Asciminib in Patients with Chronic Myeloid Leukemia Who Failed Two or More Tyrosine Kinase Inhibitors - Clinical Outcomes from a Managed Access Program in Brazil
Authors: Pagnano Katia B , Siqueira Isabela Assis de , Campos Giulia de , Rojas Guerrero Natalia Cristina , Camargo Johnny FC , Duarte Gislaine Oliveira , Duffles Guilherme , Guidini Victor H , Sabioni Bruna , Seguro Fernanda Salles , Hamerschlak Nelson , Rodrigues Morgani , Souza Emanuella Graciott , Cardoso Patricia Santos Resende , Magalhães Gustavo HR , Quixada Acy Telles De Souza , Seber Adriana , Massaut Ires Hamyra Bezerra , Fogliatto Laura Maria , Gonçalves Natalia Nunes , Vasconcelos Rafael De Sá , Vidor Simone , De Souza Carmino , Funke Vaneuza 
Published: December 2024

Introduction
Asciminib is a novel allosteric third generation tyrosine kinase inhibitor (TKI), which specifically targets the ABL myristoyl pocket. Asciminib was recently approved in third line in Brazil for chronic myeloid leukemia (CML) patient's intolerant or resistant to two TKI, with no T315I mutation, but it is still not reimbursed in the public health system.
Objectives
This study aimed to analyze the clinical outcomes of chronic myeloid leukemia (CML) patients treated with asciminib, provided by Novartis's Managed Access Program (MAP) in Brazil.
Methods
We collected demographic data, CML and medical history, previous treatments, response, and adverse events from CML patients treated with asciminib provided by the MAP program. The cut-off date of this analysis was July/2024.
Results
Between August 2018 and April 2024, 32 patients were treated with asciminib provided by the MAP program. The median age at CML diagnosis was 43 (6-74); 19 (59%) were male, 29 (90%) were in the chronic phase, 6 (18%) were low Sokal risk, 8 (25%) intermediate, 9 (28%) high risk; ELTS 16 (50%) low risk, 14 (43%) intermediate and 15 (47%) high risk. The median time from diagnosis to the start of asciminib was 66 months (17-314). At asciminib initiation, the median age of the patients was 50.5 (14-78); 26 (81%) were in CP, 4 (12.5%) were in the accelerated phase, and 2 (6%) were in blast crisis. The median lines of therapy were 3 (2-6). Eleven (34.3%) patients received two lines of therapy before asciminib, 15 (46.8%) received three lines, and 6 (18.7%) 4 or more lines, including two patients with previous HSCT. Resistance was the most frequent indication for asciminib (n=28, 87.5%), while four patients switched to asciminib for intolerance to other TKI (12.5%). Most patients were treated with asciminib 80mg once (50%) or 40mg twice daily (28%), and one patient received 20mg twice daily. Patients with T315I mutation received 200 mg twice daily. Previous to asciminib, 11 patients presented BCR::ABL1 mutations (34%), 6/32 (18,7%) had T315I mutation. 13 (40%) had no previous cardiovascular comorbidities. Five patients were previously exposed to ponatinib before asciminib. Two patients received asciminib in clinical trials before the MAP program. Two patients temporarily interrupted asciminib during non-planned pregnancy and resumed after delivery. The baseline quantitative real-time PCR (qPCR) was &gt;10% in 21 patients (65%); 1-10% (n=3), 0.1-1% (n=5). The median follow-up after asciminib start was nine months (1-75); five patients had less than six months of asciminib treatment; 8 patients had more than 12 months of treatment. The median time of asciminib treatment was 8,5 months (1-75). In the total group, the best response achieved was MMR or deeper molecular responses (n=7; 21.9%), MR2/major cytogenetic response (n=4;12.5%), hematologic response (n=17; 53%); no response (n=3; 9.4%), one not evaluated. Thirteen patients (40%) presented hematologic adverse events (thrombocytopenia or neutropenia; grade 3 or 4, n=9; anemia=1) and 7 (21.8%) non-hematologic events (nausea, increase in amylase, hypertension, rash). There was no cardiovascular event during asciminib treatment. Regarding patients with T315I mutation, 3 had a hematologic response, one had a hematologic response with PCR &lt;1%, and 2 had no response. Two progressed to blast crisis, and three died. At the last follow-up, 24 (75%) of the patients were still using asciminib. Due to low efficacy, Asciminib was discontinued in 8 patients (25%). Five patients (15,6%) died due to disease progression (n=3) or sepsis (n=2).
Conclusions: Despite the short follow-up, asciminib confirmed its efficacy and safety in this highly resistant CML cohort. There were no cardiovascular events during asciminib treatment. Management of patients resistant to multiple TKI remains a challenge.