In thin, the discussion here is one of the forest and the trees. There is obvious relapse with the DAS therapy and the culprit mutation, common with DAS therapy, has been identified. Note, however that during 8 months of DAS therapy, there was no cytopenia, suggesting that normal hemopoiesis had recovered when CML stem cell hemopoiesis was suppressed by DAS. With institution of the appropriate therapy, PON, cytopenias recurred even though the blood counts were controlled with the PON. This suggests that normal hemopoiesis is gone. There is no evidence of fibrosis or disease progression other than the mutation. So the disease is controlled by TKI, and I would presume likely would be with ASC as well, but for some reason, normal blood cell production is gone. TKI-based cytopenias are more common at diagnosis than at relapse and are not usually related to one specific drug. Is this case, even when CML is controlled with different TKIs, cytopenias recur, suggesting this is not TKI or disease related. That leaves the likelihood that something has hit normal stem cells, and there is now a second process in place. I agree with David that another event has come into play, resulting in something akin to aplastic anemia, but the CML stem cells seemed to have resisted this event. Aplastic anemia in this part of the world may be as common as acute leukemia and is usually caused by a virus such as hepatitis B.

This means there are now two things to control - CML and aplasia and the only treatment good for both would be a stem cell allograft. This poses another conundrum. With HSCT for CML, getting a patient off immunosuppression quickly is indicated to allow the graft-vs-leukemia effect to come into play, and preventing post-transplant relapse. There is a long history of studies in the literature proving more relapse with longer immunosuppression. On the other hand, with aplastic anemia, longer GVH prophylaxis is indicated as stopping immunosuppression too early, often less than 6 months, results in loss of graft. So what do you do as the immunosuppression approach for the two processes is contradictory? There is little evidence that routine post-SCT TKI makes much difference in the case of chronic phase CML allografts, and I do not see evidence here that even though there was resistant disease, there was no disease progression. This case is unique. However, since immunosuppression should probably be continued for at least 6 months for the aplasia, the GVL effect, which is the best CML therapy, will also be suppressed. I would think that reintroduction of TKI, and in this case PON because of the t315i, should be done starting around day 60 post SCT, and assuming engraftment has been good, and continue until after immunosuppression is stopped.

This is a complex case where the exact cause of cytopenia is difficult to determine. A vicious circle has developed, with repeated TKI interruptions, insufficient treatment effect, and the emergence of the T315I mutation all contributing to poor disease control. In such a young patient, I would recommend proceeding to allogeneic stem cell transplantation, as the situation is unlikely to be effectively managed with ponatinib alone.

Please keep us updated on how the patient’s condition evolves.

Thanks a lot Dr. Kim. Increasing BCR-ABL1 (>13 in IS) in the face of persistent cytopenia marrrow hypocellularity. Does that suggest disease progression is more likely cause of cytopenia than the TKI toxicity? Can it be hypothesised that a small number of blasts is not being detected morphologically but suppressing normal hematopoiesis by some cytokine mediated mechanism?

I faced similar scenario in a few cases of AML treated with Aza+Ven where hypocellularity persisted for 3-4 months and repopulated with blasts only.

This is a tricky clinical scenario.

Taking TKI = cytopenia. No TKI = molecular relapse.

Many hypothesise that such profound toxicity represent damaged or depleted Ph-negative normal stem cells, such that marrow repopulation is impeded.

Regardless - throughout the CML studies we had in Australia - we see this 1-2% of the time.

I would exclude, as much as I can, an alternative diagnosis. (eg cytotoxics / chloramphenicol; viral infection; autoimmune diathesis etc). Whilst the marrow is still hypocellular and has no excess blast - I suspect this is TKI toxicity. In our experience - these patients may have prolonged periods of cytopenia that preclude TKI dosing. However, during periods of treatment interruption, they have a high risk of progression to advanced phase disease.

I would organise an allogeneic stem cell transplant whilst awaiting count recovery - but I understand if this is difficult to organise in many resource constrained countries.

During TKI therapy, we frequently meet such a case experiencing cytopenia. Sometimes, it is difficult to differentiate between TKI-induced cytopenia vs disease progression, for which BM examination (including biopsy to exclude marrow fibrosis) and other additional testing (such as cytogenetic test and NGS test if accessible). In this case, it is also somewhat difficult to delineate if his cytopenia is from disease progression with acquisition of the T315I mutation, or purely from TKI induced myelosuppression.

From this point, while the patient continues to have myelosuppression, allogeneic stem cell transplantation should be considered thus the first step should be identification of an allogeneic stem cell donor.

Another remaining question after allogeneic stem cell transplantation is post-transplant TKI maintenance therapy. Given that this patient does have a history of T315I mutation, two TKI options are valid, Ponatinib or Asciminib. I am hesitant to go ahead with Ponatinib maintenance option due to the prolonged cytopenia history that this patient is experiencing now. I would consider Asciminib maintenance if accessible. The maintenance dose of asciminib is debatable: 200mg bid vs lower dose. In my practice, I usually go ahead with 50% of the regular dose for post-transplant maintenance for all TKI drugs.

27-year-old male with chronic phase CML with EUTOS high and ELTS intermediate risk without any
additional chromosomal abnormality, started taking generic dasatinib 100 mg March 10, 2025. He
achieved complete hematological remission by 10 weeks, however BCR-ABL1 in IS was 13.145 after 3
months of dasatinib and after 6.5 months it was 3.0036.
After 8 months of dasatinib, in November 2025, he developed, fever & sore throat, lab revealed
leukopenia (WBC 1.09K/cmm with 60% neutrophil) as well as anemia (Hb 9 gm/dl) and dasatinib was
held on November 7. Hemoglobin was recovered and ANC came >1K in 2nd December, while bone
marrow aspiration found no marrow particles.
On 23rd November sample BCR-ABL in IS was 32.2914. KD mutation testing was ordered while
Nilotinib 300 mg BID was started December 3, 2025. T315I mutation was detected. Again in
December 19, he developed thrombocytopenia (platelet 50k/cmm) and neutropenia (1.83K WBC
with 24% neutrophil). Considering high BCR-ABL1 transcript level and T315I mutation, Ponatinib 45
mg was started on 22nd December within cytopenia. And on December 26, only after 5 days of
Ponatinib, cytopenia worsened to grade 4 (platelet 12K, ANC <100 and Hb 10.6), Ponatinib was held.
After 3 week TKI free period there was still grade 4 cytopenia with little improvement on January 16,
2026 (Platelets 22K and ANC 160/cmm). Bone marrow is grossly hypocellular (5-10%) without any
blasts.
Is the scenerio related to TKI toxicity only, or it can be a early sign of disease progression? How
should he be managed from this point?