# Unprecedented Megakaryocytic Blast Phase Transformation in Chronic Myeloid Leukemia After 16 Years of Tyrosine Kinase Inhibitor Therapy

## TL;DR

A CML patient remained stable for 16 years on TKIs before suddenly progressing to a rare aggressive phase, but achieved remission with ponatinib and a bone marrow transplant.

## Contribution

Demonstrates the rare occurrence of megakaryocytic blast phase transformation after long-term TKI therapy and successful management with ponatinib.

## Key findings

- Patient achieved deep molecular response with ponatinib after progressing to megakaryocytic blast phase.
- Undetectable BCR::ABL1 transcript levels were observed within 7 months of ponatinib treatment.
- Patient maintained molecular remission for 14 months post-transplantation despite graft-versus-host disease.

## Abstract

We report the case of a 51-year-old Japanese man with chronic myeloid leukemia (CML) initially diagnosed in the chronic phase. For 16 years, the patient maintained chronic phase (CP) under treatment with first- and second-generation tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, and bosutinib, none of which resulted in ABL1 mutations. However, despite long-term disease stability, the patient experienced an abrupt progression to the megakaryocytic blast phase (MBP), a rare and aggressive form of CML. In response to this progression, ponatinib, a third-generation TKI, was introduced as a fourth-line therapy. Remarkably, within 7 months of initiating ponatinib, the patient achieved a deep molecular response (DMR), evidenced by a reduction in BCR::ABL1 transcript levels to undetectable levels (MR5.0). This molecular remission enabled the patient to proceed with an allogeneic bone marrow transplantation from a human leukocyte antigen (HLA) 8/8-allele-matched unrelated donor. Post-transplantation, the patient has maintained DMR for 14 months without recurrence, despite the challenges posed by graft-versus-host disease. This case illustrates the critical role of third-generation TKIs like ponatinib in managing advanced CML phases, especially when previous therapies fail. It also emphasizes the necessity of vigilant long-term monitoring during the chronic phase to detect and address any signs of disease progression promptly.