Multiple cranial nerve palsy in a lymphoma patient treated with rituximab

A 50 years old Caucasian woman presented in February 2004 with a one-month history of an accidental discovery of a right breast mass. Mammography performed on February 12^th showed a highly suspicious 3x2cm right breast mass located in the upper outer quadrant. Total excision on the 25^th revealed Large B-Cell Non-Hodgkin Lymphoma positive for CD20. CAT scan showed hepatospleenomegaly, bilateral suprarenal masses (3.8x2.5 cm & 5x4cm) and gastric mural thickening. Bone marrow biopsy showed positive lymphomatous infiltration. LDH was two folds elevated and performance status was one according to the ECOG scale. Her initial stage was IVA and IPI score was III. We started her on Rituximab (Mabthera®) 375mg/m2 on D0 in combination with classic CHOP on D1 on three weekly bases together with prophylactic triple intrathecal injection (TIT) in the first four cycles. Clear bone marrow was achieved after the 4^th cycle with marked regression of the abdominal disease and normalization of the LDH. Accordingly, we continued for four more cycles ending on 31/8/2004. CAT scan showed residual disease in both suprarenal glands. PET scan confirmed residual disease in both suprarenal glands as well as the stomach. We resumed Rituximab on the 10^th of October and considered the start of second line treatment. However, five days following the last (9^th) Rituximab injection, she developed lower motor neuron facial palsy. MRI brain and CAT scan to the sinuses were normal. Two days later, she developed difficulty in swallowing (glossopharyngeal affection) and squint (abducent nerve affection). CSF cytology was performed three times and all were normal with normal sugar and protein levels. Viral study done was negative. Another MRI brain with gadolinium was normal. She progressed dramatically developing metabolic encephalopathy secondary to hyponatremia and hypokalemia with deterioration of conscious level up to coma. Replacement therapy did not improve the condition and she died on December 10^th, 2004. No post-mortem examination was performed.

Rituximab (Mabthera®) is a genetically engineered human/mouse chimeric monoclonal antibody that is specific for the CD20 B-cell surface antigen ⁽¹⁾. Introduction of Rituximab in aggressive Non Hodgkin Lymphoma has yielded very impressive results after being established as a superior drug in indolent lymphoma ⁽²⁾. The GELA  LNH-98-5 trial was the bridge through which Rituximab has passed through to establish its role in the first line treatment of aggressive lymphomas. In 2000, Coiffier and his group first reported a significant benefit in terms of complete remission rates; event-free survival and overall survival ⁽³⁾ with subsequent analysis at 3 and 4 years further confirming survival benefit ⁽⁴⁾. However, the addition of Rituximab was not associated with any added toxicity apart from mild to moderate infusion related adverse events occurring basically with the first injections ⁽⁴⁾ with grade III and IV toxicity occurring equally with chemotherapy alone. In post marketing surveillance, it was reported that cranial neuropathy and facial nerve palsy had occurred in less than 1/10,000 ⁽⁵⁾ with multiple injections or months after the end of treatment. Electrolyte disturbance was not reported at all as well as metabolic encephalopathy. Delayed adverse events related to Rituximab are not clearly reasoned or explained until now. Inspite of the fact that multiple injection of Rituximab increases the plasma concentration of the drug and decreases its clearance rate ⁽⁶⁾, yet, this phenomenon was not reported to be accompanied by any form of increased toxicity. In our case, Rituximab related multiple cranial nerve palsy is just a possibility; worth reporting.

References:

1. Reff ME, Carner K, Chamber KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45

2. Marcus R, Imrie K, Belch A, et al. M39021-an international multicenter, randomized, open-label phase III trial comparing Rituximab added to CVP to CVP chemotherapy alone in untreated stage III/IV follicular NHL: final analysis. Blood 2003;102:28a

3. Coiffier B, Lepage E, Herbrecht R, et al. Mabthera plus CHOP is superior to CHOP alone in elderly patients with diffuse lare B-cell lymphoma: interim results of a randomized GELA trial. Blood 2000;95(suppl.1):223a

4. Coiffier B, Herbrecht R, Morel P, et al. GELA study comparing CHOP and R-CHOP in elderly patients with DLCL: 3-year median follow-up with an analysis according to co-morbidity factos. Hematol J 2003;4(suppl.2):111

5. Adapted from electronic Medicines Compendium. Available at :  http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=2570

6. Berinstein NL, Grillo-Lopez AJ, White CA, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low grade or follicular non-hodgkin lymphoma. Ann Oncol 1998:9:995-1001

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