aGVHD Of Skin Research Articles

Combination of ST2 With Organ-Specific Biomarker is More Sensitive and Specific for the Diagnosis of Acute Graft-vs-Host Disease

Diagnosis of acute graft-vs-host disease (aGVHD) based on clinical symptoms and biopsy of involved organ was not satisfactory; reliable plasma biomarkers or their panels would be of great value to increase the sensitivity and specificity for such a fatal complication. One hundred two patients who received allogeneic hematopoietic stem cell transplantation in our center were included in this study. Systemic biomarkers of ST2, IP10, IL-2Rα, TNFR1, and organ-specific biomarkers of Elafin, REG-3α, and KRT-18F in plasma were tested by ELISA. The correlation of each biomarker or selected panel of some systemic and organ-specific biomarker with aGVHD was investigated. The level of each systemic biomarker in aGVHD patients was significantly higher than that in patients without aGVHD. Organ-specific biomarker of Elafin, REG-3α, and KRT-18F also had predictive value for aGVHD of skin, gastrointestinal tract, and liver, respectively. Combination of ST2 with one of the 3 organ-specific biomarkers could provide more accurate prediction for aGVHD with skin, gastrointestinal tract, and liver, respectively. All the biomarkers tested in our study correlated with the severity and clinical course of aGVHD. Combination of each systemic biomarker with organ-specific biomarker could increase the sensitivity and specificity for the diagnosis of aGVHD, whereas ST2 with organ-specific biomarker is more sensitive for the diagnosis of organ-specific aGVHD.

Clinical analysis of sub-standard dose of donor stem cell infusion mobilized by granulocyte colony-stimulating factor in treatment of relapsed acute leukemia after allogenic hematopoietic stem cell transplantation

Objective To investigate the clinical effect and prognosis of sub-standard dose of donor stem cell infusion(DSI) mobilized by granulocyte colony-stimu1ating factor(G-CSF) in patients with relapsed acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods From January 2010 to April 2017, a total of 17 patients with relapsed AL after allo-HSCT in Department of Hematology, the First Affiliated Hospital of Xi′an Jiaotong University were included in the study. They were divided into DSI combined chemotherapy group (n=7) and chemotherapy alone group (n=10) according to different treatment after relapse. The basic clinical data of patients with relapsed AL after allo-HSCT were collected by retrospective analysis. The infusion dose of DSI, treatment results, adverse reactions and survival outcomes were observed in both groups. Kaplan-Meier method was used to draw the overall survival (OS) and survival after first relapse (SAR) curves of two groups. The OS and SAR rate were compared by Log-rank test between two groups. This study protocol was approved by the ethics committee of the First Affiliated Hospital of Xi′an Jiaotong University (Approoal No. XJTU1AF2010LSL-020). Informed consents were obtained from all patients before treatment. Results ① The median age of patients in DSI combined chemotherapy group was 28 years (11-49 years), 3 cases were positive in fusion gene, and 6 cases were achieved complete remission(CR)1 before transplantation, none of them had graft versus host disease(GVHD). The median age of patients in chemotherapy group was 22 years (15-37 years). The fusion gene was positive in 4 cases, and 2 cases had GVHD. ② In DSI combined chemotherapy group, 5 patients received single DSI treatment after conventional chemotherapy, and 2 patients received DSI treatment in every two weeks. Three patients (3 / 7) achieved CR. There were 4 patients with grade Ⅰ ~Ⅱ aGVHD of skin and liver, 3 patients with grade Ⅳ myelosuppression and pneumonia. Up to the end of follow-up, 1 patient survived and 6 died in DSI combined chemotherapy group. ③In the chemotherapy group, 3 patients (3 / 10) achieved CR after treatment. Up to the end of follow-up, 4 patients survived and 6 patients died. ④ The 1-year and 3-years OS rates of patients in DSI combined chemotherapy group were 57.1% and 19.0%, respectively, and those of patients in chemotherapy group were 66.7% and 17.8%, respectively. There were no significant differences between two groups (χ2 = 2.122, 0.136; P=0.58, 0.68). There was no significant difference in 1-year SAR rate between two groups (41.3% vs 29.8%; χ2=3.165, P=0.43). Conclusions The combination of G-CSF mobilized sub standard dose DSI with chemotherapy may improve the CR rate of patients with relapsed AL after allo-HSCT. Reducing dose of DSI may reduce the incidence of severe GVHD without affecting the therapeutic efficacy and graft versns leukemia(GVL) effect. Key words: Leukemia; Hematopoietic stem cell transplantation; Recurrence; Hematopoietic stem cell mobilization; Donor stem cell infusion

Survival Outcomes Following Allogeneic Stem Cell Transplantation for Inherited Bone Marrow Failure and Myeloid Germline Predisposition Syndromes

Introduction: Allogeneic stem cell transplant (HCT) is the only potential curative option for patients with inherited marrow failure (iBMF) and myeloid germline predisposition syndromes (GPD). HCT outcomes are influenced by inherent disease specific-nuances such as alkylating agent and radio-sensitivity, immune deregulation, and higher risks for graft failure and GVHD; factors contributing to transplant related mortality (TRM) and morbidity. We carried out this retrospective study to assess survival outcomes and long term complications (LTC) in patients with IBMF and GPD that underwent HCT. Patients and methods: We queried our institutional database and identified patients with iBMF and GPD as defined by the 2016 WHO classification. These included Fanconi anemia (FA), short telomere syndromes (STS), Diamond-Blackfan anemia (DBA), GATA2 and RUNX1 haploinsufficiency, congenital amegakaryocytic thrombocytopenia (CAMT), deficiency of adenosine deaminase 2 (DADA2), among others. Patients with acquired causes of BMF were excluded. Statistical analyses were performed using SAS (JMP v14.1). Results: Twenty eight patients, median age 10 years (1 month-63 years), 46% males, were included in the study (table 1). Fanconi anemia Seven (25%) patients with FA underwent HCT, 5 (71%) without myeloid transformation and 2 after transformation to MDS/AML. Five (71%) patients received a RIC, 4 (57%) prior to transformation. At a median follow up (FU) of 126 m, the median OS was 194 m (95% CI 34m; NR) and 10 year survival was 64%. Grade 1 aGVHD was seen in four (57%) and 3 (42%) developed mild cGVHD, while 1 developed a donor derived AML (sibling not tested for FA). LTC included second primary malignancy (SPM) - squamous cell cancer (SCC) of skin and muscle invasive bladder cancer (MIBC) in 1(14%) and SCC of head/neck and anogenital region in 3 patients (43%), psychosocial complications (PS) in 6(85%), premature ovarian failure (POF) in 3(43%), and avascular necrosis (AVN) in 4(57%) patients. Short Telomere Syndromes (STS) Seven patients with STS underwent HCT, 2 (28%) after transformation to MDS. Five (71%) received RIC, including both the transformed patients. At a median FU of 67m, median OS was NR (95% CI 2m; NR) and 5 year survival was 47%. One (14%) patient developed grade 2 aGVHD and mild cGVHD of skin. Three (43%) developed SPM - skin cancers in 2 and MIBC in 1. PS was noted in 1(15%), and AVN in 3(43%). Three (43%) patients had concomitant mild IPF/restrictive lung disease. GATA2 haploinsufficiency : Seven patients with GATA2 haploinsufficiency underwent HCT; 2(28.5%) after transformation to MDS and 3(43%) to AML, of which 2(40%) received MAC. At a median FU of 57m, median OS was NR (95% CI 7m; NR) and 5 year survival was 71%. Three (50%) developed grade 2 aGVHD of skin and GI tract and 2(33%) developed mild cGVHD. LTC include PTLD, AVN and POF in 1 patient each. Ribosomopathies : One patient (13y) with DBA underwent RIC HCT and developed grade 2 aGVHD, secondary iron overload, and died at 10 months due to severe fungal infection. Others : Identical twins with CAMT underwent HCT (at 4y and 5y) from the same unrelated donor and at last FU (74m and 87m, respectively) remain 100% donor without GVHD. Two children with primary immunodeficiency and marrow failure underwent HCT (at 2y and 7y), one after transformation to MDS. The non-transformed patient is currently alive (120m), while the patient with transformation died 1month after HCT from disseminated cytomegalovirus infection. One patient with germline RUNX1 deletion developed CMML and underwent a RIC HCT and is alive at a FU of 4 months, with no GVHD. One patient with DADA2 (n=1) underwent RIC HCT without LTC. Due to the smaller cohort size, we compared OS in transformed and non-transformed patients for the IBMF and GATA2 patients only (n=24, 9 with transformation) (figure1). At a median FU of 74m, the median OS of transformed vs non-transformed patients was 108m(95% CI 1;108m) and 163m(95% CI 67m; NR), respectively (p=0.033). Conclusions: Our study demonstrates that HCT remains an important intervention for IBMF and GPD, with the maximum impact being gained prior to transformation. While only mild chronic GVHD was noted (37%), inherent syndromic issues resulted in a high rate of SPM (FA/STS) and organ failure (STS- IPF). Notably, one FA patient who received an MRD HCT developed donor derived AML, underlining the importance of genetic screening in asymptomatic related individuals. Disclosures Kenderian: Lentigen: Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

T- Cell Depleted Peripheral Blood Stem Cell (TCD-PBSC) Transplants Secure Consistent Engraftment with Low Risk of Acute or Chronic Gvhd and Favorable Disease Free Survival (DFS) and Overall Survival (OS) for Pediatric Patients (

Higher cGVHD, TRM and treatment failure following sibling donor unmanipulated allogeneic PBSCT compared to BMT in children and adolescents has been reported by the IBMTR (Eapen M et al, J Clin Oncol, 2004). To determine the effect of T cell depletion (TCD) of PBSC on outcome for pediatric patients with AML or MDS, we reviewed our results with 49 patients (pts) with AML-1CR (n=18), AML-CR2 (n=11), MDS (n=10) and tAML/MDS (n=8/2) following allogeneic TCD-PBSCT transplanted between June 2003 and January 2015. Median age in this cohort was 13.9yrs (range 1.9 - 20.4) with 27 males and 19pts CMV seropositive at time of PBSCT. Donors were related HLA identical (14siblings, 1uncle), unrelated HLA 10/10 matched (n=14) or unrelated HLA mismatched (n=20: 9/10 n=12: 8/10 n=8). Cytoreduction consisted of a HFTBI containing regimen (n=14) with thiotepa and cyclophosphamide (n=12) or thiotepa and fludarabine (n=2). Alternatively, 35 pts received chemotherapy alone: BU/MEL/FLU (n=31) or other (n=4). ATG provided graft rejection prophylaxis for 43 pts either pre (n=37) or post (n=6) infusion. Six young pts with sibling donors did not receive ATG. No pt received additional GVHD prophylaxis. PBSC were CD34+ selected using ISOLEX 300i Magnetic Cell Selection System, followed by sheep erythrocyte rosetting (n=25) or CD34+ selected with Miltenyi CliniMACS device (n=24). The median CD34+ cells/Kg was 10.5x106 (range 3.3 - 33.4x106) and CD3+ cells/kg was 2.4x103 (range 0 - 29x103).All pts engrafted neutrophils and platelets at a median of 11 days (range 9 - 14 days) and 26 days (range 13 - 182 days), respectively. 42pts had platelet recovery by day 40. One patient who had late graft failure (GF) at 3.5 mos engrafted with a subsequent unmanipulated PBSCT. Seven pts developed Grade II or III aGVHD of skin or GI. No pt had Gr IV aGVHD. Six pts responded to treatment. Only 1pt developed limited cGVHD of the skin. No pt who was CMV seronegative developed CMV viremia. 7 of 19 CMV seropositive pts developed CMV viremia. Nine pts received rituximab for EBV viremia. No pt died of CMV disease or EBV-LPD. Five pts received defibrotide for treatment of VOD. Table 1N1o GF2o GFaGVHD (Gr 2-3)cGVHD (limited)CMV-CTLEBV-CTLRelapseAlive in CR p2nd SCT for GF/rel3 yrs DFS3 yr OSEntire Cohort4901(2%)6(12%)1 (2%)1(2%)1(2%)11(22%)5(4rel,1GF)72.3%87.7%AML-CR11800210043(3rel)75.6%94.4AML-CR2110020114056.0%66.7MDS1001000022(1GF,1rel)78.8%100%tAML/MDS100020001080.0%88.9%With a median follow-up of 36.3 mos the DFS and OS at for the entire cohort at 3 yrs is 72.3% and 87.7%, respectively. Although the DFS for pts with AML-CR1 is 75.6%, 3 of 4 pts are in CR2 post a second BMT for OS of 94.4%. The 4 pts with AML-CR2 who relapsed died of disease. In this series of 49 pts, 6pts died of disease, 1 pt died of aGVHD and 1 pt (Down Syndrome) died of MOF (VOD). Thus, in young pts (< 21 yrs) TCD-PBSCT is associated with low risk of acute and chronic disease, no increment in relapse and a highly favorable DFS and OS. The data support the inclusion of pediatric pts in BMT CTN 1301 trial (NCT02345850): a Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease. DisclosuresKernan:Gentium S.p.A.: Research Funding. Hasan:Atara Biotherapeutics: Research Funding. O'Reilly:Atara Biotherapeutics: Research Funding.

Upper Gastrointestinal Acute Graft-Versus-Host Disease Adds Minimal Prognostic Value When Present in Isolation or in Addition to Grade I or Other Grade II-Defining GvHD Manifestations

The clinical syndrome of acute upper gastrointestinal graft-versus-host disease (UGI aGvHD) is historically seen in 13% of MRD transplants and in 31% of recipients developing acute GvHD (aGvHD). UGI aGvHD is classified as a Grade II manifestation in the modified consensus criteria and often treated with systemic immunosuppressive therapy. We undertook a review of the CIBMTR database to assess prognostic implications of and outcomes after UGI aGvHD both in isolation and when present with other manifestations of aGvHD.Methods: 8567 adult recipients of myeloablative allogeneic HSCTs receiving T-cell replete PBSC or bone marrow grafts from siblings, well- or partially-matched unrelated donors for AML, ALL, CML or MDS between 2000 and 2012 were analyzed. The primary outcome was survival; secondary outcomes were DFS, TRM, relapse, and cGvHD. Isolated UGI aGvHD: we performed individual pairwise comparisons between recipients with isolated UGI (iUGI) aGvHD and those with no aGvHD, Grade I, Grade II or Grades III/IV aGvHD without UGI symptoms. UGI aGvHD in Addition to Other aGvHD Manifestations: we performed pairwise comparisons between recipients with aGvHD of the same grade, with and without UGI involvement. Recipients with Grade II aGvHD were reclassified for analysis based on non-UGI manifestations. Diagnoses of UGI aGvHD did not require biopsy confirmation. Analyzed covariates included age, race, KPS score, malignancy, disease stage, time from diagnosis to transplant, graft source, HLA-matching, sex match, CMV status, GvHD prophylaxis, and year of transplant. Analyses were adjusted for effect of transplant center on outcomes. Given the number of comparisons, a p value <0.01 determined significance. Recipients without aGvHD included those experiencing early death; Kaplan-Meier and incidence curves were analyzed from time of aGvHD onset.Results: 251 centers contributed. Median age of recipients was 42 years (range, 18-72). 49% of recipients received stem cells from HLA-matched siblings, 38% from well-matched and 13% from partially-matched unrelated donors. 20% of donor/recipient pairs were female->male. 71% received PBSCs. Isolated UGI aGvHD: 229 individuals had iUGI aGvHD. MRD recipients with iUGI aGvHD had the same prognoses for OS, DFS, TRM, relapse and chronic GvHD as recipients with Grades 0, I or II aGvHD without UGI symptoms in pairwise comparisons. URD recipients with iUGI aGvHD had decreased TRM and trended towards improved OS and DFS compared to recipients with Grade II aGvHD without UGI involvement (HR 2.70, p=0.0021; HR 1.59, p=0.0166; HR 1.52, p=0.0294; Table, Figure 1). Outcomes of URD recipients with iUGI aGvHD were similar to those with Grades 0 or I aGvHD in pairwise comparisons. UGI aGvHD in Addition to Other aGvHD Manifestations: UGI involvement added no significant prognostic information to analyzed outcomes when present in addition to Grades I or II aGvHD of skin or hepatic/lower GI origin (Figure 2). If UGI symptoms were removed from grading, 229 recipients would be reclassified as No aGvHD; 196 recipients would be reclassified as Grade I. The percentage of recipients with Grades 0/I GvHD would increase from 55.7% to 60.1%.Conclusions: The presence of isolated UGI aGvHD imparted limited prognostic information after MRD or URD transplantation in terms of OS, DFS, TRM, relapse or chronic GvHD when compared to recipients without aGvHD or those with Grade I or II manifestations other than UGI. Defining isolated UGI aGvHD as a Grade II entity is not supported by this analysis. The presence of UGI aGvHD in addition to other Grade I or Grade II manifestations within a given recipient likewise had minimal prognostic impact on clinical outcomes after MRD or URD HSCT. Inclusion of UGI symptoms in the current aGvHD grading schema warrants re-evaluation in light of the results of this analysis. [Display omitted] [Display omitted] [Display omitted] DisclosuresAlousi:Therakos, Inc: Research Funding.

Selective Allodepletion by TH9402-Mediated Photosensitization Results in Early Full Donor T Cell Reconstitution in the Absence of High-Grade, Acute GvHD and Is Associated with Favorable Outcome after HLA Matched Sibling SCT for Hematologic Malignancies

Selective allodepletion (SD) is a strategy to eliminate host-reactive donor T-cells from allografts to prevent graft versus host disease (GvHD) while conserving useful donor immunity. We developed a semi-closed, GMP-quality, clinical scale SD process where donor-derived lymphocytes are stimulated with patient-derived T-cell antigen presenting cells in an ex vivo mixed lymphocyte reaction (MLR). Alloactivated donor T cells preferentially retain the photosensitizer 4,5-dibromorhodamine 123 (TH9402), rendering them susceptible to elimination by exposure to visible light in a photodepletion device (Kiadis Pharma Inc, The Netherlands). After Food and Drug Administration and Institutional Review Board approval we initiated a clinical trial where HLA-identical sibling recipients with hematological (non T-cell) malignancies received a CD34-cell selected transplant (Miltenyi, Germany) containing less then 1 × 104 T cells/kg together with 5 × 106/kg viable SD donor T cells on day 0, using an age-adapted, radiation-based preparative regimen (FluCyTBI). Low-dose cyclosporine was used as sole immunosuppression in the absence of GvHD. Eleven patients (median age 43 (28–68) years with ALL, MDS, CML, mantle cell lymphoma (MCL), or AML) were transplanted with a median follow-up of 240 (43–400) days. Nine patients were considered high risk. Patients received a stem cell product containing a median of 6.0 (3.9–9.5) ×106/kg CD34+ stem cells in addition to 5×106/kg SD T cells. Absolute lymphocyte recovery was rapid (median 834 (384–2486) cells/μL day 30 post transplant) [Fig A]. Early T cell chimerism was donor-dominated (median 66% (6–95) on day 14, and 97% (82–100) on day 30, and 100% (92–100) on day 45 [Fig B]. One patient received an unmanipulated DLI to treat a delayed fall in T cell chimerism. Three patients developed steroid-sensitive grade II aGvHD of skin (N=2) and gut (N=1) but no grade III–IV aGvHD occurred after transfusion of the photodepleted lymphocytes [Fig C]. Two patients developed limited chronic GvHD. Only one patient, transplanted for refractory MCL, relapsed 340 days after transplant. One patient died of infectious complications and GvHD 330 days after transplant after receiving an unmanipulated DLI in her home country for suspected, but subsequently unconfirmed relapse. Eight patients reactivated CMV but were successfully treated. These results demonstrate for the first time clinical feasibility of photodepletion-based SD stem cell allotransplants in matched siblings. Robust lymphocyte recovery and early donor chimerism with a low relapse incidence in a high-risk population suggest functionality of SD T cells in the absence of severe GvHD, which should allow further reduction of immunosuppression to optimize disease control in future studies.