Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) are high, with more than 85% of patients surviving without experiencing a relapse; however, even with effective contemporary therapies, a subset of patients will still relapse and survival among this subset of patients is poor.

Of the 1961 children who participated in the Children’s Cancer Group ALL trials spanning from 1988 to 2002 and relapsed, the 5-year overall survival (OS) rate was only 36%. Other large studies have shown similar results: in the Berlin-Frankfurt-Münster (BFM) ALL-REZ-BFM 90 trial the 10-year OS was 36%. More recent data show some improvement, with 5-year OS rates of approximately 50% for first relapse of ALL.

Risk factors for outcomes following first relapse have been described and are now used in developing risk stratification algorithms. These include the time from diagnosis to relapse (shorter associated with poorer survival), site of relapse (marrow worse than extramedullary), immunophenotype (T worse than B), and minimal residual disease (MRD) response to subsequent treatment. While survival has historically been poor after a second or later relapse, or a relapse following hematopoietic stem cell transplantation (HSCT), the introduction of newer immunotherapies, such as chimeric antigen receptor redirected (CAR) T cells could change this paradigm.

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However, the optimal therapeutic regimen following relapse, including the use of immunotherapy, remains undefined. Critical questions that clinicians need to address include which chemotherapy strategy should be used for relapsed cases, when HSCT should be administered in the second complete remission (CR2), and what role immunotherapies, including blinatumomab, inotuzumab ozogamicin, and CAR T cells, should play.

In a review paper published in Blood, Stephen Hunger MD, from the Perelman School of Medicine at The University of Pennsylvania in Philadelphia, and Elizabeth Raetz MD, from New York University Langone Medical Center in New York City, described the approach they use to address these challenges, which is informed by their experience with Children’s Oncology Group (COG) trials. They presented several case scenarios that highlighted treatment decision-making in the era of immunotherapy.

“I think this is a fast moving area,” said Dr Hunger in an interview. “CAR-T cell therapy is very active in multiple relapsed [diseases] and there is a high rate of getting patients back into remission.”

“[What] we don’t know is how this fits into our armamentarium of therapies and when cell therapies should be used as a so-called bridge to transplant, and when [they] should be used as a definitive therapy.”

“There is clearly not established proof and some people have preferences, but we don’t know [what] the best approach is,” Dr Hunger said.