V. Ahya

Treatment of PTLD with Rituximab or Chemotherapy

Information regarding treatment of post‐transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty‐five patients met inclusion criteria. Twenty‐two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein‐Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty‐three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty‐six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV‐positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV‐negative tumors or need a rapid response.

Interobserver Variability in Grading Transbronchial Lung Biopsy Specimens After Lung Transplantation

BACKGROUNDnAcute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies.nnnMETHODSnWe examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients.nnnRESULTSnA total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection.nnnCONCLUSIONSnThese results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists.nnnTRIAL REGISTRYnClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rabbit ATG in the Prophylaxis of Acute Rejection in Lung Transplantation

ATG‐Fresenius S (ATG‐F) is a polyclonal anti‐human‐T‐lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG‐F at doses of 5 and 9u2009mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow‐up within 12 months of transplantation. The interim analysis showed the ATG‐F 5u2009mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9u2009mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG‐F 9u2009mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single‐dose induction therapy with ATG‐F within the first year after lung transplantation.