Updated Results of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL

Ponatinib and blinatumomab are effectual treatments for patients diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The amalgamation of these two agents may present a viable strategy devoid of chemotherapy for these patients. The efficacy and safety of ponatinib and blinatumomab were assessed by researchers in patients diagnosed with newly diagnosed (ND), relapsed/refractory (R/R) Ph+ ALL or CML in lymphoid blast phase (CML-LBP). In patients diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the complete molecular response (CMR) rate was the primary endpoint. In patients diagnosed with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, the main objective was to evaluate the complete remission or complete remission with an incomplete hematologic recovery rate. The secondary endpoints encompassed safety, event-free survival (EFS), and overall survival (OS).

This phase II study enrolled adult patients who presented with ND Ph+ ALL, R/R Ph+ ALL, or CML-LBP. Patients were mandated to possess a performance status of less than or equal to 2, total bilirubin less than or equal to two times the upper limit of normal (ULN), and ALT and AST less than or equal to three times the ULN. Patients presenting with uncontrolled cardiovascular disease or clinically significant comorbidities of the central nervous system (excluding CNS leukemia) were not included. The patients were administered blinatumomab for a maximum of five cycles through a continuous infusion at standard dosages. The patient was administered Ponatinib at a daily dose of 30mg during the first cycle, which was subsequently reduced to 15mg daily upon achieving complete molecular response (CMR). After administering 5 cycles of blinatumomab, ponatinib was sustained for a minimum of 5 years. The patient received 12 prophylactic intrathecal chemotherapy doses, alternating between cytarabine and methotrexate. Out of the 35 patients diagnosed with ND Ph+ ALL, 12 were in complete remission at enrollment, including 2 patients in complete molecular remission. Ninety-six percent of the 23 assessable patients attained complete or complete remission with incomplete blood count recovery. A patient expired on the 18th day due to intracranial hemorrhage in the context of chemotherapy administered before enrollment. Following one cycle, 64% (21/33) of patients achieved complete metabolic response (CMR), while 85% (28/33) of patients achieved CMR at any given time. Eleven out of fifteen tested patients (73%) also achieved minimal residual disease negativity, as determined by a next-generation sequencing assay with a sensitivity of 1×10-⁶.

Complete remission/complete remission with incomplete hematologic recovery was attained in 12 out of 13 evaluable patients, representing a 92% success rate in the context of relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Complete metabolic response (CMR) was attained in 10 patients (71%) following the first cycle and in 11 patients (79%) overall. Five out of six patients diagnosed with chronic myeloid leukemia with low blast phase have achieved complete remission or complete remission with incomplete blood count recovery, while one patient has achieved partial remission as the best response. The patient has achieved a cardiac magnetic resonance imaging (CMR) score of 2 points, representing 40% of the total possible score. In the cohort of patients with ND Ph+ ALL, one out of thirty-four individuals who underwent at least one complete cycle passed away while in CR. The remaining thirty-three patients are currently experiencing ongoing hematologic remission. A singular patient underwent stem cell transplantation (SCT) during their initial remission phase due to the continued detection of BCR/ABL1 transcripts. In the cohort of patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, 13 individuals were evaluated. Of these, 6 patients underwent stem cell transplantation, 4 patients did not receive stem cell transplantation and subsequently experienced relapse, 1 patient passed away while in complete remission, and 2 patients are currently in ongoing remission without undergoing stem cell transplantation. In the cohort of patients with chronic myeloid leukemia and low back pain, three out of the five patients who exhibited a response to treatment experienced subsequent relapse.

The median duration of observation is 11 months, with a range of 1 to 46 or more. In cases of ND Ph+ ALL, the 2-year event-free survival (EFS) and overall survival (OS) rates are both 93%. There were no instances of relapse or mortality related to leukemia observed in this particular group. The 2-year event-free survival (EFS) rate and overall survival (OS) rate in the relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (R/R Ph+ ALL) cohort were 42% and 61%, respectively. The cohort of patients with chronic myeloid leukemia and low back pain exhibited a 2-year event-free survival rate of 33% and a 2-year overall survival rate of 60%. The therapeutic intervention was well-tolerated, with the majority of adverse events being grade 1-2 and in line with the established toxicities of the two agents. Two patients ceased the administration of ponatinib owing to adverse effects, one of which was a cerebrovascular accident and the other a deep vein thrombosis. One patient discontinued using blinatumomab due to a persistent grade 2 tremor. The chemotherapy-free treatment protocol involving concurrent administration of ponatinib and blinatumomab has been deemed safe and efficacious for patients diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Source:https://library.ehaweb.org/eha/2022/eha2022-congress/356979/nicholas.short.ponatinib.and.blinatumomab.for.patients.with.philadelphia.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26845%2Amarker%3D1751%2Afeatured%3D17676

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03147612

Nicholas Short, Hagop Kantarjian, Marina Konopleva, Nitin Jain, Farhad Ravandi, Xuelin Huang, Walid Macaron, William Wierda, Gautam Borthakur, Tapan Kadia, Koji Sasaki, Ghayas Issa, Guillermo Montalban-Bravo, Yesid Alvarado, Guillermo Garcia-Manero, Courtney Dinardo, Jennifer Thankachan, Ricardo Delumpa, Ejiroghene Mayor, Wuliamatu Deen, Anna Milton, Juan Rivera, Lourdes Waller, Christopher Loiselle, Rebecca Garris, Elias Jabbour/PONATINIB AND BLINATUMOMAB FOR PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: UPDATED RESULTS FROM A PHASE II STUDY/Inc, M. G. (n.d.). PONATINIB AND BLINATUMOMAB FOR PATIENTS WITH PHILADELPHIA… by Dr. Nicholas Short. Library.ehaweb.org. Retrieved May 2, 2023, from https://library.ehaweb.org/eha/2022/eha2022-congress/356979/nicholas.short.ponatinib.and.blinatumomab.for.patients.with.philadelphia.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26845%2Amarker%3D1751%2Afeatured%3D17676