Treatment of Bone Marrow Relapse
Initial treatment of relapse consists of induction therapy to achieve a CR2. 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 CR2 at the end of the first month of treatment.;[Level of evidence: 2A]; [Level of evidence: 2Di] A United Kingdom-based randomized trial of patients with relapsed ALL compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse was reported.[Level of evidence: 1iiA] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) compared with those with late marrow relapses (approximately 95%).[17,22] Compared with patients with B-precursor phenotype, patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens. Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%. The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.
Other combinations of agents have been reported to induce remissions in patients with multiple-relapsed or refractory ALL. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 56% of patients with refractory or relapsed disease.
Postreinduction therapy (second complete remission)
Post-CR2 therapy for patients who experience a bone marrow relapse (either isolated or combined) while on therapy or within 6 months of discontinuing therapy generally includes hematopoietic stem cell transplantation (HSCT).[27,28] For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in longer leukemia-free survival when compared with a chemotherapy approach.[7,21,29,30,31,32,33,34,35] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%.
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[9,36,37] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no SCT) in CR2. In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in CR2, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were MRD-negative. Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires further study.