Severe Myelodysplasia with Monosomy 7 Developing during Imatinib Treatment of Philadelphia-Positive Chronic Myeloid Leukemia: Two Cases Evolving with Different Outcome.
Authors: Navarro José-Tomás , Feliu Evarist , Grau Javier , Colomer Dolors , Espinet Blanca , Granada Isabel , Xicoy Blanca , Orna Elisa , Oriol Albert , Lloveras Natalia , Junca Jordi , Ribera Josep-Maria , Milla Fuensanta 
Published: April 2020

Background. Several studies have reported cases of Ph-positive CML treated with imatinib developing chromosomal abnormalities in Ph-negative cells. Trisomy 8 is the most frequent of these abnormalities, but monosomy 7 has also been detected. The association of these cytogenetic alterations with severe myelodysplasia has been scarcely reported. We present 2 cases of monosomy 7 with severe myelodysplasia arising during imatinib treatment of Ph-positive CML, one evolving as a transient clonal abnormality, and the other with a fatal evolution to AML.

Case 1. A 55 year-old man was diagnosed with Ph-positive chronic phase CML in July 2000. He started treatment with IFN-α without cytogenetic response, and in October 2002 he began imatinib-mesylate (400 mg/day). After 6 months on imatinib he developed anemia and neutropenia, with severe dysplastic features on peripheral blood. Dysplastic features in the 3 series with 70% of ring syderoblasts were observed in the bone marrow. The ultrastructural study showed numerous erythroblasts with iron-loaded mitochondria and some “ring forms”. The cytogenetic study was: 46,XY,t(9;22)(q34;q11)[4]/ 45,XY,-7[12]/46,XY[6]. The dose of imatinib was reduced (300 mg/day). Three months later, peripheral blood cell counts were normal, the myelogram showed mild dyserythropoiesis without ring syderoblasts and the cytogenetic study was: 46,XY,t(9;22)(q34;q11)[7]/47,XY,+8[15]. Monosomy 7 was not detected by FISH. From January 2004 he has been treated with imatinib (300 mg/day) and IFN-α and the karyotype is: 46,XY,t(9;22)(q34;q11)[15]/ 46,XY[6]. Monosomy 7 and trisomy 8 have not been detected.

Case 2. A 47 year-old man was diagnosed with Ph-positive chronic phase CML in October 2001. He was initially treated with hydroxyurea and in February 2002 a peripheral blood allogeneic stem cell transplant from a HLA-identical sibling, conditioned with busulfan and cyclophosphamide, was performed. Seven months later Ph chromosome was detected in 100% of metaphases and the patient was treated with 2 donor lymphocyte infusions without response. Imatinib at a dose of 400 mg/day plus G-CSF was started. After 14 months on imatinib, a complete cytogenetic response was obtained and 9 months later, molecular response was achieved too. Three months later (March, 2005), pancytopenia was detected. In the bone marrow, severe dysplasia in the 3 series with predominance of erythroid precursors and 41% of ring syderoblasts, were observed. The cytogenetic study showed a complex karyotype harboring monosomy 7: 45,XY,-7[9]/45,X,add(Y)(q12),-7[4]/46,XY,-7,+21[2]/46,XY[5]. Imatinib was stopped and 2 months later the patient was diagnosed with refractory anemia with excess of blasts. He rapidly progressed to AML and has been treated with idarubicine, cytarabine and etoposide as induction therapy without response.

Monosomy 7 (2 cases) and trisomy 8 (case 1) were not retrospectively detected by FISH, prior to the introduction of imatinib. Conclusions. Severe myelodysplasia with monosomy 7 can develop in Ph-negative metaphases of patients with CML treated with imatinib. Although in some cases these alterations are transient, in others the evolution can be fatal to AML. Imatinib may play a role in the appearence of these clonal abnormalities.