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

Among the elderly patients, the patients who achieved CR1 (CR after the first induction chemotherapy) showed significantly longer survival compared with those who did not achieve CR1 (median OS, 13.1 vs. 2.6 months; *p* = 0.001). Furthermore, CR1 was the only independent prognostic factor for OS in elderly patients with ALL (*p* = 0.001). Although the OS of elderly patients aged 60–69 tended to be longer than that of those aged 70 or over, the difference did not reach statistical significance (median OS, 11.2 vs. 3.7 months; *p* = 0.073).

In the survival analysis using the factors at the initial ALL diagnosis, the probable poor prognostic factors for CR were age ≥ 70 years (relative rate of remission [RR], 0.14; 95% CI, 0.013–1.45; *p* = 0.098) and leukocytosis (≥30,000/μL) (RR, 6.00; 95% CI, 0.93–38.63; *p* = 0.059). T-cell lineage and the presence of lymphadenopathy were significant factors in poor prognosis for OS in the univariate analysis (hazard ratio [HR], 3.11 and 3.14; 95% CI, 1.14–9.34, and 1.01–9.99; *p* = 0.033 and 0.041, respectively). T-cell lineage and Ph-positive status tended to increase the HR for leukemia free survival (LFS) (HR, 8.49 and 4.49; 95% CI, 0.53–135.82 and 0.8–25.21; *p* = 0.069 and 0.064, respectively).

Univariate analysis for complete remission, overall survival, and leukemia-free survival in elderly patients with ALL (≥60 year) (n = 26).


ALL, acute lymphoblastic leukemia; RR, relative rate of remission; CI, confidence interval; HR, hazard ratio; Ph, Philadelphia chromosome; WBC, white blood cell.

The low response to chemotherapy in the elderly patients with ALL could be related to several factors. The first factor may be chemotherapy intensity. Intensified combination induction chemotherapy can result in an improvement in the CR proportion, and high-dose postremission methotrexate (MTX) or cytarabine therapy is effective for treating adult ALL. However, most elderly patients with ALL in our study could not receive the postremission therapy after the induction therapy with a standard or reduced dose and also could not be treated with intensified postremission regimens such as cyclophosphamide or MTX, though they received postremission therapy. The second factor may be drug-resistance mechanisms such as the presence of multidrug-resistance gene 1 and multidrug-resistance-related protein.

Although intensified induction chemotherapy was not introduced, and postremission therapy was not performed appropriately in most elderly patients with ALL, the survival benefit was definite in the patients who achieved CR. Our study did not show a statistical difference in nondisease-related mortality rates between the elderly and younger adult groups. However, the actual risk of nondiseaserelated mortality might be significantly higher in the elderly patients considering that only a few patients could receive highly toxic therapy such as HSCT, and our results indicated that about half (43.8%) of nondisease-related mortality was related to HSCT in the younger adult patients with ALL [40–43].

#### **8.1 New treatment options in older patients with ALL**

ALL blasts express a number of antigens, such as CD33, CD22, CD19, and CD52, which could be targets for antibody therapy. The majority of older patients suffer

**153**

effectiveness.

*Overview and Current News in Acute Lymphoblastic Leukemia*

from B-precursor ALL. In this subtype, approximately half of the patients show

promising data for the combination of chemotherapy and rituximab have been reported. Outcome of older patients could be hampered by a higher mortality due to infections in CR, which underlines the need for intensive supportive care for older

hematologic remission with persistent MRD after intensive chemotherapy, the molecular remission rate was 84%. A number of older patients who were not able to receive an SCT remained in remission for more than 1 year. More recently, a CR rate of 68% was reported for relapsed ALL. All patients with CR also achieved a molecular CR. Treatment with the final dosing regimen was well tolerated, and a number of older patients experienced a benefit. The CD22 directed, calicheamicinconjugated antibody inotuzumab induced 18% CRs and 39% marrow CRs in

A great majority of cases with ALL in elderly patient correspond to B-precursor lineage, one of the characteristics of this lineage is the expression of CD20 on its surface, which makes it susceptible to treatments focused on this marker, such as rituximab, this treatment approach has already shown to be highly effective in young patients, which could be transposed to the population over 65 years of age. A promising new approach is the administration of a bispecific CD19 antibody, blinatumomab, which has the potential to engage cytotoxic T cells in patients for

leukemia cells. In 19 patients with refractory disease, defined as

ALL. Toxicity appeared to be manageable, and the mortality of

4% within 4 weeks was moderate. Successful future use of antibody treatment will certainly depend on well-designed combination regimens with chemotherapy that

In recent years, there have been advances and new therapeutic options in the management of ALL, one of the most promising is immunotherapy, specifically bispecific antibodies, the first of which useful information was disclosed was blinatumomab, this antibody that acts by binding to T lymphocytes, activating them and forcing them to destroy CD19 receptor expressing cells, such as blasts, already has multiple studies in various population groups that demonstrate their effectiveness against the disease, achieving significant response rates (84%) and negativization of the MRD. Another new specific antibody against the CD22 receptor, inotuzumab, has also been shown to be effective, at least in its initial studies, with a tolerable safety profile. The great advantage of these new treatments is that they do not confer the implicit risk in chemotherapy; however, there are no studies

Several other new drugs are of interest for optimizing treatment in older ALL patients. Although the number of older patients with T-ALL is low, the use of nelarabine is of interest after promising results and acceptable toxicity in relapsed T-ALL including older patients. Liposomal cytarabine for intrathecal application showed activity and tolerability in CNS relapse of ALL, although in combination with systemic neurotoxic regimens, severe toxicities may be observed. The use of liposomal cytarabine in prophylaxis of CNS relapse is of interest, particularly in older patients, since it allows reduction of the number of intrathecal injections and may induce fewer systemic toxicities compared to conventional intrathecal therapy. Other drugs of current interest include nelarabine, indicated for use in cases of T-ALL. The prophylactic treatment to CNS has also had new protagonists in its field, liposomal cytarabine is one of these; this drug used for both prophylaxis and management of relapse to CNS has shown to be safe, although when combined with other neurotoxic agents, there is considerable toxicity. Despite this, safety is comparable to that presented by conventional cytarabine, with a higher rate of

aim to achieve long-term responses, particularly in older ALL patients.

ALL, the first

CD20 expression on their blast cells. In younger patients with CD20<sup>+</sup>

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

patients throughout the entire treatment period.

lysis of CD19+

relapsed CD22+

specifically in elderly patients.

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

*Geriatric Medicine and Gerontology*

(median OS, 11.2 vs. 3.7 months; *p* = 0.073).

0.8–25.21; *p* = 0.069 and 0.064, respectively).

survival in elderly patients with ALL (≥60 year) (n = 26).

related to HSCT in the younger adult patients with ALL [40–43].

**8.1 New treatment options in older patients with ALL**

who did not achieve CR1 (median OS, 13.1 vs. 2.6 months; *p* = 0.001). Furthermore, CR1 was the only independent prognostic factor for OS in elderly patients with ALL (*p* = 0.001). Although the OS of elderly patients aged 60–69 tended to be longer than that of those aged 70 or over, the difference did not reach statistical significance

In the survival analysis using the factors at the initial ALL diagnosis, the probable poor prognostic factors for CR were age ≥ 70 years (relative rate of remission [RR], 0.14; 95% CI, 0.013–1.45; *p* = 0.098) and leukocytosis (≥30,000/μL) (RR, 6.00; 95% CI, 0.93–38.63; *p* = 0.059). T-cell lineage and the presence of lymphadenopathy were significant factors in poor prognosis for OS in the univariate analysis (hazard ratio [HR], 3.11 and 3.14; 95% CI, 1.14–9.34, and 1.01–9.99; *p* = 0.033 and 0.041, respectively). T-cell lineage and Ph-positive status tended to increase the HR for leukemia free survival (LFS) (HR, 8.49 and 4.49; 95% CI, 0.53–135.82 and

Univariate analysis for complete remission, overall survival, and leukemia-free

ALL, acute lymphoblastic leukemia; RR, relative rate of remission; CI, confidence interval; HR, hazard ratio; Ph, Philadelphia chromosome; WBC, white blood cell. The low response to chemotherapy in the elderly patients with ALL could be related to several factors. The first factor may be chemotherapy intensity. Intensified combination induction chemotherapy can result in an improvement in the CR proportion, and high-dose postremission methotrexate (MTX) or cytarabine therapy is effective for treating adult ALL. However, most elderly patients with ALL in our study could not receive the postremission therapy after the induction therapy with a standard or reduced dose and also could not be treated with intensified postremission regimens such as cyclophosphamide or MTX, though they received postremission therapy. The second factor may be drug-resistance mechanisms such as the presence of multidrug-resistance gene 1 and multidrug-resistance-related protein. Although intensified induction chemotherapy was not introduced, and postremission therapy was not performed appropriately in most elderly patients with ALL, the survival benefit was definite in the patients who achieved CR. Our study did not show a statistical difference in nondisease-related mortality rates between the elderly and younger adult groups. However, the actual risk of nondiseaserelated mortality might be significantly higher in the elderly patients considering that only a few patients could receive highly toxic therapy such as HSCT, and our results indicated that about half (43.8%) of nondisease-related mortality was

ALL blasts express a number of antigens, such as CD33, CD22, CD19, and CD52, which could be targets for antibody therapy. The majority of older patients suffer

**152**

from B-precursor ALL. In this subtype, approximately half of the patients show CD20 expression on their blast cells. In younger patients with CD20<sup>+</sup> ALL, the first promising data for the combination of chemotherapy and rituximab have been reported. Outcome of older patients could be hampered by a higher mortality due to infections in CR, which underlines the need for intensive supportive care for older patients throughout the entire treatment period.

A great majority of cases with ALL in elderly patient correspond to B-precursor lineage, one of the characteristics of this lineage is the expression of CD20 on its surface, which makes it susceptible to treatments focused on this marker, such as rituximab, this treatment approach has already shown to be highly effective in young patients, which could be transposed to the population over 65 years of age.

A promising new approach is the administration of a bispecific CD19 antibody, blinatumomab, which has the potential to engage cytotoxic T cells in patients for lysis of CD19+ leukemia cells. In 19 patients with refractory disease, defined as hematologic remission with persistent MRD after intensive chemotherapy, the molecular remission rate was 84%. A number of older patients who were not able to receive an SCT remained in remission for more than 1 year. More recently, a CR rate of 68% was reported for relapsed ALL. All patients with CR also achieved a molecular CR. Treatment with the final dosing regimen was well tolerated, and a number of older patients experienced a benefit. The CD22 directed, calicheamicinconjugated antibody inotuzumab induced 18% CRs and 39% marrow CRs in relapsed CD22+ ALL. Toxicity appeared to be manageable, and the mortality of 4% within 4 weeks was moderate. Successful future use of antibody treatment will certainly depend on well-designed combination regimens with chemotherapy that aim to achieve long-term responses, particularly in older ALL patients.

In recent years, there have been advances and new therapeutic options in the management of ALL, one of the most promising is immunotherapy, specifically bispecific antibodies, the first of which useful information was disclosed was blinatumomab, this antibody that acts by binding to T lymphocytes, activating them and forcing them to destroy CD19 receptor expressing cells, such as blasts, already has multiple studies in various population groups that demonstrate their effectiveness against the disease, achieving significant response rates (84%) and negativization of the MRD. Another new specific antibody against the CD22 receptor, inotuzumab, has also been shown to be effective, at least in its initial studies, with a tolerable safety profile. The great advantage of these new treatments is that they do not confer the implicit risk in chemotherapy; however, there are no studies specifically in elderly patients.

Several other new drugs are of interest for optimizing treatment in older ALL patients. Although the number of older patients with T-ALL is low, the use of nelarabine is of interest after promising results and acceptable toxicity in relapsed T-ALL including older patients. Liposomal cytarabine for intrathecal application showed activity and tolerability in CNS relapse of ALL, although in combination with systemic neurotoxic regimens, severe toxicities may be observed. The use of liposomal cytarabine in prophylaxis of CNS relapse is of interest, particularly in older patients, since it allows reduction of the number of intrathecal injections and may induce fewer systemic toxicities compared to conventional intrathecal therapy.

Other drugs of current interest include nelarabine, indicated for use in cases of T-ALL. The prophylactic treatment to CNS has also had new protagonists in its field, liposomal cytarabine is one of these; this drug used for both prophylaxis and management of relapse to CNS has shown to be safe, although when combined with other neurotoxic agents, there is considerable toxicity. Despite this, safety is comparable to that presented by conventional cytarabine, with a higher rate of effectiveness.

Liposomal vincristine is another drug of interest, particularly in older patients. Results are still pending on the major question of whether liposomal encapsulation allows a higher dose intensity with lower risk of neurotoxicity. Bendamustine could be of interest, since it has shown limited toxicity and favorable results in older patients with B-cell lymphoma. New drugs with different mechanisms of action may, in the future, be used in combination with chemotherapy, such as proteasome inhibitors, histone-deacetylase inhibitors, hypomethylating agents, or targeted drugs such as Flt3 inhibitors or Jak2-inhibitors in defined subgroups of ALL. Currently, these compounds are either available in clinical trials or could be considered in individual patients with poor response to standard chemotherapy, including patients with molecular failure [12, 23, 43, 44].

Bendamustine and liposomal vincristine are new tools already known, the first one, a drug developed in the 1960s, has shown its effectiveness in various studies in the management of ALL and other lymphoproliferative disorders, with adequate safety in elderly patients. New mechanisms of action must be explored in order to give variety to the maneuvers against the disease. The study of new prognostic and risk markers that can be targeted by these drugs is crucial for their development. Currently, a large number of studies are underway in the world, both with new combinations of already known drugs and with novel molecules applicable to ALL [12, 23, 43, 44].

#### **9. Conclusion**

All older ALL patients need a comprehensive diagnostic classification, including, at least, immunophenotyping, molecular diagnostics, and setup of an assay for MRD evaluation. The identification of Ph+ ALL is crucial since, even in very old and frail patients, TKIs induce a high CR rate with reasonable durability. Furthermore, the biological characterization of older ALL patients needs to be improved. Biobanking for future scientific investigations within clinical trials should therefore be standard in older as it is in younger patients.

Altogether, in older as in younger patients, a pediatric-based induction strategy is recommendable in Ph− ALL. Dose reductions for anthracyclines are essential, and asparaginase during induction cannot be recommended outside of clinical trials. Dexamethasone appears to increase efficacy in younger patients, but prolonged use should be avoided. For fit older patients, consolidation chemotherapy may be intensified. Moderate-dose consolidation, including methotrexate, cytarabine, and reinduction therapy, appears to be feasible, and maintenance treatment is an essential treatment element.

In unfit older patients, a dose-reduced induction therapy is recommended with the aim of controlling and achieving a prolonged low-level disease. ALL-specific approaches should be considered, including vincristine, steroids, intrathecal therapy, and maintenance with mercaptopurine and methotrexate. Many physicians have more experience with older AML patients; however, there is no rationale for using AML regimens such as low-dose cytarabine or hydroxyurea in ALL.

When they are available, targeted drugs such as nelarabine, monoclonal antibodies, or other new drugs with potentially reduced or alternative toxicity should be added to treatment strategies in older patients, preferably in clinical trials. Since many of these compounds are used off-label, it may be useful to make the indication based on persistent MRD, which, in addition, offers a chance to evaluate effects immediately. Treatment options may change as soon as new drugs or strategies become available. With effective drugs for prolonged maintenance, it may be possible to further reduce intensity of induction therapy and avoid early mortality in unfit patients.

**155**

**Author details**

Mexico

Martha Alvarado Ibarra\* and Jose Antonio De La Peña Celaya

\*Address all correspondence to: normoblasto@gmail.com

provided the original work is properly cited.

Hematologists at Centro Médico Nacional "20 de Noviembre", ISSSTE Mexico City,

© 2019 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,

*Overview and Current News in Acute Lymphoblastic Leukemia*

Patients should be considered as candidates for RIC SCT.

In Ph+ ALL, it is still not clear whether further reduced induction chemotherapy adds an effect to TKI therapy and which inhibitor is preferable. I favor a combination therapy. Moderate dose consolidation and maintenance should be offered.

Whereas full-conditioning regimens before SCT are clearly not recommended, RIC SCT is an option in older patients. For indication, it will be crucial to define prognostic factors. Because persistence of MRD is one of the most important risk factors, MRD evaluation should take place in older patients to identify those who could benefit from experimental therapies or SCT. This also applies to Ph+ ALL

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

regarding the option of changing the TKI.

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

*Geriatric Medicine and Gerontology*

[12, 23, 43, 44].

**9. Conclusion**

essential treatment element.

Liposomal vincristine is another drug of interest, particularly in older patients. Results are still pending on the major question of whether liposomal encapsulation allows a higher dose intensity with lower risk of neurotoxicity. Bendamustine could be of interest, since it has shown limited toxicity and favorable results in older patients with B-cell lymphoma. New drugs with different mechanisms of action may, in the future, be used in combination with chemotherapy, such as proteasome inhibitors, histone-deacetylase inhibitors, hypomethylating agents, or targeted drugs such as Flt3 inhibitors or Jak2-inhibitors in defined subgroups of ALL. Currently, these compounds are either available in clinical trials or could be considered in individual patients with poor response to standard chemotherapy,

Bendamustine and liposomal vincristine are new tools already known, the first one, a drug developed in the 1960s, has shown its effectiveness in various studies in the management of ALL and other lymphoproliferative disorders, with adequate safety in elderly patients. New mechanisms of action must be explored in order to give variety to the maneuvers against the disease. The study of new prognostic and risk markers that can be targeted by these drugs is crucial for their development. Currently, a large number of studies are underway in the world, both with new combinations of already known drugs and with novel molecules applicable to ALL

All older ALL patients need a comprehensive diagnostic classification, including, at least, immunophenotyping, molecular diagnostics, and setup of an assay for MRD evaluation. The identification of Ph+ ALL is crucial since, even in very old and frail patients, TKIs induce a high CR rate with reasonable durability. Furthermore, the biological characterization of older ALL patients needs to be improved. Biobanking for future scientific investigations within clinical trials

Altogether, in older as in younger patients, a pediatric-based induction strategy is recommendable in Ph− ALL. Dose reductions for anthracyclines are essential, and asparaginase during induction cannot be recommended outside of clinical trials. Dexamethasone appears to increase efficacy in younger patients, but prolonged use should be avoided. For fit older patients, consolidation chemotherapy may be intensified. Moderate-dose consolidation, including methotrexate, cytarabine, and reinduction therapy, appears to be feasible, and maintenance treatment is an

In unfit older patients, a dose-reduced induction therapy is recommended with the aim of controlling and achieving a prolonged low-level disease. ALL-specific approaches should be considered, including vincristine, steroids, intrathecal therapy, and maintenance with mercaptopurine and methotrexate. Many physicians have more experience with older AML patients; however, there is no rationale for using AML regimens such as low-dose cytarabine or hydroxyurea in ALL.

When they are available, targeted drugs such as nelarabine, monoclonal antibodies, or other new drugs with potentially reduced or alternative toxicity should be added to treatment strategies in older patients, preferably in clinical trials. Since many of these compounds are used off-label, it may be useful to make the indication based on persistent MRD, which, in addition, offers a chance to evaluate effects immediately. Treatment options may change as soon as new drugs or strategies become available. With effective drugs for prolonged maintenance, it may be possible to further reduce intensity of induction therapy and avoid early mortality in unfit patients.

should therefore be standard in older as it is in younger patients.

including patients with molecular failure [12, 23, 43, 44].

**154**

In Ph+ ALL, it is still not clear whether further reduced induction chemotherapy adds an effect to TKI therapy and which inhibitor is preferable. I favor a combination therapy. Moderate dose consolidation and maintenance should be offered. Patients should be considered as candidates for RIC SCT.

Whereas full-conditioning regimens before SCT are clearly not recommended, RIC SCT is an option in older patients. For indication, it will be crucial to define prognostic factors. Because persistence of MRD is one of the most important risk factors, MRD evaluation should take place in older patients to identify those who could benefit from experimental therapies or SCT. This also applies to Ph+ ALL regarding the option of changing the TKI.
