24-year-old young man was diagnosed as low ELTS (1.34) and EUTOS (66) risk  CML and there was no additional chromosomal abnormality. Imatinib (generic) was started on March 3, 2024. He achieved CHR at 2 month, however molecular response at 3 month was not done due to poor adherence to follow up. He came for follow up after 6 months (mid September, 2024) of therapy when his BCR-ABL1 in IS was 0.4402. However, at the same time he had grade IV pancytopenia- Hb 7.1 g/dL,  WBC 1.82K/cmm with 18% neutrophil and 77% lymphocytes, without any immature cells and platelets were 4K/cmm. His TKI was suspended but pancytopenia persisted to same extent after 2 weeks, when his bone marrow aspirate was hypocellular without any significant blasts. 

He was followed weekly for 3 more weeks without any improvement in cell count. In the meantime he required 2 units of RCC and 2 unit of platelet transfusion. His bone marrow aspirate has been assessed again after 5 weeks of imatinib discontinuation, showing still hypocellular in all cell lines without any blast, and prominent lymphoid cells. His BCR-ABL1 has been measured again which is 0.9987; only two fold elevation after 5 weeks of TKI discontinuation. His bone marrow biopsy report is waiting. To note that he doesn't have any constitutional symptom, organomegaly or lymphadenopathy.

What can be the probable explanation of such prolonged cytopenia and how can I manage him? 

Cytopenia associated with TKI initiation continues to be a clinical challenge in CML management. They are common and frequently resolves with ongoing treatment, as Ph neg stem cells repopulate the marrow niche and gradually take over haematopoietic functions in the months following TKi commencement. Some patients may need transfusional or growth factor support.

There is a small group of patients who experience prolonged cytopenia after brief TKI exposure, or have recurrent cytopenias with TKI re-challenge. Historical cohorts of ALLG studies suggests that regardless of the TKI used, there will be ~2-3% of patients who are poorly tolerant of TKI therapy due to cytopenias. In the most recent asciminib frontline study, for instance, 2% of patients proceeded to allogeneic stem cell transplant because of this problem. We speculate that these patients have a depleted repertoire of Ph neg normal stem cells, and that haematopoiesis is entirely dependent on the Ph+ clone.

In this particular patient, I would do tissue typing and refer for consideration of an allogeneic stem cell transplant, if this is a realistic option, but I suspect access is limited in Bangladesh. I would continue to offer supportive and transfusional therapy, given that cytopenia is currently the biggest risk. Upon full haematological recovery, I would attempt to re-institute therapy using low doses of TKI (perhaps 100mg imatinib) and gradually build the dose up, acknowledging that toxicity and efficacy may be directly related in this case. In the past, we have also tried low dose or alternate day dasatinib, though there is no convincing evidence arguing for a particular approach.

A resistant mutation is evolving and this clearly signifies treatment failure. However, a bone marrow biopsy should help exclude secondary myelofibrosis.

Prolonged persistent cytopenias to multiple TKIs do occur in a small minority of patients. I have not seen a reported clear explanation for that. I agree with Dr. Yeung's opinion. Would consider dasatinib 20 mg daily when the counts recover.

I think the comments are missing the mark. The TKI has worked very well. The problem is not one of effectiveness. Switching drugs will not improve things. Reducing the dose may only reduce the effectiveness. The problem is not one of toxicity either. The TKI is not suppressing recovery of normal hemopoiesis. There are no TKI targets to any great extent on normal cells. This is seen on rare occasions. Normal cell growth is gone or persistently dormant. The reason is unknown, at least to my knowledge, but not due to the TKI. Treating physicians can play with the TKI, but the risks of the cytopenia will persist and the potential for disease progression will be there. Under situations like this, the only salvage for both the CML and the cytopenia is an allograft, if donor, transplant centre, consent, etc are available. Delay is risky.