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Blinatumomab extends OS for patients with relapsed, refractory ALL
Adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia had longer OS after treatment with blinatumomab than with chemotherapy, according to results of a prospective clinical trial.
“We can hopefully use these new agents in frontline therapy to increase the cure rate in adult ALL, and reduce the need, duration and complications of the chemotherapy, which is today needed for 3 years,” Hagop M. Kantarjian, MD, professor and chair of the department of leukemia at The University of Texas MD Anderson Cancer Center, told HemOnc Today.
Kantarjian and colleagues conducted a multi-institutional trial to determine efficacy and safety of treatment with blinatumomab (Blincyto, Amgen) — a bispecific T-cell engager antibody construct designed to direct cytotoxic T cells to CD19–expressing B cells — among patients with Philadelphia chromosome (Ph)–negative B-cell precursor ALL. Patients were refractory to primary induction therapy or intensive combination chemotherapy, were in first relapse with the first remission lasting less than 1 year, were in a second or greater relapse, or were in relapse any time after allogeneic stem cell transplantation.
Patients were randomly assigned 2:1 to receive either blinatumomab (n = 271) or chemotherapy (n = 134). Of 405 patients assigned, 376 received at least one dose of either drug.
Median follow-up was 11.7 months in the blinatumomab arm and 11.8 months in the chemotherapy arm.
Median OS was longer among patients treated with blinatumomab compared with patients treated with chemotherapy (7.7 months vs. 4 months; HR = 0.71; 95% CI, 0.55-0.93).
A greater proportion of patients treated with blinatumomab achieved complete remission with full hematologic recovery rates within 12 weeks of the start of treatment (34% vs. 16%; P < .001), and complete remission with full, partial or incomplete hematologic recovery (44% vs. 25%; P < .001).
The median duration of remission with full, partial or incomplete hematologic recovery was 7.3 (95% CI, 5.8-9.9) months in patients treated with blinatumomab compared with 4.6 months (95% CI, 1.8-19) in patients treated with chemotherapy.
Further, more patients assigned blinatumomab achieved 6-month EFS (31% vs. 12%). The HR for a relapse after achieving a complete remission with full, partial or incomplete hematologic recovery, or death was 0.55 (95% CI, 0.43-0.71).
A majority of patients in each treatment group reported adverse events (99% for both); the rates of serious adverse events were 62% in the blinatumomab group and 45% in the chemotherapy group.
Fatal adverse events — which included sepsis, septic shock, multiorgan failure, respiratory failure and bacteremia — occurred in 19% of patients in the blinatumomab group and 17% of the chemotherapy group. Treatment-related fatal events occurred in 3% of the blinatumomab group (n = 8) and 7% in the chemotherapy group (n = 8).
This trial showed similar results to another trial that compared inotuzumab (CMC-544, Pfizer) with chemotherapy, the researchers wrote. The median OS was 7.7 months in the experimental groups in both clinical trials, and the median OS was 4 months in this trial compared with 6.7 months in the inotuzumab trial.
However, the researchers suggested the patient population in the blinatumomab trial had more aggressive disease, which affected response. In addition, the inotuzumab trial included patients with Ph-positive ALL.
The researchers wrote that these differences, among others, suggest patients were at greater risk for mortality or complications in this trial compared with the inotuzumab trial, indicating the two trials should not be compared.
Kantarjian described the two agents as “complementary,” but different.
“Blinatumomab is a bispecific antibody construct that targets CD19; it works by allowing CD3 T cells to kill ALL cells,” Kantarjian said. “Inotuzumab is a CD22 monoclonal antibody bound to calicheamicin, a toxin that kills ALL cells.”
“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatments, the activity of an immune-based therapy such as blinatumomab, which depends on functioning T cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” the researchers wrote. – by Melinda Stevens
For more information:
Hagop Kantarjian, MD, can be reached at hkantarjian@mdanderson.org.
Disclosures: Kantarjian reports grant support from Amgen, Ariad Pharmaceuticals, Bristol-Myers Squibb, Novartis Pharmaceuticals and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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For adults with B-cell precursor acute lymphoblastic leukemia who failed initial intensive chemotherapy, such as rituximab (Rituxan, Genentech, Biogen) with hyper-CVAD, the prognosis is dismal with very few long-term survivors. In fact, most were not even eligible for allogeneic transplant, because they failed to achieve an adequate response with salvage treatment.
In The New England Journal of Medicine, Kantarjian and colleagues conducted a phase 3 study comparing blinatumomab (Blincyto, Amgen) and standard-of-care chemotherapy for patients with relapsed/refractory B-precursor ALL. Blinatumomab improved response rates, EFS and OS.
On the other hand, blinatumomab prolonged the remission duration only by 2.7 months and the absolute OS benefit was 3.7 months — the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm. In addition, the percentage of patients consolidated with an allogeneic transplant were limited to approximately 25% and was similar in both arms.
Based on the results from this study, blinatumomab should become the new standard of care for patients with refractory adult ALL, but using it at the relapsed/refractory setting will not significantly alter the natural history of the disease. Future studies will incorporate blinatumomab into existing induction/consolidation regimens and hopefully this will make outcomes of adult ALL similar to pediatric ALL.