Adult Acute Lymphoblastic Leukemia (ALL)

Standard Treatment Options for Untreated Adult ALL
1.Remission induction therapy, including the following:
• Combination chemotherapy.
• Imatinib mesylate (for patients with Philadelphia chromosome [Ph1]-positive ALL).
• Imatinib mesylate combined with combination chemotherapy (for patients with Ph1-positive ALL)
• Supportive care.

2.Central nervous system (CNS) prophylaxis therapy, including the following:
• Cranial radiation therapy plus intrathecal (IT) methotrexate.
• High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
• IT chemotherapy alone.

SUMMARY:
# Combination chemotherapy with prednisone, vincristine, and an anthracycline with or without asparaginase.
# In patients with Ph1-positive ALL, add Bcr-abl tyrosine kinase inhibitors to combination chemotherapy with prednisone, vincristine, and an anthracycline, without asparaginase.

#Supportive care
• Prophylactic platelet transfusions (pooled platelet concentrates) at a level of 10,000/mm³ - 20,000/mm³. The incidence of platelet alloimmunization was similar among groups randomly assigned.
• Empiric broad-spectrum antimicrobial therapy for febrile patients who are profoundly neutropenic.
Careful instruction in personal hygiene and dental care and in recognizing early signs of infection.
• White blood cell transfusions in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.
• Prophylactic oral antibiotics in patients with expected prolonged, profound granulocytopenia (<100/mm³ for 2 wk), though further studies are necessary.
• Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms.
• The use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.

Sixty percent to 80% of adults with ALL usually achieve a complete remission status following appropriate induction therapy. Appropriate initial treatment, usually consisting of a regimen that includes the combination of vincristine, prednisone, and an anthracycline, with or without asparaginase, results in a complete response rate of up to 80%. In patients with Ph1-positive ALL, the remission rate is generally greater than 90% when standard induction regimens are combined with Bcr-abl tyrosine kinase inhibitors. In the largest study published to date of Ph1-positive ALL patients, overall survival (OS) for 1,913 adult ALL patients was 39% at 5 years.

Patients who experience a relapse after remission usually die within 1 year, even if a second complete remission is achieved. If there are appropriate available donors and if the patient is younger than 55 years, bone marrow transplantation may be a consideration in the management of this disease. Transplant centers performing five or fewer transplants annually usually have poorer results than larger centers. If allogeneic transplant is considered, a recommendation is that transfusions with blood products from a potential donor be avoided, if possible.

Combination chemotherapy
Most current induction regimens for patients with adult ALL include combination chemotherapy with prednisone, vincristine, and an anthracycline. Some regimens, including those used in a Cancer and Leukemia Group B (CALGB) study (CLB-8811), also add other drugs, such as asparaginase or cyclophosphamide. Current multiagent induction regimens result in complete response rates that range from 60% to 90%.

■ Imatinib mesylate (Bcr-abl tyrosine kinase inhibitor)
Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in Ph1-positive ALL.[Level of evidence: 3iiiDiv] More commonly, particularly in younger patients, imatinib is incorporated into combination chemotherapy regimens. There are several published single-arm studies in which the complete response rate and survival are compared with historical controls.

Evidence (Imatinib mesylate):
Several studies have suggested that the addition of imatinib to conventional combination chemotherapy induction regimens results in complete response rates, event-free survival rates, and OS rates that are higher than those in historical controls. At the present time, no conclusions can be drawn regarding the optimal imatinib dose or schedule.
DOSAGE & INDICATIONS: GoTo Bcr-abl tyrosine kinase inhibitors

Supportive care
Since myelosuppression is an anticipated consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during remission induction treatment. Facilities must be available for hematological support and for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions, when appropriate.

Evidence (Supportive care):
1.Randomized clinical trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm³ rather than at a level of 20,000/mm³.
2.The incidence of platelet alloimmunization was similar among groups randomly assigned to receive one of the following from random donors:
• Pooled platelet concentrates.
• Filtered, pooled platelet concentrates.
• Ultraviolet B-irradiated, pooled platelet concentrates.
• Filtered platelets obtained by apheresis.

Empiric broad-spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. Careful instruction in personal hygiene and dental care and in recognizing early signs of infection are appropriate for all patients. Elaborate isolation facilities, including filtered air, sterile food, and gut flora sterilization, are not routinely indicated but may benefit transplant patients.

Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that are not responding to antibiotics.[27] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 wk), though further studies are necessary.[28] Serial surveillance cultures may be helpful in detecting the presence or acquisition of resistant organisms in these patients. As suggested in a CALGB study (CLB-9111), the use of myeloid growth factors during remission-induction therapy appears to decrease the time to hematopoietic reconstitution.

2. CNS prophylaxis therapy
The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease.

Special Considerations for B-Cell and T-Cell Adult ALL
Two additional subtypes of adult ALL require special consideration. B-cell ALL, which expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14), t(2;8), and t(8;22), is not usually cured with typical ALL regimens. Aggressive brief-duration high-intensity regimens, including those previously used in CLB-9251 (NCT00002494), that are similar to those used in aggressive non-Hodgkin lymphoma have shown high response rates and cure rates (75% complete response; 40% failure-free survival). Similarly, T-cell ALL, including lymphoblastic lymphoma, has shown high cure rates when treated with cyclophosphamide-containing regimens.

Whenever possible, patients with B-cell or T-cell ALL should be entered in clinical trials designed to improve the outcomes in these subsets. (Refer to the Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma and Lymphoblastic lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Standard Treatment Options for Adult ALL in Remission
1. Postremission therapy, including the following:
• Chemotherapy.
• Ongoing treatment with a Bcr-abl tyrosine kinase inhibitor, such as imatinib, nilotinib, or dasatinib.
• Autologous or allogeneic bone marrow transplant (BMT).

2. Central nervous system (CNS) prophylaxis therapy, including the following:
• Cranial radiation therapy plus intrathecal (IT) methotrexate.
• High-dose systemic methotrexate and IT methotrexate without cranial radiation therapy.
• IT chemotherapy alone.


Good prognoses were found for patients with T-cell lineage ALL,
Poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11).
Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.

SUMMARY:
Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
• Longer-term therapy at lower doses (maintenance therapy).
• Allogeneic bone marrow transplant.
Because the optimal postremission therapy for patients with ALL is still unclear, a consideration is participation in clinical trials.

Aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.

Allogeneic BMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.

The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high-risk or Ph1-positive ALL. This was confirmed in the ECOG-2993 (NCT01505699) study.
The results of the International ALL Trial (ECOG-2993) suggest the existence of a graft-versus-leukemia effect for adult Ph1-negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long-term survival for patients with standard-risk adult ALL in first remission. The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.

1. Postremission therapy

Current approaches to postremission therapy for adult ALL include short-term, relatively intensive chemotherapy followed by any of the following:
• Longer-term therapy at lower doses (maintenance therapy).
• Allogeneic bone marrow transplant.

Because the optimal postremission therapy for patients with ALL is still unclear, a consideration is participation in clinical trials.

Evidence (Chemotherapy):
1.Several trials, including studies from the Cancer and Leukemia Group B (CLB-8811) and the completed European Cooperative Oncology Group (ECOG-2993 [NCT00002514]), of aggressive postremission chemotherapy for adult ALL have confirmed a long-term disease-free survival (DFS) rate of approximately 40%.
• In two series, especially good prognoses were found for patients with T-cell lineage ALL, with DFS rates of 50% to 70% for patients receiving postremission therapy.
• These series represent a significant improvement in DFS rates over previous, less intensive chemotherapeutic approaches.

2.In contrast, poor cure rates were demonstrated in patients with Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3 phenotype (surface immunoglobulin positive), and B-cell lineage ALL characterized by t(4;11).

Administration of the newer dose-intensive schedules can be difficult and should be performed by physicians experienced in these regimens at centers equipped to deal with potential complications are necessary. Studies in which continuation or maintenance chemotherapy was eliminated had outcomes inferior to those with extended treatment durations.[8,9] Imatinib has been incorporated into maintenance regimens in patients with Ph1-positive ALL.

Evidence (Allogeneic and autologous BMT):
AlloBMT results in the lowest incidence of leukemic relapse, even when compared with a BMT from an identical twin (syngeneic BMT). This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD). The improvement in DFS in patients undergoing alloBMT as primary postremission therapy is offset, in part, by the increased morbidity and mortality from GVHD, veno-occlusive disease of the liver, and interstitial pneumonitis.

1.The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high-risk or Ph1-positive ALL. This was confirmed in the ECOG-2993 (NCT01505699) study.
•The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decade.
•The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.

2.Following on the results of earlier studies, the International ALL Trial (ECOG-2993) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively; patients were accrued from 1993 to 2006. Patients with Ph1-negative ALL between the ages of 15 years and 59 years received identical multiagent induction therapy resembling previously published regimens. Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation therapy. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS); event-free survival, relapse rate, and nonrelapse mortality were secondary outcomes. A total of 1,929 patients were registered and stratified according to age, white blood cell (WBC) count, and time to remission. High-risk patients were defined as those having a high WBC count at presentation or those older than 35 years.
a.Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 had an HLA-identical sibling, 310 of whom underwent an alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT.
b. By donor-to-no-donor analysis, standard-risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01).
c.In a subgroup analysis, the advantage for patients with standard-risk ALL who had donors remained significant (OS = 62% vs. 52%; P = .02).
•For patients with high-risk disease (older than 35 y or high WBC count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2).
•Relapse rates were significantly lower (P < .00005) for both standard- and high-risk patients with HLA-matched donors.
d.In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-y OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03).
e.The results of this trial suggest the existence of a graft-versus-leukemia effect for adult Ph1-negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long-term survival for patients with standard-risk adult ALL in first remission.[Level of evidence: 2A]
f.The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[Level of evidence: 2A]

The use of matched unrelated donors for alloBMT is currently under evaluation but, because of its current high treatment-related morbidity and mortality, it is reserved for patients in second remission or beyond. The dose of total-body radiation therapy administered is associated with the incidence of acute and chronic GVHD and may be an independent predictor of leukemia-free survival.[Level of evidence: 3iiB]

Evidence (B-cell ALL):
Aggressive cyclophosphamide-based regimens similar to those used in aggressive non-Hodgkin lymphoma have shown improved outcome of prolonged DFS for patients with B-cell ALL (L3 morphology, surface immunoglobulin positive).

1.Retrospectively reviewing three sequential cooperative group trials from Germany, one group of investigators found the following:[19] •A marked improvement in survival, from zero survivors in a 1981 study that used standard pediatric therapy and lasted 2.5 years, to a 50% survival rate in two subsequent trials that used rapidly alternating lymphoma-like chemotherapy and were completed within 6 months.

2. CNS prophylaxis therapy

The early institution of CNS prophylaxis is critical to achieve control of sanctuary disease. Some authors have suggested that there is a subgroup of patients at low risk for CNS relapse for whom CNS prophylaxis may not be necessary. However, this concept has not been tested prospectively.

Aggressive CNS prophylaxis remains a prominent component of treatment. This report, which requires confirmation in other cooperative group settings, is encouraging for patients with L3 ALL. Patients with surface immunoglobulin and L1 or L2 morphology did not benefit from this regimen. Similarly, patients with L3 morphology and immunophenotype, but unusual cytogenetic features, were not cured with this approach. A WBC count of less than 50,000 per microliter predicted improved leukemia-free survival in a univariate analysis.

Standard Treatment Options for Recurrent Adult ALL
1.Reinduction chemotherapy and/or blinatumomab followed by allogeneic bone marrow transplantation (alloBMT).
2.Palliative radiation therapy (for patients with symptomatic recurrence).
3.Dasatinib (for patients with Philadelphia chromosome [Ph1]-positive ALL).

SUMMARY:
1.Reinduction chemotherapy and/or blinatumomab followed by allogeneic bone marrow transplantation (alloBMT).
Blinatumomab should be considered as an option for reinduction therapy for patients with primary refractory disease, which is refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.
2.Palliative radiation therapy (for patients with symptomatic recurrence).
3.Dasatinib (for patients with Philadelphia chromosome [Ph1]-positive ALL).

1. Reinduction chemotherapy

Patients with ALL who experience a relapse following chemotherapy and maintenance therapy are unlikely to be cured by further chemotherapy alone. These patients should be considered for reinduction chemotherapy followed by alloBMT.

■ Blinatumomab
Evidence (blinatumomab):
1.A randomized phase III study of blinatumomab versus one of four standard reinduction regimens was conducted in patients with primary refractory disease, which was refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation. The four regimens included the following:
fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline;
a high-dose cytosine arabinoside–based regimen;
a high-dose methotrexate-based regimen; or
a clofarabine-based regimen.
• Remission rates were 43.9% for the blinatumomab-treated group versus 24.6% in the standard-treatment group (odds ratio, 2.40; 95% confidence interval [CI], 1.51–3.80).
• Overall survival was superior in the blinatumomab-treated group (7.7 mo vs. 4.0 mo in the standard-treatment group) with a hazard ratio of .71 (95% CI, 0.55–0.93), favoring blinatumomab.
• Adverse events occurred at similar rates in both groups, and the only unique side effect of blinatumomab was cytokine-release syndrome, which was seen in 4.9% of patients.

Blinatumomab should be considered as an option for reinduction therapy for patients with primary refractory disease, which is refractory to salvage, with a first relapse lasting fewer than 12 months, a second or greater relapse, or any relapse after allogeneic transplantation.[Level of evidence: 1iiA]

2. Palliative radiation therapy

Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.

3. Dasatinib

Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR-ABL mutations, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leukemia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL.

Evidence (Dasatinib):
1. In one study, ten patients were treated with dose-escalated dasatinib. Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood cell counts), three of whom had a complete cytogenetic response.
• The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%).
• Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.

Treatment Options Under Clinical Evaluation for Recurrent Adult ALL
Patients for whom an HLA-matched donor is not available are excellent candidates for enrollment in clinical trials that are studying the following:
1. Autologous transplantation.
2. Immunomodulation.
3. Chimeric antigen receptor (CAR) T-cell therapy.
4. Novel chemotherapeutic or biological agents.