aGVHD Grade Research Articles

Early Treatment of Acute Graft-Versus-Host Disease With High- or Low-Dose 6-Methylprednisolone: A Multicenter Randomized Trial From the Italian Group for Bone Marrow Transplantation

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (</≥ 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P= .9), evolution to aGvHD grade III-IV 17% versus 20% (P= .6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy.

A Novel Clinical Risk Factor Based Scoring System to Predict the Severity of Acute Graft Versus Host Disease and Steroid Response in Resource Constrained Settings

INTRODUCTION Acute Graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT), affecting about 50% of transplants. Grading of aGVHD can serve a variety of purposes, including retrospective assessment of peak severity, real-time assessment of severity at prespecified time points, and determination of the need for treatment. But several problems hamper the application of grading systems to predict outcomes among patients with aGVHD: (1) Assignment of a peak GVHD score is done retrospectively; clinicians cannot use the current grading system for peak score in real-time1. (2) The systems do not account for the time to the response after treatment1. (3) Assignment of grade IV GVHD is often used to indicate that GVHD caused a death, irrespective of the severity. In this situation, the grading reflects the outcome and cannot be used to predict the outcome1. Recently serum biomarkers have emerged as an additional potential measurement of acute GVHD severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) Group, has validated MAGIC algorithm probability (MAP) that combines two GI biomarkers (ST2 and REG3α) into a single value. The MAP predicts response to treatment, GVHD severity. But in resource-limited settings, like transplant centers in India lack testing features. In this study we have developed a risk scoring based on clinical and easily available biochemical parameters to predict the severity of aGVHD. AIMS AND OBJECTIVES To predict the aGVHD severity at the onset based on risk factor score. To assess the steroid response in different risk groups MATERIAL AND METHODS The study included patients who underwent allogeneic HCT at Narayana hrudayalaya hospital, between January 2015 and April 2020 and developed acute GVHD within 100 days of transplant. After taking institutional ethics committee approval, data were collected from medical records. Baseline patient characteristics are mentioned in table 1. The following parameters were analyzed as risk factors for the development of severe GVHD (MAGIC grade 3 and 4): 1. Age &amp;gt;18 yrs, 2. MDR organisms in baseline stool culture, 3. HCT comorbidity index &amp;gt;1, 4. Peripheral blood as a source of stem cells, 5. Female to male transplants, 6. Myeloablative regimens, 7. Suboptimal GVHD prophylaxis, 8. CD34 dose &amp;gt; 6 x 106/kg, 9. Grade 3/4 mucositis 10. Early-onset GVHD (within 28 days), 11. Albumin level at the onset of GVHD, 12. Albumin drop from baseline3, and 13. Bloodstream infection. Risk factors with a p-value of &amp;lt;0.05, were given score 2 and score 1 was given to other parameters. The total score ranged from 0 to 17. The study population was divided into 3 groups (Group 1 with score 0-4, Group 2 with score 5-7, Group 3 with score &amp;gt; 8). The following outcomes were assessed in each group; severity of GVHD (Grade I/II vs Grade III/IV) and response to steroids. RESULTS Out of 148 patients, 35.5% of Group 1, 56.5% of Group 2 patients and 85.5% of Group 3 patients developed Grade 3 or 4 GVHD respectively (P-value &amp;lt;0.001). Positive predictive value of score &amp;gt; 8 to predict Grade 3/4 GVHD is 85.4%, negative predictive value is 50.6%, sensitivity is 50.5%, and specificity is 85.5%. From Group 1 and 2, only 30% of patients were steroid non responders, while 55.3% of Group 3 patients are steroid non responders (P-value - 0.04). CONCLUSION Traditional GVHD scoring systems reflect the outcome and cannot be used to predict the outcome. Various biomarker-based scoring systems are helpful in this situation, but in resource-limited settings, it might not be easily feasible. Clinical scoring systems like risk factor-based scoring systems are very helpful, which can predict the severe GVHD at early time points leading to management decisions such as upfront initiation of aggressive treatments and earlier introduction of second-line agents. References Leisenring WM, et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. Blood. 2006;108(2):749-55. 2.Rashidi A, et al. Peritransplant Serum Albumin Decline Predicts Subsequent Severe Acute Graft-versus-Host Disease after Mucotoxic Myeloablative Conditioning. Biol Blood Marrow Transplant. 2016;22(6):1137-41. Disclosures No relevant conflicts of interest to declare.

Impact of Severity of Acute Graft-Versus-Host Disease on Healthcare Resource Utilization, Cost and Outcomes

Introduction: Acute GVHD (aGVHD) contributes to poor outcomes and increased healthcare resource utilization (HRU) after allogeneic stem cell transplantation (allo-HCT). However, HRU and the economic burden of aGVHD based on severity of the disease and organ involvement is not well characterized. We examined the HRU, cost and mortality associated with aGVHD severity from initial hospitalization (index admission) up to 100 days post allo-HCT. Methods: Study cohort included 290 adult (≥ age 18) recipients of a first allo-HCT at the University of Florida between 1/2010 and 1/2019. The electronic medical records were reviewed for all patients who developed aGVHD as well as 116 patients without aGVHD who lived at least 1 month after HCT. Clinical measures that characterize the severity of aGVHD and extent of organ involvement were collected from electronic medical records. Medical costs and total hospital days were retrieved from administrative data that allocate costs to services based on departmental input for resource use and were adjusted to 2018 dollars. Wilcoxon rank sum test was used to compare number of inpatient days and total cost. Chi-squared test was used to compare ICU admission rate. Multivariable linear regression was fitted on log transformed cost. Results are shown as cost multipliers that represent ratios on original cost scale. Results: Of the 290 patients, 174 developed aGVHD within 100 days of allo-HCT. A higher proportion of patients with aGVHD had a Karnofsky performance status &amp;lt;80%, underwent matched unrelated donor HCT, and received calcineurin based GVHD prophylaxis. The mean number of days in the hospital for patients with aGVHD compared to those without aGVHD was 28 vs. 22 days, P&amp;lt;0.001 (Figure 1A). The mean number of hospital days for patients with grade I-II compared to those without aGVHD was 25 days vs. 22 days (P= 0.04) and for grade III-IV the mean number of days in the hospital compared to those without aGVHD was 48 days vs. 22 days (p &amp;lt; 0.001). In addition, presence of Lower gastrointestinal (GI) aGVHD was associated with more mean number of days in the hospital compared with those without aGVHD (43 vs. 22 days, P&amp;lt; 0.001). The ICU admission rates in patients with and without aGVHD were 13.2% and 6%, respectively (P=0.07) (Figure 1B). Analysis of ICU admissions based on grade of aGVHD revealed a significantly higher rate of ICU admission among patients with higher grade (grade III-IV) acute GVHD compared to those without aGVHD (22.3% vs. 6.0%, P=0.002). The early mortality rate in the first 100 days in aGVHD patients was twice that of the no aGVHD patients (14.9% vs. 7.8%; P=0.09). Compared to patients without aGVHD, early mortality was significantly higher in patients with aGVHD grade III-IV (7.8% vs. 33.9%; P&amp;lt; 0.001) and lower GI aGVHD (7.8% vs. 25.7%; P=0.001). Development of aGVHD was associated with a significantly higher total (inpatient and outpatient) cost. The mean total cost for patients with and without aGVHD were $226,545 and $165,622, respectively (P&amp;lt;0.001). Mean total costs associated with grades I, II and III-IV aGVHD were $183,693 (p = 0.44), $201,737 (p = 0.04) and $286,551 (&amp;lt;0.001), respectively (compared to $165,622 for those without aGVHD). Acute GVHD with GI involvement was significantly associated with higher mean total cost compared with aGVHD without GI involvement ($255,283 vs. $177,151, P&amp;lt;0.001). Among aGVHD cohort with GI involvement (Lower and/or upper GI), the mean cost was higher in patients with lower GI (LGI) compared with those without LGI aGVHD ($280,290 vs. $203,879, P=0.04). A multivariable analysis of risk factors for HCT cost identified presence of aGVHD, younger age at HCT, higher comorbidity index, and donor other than matched related donor as being associated with significantly higher costs (Table 1). Conclusion: HRU, cost, and clinical outcomes were associated with the severity of aGVHD. Development of higher grades of aGVHD and LGI aGVHD were associated with a poor clinical outcome and considerably increased healthcare economic burden. Given these clinical and economic risks it is imperative that new therapeutic strategies are developed for this patient population. Disclosures Farhadfar: Incyte pharmaceutical: Other: Member of GVHD advisory forum; CSL Behring: Research Funding. Leather:CSL Behring: Research Funding. Itzler:CSL Behring: Current Employment, Current equity holder in private company. Wingard:CSL Behring: Research Funding.

Evaluating Gvhd Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haplo-Identical Setting: A Single Center Experience

Background: The use of post-transplant cyclophosphamide (PTCy)/tacrolimus/mycophenolate mofetil (MMF) for GVHD prophylaxis has improved outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT). PTCy is now being evaluated in matched-related (MRD) and matched-unrelated (MUD) allo-HCT. Previous studies demonstrated improved GVHD-free/relapse-free survival (GRFS) when PTCy was combined with two immunosuppressive agents and PTCy has also been associated with better relapse-free survival (RFS) as demonstrated in De Jong et al 2019, though only one immunosuppressive agent was used. Currently, there is limited published data comparing outcomes using PTCy/tacrolimus/MMF to standard MRD/MUD GVHD prophylaxis of methotrexate (MTX)/tacrolimus. The importance of studying this comparison may help to improve GVHD outcomes in MRD and MUD allo-HCT. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 19) who received allo-HCT from 2018 to 2020. The primary end-points assessed were incidence and severity of 1-year aGVHD and cGVHD. Secondary end-points included day+100 mortality, 1-year overall survival (OS), 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HCT period. Results: A total of 65 adult MRD and MUD allo-HCT recipients and 53 haplo-HCT patients were reviewed. Of the MRD/MUD patients evaluated, approximately 51% (n = 33) were female and 49% (n = 32) were male. The age range was 20-69 years old (median = 46), and the most common diseases included ALL (46%), AML (31%), MDS (11%), and others (i.e. lymphoma, aplastic anemia (AA), myelofibrosis) (12%). 34% (n = 22) of patients received PTCy on D+3 and D+4 with tacrolimus/MMF/ on D+5 as GVHD prophylaxis and 66% (n = 43) of patients received MTX/tacrolimus on D+1, +3, +6, and +11 as GVHD prophylaxis. All haplo-HCT patients received standard PTCy/tacrolimus/MMF. Stem cell source was primarily PBSC except in HLH and AA patients. The PTCy group had more MUD allo-HCT (64%), degree of antigen mismatch (56%), and median age of 50.5 years compared with the MTX group at 44%, 47%, and 44 years respectively. 70% in the MTX group received MAC compared with 45% in the PTCy group. The haplo group had similar demographics to the MTX group. The mean CD34 cell doses in the PTCy, MTX, and haplo groups were 4.87, 5.36, and 7.24x106 cells/kg respectively. Incidences of total GVHD, aGVHD, and aGVHD grade 3 or 4 in the PTCy group were 55%, 50%, and 4.5% respectively compared with 65%, 35%, and 7% in the MTX group, though not significant. The haplo group had 68%, 55%, and 1.9% respectively. Incidence of total cGVHD and cGVHD requiring systemic therapy in the PTCy group was 4.5% and 0% respectively compared with 30% (p = .02) and 23% (p =.01). The haplo group had 13% and 1.9% respectively. Day+100 mortality, 1-year OS, 1-year RFS, 1-year TRM, and 1-year GRFS in the PTCy group were 0%, 80%, 60%, 0%, and 64% respectively compared with 7%, 88%, 90%, 7.3%, and 59%. The haplo group had 3.8%, 86%, 89%, 14%, and 66%. In a univariate analysis, factors significantly associated with GVHD were disease status (p = .0.12) and CD34 dose (p = 0.015) and antigen mismatch (p = 0.04) was associated with increased mortality. Discussion: Our results demonstrate improved overall and extensive cGVHD outcomes in the PTCy group and thus an improvement in 1-year GRFS. Furthermore, incidence and severity of 1-year cGVHD in this group are improved when compared with previously reported outcomes. 1-year GRFS reported in De Jong et al 2019 was 45% and 1-year GRFS reported for all groups in our study is higher at 66%, 64%, and 59% for the haplo, PTCy, and MTX groups respectively. Although this was not significant, it may be clinically meaningful given the significant improvement in extensive GVHD and improvement in all other secondary end-points except 1-year OS and RFS. Furthermore, the PTCy group had a higher percentage of mismatched antigens yet demonstrated superior outcomes. 1-year OS and RFS were superior in the MTX group however this is likely due to sample size differences. The improved extensive cGVHD and GRFS outcomes observed using PTCy/tacrolimus/MMF in the MRD/MUD setting should continue to be evaluated and currently there is an ongoing prospective, randomized study to further investigate. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study

Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study

Safety Analysis of Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients (pts) with Steroid-Refractory (SR) Acute Graft-Vs-Host Disease (aGVHD) in the Randomized Phase 3 REACH2 Study

Safety Analysis of Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients (pts) with Steroid-Refractory (SR) Acute Graft-Vs-Host Disease (aGVHD) in the Randomized Phase 3 REACH2 Study

Risk Factors for Overall Survival in Children with High Risk Acute Myeloid Leukemia (HR AML) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with Different Intensity of Conditioning Regimens

Background: Traditionally, children with AML undergo аllo-HSCT with myeloablative conditioning (MAC). It is known that MAC is associated with significant transplant-related morbidity and mortality. Reduced-intensity conditioning (RIC) is used in patients not eligible for conventional conditioning therapy due to poor performance status and severe toxic complications after previous chemotherapy. RIC is a well-established treatment strategy in adult patients with comorbidities. But there is no conclusive evidence to support efficacy of RIC allo-HSCT in children suffering from different malignant diseases including AML. The aim: To compare efficacy of different intensity conditioning regimens in children with high risk (HR) AML (according to AML-BFM protocols 1998 and 2004) and to identify factors which have a prognostic significance for overall survival (OS). Patients and methods: Retrospective analysis was performed in 192 patients (pts) with AML (median age of 10 years (0.5-18 y.o.), who received allo-HSCT at R.M. Gorbacheva Research Institute between 08/2000 and 09/2019. MAC (busulfan- or treosulfan-based) were used in 109 pts: 1st CR - 46 pts (MRD+ n=11), 2nd CR - 18 pts, 3rd CR - 1 pt, relapse - 44 pts. Allo-HSCT with RIC were performed in 83 pts: 1st CR - 32 pts (MRD+ n=13), 2nd CR -19 pts, 3rd CR - 4 pts, relapse -28 pts (p=0,674). RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melphalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Indication for RIC allo-HSCT was poor performance status (Lansky/Karnofsky score ≤70%), or organ dysfunction due to previous therapy, or infectious complications at the moment of allo-HSCT. Allo-HSCT from matched related donor was performed in 30 pts (16%), from matched unrelated donor - in 98 pts (51%), haploidentical - in 64 pts (33%) and the donor distribution was not different between groups (p=0,878). Post-transplant Cy was included in GVHD prophylaxis regimens in 102 pts (53%). OS were estimated using Kaplan-Meier curves. Univariate analyses were performed using the log rank test for OS, Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model. Results: Median follow-up was 5 years for МАС, 4.5 years for RIC. In both groups the median time to neutrophil engraftment &amp;gt;=0,5x109/l was D+16 (range D+8-52). Engraftment was observed in 67 pts (81%) after RIC and 94 pts (86%) after MAC (p=0,231). OS after RIC allo-HSCT in the 1st CR was 76% and after MAC - 68% (p=0,014), in 2nd CR 50% after RIC and 54% after MAC (p=0,058), in advanced disease 14% after RIC and 16% after MAC (p=0,394). The transplant-related mortality rate was 19% after RIC and 22% after MAC (p=0,546). Risk of relapse was 28% after RIC and 26% after MAC (p=0,456). Factors influencing OS after MAC were: 1) Remission status at the moment of allo-HSCT (р=0.001); 2) Presence of aGVHD grade I-II (р=0,005); 3) Relapse or MRD+ status after allo-HSCT (р=0.012); 4) Lansky score &amp;gt;70% (р=0,024). Factors influencing OS after RIC were: 1) Remission status at the moment of allo-HSCT (1st remission) (p=0,001); 2) Lansky score &amp;gt;70% (р=0,004). Conclusion: The effectiveness of RIC and MAC is comparable in children with HR AML, but RIC demonstrated better results in 1st CR. The presence of I-II grade aGVHD had positive effect in MAC. Factors influencing OS in both groups were disease status at the moment of allo-HSCT and performance status before allo-HSCT The use of RIC can be effective in patients, especially those who have undergone allo-HSCT in the 1st remission, while minimizing regimen-related toxicity in children who have undergone previous intensive treatment. Multicenter studies are warranted, especially for patients in the first CR, where long-term complications are of most importance. Disclosures No relevant conflicts of interest to declare.

Plasma Short Chain Fatty Acids As a Predictor of Response to Therapy for Life-Threatening Acute Graft-Versus-Host Disease

Introduction Minnesota High Risk and steroid-refractory acute graft-versus-host disease (aGVHD) are life-threatening complications of allogeneic hematopoietic cell transplantation (HCT). Recent data suggests dysbiosis may relate to GVHD outcomes. Bacteria in the lower gastrointestinal tract (LGI) produce short chain fatty acids (SCFAs) as fuel for enterocytes and modulators of mucosal immunity. LGI damage caused by aGVHD and antibiotic administration may be detrimental to SCFAs production and thus intestinal repair. However, limited data exists on how plasma SCFA levels vary between aGVHD patients who respond to treatment and those who do not. This study examined how aGVHD treatment response relates to plasma levels of five common SCFAs: acetate, propionate, butyrate, isovalerate, and valerate. Patients and Methods Serial plasma samples (n=221) were collected from 49 patients who underwent treatment for Minnesota High Risk or steroid-dependent/refractory aGVHD on NCT02525029 at study baseline and at 7, 14, 28 and 56 days post-treatment initiation. GVHD severity was graded using Minnesota criteria. Patients were categorized by their response to therapy at day 28 (complete/partial response [CR/PR], n=35 versus no response or death [NR], n=14). Plasma SCFA levels were quantified via liquid chromatography and cytokines measured by multiplex cytokine array. Changes in SCFA over time were assessed by repeated measures ANOVA. SCFA levels responders versus non-responders at individual time points were compared using Mann-Whitney testing and principal component analysis (PCA). SCFA, cytokines, and GVHD biomarkers including ST2, REG3a, and AREG were correlated using Spearman's rho with Bonferroni correction for multiple comparisons. Results Patients with CR/PR had higher levels of propionate (p=0.02) and butyrate (p=0.008) in comparison to NR among all samples analyzed (Figure 1a). Only butyrate levels varied significantly over time (p=0.018, with a significant difference in CR/PR vs NR at day 7, Figure 1b). The overall metabolomic profile of CR/PR patients was more stable than NR patients as determined by PCA. Neither initial clinical nor histologic grade of LGI aGVHD were associated with baseline plasma SCFA. Recent Clostridium difficile infection (n=5, p=NS) and total parenteral nutrition use (n=26, p=NS) did not influence baseline SCFA concentrations. Patients with high levels of butyrate also had high propionate (rho 0.9, p&amp;lt;0.001) and valerate (rho 0.84, p&amp;lt;0.001) and low isovalerate (rho -0.34, p&amp;lt;0.001). Plasma levels of interleukin-6 were higher in patients with low propionate and valerate (rho -0.33, p=0.008 and rho -0.36, p=0.002 respectively). Discussion Plasma SCFA profiles in patients with life-threatening GVHD suggest that differences in intestinal commensal microbe-derived SCFA production may relate to response to treatment. Patients responding to therapy have higher levels of plasma propionate and butyrate, especially early in the course of therapy. Patients with NR at day 28 appear to have increasing butyrate over time, possibly due to survival bias and/or stabilization on 2nd line therapy. Patients with higher concentrations of propionate and valerate have lower circulating IL-6 levels, which may indicate reduced systemic inflammation. Figure. (A) Comparison of short chain fatty acid (SCFA) plasma concentrations and clinical response (complete/partial response [CR/PR] vs no response [NR]) among all samples and (B) with butyrate over time. (C) Correlation of plasma SCFA, cytokines, and graft-versus-host disease biomarkers. Disclosures MacMillan: Equillium, Inc.: Consultancy; Mesoblast: Consultancy; Talaris Therapeutics, Inc: Consultancy; Fate Therapeutics, Inc.: Consultancy; Angiocrine Biosciences, Inc.: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Blazar:Tmunity: Other: Co-founder; Fate Therapeutics Inc.: Research Funding; KidsFirst Fund: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy. Betts:Patent Pending: Patents &amp; Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Holtan:Incyte: Consultancy; Generon: Consultancy; CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy.

Improvement in Non-Relapse Mortality Following Allogeneic Transplantation for Chronic Lymphocytic Leukaemia in Australia and New Zealand: An Australasian Bone Marrow Transplant Recipient Registry Study

Background The treatment landscape for chronic lymphocytic leukaemia (CLL) has significantly changed over the past decade with the advent of targeted therapies. Subsequent improvement in remission rates has been seen in all patient groups, however patients with high-risk genetic features (del17p, TP53 mutation) continue to have poorer outcomes. In such patients, and in multiply relapsed/refractory standard risk patients, allogeneic stem cell transplantation remains a viable management option despite the associated morbidity and mortality. The aim of this study was to examine trends in allogeneic stem cell transplantation for CLL in Australia and New Zealand over the past decade, and to identify predictive factors for overall survival (OS) and progression free survival (PFS). Methods Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving a first allogeneic stem cell transplantation for CLL, in the absence of Richter's transformation, between January 2009 and December 2018. Transplant outcomes were compared between 2 time periods, 2009-2013 and 2014-2018 using log rank test for survival and Gray's test for cumulative incidence curves. Cox regression analysis was performed to identify factors predictive of survival. Medians are reported with ranges, hazard ratios (HR) and cumulative incidence with 95% confidence intervals (CI). Results A total of 153 patients (75% males) were included. Median age at transplantation was 55 years (range 23-69) with a median time from diagnosis to transplantation of 5.7 years (range 100days - 24.7years). Most patients received reduced intensity or non-myeloablative conditioning (84.3%, n=129) and did not receive T cell depleting therapy (73%, n=94). The median follow up was 5.9 years (range 0.8-11years). Median time to neutrophil engraftment was 16 days (range 6-49) and median time to platelet engraftment was 18 days (range 1-69). At 100 days following transplantation the cumulative incidence of graft failure was 3.9%, CMV reactivation 41% (95% CI 31-50%) and CMV disease 3.2% (95% CI 1-8%). Acute graft versus host disease (aGVHD) grade II-IV occurred in 39% (95% CI 29-49%) of patients and grade III-IV in 17% (95% CI 9-25%). The cumulative incidence of chronic GVHD (cGVHD) was 65% (95% CI 53-76%) at 5 years; extensive cGVHD occurred in 77% of patients with cGVHD. Median OS was 4.3 years (95% CI 3.6-not reached) and PFS was 2.6 years (95% CI 1.7-3.9). The most common contributors to mortality were infection (43%), GVHD (40%) and persistent disease or relapse (24%). In a multivariate analysis active disease at time of transplantation was associated with a worse OS (HR 2.16, 1.01-4.63), however, age, matched sibling donor, myeloablative conditioning and the use of T cell depleting therapies did not have a significant impact. The use of myeloablative conditioning was associated with improved PFS (HR 1.85, 1.1-3.1) in a univariate analysis but lost significance in multivariate analysis. Ninety-seven patients underwent transplantation between 2009-2013 and 56 patients between 2014-2018. There was no statistical difference in patient age, performance status, donor or disease status at transplantation between the groups. Myeloablative conditioning was used in 18.6% and 8.9% (p=0.197), and T cell depleting therapy in 25% and 31% (p=0.58), for the 2009-2013 and 2014-2018 periods respectively. There was a significant improvement in 5-year non-relapse mortality (NRM) from 41.5% (31-52%) to 23.4% (13-29%; p=0.04). Five year OS (46% vs 56%), PFS (36% vs 46%) and relapse rates (21% vs 31%) were not statistically different. Cumulative incidence of both acute and chronic GVHD was reduced in the later cohort; aGVHD 51% (95% CI 34-65%) vs 29% (95% CI 16-43%; p=0.03), cGVHD 76% (95% CI 57-88%) vs 53% (36-66%; p=0.02). Kaplan-meier and cumulative incidence curves for these outcomes are presented in figure 1. Conclusion The number of allogeneic stem cell transplantations performed for CLL has reduced over the past decade in Australasia. There has been an improvement in NRM and incidence of GVHD, however OS and PFS have not significantly changed. This may reflect improved GVHD prophylaxis and management, or advances in supportive care. Further analysis of impact of high-risk genetic factors at transplantation is pending at the time of abstract submission. Figure Disclosures Spencer: Celgene, Janssen and Takeda: Speakers Bureau; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria. Greenwood:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding. Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

Total Marrow Irradiation for Second Allogeneic Haematopoietic Stem Cell Transplantation in Patients with Advanced Acute Leukemia

Background. Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is associated with very poor outcomes. A myeloablative conditioning regimen for patients with advanced acute leukemia before second allogeneic HSCT is crucial to better control the disease, but the risk of transplant mortality due to toxic complications is very high. Total Marrow Irradiation (TMI) is a novel high precision radiation treatment, alternative to standard Total Body Irradiation (TBI) conditioning regimen, allows to deliver therapeutic radiation doses over extensive selected targets while substantially reducing radiation to vital organs to preserve their functions. Aim of the pilot study. To evaluate the efficacy of high dose per fraction TMI in combination with thiotepa, fludarabine and alkeran as conditioning regimen in 9 patients with acute leukemia relapsed after a first allogeneic HSCT. Patients and Methods. Nine patients relapsed after first allogeneic HSCT received a second allogeneic HSCT, 7 from haploidentical, 1 from unrelated (UD) 10/10 and 1 from HLA-identical sibling (SIB) donor. The conditioning regimen consisted of: TMI 8 Gy in 5 patients on day -8 -7 or TMI 12 Gy in 4 patients on day -9 -8 -7, plus Thiotepa 5 mg/Kg on day -6, Fludarabine 50 mg/mq on day -5 -4 -3, alkeran 140 mg/mq on day -2. TMI was delivered in daily single fraction dose of 4 Gy, instead of the conventional 2 Gy in order to potentially enhance the biological effective dose approximately 20% to 60% (for a total dose of 12 Gy), considering alpha/beta ratio between 10-1.49, while total dose of 8 Gy in 2 fractions schedule is potentially equivalent to six fractions of conventional TBI for low alpha/beta ratio. Graft versus host disease (GvHD) prophylaxis for SIB and UD consisted of cyclosporine methotrexate and ATG, whereas for HAPLO it was high dose post-transplant cyclophosphamide (PT-CY), cyclosporine and mycophenolate. The median age was 45 years (range, 19-70 years); 3 patients were in remission, 6 had active disease at the time of the second allogeneic HSCT. The median number of nucleated cells infused was 4.3 x 10e8/Kg (range 2.6-7.7). Four patients received peripheral blood and 5 patients received unmanipulated bone marrow cells. Results. The median time to neutrophil counts of &amp;gt; 0.5 x 10e9/L was 16 days (range 13-22) and to platelet counts of &amp;gt; 20 x 10e9/L was 19 days (range 11-27) respectively. All the patients showed a full donor chimerism on day 30 after transplant; none of the patients had rejection. Three patients developed acute graft versus-host disease (aGvHD) grade I-II and 1 patient had moderate chronic GvHD. During the neutropenic phase of the transplant one patient developed a sepsis from Pseudomonas Aeruginosa; one patient had pericardial effusion and one patient had mucositis grade II. The median follow up was 528 days (range 227-858). Day +30 and day +100 transplant related mortality were 0. Two patients died of transplant related complications; both died of interstitial pneumonia and received TMI 12 Gy. Two patients died of leukemia and they were not in remission at the time of the transplant. The actuarial 17 months disease free-survival (DFS) is 53%. Conclusions. This is the first report demonstrating the safety and the efficacy of the TMI conditioning regimen in patients with advanced acute leukemia receiving second allogeneic transplantation with encouraging outcome in terms of engraftment, early toxocity, GvHD and relapse. Disclosures No relevant conflicts of interest to declare.

Early Reconstitution of CD6+ T Cells after Hematopoietic Cell Transplantation Identifies a Suitable Target for Acute Graft Versus Host Disease Treatment Using Anti-CD6 Monoclonal Antibody Itolizumab

Early Reconstitution of CD6+ T Cells after Hematopoietic Cell Transplantation Identifies a Suitable Target for Acute Graft Versus Host Disease Treatment Using Anti-CD6 Monoclonal Antibody Itolizumab

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.

Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants

Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants

Efficacy of Remestemcel-L Treatment in Steroid Refractory Acute Graft-Versus-Host Disease in Children: An Aggregate Analysis

Introduction: Steroid-refractory acute graft-versus-host dose disease (SR-aGVHD) is a frequent and potentially fatal complication of hematopoietic stem cell transplantation (HSCT). There are no approved therapies specifically indicated for use in children with SR-aGVHD &amp;lt; 12 years old. Treatment with culture-expanded, adult human allogeneic bone marrow (BM)-derived mesenchymal stromal cells (remestemcel-L) has shown excellent safety and efficacy in clinical trials conducted over the past 10 years. Here we describe aggregate results of remestemcel-L treatment of SR-aGVHD in the pediatric population. Methods: 309 pediatric subjects with SR-aGVHD were treated with remestemcel-L across 3 protocols. Data were derived from a phase 3, single arm study as first line after steroid failure with no other second line aGVHD therapies added through day 28 (NCT02336230, n=54), an expanded access program in subjects with aGVHD that had not responded to multiple other treatments (NCT00759018, n=241) and the pediatric subset of a randomized controlled trial (NCT00366145, n=14) in which remestemcel or placebo were given with a concomitant second line aGVHD therapy. Subjects in each protocol received 8 intravenous infusions of remestemcel-L (2 x 106 cells/kg twice weekly for 4 weeks). Those achieving a partial response could receive an additional 4 doses (once weekly for the subsequent 4 weeks). This analysis included 309 subjects who received at least one remestemcel-L dose. Response was assessed 28 days after the first dose. Survival was evaluated through day 100. Results: At baseline, mean age was 8.9 years (range 0.3 to 18.2 years) and aGVHD severity by IBMTR grade was C or D in n=252 (82%). Sources of grafts were bone marrow (BM: 46%), mobilized blood (MB: 20%) and cord blood (CB: 31%). Donor grafts were HLA matched related (9%) or unrelated (44%) or HLA-mismatched (46%). Subjects received a mean (standard deviation) of 10.3 (4.2) remestemcel-L infusions for a mean cumulative dose of 660.8 (484.1) x 106 cells. The primary endpoint, overall response (complete + partial response) at day 28 (OR) was observed in 66% of subjects (204/309) and survival at day 100 (OS) was 68% (211/309). Day 28 OR strongly predicted day 100 survival. Among subjects who were alive at day 28 (N=284), 170 of the 204 (83%) responders survived through day 100. In contrast, 41/80 (51%) of non-responders survived through day 100. Day 28 OR frequencies and day 100 OS rates were consistent across baseline aGVHD grades: Grade B OR 70%, OS 77%; Grade C or D OR 65%, OS 66%. Comparable day 28 response frequencies and day 100 survival rates were observed across type of HSCT: OR was achieved in 65%, 64% and 71% of BM, MB and CB, respectively and 67%, 70% and 70% of BM, MB and CB recipients survived through day 100. Comparable OR and OS were observed in HLA compatibility and donor types with OR in 71%, 66% and 66% and day 100 OS in 64%, 66% and 71% of matched related or unrelated and mismatched, respectively. Remestemcel-L was well tolerated with no infusion-related toxicity or other safety concerns. Most treatment-emergent serious adverse events were attributable to aGVHD or the underlying pre-transplant disease. Conclusions: In this large, diverse sample of pediatric subjects with SR- aGVHD, treatment with remestemcel-L was associated with a high and consistent overall response rate and survival rate through 100 days. Day 28 OR was highly predictive of day 100 survival. Remestemcel-L was well tolerated and effective across transplant types, donor sources, moderate to severe grades of GVHD and prior or concurrent treatment paradigms as defined by the individual protocols in this aggregate analysis. Remestemcel-L is a safe and effective treatment for children with SR- aGVHD addressing an unmet medical need for this highly vulnerable population. Disclosures Kurtzberg: Mesoblast, Inc,: Consultancy, Honoraria. Martin:Abgenomics: Research Funding; Enlivex: Consultancy; Procter and Gamble: Current equity holder in publicly-traded company; Pharmacyclics LLC: Membership on an entity's Board of Directors or advisory committees; Neovii: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfzier: Membership on an entity's Board of Directors or advisory committees; Xenikos: Research Funding; Talaris: Consultancy; Rigel: Consultancy; Mesoblast, Inc.: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Prockop:Atara: Research Funding; Jasper: Research Funding; Mesoblast, Inc,: Consultancy, Honoraria, Research Funding. Burke:Mesoblast, Inc,: Current Employment. Segal:Mesoblast, Inc,: Current Employment.

Real World Experience of Etanercept in Steroid Refractory Acute Graft Versus Host Disease from a Tertiary Cancer Centre in India

Introduction Acute graft versus host disease (aGVHD) is an important complication of allogeneic hematopoietic stem cell transplant (AHSCT). Steroid refractory (SR) aGVHD is seen in about 40- 50% of patients with no recommended standard of care. We report our experience with etanercept (ETA) as the initial agent in SR aGVHD. Materials and Methods We retrospectively analysed 43 AHSCT patients from 2010 to 2019 who received ETA as initial agent for SR aGVHD amongst 311 patients who underwent AHSCT in the same period. Patients received myeloablative (MAC) or reduced intensity conditioning (RIC). The transplants were from matched sibling donor (MSD), matched unrelated donor (MUD) and haploidentical donor (Haplo). GVHD prophylaxis was calcineurin inhibitor (CNI) plus methotrexate (MTX)/ mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide (PTCy) with CNI and MMF. aGVHD was graded as per the modified Glucksberg criteria. Additionally, all aGVHD episodes were also classified as per the Minnesota Scoring into High Risk (HR) and Standard Risk (sr) GVHD. First line treatment of aGVHD Grade II-IV was systemic steroids with methylprednisolone 1-2 mg/kg/day. SR aGVHD was defined as per standard criteria. ETA was started as 25 mg (0.4 mg/kg in children) subcutaneously every 72 hours initially and was tapered gradually depending on response. Response of SR aGVHD to ETA was defined as follows:Complete response (CR) was the complete resolution of aGVHD manifestations in all organs. Partial response (PR) was improvement in GVHD stage in at least 1 of the initially involved organs without CR and worsening in any other organs. Very good partial response (VGPR) was improvement in GVHD in all initial organs, with maximum stage I involvement in 1 or more organs (except upper gut). No response (NR)/Progression/Failure of therapy was defined as same grade or progression of GVHD in any organ or the addition of further GVHD therapy beyond ETA. Death prior to 1st response assessment was taken as NR. Response assessment was done at 3 time points - Day 14, Day 28 and Day 56 after initiation of ETA. Reduction of initial systemic steroid dose by ≥30% from baseline on day 28 after start of ETA was analysed as a subgroup to assess outcomes of patients. Results The characteristics of all 43 patients are shown in Table 1. ETA was required in a total of 45 episodes in 43 patients. The overall grade of GVHD and organs involved at the start of first line treatment are as in Table 2. The median day of onset of acute GVHD was 58 days (range 8-738 days). The median day of start of ETA was 86 days (range 16-74 days). The median number of days steroid was given prior to start of ETA was 7 days. The median number of ETA doses given were 11 (range 2-25). Response assessment on the predetermined time points are as in Table 2. The response rates (CR+VGPR+PR) at Day 14, Day 28 and Day 56 were 62%, 69% and 64% respectively. The organ specific response rates (CR+VGPR+PR) were 70% for lower gut, 67% for skin and 50% for liver. A third line agent for aGVHD was added in 10 patients, which included ruxolitinib, cyclosporine, mycophenolate mofetil, basiliximab or low dose weekly cyclophosphamide. The median OS of the whole cohort of SR aGVHD was 5.2 months. The median OS of the responders (CR+PR+VGPR) at Day 28 from ETA start was 6.8 months versus 2.8 months (p=0.0003) in non-responders (Fig 1). The median OS of sr group of Minnesota Grading was 24 months versus 10 months in HR group (p=0.085) (Fig 2). Patients, in whom reduction in the systemic steroid dose ≥ 30% at Day 28 from start of ETA was possible, had a significantly better median OS (9.5 months versus 3.5 months; p=0.000021) (Fig 3). In multivariate analysis, steroid dose reduction on day 28 of start of ETA was the most significant factor (p=0.008; hazard ratio 3.33; CI 1.3-8.1) CMV reactivation was seen in 64% of the patients. Fungal infections in 51% and bacterial infections in 78% patients after start of ETA. The causes of death were infection in 25 (58%) patients, refractory GVHD in 8 (18%), combination of GVHD and infection in 2 (5%) and relapse in 4 (9%) patients. Conclusion ETA used as initial agent has shown acceptable response rates for SR aGVHD in our cohort, especially for lower gut and skin. However, infections were the major cause for mortality for this cohort and early tapering of systemic steroids may be the key to improving outcomes. Disclosures No relevant conflicts of interest to declare.

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

Bridging the Gap in Access to Transplant for Underserved Minority Patients Using Mismatched Unrelated Donors and Post-Transplant Cyclophosphamide: A National Marrow Donor Program/be the Match (NMDP/BTM) Initiative

A multicenter prospective, randomized, placebo-controlled phase II/III trial for preemptive acute graft-versus-host disease therapy

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2–2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66–4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.

Prebiotics protect against acute graft-versus-host disease and preserve the gut microbiota in stem cell transplantation

AbstractAcute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, management of aGVHD is important for successful transplantation. Mucosal damage and alteration of the gut microbiota after allo-HSCT are key factors in the development of aGVHD. We conducted a prospective study to evaluate the ability of prebiotics, which can alleviate mucosal damage and manipulate the gut microbiota, to mitigate posttransplantation complications, including aGVHD. Resistant starch (RS) and a commercially available prebiotics mixture, GFO, were administered to allo-HSCT recipients from pretransplantation conditioning to day 28 after allo-HSCT. Prebiotic intake mitigated mucosal injury and reduced the incidence of all aGVHD grades combined and of aGVHD grades 2 to 4. The cumulative incidence of skin aGVHD was markedly decreased by prebiotics intake. Furthermore, the gut microbial diversity was well maintained and butyrate-producing bacterial population were preserved by prebiotics intake. In addition, the posttransplantation fecal butyrate concentration was maintained or increased more frequently in the prebiotics group. These observations indicate that prebiotic intake may be an effective strategy for preventing aGVHD in allo-HSCT, thereby improving treatment outcomes and the clinical utility of stem cell transplantation approaches. This study was registered on the University Hospital Medical Information Network (UMIN) clinical trials registry (https://www.umin.ac.jp/ctr/index.htm) as #UMIN000027563.

Irradiation-free RIC HSCT has a tolerable safety profile and is effective therapy for pediatric bone marrow failure syndromes.

For patients with bone marrow failure syndromes (BMFS) who may tolerate gradual donor engraftment and achieve adequate disease control with stable mixed chimerism, RIC regimens may be preferable to myeloablative regimens. We performed a retrospective analysis of outcomes for patients who underwent HSCT at our institution between 2009 and 2017 for BMFS using an irradiation-free RIC regimen. Fourteen pediatric patients with BMFS received fludarabine (30mg/m2 IV daily×3), thiotepa (5mg/kg IV every 12hours×2), and melphalan (70mg/m2 IV daily×2) prior to HSCT. Our cohort included the following diagnoses: SAA (n=7), CAMT (n=4), SCN (n=1), DBA (n=1), and non-Fanconi congenital BMF (n=1). Seven patients underwent a MSD transplant; seven underwent an unrelated donor transplant. All patients are alive with median follow-up of 1112days (range 455-2549days). The median time to neutrophil engraftment was 16days (range 10-26days). All were transfusion independent by day+100. The highest grade of aGVHD was grade 2; 8 (57%) did not develop aGVHD. Four (28.5%) developed extensive cGVHD, 4 (28.5%) developed limited cGVHD, and 6 (43%) did not develop cGVHD. No patients developed SOS. None died from GVHD or infectious complications. HSCT with RIC with fludarabine, thiotepa, and melphalan for BMFS was effective with a tolerable safety profile. Probability of OS at 100days and 1year was 100%.

Carfilzomib combined with cyclosporine and methotrexate for the prevention of graft-versus-host disease after allogeneic stem-cell transplantation from unrelated donors

Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m2, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II-IV, 6 months post transplant was 11% (95% CI, 4-32) and 39% (95% CI, 30-50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32-75) and 41% (95% CI, 33-52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4-33) and 18% (95% CI, 12-27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2-29) and 26% (95% CI, 18-36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66-96) and 56% (95% CI, 46-66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.