Blinatumomab Conundrum in Low-Risk Relapsed B-Cell ALL

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.BACKGROUNDThe Children's Oncology Group (COG) AALL1331 trial demonstrated improved survival and less toxicity in children with high-/intermediate-risk relapsed ALL receiving blinatumomab compared with intensive chemotherapy before hematopoietic stem-cell transplant (HSCT). The low-risk arm of AALL1331 compared addition of three cycles of blinatumomab to chemotherapy alone, but a survival improvement was not noted. Secondary analyses showed improvement in disease-free survival (DFS) and overall survival (OS) of low-risk patients with bone marrow disease +/- extramedullary (EM) involvement (4-year DFS 72.7% +/- 5.8% v 53.7% +/- 6.7%; 4-year OS 97.1% +/- 2.1% v 84.8% +/- 4.8%), but failed to show an advantage with blinatumomab for patients with isolated EM relapse. Of note, DFS of isolated CNS (iCNS) relapse was worse than previous studies at 24% on both arms, likely because of decreases in CNS-intensive therapy compared with previous approaches and inadequacy of blinatumomab for controlling CNS disease.CASEOur case of late isolated CNS B-cell ALL relapse outlines challenges for clinicians attempting to decrease toxicity and avoid HSCT: (1) defining of low risk appropriately, (2) attempting to reduce the treatment burden of past protocols, and (3) understanding approach and timing of cranial irradiation.APPROACHAlthough AALL1331 therapy without blinatumomab leads to excellent survival in patients with isolated testicular relapse, we recommend a modified AALL02P2 backbone of chemotherapy with 1,800 cGy cranial radiotherapy for patients with late iCNS relapse. Future studies integrating chimeric antigen receptor T cells, which have better CNS penetration, may help decrease the intensive treatment burden for patients with late iCNS recurrence.