Dataset Information

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data.

ABSTRACT:

Introduction

Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years.

Methods

The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset. Conditional survival probabilities of blinatumomab-treated patients beyond month 60 were assumed to be the same as the US general population.

Results

At month 60, the estimated proportion of blinatumomab-treated patients alive was more than double that of historical patients (12.6% vs 5.4%). The mean overall survival was 76.1 months for blinatumomab patients and 39.8 months for historical patients. Sensitivity analyses including additional follow-up data from the clinical study showed consistent results.

Conclusions

These findings suggest that blinatumomab provides substantial overall survival benefit to patients with (R/R) Ph(-) B-precursor ALL compared with salvage chemotherapy.

Funding

Amgen.

Trial registration

ClinicalTrials.gov identifier NCT01466179 and NCT02003612.

SUBMITTER: Barlev A

PROVIDER: S-EPMC5216100 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBlinatumomab is a CD19 BiTE (bispecific T-cell engager) immuno-oncology therapy that mediates the lysis of cells expressing CD19.MethodsA pooled analysis of long-term follow-up data from 2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia was conducted.ResultsA total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval [CI], 5.5-8.5 months); the median follow-up time for OS was 36.0 months (range, 0.3-60.8 months). The median relapse-free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2-10.0 months); the median follow-up time for RFS was 35.0 months (range, 9.5-59.5 months). OS and RFS plateaued with 3-year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3-year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3-30.0 months) with a 3-year survival rate of 37.2%.ConclusionsThese data suggest that long-term survival is possible after blinatumomab therapy.Lay summaryImmuno-oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells. This study combined follow-up data from 2 blinatumomab-related clinical trials to evaluate long-term survival in patients with relapsed and/or refractory B-cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes. Among patients who achieved a deep response with blinatumomab, one-third lived 3 years or longer. These findings suggest that long-term survival is possible after treatment with blinatumomab.

Project description:On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7-month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative.