutations associated with TKI resistance. The largest prospective study so far in older patients with Ph+ ALL used an EWALL chemotherapy backbone with vincristine, dexamethasone, and dasatinib (140 mg) for induction. Consolidation and maintenance according to the EWALL backbone was combined with intermittent dasatinib applications. In 71 patients, the CR rate was 96%. The regimen was feasible and the survival after 5 years of follow-up was 36%, which is promising. Persistent MRD above 0.1% after induction and consolidation was associated with poorer remission duration of only 5 months. A subsequent EWALL trial with a similar backbone but with nilotinib (400 mg twice daily) instead of dasatinib was started subsequently. Again, a high CR rate of 97% was reported. About 30% of patients achieved a complete molecular remission after induction. Overall, there is increasing evidence that second-generation TKIs in combination with dose-reduced chemotherapy can induce very high CR rates with low mortality in older patients. The rate of molecular remissions appears to be higher compared with imatinib-based regimens. Moderate intensive consolidation therapies in combination with TKIs are tolerated well. Long-term results have to be assessed after 5 or more years and show a still high rate of relapses. New approaches may include reduced intensity stem cell transplantation (SCT), MRD-based change of TKIs, or use of new immunothera-

In other study, 127 patients with ALL were enrolled including 26 elderly patients (≥60 years) and 101 younger adult patients (<60 years). The median follow-up durations were 6.0 months (range, 0.4–113.2) in the elderly patients

,

*DOI: http://dx.doi.org/10.5772/intechopen.86662*

*coli* asparaginase was tolerated [24, 26, 30].

*Geriatric Medicine and Gerontology*

that induction therapy designed for younger patients may be too intensive for older patients. Patients may acquire severe infections, nonpredefined treatment modifications occur frequently, and treatments may be interrupted or even stopped due to severe complications. Overall, potential conclusions from these studies are very limited. Prospective studies of protocols for older ALL patients specifically designed for older ALL patients have the theoretical aim to provide a chance of cure on the one hand and to limit toxicity, early mortality, and hospitalization duration on the other hand, and the therapy maintains as much quality of life as possible. One central question is whether and/or which anthracycline has to be included in induction regimens for older patients, because these drugs contribute considerably to bone marrow toxicity [5, 6, 15, 31]. One approach is the use of idarubicin in induction, based on a potentially lower cardiac and hepatic toxicity. The results of liposomal anthracyclines in elderly ALL are not convincing so far. Asparaginase is an essential compound in the treatment of ALL. The PETHEMA group reported the results of an intensive induction regimen, including asparaginase for older ALL patients. The early death rate, mainly due to infection, was rather high (36%) and was reduced after omission of asparaginase and cyclophosphamide. A high early mortality rate (29%) and a number of complications including infections (71%), cardiac toxicity (18%), and hyperglycemia (24%) were also observed in another trial utilizing asparaginase during induction therapy. Furthermore, a pediatric-based regimen using pegylated asparaginase during induction in older patients revealed grade 3–4 bilirubin increases in 33% of the patients. Thrombosis and pancreatitis are other relevant toxicities of asparaginase. Altogether, there is some evidence that the use of asparaginase during induction therapy may be associated with increased risks in older patients. Therefore, it would be advisable to start asparaginase in older patients later during consolidation. The majority of complications in older ALL patients is observed during induction; thus, there is still space for intensification of consolidation therapy [14, 23, 32]. Based on this assumption, a consensus treatment protocol for older patients with ALL was defined by the European Working Group for Adult ALL (EWALL). The 4-week, pediatric-based induction comprises dexamethasone, vincristine, and idarubicin in phase 1 and cyclophosphamide and cytarabine in phase 2. Consolidation consists of six alternating cycles with intermediate-dose methotrexate combined with asparaginase and high-dose cytarabine, followed by maintenance. The median age at enrollment was 66 (56–73) years with 22% at 70 years. The incidence of grade 3–4 cytopenias was 90%, and infections during phases 1 and 2 of induction occurred in 16 and 25% of the patients, respectively. Toxicities were less pronounced during consolidation, and asparaginase was well tolerated. CR, survival, and continuous CR rates after 1 year were 85, 61, and 49%, respectively. Another report based on the same backbone showed CR rates of 74% and an OS of 30% at 2 years [18, 20, 33]. The authors also observed grade 3–4 infections in 62% of the patients during induction therapy with a median duration of neutropenia of 24 days, whereas consolidation was far better tolerated even when including the use of asparaginase [18, 20, 23, 34]. The GMALL has conducted thus far the largest prospective trial specifically designed for older patients with Ph/BCR–ABL-negative ALL. Pediatric (Berlin-Frankfurt Munster)-based, dosereduced induction therapy with idarubicin, dexamethasone, vincristine, cyclophosphamide, and cytarabine was followed by alternating consolidation cycles for 1 year and maintenance. Patients with CD201 ALL received rituximab in combination with chemotherapy. The median age of this cohort was 67 (55–85) years. In 268 patients, the CR rate was 76%, early death rate 14%, mortality in CR 6%, continuous remission 32%, and survival 23% at 5 years. Patients aged 75 years with an Eastern Cooperative Oncology Group performance status below 2 had an 86% CR rate, 10% early death, and 36% survival at 3 years. Interestingly, the replacement

**148**

of triple intrathecal therapy during induction resulted in a reduced early mortality. Moderate intensification of consolidation as in the EWALL regimen, with inclusion of high-dose cytarabine and intermediate-dose methotrexate and native *Escherichia coli* asparaginase was tolerated [24, 26, 30].

Overall, mortality in CR was 6% only. Overall, pediatric-based regimens in ALL are undoubtedly successful and should be scheduled with prospectively defined adaptations with respect to tolerability in older patients. The most important modification of induction therapy in older patients is probably the omission of asparaginase, and the flexible, reduced dose of anthracyclines. In consolidation, intensified treatment should be attempted, and during this treatment phase, even asparaginase may be surprisingly well tolerated at moderate doses [29, 34]. In this treatment, patients aged 55–70 years and 70–75 years tolerated pegylated asparaginase at dose levels of 1000 and 500 U/m2 , respectively, as single-drug interim therapy during consolidation. Combination with high-dose methotrexate will be further explored and careful use is recommended in patients with preexisting liver disease. [23, 24, 26, 30, 35]. Nowadays, older patients with Ph+ ALL may have a better chance to achieve a CR than patients with Ph+ ALL. The use of TKIs upfront is most promising. The GMALL conducted a first randomized study to evaluate the efficacy of imatinib single-drug induction compared with chemotherapy. The remission rates were 96 and 50%, respectively. Only 11% of the patients achieved a molecular remission. A follow-up including nonrandomized data yielded a CR rate of 88% in 121 patients, together with a 22% 5-year survival rate. The Gruppo Italiano Malattie Ematologiche dell'Adulto trial used imatinib (800 mg) with prednisone for induction, followed by imatinib single-drug treatment. The CR rate, survival, and disease-free survival were 100, 74, and 48%, respectively, after 1 year. A subsequent trial with dasatinib (140 mg) and prednisone, followed by dasatinib singledrug treatment, was not specifically designed for older patients (range, 24–76 years). The CR rate was 92% and survival was 69% at 20 months. Postremission therapy was at the discretion of the treating physician and 14 of 19 patients with TKI monotherapy relapsed with a high frequency of T315I mutations [31, 33, 35]. Another trial was based on a rotating schedule with 6 weeks of nilotinib treatment alternating with imatinib treatment. In 39 patients, the CR rate was 94% and the OS at 1 year was 79%. Nearly, all relapsed patients in this trial showed mutations associated with TKI resistance. The largest prospective study so far in older patients with Ph+ ALL used an EWALL chemotherapy backbone with vincristine, dexamethasone, and dasatinib (140 mg) for induction. Consolidation and maintenance according to the EWALL backbone was combined with intermittent dasatinib applications. In 71 patients, the CR rate was 96%. The regimen was feasible and the survival after 5 years of follow-up was 36%, which is promising. Persistent MRD above 0.1% after induction and consolidation was associated with poorer remission duration of only 5 months. A subsequent EWALL trial with a similar backbone but with nilotinib (400 mg twice daily) instead of dasatinib was started subsequently. Again, a high CR rate of 97% was reported. About 30% of patients achieved a complete molecular remission after induction. Overall, there is increasing evidence that second-generation TKIs in combination with dose-reduced chemotherapy can induce very high CR rates with low mortality in older patients. The rate of molecular remissions appears to be higher compared with imatinib-based regimens. Moderate intensive consolidation therapies in combination with TKIs are tolerated well. Long-term results have to be assessed after 5 or more years and show a still high rate of relapses. New approaches may include reduced intensity stem cell transplantation (SCT), MRD-based change of TKIs, or use of new immunotherapies [23, 36, 37].

In other study, 127 patients with ALL were enrolled including 26 elderly patients (≥60 years) and 101 younger adult patients (<60 years). The median follow-up durations were 6.0 months (range, 0.4–113.2) in the elderly patients

and 21.7 months (range, 1.0–122.7) in the younger patients. The median age of the younger patients with ALL was 30 years (range, 15–58), whereas that of the elderly patients with ALL was 65 years (range, 60–82). No significant differences in the baseline characteristics of the two groups were observed, except in history of malignancy; a larger portion of elderly patients with ALL had a history of malignancy (*p* = 0.001). The composition of ALL subtypes and the frequencies of Ph+ status were not statistically significant between the two groups. The peripheral blood sample laboratory findings showed more severe anemia in younger adult patients with ALL than in the elderly patients (*p* = 0.023); of 26 elderly patients with ALL, abnormal karyotypes were found in 14 patients (53.8%) [38, 39].

All patients, with the exception of two elderly patients who received supportive care only, received induction chemotherapy. About half of the elderly patients (12 patients, 46.2%) received the VPDL regimen as an induction therapy. Five elderly patients (19.2%) were administered the VPD regimen, and one (3.8%) was administered the hyper-CVAD (cyclophosphamide 300 mg/m2 , D1–3; vincristine 2 mg D4,11; Adriamycin 50 mg/m2 , D4; dexamethasone 40 mg D1–4, D11–14) regimen. The overall CR rate was much higher in the younger adult patients than that in the elderly patients (94.1 vs. 57.7%, *p* < 0.001). Early mortality within 3 months from the start of induction chemotherapy was remarkably higher in the elderly patients (26.9% vs. 5.0%, *p* = 0.003).

The median number of postremission consolidation therapy sessions was three (range, 1–5) in the elderly patients with ALL. The regimen in the elderly patients was vincristine and prednisolone in seven patients. Two patients received only imatinib due to severe comorbidities. One patient received the CALGB 9251 regimen, and the other patient received nonmyeloablative hematopoietic stem cell transplantation (HSCT) from a matched sibling donor. Of 15 elderly patients who achieved CR, only 11 received postremission therapy. The overall nondisease-related mortality rate in the elderly patients was higher than that in the younger adult patients.

Cumulative hazards of disease-related and nondisease-related mortality in younger adult patients (<60 years) with acute lymphoblastic leukemia (ALL) and in elderly patients (≥60 years) with ALL (*p* = 0.001 and 0.12, respectively).

The median OS of the younger patients was 26.3 months (95% confidence interval [CI], 19.6–33.0), whereas that of the elderly patients was 10.3 months (95% CI, 3.5–17.2) (*p* = 0.003). The survival difference according to age was not reproduced

**151**

*Overview and Current News in Acute Lymphoblastic Leukemia*

consistently found in the patients with Ph-negative ALL.

in the subpopulation of patients with Ph-positive ALL (data not shown), but was

**A.** Overall survival (OS) of elderly and younger adult patients with acute lymphoblastic leukemia (ALL): OS of elderly patients with ALL (≥60 year) was shorter than that of younger adult patients with ALL (<60 year) (median OS 10.3 vs.

**B.** OS of the elderly and younger adult patients with Philadelphia chromosome

was shorter than that of adult patients with Ph-negative ALL (<60 year)

**C.** OS according to complete remission in elderly patients with ALL: OS of elderly patients with complete remission was longer than that of elderly patients with-

**D.** OS according to age (60–69 vs. ≥70 years) in elderly patients with ALL: OS of elderly patients aged 70 years or more was not significantly different from that of the other elderly patients (median OS, 11.2 vs. 3.7 months, *p* = 0.073) [40, 41].

Among the elderly patients, the patients who achieved CR1 (CR after the first induction chemotherapy) showed significantly longer survival compared with those

out complete remission (median OS, 13.1 vs. 2.6 months, *p* = 0.001).

(median OS, 10.3 vs. 29.2 months, respectively, *p* = 0.01).

**8. Survival analysis for elderly patients with ALL**

(Ph)-negative ALL: OS of the elderly patients with Ph-negative ALL (≥60 year)

26.3 months, respectively, *p* = 0.003).

*DOI: http://dx.doi.org/10.5772/intechopen.86662*

*Geriatric Medicine and Gerontology*

and 21.7 months (range, 1.0–122.7) in the younger patients. The median age of the younger patients with ALL was 30 years (range, 15–58), whereas that of the elderly patients with ALL was 65 years (range, 60–82). No significant differences in the baseline characteristics of the two groups were observed, except in history of malignancy; a larger portion of elderly patients with ALL had a history of malignancy (*p* = 0.001). The composition of ALL subtypes and the frequencies of Ph+ status were not statistically significant between the two groups. The peripheral blood sample laboratory findings showed more severe anemia in younger adult patients with ALL than in the elderly patients (*p* = 0.023); of 26 elderly patients with ALL,

All patients, with the exception of two elderly patients who received supportive care only, received induction chemotherapy. About half of the elderly patients (12 patients, 46.2%) received the VPDL regimen as an induction therapy. Five elderly patients (19.2%) were administered the VPD regimen, and one (3.8%) was administered the

much higher in the younger adult patients than that in the elderly patients (94.1 vs. 57.7%, *p* < 0.001). Early mortality within 3 months from the start of induction chemotherapy

The median number of postremission consolidation therapy sessions was three (range, 1–5) in the elderly patients with ALL. The regimen in the elderly patients was vincristine and prednisolone in seven patients. Two patients received only imatinib due to severe comorbidities. One patient received the CALGB 9251 regimen, and the other patient received nonmyeloablative hematopoietic stem cell transplantation (HSCT) from a matched sibling donor. Of 15 elderly patients who achieved CR, only 11 received postremission therapy. The overall nondisease-related mortality rate in the elderly patients was higher than that in the younger adult patients.

Cumulative hazards of disease-related and nondisease-related mortality in younger adult patients (<60 years) with acute lymphoblastic leukemia (ALL) and in

The median OS of the younger patients was 26.3 months (95% confidence interval [CI], 19.6–33.0), whereas that of the elderly patients was 10.3 months (95% CI, 3.5–17.2) (*p* = 0.003). The survival difference according to age was not reproduced

elderly patients (≥60 years) with ALL (*p* = 0.001 and 0.12, respectively).

, D4; dexamethasone 40 mg D1–4, D11–14) regimen. The overall CR rate was

, D1–3; vincristine 2 mg D4,11; Adriamycin

abnormal karyotypes were found in 14 patients (53.8%) [38, 39].

was remarkably higher in the elderly patients (26.9% vs. 5.0%, *p* = 0.003).

hyper-CVAD (cyclophosphamide 300 mg/m2

50 mg/m2

**150**

in the subpopulation of patients with Ph-positive ALL (data not shown), but was consistently found in the patients with Ph-negative ALL.

