Frontline Combination of Ponatinib and Hyper-Cvad in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: 80-Months Follow-Up Results

Authors

Hagop Kantarjian
Nicholas J Short
Nitin Jain
Koji Sasaki
Xuelin Huang
Fadi G Haddad
Issa Khouri
Courtney D DiNardo
Naveen Pemmaraju
William Wierda
Guillermo Garcia-Manero
Partow Kebriaei
Rebecca Garris
Sanam Loghavi
Jeffrey Jorgensen
Monica Kwari
Susan O'Brien
Farhad Ravandi
Elias Jabbour

Language

English

Publication Date

3-1-2023

Journal

American Journal of Hematology

DOI

10.1002/ajh.26816

PMID

36600670

PMCID

MC12777642

PubMedCentral® Posted Date

1-8-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background:

The combination of ponatinib, a third generation BCR::ABL1 tyrosine kinase inhibitor (TKI), with Hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for SCT in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients followed with longer follow-up would establish this regimen as a new standard of care.

Methods:

Adults with newly diagnosed Ph-positive ALL were treated with the Hyper-CVAD regimen. Ponatinib was added as 45 mg daily x 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR:ABL1 transcript by RT-qPCR at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982.

Findings:

Eighty-six patients were treated. Their median age was 46 years (range, 21–80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic stem cell transplantation (SCT). With a median follow up of 80 months (range, 16–129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3–5 adverse events included infection (n=80, 93%), increased liver transaminases (n= 26, 31%) and total bilirubin (n=13, 15%), hypertension (n=15, 17%), pancreatitis (n=13,15%), hemorrhage (n=12, 13%), and skin rash (n=9, 10%). Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed.

Conclusion:

The long-term results of ponatinib and Hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

Keywords

Adult, Humans, Middle Aged, Cyclophosphamide, Doxorubicin, Philadelphia Chromosome, Follow-Up Studies, Dexamethasone, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Vincristine, Antineoplastic Combined Chemotherapy Protocols, Imidazoles, Pyridazines, Philadelphia-positive ALL, ponatinib, TKI, BCR::ABL1, outcome

Published Open-Access

yes

Recommended Citation

Kantarjian, Hagop; Short, Nicholas J; Jain, Nitin; et al., "Frontline Combination of Ponatinib and Hyper-Cvad in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: 80-Months Follow-Up Results" (2023). Faculty, Staff and Student Publications. 5871.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5871