Secondary Leukemia after Imatinib Mesylate (IM) Therapy for Chronic Myelogenous Leukemia (CML).
Authors: Kovitz Craig A. , Kantarjian Hagop M. , Garcia-Manero Guillermo , Abruzzo Lynne V. , Cortes Jorge E. 
Published: October 2019

Disease progression in CML is often marked by the acquisition of cytogenetic abnormalities beyond the Philadelphia chromosome (Ph), referred to as clonal evolution (CE). In contrast, some patients (pts) develop chromosomal abnormalities in Ph-negative cells while on various therapies for CML, including IM. These abnormalities are frequently transient and their clinical consequence is unclear. Although some reports have suggested these abnormalities might be associated with secondary myelodysplastic syndrome (MDS), the diagnosis has not been established using standard criteria, usually only with megaloblastoid changes and, rarely with increased blasts. We report 2 cases of pts treated with imatinib for CML who subsequently developed chromosomal abnormalities in Ph negative cells, one of whom later developed MDS (RAEB II) and the other acute myelogenous leukemia (AML), a clinical consequence as yet unreported in the literature.

Patient #1: A 51-year-old woman presented to MDACC in January 2001 having been diagnosed with CML in October 1999. Her only treatment in the preceding 14 months had been hydroxyurea. She was begun on treatment with imatinib at a dose of 400 mg daily. With no evidence of a major cytogenetic response after six months, the dose was increased to 600mg daily. She developed pancytopenia, requiring the use of filgrastim (G-CSF), erythropoietin and frequent red cell and platelet transfusions. Bone marrow biopsy showed significant dysplasia with 4% blasts and no evidence of CML. Cytogenetic analysis showed 4/20 (20%) of Ph-negative cells with monosomy 7, and no cells with Ph. IM was held for 6 weeks with no improvement in pancytopenia. Repeat bone marrow biopsy showed 14% blasts and cytogenetic analysis continued to show the presence of 20% Ph-negative cells with monsomy 7. Fluorescence in situ hybridization (FISH) performed on the blasts showed only the presence of monosomy 7 with no Ph thus confirming the diagnosis of a secondary MDS (RAEB II).

Patient 2: A 64-year-old man presented in January 2001 with CML. He was initially treated with hydroxyurea followed by interferon and cytarabine. Treatment related toxicities dictated a change to IM 400 mg daily. With no major cytogenetic response after 12 months, the dose was increased to 600 mg daily with filgrastim and erythropoietin to support suppressed cell counts. Twenty months later, a repeat bone marrow biopsy showed 12% blasts, suggesting a transformation to accelerated phase. Cytogenetics showed a dual population of cells, 2/10 (10%) Ph-positive with -Y and 3/20 (15%) with monosomy 7 and no Ph. Sixteen days later, after initiation of therapy with the experimental compound, AMN-107, the bone marrow showed 38% blasts. Repeat bone marrow biopsy 2 weeks later showed 62% blasts which by FISH showed monosomy 7 and no Ph confirming a secondary AML. To our knowledge these are the first cases of secondary high-risk MDS (RAEB II) and AML after imatinib mesylate therapy occurring in pts with chromosomal abnormalities in Ph-hegative metaphases. Interestingly, both patients had monsomy 7. This is a rare phenomenon as these represent 2 of 1186 pts (0.1%; 95CI 0.00, 0.01) treated with IM at our institution over more than 5 years. This underscores the need to monitor periodically with cytogenetic analysis pts. with CML treated with imatinib.