Incidence Of Grade II-IV aGVHD Research Articles

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P=.04 and .007, respectively), NRM (P=.007 and P < .0001, respectively), and grade III-IV aGVHD (P=.0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P=.001) and chronic GVHD (P=.002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P=.006) and a poorer OS (P=.001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.

Haploidentical Transplantation with Modified Post-transplantation Cyclophosphamide for Patients with Primary Aplastic Anemia: A Multicenter Experience

Aplastic anemia (AA) is a life-threatening hematological disorder that can be cured by hematopoietic stem cell transplantation. Haploidentical transplantation becomes an alternative choice for patients in the absence of a matched sibling donor. We used a retrospective study aimed to confirm the feasibility of busulfan-based modified post-transplantation cyclophosphamide (PTCY) strategy in haploidentical hematopoietic stem cell transplantation for AA patients. We analyzed the outcomes of 27 patients from 3 clinical centers who had undergone haploidentical transplantation between October 2018 and July 2020. The modified condition regimen consisted of anti-thymoglobulin/antilymphocyte globulin, fludarabine, busulfan and low-dose cyclophosphamide, and high-dose cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus were administered as graft versus host disease (GVHD) prophylaxis after transplantation. The median follow-up time was 370 (range 65-721) days. One patient developed primary graft failure, and successful engraftment was observed in 96.29% (95% confidence interval [CI], 93.45%-97.91%) of patients. The median times for neutrophil and platelet engraftment were 13 (range 11-18) days and 13 (range 11-28) days, respectively. The most common regimen-related toxicity was bladder toxicity, followed by stomatitis and gastrointestinal toxicity. The cumulative incidence of grade II-IV aGVHD was 25.93% (95% CI, 5.84%-52.64%), whereas the cumulative incidence of grade III-IV aGVHD was 7.4% (95% CI, 0%-52.16%). Chronic GVHD was observed in 3 patients by the end of follow-up. All 27 patients are alive, with a failure-free survival rate of 96.30% (95% CI, 6.49%-99.47%) and GVHD relapse-free survival rate of 88.89% (95% CI, 69.39%-96.28%). Virus reactivation was comparable, with rates of 53.54% for cytomegalovirus (CMV) reactivation and 41.57% for Epstein-Barrvirus, but the CMV diseases and post-transplantation lymphoproliferative disorder were rare. Our study using haploidentical transplantation with modified PTCY demonstrated an encouraging result with prolonged survival and reduced complications for aplastic anemia patients.

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell–Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia

Depletion of αβ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αβ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P=.07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p=ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P=.002). Recovery of both αβ- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αβ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.

Rapid Engraftment, Immune Cell Reconstitution and Sustained Donor Chimerism in Patients Receiving G-CSF Mobilized Peripheral Blood Stem Cells (PB-SC) from Related or Unrelated Donors Undergoing CD34 Enrichment with Mononuclear Cell (T cell) Addback in Children, Adolescents, and Adults with Malignant and Nonmalignant Diseases

Background: Graft versus host disease (GVHD) is a life-threatening complication following allogeneic stem cell transplantation (AlloSCT), which results from allo-reactive donor T-cells reacting against human leukocyte antigen (HLA) disparate host antigens. Despite the use of prophylactic immunosuppresants, 40 to 70 percent of patients undergoing HLA matched related and unrelated transplants will develop grade II-IV acute GVHD (Goker et al, Ex Hem, 2001; Nademanee, Blood, 1995; Rutuu et al, BMT, 1997).CD34+ enrichment of GCSF mobilized peripheral blood stem cells (PBSCs) obtained by apheresis is a method for T-cell depletion to reduce the risk of Grade II-IV aGVHD but unfortunately maybe concomitantly associated with delayed immune reconstitution, increased opportunistic infection and/or malignant relapse. To circumvent these latter complications, we previously demonstrated the results of a CD34+ enrichment with mononuclear cell (MNC) addback fixed at 2x105 CD3/kg of recipient weight in pediatric MUD recipients demonstrating rapid engraftment, robust immune reconstitution, and a low incidence of Grade II-IV aGVHD (Geyer/Cairo, BJH, 2012).More recently, we demonstrated a similar approach in children, adolescents, and young adults with high-risk SCD following familial haploidentical stem cell transplantation resulting in a rapid engraftment, probability of 6.7% of Grade II-IV aGVHD and 90% 1-year OS (Cairo et al, JAMA Peds, 2020). This approach of PBMNC addback with a fixed dose of 2x105 CD3/kg facilitated the infusion of additional NK, NKT, B, DC, DC2 cells at that same time (Chu/Cairo et al, ASH, 2020). Objective: To determine the safety, hematopoietic engraftment, probability of Grade II-IV GVHD following HLA related and unrelated PBSC transplantation following CD34+ enrichment with MNC cell addback (2x105 T-cell/kg fixed dose) in patients with malignant and non-malignant diseases. Design/Methods: Eligible patients were enrolled on study. Patients received individualized conditioning regimens determined by the PI stratified by disease, disease status, and donor source and received CD34+ enriched products processed by using the CliniMACSâ CD34+ Reagent System (Miltenyi Biotec, Bergisch Gladbach, Germany). The CD34+ cell product was either infused or cryopreserved and stored until time of transplantation. A target of 5x106 CD34+/kg recipient weight with a PBMNC fixed dose of 2x105 T cell CD3 dose/kg was infused as we previously demonstrated (Cairo et al, JAMA Peds, 2020). Patients were followed for safety, engraftment, donor chimerism, probability of Grade II-IV aGVHD and chronic GVHD. Results: Thirty-eight patients underwent HSCT with median age of 35.2 years (21 months to 71 years). Patients' disease status was as follows: complete remission (CR) 3 in 1 AML patient, CR2 in 8 AML patients, CR1 in 14 AML patients, CR2 in 4 ALL patients, CR1 in 2 ALL patients, PR in 1 MDS patient, Lymphohistiocytosis (n=1), Macrophage Activating Syndrome (n=1), Diamond Blackfan (n=1), Aplastic Anemia (n=2), Sickle Cell Disease (n=1), 1 CNL patient, CR2 in 1 Non-Hodgkins Lymphoma patient. Sixteen patients received allogeneic 10/10 HLA-matched unrelated donors, 5 from 9/10 HLA-matched unrelated donors, 12 from 6/6 HLA-matched sibling donors, 5 from related haplo donors. PB-HPC products contained 2x105 CD3/kg (±0.25 x 105), and 9.72x106 CD34/kg (±0.97 x106). After CD34 enrichment, the PB-HPC product processed was 76.09% CD34+ (±2.7%) (Fig. 1A) enriched with mean ± SEM log T cell depletion of 4.01 (±0.17) (Fig. 1B). The target HSCT dose per patient was 5x106 CD34/kg. Thirty-seven patients had myeloid engraftment and 32 patients had platelet engraftment with a median of 11 and 17 days, respectively. Six patients died prior to platelet engraftment - three due to multi-organ system failure following septic shock, two due to refractory disease, and one due to adenoviremia. Early and late peripheral blood chimerism was ³ 95% at 14- and 100-days following transplantation. The probability of grade II-IV aGVHD was 28.1% (CI95: 9.3-50.7) (Fig. 2). The probability of cGVHD was 4% (CI95: 0-63.5). Conclusion: This study demonstrates safety, rapid hematopoietic engraftment, sustained donor chimerism of CD34+ enriched PBSC products with MNC cell addback with a fixed 2x105 CD3/kg dose in alloSCT recipients with a low probability of Grade II-IV aGVHD.and cGVHD. Disclosures Seiter: Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Forma: Research Funding; Sun Pharma: Research Funding; Amphivena: Research Funding; Roche: Research Funding; AbbVie: Speakers Bureau; Alexion: Speakers Bureau; Onconova: Research Funding. Flower:Lentigen Technology Inc/Miltenyi Biotec: Research Funding. Cairo:Miltenyi: Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience

Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience

Post-Transplant Cyclophosphamide for Graft Vs Host Disease Prophylaxis in Multiple Myeloma Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation: First Comparison By Donor Type; A Study from the Chronic Malignancies Working Party of the EBMT

Introduction Acute and chronic graft vs. host disease (a/cGVHD) are major causes of treatment failure and non-relapse mortality (NRM) in multiple myeloma (MM) patients (pts) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Use of post-transplant cyclophosphamide (PTCy) is now an established method for GVHD prophylaxis after HLA haplo-identical (haplo)-HCT. We previously reported data in MM pts undergoing haplo-HCT (EBMT/CIBMTR) and showed that PTCy was associated with promising overall survival (OS) (Sahebi et al., BBMT 2019). However, data using PTCy for GVHD prophylaxis in other donor types are very limited in MM. Methods We evaluated PTCy as GVHD prophylaxis in MM pts who underwent a first allo-HCT using matched related (MRD), matched unrelated (MUD), mismatched related or unrelated (MMRD/MMUD, one antigen), and haplo donors within EBMT centers. OS and progression free survival (PFS) were determined by means of the Kaplan-Meier estimator. Neutrophil and platelet engraftment, relapse and NRM, and a/cGVHD were analyzed individually in a competing risks framework with relapse and death as competing events. Cox proportional hazards regression was used in the multivariable analyses. All estimates include 95% confidence intervals. All included covariates are listed in the Table. Patient Characteristics Between 2012-2018, a total of 295 MM pts received PTCy as GVHD prophylaxis. Median age at transplant was 55 yrs. Allo-HCT was given at a median interval of 34.9 mo from MM diagnosis. The conditioning regimen included reduced intensity (RIC, 193, 65.4%) and myeloablative (MAC, 102, 34.6%). All pts except 10 (3.4%) had prior autologous HCT; all of these 10 pts received a haplo-HCT. GVHD prophylaxis included PTCy + cyclosporine A or tacrolimus +/- mycophenolate mofetil in the majority of patients (239, 81%), and this combination was used in nearly every patient with haplo-HCT. Overall, peripheral blood was used as the stem cell source in about 80% of pts, but bone marrow was used in nearly 40% of haplo-HCTs. Results (Median and 95% confidence interval are provided)1) Median time to neutrophil engraftment was 19 d (18-19 d) with no apparent difference among donor types.2) Median time to platelet engraftment was 23 d (21-26 d), whereas haplo-HCT engraftments were longer (27 d (25-33 d)).3) NRM at 1 yr was 18% (12-22%) and at 2 yrs was 19% (14-24%), with no significant difference among different donor types. Age &amp;lt; 50 yrs significantly decreased NRM to 9% (2-16%, p=0.027) at 2 yrs.4) Cumulative incidence of grade II-IV aGVHD at +100 d was 30% (25-36%), and 1 yr cGVHD was 27% (21-32%), with no apparent difference among donor types.5) OS was 63% (57-69%) at 1 yr and 51% (45-58%) at 2 yrs for the whole group, with no statistical difference among different donor types after a median follow-up of 26.1 mo. Disease status at transplant &amp;lt; PR significantly decreased OS to 35% (22-47%, p=0.005) at 2 yrs.6) PFS was 42% (36-49%) at 1 yr and 26% (20-32%) at 2 yrs for the whole group without apparent significant difference among donor types. Disease status at transplant &amp;lt; PR significantly decreased PFS to 16% (6-26%, p=0.028) at 2 yrs.7) However, in multivariable analyses, donor type using haplo, HR 1.65 (0.56-1.67, p=0.03), was associated with increased mortality in addition to disease status at allo-HCT &amp;lt; PR, HR 1.93 (1.25-2.97, p=0.003). Finally, MUD was associated with an improved PFS, HR=0.63 (0.4-0.99, p=0.04). Disease status &amp;lt; PR, HR=1.85 (1.24-2.74, p=0.002) was again associated with inferior PFS. Summary PTCy in MM patients undergoing allo-HCT throughout donor types resulted in a low incidence of aGVHD grade II-IV of 30% and cGVHD of 27%, with OS of 51% and PFS of 26% at 2 yr. Our first donor comparison using PTCy revealed improved survival in matched (MRD and MUD) versus haplo allo-HCT after adjusting for other risk factors. Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Tarella:TG-therapeutics: Research Funding; ImmunoGen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Milpied:Roche: Honoraria, Other: Travel support; Astellas: Honoraria; Gilead Sciences: Other: consultancy or advisory role; Celgene: Other: Travel support; Sandoz: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Schonland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding.

Unmanipulated haploidentical hematopoietic stem cell transplantation for children with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders and is rare in children. Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly used in children with MDS with excess blasts and in patients with refractory cytopenia of childhood (RCC) associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. We recruited27 children with MDS who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT). At transplantation, 10 patients had RCC, 12 patients had advanced MDS (RAEB and RAEB-T), and 5 patients had myelodysplasia-related acute myeloid leukemia (MDR-AML). All patients received granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow cells and peripheral blood stem cells. At a median follow-up of 24.1months (range: 2.0-74.5months) after HSCT, the estimated probabilities of 3-year disease-free survival (DFS) and overall survival (OS) were both 81.9% (95% CI, 66.8-100.0%). The estimated 3-year incidences of relapse (CIR) and non-relapse mortality (NRM) were both 7.4% (95% CI, 1.2%-21.4%). The 100-day cumulative incidence of grade II-IV aGVHD was 52.6% (95% CI, 42.9-62.3%), while that of grade III-IV aGVHD was 11.1% (95% CI, 5.1-17.1%). The 3-year cumulative incidences of overall and extensive cGVHD were 42.3% (95% CI, 19.8%-57.5%) and 21.1% (95% CI, 2.5%-63.2%), respectively. Univariate analysis showed that chronic GVHD significantly affected OS and DFS. Haploidentical HSCT may be an effective treatment option with easier donor availability for pediatric patients with MDS.

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD.

Early tacrolimus (TAC) concentrations correlate with the risk of acute graft-versus-host disease (aGVHD); however, whether the variability of early TAC concentrations after allo-HSCT governs the occurrence of aGVHD remains unknown. Here, we evaluate the correlation between the intrapatient variability (IPV) of initial TAC concentrations and the development of aGVHD. We retrospectively assessed 202 patients who underwent allo-HSCT and received standard GVHD prophylaxis by continuous intravenous (iv) infusion of TAC and iv methotrexate. IPV was calculated by using the % coefficient of variation in the initial 4weeks. With median follow-up duration of 20.7months, 24 patients were diagnosed with grades II-IV aGVHD. Overall survival (OS) and relapse at 12months after allo-HSCT were 70.6% (95% confidence interval [CI], 63.7%-76.4%) and 18.9% (95% CI, 13.0%-24.4%), respectively. When IPV was categorized into two groups (high: ≥9.5%; low: <9.5%), the cumulative incidence of grades II-IV aGVHD was greater in the IPV-high group at week 3 (odds ratio: 4.15; 95% CI, 1.37%-12.6%, P=.01). No significant differences were observed in OS and relapse between the two groups. We concluded that adjusting early TAC concentration stable may reduce aGVHD after allo-HSCT without affecting the relapse rate.

Safety and efficacy of anti-programmed cell death-1 monoclonal antibodies before and after allogeneic hematopoietic cell transplantation for relapsed or refractory Hodgkin lymphoma: a multicenter retrospective study.

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589days. The overall and complete response rates were 75% and 40%. At 100days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1year relapse/progression rate was 47.4%, the 1year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

Effect of Early Post Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Effect of Early Post Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is &amp;gt; 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count &amp;gt;1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count &amp;gt;50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients &amp;gt; age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Outcome of Allogeneic Haematopoietic Stem Cell Transplantation in Myeloproliferative Neoplasms-Unclassifiable: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Introduction Myeloproliferative Neoplasm (MPN) unclassifiable (MPN-U), is a heterogeneous disease that presents with an MPN-type clinical/ histological phenotype yet fails to meet diagnostic criteria for other MPN entities. Incidence is &lt;5% of all MPN when stringent World Health Organisation (WHO) 2016 classification is followed. No well-defined treatment algorithm exists and therapeutic approaches vary, ranging from observation alone, cytoreductive or experimental agents, high dose chemotherapy and in some instances allogeneic Haematopoietic Cell Transplantation (allo-HCT). Outcome analysis for this allo-HCT cohort is lacking.We hereby report on a retrospective, multicentre, EBMT-registry based study of adult patients with a confirmed diagnosis of MPN-U according to updated WHO 2016 criteria that received an allo-HCT. Methods This registry-based analysis was approved by the Chronic Malignancies Working Party of the EBMT. Patient selection was performed by identifying adult patients who underwent first allo-HCT for MPN-U between 2000-2015, using either Reduced Intensity Conditioning (RIC) or Myeloablative conditioning (MAC) as defined by standard EBMT criteria. Further data collection requests (MED-C) forms were sent to centres to improve data completeness. Statistical analyses were performed with SPSS 22 (SPSS Inc./IBM, Armonk, NY) and R. Overall Survival (OS) was calculated from the date of transplant until death or last observation alive. Cumulative incidence functions were used to estimate Non-Relapse Mortality (NRM) and Relapse Incidence (RI) within a competing risk setting. Results A total of 70 patients, 48 (69%) male and 22 (31%) female, with a confirmed diagnosis of MPN-U were analysed. Median age was 57 years (range (r), 22-70 years). Of these patients, 37 (53%) underwent allo-HCT in the period 2001-2010 and 33 (47%) between 2011-2015. MAC regimens were utilised in 31 (44%) patients while 39 (56%) received RIC. Patients were most frequently transplanted within the first two years from diagnosis, with a median time to allo-HCT of 13 months (r, 3-244 months). Diagnostic karyotype was normal in 36 (51%) and abnormal in 23 (33%) patients, with data missing for 11 (16%) patients. A total of 45 (64%) patients had received prior treatment, 23 (33%) patients were untreated and data was incomplete in 2 (3%) patients. Regarding donor type, 27 (39%) patients had a Matched Sibling Donor (MSD) and 43 (61%) an Unrelated Donor (URD). Most frequent conditioning regimens were TBI-based in the MAC cohort and Fludarabine-Busulphan in the RIC cohort. A trend towards higher rates of delayed/failed engraftment was noted in the RIC compared to MAC cohort (p=0.09). Where successful, median time to neutrophil engraftment in both cohorts was similar (18 days for MAC and 17 for RIC) and both platforms demonstrated similar platelet engraftment times (17.5 days). Incidence of grade II-IV aGVHD at 3 months was higher in the MAC (37%) compared to RIC cohort (16%; p=0.05) and the 12-month cumulative incidence of cGVHD for MAC was 52% (95%CI: 32.4, 71.6) and for RIC 32.1% (95%CI: 14.8, 49.4; p=0.117)). Median follow-up was 87 months (minimum and maximum of censored cases: 31 and 196 months). The median OS estimates at 1, 3 and 5-year were 77%, 55% and 42% (MAC) and 59%, 44% and 41% (RIC), respectively (p=0.33). No significant difference existed in OS rates between those who had pre-transplant therapy versus not. Relapse remained significant: cumulative incidences of relapse at 1,3 and 5-years were 10%, 23% and 27% (MAC) and 28%, 36% and 36% (RIC), respectively (p=0.28). NRM probabilities at 1, 3 and 5-years post allo-HCT were also considerable: 19%, 29%, and 34% (MAC) and 28%, 28% and 28% (RIC), respectively (p=0.84). Main causes of NRM were infection and GVHD. Univariate analysis associated use of an URD with a significantly worse OS and NRM compared with MSD. Moreover, the presence of abnormal karyotype at time of allo-HCT was associated with a trend towards a higher risk of relapse (p=0.06). Conclusions This study highlights the potentially curative role of allo-HCT in MPN-U and provides clinicians with robust engraftment, GVHD and outcome data. Both engraftment and OS rates appear acceptable yet NRM and CIR rates in both settings remain high and need to be addressed. The impact of abnormal karyotype at the time of allo-HCT and a trend towards higher risks of relapse requires further elucidation. Disclosures McLornan: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Robin:Novartis Neovii: Research Funding. Chalandon:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Hernandez Boluda:Incyte: Other: Travel expenses paid.

A Busulfan Following Cyclophosphamide and Constant Cell Dose Protocol Improved Results in Alternative Donor Hematologic Stem Cell Transplantation in Thalassemia Major: A Result from Long-Term Large-Size Multi-Center Study

Sibling donor transplantation (SDT) is a proven curative therapy for patients with thalassemia major (TM), NF-08-TM protocol improved the outcomes of unrelated donor transplantation (UDT) in single-center. This study aim was to determine whether outcomes of NF-08-TM protocol could be proved in multicenter and long-term follow-up and to compare the outcomes of full-matched (FM) and one-locus mismatch (WM) UDT. 586 patients from 4 pediatric BMT centers in China from Dec. 2008 to Jun. 2016 received NF-08-TM protocol, a newly designed Busulfan following Cyclophosphamide and constant cell dose protocol. With a median follow-up of 57 months (range, 21-116), the 9-year OS, TFS, GR, and TRM were 94.4%, 92.8%, 2.7%, and 5.6%, respectively, in total. The corresponding rates for SDTs (n=224) were 95.9%, 95.5%, 1.4% and 4.1%; for UDTs (n=275) were 92.4%, 89.9%, 4.3% and 7.6%; for parental donor transplantation (PDT, n=40) were 95.0%, 95.0%, 0% and 5.0%; and for cord blood transplantation (CBT, n=47) were 97.9%, 95.4%, 2.6% and 2.1%, respectively.The incidence of grade II-IV aGVHD, III-IV aGVHD, mild cGVHD and moderate/severe cGVHD of the entire cohort was 8.9%, 4.6%, 3.7%, and 1.4%, respectively. There was no statistically significant difference (SSD) in OS, TFS, TRM, and GR when comparing FM-SDTs with those of FM-PDTs, FM-UDTs or FM-CBTs. Among PDTs, no SSD was found in OS, TFS, TRM, GR, and GVHD in comparison of FM-PDTs and WM-PDTs. More moderate/severe cGVHD occurred in WM-UDTs than FM-UDTs. Compared FM-SDTs, WM-UDTs had worse OS, TFS, TRM, and a higher rate of grade II-IV aGVHD and cGVHD. Current study proved that Good outcomes of NF-08-TM protocol in single-center be proved in multicenter and long-term follow-up. Compared to the outcomes of FM-UDT) those of well-UDT was worse and was not recommended to thalassemia patients. Disclosures Wing: Miltenyi Biotec: Employment.

Clinical research of HLA-haploidentical peripheral hematopoietic stem cell transplantation following reduced intensity conditioning regimen with hematological malignancy patients over 50 years old

目的分析减低剂量预处理单倍型外周血造血干细胞移植（RIC-haplo-PBSCT）治疗50岁以上恶性血液肿瘤患者的疗效。方法18例50岁以上恶性血液肿瘤患者纳入研究，男8例，女10例，中位年龄52（50~66）岁；急性髓系白血病（AML）8例，慢性髓性白血病（CML）2例，骨髓增生异常综合征（MDS）5例，急性淋巴细胞白血病（ALL）2例，急性NK细胞白血病（ANKL）1例；采用FAB+ATG（氟达拉滨+阿糖胞苷+白消安+兔抗人胸腺细胞免疫球蛋白）减低剂量预处理方案，输注供者高剂量非去T细胞外周血造血干细胞（PBSC），应用强化移植物抗宿主病（GVHD）预防方案及感染防控措施。结果16例患者在移植后15 d获得完全供者嵌合，其中1例在移植后1个月发生移植排斥，其余2例在移植后15 d为混合嵌合并于移植后1个月发生移植排斥。急性GVHD发生率为61.1%（95%CI 49.6%~72.6%），Ⅱ~Ⅳ度急性GVHD发生率为35.4%（95%CI 21.1%~49.7%），Ⅲ/Ⅳ度急性GVHD发生率为13.8%（95%CI 4.7%~22.9%）。2年慢性GVHD累积发生率为38.2%（95%CI 25.5%~50.9%），未发生广泛型慢性GVHD。中位随访14.5（3~44）个月，2年总生存率、无病生存率分别为72.6%（95%CI 60.1%~85.1%）、63.7%（95%CI 49.2%~78.2%），2年累积复发率为31.2%（95%CI 16.5%~45.9%），2年非复发死亡率为12.5%（95%CI 4.2%~20.8%）。结论RIC-haplo-PBSCT治疗50岁以上恶性血液肿瘤患者可获得较好的疗效。

Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI

AbstractThe impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)–based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.

Cyclosporine A trough concentrations are associated with acute GvHD after non-myeloablative allogeneic hematopoietic cell transplantation.

Low plasma CsA concentrations (<300–350 ng/mL) early following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of developing acute graft-versus-host disease (aGvHD). Nevertheless, the current optimal target trough concentration for CsA following HSCT is considered to be 200–400 ng/mL. Here, we performed a retrospective analysis of a homogeneous group of 129 patients who received HSCT after non-myeloablative conditioning, and we analyzed the impact of CsA trough concentration measured during the first four weeks (CsA W1-4) on the incidence aGvHD, relapse-free survival (RFS), non-relapse mortality (NRM), overall survival (OS), and toxicity. The 180-day incidence of grade II-IV aGvHD was 25% (32/129 patients). In multivariate analysis the incidence of grade II-IV aGvHD was significantly lower among patients with a CsA W1-4 concentration ≥350 ng/mL compared to patients with a concentration <350 ng/mL (18% versus 38%, respectively; P = 0.007), with a hazard ration (HR) of 0.38 (95% CI: 0.19–0.77). In contrast, we found no correlation between CsA trough concentration and RFS, NRM, or OS. Moreover, we found an increased incidence of hypomagnesemia at higher CsA concentrations, but no difference in the incidence of acute renal toxicity, hepatic toxicity, or electrolyte imbalance. Interestingly, 30% of patients experienced hyponatremia with no apparent cause other than the use of CsA, with urinalysis suggesting SIADH as the underlying cause. Our findings suggest that a CsA trough concentration of 350–500 ng/mL might be more appropriate in the first month following non-myeloablative HSCT.

Higher Pre-Transplant IL-2 Levels Correlate with Higher Incidence of Acute Graft-Versus-Host Disease

Introduction The role of T-cell helper 1 cytokines, including TNF-α and IL-6, in the pathophysiology of acute graft-versus-host disease (aGVHD) is well established. Emerging data have also implicated IL-2, a marker of activated T-cells, in the GVHD reaction. 1 We hypothesized that pre-transplant IL-2 levels may correlate with the incidence of aGVHD. We tested our hypothesis in a cohort of 16 patients who received allogeneic stem cell transplantation (SCT) following fludarabine/busulfan based conditioning regimen and tacrolimus/methotrexate GVHD prophylaxis at our institution between 7/2012 and 1/2013. Methods TNF-α, IL-6, and IL-2 plasma levels were measured by ELISA day -13 (pre-SCT), day of SCT, days +7 and +14. Results Median age of patients was 61 years (range 47-70). The majority (62%) were treated for AML/MDS, and 81% had active disease at transplant. Median comorbidity index score was 3 (range 0-6). Donors were HLA-matched related (44%) or unrelated (56%), and peripheral blood was the stem cell source for all related donors and for 50% of unrelated donors. A quarter of the donor/recipient pairs were sex-mismatched (female donor to male recipient). The majority of donors (69%) were CMV seronegative, while 75% of recipients were CMV seropositive. Of 16 patients, 6 were diagnosed with grade II-IV aGVHD at a median of 28 days (range 18-83). Median follow-up was 24 months (range 3-64) in grade II-IV aGVHD-free patients. IL-2 levels (µg/mL) pre-SCT correlated with day of SCT, day +7, and day+14 levels. Median IL-2 was 0 (undetectable) pre-SCT (range 0-3.2) and on day of SCT (range 0-4.9). Patients with detectable (>0) IL-2 levels pre-SCT (n=5, median IL-2: 1.2, range 0.3-3.2) or on day of SCT (n=6, median IL-2: 2.6, range 0.2-4.9) were at high-risk of developing grade II-IV aGVHD. The incidence of grade II-IV aGVHD was 75% in patients (n=8) with detectable IL-2 levels pre-SCT and/or on the day of SCT (Figure). In contrast, none of the patients (n=8) who had undetectable IL-2 levels at both time points developed grade II-IV aGVHD (p=0.002). TNF-α and IL-6 levels (evaluated at the median) pre-SCT or on day of SCT were not associated with the incidence of grade II-IV aGVHD. Detectable pre-SCT IL2-were not correlated with ALC (K/µL) (median: 0.65 vs 0.87, p=0.6), but were correlated with longer duration since the last chemotherapy treatment (median 101 vs 47, p=0.02). Recipient age, disease status at SCT, CMV status, comorbidity index, and sex-mismatch did not correlate with pre-SCT IL-2 levels or with the incidence of grade II-IV aGVHD. Conclusion Our data suggest that elevated IL-2 before transplant may be associated with increased risk of aGVHD. Validation of these findings in larger datasets is warranted, as they may identify patients for trials of alternative GVHD prophylaxis.

Evaluation of Tacrolimus Levels and Risk of Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant

Background Achieving therapeutic tacrolimus blood concentrations is crucial for decreasing the risk of developing acute graft-versus-host-disease (aGvHD) in allogeneic hematopoietic stem cell transplant (aHSCT) patients. Studies have suggested that tacrolimus levels in the first 1-2 weeks may affect the risk of aGVHD but therapeutic goals are not well established. This study explores tacrolimus levels and risk of GVHD during that time frame. Methods This study is a retrospective cohort single center chart review performed with 348 consecutive adult patients who received an aHSCT and were followed for at least 100 days post-transplant for aGvHD development. Patients that received a transplant from a cord blood or participated in aGvHD prophylaxis clinical trials were excluded. The primary endpoint was aGvHD grades II - IV incidence. Serum tacrolimus levels were evaluated from days -1 to +100 post-transplant. Serum tacrolimus levels were divided into time intervals of days 0 - 7 and days 0 - 14 post-transplant. Receiver operator characteristic curves (ROC) were used to quantify serum tacrolimus levels as predictors of aGvHD grades II-IV. Using the ROC analysis and Youden's Index, optimal cutpoints in the tacrolimus level distribution for the individual time intervals were assessed. From this, patients were analyzed based on whether they achieved mean tacrolimus serum levels below the cutpoint (low group) or if they achieved a mean tacrolimus level above the cutpoint (high group). Results Within the URD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 11.3 and 14.5 respectively, with significantly less aGVHD observed in the high group (38% vs 57.2%, p = 0.021). In respect to days 0-14, the low group and high group demonstrated a mean tacrolimus level of 10.4 and 13 respectively, again with significantly less aGVHD in the high group (35.6% vs 57.3%, p = 0.012). Within the RD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 10.9 and 13.7 respectively, also with significantly less aGVHD in the high group (21.7% vs 38.7%, p = 0.042). In respect to days 0-14, the low and high group demonstrated a mean tacrolimus level of 10.2 and 13.1 respectively. However, there was not a significant difference in aGVHD (25.7% vs 35.9%, p = 0.272). Conclusion Higher levels of tacrolimus in the first 2 weeks after allogeneic stem cell transplant appear to correlate with a lower incidence of grade II-IV aGVHD. Higher levels in both weeks 1 and 2 were associated with a 37% reduction in the URD group while higher levels in week 1 were associated with a 44% in the RD group. While larger studies would help to clarify more specific ranges, this data suggests that target tacrolimus levels should be 14-15 ng/ml in the first 2 weeks post allogeneic transplant to decrease rates of grade II-IV aGVHD.

A Phase 1b Study of Intravenous Vedolizumab Plus Standard of Care for Graft-Versus-Host Disease Prophylaxis in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: 6-Month Results

BackgroundSubjects with lower gastrointestinal (GI) acute graft-versus-host disease (aGvHD) generally respond poorly to therapy, and therefore have increased morbidity and mortality. Vedolizumab, a gut-selective antibody targeting α4β7 integrin, is approved for the treatment of inflammatory bowel diseases. Vedolizumab interferes with gut-trafficking of immunocompetent donor T-lymphocytes and may have a role in preventing GI aGvHD. Here we present the 6-month results of a phase 1b study of the safety, tolerability and clinical activity of vedolizumab combined with standard graft-versus-host disease (GvHD) prophylaxis.MethodsThis is an open-label, dose-finding study of the addition of vedolizumab to standard GvHD prophylaxis in adults undergoing hematopoietic stem cell transplantation (HCT). Cohort 1 comprised subjects aged 18-60 years with a hematologic malignancy undergoing human leukocyte antigen (HLA)-matched or 1 locus-mismatched, unrelated-donor myeloablative transplantation. These subjects received intravenous (IV) vedolizumab (75 mg, on days -1, +13 and +42 of HCT). If subjects in cohort 1 experienced no engraftment failures or dose-limiting toxicities (DLTs), then subsequent subjects were enrolled into a dose-expansion cohort of IV vedolizumab 300 mg (cohort 2), following the same schedule. Key inclusion criteria for cohort 2 were myeloablative regimens (subjects aged 18-60 years) or reduced-intensity conditioning regimens (subjects aged 18-75 years), donor-recipient pairs who were HLA-matched or 1-locus mismatched, and subjects receiving peripheral blood- or bone-marrow-derived stem cells. All subjects received standard GvHD prophylaxis (tacrolimus and methotrexate). The primary objective was to identify an efficacious vedolizumab dose with an acceptable safety profile for future studies, using the following primary safety endpoints: frequency of DLTs from day -1 to day 28, and the number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events from administration of the first dose of vedolizumab until 18 weeks after the final dose. Secondary endpoints included time to neutrophil engraftment, cumulative incidence of grade II-IV aGvHD and frequency by maximum severity of aGvHD by modified Glucksberg criteria. Exploratory endpoints included overall survival (OS) and aGvHD-free survival.ResultsIn total, 24 subjects were enrolled at 5 centers (3 in cohort 1, then 21 in cohort 2). The median age was 55 years (range 18-72 years). Most subjects underwent an unrelated donor HCT (83%), and all except 1 were HLA-matched (Table 1). At 6 months after HCT, no DLTs were observed in either cohort. All subjects engrafted within 28 days; the median time to neutrophil engraftment was 14 days in cohort 2. All subjects experienced at least 1 TEAE, which was serious in 13 subjects (2 in cohort 1, 11 in cohort 2). TEAEs were considered vedolizumab-related in 2 subjects in cohort 1 and 6 in cohort 2, including 1 subject in cohort 2 who experienced 2 serious TEAEs: hypotension and febrile neutropenia. The most frequent infections were cytomegalovirus (4 cases) and Clostridium difficile colitis (3 cases). No adverse events led to discontinuation of vedolizumab. There were no cases of grade II-IV aGvHD at 6 months after HCT in cohort 1. In cohort 2, 4 subjects (19%) developed grade II-IV aGvHD at 6 months after HCT; 3 (14%) grade II (1 skin only involvement, 2 skin and lower GI involvement) and 1 (5%) grade III (liver, skin and lower GI involvement). All cases of lower GI aGvHD were limited to stage 1 disease. At 6 months after HCT, 1 subject died from disease relapse in cohort 1, and 2 subjects died in cohort 2; 1 from disease relapse and 1 from aGvHD-related complications. Among subjects in cohort 2, 6-month OS and non-relapse mortality were 90% and 5%, respectively, and grade II-IV and grade III-IV aGvHD-free survival were 76% and 90%, respectively (Table 2).ConclusionsIn subjects receiving vedolizumab in addition to standard GvHD prophylaxis, there were no DLTs or engraftment failures at 6 months after HCT, and the TEAEs observed have been as expected in this population. The low cumulative incidences of grade II-IV and grade III-IV aGvHD are promising; there were no cases of lower GI aGvHD greater than stage 1. Intravenous vedolizumab 300 mg added to standard GvHD prophylaxis for the prevention of GI aGvHD merits further study. DisclosuresChen:Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy. Shah:Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Exelexis: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership. Jansson:Takeda Pharmaceuticals: Employment. Akbari:Takeda Pharmaceuticals: Employment. Chen:Takeda Pharmaceuticals: Employment. Quadri:Takeda Pharmaceuticals: Employment. Parfionovas:Takeda Pharmaceuticals: Employment. Devine:Kiadis Pharma: Consultancy.

Significantly Improved Long Term Health Related Quality of Life (HRQL) and Neurocognition Following Familial Haploidentical Stem Cell Transplantation (HISCT) Utilizing CD34 Enrichment and Mononuclear (CD3) Addback in High Risk Patients with Sickle Cell Disease (SCD)

BackgroundSCD is a chronic debilitating disease secondary to frequent veno-occlusive events resulting in chronic organ damage, including cerebral vasculopathy, acute chest syndrome (ACS), pulmonary hypertension and a significantly shortened life-span (Bunn et al, NEJM, 1997; Lanzkron et al, PHR, 2013; Platt et al, NEJM, 1994). Importantly, SCD survivors also develop significant defects in neurocognition, especially processing speed and have a poor HRQL (Stotesbury et al, Neurology, 2018); Vichinsky et al, JAMA, 2010; Panepinto et al, BJH, 2005). To date the only cure for SCD patients has been HLA matched sibling AlloSCT following either myeloablative (MAC) or reduced toxicity conditioning (RTC), (Walters et al, NEJM, 1996; Bhatia/Cairo et al, BMT, 2014; Talano/Cairo et al, EJH, 2015; Gluckman et al, Blood, 2017). Unfortunately, only approximately 15% of patients have an unaffected HLA matched sibling donor (Mentzer et al, AJPHO, 1994). We previously demonstrated the safety and efficacy of CD34 enrichment and mononuclear cell (MNC) addback (2 x 105 CD3/kg) in pediatric matched unrelated donor recipients (Geyer/Cairo et al, BJH, 2012). We now report the long term results of MAC and familial HISCT utilizing CD34 enrichment and MNC (CD3) addback in high risk SCD recipients.MethodsSCD patients with one or more high risk features (cerebral vasculopathy, repetitive ACS, repetitive VOC, abnormal TCD requiring RBC TX) underwent MAC and parental HISCT consisting of hydroxyurea, azathioprine, fludarabine, busulfan, cyclophosphamide, thiotepa, r-ATG and TLI and PBSCT utilizing CD34 enrichment (10x106 CD34/kg) (Miltenyi®) and MNC addback (2x105 CD3/kg) and tacrolimus AGVHD prophylaxis x 100 days as we have previously described (Talano/Cairo et al, ASH, 2017). Donor chimerism in WBC and RBC (CD71) enriched fractions was determined centrally as we have previously described (Geyer/Cairo et al, BJH, 2012). AGVHD & CGVHD were determined utilizing the Glucksberg and NIH consensus criteria, respectively. Transthoracic echocardiogram, TRJ velocity, PFTs, MRI/MRA were performed at baseline and 2 years. Neurocognitive testing utilizing DIVERGT screening was performed at baseline and 2 years as we have previously described (Vichinsky et al, JAMA, 2010; Krull et al, JCO, 2008). HRQL testing utilized the CHRIS-General and CHRIs-HSCT (age appropriate) at baseline and Days +45, 100, 180, 365 and 730 post HISCT as we have previously described (Kelly/Parsons et al, PBC, 2012).ResultsAmong the 19 HISCT recipients, the mean±SEM age was 13.1±1.2 years (3.3-20.0) years, gender 12/7 (M/F). There were 18 parental haploidentical donors with mean±SEM age of 41.3±1.8 (30-55) years, gender 15/3 (F/M). The mean±SEM CD34 enriched PBSC infused was 10.94±0.4x106/kg and MNC addback (2 x 105 CD3/kg). The median time to neutrophil and platelet engraftment was day +9 and +19, respectively. The 1yr mean±SEM whole WBC and RBC (CD71) mixed donor chimerism was 97.1±1.4 and 96.4±2.0%, respectively. The cumulative incidence of grade II-IV AGVHD and CGVHD was 6.2% and 6.7%, respectively (Figure 1A). The probability of 1yr EFS was 90% (CI95 64-97%). In comparison from baseline to 2yr post HISCT, PFTs were stable to improved with a significant improvement in conductance (sGAW) (p<0.026), cardiac SF and TRJ velocity were stable to improved, MRI/MRA showed no new overt and/or silent strokes and no new cerebral vasculopathy. Intellectual functioning, memory, language, and executive function were also stable to improved. Most importantly, processing speed was significantly improved (p<0.026) (Figure 1B), emotional functioning (HRQL) (p<0.03) (Figure 1C) and physical functioning (HRQL) (p<0.01) (Figure 1D) were significantly improved at 2 years vs. pre-HISCT.ConclusionMAC and familial HISCT utilizing parental donors and CD34 enrichment and MNC addback (2 x 105 CD3/kg) in high risk patients with SCD was well tolerated, resulted in rapid hematological reconstitution, long term stable WBC and RBC (CD71) donor chimerism, low cumulative incidence of A+CGVHD and stable to improved pulmonary and cardiac function. There was also a significant improvement in processing speed and emotional and physical HRQL 2yrs post HISCT. This study was registered at clinicaltrials.gov (NCT02675959) and conducted under IND (14359) (MSC) and supported in large part by FDA R01FD004090. [Display omitted] DisclosuresCairo:Janssen: Research Funding. Parsons:Seattle Genetics: Research Funding. Friedman:MedImmune/AstraZeneca: Consultancy, Speakers Bureau. Vichinsky:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Protagonist: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees.