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You Make the Call: How would you treat a patient who is in remission from CML but has positive cytogenetic and molecular tests?

June 1, 2023

June 2023

Michael W. Deininger, MD, PhD Executive Vice President and Chief Scientific Officer, Versiti Director and Senior Investigator, Versiti Blood Research Institute Professor, Medical College of Wisconsin

Michael W. Deininger, MD, PhD
Executive Vice President and Chief Scientific Officer, Versiti
Director and Senior Investigator, Versiti Blood Research Institute
Professor, Medical College of Wisconsin



A 52-year-old male patient was diagnosed with chronic myeloid leukemia (CML) in chronic phase. At diagnosis, his white blood cell (WBC) count was 2.82 × 109/L with 5% blasts, hemoglobin was 10.6 g/dL, and platelet count was 761 × 109/L. The spleen tip was palpable 5 cm below the left costal margin at the midclavicular line. In the bone marrow, the cellularity was 100% and there were 1% blasts. BCR::ABL1 fusion gene p210 type (e13/14a2) transcripts were detected, and the ratio was quantified at 58.4505% on the International Scale (IS). The patient was started on nilotinib, received only 12 days of treatment, as he was not able to tolerate it, and was then lost to follow-up.

After returning to clinic three months later (still in chronic phase), his treatment was changed to dasatinib 100 mg daily, and he has not missed any doses since. After three months of treatment, BCR::ABL1 fusion gene to ABL1 ratio was 34.4846% IS. Two months later, the ratio was 30.3079%. With little change despite five months of treatment, there was a concern for inherent resistance, but tyrosine kinase mutation analysis was performed and was negative.

After seven months of treatment with dasatinib, a repeat bone marrow biopsy was completed. At the time, his WBC count was 3.2 × 109/L, hemoglobin was 11.8 g/dL, and platelet count was 272 × 109/L. The bone marrow was hypocellular (20%) with maturing trilineage hematopoiesis biopsy and did not have any morphologic evidence of CML. Cytogenetics were positive for t(9;22), as BCR::ABL1 fusion was detected in 64.5% of interphase cells.

The patient is currently asymptomatic and in complete hematologic remission but has persistent positive cytogenetic and molecular tests. In terms of management, should this patient switch to another tyrosine kinase inhibitor (TKI)? No mutations were detected on the tyrosine kinase mutation analysis, so how should another line of therapy be chosen? Should he be referred for allogeneic hematopoietic cell transplant instead and proceed if a well-matched donor can be found?


This patient presented with an intermediate risk EUTOS long-term survival score of 1.65 and a high Sokal score of 1.5. After seven months of standard dose dasatinib, apparently with strict adherence, his BCR::ABL1 is more than 30% IS, consistent with failure of a second-​generation TKI. Based on this course, he has high-risk CML, but as far as we know it is still in chronic phase. What to recommend?

One piece of information that would aid in decision-making is a conventional bone marrow karyotype. If there was clonal evolution with a high-risk cytogenetic abnormality (a second Ph chromosome, +8, +19, isoq17, −7/7q abnormalities, inv(3)(q21;q26)), this would indicate accelerated phase.1 Additionally, a myeloid malignancy sequencing panel may also help with making a decision, although the data are less extensive. Still, mutations in RUNX1 or IKZF1 would suggest high risk of transformation to blast phase. A conundrum here is that positive data for clonal cytogenetic evolution or myeloid mutations clearly support an aggressive approach, while it’s less clear what to do in their absence. Thus, irrespective of the results, the patient should be evaluated for hematopoietic cell transplant (HCT).

I would consider the following scenarios when determining how to proceed with this patient:

Scenario 1: No clonal evolution

  • I would recommend switching the patient to ponatinib at an initial dose of 45 mg daily, then reduce to 15 mg if BCR::ABL1/ABL1 is <1%.
  • If he achieves <1%, I would watch closely but not proceed to transplant.

Scenario 2: Clonal evolution and/or RUNX1 or IKZF1 mutation

  • If the patient has a low-risk transplant option, I would start him on ponatinib 45 mg daily and treat as long as his response improves, then go to transplant.
  • If he has no low-risk transplant option, I would still start him on ponatinib 45 mg daily. Then, if he has an excellent response (<1% or even <0.1%), maintain treatment with ponatinib and watch closely. If he responds but BCR::ABL1 remains >1%, you will need to have a difficult discussion with him about bone marrow transplant versus transformation risk; or, if he does not respond to ponatinib, proceed to HCT.


Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760-6768.


I have a 31-year-old male patient with sickle cell disease who has a history of the following complications: acute chest syndrome, a cerebral vascular accident (CVA) nine years ago that resulted in temporary blindness, severe occlusive retinopathy, and priapism (occurred twice, the last time being 2018).

I started him on oral hydroxyurea about 10 months ago and increased the dose from 500 mg per day to 1,000 mg per day after six months. His calculated weight-based dose is 1,700 mg per day, so I’m slowly titrating upwards.

Now, his hemoglobin is 8.9 g/dL, so I’m considering voxelotor. I haven’t seen contraindication for voxelotor in patients with a history of cerebral vascular disease and occlusive retinopathy. Based on his hemoglobin, is he a good candidate, and at what hemoglobin level would voxelotor not be needed?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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