Reinduction chemotherapy

Initial treatment of relapse consists of reinduction therapy to achieve a second CR. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a second CR at the end of the first month of treatment.[5]; [24,41][Level of evidence B4] Patients with early marrow relapses have a lower rate of achieving a morphological second CR (approximately 70%) than do those with late marrow relapses (approximately 95%).[24,41]

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Evidence (reinduction chemotherapy):

A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination that included doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.[24]

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24

A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination that included doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.[24]

Second remission was achieved after block 1 in 68% of patients with early relapse (<36 months from initial diagnosis) and in 96% of those with later relapse.

A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination that included doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.[24]

Blocks 2 and 3 reduced MRD in 40 of 56 patients who were MRD positive after block 1.

A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[42][Level of evidence A1] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.

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A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[42][Level of evidence A1] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.

There was no difference in second CR rates or end-reinduction MRD levels between the two study arms.

A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[42][Level of evidence A1] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.

A significant improvement in the OS rate in the mitoxantrone arm was reported (69% vs. 45%; P = .007), which resulted from decreased relapse after transplant.

Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, which included high-dose methotrexate.[43]

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Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, which included high-dose methotrexate.[43]

A randomized comparison of 1 g/m2 of methotrexate delivered over 36 hours versus 5 g/m2 of methotrexate delivered over 24 hours with reinduction showed no difference in outcome, but the 36-hour infusion was associated with a higher incidence of mucositis.

The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 42% to 56% of patients with refractory or multiply relapsed disease.[44,45]; [46][Level of evidence B4]

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The combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response (with or without platelet recovery) in 70% to 80% of multiply relapsed patients with B-ALL.[47][Level of evidence C1]; [48][Level of evidence C3]

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The combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response (with or without platelet recovery) in 70% to 80% of multiply relapsed patients with B-ALL.[47][Level of evidence C1]; [48][Level of evidence C3]

This combination (using prednisone instead of dexamethasone) was tested in B-ALL patients with first relapse occurring less than 36 months from initial diagnosis.[49]

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49

The combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response (with or without platelet recovery) in 70% to 80% of multiply relapsed patients with B-ALL.[47][Level of evidence C1]; [48][Level of evidence C3] › This combination (using prednisone instead of dexamethasone) was tested in B-ALL patients with first relapse occurring less than 36 months from initial diagnosis.[49]

The second CR rate was 68%, which was not significantly different from that observed on a predecessor trial using the same reinduction platform without bortezomib.

The combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response (with or without platelet recovery) in 70% to 80% of multiply relapsed patients with B-ALL.[47][Level of evidence C1]; [48][Level of evidence C3] › This combination (using prednisone instead of dexamethasone) was tested in B-ALL patients with first relapse occurring less than 36 months from initial diagnosis.[49]

In subset analyses, the addition of bortezomib to the four-drug reinduction platform did not result in significantly better second CR rates for patients with either very early relapses (<18 months from diagnosis) or early relapses (18–36 months from diagnosis) when compared with historical controls.

Patients with relapsed T-ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with B-cell phenotype.[24] Treatment of children with first relapse of T-ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%.[50] In a trial of 28 pediatric patients with relapsed or refractory T-ALL who were treated with single-agent nelarabine, the overall response rate (CR and CR without hematological recovery) was 39.3%.[51] The combination of nelarabine, cyclophosphamide, and etoposide has also been used in patients with relapsed or refractory T-ALL, with response rates comparable to single-agent nelarabine.[52]; [53][Level of evidence C3] In a phase I/II trial of this combination in patients with relapsed or refractory T-ALL and T-lymphoblastic lymphoma, the overall best response rate (CR + CR with incomplete platelet recovery + partial response) was 38% (8 of 21 patients). The T-ALL cohort had a response rate of 33% (4 of 12 patients), and the T-lymphoblastic lymphoma cohort had a response rate of 44% (4 of 9 patients).[53][Level of evidence C3]

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The proteosome inhibitor bortezomib (in combination with chemotherapy) has also been evaluated in patients with relapsed T-ALL. In a phase II trial conducted by the COG, the combination of bortezomib plus vincristine, prednisone, pegaspargase, and doxorubicin resulted in a second CR rate of 68% in T-ALL patients in first relapse.[49]

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In the phase II open-label DELPHINUS (NCT03384654) study, daratumumab was added to induction backbone chemotherapy to treat patients with relapsed or refractory T-ALL. Daratumumab is a human IgGk monoclonal antibody that targets CD38, which is highly expressed on T-ALL blasts. Chemotherapy consisted of four-drug induction therapy. At the end of induction, the CR rates were 41.7% for children and 60.0% for young adults. The overall response rates (at any time point) were 83.3% for children and 80.0% for young adults. Patients who achieved a CR proceeded to HSCT. The 24-month EFS rates for children and young adults were 36.1% and 20.0%, respectively. The overall survival rates were 41.3% and 25.0%, respectively. The addition of daratumumab was shown to be tolerable.[54]

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Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT, especially if MRD becomes low or nondetectable. For more information about MRD risk stratification, see the Late-relapsing B-ALL section. Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment. These regimens often contain newer agents under investigation in clinical trials. Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.[55] Because studies of chimeric antigen receptor (CAR) T cells, blinatumomab, and inotuzumab have been shown to lead to high rates of remission in multiply relapsed and chemotherapy-refractory B-ALL patients, trials testing these agents after initial relapse are underway. For more information, see the Immunotherapeutic Approaches for Relapsed or Refractory ALL section.

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Reinduction chemotherapy

Studies cited in this source section

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