Unrelated Donor Allogeneic Hematopoietic Stem Research Articles

Efficacy of a modified post-transplant cyclophosphamide regimen for unrelated donor hematopoietic stem cell transplantation in patients with severe aplastic anemia: A prospective study

The aim of the present study was to examine the efficacy of the modified post-transplant cyclophosphamide (PTCy) regimen, which involved reducing the Cy dose to 40 mg on days +3 and +4, in patients with severe aplastic anemia (SAA) subjected to unrelated donor allogeneic hematopoietic stem cell transplantation (URD-HSCT). For this purpose, a prospective single-center trial was conducted and the clinical outcomes were collected from 30 patients with SAA treated with the modified PTCy regimen for URD HSCT. The median time to neutrophil and platelet engraftment was 13 days (range, 11 to 16) and 12 days (range, 5 to 33), respectively. The cumulative incidence of neutrophil and platelet engraftment was 93.1±0.3% and 96.6±0.2%, respectively. The 2-year overall survival (OS) was 97% [95% confidence interval (CI): 90%-100%] and 2-year graft-versus-host disease (GVHD) and rejection-free survival (GRFS) was 93% (95% CI: 85%-100%). The incidence rates of acute GVHD (aGVHD) and chronic GVHD (cGVHD) were 13.8±0.4% and 10.3±0.3%, respectively, and no patients developed grade III-IV aGVHD. However, only one patient developed a moderate extensive cGVHD. The incidence of reconstitution varies among different subsets of immune cells after URD HSCT. Natural killer (NK) cells first recover, followed by CD8+ T and CD19+ B cells, and finally CD4+ T cells. In conclusion, the present study demonstrates that the modified PTCy regimen, with a reduced dose of 40mg on days +3 and +4, may be an effective regimen for URD HSCT in patients with SAA and reduce the occurrence of the GVHD.

High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

Haploidentical and matched unrelated donor allogeneic hematopoietic stem cell transplantation offer similar survival outcomes for acute leukemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an effective approach for acute leukemia, primarily due to the inherent difficulty in finding human leukocyte antigen-matched unrelated donors (MUD). Nevertheless, it remains uncertain whether haplo-HSCT and MUD-HSCT can provide comparable outcomes in patients with acute leukemia. This study aimed to assess the overall survival (OS) and leukemia-free survival (LFS) outcomes between the MUD-HSCT and haplo-HSCT groups. This retrospective analysis encompassed adult patients with acute leukemia undergoing the initial allo-HSCT. Among these 85 patients, we stratified 33 patients into the MUD-HSCT group and 52 to the haplo-HSCT group. The primary outcomes were OS and LFS. The median OS was not reached in the haplo-HSCT group, while it reached 29.8 months in patients undergoing MUD-HSCT (p = .211). Likewise, the median LFS periods were 52.6 months in the haplo-HSCT group and 12.7 months in the MUD-HSCT group (p = .212). Importantly, neither the OS nor LFS showed substantial differences between the MUD-HSCT and haplo-HSCT groups. Furthermore, univariate analyses revealed that haplo-HSCT did not demonstrate a significantly higher risk of worse LFS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.25; p = .216) or OS (HR, 0.67; 95% CI, 0.36-1.26; p = .214) than MUD-HSCT. Notably, a high European Group for Blood and Marrow Transplantation risk score (HR, 1.44; 95% CI, 1.10-1.87; p = .007) and non-complete remission (HR, 2.48; 95% CI, 1.17-5.23; p = .017) were significantly correlated with worse OS. Haplo-HSCT may serve as an alternative to MUD-HSCT for the treatment of acute leukemia, offering similar survival outcomes.

A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

AbstractPatients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD–free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD–free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

A Tale of Two Rashes in a Bone Marrow Transplant Patient

A 68-year-old female patient with myelofibrosis was admitted for scheduled matched unrelated donor allogeneic hematopoietic stem cell transplant for the treatment of myelofibrosis. Her past medical history was also significant for Grover disease, also known as transient acantholytic dermatosis, characterized by chronic pruritic skin eruptions. On admission, the patient had no complaints with stable vital signs and benign physical examination. Laboratory values were notable for anemia with hemoglobin of 8.33g/dL, white blood cell count of 7.22 k/uL, and platelet count of 297 k/uL.

Outcomes with Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

BackgroundAllogeneic hematopoietic stem cell transplantation (HCT) is the optimal and potentially curative therapy in various high-risk hematologic malignancies. Although a human leukocyte antigen (HLA)-matched sibling or unrelated donor is a clinically preferred stem cell source, the use of haploidentical family donors and umbilical cord blood HCT now offers the option of HCT in patients lacking a matched donor. However, many patients lack an appropriate donor, in particular the ethnic minorities. Mismatched unrelated donors (MMUD) have historically been utilized as alternative donor source for these patients due to ease of donor availability but is associated with increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM). In this systematic review and meta-analysis, we aimed to assess the outcomes with MMUD HCT.Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for “hematopoietic stem cell transplantation”, OR “hematologic neoplasms”, AND unrelated donors“ AND ”treatment outcome“. A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 13 studies (11 retrospective, 2 prospective) reporting outcomes following MMUD HCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian-Laird Estimator.Results:We identified 2588 patients from 13 included studies who had MMUD HCT. (Table 1) Median age was 51.7 (18-76) years and 52% (n=1347) were males. Source of primary graft was bone marrow (BM) in 19% (n=478/2508) and peripheral blood (PB) in 81% (n=2030/2508) HCT recipients. Median time to transplant was 10.45 (1.5-139.6) months and median follow up was 41.5 (0.4-136.5) months. Reduced intensity conditioning (RIC) conditioning was used for 73% (n=1884) of the patients while 27.2% (n= 704) patients received myeloablative conditioning (MAC). We estimated a pooled overall survival (OS) of 59% (95% CI 0.52-0.66, I 2 = 92%, n=2563) at one year and 44% (0.36-0.53, I 2=92%, n=1972) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 39% (95% CI 0.33-0.44, I 2=84%, n=2282), 19% (95% CI 0.15-0.23, I 2=65%, n=1417), and 38% (95% CI 0.32-0.47, I 2=93%, n=2477) respectively. Progression free survival (PFS) was 39.5% (95% CI 0.31-0.48, I 2=94% n=2505). The pooled incidence of relapse rate (RR) and NRM were 31% (95% CI 0.25-0.38, I 2=90%, n=2482) and 27% (95% CI 0.21-0.34, I 2 =90% n=2448) respectively.Conclusion:Mismatched unrelated donor HCT has shown favorable outcomes with acceptable toxicity profile. MMUD HCT represents a promising option for patients lacking an HLA-matched donor and has expanded access to HCT in patients with ethnic minorities who often lack a matched donor. [Display omitted] DisclosuresAbhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Juno Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding.

Outcomes with Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation Following Reduced Intensity Conditioning: A Systematic Review and Meta-Analysis

Background:Allogeneic hematopoietic cell transplantation (HSCT) is often the optimal and only potentially curative therapy in several high-risk hematologic malignancies. Although human leukocyte antigen (HLA)-matched donors remain the preferred choice for HSCT recipients, haploidentical and umbilical cord blood HSCT has increased access to transplantation. Despite these advances, many patients lack an appropriate donor, in particular the ethnic minorities. The use of mismatched unrelated donors (MMUD) has increased over the years but concerns regarding increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM) limits the utility of MMUD HSCT. The intensity of the conditioning regimen has a significant impact on survival in case of mismatched donors. We conducted a systematic review and meta-analysis aimed to investigate the outcomes with MMUD HSCT using reduced intensity conditioning (RIC).Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for “hematopoietic stem cell transplantation”, OR “hematologic neoplasms”, AND unrelated donors“ AND ”treatment outcome“. A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 6 (4 retrospective, 2 prospective) studies reporting outcomes following RIC MMUD HSCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian Laird Estimator.Results:We identified 895 participants in the 6 studies, who had MMUD HSCT with RIC. (Table 1) Median age was 57.5 (18-76) years and 56% (n= 415) were males as reported by four studies (n=740). In five studies with available data (n=855), source of the primary graft was peripheral blood (PB) and bone marrow (BM) in 72% (n=614) and 28% (n=241) of the HSCT recipients respectively. After a median follow-up of 48 (3-125) months, we estimated a pooled overall survival (OS) of 62% (95% CI 0.52-0.72, I 2=84%, n=895) at one year and 43.5% (95% CI 0.33-0.54, I 2 =84% n=855) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 37% (95% CI 0.26-0.49, I 2=81%, n=610), 16% (95% CI 0.07-0.29, I 2=87%, n=542), and 28% (95% CI 0.13-0.47, I 2=95%, n=848) respectively. Progression free survival (PFS) and relapse rates (RR) were 46% (95% CI 0.30-0.62, I 2=92%, n=814) and 31% (95% CI 0.24-0.39, I 2=65%, n=814) respectively. The pooled incidence of non-relapse mortality (NRM) was 23% (95% CI 0.09-0.40, I 2=91%, n=707). Kasamon et al. and Shaw et al. reported 1-year OS of 75-79% with MMUD HSCT using fludarabine, cyclophosphamide and 2 Gy total body irradiation RIC, bone marrow graft and post-transplant cyclophosphamide, sirolimus and mycophenolate for GVHD prophylaxis.Conclusion:Mismatched unrelated donor HSCT has shown favorable outcomes with reduced intensity conditioning using a post-transplant cyclophosphamide-based regimen, comparable to the historical outcomes with mismatched related donor (haploidentical) HSCT. MMUD HSCT with RIC can be considered in patients lacking an HLA-matched donor. This strategy will expand access to HSCT in patients with ethnic minorities who often lack a matched donor. [Display omitted] DisclosuresMcGuirk: EcoR1 Capital: Consultancy; Allovir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.

Clinical impact of multiple DNA virus infections in nondepleted haploidentical and unrelated allogeneic hematopoietic stem cell transplantation.

Few studies have compared the clinical impact of multiple DNA-virus infections in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) and unrelated donor allogeneic hematopoietic stem cell transplantation (UD-HSCT) with thymoglobulin, so we retrospectively analyzed viral infections in the first 6mo posttransplant in these scenarios. Fifty-nine patients underwent to haplo-HSCT, and 68 to UD-HSCT. The most frequent infection was cytomegalovirus (CMV) (76.3% in haplo-HSCT and 69.1% in UD-HSCT) (P=.878) and in the group of patients with CMV reactivation, maximal CMV viral load over 2500UI/ml correlated with worse overall survival-hazard ratio (HR) 1.93 (95% confidence interval [CI] 1.04-3.59) P=.03. The cumulative incidence of multiple DNA virus within 180d of posttransplant was 78.7% for one virus and 28.4% for two or more viruses with no difference regarding the type of transplant. Viral infections, age, and acute graft versus host disease (GVHD) grades II-IV were risk factors for worse overall survival in multivariate analyses: one virus HR 2.53 (95% CI 1.03-6.17) P=.04, two or more viruses HR 3.51 (95% CI 1.37-9) P<.01, age HR 1.03 (95% CI 1.02-1.05) P<.01 and acute GVHD II-IV HR 1.97 (95% CI 1.13-3.43) P=.01. Also, age over 50y HR 4.25 (95% CI 2.01-8.97) P<.001, second CMV reactivation or having both CMV and BK polyomavirus (BKV) HR 2.65 (95% CI 1.26-5.56) P=.01 and acute GVHD grades II-IV HR 2.23 (95% CI 1.12-4.43) P=.022 were risk factors for nonrelapse mortality in the multivariate analyses. In conclusion, multiple DNA-virus infections are frequent in both haplo-HSCT and UD-HSCT and a risk factor for worse overall survival.

High-Dose Cyclophosphamide and Tacrolimus as Graft-versus-Host Disease Prophylaxis for Matched and Mismatched Unrelated Donor Transplantation

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of single-locus mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is unclear. The use of high-dose post-transplant cyclophosphamide (PTCy) after haploidentical transplantation is effective at overcoming the negative impact of HLA disparity on survival. Limited information is available regarding the efficacy of this strategy in alloHSCT from MMUDs. Most of the published studies have used the triple immunosuppressant model of haploidentical transplant combining PTCy with calcineurin inhibitors and mycophenolate mofetil or methotrexate. In our study, we propose the use of a simpler GVHD prophylaxis protocol comprising PTCy in combination with tacrolimus for MMUD and matched unrelated donor (MUD) alloHSCT. We performed a retrospective analysis of 109 consecutive recipients of alloHSCT from unrelated donors (MMUD, n=55; MUD, n=54) in a single center. Graft source was primarily peripheral blood (98%). No differences were observed between the MMUD and MUD groups with respect to 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD; 31% versus 32%, respectively, P=.9), grade III to IV aGVHD (9% versus 7%, P=.7), and moderate/severe chronic GVHD (cGVHD) at 2 years (18% versus 14%, P=.6). Both groups showed similar cumulative incidence of 1 year nonrelapse mortality (13% versus 9%; P=.5) and 3-year relapse rates (24% versus 25%, P=.7). Progression-free survival and overall survival at 3 years for MMUD and MUD were 56% and 57% (P=.9) and 64% and 65% (P=.6), respectively. The 3-year probability of survival free of moderate/severe cGVHD and relapse was 56% and 55%, respectively. GVHD prophylaxis with PTCy and tacrolimus achieves low rates of severe aGVHD and cGVHD, as well as good survival outcomes, in recipients of both MMUD and MUD peripheral blood alloHSCT. This strategy overcomes the negative impact of single-locus HLA disparity.

G-CSF-Primed Peripheral Blood Stem Cell Haploidentical Transplantation Could Achieve Satisfactory Clinical Outcomes for Acute Leukemia Patients in the First Complete Remission: A Registered Study.

G-CSF-mobilized peripheral blood (G-PB) harvest is the predominant graft for identical sibling donor and unrelated donor allogeneic hematopoietic stem cell transplantation (HSCT) recipients, but it was controversial in haploidentical related donor (HID) HSCT. In this registry study, we aimed to identify the efficacy of HID G-PB HSCT (HID-PBSCT) for acute leukemia (AL) patients in first complete remission (CR1). Also, we reported the outcomes for the use of G-PB grafts in comparison with the combination of G-BM and G-PB grafts in HID HSCT recipients. Sixty-seven AL patients in CR1 who received HID-PBSCT were recruited at Institute of Hematology, Peking University. Patients who received haploidentical HSCT using the combination of G-BM and G-PB harvests in the same period were enrolled as controls (n=392). The median time from HSCT to neutrophil and platelet engraftment was 12 days (range, 9–19 days) and 12 days (range, 8–171 days), respectively. The 28-day cumulative incidence of neutrophil and platelet engraftment after HSCT was 98.5% and 95.5%, respectively. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) were 29.9% (95%CI 18.8–40.9%) and 7.5% (95%CI 1.1–13.8%), respectively. The cumulative incidences of total and moderate-severe chronic GVHD were 54.9% (95%CI 40.9–68.8%) and 17.4% (95%CI 6.7–28.0%), respectively. The cumulative incidences of relapse and non-relapse mortality were 13.9% (95%CI 5.4–22.5%) and 3.4% (95%CI 0–8.1%), respectively. The probabilities of overall survival (OS) and leukemia-free survival (LFS) were 84.7% (95%CI 74.7–94.7%) and 82.7% (95%CI 73.3–92.1%) respectively. Compared with the HID HSCT recipients using the combination of G-BM and G-PB grafts, the engraftments of neutrophil and platelet were both significantly faster for the G-PB group, and the other clinical outcomes were all comparable between the groups. In multivariate analysis, graft types did not influence the clinical outcomes. Overall, for the patients with AL CR1, G-PB graft could be considered an acceptable graft for HID HSCT recipients. This study was registered at https://clinicaltrials.gov as NCT03756675.

Association between preconditioning absolute lymphocyte count and transplant outcomes in patients undergoing matched unrelated donor allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and anti-thymocyte globulin.

Background:Allogeneic stem cell transplantation (alloSCT) offers cure chance for various hematologic malignancies, but graft-versus-host disease (GVHD) remains a major impediment. Anti-thymocyte globulin (ATG) is used for prophylactic T-cell depletion and GVHD prevention, but there are no clear guidelines for the optimal dosing of ATG. It is suspected that for patients with low absolute lymphocyte counts (ALCs), current weight-based dosing of ATG can be excessive, which can result in profound T-cell depletion and poor transplant outcome.Methods:The objective of the study is to evaluate the association of low preconditioning ALC with outcomes in patients undergoing matched unrelated donor (MUD) alloSCT with reduced-intensity conditioning (RIC) and ATG. We conducted a single-center retrospective longitudinal cohort study of acute leukemia and myelodysplastic syndrome patients over 18 years old undergoing alloSCT. In total, 64 patients were included and dichotomized into lower ALC and higher ALC groups with the cutoff of 500/μl on D-7.Results:Patients with preconditioning ALC <500/μl were associated with shorter overall survival (OS) and higher infectious mortality. The incidence of acute GVHD and moderate-severe chronic GVHD as well as relapse rates did not differ according to preconditioning ALC. In multivariate analyses, low preconditioning ALC was recognized as an independent adverse prognostic factor for OS.Conclusion:Patients with lower ALC are exposed to excessive dose of ATG, leading to profound T-cell depletion that results in higher infectious mortality and shorter OS. Our results call for the implementation of more creative dosing regimens for patients with low preconditioning ALC.

A Phase 1 Single Dose Escalation Study of Palifermin Administered Pre-Transplant Conditioning in Subjects Undergoing Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Background: Early initiation of graft-versus-host disease (GvHD) is driven by donor alloreactive T-lymphocytes directed against recipient's histocompatibility antigens often overexposed during damage to tissues during the conditioning chemotherapy. Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF, also known as FGF7) that binds to FGF receptor 2b expressed in many epithelia including the epithelium of the epidermis, oral and GI mucosa, urothelium, and thymus, in which it exerts cytoprotective and regenerative effects. Palifermin also has immunomodulatory effects manifested as improvements in thymic function and downregulation of pro-inflammatory cytokines. Palifermin was FDA approved in 2004 at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT). A single dose of 180 mcg/kg/day appears to have similar effects. In animal models, palifermin showed efficacy in controlling acute and chronic GvHD. However, subsequent clinical studies did not confirm efficacy for prevention of GvHD or for stimulation of functional thymus recovery using a dose/schedule based on the one that had been approved for autologous HSCT. We conducted a phase 1 study (NCT02356159) to determine the maximal safe single dose level of palifermin administered prior to starting transplant conditioning. Methods: This was an open-label, dose escalation study with standard 3+3 design. Four different dose levels of palifermin (180, 360, 540 and 720 µg/kg) were administered as a single dose on day -7 pretransplant. The reduced-intensity conditioning regimen (cyclophosphamide 1200 mg/m2/day IV and fludarabine 30 mg/m2/day IV), was given on days -6 to -3. Sirolimus, tacrolimus and low-dose post-HSCT methotrexate were used for GvHD prophylaxis. On day 0 all subjects received a peripheral blood stem cell (PBSC) graft from an unrelated donor (MUD) matched at least at HLA-A, -B, -C, -DRB1. Prior to transplant, subjects received one or two cycles of disease-specific lymphodepleting induction chemotherapy (EPOCH-F/R or FLAG). Subjects must have been ≥18 years old with a high-risk hematologic malignancy, Karnofsky performance status ≥60%, and acceptable organ function. The primary objective was to assess safety of palifermin and to recommend the phase 2 study dose. DLT was defined as non-relapse mortality before day 30 post-HSCT regardless of attribution to palifermin and non-hematologic grade ≥4 adverse events (AEs) occurring within 14 days after administration. AEs were recorded according to CTCAEv4. Results: From Oct 2015 to Mar 2019, 18 subjects were enrolled (NHL=7, AML/MDS=5, ALL/LBL=2, CML=2, MPN=1 and MM=1). Kahl's relapse risk was high, standard, and low in 15, 2, and 1 subject, respectively. Median HCT-CI score was 1 (0-4) with median age 47 years (21-66); 14 (78%) were males. Six subjects received dose level 1 (subject #3 was diagnosed with achalasia and grade 4 elevated lipase without radiological signs of pancreatitis, still attributed as DLT possibly related to palifermin). No DLTs occurred afterwards. Three subjects were enrolled onto each of dose levels 2, 3 and 4, with expansion of dose level 4 to 3 more subjects for additional safety exploration. Skin rash and Increased serum amylase or lipase were the most frequent AEs (Table 1A). Grade 3 increased serum amylase and grade 3 possible pancreatitis in subject #3 were the only SAEs attributed to study drug. All subjects engrafted successfully. Day 14 median CD3 and myeloid chimerism was 97% (36-100) and 99% (82-100), respectively, with the median time to 100% CD3 chimerism of 44 days (14-181). Table 1B lists occurrence of GvHD prior to any malignancy relapse. Four subjects had relapsed malignancy, for which 3 received DLI. After a median follow up of 28 months (2-55), 5 subjects have died, 2 malignancy relapses and 3 non-relapse related causes. Conclusion: Palifermin administered at dose four-times higher than previously given in humans is safe to use in patients undergoing MUD peripheral blood HSCT. MTD was not reached. Recommended phase 2 dose for examining efficacy in prevention of GvHD is 720 µg/kg. Disclosures Rubin: NIH/NCI: Ended employment in the past 24 months, Patents &amp; Royalties; KGF/palifermin: Patents &amp; Royalties; Paradigm Shift Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Palifermin was FDA approved at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT).

A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

<h3>Background</h3> The optimal regimen for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. Post-transplant cyclophosphamide (PT-Cy) mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. We investigated the benefit of PT-Cy in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. <h3>Methods</h3> We conducted a phase II clinical trial of PT-Cy for GVHD prophylaxis following MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 to +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. <h3>Results</h3> There were 39 patients enrolled in the study. The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). The most commonly used conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV. The incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of these were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. <h3>Conclusion</h3> The use of one dose of PT-Cy in combination with MMF and tacrolimus is effective in preventing acute severe GVHD in myeloablative PBSC MUD HSCT recipients. We observe modest control over chronic GVHD with this regimen which may be explained by giving one dose of PT-Cy only. We report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD and may play a vital role in mismatched unrelated donor transplants as well.

A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Background: The use of post-transplant cyclophosphamide (PT-Cy) in combination with other immunosuppressive agents for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. PT-Cy mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. Extrapolating from the success of PT-Cy in haplo transplants, we investigated the benefit of PT-Cy (at a lower dose than that used in haplo HSCT) in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial between September 2013 and June 2018 of PT-Cy for GVHD prophylaxis following myeloablative MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 till day +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. Approval for the study was obtained from the Institutional Review Board. Results: There were 39 patients enrolled in the study (Table 1). The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). Based on disease risk index (DRI) assessment, 6 (15%) patients were DRI high, 32 (82%) were intermediate and 1 (3%) was low. The most commonly used myeloablative conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. Three patients with NHL received Fludarabine and Melphalan. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV (Table 2). The overall incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of them were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. Conclusion: We report a low incidence of acute severe GVHD with the combination of one dose of PT-Cy in combination with MMF and tacrolimus following myeloablative PBSC MUD HSCT. The single dose of PT-Cy may explain the modest control over chronic GVHD with this regimen. We also report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD HSCT and may play a vital role in mismatched unrelated donor transplants as well. Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; GSK: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD.Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch.Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone.Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes. DisclosuresRosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.

Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS

The last two authors contributed equallyElevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2 SNPs with death due to GvHD or infection within one year after HLA-matched unrelated donor HCT for AML or MDS to identify functional SNPs that could potentially aid in donor selection.We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P<.05), which validated 99% of the FHS sST2 SNP associations. To assess the contribution of these donor variants to post-HCT survival, we constructed competing risk models with clinical variables using stepwise Akaike Information Criterion (AIC), then tested each of the 1541 donor SNPs for association with each outcome in the two DISCOVeRY-BMT cohorts. Causes of death were previously adjudicated by a multi-member panel. Meta-analyses of the two cohorts identified 13 GvHD-death associated SNPs and 118 infection-death associated SNPs. Sensitivity analyses show 91/118 SNPs are still significant after excluding patients with a history of acute GvHD grade III-IV (Figure 1). When taking correlations into account, we found 10 and three independent SNPs (R2<.6) associate with death due to infection and GvHD, respectively. There were no overlapping SNP associations between GvHD-death or infection-death (Figure 1). For GvHD-death associated SNPs, alleles associated with higher sST2 levels associate with increased risk for GvHD-death, while for infection-death SNPs, alleles associated with higher sST2 levels reduced risk of infection-death.AIC multivariable models for GvHD-death included AML diagnosis, recipient obesity (>30 mg/kg2), peripheral blood cell source, donor age, rs1558645 (Pmeta=.001), and rs2310241(Pmeta=.0003), for which the risk alleles at each SNP increased risk of GvHD death ~1.5 fold. The model for infection-death included advanced disease at HCT, recipient/donor CMV status, peripheral blood cell source, rs13019803 (Pmeta=1.1 x 10-6), rs13015714 (Pmeta=5 x 10-4) and rs4851601 (Pmeta=2 x 10-6), with risk alleles at each SNP increasing risk of infection-death ~2-fold. To capture the total contribution of these donor variants to each outcome we created multi-allele models for GvHD-death (0-4 alleles) and infection-death (0-6 alleles).The multi-allele GvHD models showed a 1.5 fold increased risk of GvHD-death with each additional allele (Pmeta=3.4 x 10-6 ) (Figure 2). Individuals whose donors are homozygous for both risk alleles at each SNP have a ~3 fold, and ~2 fold higher risk of dying of GvHD versus those with zero, and 1-2 risk allele(s), respectively. The multi-allele infection models (0-6 alleles) show a ~2 fold increased risk of infection-death (Pmeta= 1.22 x 10-10) with each risk allele (Figure 2).sST2 is one of the most reproducible GvHD biomarkers to date. As hypothesized, specific alleles correlated with high sST2 levels in donors and with GvHD-death. Our novel finding is that some ST2 alleles associated with low sST2 levels correlated with infection-death. These results are not without precedent, for example the low-sST2 associated allele in rs13019803 (T) associates with higher mortality in the CHARGE consortium. The risk allele in rs13015714 (T) is significantly associated with lower IL1RL1 and IL18R1 (P= 5 x 10-10) gene expression in lung tissue, indicating biochemical functions for these SNPs. Importantly the non-risk allele in all 5 variants are common (>20%) across races and ethnicities, which means there is an opportunity to select donors without combinations of these variants and perhaps without the requirement of measuring the protein level pre-transplant. [Display omitted] DisclosuresMcCarthy:Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Takeda: Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties.

110 - Clonal Alterations and Survival after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant in Patients with Fanconi Anemia

110 - Clonal Alterations and Survival after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant in Patients with Fanconi Anemia

Single Antigen–Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide Is a Suitable Alternative for Patients Lacking HLA-Matched Donors

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing 2 contemporaneous groups: PTCy MMUD (n = 26) versus matched unrelated donor (MUD) (n = 60). Graft source was primarily peripheral blood (92%). All PTCy MMUD were HLA 7/8 (differences in HLA class I loci in 92% of patients) and received PTCy plus tacrolimus ± mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCy MMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II to IV (31% versus 22%, respectively; P = .59) and III to IV (8% versus 10%, P = .67). There was a trend for a lower incidence of moderate to severe chronic GVHD at 1 year after PTCy MMUD in comparison with MUD (22% versus 41%, P = .098). No differences between PTCy MMUD and MUD were found regarding nonrelapse mortality (25% versus 18%, P = .52) or relapse rate (11% versus 19%, P = .18). Progression-free survival and overall survival at 2 years were similar in both cohorts (67% versus 54% [HR, .84; 95% CI, .38 to 1.88; P = .68] and 72% versus 57% [HR, .71; 95% CI, .31 to 1.67; P = .44], respectively). The 2-year cumulative incidence of survival free of moderate to severe chronic GVHD and relapse tended to be higher in the PTCy MMUD group (47% versus 24%; HR, .60; 95% CI, .31 to 1.14; P = .12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD.

Leczenie pomalidomidem chorego na szpiczaka plazmocytowego po przeszczepieniu allogenicznych krwiotwórczych komórek macierzystych od dawcy niespokrewnionego

The case report presents IgA plasma cell myeloma patient treated with chemotherapy, botrezomib, autologous hematopoietic stem cell transplantation, lenalidomide, unrelated donor allogeneic hematopoietic stem cell transplantation and finally pomalidomide (POM). In spite of lack of deep, long-term response after any of the therapies, the combined treatment using all modalities currently available in Poland led to prolonged survival of the patient. Of note, POM employed as sixth-line therapy showed good efficacy and relatively few side effects over a 27-cycle treatment period.