Cases Of Chronic Graft-versus-host Disease Research Articles

Candida krusei pneumonia in graft-versus-host disease after allogeneic hematopoietic stem cell transplant for paroxysmal nocturnal hemoglobinuria: a case report

Introduction and importance: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder caused by a somatic mutation of PIGA (phosphatidylinositol glycan anchor biosynthesis, class A) gene that leads to the destruction of blood cells. Allogeneic haematopoietic stem cell transplant (HSCT) is a treatment option for PHN, but it can cause graft-versus-host disease (GVHD). Long-term immunosuppression as a treatment of GVHD increases the risk for invasive fungal infections such as Candida krusei pneumonia. Case presentation: We present the case of a 22-year-old male with C. krusei pneumonia in a known case of chronic GVHD following HSCT for PNH undergoing long-term immunosuppressive therapy. The patient presented with progressive shortness of breath, productive cough, palpitations, and difficulty swallowing. On examination, he had skin rashes and oral lesions, along with signs of severe malnutrition. Diagnosis was made on the basis of radiological imaging and fungal culture. Discussion: The combination of PNH, GVHD, and HSCT created an immunocompromised state, making the patient susceptible to opportunistic infections, including fungal pneumonia. Early recognition of this condition is challenging due to its non-specific symptoms and potential overlap with other post-transplant complications. Timely diagnosis and appropriate treatment, including antifungal therapy and immunosuppression management, are crucial for optimising patient outcomes. Conclusion: This case highlights the importance of early recognition and timely treatment of fungal infections in patients with severe conditions such as GVHD following HSCT for PNH. Timely treatment with appropriate antifungals is necessary for optimal outcomes. Additionally, more research with long-term follow-up and monitoring is necessary to address the necessary knowledge gaps in this field.

Epigenetic Priming with 5-Azacytidine Prior to Allogeneic Stem Cell Transplantation for Myeloid Malignancies with In Vivo T Cell Depletion: Results of a Phase II Trial

Background: Relapse is the main cause of death in patients who undergo allogeneic hematopoietic stem cell transplantation (HCT) for myeloid malignancies. Recent improvements in survival have been mainly due to reduction in non-relapse mortality (NRM). Acquired abnormalities of DNA methylation are frequent in myeloid malignancies and are particularly observed among patients with adverse risk features. Epigenetic priming with decitabine to induce DNA hypomethylation was investigated in a phase I trial for acute myeloid leukemia (AML) and has proven safe and feasible (Scandura et al Blood 2011). Applying the principle of chemotherapy-sensitization through hypomethylation in myeloid malignancy, we conducted a phase II trial (NCT02497404) of the epigenetic modulator -5-azacytidine given prior to a reduced intensity conditioning (RIC) regimen. Here we report the results of this trial. Methods: We designed an open label phase II study to determine the feasibility and efficacy of epigenetic priming with 5-Azacytidine prior to RIC for HCT with in-vivo T-cell depletion. Inclusion criteria were AML, myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) with an intermediate or poor risk profile by ELN and IPSS-R, respectively, and adequate organ function. Stem cell grafts were GCSF- mobilized peripheral blood stem cells from either a matched related donor (MRD) or matched unrelated donor (MUD), matched for HLA at loci A, B, C, DR, and DQ. The epigenetic priming regimen was 5-Azacytidine 75 mg/m2/daily X 5, given between days -11 to -7 (Dose reduction to 50 mg/m2/daily after 14 patients due to toxicity). The conditioning regimen consisted of Fludarabine 40 mg/m2/daily, days -6 to -3, and Melphalan 140 mg/m2, on day -3. Graft versus host disease (GVHD) - prophylaxis consisted of Alemtuzumab (total dose 60 mg for MUD and 30 mg for MRD), and Tacrolimus for 3-6 months post-transplant. The Primary objectives were overall survival (OS) and progression free survival (PFS) at 1 year. Secondary objectives were incidence of GVHD and NRM. Results: 39 adult patients with AML, MDS, and chronic neutrophilic leukemia (CNL) were enrolled prospectively between 2/2015 and 6/2018. The median age was 60 years (range, 26-74). The majority of patients had AML (33, 85%), or MDS (5, 13%). Nineteen AML patients (58%) had a poor risk karyotype. Nine cases (23%) had mutated TP53. The donor was MUD in 22 (44%), MRD in 17 (56%) of patients. Other patient characteristics are listed in Table 1. The median follow up for survivors is 6.7 years (5.8 - not reached). Thirty-eight patients engrafted neutrophils at a median of 13 days (9-16) and platelets at a median of 16 days (12-102). One patient was not evaluable due to early death on day 9. OS at 1 year was 64% (95% CI 51-81%) and 36% (95% CI 24-55%) at 4 years, (Figure 1). PFS at 1 year was 54% (95% CI 40-72%) and 33% (95% CI 21-52%) at 4 years. At 1 year, relapse was the cause of death in 21% (95% CI 18-22%) and NRM was 15% (95% CI 13-17%). At 4 years, relapse was the cause of death in 41% (95% CI 38-43%), while NRM reached 23% (95% CI 20-25%). The most common cause of NRM was infection in 5 patients (46%), followed by thrombotic microangiopathy and GVHD. The incidence of acute GVHD by day 100 was 29% (95% CI 13-43%) with grade III-IV acute GVHD found in 8% (95% CI 6-9%). The incidence of chronic GVHD at 1 year was estimated at 22% (95% CI 7.4-35%). No new cases of chronic GVHD were seen thereafter. The most common grade 3/4 toxicities were infections in 8 patients (21%) and renal failure (23%). We found 6/14 patients to have grade 3/4 renal toxicity with 2 requiring hemodialysis. After reducing the 5-azacytidine dose to 50 mg/m2/daily, we observed only 3/25 cases of grade 3/4 renal dysfunction. Conclusion: Preconditioning treatment with 5-azacytidine as epigenetic priming is tolerable with a toxicity profile overall similar to conditioning with fludarabine/melphalan. But the addition of azacytidine at 75 mg/m2/daily (total 5 doses) causes significant renal toxicity, which abates with dose reduction. The PFS in this very high-risk population with historically high relapse rates is promising. A larger number of patients is needed to further evaluate the efficacy of this approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect.Methods: We have initiated a 50 patient randomized clinical trial. Patients with hematologic malignancies in need of a transplant and with an 8/8 matched donor are randomized 1:1 to tacrolimus and methotrexate for GVHD prophylaxis (standard of care arm) or PTCy on days +3 and +4 followed by CTLA4Ig on days +5, +14,+28, +56, +84, +112, +140 and +168. Patients are stratified by conditioning regimen (myeloablative vs reduced intensity) and by donor type (matched sibling vs matched unrelated donor). The primary endpoint is chronic GVHD at 1 year as a marker of tolerance induction. Secondary endpoints include acute GVHD rate, relapse rate, overall survival, GVHD-relapse-free-survival, transplant related mortality and infection rate. Post-transplantation immune reconstitution studies include measuring T cell and NK cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points.Results: 25 patients have been treated on this study, 10 of which are on the experimental arm. Patients on the experimental arm have been followed for up to 516 days post-transplant. So far no cases of chronic GVHD or grade 3-4 acute GVHD have been observed in the experimental arm. All the patients have engrafted and there have been no treatment related deaths.Conclusions: The combination of PTCy and CTLA4Ig for GVHD prophylaxis is feasible. This ongoing study will examine its ability to induce post-transplant tolerance. DisclosuresTzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board. OffLabel Disclosure:abatacept: using as part of graft versus host disease prophylaxis

Efficacy analysis of haploidentical allogeneic hematopoietic stem cell transplantation combined with third-party umbilical cord blood infusion in treatment of high-risk lymphoblastic malignancies

Objective To evaluate the efficacy of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) combined with third-party umbilical cord blood (UCB) infusion in treatment of high-risk lymphoblastic malignancies. Methods The clinical data of 20 patients with high-risk lymphoblastic malignancies who received Haplo-HSCT from April 2012 to April 2015 in Shanghai General Hospital were retrospectively analyzed, which were compared with the data from 15 patients who underwent matched unrelated donor HSCT (MUD-HSCT) or 14 matched sibling donor HSCT (MSD-HSCT) during the same period. The efficacy of Haplo-HSCT combined with UCB infusion in treatment of high-risk lymphoblastic malignancies was evaluated. The preparative regimen mainly consisted of teniposide, cyclophosphamide and total body irradiation (TBI). Graft versus host disease (GVHD) preparative regimen included cyclosporine and a short term of methotrexate. The patients who received Haplo-HSCT combined with UCB infusion and MUD-HSCT were treated with antithymocyte globulin (ATG). Results After the transplantation, one patient in MUD-HSCT group and one in MSD-HSCT group died within 21 days, and other patients were engrafted successfully. The median time of neutrophil engraftment was 13 days (10-18 d), 12 days (9-16 d) and 12 days (9-14 d) in Haplo-HSCT + UCB group, MUD-HSCT group and MSD-HSCT group, respectively; the median time of platelets engraftment was 11 days (9-18 d), 12 days (10-23 d) and 12 days (9-14 d), respectively. There were 10, 3, 3 cases of grade Ⅱ-Ⅳ acute GVHD at day 100 in the three groups, respectively, and there were 6, 4, 3 cases of chronic GVHD in the three groups, respectively. The 2-year cumulative incidence of relapse was 40.6%, 66.2% and 26.7%, respectively. The predicted 2-year overall survival rate was 37.9%, 42.9% and 55.4%, respectively. All these data had no significant difference (all P > 0.05). Conclusion The efficacy of Haplo-HSCT combined with UCB infusion is similar to that of MUD-HSCT or MSD-HSCT in treatment of high-risk lymphoblastic malignancies, which should be recommended to the patients with high-risk lymphoblastic malignancies and without matched donors. Key words: Lymphoblastic malignancies; Allogeneic hematopoietic stem cell transplantation; Fetal blood

PF767 PHASE 2 STUDY EVALUATING THE SAFETY AND EFFICACY OF ONE OR TWO DOSES OF DONOR LYMPHOCYTES DEPLETED OF HOST ALLOREACTIVE T‐CELLS (ATIR101) FOLLOWING T‐CELL‐DEPLETED HAPLOIDENTICAL HSCT

Background:The use of ex vivo T‐cell‐depleted haploidentical hematopoietic stem cell transplantation (haplo HSCT) minimizes the risk of severe graft‐versus‐host disease (GVHD). However, delayed immune reconstitution increases the risk of serious infections and relapse. ATIR101 is a donor‐derived, T‐cell‐enriched leukocyte preparation depleted ex vivo of host‐alloreactive T cells. When administered as an adjunctive infusion after T‐cell‐depleted haplo HSCT, ATIR101 aims to deliver donor T cells that can facilitate early immune protection and provide anti‐leukemic activity while minimizing the risk of GVHD.Aims:In a previous Phase 2 study of a single ATIR101 infusion of 2 × 106 T cells/kg in patients with AML/ALL, overall survival (OS) at 1 year was 61% with no cases of Grade III/IV acute GVHD (aGVHD; Ref). It was hypothesized that two doses may improve efficacy further; therefore, a Phase 2 exploratory study was conducted (CR‐AIR‐008; NCT02500550).Methods:Seventeen patients with hematologic malignancies (who provided informed consent) received myeloablative conditioning followed by a CD34‐selected stem cell graft. Two ATIR101 infusions of 2 × 106 T cells/kg derived from the same donor were planned for 28–32 and 70–74 days post HSCT. Patients did not receive GVHD prophylactic immunosuppression. The protocol allowed for evaluation of the safety of the double dose in the initial 6 patients, permitting an adjustment to a single dose in the case of dose‐limiting toxicity (Grade III/IV aGVHD within 120 days post HSCT). The primary endpoint was the incidence of Grade III/IV aGVHD up to 180 days post HSCT and patients were followed for 1 year for secondary endpoints, including: transplant‐related mortality (TRM), relapse‐related mortality (RRM), GVHD‐free relapse‐free survival (GRFS), and OS.Results:Two of the first 6 patients that who received a double dose of ATIR101 (4 AML, 2 MDS) experienced Grade III/IV aGVHD within 120 days of HSCT (1 Grade III at 25 days, 1 Grade IV at 18 days after the second dose). In accordance with the protocol, the remaining 11 patients were scheduled to only receive a single 2 × 106 T cells/kg dose on Days 28–32 (5 AML, 3 ALL, 3 MDS). Nine of these 11 patients received ATIR101 (2 did not receive ATIR101 due to an early death and a batch rejection); 2/11 developed Grade III aGVHD within 180 days. There were 2 cases of chronic GVHD in double‐dose and none in single‐dose patients. Table 1 shows secondary outcomes at 1 year. For double‐dose patients, TRM was 67%, RRM was 0%, and the 1‐year Kaplan–Meier (KM) estimate of OS was 33% and of GRFS was 17%. For single‐dose patients, TRM was 36%, RRM was 9%, and 1‐year KM estimates of OS and GRFS were 55% and 46%, respectively.Summary/Conclusion:Administration of a single dose of ATIR101 showed a favorable safety profile. There were 2 cases of Grade III aGVHD but no Grade IV aGVHD or chronic GVHD. OS and GRFS in this study confirmed results from the larger Phase 2 study of a single ATIR101 dose, and disease relapse and TRM were limited in both studies. Based on the observed Grade III/IV aGVHD, the safety profile of a second dose at the time point evaluated does not align with previous single‐dose data with ATIR101. Further investigation is needed to clarify the cell number for a second dose of ATIR101 that can be administered safely post HSCT. Based on the two Phase 2 studies with ATIR101, a large, randomized, Phase 3 trial has been initiated, comparing a single dose of ATIR101 with PTCy in haplo HSCT (HATCY; NCT02999854).image

Pilot study using post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate GVHD prophylaxis for older patients receiving 10/10 HLA-matched unrelated donor hematopoietic stem cell transplantation.

Allogeneic SCT for older patients remains challenging at least in part due to graft-versus-host disease (GVHD) and higher non-relapse mortality (NRM). We conducted a prospective pilot study primarily for older patients undergoing matched unrelated donor (MUD) SCT using a reduced-intensity (RIC) melphalan-based conditioning and post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis with tacrolimus and mycophenolate mofetil. Twenty-two patients (median age 64, IQR 58, 66) underwent RIC MUD SCT for high-risk hematological malignancies including AML/MDS (73%), CML/MPD (18%), and other (10%). Two (9%) patients had early death; the rest (100%) engrafted. After a median follow-up of 17 months, 11 patients were alive and disease-free with an estimated 2-year progression-free (PFS) and overall (OS) survival of 48%. The cumulative incidences of grades 2-4 and 3-4 acute GVHD (aGVHD) at day + 100 and 2-years were 32 and 4%, and 59 and 24%, respectively. No cases of chronic GVHD (cGVHD) were noted. However, late acute GVHD was observed in 6 (27%) patients. In conclusion, RIC MUD SCT with melphalan-based conditioning and PTCy-based GVHD-based prophylaxis for older patients appears effective in controlling relapse. While cGVHD was not seen and early aGVHD appears controllable, a significant proportion developed late aGVHD responsible for higher NRM seen in these patients.

Fludarabine-Based Reduced Intensity Regimen for Matched Related Donor Stem Cell Transplantation in Acquired Severe Aplastic Anemia

The outcome of severe acquired aplastic anemia (SAA) has improved dramatically over the past few decades due to advances in allogeneic stem cell transplantation (allo-STC). Different conditioning regimens have been tested in matched related donor (MRD) transplants with variant results. Before 2008, we have encountered poor engraftment in our patients using high dose cyclophosphamide (200 mg/kg) and thymoglobulin (ATG). Fludarabine, low dose cyclophosphamide, ATG and total body irradiation (TBI) was used for alternative donor transplants by Bacigalubo and colleagues (1). Since 2008, we have decided to start using this regimen in our MRD transplants to improve engraftment and ultimately overall survival. To our knowledge, this abstract describes the outcome of the largest cohort of patients who received MRD allo-STC for SAA using this regimen. It represents our single institution experience over a period of 10 years.Methods: This is a retrospective chart review of all patients diagnosed with acquired SAA who underwent allo-STC between August 2005 and December 2015 at the American University of Beirut Medical Center (AUBMC)Results: A total of 22 patients underwent transplant with grafts from related HLA-matched donors. Before 2008, three patients received cyclophosphamide 50 mg/kg/day over 4 days and ATG (Fresenius) 30 mg/kg/day over 4 days. Since 2008, nineteen patients received fludarabine 30 mg/m2/day for 4 days (-6, -5, -4 and -3), cyclophosphamide 300 mg/m2/day for 4 days (-6, -5, -4 and -3) and ATG (Genzyme) 3.75 mg/m2/day for 2 days (-4 and -3). TBI at a dose of 2 Gy was added on day -1 for patients more than 15 years of age. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A with either mycophenolate mofetil (50%) or a short course of methotrexate (50%). The median age of patients was 21 years (range: 1.7-64 years). The median duration between diagnosis and transplant was 11 months (range: 1-85 months). Seven patients (31%) had failed immunosuppressive therapy before transplant. The stem cell source was bone marrow (BM) for 14 patients (64%) and peripheral blood (PB) for 8 patients (36%). The median CD34 cell dose infused was 5.4 ×106/kg (range: 1 - 19.5 ×106/kg). The 2-year overall survival rate was 82% with trend toward better survival without statistical significance when using fludarabine-based regimen (84% vs 66%, P: 0.42), if both donor and recipient had the same gender (92% vs 66%, P: 0.11), or if PB was the source of stem cells (87% vs 78%, P: 0.58). Engraftment failure was observed in 2 cases (9%). The median time for neutrophil engraftment was 20.3 days (range: 14-38 days). Neutrophil engraftment was faster when the fludarabine-based conditioning regimen was used (18 vs 38 days, P: 0.04), if PB was used as the source of stem cells (17 vs 20 days, P: 0.03) or if TBI was added to the conditioning regimen (18 vs 20 days, P: 0.07). Chimerism studies were available for 18 out of 20 engrafted patients. Two patients had partial engraftment (89% and 76%) and 16 patients had complete engraftment (>90%). The previous use of IST or the duration between diagnosis and transplant (< or > 1 or 2 years) did not affect survival or engraftment. Acute GvHD (grade I-II) occurred in 2 patients (9%). No cases of chronic GvHD or veno-occlusive disease (VOD) were reported. CMV reactivation occurred in 2 cases while CMV disease was reported in another case. EBV reactivated in one case without LPD. Hemorrhagic cystitis occurred in one case. One patient developed donor cell precursor B-cell acute lymphoblastic leukemia 2 years after transplant.Conclusions: Fludarabine-based reduced intensity regimen for MRD transplants in SAA has led to improved engraftment with minimal toxicity. This result was not affected by the previous use of IST or the long duration between diagnosis and transplant as was reported in previous studies with different conditioning regimens or donor types. Thus, this regimen may be particulary useful in countries where patients present late to transplant.

Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Improve Event-Free Survival (GRFS) and Overall Survival in a T-Cell Depleted Haploidentical HSCT: Phase 2 Trial in Patients with AML and ALL

Introduction. Haploidentical donors may resolve the shortage of available HLA-matched donors for the treatment of patients with blood cancers in need of a hematopoietic stem cell transplantation (HSCT). However, to prevent graft-versus-host disease (GVHD), haploidentical HSCT requires alloreactive T-cell depletion or suppression. We developed an ex vivo cell treatment strategy that allows additional donor lymphocytes to be infused post-HSCT without inducing severe GVHD and maintaining reactivity against viruses and leukemic cells.Patients and Methods. In this open-label, multicenter phase 2 study (CR-AIR-007; NCT01794299), 23 patients, 11 females and 12 males, with a median age of 41 years (range: 21 - 64) were treated with ATIR101. Sixteen patients had AML and seven patients had ALL (15 in CR1 and 8 in CR2). Patients underwent myeloablative conditioning, consisting of a] TBI (1200 cGy: n=11) or b] melphalan (120 mg/m2: n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d) and ATG (2.5mg/kg x 4d). A CD34+ selected stem cell graft from a haploidentical donor was given, containing a mean of 11x106 CD34+ cells/kg (range: 4.7 - 24.4x106) and 0.29x104 CD3+ cells/kg (range: 0 - 1.8x104). In addition, donor lymphocytes from the same donor were processed using a selective photodepletion technology, creating a donor lymphocyte infusion depleted of alloreactive T-cells (ATIR101). ATIR101 was infused at a median of 28 days (range: 28-73) post-HSCT at a fixed dose of 2x106 CD3+ cells/kg, without use of any post-transplant GVHD prophylaxis.Results. All patients engrafted rapidly after transplantation, with neutrophil and platelet engraftment achieved at a median of 12 days (range: 8-34 and 9-35, respectively). Median follow-up (as of August 1st, 2016) is 484 days post-HSCT, with at least 1-year follow-up for all but one patient, which will reach the 1 year endpoint end of September 2016. Ex vivo photodepletion eliminated anti-host proliferating T cells while preserving anti-third party and anti-CD3/CD28 reactivity. CD3+ T-cells were detected in patient peripheral blood from 16 weeks post-HSCT and CD19+ B cells increased rapidly from 5 weeks post-HSCT onwards. No patients developed grade III/IV acute GVHD after infusion of ATIR101. Three cases of grade II acute GVHD were reported and only one case of chronic GVHD has been reported so far. No patient died within 100 days post-HSCT and the overall survival of patients given ATIR101 was significantly improved compared to a historic control group, with a 1-year survival of 61% in the HSCT+ATIR101 group vs 20% in the control group (Table 1). Thus far two patients experienced a relapse within the first year post-HSCT, occurring at 60 and 90 days, respectively. Severe infections (grade 3-5) occurred in 9/23 subjects within the first 6 months post-HSCT, which were viral infections in 7/23 subjects. After 6 months, up to a year post-HSCT only 5/23 patients were reported to suffer from severe infections.The GVHD-free, relapse-free survival (GRFS) for HSCT + ATIR101 is estimated to be 57% at 1-year post-HSCT, which compares favorably to the T-cell depleted HSCT only control group (20%), and also against the MUD group (41%), derived from the same centers in these contemporaneous historical control groups (Figure 1).Conclusion. Administration of a high dose of donor lymphocytes in ATIR101 from a haploidentical donor does not cause severe GVHD without use of prophylactic immune suppression. Addition of ATIR101 to a T-cell depleted HSCT protocol significantly improves transplantation outcome, with improved overall survival and favorable event-free survival (GRFS). One year GRFS for HSCT + ATIR101 also compares favorably to published data on haploidentical HSCT using post-transplant cyclophosphamide for GVHD prophylaxis (Solh et al, BBMT 2016). [Display omitted] [Display omitted] DisclosuresRoy:Kiadis Pharma: Research Funding; Novartis: Consultancy; Fate Therapeutics: Consultancy; Paladin: Consultancy. Maertens:Astellas: Consultancy, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Gilead: Consultancy, Honoraria, Speakers Bureau. Rüdiger:Kiadis Pharma: Employment. Velthuis:Kiadis Pharma: Employment. Gerez:Kiadis Pharma: Employment. Rovers:Kiadis Pharma: Employment. Mielke:JAZZ Pharma: Speakers Bureau; Novartis: Consultancy; Gilead: Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; MSD: Consultancy, Other: Travel grants.

Immunotherapy for acute leukemia

Immunotherapy for acute leukemia

Adenovirus Infections in Patients Undergoing Umbilical Cord Blood Hematopoietic Stem Cell Transplantation.

Abstract 1132Poster Board I-154 BackgroundAdenovirus infections are an important source of morbidity and mortality among stem cell transplant (SCT) recipients, with infections occurring in 5-21% of patients, with an associated mortality of up to 50%. Little is known about the clinical features and incidence of adenovirus infection after cord blood SCT (CB-SCT) in adults. MethodsThe DFCI/BWH umbilical CB-SCT cohort transplanted from 2003-2008 was analyzed. Adenovirus infection was diagnosed by blood PCR, culture, immunofluorescence, or immunohistochemistry. Baseline covariates included age, sex, malignancy being treated, conditioning, graft versus host disease (GVHD) prophylaxis, incident GVHD and its severity. Data was censored on 7/1/2009. Results92 patients underwent CB-SCT during the period; 89 were double cord recipients. 68 underwent reduced-intensity conditioning consisting of fludarabine (180mg/m2), melphalan (100 mg/m2), and ATG (Thymoglobulin® 6 mg/kg). GVHD prophylaxis with sirolimus and tacrolimus was used in 57 patients, cyclosporine and mycophenolate mofetil in 17, and other combinations in the rest of the cohort. Median follow up was 363 days (range, 1-1848 days). Adenovirus testing was routinely done for persistent febrile illness, respiratory, gastrointestinal and hepatic syndromes. Adenovirus infection was diagnosed in 6/92 for a cumulative incidence of 6.5%. Three were female, median age was 51 years (range, 37-62). Underlying disease was MDS in 1, NHL in 2, AML in 2 and HD in 1. Median time to diagnosis was 152 days (range, 23-768) from CB-SCT. Three patients were diagnosed within 100 days post CB-SCT: all had diarrhea and fever. The other 3 patients were diagnosed between 8 months to 2 years after transplant: one patient each had respiratory, urinary and gastrointestinal infection. Three of the six patients developed concomitant CMV reactivation with their adenovirus infection: 2 of these occurred within 100 days of transplant, and one occurred 1 year after HSCT. Three of the 6 patients with adenovirus infection also developed grade II-IV acute GVHD and 2 developed chronic GHVD. The onset of acute GVHD was closely associated in time with the development of adenovirus infection; this was not the case of chronic GVHD. Two patients had blood adenovirus loads > 1 million copies/mL, and were treated with cidofovir with improvement in symptoms and decline in virus loads. Of the 6 patients, 3 died of relapsed disease, none died of complications attributable to adenovirus infection. ConclusionsSince recipients of T-cell depleted transplants are at higher risk for viral infections compared to those receiving unmanipulated grafts, we hypothesized that umbilical cord recipients would be at an increased risk for adenovirus infection due to the limited number of immunocompetent T-cells in cord blood grafts. Surprisingly, we detected adenovirus infection in only 6.5% of patients in this cohort, and none died as a consequence of adenovirus infection. Further study of the immunity to adenoviruses in CB-SCT adult recipients is warranted. DisclosuresOff Label Use: cidofovir for treatment of adenovirus infection.

Graft-versus-host disease--clinical and pathological analysis of 11 biopsy proven cases.

Graft-versus-host disease (GVHD) is a life threatening complication that may occur following allogenic bone marrow transplantation (BMT) in the patients with aplastic anemia, leukemia or genetic immunodeficiency. It has been known that GVHD occurs approximately 70% of recipients of BMT in western countries but no definite incidence has been reported in Korea. In our St. Mary's Hospital, GVHD occurs in about 30% of BMT recipients. Histopathologically the acute phase skin shows diffuse lymphocytic infiltrates in the upper dermis with extensive exocytosis. Scattered throughout the epidermis are many degenerated keratinocytes, which are often associated with one or more satellite lymphocytes (satellite cell necrosis). In the chronic phase, acanthosis, eosinophilic keratinocytes resembling colloid bodies and mononuclear cell infiltrates in the upper dermis are noted. We reviewed 5 cases of acute GVHD and 6 cases of chronic GVHD. All patients received allogenic BMT from Jan. 1, 1992 to July 1, 1993. Ten patients were male and one was female. The mean age was 34 (20-70). The pathologic diagnosis was 3 cases of CML, 2 of ALL, 2 of AML (FAB M2), 2 of aplastic anemia, 1 of CLL and 1 of AML (FAB M5). The interval from BMT to GVHD varied from 14 days to 4 years (median 220 days). The skin and GI tract were involved in all eleven cases. Ten cases were histologically proven by skin biopsies, and two cases by salivary gland and colonic biopsies, respectively. The histological findings of the skin, salivary gland and colonic biopsieds were described. Immunohistochemical stain of the skin was done using CD4, CD8, HLA DR and Leu 7 antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

著しい潰よう性口内炎を伴った同種骨髄移植後の慢性ＧＶＨＤの１例

著しい潰よう性口内炎を伴った同種骨髄移植後の慢性ＧＶＨＤの１例