We addressed the effect of post-transplant lymphoproliferative disorder (PTLD) treatment with rituximab monotherapy or CHOP-based chemotherapy (± rituximab) after upfront immunosuppression reduction (IR) on renal graft function in a longitudinal analysis of 58 renal transplant recipients with PTLD and 610 renal transplant controls. Changes in the estimated glomerular filtration rate over time were calculated from a total of 6933 creatinine measurements over a period of >1 year using a linear mixed model with random and fixed effects. Renal graft function significantly improved with treatment of PTLD, especially in the chemotherapy subgroup. Patients treated with IR + chemotherapy ± rituximab had a noninferior graft function compared with untreated controls suggesting that the negative impact of IR on the renal graft function can be fully compensated by the immunosuppressive effect of CHOP. The immunosuppressive effect of single agent rituximab may partially compensate the negative impact of IR on the graft function. Thus, it is possible to reduce immunosuppression when using chemotherapy to treat PTLD.
Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression.
Methods: An ongoing prospective multicenter phase II trial was initiated in January 2003. Patients were treated sequentially with rituximab at days 1, 8, 15 and 22 followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab.
Results: In this 3rd interim analysis after enrolment of 75 patients 64 patients have finished the protocol. The median follow up is 19.6 months. 58 patients were diagnosed with monomorphic PTLD, 6 with polymorphic PTLD. 23 patients were kidney, 15 liver, 12 heart, 3 lung, 2 heart+lung, 3 kidney+pancreas, 1 bone marrow transplant recipients (5 others). Median age was 53 years (range 16 to 74). 59% had stage III or IV disease. 48% of tumors were EBV positive. 79% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 67% of patients. The overall response rate of sequential therapy was 90% (CR 65%, PR 25%). Progression free survival (PFS) and disease free survival (DFS) were 71.4% and 81.2% at two years, respectively. Treatment response to rituximab (CR/PR versus SD/PD) was a significant factor predicting overall survival (OS) with OS rates of 91.3% and 56.5% at 1 year, respectively (p=0.0107). Following chemotherapy, WHO °3/4 leukopenia was observed in 38% of cycles and 16% of patients suffered from WHO °3/4 infections. There were four early therapy-associated deaths due to infections (7%). Fatal bleeding complications occurred in 3% and 5% of patients died from primary refractory disease.
Conclusions: This is one of the largest prospective studies in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective. Treatment response to rituximab is predictive for overall survival. As compared to rituximab monotherapy more patients achieve a CR with sequential therapy and PFS is very much prolonged.
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