Acute Pulmonary Toxicity By Mycophenolate Mofetil (MMF) after Haploidentical Stem Cell Transplant (SCT)

Abstract

▪CASEA 49-year old Hispanic male diagnosed with chronic phase CML in 2008 was referred for a SCT for progressive TKI-refractory disease. In May, 2014, he received a haploidentical SCT following treatment with melphalan 140mg/m2 and fludarabine 40mg/m2. GVHD prophylaxis was provided by post-transplant cyclophosphamide 50mg/kg IV on days 3 and 4, tacrolimus 0.015 mg/kg IV and MMF 15mg/kg PO tid. Bacterial, fungal and viral prophylaxis included levofloxacin, voriconazole and valacyclovir respectively.On transplant day 11, he developed asymptomatic neutropenic fever and was started on IV vancomycin and cefepime. The fevers abated by day 14, but he developed acute dyspnea and hypoxia requiring intermittent BiPAP treatment. A CAT scan showed new bilateral lung patchy ground-glass opacities [Figure 1] compared to the baseline chest X-ray. Bronchoscopy could not be performed due to the tenuous respiratory status. MMF was held and methylprednisolone (MP) 1gm/kg IV daily was started for concerns of pulmonary toxicity. His symptoms improved and the chest x-ray normalized within a few days. MMF was resumed at same dose and MP dose was reduced to 0.5 mg/kg/day; within four days there was a rapid recurrence of the pulmonary symptoms and re-emergence of diffuse airspace opacities. MMF was held again and MP was increased to the original dose, resulting in resolution of his symptoms and the radiographic findings within days. During this period, he was afebrile, infectious work-up (including comprehensive viral, bacterial and fungal testing) was negative and no RBC antibodies were detected. Table 1 summarizes his disease course.DISCUSSIONTo the best of our knowledge, this is the first reported case of potential MMF-related pulmonary toxicity after SCT, although similar associations have been reported in a few cases after renal and cardiac transplants.(1-4)The causal relationship of MMF-induced toxicity in our case is suggested by the temporal association, exclusion of other plausible causes, and temporal re-emergence when challenged again, and subsequent resolution of symptoms and x-ray findings with discontinuation of MMF. The underlying mechanism is unknown, although genetic polymorphisms in UGT, an enzyme involved in its metabolism, may explain unexpected toxicities – a phenomenon known to enhance toxicities of various drugs metabolized by this enzyme. (5)CONCLUSIONMMF should be considered as a potential etiology of post-transplant acute pulmonary toxicity in patients undergoing hematopoietic transplantation.REFERENCES:1. Gorgan M, Bockorny B, et al. Pulmonary hemorrhage with capillaritis secondary to mycophenolate mofetil in a heart-transplant patient. Arch Pathol Lab Med. 2013;137(11):1684-7.2. Gross DC, Sasaki TM, et al. Acute respiratory failure and pulmonary fibrosis secondary to administration of mycophenolate mofetil. Transplantation. 1997;64(11):1607-9.3. Morrissey P, Gohh R, et al. Pulmonary fibrosis secondary to administration of mycophenolate mofetil. Transplantation. 1998;65(10):1414.4. Reynolds BC, Paton JY, et al. Reversible chronic pulmonary fibrosis associated with MMF in a pediatric patient: a case report. Pediatr Transplant. 2008;12(2):228-31.5. Burchell B, Soars M, et al. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett. 2000;112-113:333-40. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.