Ulla Randen

High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease

Most patients diagnosed with primary chronic cold agglutinin disease (CAD) have a clonal lymphoproliferative bone marrow disorder. Treatment with rituximab is the only well-documented effective therapy, leading to 45%-60% partial responses (PR). Complete responses (CR) are rare, and median response duration is only 11 months. In a prospective multicenter trial, 29 patients received rituximab 375 mg/m(2) on days 1, 29, 57 and 85; and fludarabine orally, 40 mg/m(2) on days 1-5, 29-34, 57-61 and 85-89. Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR. Among 10 patients nonresponsive to rituximab monotherapy, 1 achieved CR and 6 PR. Median increase in hemoglobin level was 3.1 g/dL among the responders and 4.0 g/dL in those who achieved CR. Lower quartile of response duration was not reached after 33 months. Estimated median response duration was more than 66 months. Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD. Toxicity may be a concern, and benefits should be carefully weighed against risks in very old and comorbid patients. It remains to be established whether the combination should be first-line or an efficient second-line therapy in CAD patients requiring treatment.

Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma

Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20+, IgMs+, IgDs+, CD27+, CD5−/+, CD11c−, CD23−, CD38− immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM+, IgD− plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma.

Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity

One-third of all splenic marginal zone lymphomas (SMZL) use the IgH VH1-02 gene. These cases are usually not associated with hepatitis C virus infection. Of interest, the rearranged VH1-02 genes display similar complementarity determining regions 3, a finding confirmed by our study. The latter suggests that these SMZL may produce antibodies with similar reactivity. We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies. Surprisingly, the recombinant antibodies demonstrated poly- and self-reactivity as demonstrated by their reactivity with nuclear, cytoplasmic, as well as membranous antigens expressed by human cells and by reactivity with human serum. This polyreactivity was specific as demonstrated by ELISA. The antibodies did not react with proteins on the cell surface that are induced by apoptosis as shown for antibodies produced by chronic lymphatic leukemia with VH1-02 gene rearrangement. The results indicate that a common subset of SMZL arises from polyreactive B cells, a subset of marginal zone B cells that are important in the immunologic defense against infection.

Cold agglutinin-mediated autoimmune hemolytic anemia.

Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold agglutinin disease (CAD) is characterized by a clonal lymphoproliferative disorder. Secondary cold agglutinin syndrome (CAS) complicates specific infections and malignancies. Hemolysis in CAD and CAS is mediated by the classical complement pathway and is predominantly extravascular. Not all patients require treatment. Successful CAD therapy targets the pathogenic B-cell clone. Complement modulation seems promising in both CAD and CAS. Further development and documentation are necessary before clinical use. We review options for possible complement-directed therapy.

Bone Marrow Histology in Monoclonal B-Cell Lymphocytosis Shows Various B-Cell Infiltration Patterns

Monoclonal B-cell lymphocytosis (MBL) is defined as less than 5 × 10(9)/L monoclonal B cells in the blood of otherwise healthy patients and is detected in 5% to 10% of individuals older than 60 years. The bone marrow findings in MBL have hitherto not been systematically described. We have studied the histologic and immunophenotypic findings in paired trephine biopsy specimens and bone marrow aspirates of 26 patients with MBL. Abnormal lymphoid infiltration was detected in trephine biopsy specimens of 20 patients and was demonstrated by flow cytometry of bone marrow in all 26 patients. Three infiltration patterns were discerned: focal interstitial lymphoid infiltration, focal rounded and nonparatrabecular lymphoid aggregates, and discrete diffuse lymphocytosis. Focal interstitial lymphoid infiltration was seen only in patients with chronic lymphocytic leukemia (CLL)-like or atypical CLL-like MBL, whereas the other patterns were not related to a particular MBL immunophenotype. Our results show that most patients with MBL also have bone marrow lymphoid infiltration. The latter should be distinguished from lymphoma infiltration by clinical correlation.

Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial

Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a bone marrow clonal B-cell lymphoproliferation results in autoimmune hemolytic anemia and cold-induced circulatory symptoms. Rituximab monotherapy and fludarabine-rituximab in combination are documented treatment options. In a prospective, nonrandomized multicenter trial, 45 eligible patients received rituximab 375 mg/m2 day 1 and bendamustine 90 mg/m2 days 1 and 2 for 4 cycles at a 28-day interval. Thirty-two patients (71%) responded; 18 (40%) achieved complete response (CR) and 14 (31%) partial response (PR). Among 14 patients previously treated with rituximab or fludarabine-rituximab, 7 (50%) responded to bendamustine-rituximab (3 CR and 4 PR). Hemoglobin levels increased by a median of 4.4 g/dL in the complete responders, 3.9 g/dL in those achieving PR, and 3.7 g/dL in the whole cohort. The 10th percentile of response duration was not reached after 32 months. Grade 3-4 neutropenia occurred in 15 patients (33%), but only 5 (11%) experienced infection with or without neutropenia. Thirteen patients (29%) had their dose of bendamustine reduced. In conclusion, bendamustine-rituximab combination therapy is highly efficient, sufficiently safe, and may be considered in first line for patients with CAD requiring therapy. The trial was registered at www.clinicaltrials.gov as #NCT02689986.

Immunoglobulin heavy and light chain gene features are correlated with primary cold agglutinin disease onset and activity

Immunoglobulin heavy chain ( IGH ) and light chain gene sequences of 27 patients with primary cold agglutinin disease (CAD) were studied to find features explaining the heterogeneity of clinical presentation and disease activity. CAD is a hemolytic anemia mediated by monoclonal IgM anti-I

Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease

Additional Supporting Information may be found in the online version of this article: Fig S1. Survival data in 446* patients with primary myelofibrosis, stratified by absolute monocyte count and the Dynamic International Prognostic Scoring System (DIPSS)plus. Table SI. Multivariable analysis of overall survival in 291 patients with primary myelofibrosis with available information on absolute monocyte count, Dynamic International Prognostic Scoring System-plus risk status, driver mutational status and ASXL1/SRSF2 mutational status.

Mantle cell lymphoma with features of marginal-zone lymphoma

We present seven cases of mantle cell lymphoma with morphological features of marginal-zone lymphoma. Of particular interest, four of the patients had predominant involvement of the gastrointestinal tract. All cases displayed the translocation t(11;14)(q13;q32) and expressed cyclin D1. Cytogenetic analysis revealed trisomy 3 in one case and somatic hypermutation of immunoglobulin heavy genes could be demonstrated in two out of four cases. The latter features are reminiscent of marginal-zone lymphoma. The localization of these lymphomas mainly in the gastrointestinal tract and the higher exposure to antigens in this area may explain why this variant of mantle cell lymphoma harbours features of marginal-zone lymphoma.