Treatment Outcomes of Pediatric & AYA Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Upfront Generic Dasatinib & Augmented ALL IC-BFM 2009 Chemotherapy Protocol: A Single-Center Study from India
Authors: Gupta Adamya , Kumar Karthik , Singh Sashi , Satadeve Paras , Kachhwaha Arjun , Benson Reshma , Nayak Jhasaketan , Ronanki Kavya , Shah Bibhant , Dalton Prisla , Nagpal Nikhil , T Sudhahar , Kumar Vinod , Singh Neha , Nath Uttam Kumar 
Published: December 2024

Introduction

Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. Philadelphia-chromosome positive (Ph+) ALL accounts for 3-5% of pediatric ALL and about 25% of adolescent & young adult (AYA) ALL patients. The survival of Ph+ ALL patients has dramatically improved with incorporation of tyrosine kinase inhibitors (TKI) into chemotherapy regimens. The recent availability of generic preparations of dasatinib has enabled its use in Ph+ ALL patients in India. Herein we describe the outcomes in pediatric & AYA Ph+ ALL treated with upfront generic dasatinib plus ALL IC-BFM 2009 chemotherapy protocol at a single center with severe resource-limited setting.

Objectives To assess results of generic dasatinib + combination chemotherapy in pediatric & AYA Ph+ ALL with respect to morphological complete remission (CR), measurable residual disease (MRD) response, & leukemia relapse. To assess overall survival in the above patient cohort.

Methodology

The study enrolled treatment-naïve Ph+ ALL patients of age 1-39 years between April 2019 & June 2024. The patients were treated as high-risk (HR) group as per ALL IC-BFM 2009 protocol. All patients received generic dasatinib starting from day 1 of induction phase chemotherapy through end of maintenance phase chemotherapy, with temporary dasatinib dose interruptions for toxicity as indicated. Dasatinib dose was 80 mg/m2/day in children and 100-140 mg/day in AYA patients. All patients received augmented early intensification & HR blocks for consolidation. Day 33 bone marrow (BM) morphology & flowcytometric MRD was performed in all patients. Complete remission was defined as BM blasts &lt;5% with no extramedullary disease, and the cutoff for flow-MRD negativity was &lt;0.01%; molecular MRD assessment by bone marrow PCR for BCR-ABL1 could be done in selected patients due to resource constraints.

Results

Total 34 Ph+ ALL patients were treated. Median age was 16 years (range 3-39); male: female ratio 1:1. The median total leukocyte count, platelet count & hemoglobin were 118 x109/L, 40 x109/L, & 7.1 g/dl respectively. At diagnosis, 53% of patients had hyperleukocytosis, 9% had bacterial sepsis, 6% had invasive fungal infections, and 23% had CNS leukemia.

Of the evaluable patients, 85% (28/33) achieved good steroid response (peripheral blood blasts &lt;1000/µl) on day 8 of induction, 81% (25/31) and 37% (11/30) achieved marrow M1 response (&lt;5% blasts) & flow-MRD &lt;0.1% on day 15, and 96% (26/27) and 74% (20/27) achieved morphological CR & negative flow-MRD status on day 33 respectively. There were five deaths in induction phase 1A.

Out of seven patients who had positive flow-MRD on day 33, 4 patients (57%) achieved negative flow-MRD status on day 78 after receiving augmented phase IB chemotherapy plus dasatinib. Overall, 75% of evaluable patients achieved negative molecular MRD response (by BCR-ABL1 PCR) during the course of treatment. Two patients underwent allogeneic transplantation for persistent MRD positive disease, of which one died of refractory CNS disease post-transplant. Two patients had relapse of leukemia on follow-up; however one of them had defaulted treatment. None of the patients required permanent discontinuation of dasatinib due to toxicity. The causes of induction mortality were multidrug-resistant bacterial infections (n=4), & invasive fungal infections (n=1). The median duration of follow-up was 6.8 (range 1-41) months. The median overall survival is 13.3 (range 2.7-41.4) months.

Summary/Conclusion

In our single-center experience, use of generic dasatinib in combination with intensive chemotherapy (ALL IC-BFM 2009) was associated with high complete remission & MRD negativity rates and encouraging survival outcomes in pediatric & AYA Philadelphia-positive ALL patients without significant treatment-related toxicity.