Late progression of Chronic Myeloid Leukemia (CML) to blast crisis is a rare event in the era of tyrosine kinase inhibitor (TKI) therapy, and it is primarily seen in patients with resistance, a suboptimal response, or in patients who stop taking their medication. We report here a case of a woman who had an MMR and progressed to blast phase disease 18 years after her original diagnosis.

A 54-year-old female with a long-standing history of CML, maintaining a major molecular response (MMR) on dasatinib, presented to the emergency room with shortness of breath and fatigue. Further questioning revealed several months of night sweats and weight loss along with new onset gum bleeding and petechiae. Physical exam was notable for tachycardia and petechial rash without splenomegaly. Laboratory studies revealed 4.4K/uL white blood cells with 20% blasts, hemoglobin level of 8.3 g/dL, and 32K/uL platelets. Subsequent bone marrow biopsy revealed 95% blasts that expressed CD34, CD10, CD19, HLADR, CD79a, partial-positive expression of TdT, with negative-to-dim expression of CD20, consistent with Precursor B-cell Acute Lymphoblastic Leukemia (pre-B-ALL). Molecular analysis of the sample revealed BCR-ABL1 p210 transcript >10%, consistent with transformation of CML to pre-B-ALL. Next generation sequencing revealed a new V299L mutation of BCR-ABL1, consistent with resistance to dasatinib.

Her oncologic history is notable for BCR-ABL1 p210 positive CML diagnosed in 2007 in chronic phase, for which she was started on imatinib. The treatment course was complicated by therapy resistance. She was transitioned to nilotinib, followed by dasatinib due to cardiac side effects. She had an MMR, defined as a BCR-ABL1/ABL value of <0.1% on the international scale (IS), to dasatinib throughout her treatment course over the 12 years prior to her transformation. The patient was followed every 3-4 months for surveillance exams and monitoring of BCR-ABL levels. She was found to have an IS level of 0.179% six months prior to presentation. On reevaluation three months later, the patient was shown to have an IS of 0.021% indicating continuation of the MMR. There was also no evidence of blasts in peripheral blood.

This case is unique in that the patient remained in the chronic phase of CML for 18 years after initial diagnosis before transforming to blast phase disease. The estimated median onset from chronic myeloid leukemia-chronic phase (CML-CP) to chronic myeloid leukemia-blast phase (CML-BP) is 29.1 months (Brioli et. al. Leukemia 2024). Prior to the use of TKI therapies, over 20% of CML cases would progress to accelerated or blast phase leukemia, 70% being acute myeloid leukemia and 30% acute lymphoblastic leukemia, with most of these cases occurring within 3-5 years after initial diagnosis.

The introduction of TKI therapies has reduced the incidence of transformation to less than 5% of cases (Senapati et. al. Leukemia 2023). Development of CML-BP is rare in patients who have achieved deep responses, but one case series of six patients show an average of 11.6 years between diagnosis and blast crisis as well as a range of 6 to 124 months between treatment cessation and blast crisis (Dulucq et. al. Haematologica 2022). Somatic mutations and/or copy number variant were identified in each of these patients. Patients who do not achieve or who lose MMR are at a markedly higher risk of relapse, as opposed to patients who achieve DMR responses (Hehlmann et. al. J Clin Oncol 2014). Even such, blast crisis has been seen in patients with DMR without antecedent molecular relapse (Liang et. al. Acta Haematol 2025).

Although this patient experienced resistance to imatinib early in her course and required three different TKI therapies, she had a major molecular response on dasatinib for over 10 years. It is also notable that our patient was diagnosed younger than the median age of diagnosis of 55-60. This population is associated with lower rates of MMR and increased risk of progression. Furthermore, the rate of transformation from CML to ALL is much less frequent than transformation from CML to AML, with the risk of transformation dramatically declining after 5 years of starting TKI therapy. This case highlights how a rare CML patient with an MMR may still go on to blast phase disease.

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2025
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