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 initialtreatment of children, adolescents, and young adults with B-ALL is a marker ofpoor prognosis. While allogeneic hematopoietic stem cell transplantation (HSCT) is typicallyconsidered the treatment of choice for these patients, barriers to itsimplementation can include concerns related to adverse events associated withreinduction and subsequent consolidation chemotherapy, and the presence ofminimal residual disease (MRD) following administration of second-remission reinductiontherapy. Those patients who experienceearly bone marrow relapse, and those with MRD greater than 0.1% in the settingof a prolonged CR, at the end of reinduction therapy are considered to have high-riskand intermediate-risk disease, respectively.

Blinatumomab is an artificial, bispecific monoclonal antibody-basedconstruct created from the fusion of single-chain variable fragments from 2different antibodies. In the case of blinatumomab, targets include the CD3receptor on T cells and CD19 on B cells, resulting in the formation of a link betweenthese 2 cell types.

Currently, blinatumomab is approved by the US Food and DrugAdministration (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 asfor patients with relapsed/refractory B-ALL.2

In this phase 3 Childrens 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-freesurvival (DFS), with secondary study end points including MRDresponse, overall survival (OS), and ability to proceed to HSCT.

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

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

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

Regarding resultsrelated to MRD response, all of the benefit of blinatumomab with respect to MRDclearance appeared to occur in the first cycle, commented PatrickA. Brown of the Sidney Kimmel ComprehensiveCancer Center, Johns Hopkins University, Baltimore, Maryland, who was thepresenting study author.

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

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

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

For patientsreceiving blinatumomab, low-grade cytokine release syndrome (CRS), occurring in22% of patients, was generally limited to the to the first cycle. Seizuresoccurred in 4% and 0% of patients during cycles 1 and 2, respectively, and the incidenceof mostly low-grade encephalopathy was 14% in cycle 1 and 11% in cycle 2.

Accordingto the results of this scheduled interim analysis, the prespecified monitoring thresholdto the primary end point of DFS was not crossed. However, based on the overallresults of the study, the data monitoring committee recommended permanentclosure of study randomization for patients with high- or intermediate-riskdisease, with those in these risk groups immediately crossed over to theblinatumomab arm.

We believe that blinatumomab constitutes anew standard of care in this setting, concluded Dr Brown.

Disclosure:Some of the authors disclosed financial relationships with the pharmaceuticalindustry. For a full list of disclosures, please refer to the originalabstract.

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References

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Blinatumomab May Become New Standard of Care for Post-Reinduction Therapy in Young Patients With B-ALL - Cancer Therapy Advisor