Location (country): Bangladesh 

Case Report: Chronic Myeloid Leukemia in Blastic Crisis (AML Transformation)

Patient Profile: Age: 61 years

Gender: FemaleComorbidities: HTN, DM

Diagnosis: Chronic Myeloid Leukemia (CML) in Blastic Crisis with AML transformation

Date of Diagnosis: January 2024

Clinical History:The patient was initially diagnosed with CML, which later progressed to a blastic crisis. She was treated with the following regimen:1. Dasatinib (Tyrosine Kinase Inhibitor - TKI) 140mg OD2. Azacytidine (Hypomethylating agent) 100mg Day 1 – Day 73. Venetoclax (BCL-2 inhibitor)100mg on Day 1, then gradually titrated to 400 mg and continue to Day 14

Initial Treatment Response: Response after 2 cycles: Significant reduction in peripheral blood blast count.After 1 month: Blasts reappeared in the peripheral blood, indicating disease progression.BCR-ABL1 IS Ratio (6 months): Greater than 6%, indicating high disease burden and lack of response to therapy.

Investigations:Bone Marrow Aspiration: Revealed a dry tap, suggesting extensive marrow infiltration.TKI Domain Mutation Analysis: No mutations detected, ruling out TKI-resistant mutations.

Molecular Genetics: Identified major route chromosomal abnormalities, indicative of disease progression and poor prognosis.Complications:The patient developed refractory thrombocytopenia with platelet counts persistently below 10,000/mm³. Despite TKI dose adjustment, thrombocytopenia persisted. To manage the thrombocytopenia, the patient was started on Eltrombopag 50 mg once daily, a thrombopoietin receptor agonist.

Disease Progression and Adjusted Treatment: Given the progression of the disease, as evidenced by increasing blasts and continued thrombocytopenia, the treatment strategy was revised:Though best approach would be chemotherapy (Flag IDA or Azacytidine and venetoclax plus TKI with an aim to achieve second CP then allo SCT as soon as possible. She cannot manage a matched donor for Allo SCT. Also f persistent Pancytopenia TKI dose escalation was not possible. So less toxic regimen Ponatinib 15mg plus low dose subcutaneous Cytarabine 30mg has chosen for her. Ponatinib (another third-generation TKI) was introduced due to its efficacy in treating TKI-resistant CML and its activity against CML in the blastic phase.Low-Dose Cytarabine: 30 mg subcutaneously, 5 days a week, was added to the regimen to target the AML component of the disease.

Follow-up and Current Status: Blast count is 20%, WBC total count- 2000/cumm, platelet<5000/cumm, Hb <10gm/dl on RCC ( Occasionally it drop below 7gm/dl)Since beginning she can't tolerate any chemotherapy and also TKI can't continue regularly due to severe thrombocytopenia, leukopenia. She doesn't want to go with BMT. It's been 11month since her diagnosis. Is there any hope for her.

Unfortunately there are not many treatment options for the patient.

Cytogenetic and molecular additional abnormalities have not been detailed, but they have limited impact on treatment choice.

As already mentioned in the report, the preferred choice would be 1) ponatinib 30 mg combined with FLAG-Ida ( Intravenous fludarabine 30 mg/m2 for 5 days, cytarabine 2 g/m2 for 5 days, and idarubicin 8 mg/m2 for 3 days, plus G-CSF), followed by 2) allogeneic bone marrow transplantation if the patient will be able to achieve a second chronic phase (if related or unrelated HLA id are not available, consider haploidentical donor). Allo SCT in active BP is not recommended.

However, the patient is unfit for intensive chemotherapy and she refused Allo-SCT.

As an alternative, a combination of decitabine, venetoclax and ponatinib can be considered
DOI: 10.1016/S2352-3026(24)00250-3

If these options are excluded or not feasible, my preferred option would be ponatinib in monotherapy, 30 mg daily, with dose increase to 45 mg after 1 month if bone marrow biopsy will show > 10% cellularity, with the aim of hematologic response.
Cytarabine will probably increase hematologic toxicity without any significant therapeutic impact.

Growth factors (EPO, TPO agonists) can be considered but the efficacy is expetced to be low (active disease).

In case of ponatinib failure, if available, other experimental agents could be considered (olverembatinib, ELVN001).

Best regards

Fausto Castagnetti