Cold agglutinin disease revisited: a multinational, observational study of 232 patients.

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.

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.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma.

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Primary chronic cold agglutinin disease: a population based clinical study of 86 patients.

BACKGROUND AND OBJECTIVES: Our knowledge of primary chronic cold agglutinin disease (CAD) is incomplete. The aim of this study was to collect comprehensive and precise data the on epidemiology, clinical and pathological features, course, and therapy of CAD. DESIGN AND METHODS: We performed a population-based retrospective follow-up study of as many as possible of all CAD patients in Norway. Eighty-six patients were studied. RESULTS: The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year. The median age at onset was 67 years (range, 30-92) and the male to female ratio was 0.55. The median survival was 12.5 years from onset. Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%. At least 51% had received red blood cell transfusions. The mean initial hemoglobin level was 9.2 g/dL (range, 4.5-15.6) and the median monoclonal immunoglobulin level 4.0 g/L (range, 0.0-47.3). Most laboratory findings did not change significantly during a median follow-up of 5 years. Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%. An abnormal kappa/lambda ratio in bone marrow was found in 90%, lymphoma in 76%, and lymphoplasmacytic lymphoma in 50%. Transformation to aggressive lymphoma occurred in 3.5% during 10 years. Rituximab therapy was the only treatment showing acceptable response rates (60%). INTERPRETATION AND CONCLUSIONS: Primary CAD represents a spectrum of clonal lymphoproliferative bone marrow disorders, in most cases with morphological signs of lymphoma. Despite a favorable prognosis for survival, the disease is not indolent in terms of clinical manifestations.

[High-dose treatment with autologous stem cell support in a Norwegian region]. / Høydosebehandling med stamcellestøtte i Midt-Norge.

BACKGROUND: The introduction of high-dose treatment with autologous stem cell support (HMAS) in Norwegian regional hospitals in the early 1990s was controversial. Concerns that low numbers of patients would lead to unacceptably low quality were expressed. MATERIAL AND METHODS: We present treatment results in the health region of Middle Norway, based on nearly 10 years of experience and 100 treated patients. Myeloma results are compared to the results from other Norwegian regional hospitals. RESULTS AND INTERPRETATION: Overall survival for multiple myeloma after HMAS (median 6.8 years) was not significantly different in middle Norway compared to the rest of the country, and comparable with published results. Treatment-related mortality was low (1.2%). Results and complications in malignant lymphoma, breast cancer or germ cell tumours are described. HMAS can be satisfactorily given in a regional hospital with relatively few patients.