Nicola Gökbuget, MD
Treatment with single-agent blinatumomab (Blincyto) demonstrated high complete remission (CR) or CR with partial hematological recovery (CRh) rates in adult patients with Philadelphia chromosome (Ph)-positive and -negative B-cell precursor acute lymphoblastic leukemia (ALL), according to data from two phase II trials presented at the 2015 ASH Annual Meeting.
In the first study, the CR/CRh rate with blinatumomab was 36% in patients with relapsed/refractory Philadelphia chromosome (Ph)-positive ALL. Of those with a CR/CRh, 88% tested negative for minimal residual disease (MRD). A quarter of patients went on to receive subsequent stem cell transplant and the median overall survival (OS) was 7.1 months.
In the second study, the MRD-negative CR rate was 80% for blinatumomab in 103 patients with Ph-negative ALL who were experiencing an MRD-positive hematologic CR. Median OS with blinatumomab was 36.5 months and 67% of patients were able to receive a stem cell transplant.
“This is a proof-of-principle study with a new compound in an MRD-positive population with an MRD-based endpoint in which blinatumomab induced a high complete MRD response rate of 80%,” said lead investigator Nicola Gökbuget, MD, Department of Medicine, Goethe University, Frankfurt, Germany. “MRD response was associated with improved overall survival, relapse-free survival, and response duration.”
Blinatumomab has a dual affinity for CD3 and CD19, which is a highly specific B-cell marker expressed in more than 90% of B-cell malignancies. On December 3, 2014, the FDA granted an accelerated approval to the novel immunotherapy as a treatment for patients with Ph-negative relapsed/refractory B-precursor ALL.
In first phase II study presented at ASH, 45 patients received blinatumomab as a continuous intravenous infusion in a 6-week treatment cycle. The immunotherapy was administered for 4 weeks followed by a 2-week treatment-free duration. For the first week of treatment blinatumomab was administered at 9 μg/day followed by a gradual dose escalation from day 8 through 29 to a final dose of 28 μg/day, which was the dose used for subsequent cycles.
Patients enrolled in the study had greater than 5% blasts in their bone marrow with an ECOG PS ≤2. All patients were relapsed or refractory to at least one second-generation TKI or were intolerant/refractory to imatinib or second-generation TKIs, prior agents included dasatinib (87%), imatinib (56%), ponatinib (51%), and nilotinib (51%).
The primary endpoint of the study was CR/CRh within 2 cycles of treatment, with secondary outcome measures focused on MRD, duration of response, OS, and safety. Other outcome measures of the study were focused on MRD and the efficacy of blinatumomab against specific BCR-ABL
CR/CRh rates were similar across patient groups. In 27 patients who received ≥2 prior second-generation TKIs, the CR/CRh rate was 41%. Additionally, in those with T315I
resistance mutations (n = 10), the CR/CRh rate was 40%.
Responses where the same in patients ≥55 and for those 18 to <55 years of age (36% and 35%, respectively). After a median follow-up of 8.8 months, the median relapse-free survival (RFS) duration was 6.7 months in those ≥55 years old and 5.5 months in those <55.
“Equivalent CR/CRh and RFS was observed in patients less than 55 and over 55 years of age," said lead investigator Giovanni Martinelli, MD, Institute of Hematology, S.Orsola-Malpighi University Hospital, Bologna, Italy. “Hematologic and molecular responses were independent of mutational status, including presence of the T315I mutation.”
Treatment-related grade ≥3 adverse events (AEs) were seen in 44% of patients treated with blinatumomab. The most frequently observed grade ≥3 AEs were febrile neutropenia (11%), alanine aminotransferase increase (11%), aspartate aminotransferase increase (9%), anemia (9%), thrombocytopenia (7%), and pyrexia (7%).
Neurologic AEs were seen in 47% of patients treated with blinatumomab, regardless of causality. The most common of these AEs, all of which were grade 1/2, were paresthesia (13%), confusional state (11%), dizziness (11%), and tremor (9%).
“There were no grade 4 or 5 neurologic events or cytokine release syndrome observed,” said Martinelli. “Adverse events were consistent with previous blinatumomab treatment experience in the setting of Ph-negative relapsed/refractory ALL.”
In the second phase II study, 103 of 116 patients at a median age of 45 years were evaluable for the primary endpoint of complete MRD response. Secondary endpoints included MRD response, OS, and safety. Patients who had previously undergone stem-cell transplant were excluded from the trial.