The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

According to an analysis of interim results from a randomized study of young patients with high- or intermediate risk B-cell precursor acute lymphoblastic leukemia (B-ALL) at first relapse, the overall efficacy and safety of post-reinduction therapy with the bispecific T-cell engager (BiTE) blinatumomab outperformed conventional chemotherapy. The findings from this study were presented at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition held in Orlando, Florida.

Disease relapse, particularly early relapse, following initial treatment of children, adolescents, and young adults with B-ALL is a marker of poor prognosis. While allogeneic hematopoietic stem cell transplantation (HSCT) is typically considered the treatment of choice for these patients, barriers to its implementation can include concerns related to adverse events associated with reinduction and subsequent consolidation chemotherapy, and the presence of minimal residual disease (MRD) following administration of second-remission reinduction therapy. Those patients who experience early bone marrow relapse, and those with MRD greater than 0.1% in the setting of a prolonged CR, at the end of reinduction therapy are considered to have high-risk and intermediate-risk disease, respectively.

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Blinatumomab is an artificial, bispecific monoclonal antibody-based construct created from the fusion of single-chain variable fragments from 2 different antibodies. In the case of blinatumomab, targets include the CD3 receptor on T cells and CD19 on B cells, resulting in the formation of a link between these 2 cell types.

Currently, blinatumomab is approved by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with B-ALL in first or second CR, with minimal residual disease (MRD) greater than or equal to 0.1%, as well as for patients with relapsed/refractory B-ALL.2


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In this phase 3 Children’s Oncology Group study (AALL1331; ClinicalTrials.gov Identifier: NCT02101853), patients with B-ALL in first relapse between the ages of 1 and 30 years with bone marrow blasts less than 25% and/or failure to clear extramedullary disease following reinduction chemotherapy (UKALLR3 regimen3) were randomly assigned in a 1:1 ratio following risk assessment to receive either 2 blocks of intensive consolidation chemotherapy according to the UKALLR3 regimen3 or two 4-week cycles of otumumab separated by a 1-week break. Allogeneic HSCT was scheduled following these treatments.

The primary end point of the trial was intent-to-treat disease-free survival (DFS), with secondary study end points including MRD response, overall survival (OS), and ability to proceed to HSCT.

A planned interim analysis of 208 patients, performed following the occurrence of approximately 60% of expected events, included only those with high- (67%) or intermediate-risk (33%) disease. Patient ages ranged from 1 to 27 years, with a median age of 9 years.

At a median follow-up of 1.4 years, some of the key efficacy findings from this analysis included rates of 2-year DFS in the intention-to-treat (ITT) population of 41.0% for patients receiving chemotherapy and 59.3% for those treated with blinatumomab (P =.050). Rates of 2-year OS for patients in these 2 study arms were 79.4% (blinatumomab) and 59.2% (chemotherapy), (P =.005).

The percentages of those achieving undetectable MRD after reinduction chemotherapy were only 22% and 18% in the chemotherapy and blinatumomab arms, respectively. Following block 2 of chemotherapy (ie, first cycle of consolidation chemotherapy) or cycle 1 of blinatumomab, rates of undetectable MRD increased to 29% in the chemotherapy arm and 76% in the blinatumomab arm (P <.0001).

Regarding results related to MRD response, all of the benefit of blinatumomab with respect to MRD clearance appeared to occur in the first cycle, commented Patrick A. Brown of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, who was the presenting study author.

Furthermore, 45% of patients in the chemotherapy arm compared with 73% of those in the blinatumomab arm were able to proceed to HSCT (P <.0001).

Regarding patient safety, 4 and 0 patients receiving blinatumomab or chemotherapy, respectively, experienced a postinduction, induction-related toxic death.

In addition, the frequencies of specific adverse events were considerably higher in the chemotherapy vs the blinatumomab arm. For example, rates of grade 3 or higher febrile neutropenia were 44% and 46% for patients receiving the 2nd and 3rd blocks of the UKALLR3 regimen, respectively, but only 4% and 0% of patients receiving cycle 1 and cycle 2 of blinatumomab, respectively (P <.001). Similar differences between the 2 study arms were observed with respect to the rates of infections and sepsis.

For patients receiving blinatumomab, low-grade cytokine release syndrome (CRS), occurring in 22% of patients, was generally limited to the to the first cycle. Seizures occurred in 4% and 0% of patients during cycles 1 and 2, respectively, and the incidence of mostly low-grade encephalopathy was 14% in cycle 1 and 11% in cycle 2.

According to the results of this scheduled interim analysis, the prespecified monitoring threshold to the primary end point of DFS was not crossed. However, based on the overall results of the study, the data monitoring committee recommended permanent closure of study randomization for patients with high- or intermediate-risk disease, with those in these risk groups immediately crossed over to the blinatumomab arm.

“We believe that blinatumomab constitutes a new standard of care in this setting,” concluded Dr Brown.

Disclosure: Some of the authors disclosed financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.

References

  1. Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: A report from Children’s Oncology Group Study AALL1331. Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract LBA-1.
  2. Blinatumomab (Blincyto®) [package insert]. Thousand Oaks, CA: Amgen, Inc.; 2019.
  3. Parker, C., Waters, R., Leighton, C., Hancock, J., Sutton, R., Moorman, A. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009–2017.