Nicola Gokbuget, MD
At least 80% of patients with B-precursor acute lymphoblastic leukemia (ALL) had a complete minimal residual disease (MRD) response after a single cycle of treatment with the CD19-directed antibody blinatumomab, according to a report at the 2014 ASH Annual Meeting.
On December 3, 2014, the FDA granted an accelerated approval to blinatumomab as a treatment for patients with Philadelphia chromosome-negative relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), based on findings from the full cohort of patients in the phase II trial. The approval came 5 months early, based on the FDA's expected review timeline for the drug.
In the phase II study reported at ASH, 103 patients were evaluable for complete MRD response, with 82 meeting the response criteria after one cycle of blinatumomab, a bispecific T-cell engager (BiTE) antibody construct. An analysis that included all 112 patients who received at least one cycle of blinatumomab showed that 88 patients (78%) met response criteria. An exploratory analysis of MRD response (as opposed to complete MRD response) showed that 96 patients (85%) met the criteria, including 82 (85%) in the primary efficacy analysis.
“Most patients achieved a complete MRD response within one cycle of treatment,” said Nicola Gokbuget, MD, a hematologic oncologist at Goethe University Hospital in Frankfurt, Germany. “Responses occurred in all subgroups, including older patients and patients with high MRD levels. No predictive factor for MRD response was identified. The most commonly occurring adverse events were flu-like symptoms associated with T-cell activation.”
Blinatumomab’s anticancer activity comes from its ability to direct cytotoxic T-cells to CD19-positive cells, leading to serial lysis. CD19 is a highly specific B-cell marker and is expressed in more than 90% of B-cell malignancies.
Gokbuget presented results of a phase II trial involving patients with MRD-positive B-precursor ALL. Investigators defined MRD as â‰¥10-3
cells by an assay that had a minimum sensitivity of 10-4
. Patients who had previously undergone stem-cell transplant were excluded. The trial had a primary endpoint of complete MRD response after one 28-day cycle of blinatumomab. Investigators defined complete MRD as no amplification by polymerase chain reaction assay.
Patients ineligible for allogeneic transplant could receive as many as three additional cycles of blinatumomab. Transplant-eligible patients also could receive as many as three additional cycles while awaiting a suitable donor. Secondary endpoints included adverse events, 18-month hematologic relapse-free (HRF) survival, overall survival, time to hematologic relapse, and duration of complete MRD response.
Investigators enrolled 116 patients, with all but one being included in the safety analysis. Of 103 patients eligible for analysis of the primary endpoint, 102 had evaluable MRD.
Analysis of the primary endpoint showed an 80% response rate in the efficacy cohort, and 78% in the full-analysis cohort. In the exploratory analysis (MRD <10-4
), 85% of the efficacy cohort and the full-analysis cohort met response criteria.
“Two patients who achieved a reduction of MRD to below the quantifiable limit during cycle 1 achieved a complete MRD response after continued treatment in cycle 2,” said Gokbuget. “MRD responses were achieved in patients regardless of age, MRD level at baseline, or relapse history.”
In general, blinatumomab was well tolerated. The most frequently reported adverse event was pyrexia (90%), followed by tremor (29%), chills (28%), fatigue (24%), nausea (22%), vomiting (22%), and diarrhea (20%). Grade â‰¥3 adverse events were uncommon but included neutropenia (16%), pyrexia (7%), and tremor (5%).
With respect to the observed neurologic adverse events (aphasia in 13%, in addition to patient with tremor), Gokbuget called them clinically relevant but noted that few patients had severe neurologic effects.
During continued follow-up in the trial, investigators hope to determine whether the high MRD response rate translates into long-term clinical benefit, such as continued molecular remission and long-term survival.
MRD can generally be assessed in more than 90% of patients with ALL. Use of MRD response criteria allows standardized, sensitive, and individual response evaluation, said Gokbuget. MRD persistence after standard induction and consolidation therapy or reappearance of MRD after previous negative-MRD status portends an increased risk of relapse and poorer survival.
“Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy,” said Gokbuget. “MRD persistence indicates resistance to conventional chemotherapy.”