scholarly journals Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for Waldenstrom macroglobulinemia: preliminary report

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 934-937
Author(s):  
DC Jr Case
Keyword(s):  
Combination Chemotherapy ◽  
Response Rate ◽  
Waldenström’S Macroglobulinemia ◽  
Symptomatic Disease ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Initiation Of Therapy ◽  
Waldenström's Macroglobulinemia

Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52–87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.

Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for Waldenstrom macroglobulinemia: preliminary report

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 934-937 ◽  
Author(s):  
DC Jr Case
Keyword(s):  
Combination Chemotherapy ◽  
Response Rate ◽  
Waldenström’S Macroglobulinemia ◽  
Symptomatic Disease ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Initiation Of Therapy ◽  
Waldenström's Macroglobulinemia

Abstract Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52–87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.

Waldenström’s Macroglobulinemia: Clinical Features, Complications, and Management

2000 ◽  
Vol 18 (1) ◽  
pp. 214-214 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Panayiotis Panayiotidis ◽  
Lia A. Moulopoulos ◽  
Petros Sfikakis ◽  
Marinos Dalakas
Keyword(s):  
Clinical Features ◽  
Nucleoside Analogs ◽  
Low Grade ◽  
Waldenström’S Macroglobulinemia ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
The Impact ◽  
Waldenström's Macroglobulinemia

PURPOSE: To review the clinical features, complications, and treatment of Waldenström’s macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal immunoglobulin (Ig) M. METHODS: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. RESULTS: The clinical manifestations associated with Waldenström’s macroglobulinemia can be classified according to those related to direct tumor infiltration, to the amount and specific properties of circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. For symptomatic patients, standard treatment consists primarily of oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one third of previously treated patients and in up to 80% of previously untreated patients. Preliminary evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of previously treated patients and that high-dose therapy with autologous stem-cell rescue is effective in most patients, including some with resistance to nucleoside analogs. CONCLUSION: Waldenström’s macroglobulinemia has a wide clinical spectrum that practicing physicians need to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is the standard primary treatment, but cladribine or fludarabine can be used when a rapid cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of nucleoside analogs on patients’ survival. A nucleoside analog is the treatment of choice for patients who have been previously treated with an alkylating agent.

The Role of Angiopoietins System in Waldenstrom's Macroglobulinemia: Correlations with Marrow Microvessel Density and Survival

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3901-3901
Author(s):  
Efstathios Kastritis ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Maria Gavriatopoulou ◽  
Dimitrios Christoulas ◽  
Athanasios Papatheodorou ◽  
...  
Keyword(s):  
Microvessel Density ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Waldenström’S Macroglobulinemia ◽  
Vessel Formation ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Angiogenic Cytokines

Abstract Abstract 3901 Angiogenesis is elevated in many hematological malignancies, but there is limited information for angiogenesis in Waldenstrom's macroglobulinemia (WM). Several cytokines including VEGF (and its major angiogenic component VEGF-A), bFGF, angiogenin and angiopoietin-1 (Ang-1) and 2 (Ang-2) participate in the neoangiogenesis process. We have previously shown that circulating angiogenic cytokines correlate with disease severity in WM (Anagnostopoulos et al, Br J Haematol 2007;137:560–8), while it has been reported that the bone marrow (BM) microvessel density (MVD) is increased in 30%-40% of patients with WM (Rajkumar et al, Semin Oncol 2003;30:265–9). The ratio of Ang-1/Ang-2 correlates with survival in multiple myeloma, but there is no information for the prognostic value of the angiopoietins and other angiogenic cytokines in WM. To address this issue, we studied the serum levels of VEGF, VEGF-A, bFGF, angiogenin, Ang-1 and Ang-2 in the serum of 55 patients with symptomatic WM before the administration of any kind of therapy, in 5 patients with asymptomatic WM (AWM), in 12 patients with IgM MGUS and in 30 healthy controls, of similar age and gender. Circulating VEGF, VEGF-A, bFGF, angiogenin, Ang-1 and Ang-2 were measured using ELISA method (R&D Systems, Minneapolis, MN, USA for VEGF, bFGF, angiogenin, Ang-1 and, Ang-2; Diaclone SAS, Besancon, France for VEGF-A). MVD was also evaluated in the BM biopsies of all patients, according to standard methodology. Table 1 depicts the levels of the studied angiogenic cytokines. The serum levels of VEGF, VEGFA, bFGF, angiogenin and Ang-2 were markedly elevated in WM patients compared to controls (p<0.001 for all comparisons); Ang-1 levels (p<0.01) were lower in WM patients than in controls, and the corresponding Ang-1 to Ang-2 ratio was significantly lower in WM patients than in controls, further indicating an angiogenic shift in WM patients. Circulating angiogenin (p<0.001) and Ang-2 (p=0.001) levels were also increased in WM patients compared to patients with IgM MGUS but Ang-1 levels were lower (p=0.003) resulting in Ang 1/2 ratio significantly higher in IgM MGUS than WM patients (p=0.004). In symptomatic WM patients, Ang-2 levels and the corresponding Ang-1/2 ratio correlated with serum beta2-microglobulin (r=0.454, p=0.002 and r=0.459, p=0.003, respectively). Ang-2 levels correlated with ISSWM stage (1914 ± 1175 pg/ml vs. 4461 ± 2628 pg/ml vs. 3926 ± 2172 pg/ml, for ISSWM-low, intermediate and high risk, respectively, p=0.007). A strong inverse correlation of MVD to Ang-1 was found in patients with WM (r=-0.600, p=0.011), indicative of the regulatory function of Ang-1 as an antagonist of vessel sprouting and new vessel formation. The median follow-up of symptomatic WM patients was 35 months. The median overall survival (OS) has not been reached yet, while the probability for 3-year OS was 76%. The median progression-free survival (PFS) was 57 months and the 3-year probability of PFS was 56%. Patients with Ang-2 levels above the median value had significantly shorter PFS (3-year PFS rate 82% vs. 50%, p=0.032; Figure). We conclude that in patients with WM, serum levels of several angiogenic cytokines (Ang-2, angiogenin, VEGF, VEGF-A, and bFGF) are markedly elevated and for some of these cytokines there is a correlation with disease features. The levels of pro-angiogenic cytokines, such as Ang-2 increase as disease evolves for IgM MGUS to symptomatic WM, while the Ang-1 decreases. We show that the MVD in the BM strongly correlates to decreasing Ang-1 levels, probably due to the decreasing inhibitory effect of Ang-1 to vessel formation in the BM microenvironment as disease evolves. For the first time we found that Ang-2, may also have a prognostic significance, associated with significantly shorter PFS. Further follow up is needed in order to evaluate the prognostic significance of Ang-2 for the OS of patients with WM Table: Levels of the studied circulating angiogenic cytokines (mean ± SD) Controls IgM MGUS aWM WM VEGF (pg/ml) 106 ± 76 323 ± 217 116 ± 83 399 ± 248 VEGF-A (pg/ml) 6.7 ± 13.6 97.5 ± 94 28.4 ± 49.3 113 ± 113 bFGF (pg/ml) 1.3 ± 3.2 12 ± 14 9.5 ± 16 17 ± 21.6 Angiogenin (pg/ml) 2.4×105 ± 0.5×105 2.7×105 ± 0.8×105 2.8×105 ± 0.7×105 4.5×105 ± 2.1×105 Ang-1 (pg/ml) 4.8×105 ± 1.1×105 4.8×105 ± 1.9×105 2.6×105 ± 1.5×105 2.5×105 ± 2.3×105 Ang-2 (pg/ml) 1747 ± 1023 1783 ± 684 3775 ± 1296 3424 ± 2570 Ang-1/2 ratio 28.1 ± 11.6 31 ± 14 6.5 ± 1.6 14.5 ± 17.7 Disclosures: No relevant conflicts of interest to declare.

Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8513-8513
Author(s):  
M. A. Gertz ◽  
R. Abonour ◽  
L. T. Heffner ◽  
P. R. Greipp ◽  
H. Uno ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Waldenström’S Macroglobulinemia ◽  
Minor Response ◽  
Free Survival ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
A Minor ◽  
Waldenström's Macroglobulinemia

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

Bendamustine-Based Therapy Is Highly Active In Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4700-4700
Author(s):  
Steven P. Treon ◽  
Christina Hanzis ◽  
Christina Trispsas ◽  
Leukothea Ioakimidis ◽  
Christopher Patterson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Nucleoside Analogues ◽  
Waldenström’S Macroglobulinemia ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 4700 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell malignancy characterized by lymphoplasmacytic cell infiltration of the bone marrow and production of an IgM monoclonal protein. Despite advances in treatment, WM remains incurable and novel agents are needed for ongoing disease control. Bendamustine represents an important novel agent for the treatment of B-cell disorders whose activity in WM remains to be clarified. Patients and Methods: We examined the outcome of 30 previously treated patients with the clinicopathological diagnosis of WM who received bendamustine-based therapy. The median prior therapies was 2 (range 1–9), and 16 (53%) patients were refractory to their previous treatment. Baseline characteristics for all patients: Median BM involvement 60%; serum IgM 3,980 mg/dL; Hct 31.0%; serum B2M 3.5 g/L. Treatment consisted of bendamustine administered at 90 mg/m2 IV on days 1, 2 as part of a 4 week cycle, along with rituximab (375 mg/m2 IV) given once on either day 1 or 2 for 24 patients. In the remainder 6 patients, severe rituximab intolerance prevented re-administration of rituximab. In these patients, bendamustine was either administered alone (n=4) or with ofatumumab (1000 mg IV) given on day 1 (n=2) following a test dose of 300 mg IV on day -7 prior to cycle 1 only. Intended therapy consisted of 4–6 cycles of treatment. Plasmapheresis was performed prior to treatment in patients exhibiting symptomatic hyperviscosity, or who had an IgM level >5,000 mg/dL and were to receive monoclonal antibodies in order to prevent a symptomatic IgM flare. Responses were assessed using modified WM consensus criteria, and patients were eligible for response assessment if they completed > 2 cycles of therapy. Results: 21 patients completed intended therapy; 9 patients continue on treatment. The median number of treatment cycles for all patients is 4 (range 2–6). Following treatment, median serum IgM levels declined from 3,980 to 1,210 mg/dL (p<0.0001), and hematocrit rose from 31.9% to 34.7% (p=0.005) at best response. The overall and major response rates were 80% and 73%, respectively, with 3 VGPR; 19 PR; 2 MR. 6 patients were non-responders. Responders included those patients receiving bendamustine alone (4 PR), or with ofatumumab (1 PR; 1 MR). With a median follow-up of 5 months, 22/24 responders continue in response. Overall, treatment was well tolerated with grade <2 nausea and diarrhea being the most common toxicities encountered. Three patients developed superficial thrombophlebitis at the site of bendamustine infusion, warranting institution of anticoagulation in 1 patient. Prolonged myelosuppression occurred in 3 patients who received previous nucleoside analogue therapy. One patient previously treated with nucleoside analogues and cyclophosphamide developed MDS, and another patient who received previous cyclophosphamide and bortezomib based therapies transformed to diffuse large B-cell lymphoma following bendamustine-based therapy. Conclusion: Bendamustine-based therapy is active in patients with relapsed or refractory WM and produces high response rates and durable responses both as monotherapy, and in combination with CD20 directed monoclonal antibodies. In patients previously treated with nucleoside analogues, prolonged myelosuppression may occur. Long term toxicities of bendamustine-based therapy remain to be clarified in this patient population. Disclosures: No relevant conflicts of interest to declare.

Smouldering Waldenstrom's macroglobulinemia: Factors predicting evolution to symptomatic disease

2003 ◽  
Vol 30 (2) ◽  
pp. 231-235 ◽  
Author(s):  
Clara Cesana ◽  
Sara Miqueleiz ◽  
Patrizia Bernuzzi ◽  
Elisabetta Tresoldi ◽  
Valentina Rossi ◽  
...  
Keyword(s):  
Waldenström’S Macroglobulinemia ◽  
Symptomatic Disease ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia

2015 ◽  
Vol 372 (15) ◽  
pp. 1430-1440 ◽  
Author(s):  
Steven P. Treon ◽  
Christina K. Tripsas ◽  
Kirsten Meid ◽  
Diane Warren ◽  
Gaurav Varma ◽  
...  
Keyword(s):  
Waldenström’S Macroglobulinemia ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Rituximab and Cyclophosphamide Based Regimens for Treatment of Waldensterom Macroglobulemia, Lessons from Clinical Literature: A Systemic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Qasim Khurshid ◽  
Abdul Jabbar Dar ◽  
Muhammad Ali Mirza ◽  
Muhaddis Ejaz Ahmad ◽  
Sobia Aamir ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Partial Response ◽  
Overall Response Rate ◽  
Response Rate ◽  
Waldenström’S Macroglobulinemia ◽  
Overall Response ◽  
Major Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia is a rare low-grade lymphoplasmacytic lymphoma characterized by CD20 expression on malignant cells and produces a monoclonal immunoglobulin M (IgM). Rituximab is a chimeric monoclonal antibody against CD20 antigen and the most widely used therapeutic agents in WM. Rituximab works by adhering to CD20, causes B-cell lysis mainly through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Cyclophosphamide is an alkylating agent binds to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA, and to inhibition of protein synthesis. Our objective is to analyze and summarize the published literature for the efficacy of regimens containing both rituximab and cyclophosphamide for the treatment of Waldenström's macroglobulinemia (WM). Methods:We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after January 2005, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library, and Web of Science. A total of 585 articles were identified initially, and after a detailed screening, we finalized 10 studies involving 425 WM patients. Results:The total number of patients were 425. The dose was 375 mg/m2. The complete response (CR) ranged from 3-19%, very good partial response (VGPR) ranged from 4-22%, and the partial response (PR) ranged from 8-82%. The overall response rate (ORR) ranged from 79-95%. Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP): In a retrospective study by Ioakimidis et al., included 23 WM patients were given R-CHOP. The ORR was 95%, with 69% achieving a major response, 43%, PR, and VGPR OF 9%. In a randomized control trial by Buske et al., N=23, the major response rate was 91%, and PR was 82%. Treon et al. (N=13) observed a major response rate of 27%. (Table 1). Fludarabine, Cyclophosphamide and Rituximab (FCR): In a retrospective study by Peinert et al., involving 29 patients receiving the FCR regimen, the ORR was 90%, with 79%, 3%, and 10% of patients achieving PR, CR, and NR, respectively. In a study by Tedeschi et al., involving 40 patients, ORR was 80%, and the major response rate was 80%. Souchet et al., N=82 reported an ORR of 84% and a PR of 46%. Progression-free survival (PFS) was 51.2 months for Tedeschi et al. Dexamethasone, Rituximab and Cyclophosphamide (DRC) In study Paludo et al., (N=50), receiving the DRC regimen, the highest ORR was 87%, PR 64%, and major response was 68%. In a phase II study by Dimopoulos et al., (N=72), the ORR of 82% and PR of 67% was observed. PFS was 24 months in this study. (Table 1) 4.Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) In study Ioakimidis et al, N=16, the ORR was 87%, the major response rate was 62%, and the PR was 43%. Rituximab, Cyclophosphamide, and Prednisone (RCP) Ioakimidis et al., reported 19 patients who were given RCP. The ORR, PR, and the major response rate was 94%, 73%, and 73%, respectively.Lenalidomide, Rituximab, Cyclophosphamide, and Dexamethasone (LR-CD) A study by Rosenthal et al., 15 patients were given LR-CD. ORR was 80%, with a major response rate in 80% and PR in 73% of patients. PFS was 38 months. Conclusion: Rituximab and cyclophosphamide, in combination regimens for the treatment of WM showed the overall response rate of 95%. Neutropenia was the dominant side effect reported in these regimens. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing both rituximab and cyclophosphamide base combinations. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Molecular Analysis of the VH Gene Usage in a Familial Case of Waldenstrom’s Macroglobulinemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1005-1005
Author(s):  
Marina P. Siakantaris ◽  
Marie-Christine Kyrtsonis ◽  
Konstantinos Lilakos ◽  
Maria K. Angelopoulou ◽  
S. Vavourakis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Healthy Individuals ◽  
Waldenström’S Macroglobulinemia ◽  
Three Generations ◽  
Mild Anemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Lymphoplasmacytic Infiltration ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow and/or other tissues and the presence of a serum monoclonal IgM. The etiology of the disease is still unknown but the identification of family clusters may contribute to the understanding of its pathogenesis. In this study we present a family with 4 members affected by WM consisting of three generations; 2 sisters of the first generation were both suffering from WM. One of them presented to our section with mild anemia, a monoclonal serum IgM compound, 80% infiltration by lymphoplasmacytes in the bone marrow and the diagnosis of WM was made. Her sister was also suffering from WM but followed in another Centre. Our patient had two sons that at the age of 52 and 46 years presented a serum monoclonal IgM. At presentation, the first one had a monoclonal IgM value of 1680 mg/dl and a 40% BM lymphoplasmacytic infiltration with no other findings, signs or symptoms; he is regularly followed in our section for 30 months and his disease is stable. The second son, presented with a serum monoclonal IgM value of 886 mg/dl and a 10% BM infiltration by monoclonal lymphoplasmacytes and plasmacytes and was initially characterized as having an IgM-MGUS; while under follow-up examination only, he developed peripheral neuropathy with positive anti-Mag antibodies and improved with rituximab administration. Nor the mother or the sons had HCV antibodies. The first son has 3 children and the second two. Buccal and blood DNA was analysed for the IgH rearrangement by PCR. The PCR products after ligation and cloning were sequenced in an automated sequencer. Sequences obtained from each sample were aligned with germline sequences in the BLAST directory. No Ig rearrangements were detected in buccal DNA. Monoclonality was demonstrated in all affected members and in 2 healthy individuals of the third generation by PCR while immunophenotyping did not show evidence of disease in those two members. VH3 family was expressed at the highest frequency (80%). Different gene segments were recognized for the analysed sequences. D segments were attributed in all sequences. All affected and 1 healthy member had mutated VH genes. This is the first study of a family with WM consisting of three generations and reporting blood monoclonality of healthy individuals by molecular methods. The biologic value of the finding remains to be seen. Further study and a long follow-up is needed to clarify this issue.

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