Treatment without HSCT and chemotherapy of Ph + ALL with Ponatinib / Blinatumomab leads to a CR rate of 100%

Combination therapy with ponatinib (Iclusig) and blinatumomab (Blincyto) produced a complete response in all patients with Philadelphia chromosome (Ph) positive acute lymphoid leukemia (ALL) who were treated in a phase 2 study ( NCT03263572), according to a presentation at the 2021 American Society of Clinical Oncology (ASCO) annual meeting.1

The chemotherapy-free hematopoietic stem cell transplant (HSCT) sparing regimen for patients receiving first-line systemic therapy (n = 20) led to either a complete response rate (CR) or a rate of pathological CR 100%, while patients with relapsed / refractory Ph-positive ALL had a rate of 89%. In addition, patients in the first-line Ph-positive cohort exhibited 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, assistant professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, said at a oral presentation of data. . “Overall, the new chemotherapy-free combination of ponatinib and blinatumomab appears to be a promising regimen in both first-line and relapsed / refractory Ph ALL Ph-ALL, as well as in chronic myeloid leukemia in lymphoid blast phase. [CML-LBP]. Given the particularly favorable results of newly diagnosed first-line Ph-positive ALL patients 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 combined with TKI has become the standard of care in newly diagnosed Ph-positive ALL, with first and second generation TKIs giving 5-year overall survival (OS) rates of approximately 35% to 50%.2-4 In addition, while ponatinib has produced promising activity in patients with T315I mutations, which are present in up to 75% of patients at the time of relapse5 Blinatumomab has been shown to be effective as monotherapy in the setting of relapses / refractories, and in combination with dasatinib in newly diagnosed patients.6.7

The trial included patients with newly diagnosed or relapsed / refractory Ph-positive ALL, as well as accelerated or blast-phase lymphoid CML. Patients who had previously received 1 to 2 courses of chemotherapy with or without TKI were able to enroll in the newly diagnosed cohort. In addition, patients had to be over 18 years of age, with an ECOG Performance Index of 0-1 and adequate liver function to be eligible for enrollment.

Patients with uncontrolled or active cardiovascular disease, including a history of myocardial infarction, cardiovascular event or revascularization within 3 months; congestive heart failure with reduced left ventricular ejection fraction; atrial ventricular arrhythmia; a history of arterial or venous thromboembolism; or uncontrolled hypertension were unable to participate in 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 week, 2 week schedule. From there, patients received up to 4 cycles of regimen consolidation followed by maintenance ponatinib for 5 years, the dose of which was reduced to 15 mg per day once the patients achieved RMC. All patients received 12 doses of intrathecal chemotherapy with modified administration of cytarabine and methotrexate.

The main endpoint of the trial was the rate of RMC in the first-line cohort and the rate of pathological CR / CR in the relapse / refractory setting. The main secondary endpoints included event-free survival (EFS), OS, and safety.

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

Additional data indicated that the LMC-LBP cohort of patients had a 100% pathologic CR or CR rate, as well as a 60% RMM rate and a 40% RMC rate. In addition, the relapsed / refractory cohort achieved a rate of 88% for both RMM and RMC. In total, the overall patient population had a CR or pathologic CR rate of 96%, an RMM rate of 91%, and a RMC rate of 79%. No patient was reported to have died prematurely during the study.

After the first cycle of treatment, the first-line ALL cohort had an RMC rate of 58%, an RMM rate of 26%, and 16% had no response. In addition, 75% of patients in the relapsed / refractory ALL cohort and 20% of the LMC-LBP cohort had RMC after the first cycle, while 25% and 80% of patients in both cohorts did not respond. , respectively.

Of the patients who presented with CR or pathologic CR in the first-line ALL arm (n = 20), 1 died following CR due to postoperative bleeding and hypovolemic shock, while 19 continue to show continuous responses without the need for stem cell transplantation. Notably, no patient has relapsed within 6 months.

In the relapsed / refractory ALL cohort, among the responding patients (n = 9), 4 continued to receive HSCT, of which 1 relapsed and died. Another patient relapsed and developed T315I and E255V mutations at relapse. Overall, 3 patients in this cohort show a continuous response without the need for HSCT, while one patient died of the study due to unknown causes.

In the LMC-LBP arm, 2 responders (n = 5) relapsed, one of which developed blast-phase myeloid disease but is currently alive and in remission, while the other developed L248V and Y253H mutations at the time of relapse, but is currently alive and in remission after HSCT. In addition, 3 patients continue to show a continuous response without HSCT.

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

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

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

The references

1. Short NJ, Kantarjian H, Konopleva MY, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome positive acute lymphoblastic leukemia: first results from a phase II study. Presented at the 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 first-line treatment of adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematological. 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 the 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. Some blood. 2016; 126 (6): 774-782. doi: 10.1182 / sang-2016-02-700153

5. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line treatment in patients with Philadelphia chromosome positive acute lymphoblastic leukemia: long-term follow-up of a phase 2 single-center 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 B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a multicenter phase II single-arm 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 English J Med. 2020; 383: 1613-1623. doi: 10.1056 / NEJMoa2016272

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