Blinatumomab Leads to High Remission Rate in Infants With Persistent MRD-Positive ALL

Treatment with the bispecific CD19/CD3 antibody blinatumomab induced molecular remissions in most infants with persistent measurable residual disease (MRD)–positive acute lymphocytic leukemia (ALL), according to results from a small study published in Blood. Corresponding study author Ajay Vora, MD, from the Great Ormond Street Hospital in London, and colleagues believe these findings suggest that wider application of blinatumomab can improve cure rates and reduce toxicity for many infants with ALL.

“The current standard of care for infant ALL is intensive chemotherapy, including bone marrow transplant for a third of patients,” Dr. Vora told ASH Clinical News, “yet this treatment approach is associated with considerable toxicity that results in a 10% treatment-related mortality rate and significant morbidity due to nonfatal acute and late side effects.” The latter effects, he added, are particularly severe in infants who receive a hematopoietic cell transplant (HCT), prompting investigators to search for an alternative effective approach associated with less toxicity.

This retrospective study included 11 infants from the U.K. who received a diagnosis of B-cell ALL before their first birthday and were initially treated with the Interfant-06 protocol. Only patients who had not undergone a prior HCT were included in the analysis. Treatment with blinatumomab was initiated to reduce MRD prior to HCT.

At the time of blinatumomab administration, the median age of this patient population was 0.5 years (range = 0.2-2.9 years). The study also included 1 patient who experienced a late relapse of KMT2A-rearranged ALL at 2.9 years of age.

Nine patients were treated with a single 28-day blinatumomab treatment cycle, while 2 received an additional cycle, pending transplant.

After blinatumomab treatment, 9 of the 11 patients achieved MRD-negativity and the remaining 2 had a >1-log reduction in MRD prior to HCT. The authors noted that “there were no obvious differences in the presenting features or previous treatment/responses of the 2 patients [who] didn’t achieve [complete] MRD negativity.”

“A 12-month EFS of 50% [with blinatumomab] compares favorably with historical outcomes in chemotherapy-treated patients.”

—Ajay Vora, MD

Each patient then proceeded to HCT without requiring intervening treatment after blinatumomab, with a median time from starting blinatumomab to HCT of 51 days (range = 34-119 days).

In terms of safety, grade 1-2 cytokine release syndrome (CRS) was observed in 3 patients; 1 case resolved after a temporary interruption of blinatumomab with a short course of steroids and 2 cases resolved spontaneously without steroids or tocilizumab. The patient who had an interruption of blinatumomab was able to restart the therapy at a lower dose following the short steroid course, the investigators noted. One participant who had grade 2 CRS also experienced treatment-associated neurotoxicity, which manifested as confusion and somnolence, and resolved after treatment interruption. This patient was able to resume blinatumomab at a lower dose.

After the first week of blinatumomab treatment, 8 patients were discharged from the hospital and received the remaining infusion dose as outpatients. According to the study authors, this finding suggests that the treatment protocol may be associated with improved health-related quality of life, particularly in comparison with standard chemotherapy, which requires routine visits to the hospital.

During a median post-HCT follow-up of 267 days (range = 58-1,163 days), the rate of 3-year event-free survival (EFS; primary endpoint) from the time of HCT was 47% and the 3-year overall survival (OS) rate was 81%. When measured from the point of blinatumomab administration, the 3-year EFS and OS rates were 51% and 79%, respectively.

Parainfluenza pneumonitis was the cause of death in 1 patient on day 57 after transplant. Four patients experienced relapse at 35 days, 92 days, 108 days, and 133 days after transplant; 1 patient who relapsed was MRD-positive (0.05%) prior to undergoing HCT.

In addition, 3 patients experienced CD19-positive relapse, but these patients achieved remission with subsequent CD19-directed chimeric antigen receptor T-cell therapy. Another patient, who demonstrated expression of myeloid antigen CD15 at both presentation and relapse, also experienced disease relapse 35 days after transplant with lineage-switch monoblastic acute myeloid leukemia; this patient later died of progressive leukemia.

“The numbers in our series are too small to make definitive conclusions on the long-term outcome, but a 12-month EFS of 50% compares favorably with historical outcomes in chemotherapy-treated patients,” the authors concluded. Additional limitations of this study include its retrospective design and the lack of generalizability across different age groups.

Dr. Vora added that the next international infant ALL trial from the Interfant consortium and Children’s Oncology Group will expand on the present study’s findings. This study will evaluate blinatumomab as a replacement for intensive chemotherapy in the firstline treatment of infant ALL for the purposes of reducing toxicity and improving cure rates in this vulnerable population.

The authors report no relevant conflicts of interest.

Reference

Clesham K, Rao VN, Bartram J, et al. Blinatumomab for infant acute lymphoblastic leukaemia. Blood. 2020 February 10. [Epub ahead of print]