ABSTRACT
PURPOSE: Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches. PATIENTS AND METHODS: The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non-mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR). RESULTS: On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001). CONCLUSION: In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.
Subject(s)
Antineoplastic Agents/therapeutic use , Chlorambucil/therapeutic use , Lymphoma, B-Cell, Marginal Zone/drug therapy , Vidarabine/analogs & derivatives , Waldenstrom Macroglobulinemia/drug therapy , Aged , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lymphoma, B-Cell, Marginal Zone/mortality , Male , Middle Aged , Proportional Hazards Models , Vidarabine/therapeutic use , Waldenstrom Macroglobulinemia/mortalitySubject(s)
Pregnancy Complications, Hematologic/blood , von Willebrand Diseases/blood , von Willebrand Diseases/complications , Adult , Amino Acid Substitution , Female , Humans , Membrane Glycoproteins/genetics , Platelet Glycoprotein GPIb-IX Complex , Platelet Transfusion , Pregnancy , Pregnancy Complications, Hematologic/genetics , Pregnancy Complications, Hematologic/therapy , Thrombocytopenia/blood , Thrombocytopenia/complications , Thrombocytopenia/therapy , Young Adult , von Willebrand Diseases/genetics , von Willebrand Diseases/therapy , von Willebrand Factor/administration & dosage , von Willebrand Factor/metabolismABSTRACT
von Willebrand disease (VWD) caused by the R1205H mutation has distinct and reproducible clinical and laboratory features. This report describes the phenotypic and molecular investigation of seven kindreds with VWD Vicenza R1205H. All affected individuals have historically been diagnosed with moderate to severe type 1 VWD. Amongst all families with highly penetrant type 1 VWD investigated at our centre, heterozygosity for the R1205H mutation was found to be the most common underlying molecular defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed, consistent with previous published case reports; however, abnormal ultralarge high molecular weight multimers were not detected in resting plasma samples. We also provide evidence that the R1205H mutation may arise de novo--evidence that a common genetic origin for this mutation is unlikely.
