Rituximab-induced life-threatening coagulopathy occurring in a patient with Waldenström macroglobulinemia treated with fludarabine, cyclophosphamide, and rituximab combination

Rituximab is a chimeric anti-CD20 monoclonal antibody which has become the standard of care, in combination with chemotherapeutic agents, in virtually all B-lymphoid malignancies including Waldenström macroglobulinemia (WM) [1]. Its broad use has led to the detection of rare side-effects that were not predicted by phase II/III trials, such as the development of late-onset neutropenia, progressive multifocal leukoencephalopathy, reactivation of hepatitis, and interstitial pneumonitis [2]. We report here the case of a 50-year-old male patient diagnosed with WM. The M-component was 22 g/L at diagnosis. The complete blood count was: hemoglobin 86 g/L, platelets 826 10/L, and white blood cell count (WBC) 1.56 10/L (neutrophils 1.346 10/L, lymphocytes 0.146 10/L). The lactate dehydrogenase (LDH) level was 347 IU/L (200–400) and serum albumin was 35.9 g/L (40.2–47.6). The prothrombin rate (PR) was 92%; activated partial prothrombin time (APTT) was 32/32; and fibrinogen was 3.8 g/L. The patient did not take any antithrombotic therapy. Enhanced computed tomography scanning showed enlargement of the deep lymph nodes of both the thoracic and abdominal compartments, which contrasted with the absence of peripheral lymphadenopathy. No splenomegaly was detected, whereas moderate hepatomegaly was found to be due to a benign angiolipoma confirmed by magnetic resonance imaging. Treatment with rituximab 375 mg/m (day 1), cyclophosphamide 250 mg/m (days 1–3), and fludarabine 40 mg/m (days 1–3) (R-FC) was started. The first cycle of R-FC was complicated by a neutropeniarelated fever, with a favorable outcome using broad-spectrum antibiotics. There was no evidence for tumor lysis syndrome after the first cycle, or for immunoglobulin M (IgM) flare phenomenon, as the M-protein was 11 g/L just before the second cycle. Early during the second course of rituximab, the patient developed hypotension, symptoms of tissue hypoperfusion, and tachycardia. His temperature remained normal and he did not show any symptom of allergy. The arterial oxygen saturation was normal. Then he developed acute gastrointestinal bleeding, characterized by nausea, hematemesis, and profuse diarrhea with rectorrhagia. After the discontinuation of rituximab, aggressive fluid resuscitation and red blood cell transfusion improved the hemodynamic parameters. Blood tests at the onset of symptoms showed: hemoglobin 118 g/L, WBC 3.86 10/L, and platelets 1446 10/L. Two hours later, hemoglobin was 114 g/L despite two red blood cell unit transfusions, and the platelet count dropped to 486 10/L. PR was 50%, APTT was 63 s, and fibrinogen was 0.9 g/L. After 4 h, the platelet count was 466 10/L, PR was 39%, APTT was 58 s, fibrinogen was 0.5 g/L, and D-dimers were 110 400 ng/L, which confirmed the diagnosis of disseminated intravascular coagulopathy (DIC). An infectious process was ruled out by the negativity of blood and urine cultures and by the normality of a chest X-ray. Moreover, the C-reactive protein (CRP) level