Two studies presented at the ASH annual meeting focused on the use of blinatumomab for patients with acute lymphocytic leukemia (ALL), demonstrating that the bi-specific T-cell engager was safe and effective in patients with relapsed and/or refractory Philadelphia chromosome-positive (Ph+) ALL and B-cell precursor ALL.
Blinatumomab in Ph+ ALL
In the phase II, single-arm, multicenter ALCANTARA study, Giovanni Martinelli, MD, from the Institute of Hematology at S. Orsola-Malpighi University Hospital in Bologna, Italy, and colleagues evaluated the efficacy and tolerability of blinatumomab in patients with relapsed and/or refractory Ph+ ALL who had progressed or were intolerant to a second-generation or later tyrosine kinase inhibitor (TKI).
Though imatinib is often used as part of frontline therapy in Ph+ ALL, relapse is common in patients who do not undergo allogeneic hematopoietic cell transplantation (AlloHCT), Dr. Martinelli and co-authors noted.
“Acquired resistance on TKI treatment is associated with mutations in the BCR-ABL tyrosine kinase domain in the majority of patients and may be detected at low frequency prior to TKI treatment in a subset of patients,” he told ASH Clinical News. While second-generation TKIs may show activity against most of the BCR-ABL tyrosine kinase domain mutations, the clinical benefit may be short-term, thus creating the need for alternate therapy options.
The ALCANTARA study included 45 adults with Ph+ B-precursor ALL who had either relapsed after taking or were refractory to at least one second- or later-generation TKI, were intolerant to one second- or later-generation TKI, or were intolerant or refractory to imatinib. Prior TKI treatment included:
- Dasatinib (87 percent)
- Imatinib (56 percent)
- Ponatinib (51 percent)
- Nilotinib (51 percent)
Patients were able to participate in the study if they had greater than 5 percent blasts in the bone marrow and an Eastern Cooperative Oncology Group performance status of ≤2. Patients received blinatumomab via a continuous intravenous infusion for four weeks, followed by a two-week break. This six-week pattern continued for up to five cycles. For the first week of treatment, blinatumomab was administered at a dose of 9 μg/day, followed by a gradual dose escalation to 28 μg/day from day eight through 29. This dose was used for all subsequent cycles.
Rates of complete remission (CR) and CR with partial hematologic recovery (CRh) during the first two cycles of treatment – the study’s primary endpoint – were similar across patient groups. According to Dr. Martinelli, 36 percent of those in the study were able to achieve CR/CRh. Among the 27 patients who had been treated with two or more prior TKIs, the CR/CRh rate was 41 percent. In addition, 100 percent of responders with ABL-kinase domain mutations had complete minimal residual disease (MRD) responses.
One-quarter of patients went on to receive subsequent AlloHCT, and the median overall survival (OS) was 7.1 months.
CR/CRh rates were similar across patient groups, including those older than 55 years and those 18 to 55 years old (CR/CRh = 36 percent and 35 percent, respectively). Among the 27 patients who received two or more prior second-generation TKIs, the CR/CRh rate was 41 percent. Hematologic response was achieved regardless of mutational status, the authors wrote, noting that CR/CRh rate was 40 percent in patients with T315I resistance mutations (n=10).
Forty-four percent of patients experienced treatment-related grade ≥3 adverse events (AEs). The most common were febrile neutropenia (11%), alanine aminotransferase increase (11%), aspartate aminotransferase increase (9%), anemia (9%), thrombocytopenia (7%), and pyrexia (7%). Neurologic AEs were observed in 47 percent of patients treated with blinatumomab – all of which were grade 1/2.
Blinatumomab in Ph-Negative B-Cell Precursor ALL
Nicola Gökbuget, MD, from the Department of Medicine at Goethe University in Frankfurt, Germany, presented preliminary results from a phase II, prospective study of blinatumomab in adult patients with precursor B-cell ALL who had hematologic CR and MRD ≥10-3 that persisted after at least three intensive chemotherapy treatments.
“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 percent,” Dr. Gökbuget said.
A total of 116 patients (mean age = 45 years; range = 18-76 years) received blinatumomab at 15 μg/m2 per day for four weeks, followed by two treatment-free weeks. Patients who had MRD responses in the first treatment cycle were given up to three additional cycles or underwent HCT. Those who had a hematologic relapse stopped treatment.
Results from 103 patients were presented. After a median follow-up of 29.5 months, the response rate was 80 percent, with a median OS of 36.5 months (95% CI 19-not reached). Rates of OS were highest in patients who achieved MRD-negative CR during the first treatment cycle compared with those who did not (40.4 months vs. 12.0 months; p=0.001).
Median relapse-free survival (RFS) was 18.9 months (95% CI 12.3-35.2), and those who achieved first CR had a better outcome than patients in second or third CR (median RFS = 24.6 months vs. 11.0 months; p=0.005).
“[This] has confirmed high response rates to blinatumomab and, furthermore, a promising long-term outcome,” said Dr. Gökbuget.
All patients had at least one AE, with the most commonly reported AEs being tremors (30%), aphasia (13%), and dizziness (8%). Serious AEs were seen in 63 percent of patients across the full study population, with two patients experiencing a fatal event. Treatment interruptions were required for 31 percent of patients; following treatment interruption, blinatumomab was resumed at a lower dose of 5 μg/m2 per day.
Blinatumomab is being assessed in a variety of settings, and Dr. Gökbuget plans to expand the research to learn more about the role of blinatumomab in patients who are MRD-positive after receiving HCT, “to try to improve practical usability.”
Martinelli G, Dombret H, Chevallier P, et al. Complete molecular and hematologic response in adult patients with relapsed/refractory (R/R) Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia (ALL) following treatment with blinatumomab: Results from a phase 2 single-arm multicenter study (ALCANTARA). Abstract #679. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.
Gökbuget N, Dombret H, Bonifacio M, et al. Long-term outcomes after blinatumomab treatment: Follow-up of a phase 2 study in patients (pts) with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Abstract #680. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.