Κυριακή, 19 Μαρτίου 2017

BINATUMOMAB FOR ADVANCED ALL

In the phase III TOWER trial reported in The New England Journal of Medicine, Kantarjian et al found that blinatumomab (Blincyto) treatment improved overall survival vs chemotherapy in heavily pretreated patients with B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab received accelerated approval in 2014 for treatment of relapsed/refractory disease on the basis of durable remissions observed in a single-arm trial. The agent is a bispecific monoclonal antibody construct that allows CD3-positive T cells to recognize and eliminate CD19-positive ALL blasts.
Study Details
In the open-label trial, 405 patients from 101 sites in 21 countries were randomized 2:1 between January 2014 and September 2015 to receive blinatumomab (n = 271) or standard chemotherapy (n = 134). Patients had to have Philadelphia chromosome–negative B-cell precursor ALL that was refractory to primary induction therapy or salvage with intensive combination chemotherapy; in first relapse with first remission lasting < 12 months; in second or subsequent relapse; or in relapse at any time after allogeneic stem cell transplantation. The primary endpoint was overall survival in the intent-to-treat population. Among all randomized patients, 267 of 271 patients (99%) in the blinatumomab group and 109 of 134 patients (81%) in the chemotherapy group received at least one dose of study treatment.
Induction and consolidation with blinatumomab consisted of 4 weeks of treatment and 2 weeks off in 6-week cycles, with blinatumomab given at 9 μg/d during week 1 of induction cycle 1 and 28 μg/d thereafter by continuous infusion; maintenance treatment was given as a 4-week continuous infusion every 12 weeks. Chemotherapy consisted of investigator’s choice of fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline (45% of the group); a high-dose cytosine arabinoside–based regimen (17%); a high-dose methotrexate-based regimen (20%); or a clofarabine-based regimen (17%).
For the blinatumomab vs chemotherapy groups: mean age was 41 years in both; 60% vs 58% were male; 84% in both were white; geographic region was Europe for 66% vs 63%, United States or Canada for 15% vs 17%, and the rest of the world for 19% vs 19%; Eastern Cooperative Oncology Group performance status was 0 or 1 for 85% in both; 35% vs 34% had received prior allogeneic stem cell transplantation; 42% vs 49% were in the first salvage treatment phase; and maximum central or local bone marrow blasts were ≥ 50% in 74% vs 78%.
Efficacy Outcomes
At a prespecified interim analysis conducted after occurrence of 75% of the total number of planned events for the final analysis, the independent data and safety monitoring committee recommended that the trial be stopped early on the basis of benefit observed with blinatumomab treatment (data cutoff in January 2016). Median follow-up was 11.7 to 11.8 months.
Median overall survival was 7.7 months (95% confidence interval [CI] = 5.6–9.6 months) in the blinatumomab group vs 4.0 months (95% CI = 2.9–5.3 months) in the chemotherapy group (hazard ratio [HR] = 0.71, P = .01). Among the patients who received study therapy, median overall survival was 7.7 vs 4.1 months (HR = 0.69, P = .009). In an analysis censoring data at the time of allogeneic stem cell transplantation, median overall survival was 6.9 vs 3.9 months (HR = 0.66, P = .004).
A greater proportion of patients in the blinatumomab group had remission within 12 weeks after the start of treatment consisting of complete remission with full hematologic recovery (34% vs 16%, < .001) or complete remission with full, partial, or incomplete hematologic recovery (44% vs 25%, < .001). Estimated 6-month event-free survival was 31% vs 12% (HR = 0.55, P < .001, for death or relapse after complete remission with full, partial, or incomplete hematologic recovery). Median duration of remission was 7.3 vs 4.6 months. A total of 24% of patients in each group underwent allogeneic stem cell transplantation.
Adverse Events
Adverse events of grade ≥ 3 occurred in 87% vs 92% of patients. Serious adverse events occurred in 62% vs 45%, with the most common being febrile neutropenia in both groups (8.6% vs 11.0%). Fatal adverse events occurred in 19% vs 17%, including sepsis in 3% vs 4%, septic shock in 2% vs 0%, multiorgan failure in 1% vs 0%, respiratory failure in < 1% vs 2%, and bacteremia in 0% vs 2%; fatal adverse events were considered related to study treatment in 3% vs 7%. Treatment was discontinued due to adverse events in 12% vs 8%, including due to a neurologic event in 4% vs 1% and cytokine-release syndrome in 1% vs 0%. Protocol-specified treatment interruptions due to adverse events occurred in 32% of blinatumomab patients, including in 7% for infection, 6% for neurologic events, 5% for cytokine-release syndrome, 3% for infusion reaction, and 3% for neutropenia. Adverse events led to treatment interruption in 6% of the chemotherapy group.
The investigators concluded: [T]his large, randomized trial of single-agent immunotherapy with blinatumomab shows a significant survival benefit as compared with chemotherapy in adults with [Philadelphia chromosome–]negative relapsed or refractory ALL. Blinatumomab resulted in significantly higher rates of hematologic remission and longer survival than chemotherapy. 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 study was funded by Amgen.

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