Post-transplant GVHD Prophylaxis Research Articles

Sociodemographic and Patient-Related Determinants of Outcomes after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Sociodemographic and Patient-Related Determinants of Outcomes after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

The UK Impact Transplant Trials Network: An Effective National Strategy to Accelerate the Delivery of Randomized Trials in Stem Cell Transplantation

Introduction: Stem cell transplantation (SCT) is an important curative modality in patients with blood cancer whose outcome with chemotherapy is predicted to be poor and is an increasingly important therapy in non-malignant disease. However, even in 2023, 50% of patients are still destined to die after either allogeneic or autologous transplantation, either of relapsed disease or treatment toxicity. In response the transplant community continue to develop innovative strategies designed to improve patient outcome. However, despite the fact that the adoption of new therapies in haemato-oncology is, almost without exception, based on evidence generated by randomized studies fewer than 5% of transplant patients are currently recruited to prospective practice informing trials. Thus, much current transplant practice is based on retrospective registry analyses whose results can often be misleading. There is therefore an urgent need for innovative trial models with the ability to accelerate transplant trial delivery if patient outcomes after SCT are to be improved. Methodology: We reasoned that limited trials capacity at busy centres coupled with the absence of a fit-for-purpose clinical trials network represented potentially tractable barriers to transplant trial recruitment. In 2018 a $5 million grant was secured from UK blood cancer charities in order to directly fund the salaries of research nurses within the IMPACT network covering 11 major UK transplant centres and a linked clinical trials hub. Critically, up-front investment into research nurses at major transplant centres created a catchment region in excess of 20 million. The pre-stated aim of the IMPACT pilot was to recruit 400 patients to 7 new transplant trials over a 4 year period. Results Opened in 2018 the IMPACT network has now randomized 1344 patients to 7 prospective transplant trials over a 5 year period. Trials delivered include COSI, a randomized trial examining the benefit of the addition of Thiotepa to a Fludarabine/Busulphan based conditioning regimen in patients allografted for acute myeloid leukemia (AML) (n=333) and AMADEUS a randomized comparison of the benefit of post-transplant CC486 maintenance (n-326). In conjunction with recruitment to the Pro-DLI trial- a randomized study of prophylactic DLI in patients allografted for high risk AML (n=150)- the IMPACT initiative has resulted in more than 900 patients being recruited to practice informing AML transplant trials over a 5 year period. Importantly, AMADEUS has been designed and delivered in order to generate registration enabling data. Additional trials delivered by the IMPACT network include ALL-RIC the first randomized comparison of reduced intensity conditioning regimens in acute lymphoblastic leukemia (n=102, now in follow-up) and the ongoing MoTD trial a randomized comparison of post-transplant cyclophosphamide GVHD prophylaxis (n=139 to date). Sample return for bolt-on scientific studies has been in excess of 85% allowing prospective analysis of the prognostic significance of pre and post-transplant MRD, molecular determinants of transplant outcome and the biology of disease relapse in patients allografted for AML and ALL. Of note the IMPACT research nurse network demonstrated impressive resilience during the COVID-19 pandemic permitting continued trial delivery despite faltering recruitment to other cancer trials. Conclusions: The funding of a national transplant trials network has transformed recruitment to prospective randomized transplant trials in the UK. The success of the IMPACT pilot, which-out-performed its recruitment metrics by 300%, confirms the importance of innovative trial delivery models in accelerating recruitment to practice informing transplant studies and is a scalable model internationally. At the same time, IMPACT has proved a highly effective mechanism to generate linked translational data with the ability to inform future trial design. Building on similar models in Europe, such as LYSARC, the IMPACT network is now funded by a not-for-profit trials delivery vehicle Accelerating Clinical Trials Ltd (www.act4patients.com) creating a financially sustainable model within the UK for the delivery of a mixed portfolio of industry sponsored and investigator initiated transplant and cell therapy trials.

11 - Surrogates of Endothelial Injury Predict Non-Relapse Mortality Among Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis

11 - Surrogates of Endothelial Injury Predict Non-Relapse Mortality Among Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis

Donor HLA mismatch promotes full donor T-cell chimerism in the allogeneic stem cell transplant with reduced-intensity conditioning and post-transplant cyclophosphamide GVHD prophylaxis.

Full donor T-cell chimerism (FDTCC) after allogeneic stem cell transplant (allo-SCT) has been associated with improved outcomes in hematologic malignancy. We studied if donor human leukocyte antigen (HLA) mismatch improves achievement of FDTCC because mismatched HLA promotes donor T-cell proliferation where recipient T-cells had been impaired by previous treatment. Patients (N = 138) received allo-SCT with reduced-intensity conditioning (RIC) from 39 HLA mismatched donors (16 unrelated; 23 haploidentical) with post-transplant cyclophosphamide (PTCy) or 99 matched donors (21 siblings; 78 unrelated) with PTCy (N = 18) or non-PTCy (N = 81). Achievement of FDTCC by day 100 was higher with HLA mismatched donors than matched donors (82.1% vs. 27.3%, p < 00,001), which was further improved with 200cGy total body irradiation (87.9%) or lymphoid (versus myeloid) malignancy (93.8%). Since all mismatched transplants used PTCy, FDTCC was higher with PTCy than non-PTCy (68.4% vs. 25.7%, p < 0.00001), but not in the matched transplant with PTCy (38.9%), negating PTCy as the primary driver. Lymphocyte recovery was delayed with PTCy than without (median on day + 30: 100 vs. 630/µL, p < 0.0001). The benefit of FDTCC was not translated into survival outcomes, especially in myeloid malignancies, possibly due to the insufficient graft-versus-tumor effects from the delayed lymphocyte recovery. Further studies are necessary to improve lymphocyte count recovery in PTCy transplants.

Artificial Intelligence Methods to Estimate Overall Mortality and Non-Relapse Mortality Following Allogeneic Hematopoietic Cell Transplantation in the Modern Era: An EBMT Transplant Complications Working Party Study

Introduction Allogeneic hematopoietic cell transplantation (alloHCT) is a life-saving procedures for many hematological diseases. However, its toxicity counterbalances its curative potential. Several prognostic scores have been created in the last two decades. Most scores derive from small sized and monocentric cohorts of patients. Also, contemporary patients and alternative donors are usually excluded from these scores. Methods We selected patients from the EBMT registry with the following characteristics: age > 18 years old; allogeneic hematopoietic cell transplantation (alloHCT) performed between 2010 and 2019; hematological disease diagnosis (AML/ALL; MDS/MPN; NHL/HL; plasma cell dyscrasias); any disease status at transplant; use of HLA-matched (familiar or unrelated) or haploidentical donor; myeloablative or RIC/NMA conditioning regimen; peripheral blood or bone marrow graft source. The primary objective was to create a prognostic score able to predict overall mortality (OM) at +2 years. The secondary objective was to predict non-relapse mortality (NRM) at 2 years. To create a newer prognostic score, we explored the following statistic and machine-learning techniques: step-wise logistic regression, support vector machine with linear and radial kernels, random forest, gradient boosting, elasticnet. We also tested simple fully connected neural network. The score included all the pre-transplant variables with a well-known prognostic role in terms of NRM related to disease (disease type) patient (age, gender, Karnofsky score, body mass index, presence of significant comorbidities, CMV status) transplant (time from diagnosis to transplant, donor type, GVHD prophylaxis, conditioning intensity, graft type) and transplant center characteristics (JACIE accreditation, > 20 alloHCT/year). OM model development was made on 70% of the data set, optimized on 15% and validated on the 15% of remaining data. Models with the best accuracy were selected to build the prognostic score. Results A total of 48984 patients were included into the analysis (Table 1). Median follow-up time for survivors was 38.4 months. Overall mortality and NRM at +2 years were 39.5% (95% CI=39.0-40.0%) and 19.0% (95% CI=18.5-19.5%), respectively. The 5 models predicted 2-year OM and NRM with similar AUC values. Best models were, for OM, gradient boosting (XGBoost) with AUC=0.64 (95% CI 0.630-0.655) and for NRM, elasticnet with AUC=0.58 (0.566-0.594). Neural networks had slightly higher performance for NRM but has limitations regarding the explicability of results. Same results were observed also when performing the analysis with the haploidentical cohort (n=5.934, AUC 0.66 for OM and 0.57 for NRM). In the final prognostic score including all the variables, gradient boosting was used to predict OM and elasticnet to predict NRM. The score was able to furnish a personalized prediction for each patient with continuous values. Patients with the lowest score had a 2-year OM and NRM of 22.2% and 8.7%, respectively. Patients with the highest score had a 2-year OM and NRM of 81.2% and 87.1%, respectively. A visual representation of the score prediction distribution was made on the validation cohort grouping the potential results into 4 groups (figure 1). Conclusion Our score showed to be useful in improving risk stratification of OM and NRM in the current era, including haploidentical transplants and post-transplant cyclophosphamide GVHD prophylaxis which were not included in previous scores. However, a generally poor accuracy despite the robust methodology confirms previous observations highlighting that the results of a prognostic score itself should not be used to exclude patients from a life-saving procedure. In such high-risk cases, more comprehensive evaluations (e.g. geriatric scores), biological scores (e.g. EASIX scores) and the overall patient's clinical phenotype should be evaluated to establish the actual transplantation risk and help in this difficult therapeutic choice Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tocilizumab for the Management of Cytokine Release Syndrome after Haploidentical Hematopoietic Transplant with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Haploidentical hematopoietic cell transplant (HaploHCT) with post-transplant cyclophosphamide (PTCy) has expanded the donor pool and made HCT available to patients without a matched donor. Cytokine release syndrome (CRS) is a syndrome of systemic inflammation with massive cytokine release, originally described after chimeric antigen receptor T cell (CAR T) therapy, is a frequent complication early after HaploHCT. Severe CRS after HaploHCT has been associated with higher non-relapse mortality (NRM) and worse overall survival (OS). Currently, no standard guidelines exist for CRS management in HaploHCT patients other than general supportive measures. Here, we described the impact of tocilizumab, an interleukin-6 receptor inhibitor used to manage CRS in CAR T therapy setting, on clinical outcomes in patients who experienced CRS after HaploHCT. We retrospectively identified a case series of 120 patients who experienced CRS after undergoing HaploHCT with PTCy-based GvHD prophylaxis at City of Hope from 06/2019 to 06/2021; of whom 11 patients received tocilizumab for CRS management. We matched these patients in a 1:2 ratio with 21 patients with CRS post-Haplo-HCT who did not receive tocilizumab (based on age, primary diagnosis, conditioning regimen, and CRS grading), then analyzed and compared OS, disease-free survival (DFS), relapse rate (RR), NRM, cumulative incidence (CIN) of grade II-IV and III-IV acute GvHD, and chronic GvHD between the two groups by univariate analysis. P-values were 2 sided at a significance level of 0.05. Table 1 summarize patient and transplant characteristics. Median age of patients in tocilizumab (TOCI) and no-tocilizumab (NO-TOCI) cohorts were 64 years (range: 27-70) and 62 years (range: 20-76). HLA 6/12 mismatch was the most common in both cohorts (81.8% in TOCI and 66.7% in NO-TOCI). All patients received mobilized peripheral blood stem cells (PBSC) as graft source. Majority of patients received non-myeloablative or reduced intensity conditioning regimens (81.8% in TOCI and 76.2% in NO-TOCI). Grade 2 CRS was most common in both cohorts (72.2% in TOCI and 71.4% in NO-TOCI); and grade 3-4 CRS was documented in 1 patient (9.1%) in TOCI and 2 patients (9.5%) in NO-TOCI cohort. Tocilizumab doses were 4 mg/kg (n=2), or 8 mg/kg (n=9). All patients but one (90.9%) received one single dose of tocilizumab and 1 patient received 2 doses of tocilizumab at 8 mg/kg/dose. All tocilizumab doses were administered either on day +3 (45%) or day +4 (55%) post-HCT (the patient with 2 doses was counted towards day +3). No high-grade tocilizumab-related side effects were documented in those 11 patients. Day 28 CIN of neutrophil engraftment was lower in TOCI compared to NO-TOCI patients (54.5% vs 76.2%, 95% CI: 21-79 and 50-90%, P=0.07 - Figure 1a). At 12 months post HaploHCT, survival outcomes were similar with NRM of 18.2 and 19% (95% CI: 3-46% and 6-38%, P=0.92); and RR of 19.5 and 14.3% (95% CI: 3-49% and 3-33%, P=0.78) in TOCI and NO-TOCI cohorts, respectively. DFS and OS were not affected by tocilizumab administration (P=0.90 and P=0.98; respectively). Three patients in TOCI and 7 patients in NO-TOCI cohort died; their causes of death were not directly related to CRS. While CIN of day 100 grade II-IV (P=0.97) and grade III-IV acute GvHD (P=0.47) were not affected by tocilizumab administration, CIN of chronic GvHD was significantly higher in TOCI compared to NO-TOCI (60.6 vs 23.8%, 95% CI: 19-86% and 8-44%, P=0.05 - Figure 1b). In conclusion, our results indicates that tocilizumab used for CRS management after in HaploHCT setting with PTCy-based GvHD prophylaxis was well tolerated and had no effect on survival outcomes. However, our study showed a trend towards delayed neutrophil engraftment and a statistically significant higher incidence of chronic GvHD in patients who received tocilizumab. It is possible that tocilizumab may interfere with T cell expansion, which could impact PTCy-mediated elimination of alloreactive T cell clones and/or affect regulatory T cells function; both mechanisms could lead to higher incidence of chronic GvHD. Using this approach to mitigate CRS risk should be reserved to patients with high grade CRS where mortality is high. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA-Haploidentical Vs Mismatched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide-Based Gvhd Prophylaxis for AML and MDS: Is There a Winner?

Introduction: Finding a suitable donor is often influenced by race and ethnicity of the patient. Despite increased donor availability through registry, a proportion of patients does not find HLA-matched donors. In such situations, haploidentical donors or mismatched unrelated donors (MMUD) are commonly considered. Post-transplant cyclophosphamide (PTcy), given on days +3 and +4 after haploidentical donor transplants (HIDT), has significantly reduced rates of GVHD and improved outcomes. Given encouraging activity, we implemented use of PTcy in combination with tacrolimus and mycophenolate for GVHD prophylaxis in HLA-MMUD transplants and have reported promising results. This raises an important clinical question: Do outcomes of HLA-haploidentical or MMUD transplants differ when using PTcy-based GVHD prophylaxis? Does PTcy overcome adverse outcomes associated with HLA-MMUD similar to HLA-haploidentical donors? Methods: We retrospectively compared outcomes of 144 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received PTcy, tacrolimus, and mycophenolate for GVHD prophylaxis and underwent either HIDT or HLA-MMUD transplants. Propensity score-based multivariable analyses (PSCA) were performed using age, KPS, HCT-CI, diagnosis, conditioning regimen, disease status at transplant, CMV serotype, and donor/recipient sex mismatch as variables to adjust confounding effects of patient characteristics between both groups. Results: Between January 2013 and December 2021, 89 patients received HIDT and 55 received MMUD transplants. Among MMUD, 89% (n=49) were 7/8 HLA-matched and 11% (n=6) were 6/8 HLA-matched. Median age of the population was 62 years, 22% were African American, 73% had AML, 20% received myeloablative conditioning regimen. All patients received peripheral blood stem cell transplants. CRS rate was higher in the HIDT group compared to MMUD (78% vs 38%, p<0.001). The median time of onset of CRS was 1-day post-transplant, and the median duration of CRS was 3 days. Median time to neutrophil engraftment was prolonged in the HIDT group (18 vs 15 days, p<0.001), while platelet engraftment was similar (23 vs 21 days, p=0.15). Graft failure rate was 3% in both groups. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (3.4% in HIDT vs 7.3% in MMUD, p=0.30), whereas chronic GVHD at 1 year was higher with HIDT compared to MMUD transplants (28% versus 14.2%, p=0.05). At a median follow up of 2.5 years, 1-year survival was 66.7% for HIDT and 69.5% for MMUD (p=0.46), 1-year relapse-free survival (RFS) was 58.9% for HIDT and 61.7% for MMUD (p=0.48), 1-year relapse was 18.3% for HIDT and 25% for MMUD (p=0.49), and 1-year non-relapse mortality (NRM) was 22.7% for HIDT and 13.2% for MMUD (p=0.11). Using PSCA, no difference in survival, RFS, relapse, and NRM was noted between both groups. Conclusion: Our study demonstrated that transplant outcomes did not differ between HLA-haploidentical and MMUD when PTcy was used for GVHD prophylaxis. PTcy can be safely used and provided promising results in HLA-MMUD transplants. In the absence of HLA-matched donors, either haploidentical or MMUD can be used. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ALL-331 Outcomes Using “Flipped” Conditioning Regimens (Fractionated Total Body Irradiation Then Fludarabine or Cyclophosphamide) for Allo-HSCT at the University of Southern California, a Retrospective Study

Fludarabine followed by fractionated total body irradiation (Flu/FTBI) as conditioning was well-studied in allo-HSCT. Cyclophosphamide as pre-FTBI (Cy/FTBI) and post-FTBI (FTBI/Cy) has also shown acceptable outcomes, although data are limited. However, unlike FTBI/Cy, no studies have examined FTBI followed by fludarabine (FTBI/Flu). Due to logistics, we have used FTBI/Flu or FTBI/Cy with appropriate stem cell infusion timing. Report outcomes using FTBI/Flu and FTBI/Cy conditioning. Retrospective chart review. Single institution: academic hospital/county hospital. Patients (18-99 years, M/F) with hematologic malignancies diagnosed 1/2015-2/2021 who underwent allo-HSCT at our institution. Primary: OS and EFS since time of transplant, stratified between FTBI/Flu and FTBI/Cy. Secondary: Patient/treatment characteristics, GVHD, and (non-) relapse-related mortality ((N)RM) rates. P≤0.05 was considered significant. In 26 patients, median age was 47.5 years, 65% males, 65% Hispanic, 50% with ALL, and 42.3% with AML. Pre-transplant, 65.4% of patients were at CR1, and 23.1% were at CR2/3. Disease risk index (DRI) was intermediate for 73.1% and high for 23.1%. MSD was administered to 26.9%, MUD to 38.5%, and haploidentical stem cells to 34.6%. FTBI/flu conditioning was administered to 84.6% and FTBI/Cy to 15.4%. Post-transplant GVHD prophylaxis was cytoxan/tacrolimus/mycophenolate in 80.8% and tacrolimus/methotrexate in 19.2%. Since transplant, in the overall population, 3-year (3y) OS was 81% (15.4% had NRM) and 3y-EFS was 72.5% (7.7% had relapse). FTBI/Flu 2y-OS was 77.5% and FTBI/Cy 2y-OS was 100% (p=0.38). FTBI/Flu 2y-EFS was 77.5% and FTBI/Cy 2y-EFS was 50% (p=0.24). Any grade/any type acute GVHD occurred in 77.3% of FTBI/Flu patients vs. 50% of FTBI/Cy patients (p=0.29), with 15.4% of FTBI/Flu patients experiencing G3 acute gut GVHD vs 0% of FTBI/Cy patients (p=0.99). Any grade/any type of chronic GVHD occurred in 27.3% of FTBI/Flu patients vs. 50% of FTBI/Cy patients (p=0.56); however, 50% of FTBI/Flu patients experienced G3 chronic gut GVHD vs. 0% of FTBI/Cy patients(p=0.99). Given most of our patients had intermediate/high DRI, the OS and EFS using both flipped conditioning regimens were generally similar and appreciable. However, more any type/grade, acute GVHD and G3 acute/chronic gut GVHD cases were identified in the FTBI/Flu population, although not significant.

Outcome of Children with Wiskott-Aldrich Syndrome (WAS) Given TCR Alpha-Beta/CD19 Depleted Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Haploidentical Relative

Background: WAS is a rare X-linked recessive disorder, characterized by thrombocytopenia with low platelet volume, recurrent infections, eczema, autoimmunity, vasculitis and increased incidence of malignancies. Patients with classical WAS have chronic morbidities, severely impaired quality of life and a decreased life expectancy. Allogeneic HSCT is the only well-established curative treatment, gene therapy being still an experimental approach. Excellent outcome have been reported in patients transplanted at early age from either matched related and unrelated donors, with 5-year overall survival (OS) exceeding 90%. However, experience with HLA-haploidentical HSCT is limited and has been historically associated with inferior results. Haploidentical HSCT after selective depletion of α/β+ T-cells and CD19+ B-cells (TBdepl-haploHSCT) was shown to be safe and effective in children with multiple types of non-malignant disorders (Merli et al, Blood Adv 2021). To further optimize this approach and accelerate the recovery of adaptive immunity, we conducted a phase I/II trial evaluating the safety and efficacy of post-transplant infusion of a titrated number of donor T-cells transduced with the inducible caspase-9 (iC9) suicide gene (BPX-501, or rivogenlecleucel, cells) in children with either malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). We report the outcome of a cohort of 12 children affected by WAS who received a TBdepl-haploHSCT at our Center.Patients and methods: Between 2014 and 2021, 12 patients affected by WAS received a TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. Patients and transplant characteristics are depicted in Table 1. All patients received a myeloablative conditioning regimen, combining pharmacokinetic-adjusted busulfan with Thiotepa and Fludarabine. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab was administered on day -1 to prevent PTLD. No post-transplant pharmacological GvHD prophylaxis was employed. Eight subjects, enrolled in NCT02065869 trial, additionally received post-transplant infusion of BPX-501 cells (dose: 1x10 6 cells/kg) at a median time of 16 days after HSCT (range 12-20).Results: 11 patients achieved primary donor cell engraftment, while one patient experienced secondary graft failure (GF), likely triggered by CMV reactivation. Median time to neutrophil and platelet recovery was 15 (range 8-33) and 10 days (range 9-16), respectively. The patient with secondary GF was successfully re-transplanted with a second TBdepl-haploHSCT from the same donor. Grade I/II skin acute GvHD (aGvHD) occurred in 3 patients, the cumulative incidence of aGvHD being 25.9% (95% CI 0-47.7). None of these 3 patients required activation of iC9 with rimiducid and no cases of chronic GVHD (cGvHD) were observed. No patient died. With a median follow-up of 58 months (range 1 - 78), the 5-year probability of OS and event-free survival is 100% and 90.7% (95% CI 50.8-98.7), respectively. Considering the successful second allograft, the 5-year disease-free survival is 100%. Platelet recovery is reported in Figure 1A. Two months after the allograft, all evaluable subjects had a platelet count above 50.000/microL (median 202.000, range 53.000-353.000). All subjects but one have full donor chimerism at last follow-up, the remaining patient having stable mixed chimerism (40% of donor cells) without any WAS manifestation. All subjects with a follow-up of at least 6 months are independent of immunoglobulin replacement. Details on reconstitution of lymphocytes subsets are reported in Figure 1B,C,D.Conclusions: TBdepl-haploHSCT after Bu-based conditioning regimen is an highly-effective curative option for children with WAS, being characterized by high-engraftment rate with fast recovery of both neutrophils and platelets, low incidence of aGvHD and no occurrence of cGVHD. Given the prognostic impact of age in determining HSCT outcome in WAS and prompt availability of haploidentical family donors, our data suggest that this approach should be offered without delay to those patients with WAS who lack a matched donor. Infusion of BPX-501 cells contribute to accelerate the recovery of adaptive T-cell immunity, further increasing the safety of the procedure. [Display omitted] DisclosuresMerli: SOBI: Consultancy; JAZZ: Consultancy. Locatelli: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyl: Honoraria.

Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Introduction:Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment.Methods:We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis.Results:From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant).Conclusion:Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. [Display omitted] DisclosuresModi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

Sequential Fludarabine, Ara-C, Etoposide (FLAV) Followed By Fludarabine/ Busulfan Reduced Toxicity Conditioning Is Safe and Effective Salvage for Adult Patients with Refractory Acute Myeloid Leukemia and High Risk Myelodysplasia

BackgroundA significant proportion of patients with acute myeloid leukemia (AML) will either be refractory to initial chemotherapy or will suffer refractory relapse. The role of allogeneic transplantation (SCT) in active disease is contentious. There is a growing body of literature that sequential chemotherapy, pioneered by the German FLAMSA regimen, followed by RIC SCT is a safe and efficacious modality in these patients, and there have been numerous modifications of this regimen, especially as amsacrineis not widely available. Fludarabine, cytarabineand and etoposide (VP16) (FLAV) have been reported as an effective salvage regimen. Here we report on single center outcomes of a variation of the FLAMSA regimen, substituting amsacrine for etoposide with mainly myeloablative conditioning.MethodsPatients were offered this regimen if fit for allogenic HSCT and had AML which is refractory to two cycles of chemotherapy or refractory to one cycle and considered at high risk for complication with second cycles. Patients with MDS received this regimens if eligible for transplant with high or very high risk cytogenetics. All patients received cytoreductive chemotherapy consisted of fludarabine 30mg/m2/day x 4 days, Cytarabine 2g/m2/day x 4 days, etoposide 100mg/m2/day x 3days, commenced simultaneously. After 3 days of rest, conditioning chemotherapy consisted of fludarabine 30mg/m2 x 2 days and and IV busulfan 0.8mg/m2 q 6 hours; the number of busulfan doses varied between 8 - 12, depending on patient comorbidity. All patients received 2 doses of ATG at 2.5mg/m2/day on day -3 and -2. All patients received GCSF mobilized peripheral blood hematopoietic cells. Post-transplant GVHD prophylaxis consist of CsA and MMF. CsA was tapered from day+60 and stopped at day +90 in the absence of GVHD. MMF was discontinued between day +30 and day +40. Donor lymphocyte infusions were collected for planned prophylactic DLI.ResultsTwenty six patients received FLAV-SCT between March 2014 and July 2019. The median age was 38 (14-60); 16 (62%) female. Overall 12 (46%) pts had de novo AML, 10 (39%) pts had secondary or therapy related AML and 4 (15%) pts had MDS. Fourteen (54%) pts had adverse risk cytogenetics include 8 (31%) pts had complex or monosomal karyotype. Patients' characteristics are summarized in Table 1.All patients had active disease prior to FLAV-SCT. The median time for ANC and platelet engraftment was 14 (10 - 42) days and 17 (10 - 52) days respectively. Day 30 assessment shows CR in 16 (61%) pts and CR/CRi in 17 (65%) pts. Outcomes are summarized in Table 2. Three patients (12%) developed veno-occlusive disease. Acute GVHD grade II-IV and III-IV occurred in 9 (35%) pts and 2 (8%) pts respectively. Three (12%) patients developed chronic GVHD. Cumulative incidence of NRM at 100 days and 2 years was 8% and 12% respectively. The median OS for all pts was 5.2 months with 2 years rate of 32% (15 - 50). Among responders, the median OS and RFS were 19.2 months and 8.7 months, 2y-OS and RFS were 47% and 25%, respectively (Figure 1).ConclusionOur result demonstrates that transplant is an effective therapeutic modality in this very high risk refractory AML/MDS patients. Sequential chemotherapy (FLAV) followed by SCT with busulfan at myeloablative dose is tolerable with an acceptable toxicities and encouraging results. [Display omitted] DisclosuresChaudhri: Novartis: Honoraria; Abbvie: Honoraria; Astra Zeneca: Honoraria. Alzahrani: King Faisal Specialist Hospital and Research Centre: Current Employment; Novartis: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Low-Toxicity/High-Efficacy HLA Haploidentical Transplantation for Elderly/Unfit Patients with Acute Leukemia

Allogeneic hematopoietic transplantation is the most powerful therapy for patients with acute leukemia at high risk of relapse. For HLA haploidentical transplantation, we recently applied a protocol consisting of a high-intensity TBI-based conditioning regimen and a peripheral blood CD34+ hematopoietic stem cell graft combined with the adoptive transfer of naturally occurring regulatory T cells (Tregs) and conventional T cells (Tcons). No post-transplant pharmacologic immune suppressive GvHD prophylaxis was given. Such a protocol was associated with remarkably low GvHD and relapse rates (Martelli MF et al., Blood. 124:638-644, 2014; reviewed in Mancusi A et al., Blood 128:2616-2623, 2016).However, patients who are unfit (because of multiple chemotherapy cycles, previous transplants, infections, or co-morbidities) or elderly are not expected to withstand high-intensity conditioning regimens. For these patients, we developed a reduced-toxicity version based on total marrow and total lymphoid irradiation (TMI/TLI) (Rosenthal J et al., Blood. 2011;117:309-315). TMI/TLI (13.5 Gy and 11.5 Gy respectively) were administered by means of Helical Tomotherapy HI-ART (in 9 fractions delivered two times a day in 4 and a half days). Target volumes were defined as the skeletal bone and major lymph node chains and spleen. In patients with ALL the brain was added as target volume. TMI/TLI was followed by chemotherapy with Thiotepa (2,5mg/kg/day for 2 days), Fludarabine (30 mg/m2/day for 5 days) and Cyclophosphamide (15 mg/kg/day for 2 days). As per our high-intensity protocol, the hematopoietic stem cell graft was foregone by an infusion of 2x10e6/Kg freshly isolated CD4/CD25/FOXP3-positive Tregs and a subsequent infusion of 1x10e6 Tcons. No post-transplant pharmacologic immune suppressive GvHD prophylaxis was given. To date 19 patients with high-risk acute leukemia in remission were enrolled (16 AML, 3 ALL). Median age was 57 years (range: 22-68). All patients engrafted. Four patients developed aGvHD grade ≥ 2. Transplant-related mortality was 21% (2 patients died of infections, 1 of VOD and 1 of aGvHD). Remarkably, no relapse or cGvHD were observed. With a median follow up of 12 months (range: 1-24), 15 of the 19 patients are alive. Thus, leukemia/cGvHD-free survival is 79%. Of course, these data need to be confirmed in a larger cohort of patients and with longer follow up.In conclusion, the present transplantation protocol was designed to make HLA haploidentical transplantation feasible and effective for unfit or elderly patients with high-risk leukemia. It combines a reduced-toxicity conditioning regimen with safe cellular immunotherapy of leukemia. To date, the clinical results are excellent and extremely encouraging. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Regulatory T Cells for Acute Graft Versus Host Disease Prevention

BACKGROUND GVHD remains a major cause of morbidity and mortality after allo HSCT. The past few years have shown a number of successful advances in cellular therapies for the treatment of hematologic malignancies. It is logical to expand the use of these therapies earlier, in strategies aimed at prevention. Several studies showed that regulatory T cells (Treg) can reduce the incidence of aGVHD. METHODS Studies were identified using electronic databases (Medline, Embase, and Cochrane). Preclinical studies were excluded. Data analysis was performed using GraphPad Software 8.4.2. RESULTS 160 patients were identified from 7 clinical studies. 85% of the patients had acute leukemia and were in complete remission at the time of transplant. Tregs were isolated from either UCB or PB. Tregs were expanded ex-vivo using IL-2, CD3/CD28 ab coated beads and K562 cells in three studies (n=40). 1.Ex-vivo expanded Treg: In a phase I study (Brunstein et al) of UCB-derived Tregs in 23 pts undergoing double umbilical cord transplantation, Tregs were cultured with antiCD3/anti CD28 and IL-2. Ex-vivo expanded Tregs were given on day+1 and day+15. Eighteen pts received Treg cells at dose of &amp;gt;3x106 cells/kg. Grade II-IV aGvHD was seen in 39% of pts who received ≥3x106 cells/kg vs 43% in historical controls. In this study, CsA+MMF or sirolimus+MMF were used for GvHD prophylaxis. In a follow up study of 11 patients, Tregs were markedly expanded using K562 cells. Higher Treg doses were achieved up to 100x106cells/kg and the median proportion of CD4+CD127-FOXP3+ within the infused products was 87%. Grade II-IV aGVHD was 9% at 100 days vs 45% in control group. Treg cells were not detected in the peripheral blood after 14 days of infusion. In a phase II study (Kellner et al; Zeng et al), three of six pts undergoing PB MUD received ex-vivo expanded UCB-derived Tregs 1x106/kg at day-1. All developed aGVHD due to the high donor Tcon cells in the graft with donor Tcon:UCB Treg ratio as high as 356:1. Sixth patient was given 1x107 cells/kg Tregs in the presence of anti CD3/28 microbeads and IL-2 with Treg:Tcon ratio of 1:40. No aGVHD was observed in this patient compared to the others who received Treg at the dose of 1x106cells/kg. 2.Unexpanded Treg: In a study (Di Ianni et al) involving 26 high risk leukemia pts undergoing haplo-transplant with TBI based conditioning, 21 pts were infused with donor Tregs at a dose of 2x106 cells/kg and five pts were infused with Treg at a dose of 4x106 cells/kg on day -4, followed by Tcon infusion ranging from 0.5x106 to 2x106 cells/kg on day 0. No post-transplant immune suppression was given. Grade II-IV aGVHD was observed in 2 out of 26 patients who received 4x106cells/kg Tregs and 2x 106cells/kg Tcons. No GVHD was observed in pts who received 2x106cells/kg Tregs followed by 0.5-1x106 cells/kg Tcons. A phase II study by the same group (Martelli et al) reported on an additional 17 pts who received Tregs (2x106cells/kg) at day-4 co-infused with Tcon (1x106cells/kg) at day 0. Six of 41 (15%) evaluable pts developed grade II-IV aGVHD (vs 11% in historical cohort) with two pts requiring a short course of immunosuppression. Incidence of relapse was lower in Treg group than historical controls (5% vs 21%). In a phase I/II study (Meyer et al), 12 pts with hematological malignancies who underwent HLA-matched transplantation received purified Tregs (1-3x106cells/kg) on day0 followed by Tcon (1-3x106cells/kg) on day+2. GVHD was seen in 80% of pts with 50% being grade III in pts who received frozen Tregs. Upon revising protocol, 7 pts were given fresh Treg. The patients also received either tacrolimus or sirolimus for immunosuppression. None of 7 pts in revised cohort developed GVHD. Recent study applied hyper-fractionated TBI to the conditioning regimen in 12 pts out of 40 to further reduce leukemia relapse in Treg/Tcon based haplo-HSCT. Treg was administered at the dose of 2x106cells/kg and Tcon at 1x106cells/kg. No post-transplant GvHD prophylaxis was given. Grade II-IV aGVHD was observed in 12 pts. CONCLUSION These studies suggest that Treg therapy may represent an effective prevention strategy against acute GvHD (figure 1). Stimulated Treg expansion strategies and higher doses of Treg appear to be associated with lower incidence of aGVHD. Treg infusion was well-tolerated without serious adverse events. Large prospective clinical trials are warranted in order to establish the optimal infusion dose, optimal expansion strategies and dosing schedule. Disclosures No relevant conflicts of interest to declare.

Outcome of Children with Different Non-Malignant Disorders Given Alphabeta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT)

Background: allogeneic HSCT is the only potentially curative treatment for many non-malignant diseases (NMD), either inherited or acquired. However, many patients lack an HLA-matched donor (familiar (MFD) or unrelated (MUD)) and the outcome of children transplanted from an HLA-haploidentical relative (haplo) was historically inferior to that of transplants from a MFD or a MUD. We previously published promising results in a cohort of 23 children with NMD given this type of allograft (Bertaina et al., Blood 2014), demonstrating a low transplant-related mortality (TRM) and high cure rates. Here, we report the outcome of a large cohort of children affected by NMD who received a TBdepl-haploHSCT at our Center (NCT01810120). Patients and methods: Between February 2011 and June 2020, 80 consecutive patients affected by NMD received TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. Patients had many different disorders (see Table for details on patient- and transplant-related characteristics). Median time from diagnosis to transplant for the whole cohort was 12 months (range 1-177), while it was 2.5 months (range 1.3-11.2) for SCID patients. All patients, including children with SCID, received a conditioning regimen, which varied according to the original disease. Pre-transplant anti-thymocyte globulins (from day -4 to day -2) were given to modulate bi-directional donor/recipient alloreactivity, while rituximab (on day -1) was administered to prevent PTLD. Moreover, no post-transplant pharmacological GvHD prophylaxis was given. Results: fifty-eight patients (72.5%) achieved primary donor cell engraftment, while 3 patients experienced secondary graft failure (GF); the cumulative incidence of either primary or secondary GF was 27.8% (95% CI 17.2-37.0). Median time to neutrophil and platelet recovery was 13.5 (range 9-33) and 10 days (range 7-51), respectively. As expected, GF occurred more frequently in children with disorders known to be associated with an increased GF risk (i.e., HLH, thalassemia, SAA or osteopetrosis) (see also Figure 1A). Three children (4%) experiencing GF died because of infectious complications before retransplant. Sixteen of the 22 patients with either primary or secondary GF were successfully retransplanted (2 with a mismatched unrelated cord blood unit, the other having received a second TBdepl-haploHSCT from either the same donor or the other parent). Since 3 other patients died [all because of infectious complications, 2 due to disseminated adenovirus infection and 1 to CMV pneumonia)], TRM is 7.8% (95% CI 1.6-13.7). Eighteen patients experienced acute GVHD of any grade, the cumulative incidence of this complication being 22% (95% CI 13.5-31.8); 10/18 patients developed grade II acute GVHD (no patient developed grade III or IV aGVHD), this resulting into a cumulative incidence of 12.9% (95% CI 6.6-21.4). Only one patient at risk developed mild chronic GVHD. Twenty-two and 7 patients developed clinically-relevant (i.e., with a viral load &amp;gt; 1000 copies/ml and/or requiring specific antiviral-treatment) CMV and adenovirus infection, respectively, at a median time of 4 (range 0-16) and 1 (range 1-4) weeks from HSCT. Time averaged area under the curve (i.e., viral burden under the curve/weeks at risk for infection) for CMV and ADV are reported in Figure 1B. With a median follow-up of 36 months (range 2 - 110), the 5-year probability of overall survival and event-free survival for the entire cohort of patients is 92.1% (95% CI 83.3-96.4) (Figure 1C) and 68.1% (95% CI 56.4-77.2), respectively. Considering the 16/22 given a successful 2nd allograft, the 5-year disease-free survival is 88.4% (95% CI 78.9-93.8). Details on reconstitution of CD3+, CD4+ and CD8+ lymphocytes are reported in Figure 1D. Conclusions: TBdepl-haploHSCT is an effective option for children with different NMD. GF (either primary or secondary) is a challenging problem in a sub-group of patients at risk (i.e., those with HLH, thalassemia, SAA or osteopetrosis): thus, new strategies to overcome this problem are desirable. However, a second transplant is able to rescue most of these patients. Prompt availability of this type of transplant, limiting infectious risk, low incidence of both acute and chronic GvHD preserving a good quality of life in patients makes this strategy an attractive choice in patients with NMD. Figure 1 Disclosures Merli: Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Sanofi-Genzyme: Honoraria; Atara Therapeutics: Honoraria. Algeri:BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; Atara Therapeutics: Membership on an entity's Board of Directors or advisory committees. Locatelli:Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Comparison of Outcomes after Haploidentical Relative and HLA Matched Unrelated Donor Transplantation with Post-Transplant Cyclophosphamide Containing Gvhd Prophylaxis Regimens

Comparison of Outcomes after Haploidentical Relative and HLA Matched Unrelated Donor Transplantation with Post-Transplant Cyclophosphamide Containing Gvhd Prophylaxis Regimens

Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Haploidentical stem cell transplant with post-transplantation cyclophosphamide and mini-dose methotrexate in children

BackgroundHaploidentical stem cell transplantation (haplo‐SCT) is an option for patients without human leukocyte antigen‐matched related or unrelated donor. Post-transplantation cyclophosphamide (PTCy) is an effective method of graft versus host disease (GVHD) prophylaxis and permits the use of T‐cell replete grafts in settings were ex vivo manipulation is not feasible. MethodsA retrospective study among patients younger than 18 years, with a history of hematologic malignancies who underwent haplo-SCT between 2012 and 2016. All patients received a preparative regimen of fludarabine, busulfan, and 400 cGy total body irradiation or melphalan. Post-transplant GvHD prophylaxis consisted either of PTCy (50 mg/kg on Days + 3 and + 4) and cyclosporine (CSA) plus mycophenolate (MMF) (15 mg/kg/dose, thrice daily, per os), or mini-dose methotrexate (MTX; 5 mg/m2 dose) on Days + 5, +7, +10, and + 15. ResultsA total of 52 children were included, whose median age was 9 years (interquartile range, 4.9–14; range, 1.2–17 years), and 63% were males. The most common complications were cytomegalovirus reactivation (57%) and hemorrhagic cystitis (36%). The acute GVHD prophylaxis was PTCy, CSA, and mini-dose MTX in 42 (81%) patients, and 10 (19%) patients received PTCy, CSA, and MMF. The cumulative incidence of acute GvHD II–IV, acute GvHD III–IV, and chronic GvHD were 42%, 8.5%, and 19%, respectively. Grades I–IV acute GvHD occurred in 100% of the patients who received prophylaxis with CSA and MMF, and 62% who received CSA and mini-dose MTX (p = .055). The transplant-related mortality at 100 days was 18%. The 5-year overall and event-free survival were 59% and 57%, respectively. ConclusionsHaplo‐SCT with PT/Cy can be an available, safe, and feasible option for children with hematologic malignancies; meanwhile, the use of mini-dose of MTX was associated with lower rates of acute GVHD. However, our results require further support from prospective randomized studies to improve the efficacy of this prophylactic strategy.

Safety and Efficacy of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: The programmed-death 1 blockade with nivolumab demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with acceptable toxicity profile. However, most of the patients treated with immune checkpoint inhibitor (CPIs) will eventually progress on this therapy. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. Therefore, allo-HSCT is a consideration for selected patients with HL after treatment with CPIs. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT. Patients and methods: We retrospectively evaluated the results of allo-HSCT in 22 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019 at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State Pavlov Medical University (CIC 725). All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and post-transplant cyclophosphamide-based GvHD prophylaxis (PTCy). Patients received immune checkpoint inhibitors before allo-HSCT as a single-agent nivolumab or in combination with brentuximab vedotin or chemotherapy. The best response to PD-1 therapy was a complete response (CR) in 9 patients, partial response in 5 patients, 5 patients received transplant during the disease progression and 3 patients were transplanted in indetermined response according to the LYRIC. Patients received a median of 20 (range, 6-32) cycles of a PD-1 inhibitor. The median time from the last dose of anti-PD-1 therapy to HSCT was 83 days (range, 50-350). Results: At the time of analysis, median follow-up was 14 months (range, 1-26 months). Ninety one percent of patients engrafted. One patient had primary graft failure and one died on the day of the haploidentical graft transfusion due to cytokine release syndrome. The 1-year OS and EFS were 91% and 78% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 9% and 9% respectively.Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. Both patients remain alive. 4/20 of the engrafted patients developed grade 2 GvHD and all responded to steroids. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%, including 3 patients with severe, steroid-refractory cGVHD. There were no other immune-related adverse events. No cases sinusoidal obstruction syndrome was observed Conclusions: Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. We suggest that prior PD-1 blockade should not be considered a contraindication to HSCT in patients with relapsed and refractory Hodgkin lymphoma. severe The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases. The time between anti-PD-1 therapy and allo-HSCT and PTCy is likely to be important in the successful outcome of the transplant. Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants; BMS: Other: Travel grants.

Improved Outcomes for Patients Receiving High-Doses of IL-21 Ex Vivo Expanded NK Cells after Haploidentical Transplantation (haploSCT): Long-Term Follow-up of a Phase 1/2 Clinical Trial with Comparison to CIBMTR Controls

Background: Disease relapse following allogeneic stem-cell transplantation remains unacceptably high and there is an urgent need for new therapies that decrease relapse rates and improve survival post-transplant. Natural killer (NK) cells have potent antitumor effects, particularly those expended with mb-IL21 from peripheral blood. Preliminary data from a phase-1 dose-escalation study of up to 1x108 NK cells/Kg/dose and multiple dosing yielded promising results and a favorable safety profile (Ciurea SO.Blood.2017;130:18657). This report presents long-term follow-up from a phase-1/2 clinical trial in patients with high-risk myeloid malignancies (AML/MDS/CML) (clinicaltrials.gov NCT01904136) and a comparison with CIBMTR controls. Methods: Patients received conditioning with fludarabine 160 mg/m2, melphalan 140 mg/m2 and 2GyTBI, post-transplant cyclophosphamide-based GVHD prophylaxis and bone marrow graft from a haploidentical donor. Ex vivo expanded NK cells were generated from peripheral blood mononuclear cells of the same donor with a K562 feeder cells expressing mb-IL21 and 41BB and infused fresh on Day-2, and cryopreserved on Day+7 and +28 (up to Day+90). 1x108/Kg/dose was chosen for the phase 2 trial. An independent matched-pair analysis was done using controls from the CIBMTR database stratified by conditioning intensity. Results: 24/26 patients treated to date were evaluable (one short follow-up and one excluded as ineligible). 80% (19/24) of patients received all 3 doses of NK cells. The median age was 45 years (range 18-59), median follow-up was 43.6 months (range 15.1-60.9). Thirteen patients (54%) were females. 5 patients had donor-specific anti-HLA antibodies (DSA). The median HCT-CI was 2 (range 0-8), 12 patients (50%) had HCT-CI&amp;gt;3. 17 patients (72%) had AML/MDS and 7 (28%) advanced CML. Of AML/MDS patients, 10 (59%) had high-risk cytogenetics, 7 (41%) had measurable residual disease, 9 (53%) had intermediate/adverse-risk ELN2017 and 5 (29.4%) had primary induction failure. No infusion reactions or significant adverse events were observed to date. All patients (100%) achieved engraftment after a median of 19 days (range 14-42). The cumulative incidence (CI) of grade 2-4 aGVHD was 29.2% at Day100 and 41.7% at 1-year post-transplant. Only one patient developed severe grade 3-4 aGVHD and one patient had extensive cGVHD. Only one patient relapsed (a patient with DSA who did not receive desensitization prior to transplantation), 1-year CI of relapse was 5.9%. The CI of TRM at 1-year for patients without DSA was 21%. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 3-year PFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9% for patients without DSA, respectively (Figure 1). One-year and 3-years GRFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9%, respectively. An independent matched-pair analysis (at least 1:1) was conducted by CIBMTR after the first 18 patients treated on study in 07/2018 with RIC (N=57) or MAC (N=61) controls. The relapse was 1/18 vs 25/57 for RIC (p=0.037) and 15/61 for MAC (p=0.07), while the 1-year PFS was 82% vs 49% for RIC and 64% for MAC (p=0.21) (Figure 1). Updated results of this analysis will be presented at the meeting. Conclusions: Results from this long-term follow-up analysis confirm very low relapse rate and excellent GRFS after haploSCT for patients treated with high-doses of NK cells expanded with mbIL21 stimulation. A prospective multi-center phase 2 BMTCTN study will evaluate the safetly and efficacy of high doses of NK cells for the prevention of relapse in patents with AML/MDS receiving haploSCT. Figure 1 Disclosures Ciurea: Miltenyi: Research Funding; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Bashir:Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Lee:Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties, Research Funding.

1689. Active, Invasive Fungal Infection, and Hematopoietic Cell Transplantation (HCT) in Chronic Granulomatous Disease (CGD): Presentation, Procedure, and Outcomes

BackgroundIndividuals with CGD develop invasive fungal infections which are often refractory to medical therapy. Disease caused by Aspergillus nidulans (An), Scedosporium apiospermum (Sa), and Aspergillus viridinutans (Av), can be fatal due to involvement of structures contiguous to the primary pulmonary infection. Protocols for managing an active fungal infection during HCT are lacking. Here we describe 5 patients transplanted with active fungal infection and the treatments ancillary to HCT that led to successful outcomes.MethodsFour males and one female underwent peripheral blood HCT utilizing 3 different transplant platforms. Granulocyte transfusions (GCT) were used in 4 cases.ResultsAntifungal treatment and transplant outcomes are reported in Table 1. Patients 1 (Figure 1) and 4 (previously reported) had Sa infection of the lung and spine and lung and pericardium, respectively. Patients 2 (Figure 2) and 5 had An pneumonia with spinal and sternal involvement, respectively. Patient 3 had Av pneumonia involving the lower lung and diaphragm (Figure 3). The transplant protocol was modified to include a high stem cell dose to facilitate engraftment and post-transplant cyclophosphamide GVHD prophylaxis. No GCTs were used proximal to or during HCT due to the development of antineutrophil antibodies.ConclusionActive fungal infection can be managed during HCT. Combination therapy (GCTs and antifungals) lessened the burden of disease prior to and during HCT. All patients had clinical resolution of their infection post-HCT and successful engraftment. Bone disease stabilized post-HCT and remineralization occurred. One patient was successfully transplanted without GCT and its potential complications.The authors have no conflicts to report. Disclosures All authors: No reported disclosures.