Unrelated Donor Grafts Research Articles

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide Expedites Donor-Derived Immune Reconstitution in a Pediatric Severe Aplastic Anemia Cohort

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in >90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery. In a phase III clinical trial, we treated three cohorts of pediatric (age </=25 years) patients with SAA requiring alloHCT: MUD, MSD, and HAPLO. The MUD cohort included n=15 recipients of 7-8/8 HLA-matched unrelated donor grafts (n=5 7/8, n=10 8/8) with median age 14 years (range 2-17 years), following cyclophosphamide (Cy) 50 mg/kg, fludarabine (Flu) 200 mg/m 2, rabbit anti-thymocyte globulin (rATG) 9 mg/kg total dose rabbit and low dose total body irradiation (TBI) at 200 cGy. The MSD cohort included n=9 recipients of 8/8 HLA-matched sibling donor grafts with median age 15 years (range 12-24 years), following Cy 200 mg/kg and 9 mg/kg rATG. The HAPLO cohort included n=4 recipients of 4/8 HLA-matched related donor grafts with median age 8.5 years (range 2-21 years) following Cy 29 mg/kg, Flu 150 mg/m 2, 9 mg/kg rATG, and low dose TBI at 200 cGy. GvHD prophylaxis consisted of 30 days of mycophenolate mofetil, and 100 days of a calcineurin inhibitor (followed by an 8-10 week taper), with the HAPLO cohort additionally receiving post-transplant Cy (PTCy) 50 mg/kg/day on days +3 and +4. Peripheral blood lymphocyte counts and peripheral blood and bone marrow donor chimerism were evaluated on days +100, +180 and +365. Recipient characteristics were largely equivalent between cohorts, with 43% receiving IST prior to HCT. Clonality was overrepresented in the HAPLO cohort (2 of 4, 1 with monosomy 7 myelodysplastic syndrome and 1 with a large PNH clone), with only 2 of 15 in the MUD and none in the MSD cohorts. Active controlled infections at the time of HCT were additionally overrepresented in the HAPLO cohort, with disseminated pseudomonas in 1. The MUD cohort had 1 with Rhizopus invasive sinusitis (none in the MSD cohort). Achievement of neutrophil engraftment was statistically significantly delayed in the HAPLO cohort at a median of 17 days compared to 12 for MSD and 14 for MUD, p=0.004), however there were no episodes of primary or secondary graft failure. With only a single late death from intracranial hemorrhage in the MUD cohort, OS was equivalent at 2 years (100% in MSD and HAPLO cohorts, 93.3% in MUD). GvHD rates were low with only 1 (MUD) experiencing grade II acute GvHD, and 1 (MUD) experiencing mild chronic GvHD. Immune reconstitution varied by cohort with statistically significantly greater CD3 peripheral blood donor chimerism (p<0.001) as well as CD4 (p=0.04) and CD8 (p=0.03) T cell counts over time for the HAPLO recipients (CD3 chimerism in Fig 1, CD4 count in Fig 2; 2-way ANOVA fixed effects model). Considering a CD4 >200 cell/uL as clinically meaningful, we assessed the proportion of each cohort achieving this milestone at each timepoint. While each cohort had an increase in proportion achieving CD4>200 over time, the HAPLO cohort reached 50% with CD4 >200 at day +100, compared to 11% MUD and 0% MSD (p=0.09). At day +180, the proportion with CD4 >200 were 36% MUD, 25% MSD and 75% HAPLO (1 yr: 90% MUD, 100% MSD and HAPLO). Donor availability remains a challenge to successful transplant for patients with SAA, and haploidentical matches overcome donor limited accessibility. PTCy as GvHD prophylaxis is associated with low incidences of graft failure and severe GvHD. While PTCy might be anticipated to inhibit donor T cells and immune reconstitution, our data, albeit limited by small cohorts, demonstrates superior and more efficient CD3 donor engraftment and CD4 T cell count recovery following HAPLO HCT with PTCy compared to non-PTCy based MUD and MSD cohorts.

Impact of allogeneic stem cell transplantation on thyroid function.

Primary hypothyroidism is a main endocrine complication after allogeneic stem cells transplantation (allo-SCT) in children, but in adults data on post-SCT hypothyroidism are limited. The aims of this observational, cross-sectional study were to assess the prevalence of hypothyroidism in adult allo-SCT recipients according to time from transplantation, and to identify risk factors. One hundred and eighty-six patients (M 104; F 82; median age 53.4years) who underwent allo-SCT between January 2010 and December 2017 were enrolled and divided into three groups, according to time from allo-SCT (1-3years; 3-5years; > 5years). Pre-transplant TSH and fT4 levels were available for all patients. After transplantation, TSH, fT4 and anti-thyroperoxidase antibodies (TPO-Ab) were evaluated. After a follow-up of 3.7years, 34 (18.3%) patients developed hypothyroidism, with higher prevalence in females (p < 0.001) and in patients who received matched unrelated donor grafts (p < 0.05). No difference in prevalence was found at different time points. Patients who developed hypothyroidism showed higher rate of TPO-Ab positivity (p < 0.05) and higher pre-transplant TSH levels (median 2.34 µU/ml) compared to those with preserved thyroid function (median 1.53 µU/ml; p < 0.001). Multivariable analysis identified higher pre-transplant TSH levels as a positive predictor of hypothyroidism (p < 0.005). The ROC curve analysis identified a pre-SCT TSH cutoff of 1.84 µU/ml, which can predict hypothyroidism with sensitivity 74.1% and specificity 67.2%. About one out of four patients developed hypothyroidism after allo-SCT, with a greater incidence in females. Pre-transplant TSH levels seem to predict the onset of post-SCT hypothyroidism.

A new beginning: can omidubicel emerge as the next, viable alternative donor source?

Umbilical cord blood (UCB) transplantation (CBT) has been an important alternative donor option for patients lacking matched related donor (MRD) or unrelated donor (URD) grafts. Only 30% of patients with high-risk hematologic malignancies have a human leukocyte antigen (HLA)-identical sibling; subjects without a MRD option are referred for HLA-matched URD selection, or utilize alternative donor sources such as HLA-mismatched URD, UCB, or haploidentical donor grafts. While CBT demonstrates an excellent graft-versus-leukemia (GVL) effect, use of UCB as a graft source is limited due to a lower cell dose that can result in delayed engraftment and an immature immune system with increased infectious risk as a consequence. Together, increased transplant related mortality (TRM) has been associated with UCB allografts. Omidubicel is an ex vivo expanded single cord blood product that has demonstrated rapid engraftment, improved immune reconstitution, and reduced infectious complications in clinical trials. Omidubicel has now been granted U.S. Food & Drug Administration approval to enhance neutrophil recovery and decrease infectious risk. This review will focus on CBT, benefits and barriers to using this alternative donor source, and finally the potential advancements with incorporation of omidubicel in the transplant setting for malignant and non-malignant diseases.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Characterization and Function of Cryopreserved Bone Marrow from Deceased Organ Donors: A Potential Viable Alternative Graft Source

Despite the readily available graft sources for allogeneic hematopoietic cell transplantation (alloHCT), a significant unmet need remains in the timely provision of suitable unrelated donor grafts. This shortage is related to the rarity of certain HLA alleles in the donor pool, nonclearance of donors owing to infectious disease or general health status, and prolonged graft procurement and processing times. An alternative hematopoietic progenitor cell (HPC) graft source obtained from the vertebral bodies (VBs) of deceased organ donors could alleviate many of the obstacles associated with using grafts from healthy living donors or umbilical cord blood (UCB). Deceased organ donor-derived bone marrow (BM) can be preemptively screened, cryogenically banked for on-demand use, and made available in adequate cell doses for HCT. We have developed a good manufacturing practice (GMP)-compliant process to recover and cryogenically bank VB-derived HPCs from deceased organ donor (OD) BM. Here we present results from an analysis of HPCs from BM obtained from 250 deceased donors to identify any substantial difference in composition or quality compared with HPCs from BM aspirated from the iliac crests of healthy living donors. BM from deceased donor VBs was processed in a central GMP facility and packaged for cryopreservation in 5% DMSO/2.5% human serum albumin. BM aspirated from living donor iliac crests was obtained and used for comparison. A portion of each specimen was analyzed before and after cryopreservation by flow cytometry and colony-forming unit potential. Bone marrow chimerism potential was assessed in irradiated immunocompromised NSG mice. Analysis of variance with Bonferroni correction for multiple comparisons was used to determine how cryopreservation affects BM cells and to evaluate indicators of successful engraftment of BM cells into irradiated murine models. The t test (with 95% confidence intervals [CIs]) was used to compare cells from deceased donors and living donors. A final dataset of complete clinical and matched laboratory data from 226 cryopreserved samples was used in linear regressions to predict outcomes of BM HPC processing. When compared before and after cryopreservation, OD-derived BM HPCs were found to be stable, with CD34+ cells maintaining high viability and function after thawing. The yield from a single donor is sufficient for transplantation of an average of 1.6 patients (range, 1.2 to 7.5). CD34+ cells from OD-derived HPCs from BM productively engrafted sublethally irradiated immunocompromised mouse BM (>44% and >67% chimerism at 8 and 16 weeks, respectively). Flow cytometry and secondary transplantation confirmed that OD HPCs from BM is composed of long-term engrafting CD34+CD38-CD45RA-CD90+CD49f+ HSCs. Linear regression identified no meaningful predictive associations between selected donor-related characteristics and OD BM HPC quality or yield. Collectively, these data demonstrate that cryopreserved BM HPCs from deceased organ donors is potent and functionally equivalent to living donor BM HPCs and is a viable on-demand graft source for clinical HCT. Prospective clinical trials will soon commence in collaboration with the Center for International Blood and Marrow Research to assess the feasibility, safety, and efficacy of Ossium HPCs from BM (ClinicalTrials.gov identifier NCT05068401).

Handling of Allogeneic HPC Grafts in European Transplant Centers during the COVID-19 Pandemic - a Survey from the Infectious Diseases and Cellular Therapy & Immunobiology Working Parties of the EBMT

Background: For more than two years, the COVID-19 pandemic has had detrimental impact on medical practices. Because of its intrinsic complexity, the delivery of allogeneic hematopoietic cell transplantation (HCT) in this context represents an enormous challenge. Transplant centers have adapted promptly and developed strategies to enable safe HCT, by introducing significant changes in their procedures, e.g. through changes in donor types and an unprecedented use of cryopreservation for allogeneic hematopoietic progenitor cell (HPC) grafts. Methods: To explore how centers modified their strategies in terms of donor selection and implementation of new procedures (e.g. SARS-CoV-2 test strategy, cryopreservation), a 14-item survey was developed by the Infectious Disease (IDWP) & Cellular Therapy & Immunobiology (CTIWP) working parties of the European Society for Blood and Marrow Transplantation (EBMT). The survey was sent to 509 EBMT-affiliated allogeneic HCT in Q2, 2011 and re-opened between January 31st and March 18th, 2022 to also cover changes during to the infection period with the Omicron variant. Results: One hundred thirty-five of 509 (27%) centers from 31countries responded. Seventy-four percent of centers introduced COVID-19 mitigation measures for their donors (e.g. physical and social distancing) to minimize the risk of infection. Thirty-four percent of centers changed their donor search strategy, and favored recruitment of related haploidentical donors over unrelated donors (URD). In addition, 33% and 50% of centers searched for a backup donor in the related and URD settings, respectively. Only 10 (7.4 %) of centers resorted to cord blood (CB) as an alternative source to URD. Of these, four centers where pediatric centers and three, pediatric and adult transplant centers. Before COVID-19, only ten of 135 centers (7.4%) were routinely cryopreserving HPC products, whereas this percentage increased to 90% (122/135) during the pandemic. In details, 84/122 (69%) of centers cryopreserved both related and URD grafts, 34 (28%) only URD and 4 (3%) related grafts only. One hundred twenty centers responded during the re-opening of the survey to cover the situation during the Omicron wave. Of those, 78% were still considering graft cryopreservation, whereas 18/26 (70%) of centers not using cryopreservation during the Omicron wave used it before that period. In the majority of centers, changes in policies were introduced based on EBMT recommendations (88/117; 75%) and/or national guidelines (73/117; 62%). Bone marrow (BM) grafts were avoided by 52 (39%) centers (possibly because of the notorious low recovery percentage of cryopreserved BM progenitor cells). In the study period, a total of 4,443 related and 4,586 URD transplants have been reported. Of these transplants, 62% (n=2,748) related and 71% (n=3,254) of URD grafts have been cryopreserved pre-emptively and infused in the vast majority of cases. Sixty-four (2.3 %) related and hundred-eight (3.3 %) URD cryopreserved products have not been infused during the observation period. Release criteria for cryopreserved products in terms of COVID-19 were based on a negative SARS-CoV-2 test (not further specified) in 58/121 (48%), interview of the donor (medical history) in 4/121 (3%), and both in 38/121 (31%) of centers. Eighty-eight centers reported on their test strategy for related donors (multiple answers possible). A SARS-CoV-2 test was performed during check-up in 43% (38/88), before HPC mobilization in 63% (55/88) and before HPC collection in 41% (36/88) centers. Test strategies for URD were not covered by the survey. Conclusions: These data are limited by the low number of respondents, but show a historical increase in cryopreservation of allogeneic HPC grafts during the first three waves of the SARS-CoV-2 pandemic, more in URD than in related donor grafts. The use of BM decreased, and CB grafts were not used as an alternative at most centers. A significant proportion of cryopreserved products (2.8%) were not infused. The reason for this is under investigation. The clinical impact of allogeneic cryopreserved HPCs has to be further analyzed in a larger cohort of patients.

Impact of Cryopreservation of Peripheral Blood Stem Cells (PBSC) in Transplantation from Matched Unrelated Donor (MUD).

Background: Cryopreservation of PBSC for allogenic hematopoietic stem cell transplantation (allo-HSCT) was implemented due to the current Coronavirus 2019 pandemic. The impact of match unrelated donor (MUD) graft freezing on the outcome of allo-HSCT in terms of hematological recovery, graft versus host disease (GVHD), and survival are still controversial. Methods: In this study, we compared graft composition, clinical characteristics, and outcome of 31 allo-HSCT from MUD cryopreserved PBSC (Cryo Group) with 23 matched-pair allo-HSCT from fresh MUD PBSC (Fresh Group) performed in our center between January 2020 and July 2021. Results: No significant differences were recognized in clinical characteristics of patients, donors, and transplants between the Cryo and Fresh groups except for a better prognostic comorbidity index (HCT-CI) of the Cryo group. In the Cryo Group, the median time from apheresis to cryopreservation was 46.0 h (range 23.8–53.5), while the median time from cells collection and reinfusion was 13.9 days (range 5.8–28.1). In the Fresh Group, median time from apheresis to reinfusion was 35.6 h (range 21.4–51.2). The number of viable (7-AAD negative) CD34+ cells per kg patient infused was significantly lower in the Cryo Group (5.2 ± 1.9 × 106/kg vs. 7.0 ± 1.3 × 106/kg; p < 0.001). Indeed, there was a 36% (11–70) median loss of viable CD34+/kg cells after freezing. All patients engrafted: median time to neutrophil engraftment (>0.5 × 109/L) was 13.5 days (range 12–15) for Cryo Group and 14 days (range 13–16) days for Fresh Group (p = 0.522), while the median time to platelet engraftment (>20 × 109/L) was, respectively, 14 (range 12–18) and 15 (range 12–17) days (p = 0.904). The incidence of grade ≥ 2 acute GVHD was similar in the two groups (56.5% Cryo Group vs. 60.0% Fresh Group; p = 0.832) and no differences in terms of OS (p = 0.090), PFS (p = 0.200) and TRM (p = 0.970) were observed between the Cryo and Fresh groups. Conclusions: In our series, no differences between the Cryo and Fresh groups were found in engraftment, grade ≥ 2 acute GVHD incidence, OS, PFS, and TRM despite a lower CD34+ infused dose in the Cryo Group. Frozen PBSCs could be considered a safe option also for allo-HSCT from MUD but a higher amount of PBSC should be collected to warrant an adequate viable CD34+ post-thawing.

Vorinostat Combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-Term Study Outcomes

Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v. busulfan (Bu) as part of conditioning chemotherapy has been shown to be effective in controlling disease relapse; however, disease relapse remains a major cause of death following allo-HSCT. This study was conducted to determine the long-term outcomes of vorinostat with i.v. Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard i.v. Bu/Flu/Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high-risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Fifty-eight patients (85%) were in morphologic complete remission at time of transplantation, and 38 (56%) received a matched unrelated donor graft. Over the median follow-up of 37.6 months, 29 of the 68 patients died (43%), and the nonrelapse mortality (NRM) rate was 22% (n=15). The median overall survival and median NRM were not reached. Nineteen patients (28%) experienced disease progression. The median progression-free survival was 36.8 months. Thirty-seven patients (57%) developed grade II-IV acute graft-versus-host disease (GVHD), and 20 patients (31%) developed chronic GVHD. Our results suggest a lack of benefit from adding a short course of vorinostat to i.v. Bu/Flu/Clo conditioning regimens for leukemia patients undergoing allo- HSCT.

HLA-Haploidentical Family Donors: The New Promise for Childhood Acute Lymphoblastic Leukaemia?

Allogeneic haematopoietic stem cell transplantation (HSCT) is indicated in children with high-risk, relapsed or refractory acute lymphoblastic leukaemia (ALL). HLA-matched grafts from cord blood and stem cell repositories have allowed patients without suitable sibling donors to undergo HSCT. However, challenges in procuring matched unrelated donor (MUD) grafts due to high cost, ethnic disparity and time constraints have led to the exponential rise in the use of stem cells from human leukocyte antigen (HLA)-haploidentical family donors. Whilst HLA-haploidentical HSCT (hHSCT) performed in adult patients with acute leukaemia has produced outcomes similar to MUD transplants, experience in children is limited. Over the last 5 years, more data have emerged on hHSCT in the childhood ALL setting, allowing comparisons with matched donor transplants. The feasibility of hHSCT using adult family donors in childhood ALL may also address the ethical issues related to selection of minor siblings in matched sibling donor transplants. Here, we review hHSCT in paediatric recipients with ALL and highlight the emergence of hHSCT as a promising therapeutic option for patients lacking a suitable matched donor. Recent issues related to conditioning regimens, donor selection and graft-vs.-host disease prophylaxis are discussed. We also identify areas for future research to address transplant-related complications and improve post-transplant disease-free survival.

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Early Cytomegalovirus Reactivation after Allogenic Bone Marrow Transplantation Is Associated with the Loss of Recipient-Derived Humoral Immunity and Is Reduced By IL-6 Inhibition

Background:Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019).Methods and Results:In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A).Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells.To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD.We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant.Conclusion:These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. [Display omitted] DisclosuresBoeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

Cryopreservation of Allogeneic Hematopoietic Cell Grafts Did Not Adversely Affect Early Post-Transplant Survival during the First Six Months of the COVID-19 Pandemic

▪Introduction: During the COVID-19 pandemic, concerns regarding travel logistics and donor safety necessitated a substantial increase in the use of cryopreserved hematopoietic stem cell (HSC) grafts from both related (RD) and unrelated donors (URD) to ensure patients have a graft available prior to the start of conditioning for hematopoietic cell transplantation (HCT). However, pre-pandemic data beyond single center or small multi-center reports are lacking to reassure clinicians that cryopreservation of allogeneic grafts does not adversely impact post-HCT outcomes including hematopoietic engraftment and overall survival (OS). The Center for International Blood and Marrow Transplant Research (CIBMTR) has recently published three retrospective analyses of outcomes in recipients of cryopreserved compared to fresh grafts administered prior to the pandemic. Results have been conflicting and reasons for receipt of cryopreserved grafts were not routinely collected, rendering interpretation of the impact of cryopreservation on clinical outcomes problematic. Since the pandemic provided a unifying rationale (including mandatory cryopreservation required by the National Marrow Donor Program (NMDP) and other major registries) for the majority of patients to receive cryopreserved allografts, we sought to evaluate early post-HCT clinical outcomes in patients reported to the CIBMTR database who received a first allogeneic HCT using cryopreserved grafts from March through August 2020.Methods: Key study endpoints were hematopoietic engraftment and overall survival (OS). We compared these outcomes to those in patients allografted using fresh products transplanted between March through August 2019. Additional patient selection criteria included: 1) recipients in US only, 2) peripheral blood stem cell (PBSC) or bone marrow (BM) grafts, 3) consented to research, and 4) availability of both CIBMTR product infusion and post-HCT day 100 (D100) follow-up form. The Pearson chi-square test was used for comparing discrete variables; the Kruskal-Wallis test was used for comparing continuous variables. Multivariate analysis (MVA) using a Cox proportional hazards model was performed for OS after adjusting for confounders and testing the proportional hazards assumption. Neutrophil engraftment by D28 and platelet engraftment by D100 were analyzed using multivariate logistic regression.Results: This study included 959 and 2,499 recipients of cryopreserved and fresh products, respectively. Patient characteristics are presented in Table 1. Recipients of cryopreserved grafts were older, more likely to receive URD grafts, PBSC as the graft source and post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. They received lower infused PBSC and BM cell doses. Due to differences in duration of follow-up between the cohorts, follow up for the OS analysis was censored at Days 100 and 180. MVA results are presented in Table 2. No impact of cryopreservation on OS at either D100 (HR 0.93, p=0.72) or D180 (HR 1.10, p=0.34) post HCT was detected (see also Figure 1). When we performed the MVA for OS limiting the analysis to URD recipients only, the results were unchanged. Median time to neutrophil and platelet engraftment were both delayed by 1 day in recipients of cryopreserved grafts (16 vs. 15 days and 21 vs. 20 days, respectively) but there was no difference in the risk of primary graft failure by D28 (OR 1.38, p=0.96). Some delay in D100 platelet engraftment was observed in recipients of cryopreserved grafts (OR 0.67, p<0.005). There were no interactions identified between donor or graft type for OS or engraftment. Other important clinical outcomes such as secondary graft failure, acute GVHD, and early relapse are being analyzed and will be included at the time of abstract presentation.Conclusion: The shift in clinical practice to cryopreserved products necessitated during the pandemic did not adversely impact early post HCT OS or risk of primary graft failure. We caution that follow up is short and it will be critical to follow this cohort and subsequent recipients of cryopreserved grafts for much longer periods to determine the ultimate impact of cryopreservation on outcomes. Nevertheless, this large multi-center study will be useful to inform clinical decision making both during and following the pandemic. [Display omitted] DisclosuresDevine: Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment. Stefanski: Novartis: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Polycythemia Vera or Essential Thrombocythemia Transformed to Myelofibrosis or Acute Myeloid Leukemia: a Single Center Experience

In myelofibrosis (MF) which median overall survival (OS) is about six years allogeneic hematopoietic stem cell transplantation (HSCT) is the sole therapeutic procedure with a curative potential. Recent retrospective and prospective studies have reported that MF patients who receive a related donor graft have a clinical outcome better than that of patients who receive an unrelated donor graft. Thus, in order to verify this issue and identify patient- and HSCT-specific variables that influence this different clinical outcome we conducted this retrospective analysis in 31 pts with chronic and advanced-phase MF who underwent HSCT at our Institution. This series included 6 (19.3%) females and 25 (80.7%) males with a median age of 54.9 years (range 30.2-63.8) whose median follow-up was 1.7 years (range 0-11.8). Fifteen pts were classified as primary MF, 9 as secondary MF and 7 as AML post-MF. From a molecular point of view, 17 pts presented the V617F JAK2 mutation, 7 a CALR mutation, 2 a MPL mutation and 2 none of these mutations (“triple negative”). Eleven pts (35.5%) received the transplant from an identical sibling, 17 (54.8%) from a matched unrelated donor, 3 (9.7%) from a mismatched relative. The graft source was the bone marrow in three pts (9.7%) and the peripheral blood (PBSC) in 28 (90.3%). The median number of CD34+ cell infused was 7.3x106/kg. Neutrophil engraftment occurred in 27 pts (87.0%) at a median time of 16.5 days (range 11-34) and platelet engraftment occurred in 21 pts (67.8%) at a median time of 17 days (14-98). In these pts splenomegaly was associated with a significant delay in neutrophil and platelet recovery. Considering the remaining 4 pts, all with a relevant splenomegaly, 2 did not engraft and 2 experienced an autologous reconstitution. Considering all the cohort, death occurred in 13 pts (41.9%) and the 1-year cumulative incidence of nonrelapse mortality (NRM) was 32.9% (95& CI: 16.3%-50.6%). The 3-year overall survival (OS) was 59.4% (95% CI: 38.1%-75.5%) and the 5-year OS was 47.2% (95% CI: 25.3%-66.4%). The disappearance of the molecular marker present at the onset of the disease on subsequent molecular tests occurred in 10 pts (32.2%) who are still in clinical and molecular complete remission. Relapse occurred in 5 pts (16.1%) and 6-month and 3-year cumulative incidence of relapse (CIR) were 3.5% (95% CI: 0.3%-15.1%) and 19.3% (95% CI: 7.0%-36.1%). Eight pts (27.6%) experienced acute GVHD within 100-day (95% CI: 13.1%-44.3%) and 12 (38.7%) developed chronic GVHD which 6-month, 1-year, 3-years cumulative incidences were 25.2% (95% CI 11.1%-42.2%), 33.1% (95% CI 16.6%-50.6%) and 48.2% (95% CI: 27.3%-66.3%). When the clinical outcome of related donor graft group was compared to that of unrelated donor graft group, the 1-year NRM was 18.2% (95% CI: 2.9%-44.2%) for the first group of pts versus 45.5% (95% CI: 20.5%-67.6%) for the second group (p=0.07); median OS and median progression-free survival (PFS) were not reached for the first group of pts versus 2.2 and 0.7 years respectively for the second group of pts (p=0.05 and p=0.05). In addition, a borderline significance in 2-year OS was noted: 81.8% (95% CI 44.7%-95.1%) versus 51.0% (95% CI: 25.4%-71.8%) (p=0.071). The 100-days cumulative incidence of grade II-IV acute GVHD was 10% (95%CI: 0.6%-35.8%) for the first group of pts versus 43.8% (95% CI: 19.8%-65.6%) for the second group with a similar incidence of chronic GVHD. Re-transplantation of the two pts with graft failure did not result in hematopoietic reconstitution as was followed by rejection of the PBSC infused. One pt with an autologous reconstitution achieved a full donor chimerism after the third transplant from a haplo-identical donor. In conclusion, this retrospective study confirms that HSCT is a potentially curative option for MF patients despite the high relapse incidence and non-relapse mortality. DisclosuresNo relevant conflicts of interest to declare.

Towards Functional Immune Monitoring in Allogeneic Hematopoietic Stem Cell Transpant Recipients

Introduction: Serious viral infections that occur as a consequence of poor or delayed endogenous immune reconstitution are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In the post HSCT setting immune reconstitution is currently evaluated by phenotypic profiling to assess lymphocytes subset recovery over time. However, these studies fail to assess either the functional capacity or antigen specificity of the reconstituting cells. We hypothesized that utilizing functional assays in combination with phenotypic assessments would enable the rapid and accurate risk-stratification of allogeneic HSCT recipients into those whose endogenous immunity was sufficient to deal with viral challenge versus those requiring clinical intervention with targeted antiviral therapies.Methods: To evaluate phenotypic and functional immune response post-HSCT, we performed a prospective study in pediatric HSCT recipients where we monitored the frequency (by flow cytometry) and function of T cells directed against immunogenic antigens for the most common viruses detected post-transplant (CMV, EBV, HHV-6, Adenovirus, BK virus) using IFNg ELIspot assays. Assessments were performed at least monthly for up to 6 months post-transplant and weekly in patients who developed a viral reactivation post-HSCT.Results: To date we have enrolled 23 allogeneic HSCT recipients, ages 3 to 16 years. Of these, 9 received a matched related donor graft (MRD), 13 received a matched/mismatched unrelated donor graft (MUD/MMUD) and 1 patient received a cord blood (CB) donor graft. All patients underwent myeloablative conditioning for a spectrum of underlying malignant (ALL - 10, AML - 4, MDS - 2) and non-malignant diagnoses (Hemoglobinopathy - 3, SAA/Marrow failure - 4, immune deficiency - 1). Based on donor type used for transplant and underlying diagnosis, 15 of these patients received T-cell depleting conditioning regimens using Alemtuzumab for in-vivo T-cell depletion while 8 patients did not receive T-cell depletion as part of their conditioning regimen. In patients who received a non-T-cell depleting conditioning regimen immune reconstitution was rapid with recovery to a median of 524 CD3+ T cells counts/µL by day 30 post-transplant (range 333-1711) [months 2, 3, 4, 5, 6 of 1090, 1382, 2184, 2077, 2481 cells/µL, respectively; n=8]. In contrast, for patients that received T-cell depleting conditioning regimens, reconstitution was significantly slower with median CD3 T-cell counts/µL of 0 (range: 0-249) by day 30 and recovery to 500 cells/µL occurring on or after month 5 post-transplant (months 2, 3, 4, 5, 6 of 19, 138, 147, 516, 836 cells/µL, respectively; n=15). In total, we detected 32 episodes of viral infection/reactivation [CMV (n=12), EBV (n=10), HHV-6 (n=5), Adenovirus (n=3) and BK (n=2)]. Twenty four occurred in our T-cell depleted transplant recipients, while 8 in non-T-cell depleted transplant recipients. By measuring functional virus-specific T cell recovery by IFNg ELIspot assays, we were able to identify infections that could be endogenously controlled (n=23) and those that could not (n=9). This allowed for rapid intervention with additional antiviral agents in patients that could not control their infections. Of these, 3 received ‘off the shelf’ CMV-specific T cells to treat persistent and drug refractory CMV viremia.Conclusion: Screening for virus-specific T-cell responses with IFNg ELIspot assays allowed us to risk-stratify and tailor therapy for 23 pediatric HSCT recipients with viral infection/reactivation. Our encouraging results warrant further exploration in a larger cohort of patients. DisclosuresLeen:ViraCyte LLC: Equity Ownership.

Graft-Vs-Leukemia Effect in Acute Lymphoblastic Leukemia: Mild Acute Graft-Vs-Host Disease Protects Against Relapse and Improves Survival after Allogeneic Transplantation: A CIBMTR Analysis

Introduction: Graft-versus-host disease (GVHD) associated with allogeneic donor hematopoietic cell transplantation (alloHCT) provides protection against leukemia relapse, but more severe GVHD may be detrimental and increase mortality.Methods: We examined the net effect of GVHD on overall survival (OS) of 5215 patients with acute lymphoblastic leukemia (ALL) treated with alloHCT in 232 centers between the years 2000 and 2014 and reported to the CIBMTR. We examined three cohorts: a) adults in complete remission (CR1 and 2; n=2593) treated with myeloablative (MAC) or reduced intensity conditioning (RIC), b) pediatric ALL aged 1-18 in CR1/CR2 (n=1619) treated by MAC and c) patients of all ages with advanced ALL (active disease or CR≥3; n=1003) who received MAC. Transplant outcomes were compared by GVHD presence and severity: no GVHD (reference group), grade I-II acute GVHD (aGVHD), grade III-IV aGVHD, plus each with or without chronic GVHD (cGVHD).Results: Patients had B-cell (80%) or T-cell ALL (15%); 26% were Ph+. MAC was used in most patients (93%), followed by HLA-identical sibling (28%), adult HLA-matched unrelated donor (31%) or umbilical cord blood (24%) grafts. 28% received in vivo T cell depletion. Cumulative incidence of relapse and 5-year overall survival (OS) in the three cohorts are shown in table. In multivariate analysis adjusted for age, white blood cell count, donor source, KPS, GVHD prophylaxis and conditioning, aGVHD (both grade I-II and III-IV) and cGVHD yield protection from relapse as compared to no GVHD (HR 0.49-0.69) in both adult and pediatric CR cohorts (Table). Patients with advanced ALL with cGVHD or with grade III-IV aGVHD also had a lower, but still excessive risk of relapse. However, in all 3 cohorts, increased transplant-related-mortality (TRM) accompanied grade III-IV aGVHD (HR 3.91, 3.69, 2.69) and abrogated the protection from relapse resulting in inferior OS (Table). Importantly, adults in CR1/2 with grade I-II aGVHD without cGVHD had a significantly better OS compared to no GVHD (HR 0.83). A similar net survival benefit of grade I-II aGVHD occurred in children in CR1/CR2 (HR 0.76). CGVHD alone or in combination with grade I-II aGVHD augmented protection from relapse (HR varied 0.51-0.67), but had a neutral effect on OS in the two CR cohorts. Patients with advanced ALL had improved OS if they developed cGVHD with or without grade I-II aGVHD.Conclusions: Our data confirm the potent GVL effect of alloHCT in ALL in CR and demonstrate that the net beneficial effect of aGVHD on OS in ALL is confined to patients who experience grade I-II aGVHD and no cGVHD. This favorable net effect extends from pediatric to adult patients who are in remission. Those with advanced disease experience modest survival benefit from cGVHD. Nevertheless, the benefit of relapse protection is abrogated by increased mortality in patients with grade III-IV aGVHD and is weaker in those without any GVHD. Immunity-modulating interventions post-HCT and more effective GVHD therapies may better harness the potential graft-versus leukemia effect in ALL. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Bachanova:Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Pediatric Acute GVHD Grade, Risk Prediction and Response to Upfront Steroids in 370 Children Treated at the University of Minnesota

To better understand the nature of acute GVHD in children, their response to upfront steroid therapy, and to test whether our MN acute GVHD risk score which was developed primarily in adult patients (BBMT , 2015;21:761) demarcates risk in children, we examined the acute GVHD clinical stage, grade and response to prednisone 60 mg/m2 of 370 pediatric patients (median age 7 years, range 0.2-17.95 years) treated at the University of Minnesota (MN) from 1990 to 2016. Underlying diseases included malignancies (53%), inborn errors of metabolism (25%), and other non-malignant diseases (22%). Graft sources included HLA-identical sibling bone marrow or peripheral blood (BM/PB) (n=61), mismatched related BM/PB (n=8), matched unrelated BM/PB (n=104), mismatched unrelated BM/PB (n=65) single umbilical cord blood (UCB; n=97) or double UCB (n=35). The majority (95%) received myeloablative conditioning regimens.Initial GVHD organ involvement was skin only (n=250; 68%), upper and/or lower GI only (n=67;18%), liver only (n=3;1%) or multi-organ (n=50;14%) The maximum initial GVHD stage at the onset of prednisone therapy is shown in the Table. Initially, 307 (83%) patients had grade I-II GVHD, 63 (17%) had severe grade III-IV GVHD, 328 (89%) had MN standard risk GVHD and 42 (11%) had MN high risk GVHD.Overall response (CR+PR) at day 28 was observed in 65% patients with CR in 52% and PR in 13%. Initial GVHD grade did not predict overall response at day 28 (68% for grade I, 67% for grade II, 59% for grade III, and 43% for grade IV, p=0.21). However, as shown in the Figure, MN risk score significantly demarcated day 28 response with 68% standard risk patients achieving CR/PR at day 28 compared to only 48% high risk patients (p<0.01).In multiple regression analysis, the odds of day 28 CR/PR was lower in patients with MN high risk GVHD (Odds ratio [OR] 0.4, 95% CI 0.2-0.8, p=0.01) and in recipients of HLA mismatched unrelated donor grafts (OR 0.3, 95% CI 0.2-0.7, p=0.01). Patients without CR/PR at day 28 had higher transplant related mortality (TRM) at 2 years (56%, 95% CI 46-66%) than patients with CR (25%, 95% CI, 19-32%) or PR at day 28 (23%, 95% CI, 11-35%, p<0.01). Patients with MN high risk GVHD had a 1.6-fold increased risk of TRM (cumulative incidence 47%: (hazard ratio 1.6, 95% CI, 1.0-2.7, p=0.05) compared to MN standard risk acute GVHD (35% 2 year TRM). Risks of TRM were also significantly higher in older patients, recipients of HLA-partial and mismatched adult volunteer URD grafts (but not umbilical cord blood), and in those with non-malignant diseases.When compared to our previously published series of predominantly adult patients, these data demonstrate that pediatric patients with acute GVHD more often have isolated skin involvement, less liver involvement and less multi-organ involvement than adults, yet a similar proportion have MN standard versus high risk GVHD. Importantly, pediatric patients respond to upfront steroid GVHD therapy at a similar frequency as adult patients. It is imperative that children be included in future trials to investigate less toxic therapies for standard risk patients and novel approaches for those with high risk GVHD. As in the adult population, compared to initial GVHD grade, the MN GVHD risk score better demarcates risk of steroid failure and TRM in pediatric patients and should be used for risk stratification in future clinical GVHD trials. [Display omitted] DisclosuresMacMillan:Magenta Therapeutics: Research Funding. Holtan:Incyte: Other: One-time advisory board member.

Intention-to-Treat Analysis of Allogeneic Stem Cell Transplantation for Relapsed/Refractory Peripheral T-Cell Non-Hodgkin Lymphomas: A Large Italian Single-Center Experience

Introduction: Peripheral T-cell lymphomas (PTCL) encompass rare and heterogeneous forms of aggressive non-Hodgkin lymphoma generally associated with dismal clinical outcome. Given the poor prognosis, allogeneic stem cell transplantation (allo-HSCT) has been integrated in the treatment algorithms in the relapsed/refractory setting; however poor response to salvage therapies often hampers the possibility to benefit from this potentially curative approach. We report our institutional experience on the outcome of patients with relapsed PTCL eligible to allo-HSCT in an intention to treat (ITT) analysis.Methods and Results: We identified 108 adult patients with relapsed/refractory PTCL treated at the Istituto Nazionale Tumori from 1992 to 2016. Of these 108 patients, 22 (20%) were transplant-ineligible because of age >65 years; 86 patients (80%) were considered transplant-eligible upon failure of 1st line therapy: 48 (45%) received allo-HSCT, while 38 (35%) did not proceed to transplant. Main reason for failure to achieve transplantation was disease progression (35 patients, 92%).We sought to determine if specific characteristics at diagnosis and/or 1st relapse were associated to the failure to achieve transplantation. In univariate analyses, patients unable to proceed to allo-HSCT at diagnosis were older (median age 56 years vs. 46 for transplanted patients; p=0.014) and more frequently had >1 extranodal site involvement (p=0.001), however none of these variables was confirmed in multivariate analysis. As expected, patients who were not transplanted had a shorter time to 1st relapse as compared to transplanted patients (p=0.002), indicating a more aggressive, chemoresistant disease.As assessed by ITT (Figure 1A and B), the estimated 5-year overall survival (OS) for transplant-eligible patients was 35%: notably survival curves significantly differed when transplanted and not transplanted patients were separated, with 5-year OS being 49% and 16%, respectively (p<0.0001).Within the transplanted patients' cohort, clinical status at transplantation was CR in 19 patients (40%), PR in 17 (35%), SD/PD in 12 (25%). Thirty-one patients (65%) underwent a reduced intensity conditioning, 17 (35%) underwent myeloablative conditioning, with most patients (n=39, 81%) receiving a thiotepa/fludarabine/cyclophosphamide-based regimen. Donor type was matched related for 13 patients (27%), matched unrelated for 24 (50%) and haploidentical for 11 (23%). GvHD prophylaxis consisted mainly in methotrexate-cyclosporine (n=31) plus ATG in case of unrelated donor grafts. PT-Cy or ex vivo T cell depletion were employed in the haploidentical setting. With a median follow up for surviving patients of 45 months (range 2 - 208 months), the 3-year cumulative incidence of non-relapse mortality and relapse were 19% and 48%, respectively. Estimated 5-year progression-free survival (PFS) was 45%. Importantly, outcomes were more favorable in patients transplanted in CR (5-year PFS 68%, OS 70%) vs. patients transplanted in PR (5-year PFS 43%, OS 49%) or active disease (5-year PFS 0%, OS 25%; PFS: p=0.0001; OS: p=0.011) (Figure 1C and D).Conclusions: This study supports the curative potential of allo-HSCT in relapsed PTCL patients with otherwise poor survival. Allo-HSCT can provide long-term remissions and indeed a PFS plateau appears beyond 5 years for patients transplanted in CR/PR. Unfortunately, the primary barrier to curative therapy remains achieving a sufficient response to salvage therapy and future studies should be aimed at increasing the response rate in this population. [Display omitted] DisclosuresCorradini:Roche: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Amgen: Honoraria.

The impact of Recipient and Donor Characteristics on Kidney Transplant Graft Survival

IntroductionMany factors determine the outcomes of renal transplant, including characteristics of both donors and recipients. Antihuman leukocyte antigen donor-specific antibodies are strongly linked to antibody-mediated rejection and late allograft loss.AimThe aim was to determine the effect of recipient and donor characteristics on kidney transplant graft survival, with special stress on panel-reactive antibodies.Participants and methodsThis study included 168 adult recipient and donor couples. The authors analyzed data of kidney transplants performed between the years of 2008 and 2018 at National Institute of Urology and Nephrology.ResultsThe authors found a significant increase in renal failure in recipients transplanted with unrelated donor kidney and in positive hepatitis C virus antibodies (HCV Abs) recipients (P = 0.002 and 0.001, respectively) and renal complications (P ≤ 0.001). There was also a significant increase in panel-reactive antibody-positive recipients to get renal complications (P = 0.03). There was a significant increase in renal failure with old-aged recipients (P = 0.008) and with increased duration of transplant (P = 0.003). By multivariate regression, the authors deduced that young age decreases graft loss risk (hazard ratio (HR): 0.88; 95% confidence interval (95% CI): 0.79–0.97; P = 0.017). Recipients of unrelated donor graft and HCV infection were associated with higher hazard ratio graft loss (HR: 13.56; 95% CI: 2.58–71.22; P = 0.002, and HR: 7.96; 95% CI: 1.04–60.44; P = 0.45). Unrelated donors graft were associated with 4 times higher hazard ratio renal complication (HR: 4.18; 95% CI: 2.01–8.72; P = 0.003). HCV infection increases risk three times (HR: 3.24; 95% CI: 1.31–7.99; P = 0.010). Unrelated donor was a significant independent predictor for recipient graft loss risk in a period of more than 5 years after transplantation.ConclusionThe authors concluded that recipient and donor characteristics have important roles on kidney transplant graft survival and also on renal complications.

Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era

Objective/BackgroundRelapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). MethodsWe reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1–64) months after their first alloHCT in 2010–2018 were included. ResultsMedian follow-up was 19 (range, 6–80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of grade II–IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6–12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival. ConclusionOutcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.