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Post transplant lymphoproliferative disorder: Risk factors and prognosis Melissa Schapiro, MD September 1, 2011 PTLD: description • Spectrum of disease ranging from benign polyclonal B cell hyperplasia to malignant monoclonal non-Hodgkin’s lymphoma that develops in transplant recipients • Can be localized or disseminated PTLD: pathophysiology • EBV-associated PTLD: – Cytotoxic T cell response is blunted by immunosupression – EBV-infected B cells proliferate – Clonal outgrowth and malignant transformation occur PTLD: pathophysiology • EBV-associated PTLD: (Tanner and Alfieri, 2001) PTLD: pathophysiology • EBV-negative PTLD may be a distinct clinical entity from EBV-associated PTLD (Leblond et al., 1998) PTLD: EBV associated vs. negative • Leblond et al. (1998) compared 11 patients with EBV- negative PTLD (group 1) to 21 patients with EBV- associated PTLD (group 2) – Time between transplantation and PTLD diagnosis was 180-10220 days (median 1800) in group 1 versus 60-2100 days (median 180) in group 2 (P=0.02) PTLD: EBV associated vs. negative • 8/8 B-cell PTLDs in group 1 were monomorphic diffuse large B-cell lymphomas versus 8/20 in group 2 • Overall median survival was 1 month in group 1 and 37 months in group 2 (P<0.01) • Probability of survival was 14% at 44 months in group 1 versus 41% at 96 months in group 2 (Leblond et al., 1998) PTLD: EBV associated vs. negative • Nelson et al. (2000) compared the clinic features of EBV-negative PTLDs with those of EBV-positive cases – 17/80 patients had EBV-negative PTLD – Compared to the EBV-positive cases of PTLD, the EBV- negative cases were often late appearing (statistical significance unknown) and were more likely to be monomorphic (p<0.05) A case of late-presenting non-EBV- associated PTLD in a pediatric cardiac transplant patient Clinical case • J.B. is a 14 y.o. boy with a history of orthotopic heart transplant at 2.5 m.o. due to severe aortic stenosis. • He has been on tacrolimus (Prograf) and azathioprine (Imuran) for the past several years. • At a routine lab check on 7/5/11, he was found to have a platelet count of 51,000; CBC was otherwise within normal limits. • No recent viral symptoms, bruising, bleeding, fatigue, night sweats. Clinical case, continued • On 7/9, he presented to an OSH ED with hemorrhagic bullae in mouth, epistaxis x 1, and scattered petechiae on his chest and thighs. Platelet count 2,000. • Imuran (75mg daily) discontinued on 7/10. • He received WinRho on 7/11, and was discharged with a platelet count of 16,000. • He received IVIG on 7/15. Follow up platelet count was 3,000. Clinical case, continued • Scheduled for bone marrow biopsy on 7/22, with plan to start steroids and Rituximab. • On 7/22, he admitted that he had been having black stools and periumbilical pain since the week before. His hemoglobin was 6.0. • Admitted, transfused with PRBCs, GI consulted, started on IV pantoprazole and IV steroids, tranfused with platelets. Clinical case, continued • Abdominal CT on 7/23 showed markedly enlarged mesenteric lymph nodes (up to 5 cm). • Bone marrow aspiration on 7/26 showed no signs of malignancy. • Lymph node biopsy on 7/26 showed large B cell lymphoma CD20+. • CSF on 8/9 was negative for malignancy. Clinical case, continued • He was started on COG ANHL0221 on 7/28. – Prednisone – Low-dose cytoxan – Rituximab • Tacrolimus was discontinued. • Most recent endomyocardial biopsy on 8/9 showed no evidence of rejection. • He is currently on week 3 of cycle 2 of ANHL0221. What are the risk factors for PTLD in pediatric cardiac transplant patients? PTLD: risk factors • In a case-control study that included 22 cases of PTLD in 179 pediatric solid organ transplant patients, Allen et al. (2005) found: – PTLD cases occurred in 13/39 liver transplants, 5/57 heart transplants, 3/77 kidney transplants, and 1/5 lung transplants – Cases occurred 1-131 months post-transplant (median 22.8) – Cases had higher post-transplant mean baseline EBV load than controls, but were not more likely to be EBV- seronegative pre-transplant than controls – 1 in 4 PTLD cases were EBV seropositive pre-transplantation – Occurrence of PTLD was not associated with any specific immunosuppressive medication PTLD: risk factors • In a case-control study that included 9 cases of PTLD in 95 pediatric cardiac transplant recipients, Katz et al. (2007) identified risk factors: PTLD: risk factors • In a retrospective study that included 12 cases of PTLD in 146 pediatric heart transplant patients, Schubert et al. (2009) identified risk factors: What is the prognosis for pediatric cardiac transplant patients with PTLD? PTLD: prognosis • Highly variable (Aull et al., 2004) • Median survival time was 1 month in EBV-negative PTLD patients and 37 months in EBV-positve PTLD patients (p<0.01) (Leblond et al., 1998) • Most EBV-negative PTLDs with monomorphic histology do not have a favorable outcome even with aggressive treatment (Nelson et al., 2000) PTLD: prognosis • In a multicenter study of 274 cardiac transplant recipients with PTLD, Aull et al. (2004) found low long- term survival rates • Overall, 80% of patients died (median follow up was 53 months after transplantation) • Common causes of death included PTLD (51%), cardiovascular collapse due to withdrawal of immunosuppression (21%), and infection (10%) PTLD: prognosis • Figure 2a (left) shows overall survival after cardiac transplantation: 81%, 68%, 47%, and 20% at 1, 2, 5, and 10 years • Figure 2b (right) shows survival after PTLD diagnosis: 45%, 33%, 30%, and 13% at 1, 3, 5, and 10 years • (Aull et al., 2004) PTLD: prognosis • Aull et al. (2004) identified factors associated with survival: – Single PTLD site (P<0.001) – Receiving immunosuppression reduction as a component of treatment (P<0.001) – Receiving surgery for PTLD (P=0.02) – Transplant 1991-1998 (P<0.001) • Factors not associated with survival: – Polyclonal vs. monoclonal – Receiving chemotherapy – Diagnosis within one year of transplant PTLD: prognosis • In a retrospective study of 30 pediatric and adult patients with late-presenting PTLD, Dotti et al. (2002) found that survival was significantly influenced by treatment – Three patients died before any patients initiated – 26/27 patients underwent reduction of immunosuppresion (cyclosporin reduced; tacrolimus and azathioprine discontinued) – 8/27 patients underwent surgery or radiotherapy for localized disease – all attained complete remission – 18/27 patients received chemotherapy – clinical response was attained in 6 • 9 patients died of toxicity, 3 died of PTLD, 6 died of infectious complications PTLD: prognosis • In a retrospective multicenter study of 80 PTLD patients, Evens et al. (2010) found PTLD: prognosis • In a multicenter retrospective study of pediatric cardiac transplant patients, Webber et al. (2006) found: – PTLD developed in 56 of 1184 (5%) patients – Probability of survival was 75% at 1 year, 68% at 3 years, and 67% at 5 years after diagnosis – Death from graft loss was as frequent as death from PTLD – No significant predictors of survival PTLD: prognosis • In a retrospective study of 12 cases of PTLD in pediatric heart transplant patients, Schubert et al. (2009) found that all patients demonstrated full remission without death related to PTLD or treatment (median follow-up time 3.9 years) PTLD: prognosis • In a case-control study that included 9 cases of PTLD in 95 pediatric cardiac transplant recipients, Katz et al. (2007) found that patients who developed PTLD were at no greater risk of death than control patients What is the best management for pediatric cardiac transplant patients with PTLD? PTLD: management • Reduction in immunosuppresive medications is typically the first-line treatment – many patients do not respond or initially respond and then relapse (e.g., Reshef et al., 2011) • Surgery and radiotherapy are options for some patients with localized disease • There is no standard chemotherapy regimen for PTLD – CHOP is frequently used in adult patients (e.g., Choquet et al., 2007) PTLD: management • In a retrospective study of 35 adult patients with PTLD who were treated with rituximab, chemotherapy, or both, Elstrom et al. (2006) found: – 32 patients were initially treated with reduction of immunosuppression – 22 patients were treated with rituximab – overall response rate 68% - median overall survival 31 months – 23 patients received chemotherapy – overall response rate 74% - median overall survival 42 months PTLD: management • In a prospective multicenter study of rituximab treatment including 46 adult patients with B cell PTLD, Choquet et al. (2006) found: – 32/43 patients completed the full course of rituximab – Overall response rate 44% at day 80 – Normal LDH level was the only factor predictive of response at day 80 – Overall survival rate 67% at day 360 – Number of PTLD sites was the only factor predictive of overall survival PTLD: management • In a pilot study of 6 pediatric PTLD patients treated with rituximab, prednisone, and low-dose cytoxan, Orjuela et al. (2003) found an overall response rate of 100% (5 complete remissions, 1 partial remission) PTLD: management • In a retrospective study of 30 pediatric PTLD patients, Gupta et al. (2010) compared rituximab/low-dose chemotherapy with interferon, rituximab/prednisone, and other chemotherapy PTLD: management • Gross et al. (unpublished) enrolled 55 pediatric patients in the COG ANHL0221 study – All patients had CD20+ and EBV+ disease that had been refractory to reduction of immunosuppression – Six 3-week cycles of therapy • Cycles 1-2: Low-dose cytoxan, prednisone, weekly rituximab • Cycles 3-6: Low-dose cytoxan, prednisone – Event free survival 64% at 2 years – Overall survival 81% (median follow up 3.6 years) References • Allen UD, et al. (2005). Risk factors for post-transplant lymphoproliferative disorder in pediatric patients: A case control study. Pediatr Transplant. 9(4):450-5. • Aull MJ, et al. (2004). Experience with 274 cardiac transplant recipients with posttransplant lymphoproliferative disorder: a report from the Israel Penn International Transplant Tumor Registry. Transplantation. 78(11):1676-82. • Choquet S, et al. (2006). Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood. 107(8):3053-7. • Choquet S, et al. (2007). CHOP-21 for the treatment of post-transplant lymphoproliferative disorders (PTLD) following solid organ transplantation. Haematologica. 92(2):273-4. • Dotti G, et al. (2002). Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation. 74(8):1095-102. • Elstrom RL, et al. (2006). Treatment of PTLD with rituximab or chemotherapy. Am J Transplant. 6(3):569-76. • Evens AM, et al. (2010). Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 28(6):1038-46. • Gross TG, et al. (unpublished). Low-dose chemotherapy and rituximab for post-transplant lymphoproliferative disease (PTLD): Children’s Oncology Group report. • Gupta S, et al. (2010). Post-transplant lymphoproliferative disorder in children: recent outcomes and response to dual rituximab/low-dose chemotherapy combination. Pediatr Transplant. 14(7):896-902. • Katz BZ, et al. (2007). Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort. Pediatr Transplant. 11(1):58-65. • Leblond V, et al. (1998). Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 16(6):2052-9. References • Nelson BP, et al. (2002). Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol. 24(3):375-85. • Orjuela M, et al. (2003). A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in patients with post-transplant lymphoproliferative disorder following solid organ transplantation. Clin Cancer Res. 9(10 Pt 2):3945S-52S. • Reshef R, et al. (2011). Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder. Am J Transplant. 11(2):336-347. • Schubert S, et al. (2009). Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients. Pediatr Transplant. 13(1):54-62. • Tanner JE, Alfieri C. (2001). The Epstein-Barr virus and post-transplant lymphoproliferative disease: interplay of immunosuppression, EBV, and the immune system in disease pathogenesis. Transpl Infect Dis. 3(2):60-9. • Webber SA, et al. (2006). Lymphoproliferative disorders after paediatric heart transplantation: a multi- institutional study. Lancet. 367(9506):233-9.
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