Ponatinib/Blinatumomab Combo Shows Promising Efficacy and Safety in Ph+ ALL


Phase 2 study shows ponatinib and blinatumomab to represent a promising chemotherapy-free, hematopoietic stem cell transplant–sparing treatment for patients with Philadelphia chromosome–positive acute lymphocytic leukemia.

In patients with newly diagnosed and relapsed/refractory Philadelphia chromosome positive (Ph)-positive acute lymphoblastic leukemia (ALL), the chemotherapy-free combination of ponatinib (Iclusig) plus blinatumomab (Blincyto) led to high rates of complete molecular response, according to findings from a phase 2 trial (NCT03263572).1

Among the patients with Ph-positive ALL enrolled in the trial, 33 (87%) of 38 had a complete molecular response. Five (83%) patients with chronic myeloid leukemia (CML) in the lymphoid blast phase also had an overall response, and 2 (33%) had a complete molecular response.

Based on these results, patients with Ph-positive ALL may be spared the toxicities associated with chemotherapy by using the combination studied. Further, the need for allogeneic hematopoietic stem-cell transplantation (HSCT) in the first response could be eliminated.

“In this phase 2 study, the chemotherapy-free combination of ponatinib and blinatumomab was safe and active in patients with Ph-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast phase. In patients with newly diagnosed Ph-positive acute lymphoblastic leukemia, the complete molecular response rate was 87% and 1-year overall survival was 95%, with no relapses observed,” wrote the study authors in findings published within The Lancet Hematology.

“This is a true chemotherapy-free regimen with 2-year survival of 95%.It will become a new standard of care for Ph-positive ALL,” Elias Jabbour, MD, professor of Medicine in the Department of Leukemia, Division of Medicine, MD Anderson Cancer Center, told Targeted Oncology™.

This single-center, single-arm, phase 2 study enrolled patients aged 18 years or older with newly diagnosed or relapsed/refractory Ph-positive ALL or CML in the lymphoid blast phase. Enrollment was open to patients with an ECOG performance status of 0-2, those who had a total bilirubin concentration 2 times the upper limit of normal (ULN) or less, alanine aminotransferase and aspartate aminotransferase concentration no more than 3 times the ULN, and serum lipase and amylase concentrations no more than 3 times the ULN.

Patients were administered oral ponatinib at 30 mg along with continuous intravenous blinatumomab 28 μg over 24 h for 28 days each cycle for up to 5 42-day cycles. This was then followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as central nervous system (CNS) prophylaxis.

The primary end points assessed in the study included complete molecular response, overall response rate, relapse-free survival, event-free survival, and overall survival (OS).

Once the trial completed its original target accrual, it was amended on March 23, 2022, and enrolled an additional 30 patients into the study.

A total of 72 were assessed for eligibility and of 60 (83%) were enrolled and given ponatinib and blinatumomab between February 6, 2018-May 6, 2022. Among those given the combination, 40 (67%) patients had newly diagnosed Ph-positive ALL, 14 (23%) had relapsed/refractory Ph-positive ALL, and 6 (10%) had CML in the lymphoid blast phase.

The trial included 32 (53%) males and 28 (47%) women, and their median age was 51 years (interquartile range [IQR], 36-68). Fifty-one (85%) patients were White or Hispanic and for the entire cohort, the median duration of follow-up was 16 months (IQR 11–24).

At the time of enrollment, 12 (30%) of the 40 patients with newly diagnosed Ph-positive ALL were in a complete response. This included 7 patients with negative minimal residual disease (MRD) confirmed by flow cytometry, and 2 patients in complete molecular response. Another 28 (70%) patients were evaluable for hematological response.

Induction therapies were used in the 12 patients in who were in complete response at enrollment and at the time of diagnosis, 2 patients had CNS involvement of leukemia, both of whom had complete responses at the time of enrolment and no leukemic involvement at the time of the start of protocol therapy. Additionally, complete responses were seen in 26 (93%) of 28 evaluable patients with 1 (4%) patient who had a complete response with incomplete hematologic recovery.

Within the setting of thrombocytopenia from cytoreductive chemotherapy given prior to the trial enrollment, 1 (3%) patient died on day 18 from intracranial hemorrhage. Further, all hematological responses occurred after 1 cycle of ponatinib and blinatumomab.

After 1 cycle, findings revealed 26 (68%) of the 38 evaluable patients with newly diagnosed Ph-positive ALL had a complete molecular response to have a complete molecular response with 33 (87%) evaluable patients having a complete molecular response at any time over the course of therapy. Among the 25 tested patients in the newly diagnosed cohort, 22 (88%) became negative for MRD. Three (14%) of these patients had a detectable BCR–ABL1 by PCR at 3, 6, and 29 months (range, 0.01%- 0.05%).

Then, of the 13 evaluable patients with relapsed or refractory Ph-positive ALL, 11 (79%) had a complete molecular response and 1 (8%) had a complete response with incomplete hematologic recovery. For patients with CML in the lymphoid blast phase, 5 (83%) of the 6 patients had an overall response and 2 (33%) had a complete molecular response.

Looking at safety, the most common grade 3-4 adverse events (AEs) which occurred in over 5% of patients consisted of infection (37%), increased amylase or lipase concentration (8%), increased alanine aminotransferase or aspartate aminotransferase concentration (7%), pain (7%), and hypertension (7%). There were no grade 4-5 AEs reported.

Five (8%) of the 60 patients enrolled had a dose reduction of a study drug due to AEs. Blinatumomab treatment was discontinued by 1 (2%) patient because of a tremor, and 3 (5%) patients discontinued ponatinib due to cerebrovascular ischemia, portal vein thrombosis, or coronary artery stenosis. There were no treatment-related deaths reported in the study.

Overall, this phase 2 study showed the combination of ponatinib and blinatumomab to be safe and effective when administered to patients with Ph-positive ALL or CML in the lymphoid blast phase. Patients with newly diagnosed Ph-positive ALL elicited a complete molecular response rate of 87%. Further, the 1-year OS was 95% and no relapses were observed.

“These encouraging results were observed even though only one patient in this cohort received consolidation with allogeneic HSCT. This very low rate of allogeneic HSCT [2.5%] contrasts with most other prospective studies of Ph-positive acute lymphoblastic leukemia in which a substantial proportion of patients had allogeneic HSCT in first response. Of note, these outcomes were reported without the toxicities associated with conventional cytotoxic chemotherapy,” concluded the study authors.

Jabbour E, Short NJ, Jain N, et al. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(1):e24-e34. doi:10.1016/S2352-3026(22)00319-2
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