Severe Viral Related Complications Following Allo-HCT for Severe Aplastic Anemia Liat Shragian Alon, MD Rabin Medical Center, ISRAEL #EBMT15 www.ebmt.org
Patient: 25-year-old male No prior medical history Diagnosed with very severe aplastic anemia (SAA) in December 2014. Referred for allogeneic PBSCT from a fully matched young sibling donor. 2 2
Documented infections prior to transplantation: E. coli bacteremia Treated with IV piperacillin / tazobactam Multiple lung nodules with surrounding ground-glass infiltrates ( halo sign) on chest CT were highly suspicious for invasive pulmonary aspergillosis Treated with oral voriconazole Transplantation regimen: Bacigalupo conditioning regimen Fludarabine - 30 mg/m2/day, days -6 to -3 Cyclophosphamide - 30 mg/kg/day, days -6 to -3 Thymoglobulin - 3.75 mg/kg/day, days -4 and -3 TBI 200 rad on day -1 GVHD prophylaxis cyclosporine plus short-course methotrexate Donor: 13 year old HLA-matched male sibling with negative CMV and EBV serology Patient with documented past infection of CMV and EBV Patient engrafted on day 12 3 3
Post transplantation course Day 26 - BK virus cystitis >3,250,000 copies/ml Resolved with symptomatic treatment only Day 34-1 st CMV reactivation. Pre-emptive treatment with valganciclovir Day 61- grade III acute GVHD with skin and GI involvement Treated with high-dose corticosteroids Day 75 2nd CMV reactivation. Renewal of pre-emptive treatment with valganciclovir Day 93 Bilateral pneumonia with cavity formation in LT lung, pathogens isolated: Pneumococcus in blood Influenza virus with nasal wash 4 4
1 st CMV reactivation 2 nd CMV reactivation BK virus cystitis GVHD Bilateral Pneumonia 5 5
Resistance testing foscarnet foscarnet ganciclovir valganciclovir 6 6
EBV associated monomorphic PTLD: Day 130 - Fever and lower abdominal pain, abdominal CAT scan revealed RLQ lymph node mass of 5X7 cm. Day 141 laparoscopic biopsy: Large cell lymphoma Stained positively for: CD20, MUM-1, CD79A, with >50% of the malignant cells positive for membranous CD30. KI-67 index proliferation of 70%. Positive immunologic stains for EBV and CISH EBER Diagnosis: EBV monomorphic B-cell PTLD with post germinal center phenotype Blood PCR level for EBV at diagnosis was 2.8 10 4 cop/ml 7 7
Abdominal lymph node biopsy: CD20 MUM1 CISH EBER 8 8
Immunosuppressive treatment (CsA & prednisone) tapered down rapidly and stopped. Day 146 Rituximab, 375 mg/m 2 weekly X 4. Day 185 PET-CT revealed: Progressive abdominal disease Diffuse nasopharyngeal FDG uptake LUL cavitary lesion, with high FDG uptake. 9 9
Day 190 R-CHOP initiated. Day 245 Interim PET-CT (after R-CHOP x 3): Resolution of abdominal lymphadenopathy Localized 1.8 cm mass in right nasopharynx with high FDG uptake Persistent LUL cavitary lesion Biopsy from ulcerated nasopharyngeal lesion DLBCL: Highly positive immune stains for EBV and CISH EBER Positive immune stains for MUM-1 and CD79A CD20 and CD30 stains became negative 10 10
EBV cytotoxic T-cells from a 3 rd party donor were ordered, yet to be administered (MSKCC). Ibrutinib (BTK inhibitor) was started (non GCB phenotype of lymphoma). Despite clinical improvement following three weeks of ibrutinib treatment, recent PET-CT revealed an increase of the right nasopharyngeal lesion to 3cm and the LUL lesion resolved. 11 11
Discussion Points for discussion: Persistence viremia with CMV post allo-hct vs. post solid organ transplantation. Rare case of a recipient-derived EBV-PTLD. PTLD in HCT recipients most commonly donor-derived. Can we prevent EBV-related PTLD? Should EBV status (donor, recepient) impact donor selection? Different conditioning regimens? Alemtuzumab vs. ATG (Bacigalupo A, Haematologica 2010) Rituximab prophylaxis? (Dominieto A. BMT 2013) Rituximab preemptive treatment? 12 12
Discussion Rituximab prophylaxis does it put the patient at risk for CD20-negative Rituximab-refractory disease? Rituximab-refractory EBV-PTLD CD20 negative not treatment-refractory (Muramats H, Int J Hematology 2011 : radiotherapy, Comoli P, Am J Transplant 2007 : EBV-CTL) Is there a role for ibrutinib? In DLBCL In EBV-related PTLD Role of EBV CTL 13 13