Chronic myeloid leukemia with three-way translocation t(4;9;22) and multiple myeloma - A rare case of comorbidity
Authors: N. Petkova, L. Grahlyova, R. Hristoskova, A. Nedeva, L. Mitev, J. Raynov
Journal: HemaSphere (2021)

Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of pluripotent hematopoietic stem cells, that is genetically characterized by Philadelphia (Ph') chromosome in 90% of cases, consisting of reciprocal t(9;22)(q34;q11) translocation. About 5-10% of CML patients develop variant translocations involving one or more chromosomes beside 9 and 22. Multiple myeloma (MM) is a monoclonal disorder of plasma cells which have differentiated from lymphoid B cells. Since different cell lines give rise to CML and MM, the occurrence of both MM and CML in the same patient is extremely rare. Aims: We describe a rare case of a patient with CML with t(4;9;22) (q21;q34;q11) three-way translocation and MM diagnosed and treated in our Clinic. Methods: Case report. Data was collected form medical history and clinical charts. Relevant literature was reviewed. Results: We present a case of 71-year-old man with leukocytosis, mild anemia and splenomegaly, who was initially diagnosed with CML, chronic phase. The bone marrow aspirate was typical of CML with granulocyte hyperplasia and 1% myeloblasts. The cytogenetic analysis revealed the presence of an uncommon three-way translocation 46,XY,t(4;9;22)(q21;q34;q11) in all metaphases obtained from the bone marrow, confirmed with positive dual fusion FISH probe for t(9;22)BCR/ ABL. The qRT-PCR detected BCR/ABL1 transcripts. Treatment with tyrosine kinase inhibitor (TKI), nilotinib (300mg bid), was started and the patient achieved a complete hematologic response and at 3 months - complete cytogenetic response with normal bone marrow karyotype and early molecular response. Six months after initial therapy with TKI, mild anemia with a rise of total serum protein were detected and serum protein electrophoresis revealed a monoclonal IgG lambda M-spike of 27g/L. Bone marrow biopsy at that time showed 35-40% CD138+/CD56+ plasma cells infiltration, and no increased blast cells. FISH analysis for BCR/ABL of bone marrow was negative, but quantitative RT-PCR detected M-BCR/ABL with a level of expression of 0.63%. MM was diagnosed, in addition to CML. The revision of the bone marrow at initial CML diagnosis was negative for plasma cells. Chemotherapy with weekly bortezomib, cyclophosphamide and dexamethasone was preferred considering the risk of drug interactions and pancytopenia when combined with nilotinib for CML. The patient achieved complete response with 6 courses of chemotherapy for MM, deep molecular response (DMR) of CML at the first year of TKI therapy;therapy was well tolerated. One year later he developed myeloma relapse with anemia, while DMR of CML remained stable with nilotinib. The patient was treated for relapsed myeloma, but he experienced a complicated COVID-19 infection with pneumonia and renal failure, and had fatal outcome in few weeks. Summary/Conclusion: While other than 9 and 22 chromosomes are frequently involved in three-way translocations, chromosome 4 is a very rare event in CML complex variant, with only seven cases with breakpoint 4q21 reported in cytogenetic databases. The coexistence of CML and MM is another extremely uncommon event with only ten patients described in medical literature diagnosed first as having CML, and then MM. This is for the first time that CML patient with three-way translocation t(4;9;22)(q21;q34;q11) is diagnosed with MM. Due to the rarity of coexistence of two hematological malignancy in the same patient, we have scarce data on treatment approach. Our case demonstrates that nilotinib combined with certain myeloma therapy can be considered safe and efficient in a case of CML and MM comorbidity.