Leukemia & Lymphoma | 2019
Complete remission of immunochemotherapy-refractory monomorphic post-transplant lymphoproliferative disorder mediated by endogenous T-cell recovery
Abstract
A 56-year-old woman with a history of cadaveric renal transplant in 1986 for renal failure of unknown cause was found to have an 8.1 6.3 cm right iliac fossa mass, adjacent to the transplanted kidney, following an investigation into a Proteus urinary tract infection in February 2015. Biopsy demonstrated sheets of large atypical lymphoid cells staining for CD20, CD79a, MUM1, Bcl-2 but not CD10, Bcl-6, or Cyclin D1. EBV-encoded small RNAs (EBER) were strongly positive, confirming EBV positive monomorphic PTLD (diffuse large B cell lymphoma [DLBCL] histology). High levels of EBV DNAemia were evident by qPCR on peripheral blood (142,962 copies/ml). As a result of prior significant cytomegalovirus (CMV) reactivation, and recurrent episodes of bacterial infection of ulcerated skin lesions, significant reductions in immunosuppression (RIS) had already been necessary. At PTLD diagnosis, the patient had been on MMF 500mg twice daily and prednisolone 5mg once daily for the previous year with an estimated glomerular filtration rate of 33 mls/min. Past medical history included hyperparathyroidism, hyperlipidemia, osteoporosis, and obesity. The patient had an ECOG performance status of 3 and required walking aids to mobilize. The large right iliac fossa mass was palpable and invading through the anterior abdominal wall with visible tissue destruction and ulceration. Further large areas of ulceration were evident under both breasts, together with a grade two sacral pressure ulcer. The left chest wall mass was biopsied and was consistent with polymorphic PTLD. Staging by PET-CT confirmed a highly FDG-avid 10.0 5.9 cm mass extending cutaneously as well as two regions of intense activity in cutaneous and subcutaneous tissues of the left breast and right buttock (Figure 1(a)). The international performance index (IPI) [NEJM 1993] was three on the basis of stage IV disease, LDH 506 and poor performance status. Further RIS was not deemed feasible given the relatively modest doses of immunosuppression and renal function. Baseline echocardiogram was normal and virology negative, and the patient received four cycles of rituximab 375mg/m monotherapy with regular monitoring of EBV and CMV by peripheral blood qPCR. Clinical response to Rituximab was evidenced by improvement in performance status and minor healing of cutaneous ulceration, but no clinical change in her palpable mass. The patient subsequently received four cycles of R-CHOP three weekly to June 2015. The EBV viral load reduced significantly during therapy but remained detectable throughout and following the final cycle of treatment (<500 copies/ml). Treatment was complicated, but not delayed, by CMV reactivation treated with oral valganciclovir and anemia requiring red cell transfusion. The areas of cutaneous ulceration improved but did not resolve. Six weeks posttreatment, PET-CT imaging showed the abdominal mass to have enlarged (Figure 1(a)) while peripheral blood EBV viral load had rapidly increased to 2.7 10 copies/ml. Flow cytometric analysis of peripheral blood showed a complete absence of CD19 positive B-cells, suggesting the viremia was derived from tumor cell-free DNA, and further rituximab was considered futile. An application for NHS funding for third-party HLA-matched EBV-specific cytotoxic T-lymphocytes (CTLs) was not supported. Given the lack of other therapeutic options, after discussion with the renal transplant team, MMF was ceased and prednisolone was rapidly weaned and stopped, with no clinical suggestion of subsequent adrenal insufficiency. Notwithstanding the expectation of a dismal prognosis of RCHOP-refractory monomorphic PTLD, we observed a rapid reduction in the palpable mass and improvement in areas of cutaneous ulceration. A dramatic reduction in EBV viral load to 875 copies/ml was documented four months following cessation of immunosuppression,