The combination of ponatinib and blinatumomab has led to rapid and durable remissions in patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to data presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.1
Results of the phase II study demonstrated a 96% composite complete response and complete response with incomplete blood cell count recovery rate, with 87% of patients achieving a complete molecular response and 88% testing negative for measurable residual disease (MRD) using a highly sensitive next-generation sequencing assay. The study authors also reported that responses were rapid, with most patients achieving complete molecular remission within 2 to 4 weeks of treatment.
“Overall, the novel chemotherapy-free combination of ponatinib and blinatumomab is a promising regimen for patients with newly diagnosed Ph-positive ALL,” said lead study author Nicholas J. Short, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Given the favorable outcomes of patients with newly diagnosed, Ph-positive ALL who [do not undergo transplantation] in first remission, these data suggest this regimen may serve as an effective transplant-sparing regimen in this population, although longer-term follow-up will be needed to evaluate the risk of late relapses with this regimen.”
“The novel chemotherapy-free combination of ponatinib and blinatumomab is a promising regimen for patients with newly diagnosed Ph-positive ALL”— Nicholas J. Short, MD
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As Dr. Short explained, the historical standard of care for most patients with newly diagnosed Ph-positive ALL is chemotherapy plus a BCR-ABL tyrosine kinase inhibitor followed by allogeneic stem cell transplantation in first remission. With this treatment regimen, said Dr. Short, 5-year overall survival rates of approximately 35% to 50% have been achieved in most studies, but relapses are common and are frequently driven by the development of T315I mutations, which may be present in up to 75% of cases at the time of relapse.
Ponatinib is a pan–BCR-ABL tyrosine kinase inhibitor that has demonstrated activity against these T315I mutations. In a phase II study, the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) and ponatinib was associated with high rates of complete molecular response, which translated to a 5-year overall survival of 74%, with most patients having long-term survival without transplant in first remission.2
Blinatumomab is another effective drug in Ph-positive ALL. Recently, the combination of dasatinib plus blinatumomab demonstrated a 4-year overall survival rate of 78% in newly diagnosed Ph-positive ALL, with half of patients undergoing transplantation in first remission.
Study Methods
For this phase II study of ponatinib and blinatumomab, Dr. Short and colleagues enrolled adults with newly diagnosed Ph-positive ALL, relapsed or refractory Ph-positive ALL, or lymphoid accelerated- or blast-phase chronic myeloid leukemia. Dr. Short’s abstract presented data specifically from the newly diagnosed Ph-positive ALL cohort.
Patients received an induction cycle of ponatinib at 30 mg daily along with standard-dose blinatumomab on a 4-week-on, 2-week-off schedule. Patients then received up to four consolidation cycles of this regimen, followed by maintenance ponatinib for at least 5 years. Notably, the ponatinib dose was decreased to 15 mg once patients achieved a complete molecular response. All patients received 12 doses of intrathecal chemotherapy with alternating administration of cytarabine and methotrexate.
For patients in the newly diagnosed cohort, the primary endpoint was complete molecular response rate, defined as the absence of a quantifiable BCR-ABL polymerase chain reaction (PCR) transcript. Secondary endpoints included event-free survival, overall survival, and safety of the regimen.
Rapid and Durable Responses in Most Patients
As Dr. Short reported, the median age of the front-line cohort was 57 years, with 43% of patients 60 years or older. In addition, 60% of patients had at least one well-controlled cardiovascular risk factor at the time of study entry.
“Among evaluable patients, the complete response or complete response with incomplete blood count recovery rate was 96%,” said Dr. Short, who noted that 87% of patients achieved a complete molecular response and 68% achieved a complete molecular response after one cycle of therapy.”
In addition, 88% of patients were found to have achieved MRD negativity via a highly sensitive next-generation sequencing assay. Of note, said Dr. Short, three patients who achieved MRD negativity by this next-generation sequencing assay still had low-level BCR-ABL detected by PCR.
Serial monitoring of peripheral blood BCR-ABL transcripts in cycle 1 showed a rapid reduction of PCR transcripts in most patients; within 2 weeks of treatment, 58% of tested patients had already achieved a complete molecular response in the peripheral blood compartment.
“With median follow-up of 18 months, the estimated 2-year event-free survival was 92%, and the 2-year overall survival rate was 95% despite only one patient undergoing transplantation in first remission,” said Dr. Short.
One patient died early of intracranial hemorrhage in the setting of thrombocytopenia from cytoreductive
chemotherapy that was administered prior to trial enrollment, and one patient died in complete response.
Two relapses have been observed to date, both of which were extramedullary only.
Of note, there were no grade 4 or higher treatment-related adverse events on study. Ponatinib was discontinued in three patients due to adverse events (one grade 2 cerebral vascular ischemia, one grade 3 coronary artery stenosis, and one grade 3 rash). No grade 3 or higher adverse events related to blinatumomab were observed.
DISCLOSURE: Dr. Short has served as a consultant or advisor to Novartis, NKarta, GlaxoSmithKline, Pfizer, Takeda Oncology, and Amgen; has received research funding from Stemline Therapeutics, NextCure, Takeda Oncology, and Astellas; and has received honoraria from Adaptive Biotechnologies, Amgen, Sanofi, and Astellas.
REFERENCES
1. Short N, Kantarjian H, Jain N, et al: Ponatinib and blinatumomab for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: A subgroup analysis from a phase II study. 2022 ASH Annual Meeting and Exposition. Abstract 213. Presented December 10, 2022.
2. Jabbour E, Short NJ, Ravandi F, et al: Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: Long-term follow-up of a single-centre, phase 2 study. Lancet Haematol 5:e618-e627, 2018.
