Biclonal Origin Prevails in Concomitant Chronic Lymphocytic Leukemia and Multiple Myeloma
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Letters to the Editor 885 Biclonal origin prevails in concomitant chronic lymphocytic leukemia and multiple myeloma Leukemia (2010) 24, 885–890; doi:10.1038/leu.2009.294; compartment were not measurable by flow cytometry. Copy published online 21 January 2010 number analyses using Affymetrix 50K and 250K NspI SNP arrays revealed no chromosomal aberration in unselected BM B-cell chronic lymphocytic leukemia (B-CLL) is a common and CD19 þ selected PB cells (Table 1). Despite rigorous hematological malignancy that typically follows an indolent analysis, the clonal relationship of concomitant MM/B-CLL in course over many years. However, with longer disease course this patient remained unclear. Because of stage IIIB MM and and recurring anti-B-CLL therapy, in addition to yet undefined B-CLL Rai 0 disease, he received two cycles of vincristine, causes, transformation to aggressive B-cell lymphoma may doxorubicin, dexamethasone (VAD), PB stem cells (PBSCs) were occur. Coincidence of B-CLL with other hematological disorders mobilized with epirubicine, etoposide, cyclophosphamide has also been observed, nevertheless, the simultaneous (EVC), followed by an autologous PBSC (auto-PBSC) transplan- appearance of B-CLL and multiple myeloma (MM) is a rare tation. According to European Group for Blood and Marrow phenomenon.1,2 The clonal relationship between B-CLL and Transplantation (EBMT) criteria, the patient obtained a partial MM remains controversial. Two hypotheses have been postu- remission of his MM, and has remained stable of both his MM lated, either that both malignancies develop from two distinct and B-CLL with thalidomide maintenance therapy (Supplemen- clones, or that both evolve from the same B progenitor. tary Table 2). To unravel the clonality of concomitant B-CLL and MM, different The second 76-year-old male patient presented with leuko- experimental strategies have been pursued. Early publications cytosis and IgG lambda (l) paraprotein in January 2006. Via BM focused on different vs identical light chain (LC) expression in biopsy, l-positive mPCs (30%) and k-positive B-CLL-infiltrates both diseases.1 Hoffmann and Rudders3 described a patient in (10%) were detected. IgVH analysis from cDNA showed a whom B-CLL and malignant plasma cells (mPCs) expressed mutated clonal transcript in PB cells. The 50K SNP assay different LCs, suggesting a different clonal origin. Nevertheless, performed on unselected PB cells revealed a 5.8 Mb deletion of despite different LCs and immunglobulin (Ig) isotypes with the 13q14 region (Table 1). The quality and quantity of the BM B-CLL-cells expressing IgM kappa (k) and mPCs IgA lambda (l), sample did not allow CD138 þ selection of mPCs, nevertheless, Saltman et al.4 postulated a monoclonal B-CLL/MM origin, as FISH using multicolor DNA probes on BM cytospins revealed they detected identical heavy chain gene rearrangements in deletion of at least two regions on chromosome 13 (one signal B-CLL cells and mPCs. The second approach to solve the clonal for 13q14 and one signal for 13q34) in 19 of 20 analyzed mPCs relationship is based on different cytogenetic aberrations (Figure 1a). The DNA probe used in the 13q14 locus D13S319 discovered in B-CLL and MM.5 As B-CLL and MM are difficult overlapped with the 5.8 Mb deletion detected by the SNP array to examine by conventional cytogenetics (due to their low (UCSC Genome Browser, http://genome.ucsc.edu). However, proliferation and metaphase quality), interphase fluorescence the more telomeric DNA probe at 13q34 was outside the in situ hybridization (FISH) technology, together with simulta- detected 5.8 Mb deletion, indicating monosomy of chromosome neous detection of cytoplasmatic LCs, have been used recently 13 in mPCs. Immunophenotyping showed different expression to prove a biclonal origin of both diseases.2 In this study, we of LCs for B-CLL (k) and mPCs (l), suggesting biclonality describe five Caucasian male patients with concomitant B-CLL of B-CLL and MM diseases. Because of concurrent stage Rai 0 and MM diagnosed at our center within a 4-year period B-CLL and stage IIIA MM by S&D, the patient received (2005–08). To resolve the clonal relationship, we combined melphalan, prednisone (MP) and achieved a partial remission Affymetrix (Santa Clara, CA, USA) single-nucleotide polymor- of his MM. At 17 months after the diagnosis of B-CLL and MM, phism (SNP) mapping array and FISH analyses on bone marrow the patient acquired acute myeloid leukemia (AML) (French- (BM) smears. The SNP technology is highly efficient in the American-British (FAB) M0), classified as therapy-induced detection of recurrent and new chromosomal aberrations in B-CLL (t-AML). The analysis of AML blast cells did not show del and MM,6 and FISH on BM smears allowed us to connect specific 13q14/monosomy 13, arguing for oligoclonality as well. chromosomal aberrations to different cell compartments. Because of t-AML, mitoxantrone, etoposide, cytarabine (MICE) Among our five patients, the first patient was a 64-year-old induction and consolidation chemotherapy was performed, male, being evaluated in August 2005 because of weight loss, achieving a complete remission. After 10 months, AML relapse leukocytosis, anemia, foamy urine and increased creatinine. occurred, and the patient eventually died of AML progression Detailed diagnostics revealed a Bence-Jones k-proteinuria, and septic complications. Autopsy revealed overt AML, but of elevated serum k-LCs and via BM biopsy mPCs (40%) as well note no MM or B-CLL residues (Supplementary Table 2). as lymphocytic infiltrates (45%). Immunohistology confirmed The third patient was a 73-year-old male diagnosed with stage the simultaneous BM infiltration of mPCs and B-CLL cells. The Rai II B-CLL in 2003. Flow cytometry revealed a typical B-CLL diagnosis of concomitant MM stage IIIB (Salmon & Durie) and phenotype, with monoclonal k-positive PB and BM B-CLL cells. B-CLL stage Rai 0 was made (Supplementary Table 1). Identical In August 2005, the patient was admitted to the orthopedic unmutated clonal IgVH transcripts (VH 4-39) were present in department due to progressive lumbago and deteriorating both peripheral blood (PB) and BM cells (Table 1). As this clinical condition. Serum immunoelectrophoresis revealed an transcript was cloned by amplifying mRNA of IgM (m) type and IgA paraprotein and BJ-k proteinuria. Skeletal survey showed the vast majority of MM undergo class switch, it was postulated multiple osteolytic lesions and diffuse osteopenia. BM biopsy as derived from the B-CLL clone present in both PB and BM displayed 30% B-CLL and 15% CD38- and CD138-positive cells. The same transcript was detected with a low frequency in mPCs. A diagnosis of B-CLL (stage Rai II) and IgA k-MM CD19 þ selected PB cells in December 2007, when the patient (IIIA by S&D) was made (Supplementary Table 1). A mutated had stable MM and B-CLL diseases. LCs expressed by the B-CLL IgVH status and biallelic deletion of chromosome 13q14 were Leukemia Letters to the Editor 886 Table 1 Immunological and molecular features of concomitant CLL and MM patients Patients CLL Specimen description IgVH family/ SNP-array copy number results Specimen FISH Clonality vs used for molecular mutation used for MM analysis status FISH analysis #1 CLL DNA from CD19+ VH-4-39/ No aberration n.d. Not CLL/MM PB cells unmutated resolved MM DNA from unselected VH-4-39/ No aberration n.d. BM cells unmutated #2 CLL cDNA and DNA from VH 3-15/ del 13q14 (5.8 Mb) n.d. Biclonal CLL/MM unselected PB cells mutated MM s.n.o. s.n.o n.d. BM smears (del 13q14 and and cytospins del 13q34) #3 CLL DNA and cDNA from VH 3-72/ Bi-allelic del 13q14 (5.6/2.7 Mb) n.d Biclonal CLL-MM CD19+ PB cells mutated in CD19 + cells MM s.n.o. n.d. n.d. BM smears Trisomy 11 #4 CLL DNA and cDNA from VH 4-34/ No aberration in CD19 +cells n.d. Biclonal CLL-MM CD19+ PB cells mutated MM DNA from CD138+ VH 1-18/ Complex aberrations: gain 4p (19.9 Mb), n.d. BM cells mutated del10q (6.6 Mb), gain 11q(53.4 Mb), del 12p (15.8 Mb), del 17p (8.1 Mb) #5 CLL DNA and cDNA from VH 3-9 (cDNA) del 11q23 (15.4 Mb), del 11q24 (5.5 Mb) Unselected del 11q23 Biclonal CLL-MM unselected BM CLL cells VH 3-15 (DNA)/ in unselected BM and PB cells BM cells unmutated MM DNA from unselected VH 3-9 (DNA) n.d. Unselected t(11;14), BM MM cells VH 3-15 (DNA)/ BM/BM hyperdiplody unmutated smears of chr. 11 Summary CLL IgVH mut:unmut 3:2 CLL SNParray CLL FISH bc: n ¼ 4 MM IgVH mut:unmut 1:2 abnor:nor 3:2 abnor:nor 1:0 MM SNParray MM FISH abnor:nor 1:1 abnor:nor 3:0 Abbreviations: bc, biclonal; BM, bone marrow; CLL, cell chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; MM, multiple myeloma; PB, peripheral blood; n.d., not done; SNP, single-nucleotide polymorphism; s.n.o., sample not obtained. detected in CD19 þ selected PB (B-CLL) cells. Moreover, the showed 50% B-CLL cells and 40% coexisting monoclonal two deleted alleles were 5.62 and 2.70 Mb in size, both k-expressing mPCs. Differently mutated clonal IgVH transcripts, overlapping micro RNA genes MIRNA15A/MIRN16-1 (Table 1). VH4-34 and VH1-18, were present in CD19 þ PB and We performed FISH analyses on BM smears on 50 mPCs and CD138 þ BM cells, respectively, strongly implying a biclonal all showed two signals for the chromosomal region 13q14, origin of both diseases (Table 1).