Some monoclonal proteins from patients with Waldenstrom's macroglobulinemia (WM) or immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance possess antigen-binding activity directed to autogenous or foreign antigens. These monoclonal IgM autoantibodies include cold agglutinins, mixed cryoglobulins, and antineural components. Because of the antigenantibody interaction, patients with these autoimmune syndromes often present with hemolytic anemia, mixed cryoglobulinemia, or peripheral neuropathy, respectively, at an earlier stage than patients with typical WM who do not have evident antibody activity. The presence of monoclonal macroglobulin autoreactive antibodies thus influences clinical presentation and natural history. Monoclonal IgM antibodies display polyreactivity to antigens of microbial origin in addition to autogenous antigens and may arise through T-independent as well as T-dependent pathways. Waldenstrom proteins with antibody activity appear to provide a link between autoimmunity, infection, and lymphoproliferative disease. Study of the antigens reacting with monoclonal IgMs may provide further insight into the pathogenesis of WM.
We analyzed the clinical features and prognostic factors for transformation of immunoglobulin Mrelated disorders (IgM-RDs) to malignant lymphoproliferative disease (MLD) in 83 patients with IgM-RDs. We studied 19 patients with type I cryoglobulinemias, 56 patients with type II cryoglobulinemias, 5 patients with peripheral neuropathies (PNs), and 3 patients with idiopathic thrombocytopenic purpuras. Fourteen patients with cryoglobulinemias presented with mild to moderate hepatomegaly with or without splenomegaly. Fourteen patients with type II cryoglobulinemias had arthralgias and/or vascular purpura (12 receiving corticosteroids), and 7 presented with PN. These latter patients and those with PNs without cryoglobulinemia were treated with steroids, cyclophosphamide, or polychemotherapy with/without plasma-exchange. Cumulative probability of evolution to MLD at 5 years was 15% (95% CI; 5%-25%). At a median of 62 months (12-195 months), 8 cases of IgM-RDs (8.4%) evolved to overt Waldenstrom's macroglobulinemia (n = 6), 1 case to non-Hodgkin's lymphoma, and 1 case to B-cell chronic lymphocytic leukemia. At univariate analysis, male sex (P = 0.02), IgM level > or = 3 g/dL (P < 0.0001), detectable Bence Jones proteinuria (P = 0.0005), lymphocytosis (P = 0.049), and high erythrocyte sedimentation rate (P = 0.003) significantly correlated with the evolution risk. Age, blood cell counts, b2-microglobulin level, degree of marrow lymphoplasmacytic infiltration, type of cryoglobulinemia, and hepatitis C virus positivity did not correlate with transformation. Although IgM-RDs represent a distinct clinical entity frequently requiring treatment in view of the IgM-related symptoms, their evolution probability and prognostic factors for malignant transformation seem to widely overlap those described for asymptomatic IgM monoclonal gammopathies.
PURPOSE:Non-Hodgkin's lymphoma of the breast represents 0.04%-0.50% of malignant lesions of the mammary gland. In this article, we report a single institution's experience with this rare disease.MATERIALS AND METHODS:Between 1982 and 1997, 19 patients with breast lymphoma were diagnosed, treated, and followed at this institution.RESULTS:There were 18 female patients and 1 male patient. All but one were cases of aggressive B-cell lymphoma. Ann Arbor stages were IE (n=5), IIE (n=9), IIIE (n=2), and IV (n=3). International Prognosis Index scores were 0 (n=2), 1 (n=8), 2 (n=7), and 3 (n=2). According to the Wiseman and Liao classification established in 1972, 11 cases were primary lymphomas of the breast, and 8 cases were secondary involvement of the breast. Median survival time was 21.5 months (range, 5.1-114.7 months). The 5-year overall survival was 29%. Median event-free survival time was 8.3 months. The clinical, radiologic, and histologic patterns of presentation match previously published data, even if the response rates and the survival times seem disappointing, probably because of the initial treatment by tumorectomy or mastectomy for some patients.CONCLUSIONS:Systemic chemotherapy should be the mainstay of treatment. Based on our experience and a review of the literature, the use of Wiseman and Liao's classification is questionable. In fact, it fails to detect whether some lymphomas of the breast present a specific natural history and therefore require specific management. New clinical and histologic criteria are to be identified.
Clonotypic B cells of Waldenstrom's macroglobulinemia (WM) are CD20+ immunoglobulin (Ig) M+ IgD+ cells that lack ongoing somatic hypermutation and class switch recombination (CSR). Only a small compartment of clonotypic B cells express activation-induced cytosine deaminase. Activation by CD40L/interleukin-4 does not stimulate WM class switching. However, we found that the mutation of switch regions essential for CSR were present in IgM monoclonal gammopathy of unknown significance (MGUS) but absent from WM B cells, suggesting the possibility that not all IgM MGUS have the potential to give rise to WM, and further strengthening the hypothesis that the target cell in transformation to WM is an unusual type of B cell.
Intravascular large B-cell lymphoma (ILBCL) is a rare subtype of diffuse large B-cell lymphoma (as currently recognized by the World Health Organization classification) and is characterized by proliferation of mature B-cells within the lumina of small and medium vessels. We report on a 66-year-old man who presented with a fever of undetermined origin, a splenomegaly, and an elevated lactate dehydrogenase level. The diagnosis of ILBCL was established by a bone marrow biopsy that showed CD20+ tumor cells confined within the lumina of sinuses. A karyotypic analysis obtained from the bone marrow aspirate showed a hypotetraploid clone. Magnetic resonance imaging of the brain revealed multiple high-signal areas in the periventricular white matter above the tentorium. Focal dural enhancement (pachymeningitis) close to the medium third of the superior sagittal sinus was also observed and was related to a partial superior sagittal sinus thrombosis as confirmed by venous magnetic resonance angiography. After 8 courses of a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab regimen, normalization of the superior sagittal sinus and of the bone marrow was obtained. With a follow-up of 15 months, the patient is still considered in complete remission. This observation highlights an unusual vascular aspect of ILBCL and the efficacy of the current standard treatment for this age group (CHOP/rituximab) in this particularly aggressive lymphoma subtype.
Burkitt's lymphoma is a mature B-cell lymphoma that is characterized by a rapid proliferative rate and propensity for extranodal sites of involvement such as the gastrointestinal tract and central nervous system. This subtype of non-Hodgkin's lymphoma is associated with unique cytogenetic translocations involving the c-MYC oncogene on chromosome 8, which appears to be involved in the pathogenesis of this disease. Although current literature is limited by a lack of randomized trials, Burkitt's lymphoma appears to be curable in a high proportion of cases if treated with aggressive multiagent chemotherapy regimens. The use of autologous stem cell transplantation appears to benefit patients who have had chemotherapy-sensitive relapses. The role of allogeneic stem cell transplantation for this disease remains uncertain. Patients with HIV-associated Burkitt's lymphoma appear to have a better prognosis today, which is likely a result of more effective antiretroviral therapy and the ability to treat selected patients with more aggressive chemotherapeutic regimens than before. This article will review the epidemiologic, biologic, diagnostic, and therapeutic aspects of Burkitt's lymphoma in adults.
Rituximab is an active agent for the treatment of Waldenstrom's macroglobulinemia. However, many patients do not respond to this agent and several others develop secondary resistance. In order to identify clinical and laboratory parameters that could predict a higher likelihood for response, we evaluated 54 patients who were treated with single-agent rituximab. Twenty-four patients (44%)exhibited > or = 50% reduction of serum monoclonal protein. Previously untreated and pretreated patients had the same probability for response. Low response rates were noted in patients with serum monoclonal protein level > or = 40 g/L (17%) and serum albumin level < 35 g/L (14%). Furthermore, a multivariate analysis indicated that high serum monoclonal protein and low albumin were the dominant variables associated with shorter time to progression. The presence of 2, 1, or none of these variables was associated with median times to progression of 4 months, 11 months, and approximately 48 months, respectively. We conclude that patients with low levels of monoclonal protein and normal albumin are the best candidates for treatment with rituximab.
Immunoglobulin (Ig) M myeloma is a distinct entity with features of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). The malignant cells in IgM myeloma have a distinctive chromosomal translocation that differentiates them from WM. These cells are postgerminal–center in origin with isotype-switch transcripts. They appear to be arrested at a point of maturation between that of WM and MM. Preliminary data indicate that a pattern of osteoclast-activating factor and osteoprotegerin expression similar to that observed in classic MM is present in IgM myeloma. Additional studies on patients with this rare tumor may provide further insight into the pathogenesis of bone disease in plasma cell dyscrasias.
We translated these laboratory findings to a single-arm, phaseII clinical study in which patients with previously untreatedstage III/IV follicular lymphoma were initially treated intominimal residual disease (MRD) state with a uniformchemotherapy regimen, PACE (prednisone/doxorubicin/cyclophosphamide/etoposide), a modified ProMACE regimen(cyclophosphamide/etoposide/doxorubicin/mechlorethamine/procarbazine plus high-dose methotrexate with leucovorin rescueand prednisone) without methotrexate.
PURPOSE To investigate the feasibility of high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) for aggressive non-Hodgkin's lymphoma (NHL), we conducted HDCT with ASCT using a drug-only protocol without total body irradiation. Previously untreated and treated adult patients with aggressive lymphoma were enrolled onto this study. For the HDCT protocol, we developed the AECC regimen, a drug-only regimen consisting of etoposide, carboplatin, cyclophosphamide, and nimustine (ie, ACNU). Mobilized peripheral blood stem cells were used mainly as a source for ASCT and were used based on collection rates of CD34 cells. PATIENTS AND METHODS Fifty-six patients were enrolled and assessed for this study. The median length of follow-up was 6.5 years, with a range of 0.2-12.5 years. Retrospective immunophenotypic examination indicated that the majority of the patients were diagnosed with B-cell lymphoma. RESULTS Before HDCT, 37 patients still had disease (26 partial responses [PRs] and 11 cases of no response), and 19 patients exhibited a complete response (CR) before HDCT with ASCT. Among 56 patients, 37 (66%) exhibited a CR, including patients continuing their first CR and those experiencing a second or further CR, and 11 patients (19.6%) exhibited PR on HDCT with ASCT. Outcomes of patients without CR were significantly poorer than those of the patients with CR, and 7-year overall survival rates of patients with and without CR were 63% and 27.2%, respectively. No patients developed a second malignancy, including leukemia or myelodysplastic syndrome. CONCLUSIONS High-dose chemotherapy followed by ASCT is one of the available consolidation therapies for aggressive NHL, and additional involved-field irradiation could play a role in the management of patients with NHL who do not exhibit a CR after treatment with HDCT containing a drug-only program.
The hyaluronan synthase 1 (HAS1) gene encodes a plasma membrane protein that synthesizes hyaluronan, an extracellular matrix molecule. Previously, in patients with Waldenstrom's macroglobulinemia (WM), we detected upregulation of HAS1 transcripts and identified aberrant splice variants of this gene. Aberrant splicing of HAS1 results from activation of cryptic splice sites. In turn, activation of cryptic donor and acceptor splice sites can be promoted by mutations occurring upstream of these sites and/or at the branch point of slicing. We measured the frequency of the HAS1 833A/G polymorphism (ie, single-nucleotide polymorphism; SNP) in patients with WM and healthy donors. Additionally, HAS1 gene expression was evaluated in the same group of patients. Our observations so far suggest that HAS1 833A/G SNPs contribute to aberrant splicing of this gene; this idea is supported by the fact that 833A/G SNP is located on an exonic splicing enhancer motif. Based on the results obtained thus far, we speculate that individuals with HAS1 833G/G genotype are predisposed toward aberrant HAS1 splicing and expression of HAS1 variants, resulting in an enhanced risk of developing WM. Study of a larger group of patients and healthy donors is needed to confirm these speculations and to evaluate the prognostic significance of these findings.
Clinical Lymphoma June 2005 Treatment for Aggressive Non-Hodgkin’s Lymphoma Anthracycline-containing combination chemotherapy regimens such as CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) remain the standard of care for initial treatment of aggressive non-Hodgkin’s lymphoma (NHL).1-4 Based on several recent studies, standard first-line therapy of aggressive B-cell lymphoma now includes rituximab in combination with chemotherapy.5-8 After first-line therapy, patients with relapsed or refractory disease will generally receive a platinum agent–based second-line or salvage therapy. For younger patients (generally ≤ 65 years of age) who respond to salvage therapy, autologous stem cell transplantation (ASCT) is the standard of care.4,9 Optimal benefit from a salvage regimen may best be measured by the transplantation rate, which accounts for response to treatment, adequate mobilization of stem cells, and recovery from the treatment-related toxicities. Typical salvage or second-line regimens include DHAP (dexamethasone/cytarabine/cisplatin); ESHAP (etoposide/methylprednisolone/ara-C/cisplatin); ICE (ifosfamide/carboplatin/ etoposide); and mini-BEAM (carmustine/etoposide/araC/melphalan).4,9 In the pretransplantation setting, these therapies have modest efficacy, and their effectiveness is limited by bone marrow toxicity (as well as other treatment-induced morbidities), resulting in febrile neutropenia, the increased need for red blood cell and platelet transfusions, and frequent hospitalization. Additionally, toxicity to the progenitor cells leads to difficulty in mobilizing the peripheral blood stem cells required to support subsequent high-dose chemotherapy. In most reports, approximately 45%-65% of patients considered candidates for ASCT will adequately respond to salvage therapy and proceed to receive ASCT.10 Based on these limitations, better therapeutic options are needed. Despite the increase in survival associated with ASCT, approximately 50% of patients will experience disease relapse.11 Further intensification of high-dose regimens has been investigated with limited success. Adjuvant therapy with rituximab after transplantation for CD20+ lymphoma subtypes could potentially eliminate residual cells contributing to relapse, thereby improving patient outcome.
Myelodysplastic syndromes (MDSs) are characterized by an intrinsic defect of hematopoietic stem cells, in particular of erythropoietic progenitors. As a consequence, anemia is the most frequent and disabling symptom in patients with MDS. In a recent issue of Clinical Lymphoma, Stein summarized the current status of the treatment of anemia with recombinant erythropoietin (rEPO) in patients with MDS.1 This subject is discussed further in this communication.
CD5, CD10, and CD23 are cell surface antigens used to distinguish B-cell disorders. The expression of these antigens and their clinical significance in Waldenstrom's macroglobulinemia (WM), an uncommon B-cell disorder, remains to be clarified. We therefore determined expression of CD5, CD10, and CD23 by flow cytometric analysis on bone marrow lymphoplasmacytic cells (CD19+ k/l light chain restricted) for 171 serially biopsied patients with findings of the consensus panel definition of WM. Importantly, we also correlated laboratory and clinical data, as well as existence of a familial history of a B-cell disorder in view of reports suggesting familial predisposition in WM. These studies demonstrated tumor cell expression of CD5, CD10, and CD23 in 15 of 171 patients (9%), 11 of 161 patients (7%), and 37 of 105 patients (35%), respectively. Coexpression of CD23 with CD5 or CD10 was common. Tumor Lymphoplasmacytic from 10 of 15 (66%) and 3 of 11 (27%) patients with WM that expressed CD5 and CD10, respectively, also showed expression of CD23 (P = 0.01 and P = 0.08, respectively). Among patients with CD23 expression, increased serum immunoglobulin (Ig) M levels were observed compared with patients without CD23 expression (P = 0.05). No differences in age at diagnosis; presence of adenopathy and/or splenomegaly; bone marrow involvement; serum IgA, IgB, and b2 macroglobulin levels; hematocrit; platelet count; or familial history of WM or a related B-cell disorder were observed among patients with and without CD5, CD10, and CD23 expression. These studies demonstrate that CD5, CD10, and CD23 are commonly found in WM and that their expression should not exclude the diagnosis of WM. Moreover, expression of CD23 may define a clinically distinct subset of patients with WM.
Waldenström's macroglobulinemia (WM) is considered in the World Health Organization classification as a clinical syndrome associated with monoclonal immunoglobulin (Ig) M secretion, mainly observed in patients with lymphoplasmacytic lymphoma (LPL) and occasionally with other small B-cell lymphomas. Some authors consider it a rare distinct lymphoproliferative disorder with primary bone marrow infiltration and IgM monoclonal gammopathy. As LPL shares important morphologic and immunophenotypic overlaps with marginal zone B-cell lymphomas (MZLs) in cases showing plasmacytic maturation, it remains unclear if they constitute unique or distinct entities. Both diseases are composed of lymphocytes, lymphoplasmacytoid cells, and tumoral plasma cells with a surface (s) IgM-positive sIgD+/– cytoplasmic IgM–positive CD19+ CD20+ CD27+/– CD5– CD10– CD23– phenotype, without a specific marker. Extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL (NMZL), and splenic MZL (SMZL) are distinct entities displaying common morphologic, immunophenotypic, and genetic characteristics. MALT lymphoma is clearly distinct from LPL, although bone marrow infiltration and IgM paraprotein are not rare. Splenic MZL and NMZL are incompletely characterized, but a plasmacytoid/plasmacytic differentiation, autoimmune manifestations, and monoclonal component are frequent in both diseases. Bone marrow involvement is constant in SMZL and present in 60% of NMZLs. Molecular IgVH gene analysis has confirmed this heterogeneity, particularly within SMZL, with mutated and unmutated cases. Further studies are needed to clarify the pathogenesis of these MZLs and their relationship with LPL.
We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM-MG) into symptomatic lymphoproliferative disease in 384 patients, in subgroups of patients with IgM MG of undetermined significance (MGUS) and smoldering Waldenstrom's macroglobulinemia (sWM). One hundred seventy-two patients with aIgM-MG with bone marrow (BM) histopathology and immunophenotyping were available for analysis. After a median of 45 months (range, 12-233 months), 45 cases of aIgM-MG (11.7%) evolved into lymphoproliferative disease, as follows: symptomatic WM (n = 41), non-Hodgkin's lymphoma (NHL; n = 2), IgM multiple myeloma (IgM-MM; n = 1), and primary amyloidosis (n = 1). Cumulative transformation probability at 5 and 10 years was 8% and 29%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, hemoglobin (Hb) level, IgM size, and peripheral lymphocytosis; at multivariate analysis, the parameters were IgM size and peripheral lymphocytosis, with Hb level associated with a trend toward higher progression risk. Of the 138 cases of IgM-MGUS, 14 (10.1%) evolved (13 WM, 1 IgM-MM) after a median of 75 months (range, 12-117 months); of the 34 cases of sWM, 13 (38.2%) progressed to WM after 55 months (range, 13-154 months). In patients with IgM-MGUS, event-free survival at 5 and 10 years was 95% and 83%, respectively, and in patients with sWM, 77% and 42%, respectively (P = 0.0001). Among patients with aIgM-MG, those at high risk of evolution are patients with sWM, a distinct entity with clear BM evidence of NHL.
Peripheral T-cell lymphomas (PTCLs) are post-thymic malignancies characterized by an aggressive clinical course and an inferior outcome with standard therapies. The authors report significant clinical activity of infusional gallium nitrate in a patient with stage IV PTCL disease refractory to chemotherapy.
Recently, a consensus panel of experts recommended that patients with Waldenstrom's macroglobulinemia (WM) who are candidates for future autologous transplantation should have limited alkylator or nucleoside analogue exposure due to potential stem cell harm. Cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (CHOP-R) is a stem cellsparing regimen that has been extensively evaluated in patients without WM or non-Hodgkin's lymphoma. As such, we analyzed the outcome of 13 patients with WM who received CHOP-R at our institution. Patients had a median age of 54 years and a median of 1 previous therapy. Ten of 13 patients (77%) had relapsed (n = 3) or refractory (n = 7) disease. Eight and 6 patients had previously received fludarabine and rituximab, respectively. Intended therapy consisted of 6 cycles of standard-dose CHOP and 6 infusions of rituximab (375 mg/m2). Three patients received additional rituximab as maintenance therapy. Median immunoglobulin M and serum viscosity for all patients decreased from 5230 mg/dL to 1690 mg/dL (P < or = 0.001) and from 2.9 cP to 1.6 cP (P = 0.01), respectively, and the median hematocrit level rose from 30.5% to 39.3% (P < or = 0.001). Clinical responses were as follows: 3 complete responses unconfirmed, 8 partial responses, 1 minor response. At a median follow-up of 9 months (range, 6 to > 37 months), 10 of the 11 patients who had a major response remained in remission. Therapy was well tolerated for most patients. Two patients had febrile neutropenia with documented bacteremia and recovered without complications. Circulating effector cell levels were also evaluated in 6 patients before and after CHOP-R, because rituximab activity is mediated in part by antibody-dependent cell-mediated cytotoxicity activity. No significant change in CD3+, CD4+, CD8+, and CD16+/CD56+ effector cell levels occurred following CHOP-R as assessed by multicolor flow cytometry.
Although numerous treatment approaches are proposed for patients with follicular lymphoma, criteria to help in choosing a treatment for a given patient and for comparing trial results are lacking. Several retrospective studies have analyzed prognostic factors, but their conclusions rely on limited numbers of patients treated during long periods, and their results are discordant. The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide. Five factors are used (age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level) to build a 3-category index. This index, together with new biologic markers such as gene profiling and proteomics, could help provide an optimal treatment option for patients with follicular lymphoma.
PURPOSE The goal of this study was to evaluate the efficacy of the fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. PATIENTS AND METHODS Thirty-four patients (CLL, n=16; low-grade NHL, n=18) were enrolled. The median number of previous treatments was 2. Patients received 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF. Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received >or=3 cycles of treatment and were evaluated for response. RESULTS Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced >or=1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. CONCLUSIONS The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.
