De Novo Acute Myeloid Leukemia in a Patient with Chronic Myeloid Leukemia Under Excellent Control with Tyrosine Kinase Inhibitor

Introduction:
The advent of tyrosine kinase inhibitors (TKI) has significantly improved the survival of patients with chronic myeloid leukemia (CML). A second de novo myeloid malignancy such as acute myelogenous leukemia (AML) in patients undergoing adequate treatment for CML is rare and poses diagnostic and treatment challenges.
Methods:
A 77-year-old gentleman who initially presented in 2016 with leukocytosis (WBC 400,000 x10 /ul) and was diagnosed with chronic phase CML. He was started on imatinib 400mg daily. He achieved a complete molecular remission (CR) in October 2016. In December 2017, he lost the molecular CR with peripheral blood bcr-abl transcript of 4.3%. He also had the bone marrow aspiration and biopsy (BMBx) which showed 2.5% of bcr-abl transcript. TK mutation analysis was performed and it was negative. After stressing the importance of compliance to imatinib, he regained the control of his disease with a reduction of the bcr-abl transcript to 0.09% over a period of 6 months. In July 2020, he was noted to have an increased in the peripheral blood bcr-abl transcript 0.5% and seizure episode after stopping the antiepileptic medications. Due to the potential interactions with antiepileptic medications, imatinib was further increased to 800mg daily. However, he was not able to tolerate the increased dose. He was subsequently switched to dasatinib 50mg daily. In May 2022, he presented to the emergency room with chest pain and was noted to have have up to 4% blasts in the peripheral blood. A BMBx was done which was compatible with AML with up to 64% of blast. Cytogenetics showed gain of chromosome 8. No other molecular markers identified. Bcr-abl transcript was not detected in the peripheral blood nor in the BMBx. TK mutation analysis was also negative. Induction treatment was started with low dose subcutaneous cytarabine 20mg BID for 10‚Äâdays, cladribine 5mg/m2 intravenously for 5‚Äâdays and venetoclax 100mg daily for 14‚Äâdays with voriconazole 200mg BID. He continued on dasatinib 50mg daily. He achieved a CR of the AML and continue to have a molecular CR of the CML. Currently he is undergoing consolidation therapy for his AML.
Results:
De novo AML in patient with CML is different from CML myeloid blast crisis as patients with de novo AML have negative Ph blasts. A retrospective series performed by Kovitz et.al on 1701 CML patients on imatinib identified 3 cases of MDS and AML. Moreover, patients with CML in remission have also been described to have transient clonal cytogenetic abnormalities or persistent abnormalities that can progress to a second myeloid malignancy. Secondary myeloid malignancy or de novo AML carries a poor prognosis particularly in older patients afflicted by other medical co-morbidities.
Discussion:
The occurrence of AML in patient with CML on TKI is a rare phenomenon. With the advent of TKIs and increase survival of patients with CML, we may see more CML patients presenting with AML either de novo or secondary to clonal hematopoiesis of indeterminate potential.