Treatment Options for Second and Subsequent Bone Marrow Relapse

Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant has generally been considered a reasonable approach for those achieving remission. Long-term survival for ALL patients after a second relapse is particularly poor, in the range of less than 10% to 20%.[62] One of the main reasons for this is failure to obtain a third remission. Numerous attempts at novel combination approaches have resulted in only about 40% of children in second relapse achieving remission.[75] However, two studies that added bortezomib to standard reinduction agents in multiply relapsed or refractory patients have resulted in 70% to 80% CR rates.[47][Level of evidence C1]; [48][Level of evidence C3] Clofarabine as a single agent has also been used in patients with multiply relapsed and refractory leukemia. In an analysis of 12 clinical studies of clofarabine in pediatric patients with relapsed or refractory ALL, the overall remission rate (CR plus CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery) was 28%.[76]

A phase I trial tested the combination of venetoclax (BCL2 inhibitor) and navitoclax (BCL2 and BCL-XL inhibitor) given along with standard chemotherapy (vincristine, dexamethasone, with/without pegaspargase) in adult and pediatric patients with multiply relapsed or refractory B-ALL or T-ALL. The combination was well tolerated in general (the major toxicity was prolonged myelosuppression) and CR was achieved in 60% of patients, 57% of whom had nondetectable MRD.[77]

For multiply relapsed patients who achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring because of high rates of relapse and transplant-related mortality.[78-82][Level of evidence C1]

Given the poor outcomes for multiply relapsed B-ALL patients who are treated with chemotherapy followed by HSCT, CAR T-cell therapy has come to be used as standard in this population and has resulted in high rates of remission and improved survival (although direct comparative trials are lacking). For more information, see the CAR T-cell therapy section.

Immune therapies such as blinatumomab and inotuzumab have been used in this population and have improved rates of remission, which has then often led to cure when followed by HSCT.[83-87] Comparative studies of immune and cell therapy approaches have yet to be performed in this population, so data to inform optimal approaches to first therapy or sequence of therapies are lacking.