Background and Objectives: The outcome of patients with B-cell post-transplant lymphoproliferative disorders (PTLD) has improved with the introduction of rituximab as first line therapy. The purpose of this report is to provide longer follow-up of the phase II trial (González-Barca et al, Hematologica 2008;92:1489) with extended doses of rituximab in patients with PTLD after solid organ transplantation, and to compare these results with a cohort of patients diagnosed of PTLD after the trial was closed, and treated in real life with the same therapeutic regimen.
Patients and Methods: The phase II trial included 38 patients that were treated with reduction of immunosuppression and four to eight weekly infusions of rituximab. Patients without complete response (CR) or progression were allowed to receive a short course of 3-4 cycles of R-CHOP /R-CHOP-like chemotherapy. A cohort of 21 pts treated with the same regimen in real life was used for comparative purposes. The real life patients were significantly older (median age 63.0 vs 55.4 yrs, p=0.013), but all the other characteristics at diagnosis were comparable. Response was evaluated with CT scans in patients included in the clinical trial and with PET/CT in 86% of real life patients. Progression free survival (PFS) was calculated from the time of diagnosis to the time of progression / relapse or death due to lymphoma; deaths from other causes were censored. Predictive factors for CR to rituximab were analyzed with a binary logistic regression model. Univariate analysis for survival was performed with Kaplan-Meier estimation and Log-rank test, and multivariate analysis with a Cox regression model. Factors included in the different analyses were: age, gender, Ann Harbor stage, graft involvement, bulky disease, extranodal involvement, B symptoms, ECOG, LDH, and time from transplant to PTLD.
Results: Twenty-three (60.5%) out of 38 patients treated within the clinical trial achieved a CR/CRu after rituximab treatment. With a median follow-up for the alive patients of 13.0 yrs, 21 (55.3%) died; 13 (34%) due to progression, 3 due to infections (pneumonia, hepatic abscesses, septic shock), 1 of a secondary malignancy, a Hodgkin Lymphoma. PFS at 5 and 10 yrs was 68.6% (95%CI: 52.9% - 84.3%) and 64.7% (95%CI: 48.2% - 81.2%), respectively. Overall survival (OS) at 10 yrs was 49.5% (95%CI: 32.8% - 66.2%). For those patients that achieved a CR with rituximab, PFS at 5 and 10 yrs was 94.4% (95%CI: 83.8% - 100%) and 88.1% (95%CI: 72.6% - 100 %), respectively. Among the 21 real life patients, 8 (38.1%) achieved CR with rituximab. With a median follow-up for the alive patients of 6.5 yrs, 7 (33%) patients died; 4 (19%) due to progression. PFS and OS at 5 yrs was 75.2% (95%CI: 56.4% - 94.0%) and 62.7% (95%CI: 40.4% - 85.0%), respectively. PFS at 5 yrs was 87.5% (95%CI 64.6% - 100%) in those patients that achieved CR with rituximab. Factors that could predict a CR to rituximab therapy were not found. ECOG 2-4 was the only significant independent prognostic factor for DFS [HR 3.2 (95%CI 1.05-9.3)]
Conclusions: Patients with PTLD who achieve CR with rituximab monotherapy have an excellent long term outcome in both clinical trial and real life; unfortunately, factors at diagnosis that could predict response to rituximab were not found. Patients with prolonged CR have a very low risk of progression after 5 years. However, around one third of PTLD patients still die due to progressive disease. Patients that do not achieve a CR with rituximab should be included in prospective clinical trials.
Gonzalez-Barca: Gilead: Consultancy; Sandoz: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Capote Huelva: Roche: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau. Gomez Codina: Roche: Consultancy. Salar: Roche: Speakers Bureau; Janssen: Speakers Bureau; Servier: Speakers Bureau. Ribera: Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau.
Asterisk with author names denotes non-ASH members.