Ponatinib Plus Blinatumomab Shows Potential as a Chemo-Free Option for Ph+ ALL


Early results of a phase 2 study show that the efficacy achieved with the combination of ponatinib and blinatumomab represents a potentially promising chemotherapy-free, hematopoietic stem cell transplant–sparing treatment for patients with Philadelphia chromosome–positive acute lymphocytic leukemia.

Nicholas James Short, MD

Nicholas James Short, MD

Early results of a phase 2 study (NCT03263572) show that the efficacy achieved with the combination of ponatinib (Iclusig) and blinatumomab (Blincyto) represents a potentially promising chemotherapy-free, hematopoietic stem cell transplant (HSCT)–sparing treatment for patients with Philadelphia chromosome (Ph)–positive acute lymphocytic leukemia (ALL),according to a presentation given during the 2021 ASCO Annual Meeting.1

Results from the trial showed that patients with frontline Ph–positive ALL (n = 20) achieved a complete response (CR) rate or pathologic CR rate of 100%, while patients with relapsed/refractory Ph–positive ALL had a rate of 89%. Moreover, patients in the frontline Ph–positive cohort had a major molecular response (MMR) of 100% and a complete molecular response (CMR) of 85%.

“The combination of ponatinib and blinatumomab is safe and effective in Ph-positive ALL,” Nicholas James Short, MD, an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said during an oral presentation of the data. “Overall, the novel chemotherapy-free combination of ponatinib and blinatumomab appears to be a promising regimen in both frontline and relapsed/refractory Ph-ALL, as well as in chronic myeloid leukemia in lymphoid blast phase [CML-LBP]. Given the particularly favorable outcomes of newly diagnosed patients with frontline, Ph-positive ALL who were not transplanted in first remission, these data suggest that this regimen may serve as an effective transplant-sparing regimen in this population.”

Chemotherapy plus a TKI has become the standard of care in newly diagnosed Ph-positive ALL, with first- and second-generation TKIs yielding 5-year overall survival (OS) rates of approximately 35% to 50%.2-4 Moreover, while ponatinib has yielded promising activity in patients with T315I mutations, which are present in up to 75% of patients at relapse,5 blinatumomab has demonstrated efficacy as a monotherapy in the relapsed/refractory setting, and in combination with dasatinib in newly diagnosed patients.6,7

The trial enrolled patients with newly diagnosed or relapsed/refractory Ph-positive ALL, as well as lymphoid accelerated or blast phase CML. Patients who had previously received 1 to 2 courses of chemotherapy with or without a TKI were able to enroll in the newly diagnosed cohort. Additionally, patients needed to be over 18 years of age, with a ECOG performance status of 0-1, and adequate hepatic function in order to enroll.

Patients with uncontrolled or active cardiovascular disease, including a history of myocardial infarction, cardiovascular accident, or revascularization within 3 months; congestive heart failure with reduced left ventricular ejection fraction; atrial of ventricular arrhythmia; a history of arterial or venous thromboembolism; or uncontrolled hypertension were not able to enroll on the study. Additional exclusion criteria included significant central nervous system (CNS) pathology with the exception of CNS leukemia.

Patients received a 30 mg induction dose of ponatinib and a standard dose of blinatumomab on a 4 weeks on, 2 weeks off schedule. From there, patients received up to 4 consolidation cycles of the regimen followed by maintenance ponatinib for 5 years, the dose of which decreased to 15 mg daily once patients achieved a CMR. All patients were given 12 doses of intrathecal chemotherapy with an altering administration of cytarabine and methotrexate.

The primary of end point of the trial was CMR rate in the frontline cohort, and CR/pathologic CR rate in the relapsed/refractory setting. Key secondary end points included event-free survival (EFS), OS, and safety.

“To date, 20 frontline patients have been treated, 10 with relapsed/refractory disease, and 5 with CML-LBP,” Short explained. “The median age of the frontline cohort was 62 years [range, 34-83]. Among the 10 patients with relapsed/refractory Ph-positive ALL, 1 was primary refractory to [a] previous regimen, 4 were treated in first salvage, and 5 in second or later salvage. Among the 5 patients with CML-LBP, 3 had not received any prior therapy for blast phase disease, 1 was treated in first salvage, and 1 in second salvage.”

Additional data indicated that the cohort of patients with CML-LBP had a CR or pathologic CR rate of 100%, as well as an MMR rate of 60%, and CMR rate of 40%. Moreover, the relapsed/refractory cohort achieved a rate of 88% in both MMR and CMR. In total, the overall patient population had a CR or pathologic CR rate of 96%, an MMR rate of 91%, and a CMR rate of 79%. No patients were reported to have an early death while on the study.

After the first cycle of treatment, the frontline ALL cohort had a CMR rate of 58%, an MMR rate of 26%, and 16% did not experience a response. Moreover, 75% of patients in the relapsed/refractory ALL cohort, and 20% in the CML-LBP cohort had a CMR after the first cycle, while 25% and 80% of patients from both cohorts did not respond, respectively.

Of the patients who experienced a CR or pathologic CR in the frontline ALL arm (n = 20), 1 died following CR due to post-procedural bleeding and hypovolemic shock, while 19 continue to experience ongoing responses without the need for stem cell transplantation. Notably, no patients in this have relapsed within 6 months.

In the relapsed/refractory ALL cohort, of the patients who responded (n = 9), 4 went on to receive HSCT, 1 of whom relapsed and died. Another patient relapsed and developed T315I and E255V mutations at relapse. Overall, 3 patients from this cohort are experiencing an ongoing response without the need for HSCT, while 1 patient died off study due to unknown causes.

In the CML-LBP arm, 2 responders (n = 5) relapsed, one of whom developed myeloid blast phase disease but is currently alive and in remission, while the other developed L248V and Y253H mutations at relapse but is currently alive and in remission following HSCT. Additionally, 3 patients continue to experience an ongoing response without HSCT.

After a median follow up of 12 months, the overall patient population is estimated to have 1- and 2-year EFS of 76% and 70%, respectively. Moreover, the estimated 1-year and 2-year OS were 93% and 80%, respectively. Notably, the relapsed/refractory AML cohort had an estimated 1- and 2-year EFS of 61% and 41%, respectively, as well as an estimated 1- and 2-year OS of 80% and 53%, respectively. Additionally, the CML-LBP arm had 60% estimated EFS rate at 1 and 2 years, respectively, as well as a 100% estimated 1- and 2-year rate.

Notably, there were no grade 4 or higher adverse effects (AEs) reported on the study. Common grade 3 AEs related to ponatinib in patients with ALL included elevated lipase (6%), alanine aminotransferase increase (ALT; 3%), cerebrovascular ischemia (3%), hypertension (3%) pancreatitis (3%), and deep vein thrombosis (3%). Grade 2 AEs included rash (11%), ALT increase (3%), and cerebrovascular ischemia (3%) and grade 1 AEs included rash (11%) and ALT increase (3%).

Although most AEs related to blinatumomab were grade 1 or 2 in patients with ALL, 1 patient developed grade 3 encephalopathy that was resolved by corticosteroids and treatment interruption, according to Short. Common grade 2 AEs included cytokine release syndrome (6%) and tremors (3%), as well as 1 patient who developed grade 1 tremors.


1. Short NJ, Kantarjian H, Konopleva MY, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 7001.

2. Daver N, Thomas D, Ravandi F, et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015;100(5):653-651. doi:10.3324/haematol.2014.118588

3. Ravandi F, O’Brien S, Cortes J, et al. Long-term follow-up of phase II study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia. Cancer. 2015;121(23):4158-4164. doi:10.1002/cncr.29646

4. Rousselot P, Coudé MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL. Blood. 2016;126(6):774-782. doi:10.1182/blood-2016-02-700153

5. 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. 2018;5(12):e618-e627. doi:10.1016/S2352-3026(18)30176-5

6. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35(16):1795-1802. doi:10.1200/JCO.2016.69.3531

7. Foà R, Bassan R, Vitale A, et al. Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383:1613-1623. doi:10.1056/NEJMoa2016271

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