Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation, which results in the BCR::ABL1 fusion gene. This oncogene serves as the therapeutic target for tyrosine kinase inhibitors (TKIs). Recent studies have identified mutations in ASXL1, a gene involved in epigenetic regulation, whose presence is associated with poor prognosis, lack of response to standard treatment, and increased TKI resistance. These mutations are estimated to occur in 9% of cases, presenting with an aggressive clonal disease phenotype and a higher relapse rate. This subgroup represents an area of active research and a clinical scenario where allogeneic transplantation may be the preferred therapeutic strategy. Here, we present the cases observed at our institution and their clinical outcomes. We present 4 cases of patients with CML and ASXL1 mutations with more aggressive disease development and poor response.

Case 1: Female, 51y, started with six months evolución myalgia. Initial blood count (IBC) Leu 17.27, Bas 2.36%, Hb 8.7g/dL and PLT 350 10^9/L ,Initial flow cytometry (FC): blasts 8.2%., FISH present BCR::ABL+ (p210) and Karyotype show t(9;22) and -8. Diagnosed with accelerated-phase CML, high risk Sokal and ELTS. Initial treatment: nilotinib 800 mg/day, reduced to 200 mg BID due to hematologic toxicity. In May 2025 present liver dysfunction; ultrasound showed infiltration, and biopsy confirmed myeloid blast phase. Persistent presence of BCR/ABL. Flow cytometry 05/13/2025: blasts 25.9%. 07/01/2025:M351T mutation,NGS 07/11/2025: ASXL1 c.1747T>A p.Trp583Arg VAF 1.25 % (Tier 1) and multiple Tier 2 mutations (CEBPA, GATA2, EZH2);. Started 7+3 (cytarabine + daunorubicin) + ponatinib on 05/20/2025. Currently MRD negative, MR 3.0 awaiting consolidation with allogenic transplant

Case 2: Female, 25y, initiated with increased abdominal girth, asthenia, adynamia, and weight loss. Admitted in May 2025. Initial IBC Leu 234,180/μL, blasts 4%, Bas 10% Hb 7.1 g/dL and PLT 245 10^9/L, Initial BCR::ABL transcript 29.09%. NGS: ASXL p.k726Rfs*18VAF 2.14%Diagnosis: accelerated-phase CML, high-risk ELTS. Treatment initiated with imatinib 400 mg/day. Response evaluation pending.

Case 3: Female, 18 years. Initiated in 2022 with weight loss,abdominal pain, fatigue, dysnea and occasional epistaxis. Initial IBC Leu 673,000, blast 3% Bas 9%, Hb 6.3g/dL PLT 1,835,000 10^9/L. BCR::ABL positive (p210). Diagnosed in December 2024 with chronic-phase CML, high risk (Sokal and ELTS). Initiated treatment with imatinib 400 mg/day, discontinued due to grade IV pancytopenia. Restarted at 200 mg/day, escalated to 400 mg/day. At 6 months: BCR::ABL PCR 19.99%. NGS: ASXL1 c.1933_1934dup p.Gly646Valfs*5 VAF 1.92 % (Tier 1) and multiple Tier 2 mutations (CEBPA, GATA2, EZH2). Not a candidate for second-generation TKIs due to cardiovascular risk. Continues on imatinib, plan to escalate to 600 mg/day. Reevaluation pending.

Case 4: Female, 46 years. initiated in 2022 with weight loss, splenomegaly, IBC Leu 200,000, blasts 10% Bas 3% Hb 9.3 g/dL PLT 41610^9/L. BCR::ABL 56.19% Diagnosis: accelerated-phase CML, high-risk ELTS. Initial treatment: imatinib 400 mg/day, escalated to 600 mg/day, reduced to 300 mg/day due to grade 3 hematologic toxicity. At 6 months: BCR::ABL 13.51%. In April 2025, persistent pancytopenia. Flow cytometry: CD20+ B-cell blasts (27%). Positive CSF, progression to blastic phase. NGS:WT1 p.C29_L30insCRHPGPEPRSVC* VAF 1.39%, ASXL1 p.G645Vfs*58 VAF 1.55%, ASXL1 p.E929G VAF 1.46% ,ASXL1 p.T936= VAF 1.41%(Tier 1) Started R-HyperCVAD + dasatinib. Severe complications: mixed shock, pulmonary aspergillosis, meningitis due to S. agalactiae, herpes zoster encephalitis. Died from infectious complications.

In the current era of CML targeted therapy with TKIs or myristoyl inhibitors, the presence of associated genetic alterations (AGAs) becomes relevant, as they may predict aggressive behavior and open a window to evaluate transplantation in these patients for better therapeutic responses. Imatinib is not benefical in this patients.

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2025
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