Prolonged Bone Marrow Failure Following Rituximab Therapy of Follicular Lymphoma

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Prolonged Bone Marrow Failure following Rituximab Therapy of Follicular Lymphoma Laura Debatin, Annette Schmitt-Graeff*, Hendrik Veelken Depts. of Hematology/Oncology and *Pathology, University Medical Center Freiburg Rituximab (R) is a mainstay in B-NHL therapy. Apart from infusional reactions and prolonged B cell depletion, severe R side effects are relatively rare. A 65 year-old, previously healthy woman presented with anemia (Hb 9.3 mg/dl), thrombocytopenia, and cervical lymphadenopathy. A submandibular lymph node biopsy showed CD20+CD10+CD79a+ follicular infiltrates. Diagnosis of follicular lymphoma was supported by detection of an IgH-BCL2 gene rearrangement by FISH. CT scans revealed generalized lymphadenopathy and hepatosplenomegaly. The BM was infiltrated with 68% clonal CD20+CD10+CD79a+ B cells. Due to advanced (stage IVA) and high-risk disease (FLIPI 4/5), 200 mg/m2 cyclophosphamide/100 mg prednisone/day (d) were given for 5 days, followed by a single dose of 375 mg/m2 R. Grade 4 neutropenia developed 4 days later and precluded the planned CHOP chemotherapy. A BM biopsy on d+21 post R showed marked BM hypoplasia consistent with drug-induced changes, but no residual lymphoma. Serologic testing ruled out Parvovirus B19, HBV, HCV and HIV infections. Leukocytes recovered to >1/nl 3,5 weeks after R administration. No further cytoreduction was given due to prolonged cytopenia and documented PR. Despite this history, Bendamustin/R (200 mg) was given for eventual BM relapse at a different hospital 11 months later. Grade 4, filgrastim-refractory cytopenia with the same BM histology developed promptly and lasted for 4 weeks. The patient was transferred to our institution because of multiple opportunistic infections including pulmonary aspergillosis, E. faecium sepsis, and destructive mucor mycosis of the right maxillary sinus. Posaconazole and liposomal amphotericin were given for 5 months. 13 months after the 2nd R infusion, the patient had to undergo reconstructive surgery with a flap plasty to cover an extensive, disfiguring facial and maxillary necrosis. Since different alkylators were given at moderate doses, a causal relationship to similar episodes of rapid-onset, extended BM failure appears unlikely. R, administered immediately prior to both episodes, appears to be the causative agent in this case. Since hematopoietic precursors and the myeloid lineage do not express CD20, the mechanism for this near-fatal BM failure is unknown and suggestive of an idiosyncratic component. The BM findings are incompatible with a metamizol-type allergic agranulocytosis. Severe BM failure appears to be a rare but grave potential side-effect of rituximab.