Blinatumomab Produces 'Notable' Results in High-Risk ALL

Roxanne Nelson

December 31, 2014

The results seen with the recently approved novel agent blinatumomab (Blincyto, Amgen Inc) are "notable," say authors reporting a trial in which monotherapy produced complete remission in almost half of patients with relapses or refractory B-precursor acute lymphoblastic leukemia (ALL).

Complete remission was seen in 43% of patients after two cycles of therapy. A third of these patients subsequently underwent allogeneic hemopoietic stem cell transplantation.

This patient population was selected according to unfavorable prognostic features, so these results seen after single-agent therapy are worth noting, say the authors, led by Max S. Topp, MD, from the Universitätsklinikum Würzburg in Germany.

Findings from this multicenter phase 2 trial were initially reported earlier this month at the American Society of Hematology (ASH) 56th Annual Meeting and have now been published in the January 2015 issue of Lancet Oncology.

Blinatumomab is the first of a novel class of drugs known as bispecific T-cell engagers and is designed to direct cytotoxic T cells to CD19-expressing cancer cells. CD19 is a protein expressed on the surface of B-cell-derived ALLs and non-Hodgkin's lymphomas.

The drug was recently approved by the US Food and Drug Administration for patients with Philadelphia chromosome-negative precursor B-cell ALL who have relapsed or who were refractory to previous treatment.

At the ASH meeting, one expert commented that she believes that new therapies such as this one will revolutionize treatment of hematologic cancers.

"This is an important study, and ultimately, I think our goal is to overcome the use of chemotherapy and radiation, which can destroy healthy cells along with malignant ones," commented Catherine Bollard, MD, MBChB, a bone and marrow transplant specialist at George Washington University/Children's National Medical Health System, Washington, DC. "This strategy, along with others, is harnessing our immune system to target cancer cells."

Further Investigation Warranted

Another expert agrees. In an editorial published alongside the study, Xavier Thomas, MD, PhD, from the Hospices Civils de Lyon, Lyon-Sud Hospital, France, points out that many drugs have entered the marketplace, with the "potential to change the standard of care for adult patients with ALL."

He adds, "Combination of several agents targeting more than one antigenic determinant, gene mutation, or signal transduction pathway might be the most effective strategy, and could hold the promise of substantial benefit, and could represent a targeted solution similar to the total therapy approach pioneered by Don Pinkel in the 1960s with chemotherapeutic agents."

However, although the current findings with blinatumomab are very encouraging, Dr Thomas notes that the patient population most likely to benefit from its use has yet to be defined.

As reported with other monoclonal antibodies, life-threatening reactions can potentially result from massive release of cytokines, and blinatumomab also causes B-cell depletion, leading to further decreases in immunoglobulin levels, and thus increasing the risk for infections, he writes.

Blinatumomab also has a fairly short half-life, making its optimal mode of delivery a continuous infusion over the course of 4-week cycles. All these features could present challenges for use in certain populations, such as children or frail patients, Dr Thomas says.

Questions also remain about how best to use blinatumomab, Dr Thomas notes. Should it be used as "a single agent or in combination therapy, for induction, consolidation, or maintenance, or as part of a large combination or succession of treatments?" he asks. "The incorporation of blinatumomab into conventional chemotherapy backbones, potentially including other monoclonal antibodies, should produce opportunities to assess the feasibility of such combinations and to increase treatment efficacy," he writes.

However, blinatumomab's dependence on circulating immune cells may limit the ability to combine it with myelosuppressive therapies, Dr Thomas notes. "It seems more likely that we should use blinatumomab sequentially with chemotherapy instead of concurrently."

The study authors also acknowledge that further assessment of blinatumomab is needed. For example, can it improve long-term outcomes compared with standard chemotherapy, and can it be used earlier in the course of the disease and in combination with other treatment approaches?

Study Details

The study reported by Dr Topp and colleagues enrolled 189 patients with Philadelphia chromosome-negative, primary refractory or relapsed disease (first relapse within 12 months of first remission, relapse within 12 months after allogeneic hemopoietic stem cell transplantation, or no response to or relapse after first salvage therapy or beyond).

Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day afterward) by continuous intravenous infusion over the course of 4 weeks every 6 weeks (up to 5 cycles), per protocol.

The primary endpoint was complete remission or complete remission with partial hematologic recovery of peripheral blood counts within the first 2 cycles.

At a median follow-up of 8.9 months, 37 (45%) of the 82 patients who had achieved complete remission were still alive and in remission. The remaining 45 patients had either relapsed (37 patients) or died without documented relapse.

The median relapse-free survival was 5.9 months for patients who had achieved either a complete remission or a complete remission with partial hematological recovery. The median overall survival was 6.1 months for all 189 patients, with a median follow-up of 9.8 months.

Adverse events were common, as nearly all patients (99%) experienced adverse effects of any grade, primarily pyrexia (113 patients, 60%) and headache (65 patients, 34%). The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anemia (27 patients, 14%).

In addition, three (2%) patients had grade 3 cytokine release syndrome. Three deaths (resulting from sepsis, Escherichia coli sepsis, and Candida infection) occurred and were thought to be treatment-related by the investigators.

The study was funded by Amgen. Several of the coauthors have received funding from Amgen and have relationships with other companies, as noted in the article.

Lancet Oncol. 2015;16:57-66. Article abstract, Editorial extract

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