Abstract Background. Progression of chronic myeloid leukemia (CML) to blast crisis (CMLBC) is associated with poor prognosis, particularly in patients (pt) who develop resistance to multiple tyrosine kinase inhibitors (TKIs). Despite the introduction of second and third generation TKIs, outcomes after progression remain dismal. Currently, there is no consensus on optimal management for these patients (pts) ; conventional cytotoxic chemotherapy is often employed but frequently fails to achieve durable remissions and adds significant toxicity—particularly problematic in those pts who must subsequently undergo allogeneic stem cell transplantation (BMT). Ponatinib is a third generation multitarget TKI with activity against the T315I mutation and other resistance conferring variants; Asciminib is the firstinclass STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that binds an allosteric site of BCRABL1. Preclinical data demonstrate in vitro synergy when these agents are combined, due to their distinct binding sites on the ABL1 kinase domain. Clinical experience with this combination in advanced CML is still scarce. Objectives. To evaluate hematologic, morphologic, and molecular responses (MR), along with safety and tolerability, of combined Ponatinib and Asciminib (P+A) in three patients with advanced, TKIresistant CML treated at a single Italian hematology center. A key aim was to avoid the use of chemotherapy, reducing treatment-related toxicities that could increase the risk of BMT, while achieving sufficient disease to allow pts to proceed to BMT. Methods. Three Ph positive CML pts in advanced phase who had failed at least 2 prior TKIs were enrolled. Treatment consisted of Ponatinib 45 mg orally once daily combined with Asciminib 200 mg orally twice daily until at least hematological response was reached. Response assessments included monthly evaluation of: Complete Hematologic Response (CHR): Absence of circulating and bone marrow blasts. Cytogenetic Response: Conventional karyotyping of ≥ 20 metaphases, with complete cytogenetic response (CCyR) defined as 0/20 Philadelphia positive metaphases. Molecular Response (MR): Quantification of BCR: ABL1 transcripts by realtime PCR. Adverse events (AEs) were graded per CTCAE v5. 0. Pts achieving sufficient disease control (at least hematological response) proceeded to BMT. Pts Characteristics. Pt1: Male, CML diagnosed at age 21; prior TKIs: imatinib, dasatinib, bosutinib; progressed to CML-BC at age 26; no response to ponatinib in monotherapy after two months so asciminib was added for 1 months of combination therapy. Pt2: male, CML diagnosed at age 18; prior TKIs: nilotinib, dasatinib; progressed to blast crisis at age 28. Started Ponatinib and after 2 weeks for persistent hyperleukocytosis and circulating blasts asciminib was added for combination therapy for 3 months. Pt 3: Male, age 37 at diagnosis; CML-BC at 51; prior TKIs: imatinib, nilotinib, bosutinib; started asciminib and ponatinib for 2 months then 1 months of asciminib in monotherapy for toxicity related to Ponatinib. Results. Efficacy: All 3pts achieved CHR by Day 28. At 3 months: Cytogenetics: Pt 1: 8/9 Ph positive metaphases; Pt2: 18/20 ph+ metaphases; Pt 3: 0/20 (CCyR). MR: Patient 2: MR¹; Patient 2: MR¹, Patient 3: MR³;. These improvements enabled all pts to proceed to BMT. Safety: No Grade 3–4 nonhematologic toxicities were observed in pt 1 and 2; Anemia grade 1 was noted; Pt 3 experienced acute myocardial infarction after 2 months of combined treatment, necessitating discontinuation of ponatinib and placement of a drug eluting stent; asciminib was continued for 1 additional month without further complications. Grade 1–2 fatigue was noted. Conclusions. In this small, single center series, combined Ponatinib plus Asciminib induced rapid responses that facilitated BMT in heavily pretreated, CML-BC pts without the need for cytotoxic chemotherapy and its associated toxicities—an approach that may reduce pretransplant fitness and improve eligibility. By avoiding chemotherapy, patients entered transplant in better condition, thereby lowering the risk of adverse events both during conditioning and in the posttransplant period. The distinct yet complementary mechanisms of TKIs were well tolerated in pt 1 and 2; its use in patients older than 50 years could require caution moreover if precedently treated with nilotinib. These preliminary results warrant further confirmation in larger prospective trials.
Carlo Gambacorti‐Passerini (Mon,) studied this question.