Early cytopenias were first seen when the initial imatinib studies were done. The first rule is to ensure there is no marrow fibrosis or transformation, and this has been done.

Cytopenias that occur as a result of TKI therapy are because a patient's hematopoiesis is still clonal. In the usual situation, clonal will be shut down by the TKI regardless of which one is used. With the holding of the TKI, it is hoped that normal polyclonal hemopoiesis will recover and this is not a target of the TKI as these stem cells do not carry BCR::ABL1. This is the usual situation. In some cases such as the patient described here, the drug holiday has not resulted in recovery of normal hemopoiesis and the cytopenias recur with each restarting of the TKI as the "normal" appearing hemopoiesis is still clonal. This is not a specific side effect of any one TKI, but a problem with ongoing dormancy of normal polyclonal hemopoiesis. For this reason, switching to another, perhaps even more powerful TKI will have the same effect and thus is unlikely to be a successful solution. It could be tried, but in all honesty will likely result in the same outcome.

This is one of the indications for a stem cell allograft if feasible. If not, then continuing the TKI with growth factor support, tolerance for lower counts, and drug holidays as needed, and hope that the dormancy will abate before disease progression steps in.

The details are quite limited. The patient is poorly tolerant of imatinib due to haematological toxicity and looks to have never achieved a cytogenetic response. In this situation, I would switch to a second generation TKI – bosutinib would be my preference, but nilotinib or dasatinib would also be OK, depending what local experience and preference are. I would also support with G-CSF and Erythropoietin if required and if available locally.

Mrs. A, a 68years old,normotensive non-diabetic female, previously diagnosed with CML- CP (EUTOS score 83)  in September,2023 with H/O anaemia, and abdominal discomfort. Qualitative BCR-ABL1 positive for mBCR(210kD). The patient was treated with 400mg of imatinib and had a complete hematologic response within one and a half months. At 3 months of starting Imatinib, the patient developed pancytopenia (Grade 2 Hematologic toxicities; Hb 7.8g/dl, ANC 1450/cmm, platelet -56000/cmm) which persisted for more than 2 weeks. Imatinib was stopped for 2 wks, and count recovered within 10 days of discontinuation of imatinib. Then 300mg of imatinib was started and one month of 300mg imatinib again grade 2 hematologic toxicities developed. Again imatinib stopped for 2 wks and after count recovered imatinib 200mg started. This 200mg dose maintained for 12 months with CBC monitoring only.

No molecular and cytogenetic response was monitored during this course of illness. At 17 months of imatinib  CBC shows grade 3 haematologic toxicity.  Again imatinib stopped and count didn’t recover even after 4 wks of discontinuation. So, pt undergone Bone marrow study, which shows Hypocellular marrow without any atypical cells and this time BCR- Abl quantitative PCR shows 36.7% BCR-ABL oncogene in IS%.
[25/11, 9:36 am]. Now what do we do next?