Pretransplant Bridging With Blinatumomab Reduces MRD in Children With B-Cell Acute Lymphocytic Leukemia

In a study of children with B-cell acute lymphocytic leukemia (B-ALL) who are about to undergo allogeneic hematopoietic cell transplantation (alloHCT), bridging with blinatumomab was associated with reductions in measurable residual disease (MRD) and improvements in survival outcomes. The findings, which were published in Blood Advances, suggest that the agent also was associated with few side effects and helped patients proceed to transplant quickly.

“Transplant physicians all hope to bring patients to transplant in the deepest remission possible with no evidence of MRD,” lead author Amy K. Keating, MD, of the University of Colorado School of Medicine and Children’s Hospital Colorado, told ASH Clinical News. “This study retrospectively demonstrated that children who still had a small disease burden immediately prior to transplant could be treated quickly and effectively with blinatumomab without delaying transplant or causing toxicity that would prevent transplant later.”

The retrospective study analyzed de-identified data from patients with B-ALL between the ages of 0 and 21 years who previously underwent an alloHCT at a pediatric center. While all patients were referred to the center in complete morphological remission (CR), defined as <5% blasts in the bone marrow, those included in the analysis had persistent MRD at enrollment.

Between 2016 and 2017, patients were treated with blinatumomab to either reduce or eliminate MRD before alloHCT. The researchers assessed overall survival (OS), leukemia-free survival (LFS), time to relapse, and transplant-related mortality.

A total of 15 pediatric patients (median age = 9 years; range = 0.5-19 years) with B-ALL were included. Most patients (n=12) received a single 28-day blinatumomab treatment course at 15 µg/m2 per day before alloHCT. Two patients had their initial cycle of blinatumomab shortened to start their alloHCT preparative regimen and one patient received two blinatumomab courses for a total of 66 days.

“Pretransplant use of blinatumomab had minimal impact on the patients’ peripheral blood counts,” the authors reported. There was a mild reduction in the absolute neutrophil count (ANC) from the start of therapy to the end of therapy (3.39×109/L to 2.21×109/L, respectively). Conversely, there was an increase in absolute lymphocyte count (ALC) from start of therapy to end of therapy (0.866×109/L to 1.115×109/L).

The researchers noted that blinatumomab bridging therapy was associated with few adverse events. While one patient with central nervous system leukemia did experience a grade 3 seizure, there were no other grade 3 or 4 toxicities or instances of cytokine release syndrome.

A total of 14 patients achieved MRD negativity following bridging therapy and subsequently proceeded to alloHCT, with a median time from end of therapy to start of preparative approach of 14 days (range = 1-35 days).

At a median of 355 days following alloHCT (range not reported), four patients had a relapse of CD19-positive ALL, representing a cumulative relapse incidence of 27.8% at one year after alloHCT. The authors noted, however, that all of these patients achieved subsequent remission with CD19-directed therapy and continue to have a sustained CR.

“Children who still had a small disease burden immediately prior to transplant could be treated quickly and effectively with blinatumomab.”

—Amy K. Keating, MD

Bridging with blinatumomab also resulted in 93.3% of patients alive at one year following alloHCT and no transplant-related mortality in the first 100 days. Furthermore, MRD was reduced to undetectable levels in 93% of patients without serious infection or organ toxicity.

“We were surprised to discover that blinatumomab could reduce even very small disease burdens so effectively and that patients who [had greater immune suppression] with very low lymphocyte counts still had effective responses to treatment,” Dr. Keating said.

However, limitations of the study include its retrospective nature, the small sample size, the recruitment of only pediatric patients and young adults, lack of a comparator group, and the relatively short post-alloHCT follow-up duration of 371 days.

“The most interesting next question in this setting will be determining which – out of our many choices for immune therapy – is the quickest and most efficacious therapy,” Dr. Keating explained. “Also, I think it will be interesting to see if deeper-level MRD testing (such as polymerase chain reaction tests or next-generation sequencing) affects our decision-making heading into transplant and, if so, whether blinatumomab can be used effectively in these patients as well.”

The authors reported no conflicts of interest.

References

  1. Keating AK, Gossai N, Phillips CL, et al. Reducing minimal residual disease with blinatumomab prior to HCT for pediatric patients with acute lymphoblastic leukemia. Blood Adv. 2019;3:1926-9.

“The authors of this study present favorable data on safety, efficacy, and survival outcomes, which support use of blinatumomab in this setting. Blinatumomab was not associated with significant myelosuppression or cytokine release syndrome, and only a single case of seizure in a patient with other risk factors [for seizure].

Blinatumomab has a great advantage over conventional intensive bridging chemotherapy in avoiding significant myelosuppression and the consequent risk of infectious toxicities, which may delay or prevent patients from proceeding to hematopoietic cell transplantation (HCT). Moreover, the blinatumomab-specific toxicities of cytokine release syndrome and neurotoxicity did not pose significant risks.

Data from large, prospective studies will be needed to provide answers to some of the key remaining questions faced by clinicians, such as: Is blinatumomab superior to chemotherapy and/or other molecular immunotherapies as a bridge to HCT? Are there biomarkers to predict blinatumomab non-responders, and do checkpoint inhibitors enhance response? Nevertheless, in this era of multiple emerging immunotherapy options, this study provides encouraging results supporting the use of blinatumomab in an important clinical setting for which data are lacking.”

Karen Rabin, MD, PhD
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX

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