Ponatinib plus blinatumomab may provide chemotherapy-free regimen for leukemia subset
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Ponatinib and blinatumomab induced high rates of complete molecular remission among patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to research presented during the virtual ASCO Annual Meeting.
The durable responses observed with ponatinib (Iclusig, Millennium/Takeda Oncology), a BCR-ABL tyrosine kinase inhibitor, and blinatumomab (Blincyto, Amgen) a bispecific T-cell engager, potentially could eliminate the need for chemotherapy and allogeneic hematopoietic stem cell transplant among these patients, particularly as front-line therapy, researchers said of the single-arm, phase 2 study.
“We were initially apprehensive about entirely abandoning chemotherapy for this disease, particularly in younger patients, in whom chemotherapy plus a TKI has been long considered the standard of care. However, we have been encouraged by the very promising results thus far,” Nicholas J. Short, MD, assistant professor in the department of leukemia of the division of cancer medicine at The University of Texas MD Anderson Cancer Center, told Healio. “The ponatinib-blinatumomab combination was well-tolerated and highly effective in both newly diagnosed and relapsed/refractory patients.”
Short and colleagues recognized ponatinib and blinatumomab as two of the most active single agents in Philadelphia chromosome-positive ALL (Ph+ALL) and, with no previous studies evaluating them in combination, examined the safety and efficacy of the chemotherapy-free regimen among patients both with newly diagnosed and relapsed/refractory disease.
The analysis included 35 patients (median age, 59 years; range, 24-83 years; 51.4% Hispanic, 40% white) with newly diagnosed (n = 20) or relapsed/refractory (n = 10) Ph+ALL, or with chronic myeloid leukemia in lymphoid blast crisis (n = 5).
Patients underwent up to five cycles of standard-dose blinatumomab as a continuous infusion. During cycle one, patients received 30 mg of ponatinib daily, with the dose decreasing to 15 mg daily upon reaching complete molecular response.
Following completion of blinatumomab, responding patients continued ponatinib for at least 5 years. Patients also received 12 doses of prophylactic intrathecal chemotherapy.
Complete molecular remission rate among patients with newly diagnosed disease and overall response rate — defined as the composite of complete remission and complete remission with incomplete platelet recovery — among patients with relapsed/refractory disease served as the study’s primary endpoints.
Median follow-up was 12 months (range, 1-37).
Results showed ORRs of 100% among newly diagnosed patients and among those with CML in lymphoid blast crisis, and 89% in the relapsed/refractory group.
Researchers reported complete molecular remission rates of 85% in the newly diagnosed cohort, 88% in the relapsed/refractory cohort, and 40% in the CML cohort.
“The results were particularly encouraging in the front-line setting, where all patients responded and 85% achieved a complete molecular response (ie, minimal residual disease negativity),” Short said. “This translated to a 2-year OS of 93% among newly diagnosed patients. Notably, none of the front-line patients underwent transplant in first remission and none have relapsed.”
Median duration of complete remission in the front-line cohort was 6 months (range, 1+ to 33+).
Two-year OS was 53% in the relapsed/refractory Ph+ALL population and 100% in the CML cohort. Of the nine patients in the relapsed/refractory cohort in complete remission, three had an ongoing response without HSCT; four proceeded to HSCT, one of whom subsequently died; one relapsed; and one who was off-study died of an unknown cause.
Overall, the ponatinib-blinatumomab combination appeared well-tolerated, with most adverse events being grade 1 or grade 2. The most common of these was rash (grade 1 and grade 2, 11% each), fever/febrile neutropenia (grade 2, 9%), constipation (grade 1 and grade 2, 9% each), fatigue (grade 1, 9%; grade 2, 6%) and cytokine release syndrome (grade 2, 6%).
“These data provide further evidence that chemotherapy-free regimens may become the new standard of care for adults of all ages with newly diagnosed Ph+ALL,” Short said. “Given the durable responses we have observed, the combination of ponatinib plus blinatumomab may obviate the need for transplant in first remission for these patients.”
Perspective
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Ph+ALL historically carried a very poor prognosis when treated with standard, intensive chemotherapy. With the advent of TKIs, outcomes significantly improved; however, resistance and relapse have remained problematic. More recent advances, including the third-generation TKI ponatinib and the bispecific antibody blinatumomab, have shown efficacy as single agents in treating Ph+ALL. Further, excellent responses, including a complete remission rate of 98%, were seen among newly diagnosed patients with Ph+ALL treated with the chemotherapy-free combination of the second-generation TKI dasatinib (Sprycel, Bristol Myers Squibb) and blinatumomab
Short and colleagues presented highly promising results with ponatinib plus blinatumomab for the treatment of newly diagnosed and relapsed/refractory patients with Ph+ALL. This regimen yielded rapid, deep and durable responses, particularly for the newly diagnosed patients. Moreover, the combination was very well-tolerated (even up to the age of 83 years), with no deaths within the first 4 weeks. Although still promising, the results in the relapsed/refractory population were more modest, with a 1-year EFS rate of only 55%.
Although the 1-year survival rates were quite impressive with this chemotherapy-free regimen, the sample size was limited and longer follow-up is needed to confirm the duration of remission (ie, curative potential). Thus, it remains unclear whether this combination may truly eliminate the need for allogeneic HSCT in these patients; but, these initial results compare favorably to those obtained with intensive chemotherapy plus ponatinib. In fact, the favorable toxicity profile of this regimen makes it a particularly attractive option for elderly and/or unfit patients.
Relapsed/refractory Ph+ALL still poses a significant challenge, and the poorer outcomes in this population emphasize the importance of aggressive, upfront treatment of this disease, before resistance develops. Given the limited toxicity of ponatinib plus blinatumomab, there may be the potential to add other agents to this regimen, such as chimeric antigen receptor T cells, to further improve outcomes.
References:
Foà R, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2016272.
Jabbour E, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00207-7.
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Short NJ, et al. Abstract 7001. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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