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Biclonal origin prevails in concomitant chronic lymphocytic leukemia and multiple myeloma

Leukemia volume 24, pages 885–890 (2010)Cite this article

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B-cell chronic lymphocytic leukemia (B-CLL) is a common hematological malignancy that typically follows an indolent course over many years. However, with longer disease course and recurring anti-B-CLL therapy, in addition to yet undefined causes, transformation to aggressive B-cell lymphoma may occur. Coincidence of B-CLL with other hematological disorders has also been observed, nevertheless, the simultaneous appearance of B-CLL and multiple myeloma (MM) is a rare phenomenon.1, 2 The clonal relationship between B-CLL and MM remains controversial. Two hypotheses have been postulated, either that both malignancies develop from two distinct clones, or that both evolve from the same B progenitor. To unravel the clonality of concomitant B-CLL and MM, different experimental strategies have been pursued. Early publications focused on different vs identical light chain (LC) expression in both diseases.1 Hoffmann and Rudders3 described a patient in whom B-CLL and malignant plasma cells (mPCs) expressed different LCs, suggesting a different clonal origin. Nevertheless, despite different LCs and immunglobulin (Ig) isotypes with B-CLL-cells expressing IgM kappa (κ) and mPCs IgA lambda (λ), Saltman et al.4 postulated a monoclonal B-CLL/MM origin, as they detected identical heavy chain gene rearrangements in B-CLL cells and mPCs. The second approach to solve the clonal relationship is based on different cytogenetic aberrations discovered in B-CLL and MM.5 As B-CLL and MM are difficult to examine by conventional cytogenetics (due to their low proliferation and metaphase quality), interphase fluorescence in situ hybridization (FISH) technology, together with simultaneous detection of cytoplasmatic LCs, have been used recently to prove a biclonal origin of both diseases.2 In this study, we describe five Caucasian male patients with concomitant B-CLL and MM diagnosed at our center within a 4-year period (2005–08). To resolve the clonal relationship, we combined Affymetrix (Santa Clara, CA, USA) single-nucleotide polymorphism (SNP) mapping array and FISH analyses on bone marrow (BM) smears. The SNP technology is highly efficient in the detection of recurrent and new chromosomal aberrations in B-CLL and MM,6 and FISH on BM smears allowed us to connect specific chromosomal aberrations to different cell compartments.

Among our five patients, the first patient was a 64-year-old male, being evaluated in August 2005 because of weight loss, leukocytosis, anemia, foamy urine and increased creatinine. Detailed diagnostics revealed a Bence-Jones κ-proteinuria, elevated serum κ-LCs and via BM biopsy mPCs (40%) as well as lymphocytic infiltrates (45%). Immunohistology confirmed the simultaneous BM infiltration of mPCs and B-CLL cells. The diagnosis of concomitant MM stage IIIB (Salmon & Durie) and B-CLL stage Rai 0 was made (Supplementary Table 1). Identical unmutated clonal IgVH transcripts (VH 4-39) were present in both peripheral blood (PB) and BM cells (Table 1). As this transcript was cloned by amplifying mRNA of IgM (μ) type and the vast majority of MM undergo class switch, it was postulated as derived from the B-CLL clone present in both PB and BM cells. The same transcript was detected with a low frequency in CD19+ selected PB cells in December 2007, when the patient had stable MM and B-CLL diseases. LCs expressed by the B-CLL compartment were not measurable by flow cytometry. Copy number analyses using Affymetrix 50K and 250K NspI SNP arrays revealed no chromosomal aberration in unselected BM and CD19+ selected PB cells (Table 1). Despite rigorous analysis, the clonal relationship of concomitant MM/B-CLL in this patient remained unclear. Because of stage IIIB MM and B-CLL Rai 0 disease, he received two cycles of vincristine, doxorubicin, dexamethasone (VAD), PB stem cells (PBSCs) were mobilized with epirubicine, etoposide, cyclophosphamide (EVC), followed by an autologous PBSC (auto-PBSC) transplantation. According to European Group for Blood and Marrow Transplantation (EBMT) criteria, the patient obtained a partial remission of his MM, and has remained stable of both his MM and B-CLL with thalidomide maintenance therapy (Supplementary Table 2).

Table 1 Immunological and molecular features of concomitant CLL and MM patients
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Acknowledgements

We thank the anonymous internal and external reviewers for valuable comments and Dr Anke Spoo and Professor Dr Dr h.c. Roland Mertelsmann for fruitful discussions and continuous support. This article is dedicated to Professor Dr Norbert P Südkamp, Department of Orthopedic Surgery and Traumatology, Freiburg University Hospital, for his exceptional support, medical enthusiasm and thrive to best and innovatively treat his and our joint myeloma patients.

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  1. Department of Hematology and Oncology, Core facility Genomics, University Medical Center Freiburg, Freiburg, Germany

    M Pantic & D Pfeifer

  2. Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany

    P Schroettner, J Rawluk, U Denz, H Veelken, R Wäsch & M Engelhardt

  3. Pathology Department, University Medical Center Freiburg, Freiburg, Germany

    A Schmitt-Gräff

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Correspondence to M Engelhardt.

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Pantic, M., Schroettner, P., Pfeifer, D. et al. Biclonal origin prevails in concomitant chronic lymphocytic leukemia and multiple myeloma. Leukemia 24, 885–890 (2010). https://doi.org/10.1038/leu.2009.294

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