Well-matched Unrelated Donor Research Articles

TBI-Containing with T-Cell Replete Full Haplotype Mismatched Hematopoietic Stem Cell Transplantation in Adult Patients with De Novo Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the 2nd most frequent developing hematologic malignancy with deep heterogeneity, but unfortunately the majority of patients relapse even after allogeneic hematopoietic stem cell transplantation (HSCT) in complete remission (CR). We have developed allogeneic HSCT from familial mismatched/haploidentical donors (FMT) in adult patients with a single disease entity of AML lacking of both HLA-identical siblings and well-matched unrelated donors (WMUD) from the mid 1990s. Previously, several pilot studies of FMT performed with various total body irradiation (TBI)-based conditioning regimens (2~12 gray) with or without post-transplant cyclophosphamide (PT-Cy) as a graft-versus-host disease (GvHD) prophylaxis were reported. Here, we demonstrate about the encouraging outcomes of FMT using unmanipulated peripheral blood donor stem cells (PBSCs) and de-escalated dose of TBI (4~8 gray) containing conditioning regimen without T-cell depletion manner. Although PT-Cy as a specific GvHD prophylaxis regimen is increasingly used for both adult and pediatric FMT, our group investigated the clinical outcomes in adult patients with de novo AML who received full haplotype mismatched HSCT after TBI containing preparation regimen consisted of fractionated TBI (total 4 gray for elderly and 8 gray for <60 years old), fludarabine (150 mg/m 2/day), busulfex (6.4mg/kg/day), and anti-thymocyte globulin (ATG). For GvHD prophylaxis, rabbit ATG (thymoglobulin, Genzyme, 1.25mg/kg/day for 4 days at D-4 to D-1) and a combination of tacrolimus and short-term methotrexate was used. G-CSF mobilized unmanipulated PBSCs were used with a median CD34+ dose of 6.5 x 10 6/kg (1~25.6). From 2008 to the end of 2022, total 429 adult patients were enrolled, and data demonstrated that our trial of intermediate-dose of ATG and reduced toxicity of TBI-containing conditioning regimen to reduce graft-failure even for high levels of donor-specific antibody titer, early transplant-related mortality, critical cytomegalovirus (CMV) disease, and emerging post-transplant lymphoproliferative disease with rapid immune recovery has shown very successful outcomes. Briefly, the median absolute neutrophil count recovery was 12 days (10~26) and the platelet of 14 days (5~38). There was no either primary or secondary graft-failures at all. With a median follow-up of 36.5 months (2~242) for survivors, overall survival rate (OS) and relapse-free survival (RFS) for patients in any CR (n=338) and relapse/refractory status (n=91) were 62.9% vs. 34.3% and 59.5% vs. 32.2%, respectively. Although there was no significant difference in the subgroup analysis, de novo and young aged patients in any CR showed the best OS 73% (Figure 1). Cumulative incidences of acute GvHD and chronic GvHD were 66% (59-73), 70% (63-76), respectively. The incidences of moderate to severe acute GvHD and chronic GvHD were 16.1%, 30.5%, respectively. By univariate and multivariate analyses, patient's age <54 (p=0.043), pre-HSCT CR1 (p <0.001), absence of mod to severe chronic GvHD (p <0.001), and use of post-transplant iron-chelating agent (p=0.001) were the statistically significant in the study. The GvHD-free and relapse-free survival rate in CR1 was 62.4% for younger patients (age <54) and 47.9% for older patients (p=ns). The non-relapse mortality rate was 27.2% for all enrolled patients and 16% for CR patients. The rapidity of immune recovery was also compared with our old control cohort when we performed T-cell depletion using the CliniMACS system, and it showed a significant reconstitution of CD4+ cells (>300/ul) at 3 months post-FMT compared to the much delayed T-cell depleted FMT. Of note, CMV DNAemia was relatively higher (76.9%) than reported in other studies, likely due to the use of ATG and the endemic region of our country. Therefore, we suggest that the strategic reduction of fractionated TBI 4~8 gray-based conditioning with unmanipulated PBSCs graft without PT-Cy seems feasible with favorable outcomes for adult patients with de novo AML undergoing FMT in CR, especially even in a certain subgroup of elderly patients with AML.

Existence of HLA-Mismatched Unrelated Donors Closes the Gap in Donor Availability Regardless of Recipient Ancestry

In patients without a matched sibling donor (MSD) or well-matched unrelated donor (MUD), hematopoietic cell transplantation (HCT) can still be successful when using an HLA-mismatched unrelated donor (MMUD) in combination with post-transplantation cyclophosphamide (PTCy), abatacept, or other novel approaches. This may allow clinicians to choose a suitable donor from a wide range of donor options while optimizing other donor selection characteristics, including donor age. We hypothesized that allowing for a 5/8 HLA match level considering high-resolution matching at HLA-A, -B, -C and -DRB1, there is a potential to close the donor availability gap for all patients regardless of their race/ethnicity. In this work, we estimate the likelihood of matching for all racial/ethnic groups at different HLA match thresholds. Our study aimed to assess the potential for identifying an available MUD or MMUD in the National Marrow Donor Program (NMDP)/Be The Match (BTM) donor registry for 21 detailed and 5 broad racial/ethnic groups, using high-resolution HLA matching for HLA-A, -B, -C, and -DRB1 at various levels (8/8, 7/8, 6/8, and 5/8). We used donor registry population data from the NMDP/BTM in 2020 and redistributed the donor registry data according to existing population ratios, accounting for demonstrated donor availability. Finally, we used a genetic model at the population level to estimate the match likelihood for detailed and broad racial/ethnic groups. Likelihood of 8/8 HLA match ranging from 16% to 74% were obtained for various detailed racial/ethnic groups with available donors age ≤35 years. When considering more mismatches in the HLA loci, registry coverage became >99% with a 5/8 HLA match level for donors of all ages or those age ≤35 years, with HLA-DPB1 T cell epitope permissive matching, or when searching for donors outside of their racial/ethnic group. Our registry models demonstrate the potential for using MMUDs at various HLA match levels to study whether this will expand access to HCT across racial/ethnic groups. Expanded donor options may erase the donor availability gap for all patients while allowing for selection of MMUDs with favorable characteristics, such as younger age.

Hematopoietic Stem Cell Transplant in Nuclear Factor KB Essential Modulator Deficiency: A Case Report

IntroductionInborn errors of immunity (IEI) are genetic defects characterized by recurrent infections, autoimmunity, and malignancy and often have hematopoietic functions. Therefore, replacement of poorly functioning stem cells by healthy donor hematopoietic stem cell transplantation (HSCT) represents a reasonable therapeutic approach. Herein, we describe the initial management and outcome of a patient with nuclear factor KB (NF-kB) essential modulator (NEMO) deficiency, a rare IEI, who was referred for HSCT. Case DescriptionA 12-month-old male with genetically confirmed NEMO deficiency syndrome was referred for curative correction via HSCT for underlying IEI. Prior to transplantation, he had oral thrush, multiple episodes of gram-negative bacteremia, complicated by septic emboli to the brain and lungs, persistent norovirus gastroenteritis, SARS-CoV-2 respiratory tract infection, and adenoviremia. Multiple GI biopsies were inconclusive for colitis. At the time of HSCT, the only persistent symptom was loose stools secondary to norovirus. There were no well-matched unrelated or sibling donors, so his unaffected father who was a 6/10 match was selected. He underwent a reduced toxicity preparative with fludar-abine/busulfan/rabbit Anti-thymocyte globulin. 12 days following HSCT, prior to engraftment, the patient developed fevers and hypotension and required transfer to the PICU. Unfortunately, the patient died 2 days later secondary to Stenotrophomonas bacteremia. Discussion/ConclusionHSCT is the only curative treatment option for patients with IEI. NEMO deficiency syndrome displays variability in clinical and immunological phenotype, and not all patients require curative treatment. In current literature, HSCT has been performed in 29 patients with NEMO deficiency syndrome. The global survival rate at 5 years is 74% with severe infection being the leading cause of death. Following HSCT, most surviving patients achieve reconstitution of the immune system including immunoglobulin levels though response to vaccinations is often poor. HSCT does not improve non-hematopoietic abnormalities, particularly colitis. Case reports indicate that colitis can persist or worsen following HSCT. Despite the challenges that persist with HSCT for NEMO deficiency syndrome, curative therapy should remain a consideration for profound immune deficiency, and additional studies are needed to improve post-HSCT survival and management of non-hematopoietic complications.

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Thalassaemia: A Single Institution Experience of 53 Patients

AbstractBackground: Thalassemia major (TM) is a fatal genetic disease currently only curable with allogeneic stem cell transplantation, which is limited by the lack of suitable donors. For patients lacking matched related donors, unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) is increasingly being utilized. Despite this success in leukemia patients, UD-PBSCT is not widely practiced in thalassemia patients because of higher graft-versus-host disease (GVHD) risk and increased transplant-related mortality (TRM).Methods: The purpose of the study is to assess the safety and efficacy of UD-PBSCT for patients with thalassemia major. The trial was designed as a prospective, open-label, single-center clinical protocol, where 53 TM patients were enrolled between March 2013 and April 2017 and transplanted with peripheral blood stem cell (PBSC), from an HLA-matched unrelated donor. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR). The primary end point was 2-year thalassemia free survival (TFS). Secondary end points included 2-year overall survival (OS), the cumulative incidence of GVHD, transplant related mortality (TRM), graft rejection (GF). The conditioning regimen were: 1) busulphan (BU) 1mg/kg given intravenously (IV) four times per day for 4 days (day -9 to day -6); 2) fludarabine (FLU) (50mg/m2/day) given IV for 3 days (day -12 to day -11); 3) cyclophosphamide (CTX) (50 mg/kg/day) given IV for 4 days (day -5 to day -4); 4) anti-thymocytes globulin (ATG, Genzyme ) (2.5 mg/kg/day) given IV for 4 days (days -4 and day -1). All patients were placed on 30 mg/kg hydroxyurea orally once daily for 2-3 months before transplantation. GVHD prophylaxis consisted of a combination of cyclosporin A, methotrexate and mycophenolate mofetil regimen.Results: Data cut off for survival follow-up was June 30, 2017. The median follow-up time was 22 months (range, 4 months -58 months). The median age of patients was 5 years (range, 2-13 years). The median numbers of MNCs and CD34 cells infused per graft were 17.6 ×108/kg (range, 10.0 to 34.6)and 9.2×106/kg (range, 3.5 to 32.9), respectively. A total of 52 (98.1%) patients achieved sustained myeloid engraftment. The median time of absolute neutrophil count engraftment was 11(range 9-15) days. The median time of platelet engraftment was 13(range, 9 to 35) days. The rate of Graft rejection was 1.9%. The cumulative incidence of acute (a)GVHD and grade II-IV aGVHD were 41.5% (95% confidence interval [CI], 29.1 to 56.2) and 32.0% (95% CI, 21.1 to 48.6) , respectively . The chronic (c)GVHD and extensive cGVHD were 6.2% (95% confidence interval [CI], 2.1 to 16.6) and 2.2% (95% CI, 0.3 to 15.1), respectively. The cumulative incidence of TRM at 2 years was 8.0% (95% CI, 3.1 to 20.4). The OS and TFS at 2 years were 92.0% (95% CI, 87.8 to 100) and 90.1% (95% CI, 85.0 to 99.6), respectively. (Figure 1)Conclusion: Our results demonstrate that MUD-PBSCT in TM yields excellent engraftment rate and TFS when the protocol consisted of busulphan, cyclophosphamide, fludarabine and antithymocyte globulin was used, and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for MUD-PBSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Promising Results at 1 Year Follow-up Following Familial Haploidentical (FHI) T-Cell Depleted (TCD) with CD34 Enrichment and T-Cell (CD3) Addback Allogeneic Stem Cell Transplantation in Patients with High-Risk Sickle Cell Disease (SCD) (IND 14359)

AlloSCT from HLA-matched MSD has been successful for high-risk SCD, and is the only known curative therapy (Talano/Cairo et al EJH, 2014). We have recently demonstrated 100% EFS and absence of sickle cell symptoms following reduced toxicity conditioning in HLA matched sibling donor (MSD) or cord blood AlloSCT (Bhatia/Cairo et al BMT, 2014). However, 5 out of 6 children lack an HLA MSD without SCD. Only 19% of recipients of African descent will identify a well-matched unrelated donor (MUD) and results after unrelated UCBT are poor (Radhakrishnan/Cairo et al BBMT, 2013). Recent results utilizing matched unrelated donors in a multi-center trial showed unacceptable rates of cGVHD at 62% (95% CI 41-77) (Shenoy et al Blood, 2016). We demonstrated CD34+ selection followed by T-cell addback from MUD in pediatric recipients led to 100% engraftment with minimal aGVHD (Geyer/Cairo et al BJH, 2011). Limitations in the past of various T-cell depletion methods have included a higher incidence of graft failure, delayed immune reconstitution, opportunistic fungal infection and higher incidence of cGVHD. FHI TCD AlloSCT utilizing the approach of CD34+ enrichment and T-cell addback could expand the donor pool and improve outcomes for patients with high risk SCD and have similar outcomes to AlloSCT from HLA MSD.This SCD consortium trial (www.sicklecelltransplantconsortium.org) (NCT01461837) is investigating the safety, feasibility, EFS, donor chimerism, graft failure, aGVHD and cGVHD after FHI TCD AlloSCT in high-risk SCD patients.High risk included: ≥1 CVA, ≥2 ACS, ≥3 VOC in past 2 years, or 2 abnormal TCDs. Patients (2-<21 yrs) who have ≥1 high-risk SCD features were eligible. Patients received hydroxyurea and azathioprine, day -59 - day -11, fludarabine (150mg/m2), busulfan (12.8mg/kg) (targeted trough Css of 600-900), thiotepa (10 mg/kg), cyclophosphamide (200mg/kg), R-ATG (8mg/kg), and TLI (500cGy) followed by FHI T-cell depleted AlloSCT. AGVHD prophylaxis: tacrolimus. We utilized the CliniMACS to enrich for peripheral blood HPC's; target dose of 10 x 106 CD34+ cells/kg with a fixed dose of 2 x 105 CD3+ T cells/kg. The Child Health Rating Inventories (CHRIs) was used to serially collect parent proxy-rated health-related quality of life (HRQL).Twenty-one patients have been enrolled. Nineteen patients have received AlloSCT to date. Fifteen patients utilized maternal donors and 4 patients utilized paternal donors. Two donors encountered thrombocytopenia that resolved spontaneously. The mean ± SD CD34+ enrichment prior to cryopreservation was 12.66 ± 3.3 x 106/kg and log T-cell depletion was 4.8 ± 0.58. Evaluable pts had early neutrophil engraftment (median day +9), and ≥95% whole blood and RBC (CD71) donor chimerism at 1yr. Probability of aGVHD n=17, 7.1% (CI95: 0-70.0); cGVHD n=17, 20% (CI95: 0.7-59.6) (Figure 1A and 1B). Probability of 1-Year Overall Survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Figure 1C). Immune reconstitution was robust with 1 yr NK, CD3, CD4 and CD8 204±37 cells/μL, 795±168 cells/μL, 408±102 cells/μL and 375±90 cells/μL, respectively. Two-yr PFT results were also robust with % predicted FVC, FEV1, TLC and DLCO of 89%, 84%, 82%, and 68%, respectively. All survivors are free of SCD symptoms and without signs of progression of multi-organ toxicity. One patient developed late hepatic SOS and died at day +59; one patient died at day +390 due to complications of CGVHD, and one patient died at day +141 of steroid refractory aGVHD, the remainder are alive and free of SCD symptoms with a median follow-up of +711 days (range, +231 to +1684 days). Most importantly, mean + SD HRQL score (0-100) reported at 1 yr for emotional, physical functioning, role, and global scores were 82.9±9.7 points, 82.8±15.8 points, 89.6±13.3 points, and 86±8.2 points, respectively.Early results indicate promising results in 1 yr OS, stable donor chimerism, and low incidence of acute and/or cGVHD after FHI HCT utilizing CD34 enrichment and CD3/MNC addback in high-risk SCD patients who lack a MSD or URD. A longer term follow-up is needed to assess long-term safety and outcomes. This research was supported by RO1FD004090-01A1. [Display omitted] DisclosuresWalters:AllCells, Inc: Other: Medical Director; bluebird bio: Research Funding; Sangamo Therapeutics: Consultancy; ViaCord Processing Lab: Other: Medical Director. Cairo:Jazz Pharmaceuticals: Speakers Bureau.

Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Time-Restricted Versus Standard Duration Immunosuppression after Allogeneic Hematopoietic Stem Cell Transplantation: Results from the Prospective Randomized Phase III HOVON-96 Trial

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality. The current standard Dutch regimen for prevention of GVHD in T-cell replete (TCR) alloHSCT following reduced intensity conditioning (RIC) consists of mycophenolic acid (MA) and cyclosporine A (CyA) for three and six months post-transplant, respectively. However, as approximately 30% of patients will never develop GVHD, immunosuppressive overtreatment is of concern and might impair outcome. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare time-restricted immunosuppression versus a standard immunosuppressive regimen. The primary objective was to increase the proportion of patients with non-severe GVHD (either acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment) within 180 days after transplantation and to reduce the relapse rate, without increasing severe GVHD. Secondary endpoints included time to acute and chronic GVHD, progression-free survival (PFS), GVHD-free/relapse-free survival (GRFS), overall survival (OS), and adverse events. Methods Hematological patients planned to undergo TCR alloHSCT with a related or unrelated 8/8 HLA matched donor were included. The trial randomized patients between three treatment arms. The current analysis includes all patients randomized between arms A and B. Immunosuppression consisted of CyA twice daily aiming for serum trough levels of 250-350 µg/L and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day. The standard regimen (arm A) prescribed to discontinue MA at day 84 post-transplant and CyA was continued until day +120 followed by tapering until day +180. In those randomized for the time-restricted regimen (arm B) MA was discontinued at day 28 post-transplant and CyA was continued until day +84 followed by tapering. Results A total of 389 patients were randomized 1:1 between arms A and B, of whom 95% (184 in arm A versus 185 in arm B) proceeded to transplant. The median age was 55 (range: 18-71), 57% were male. Fifty-one patients received myeloablative conditioning and 318 (86%) patients RIC. Donors were matched siblings for 135 patients and matched unrelated donor (MUD) for 233 patients. The majority of patients received peripheral blood stem cells, consisting of median 6.46x106/kg CD34+ cells/kg (range: 0.94-26.3) and median 230x106/kg CD3+ T cells (range: 0-936). Baseline patient and transplantation characteristics were equally distributed between the treatment arms. The proportion of patients developing non-severe GVHD within 180 days post-alloHSCT was 24% in both treatment arms, with an odds ratio (OR) of 1.01 (95% confidence interval 0.61-1.67, p 0.98). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GVHD at 6 months post-alloHSCT was not significantly different between the two arms (47% and 15% versus 52% and 18%), nor was the maximum grade or organ involvement of acute GVHD. In addition, no difference was seen in the two-year CI of chronic extensive GVHD between the two treatment arms (51% versus 49%). The three-year estimate of PFS was 51% (44-59%) versus 52% (44-59%), respectively. The three-year CI of progression/relapse was 28% in arm A versus 27% in arm B. OS at three years was 59% (0.51-0.66%) versus 57% (0.50-0.64%). The one-year estimate of the composite endpoint GRFS was 14% (9-19%) in arm A, and 17% (12-22%) in arm B. Incidences and nature of adverse events were comparable in both arms. Conclusion A time-restricted combination of MA and CyA did not increase the proportion of patients with non-severe GVHD within 180 days after transplantation and resulted in similar outcome as compared to standard immunosuppression following alloHSCT using sibling and well-matched unrelated donors. Given the observed high CI of acute grade II-IV and chronic extensive GVHD and low GRFS for both the time-restricted and standard regimen, recipients of TCR RIC alloHSCT should be considered for more intensive immunosuppression. Figure Disclosures Nur: Novartis: Consultancy. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Reduced Toxicity Conditioning for Non-Malignant Hematopoietic Cell Transplants

Background. Reduced-intensity conditioning (RIC) regimens are commonly used for hematopoietic cell transplantation (HCT) in non-malignant disorders to minimize potential drug-related toxicity from myeloablative conditioning (MAC). However, melphalan-based RIC regimens are associated with poor engraftment and need for second HCT or donor lymphocyte infusions (DLIs). This study expands on our previous experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity but myeloablative regimen to achieve sustained donor engraftment. Methods. We conducted a retrospective analysis of patients ≤25 years of age with non-malignant disorders who received targeted busulfan, fludarabine and IV alemtuzumab as conditioning for their first HCT between 2004 and 2018. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitors in all patients, plus methotrexate (n=59), methylprednisolone (n=2), or mycophenolate (n=1). The primary end point was 3-year overall survival (OS). Secondary end points included treatment-related mortality (TRM), event-free survival (EFS) defined as alive without second HCT or disease progression, and incidence of acute and chronic GVHD (aGVHD and cGVHD). Other end points included incidence of graft failure (GF) defined as &lt;5% donor chimerism in whole blood, sinusoidal obstruction syndrome (SOS) and CMV viremia. Analysis was stratified by era of HCT (2004-2011 vs. 2012-2018). Results. We identified 62 patients with a median age of 5.5 years and male:female of 46:16. Diagnoses included primary immune deficiencies (60%), hemoglobinopathies (22%), bone marrow failure disorders (8%) and inherited metabolic disorders (10%). The median busulfan cumulative area-under-the-curve (cAUC) was 70 mg*h/L (range, 57-108 mg*h/L). Donors were matched sibling (MSD) in 27%, 8/8 allele-matched unrelated (MUD) in 50% and Class I allele-mismatched (MM) in 23%. All but 2 of the Class I allele-MM donors were unrelated. The source was bone marrow (BM) in 74% and peripheral blood stem cells (PBSC) in 26%. The cumulative incidence (CI) of GF was 8% (95% CI, 1-16%). In engrafted patients, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 at 1-year was 96%, 90%, 99%, and 99%, respectively. Only 1 patient required DLIs for poor chimerism. T-cell reconstitution (CD4 &gt;200 x 109/L and PHA response &gt;50% control) was achieved at a median of 182 days (range, 76-585 days). Two patients died following disease progression despite 100% donor chimerism. The CI of TRM was 10% (95% CI, 2-17%). Causes of TRM included infectious complications (n=2), hemorrhage (n=1), respiratory failure (n=3 with 2 following subsequent transplants after graft rejection). TRM incidence was significantly higher in patients with Class I MM compared to those with MSD or 8/8 allele-MUD (29% vs 6% vs 3%; p=0.024; Figure 1A). SOS occurred in 5% of patients and all resolved with supportive therapy (n=1) or defibrotide (n=2). Post-transplant CMV viremia occurred in 26% of all patients and in 71% of CMV seropositive patients. None developed CMV disease and all infections resolved with anti-viral therapy. OS and EFS at 3-years were 87% (95% CI, 78-95%) and 80% (95% CI, 70-90%), respectively. HCTs performed in the more recent era showed an OS of 97% compared to 79% in HCTs performed earlier (p=0.057; Figure 1B). OS was 97% in patients with 8/8 allele-MUD compared to 79% in those with MSD and 71% in those with Class I allele-MM (p=0.051). The 6-month CI of grade II-IV aGVHD was 7% (95% CI, 3-13%), while the 3-year CI of cGVHD was 5% (95% CI, 0-11%). GVHD incidence was higher in patients receiving PBSC compared to BM (25% vs 0%; p&lt;0.001) and in patients ≥5 years of age compared to those &lt;5 years of age (13% vs 0%; p=0.043). Patients with inherited metabolic disorders showed significantly worse OS (44%, p=0.016), EFS (33%, p=0.001) and aGVHD (33%, p=0.008) than those in other disease groups. Univariate analysis did not show any significant differences in survival or GVHD incidence by race or sex. Conclusions. Use of targeted busulfan, fludarabine and IV alemtuzumab as myeloablative conditioning in pediatric patients with primary immunodeficiencies, hemoglobinopathies, and bone marrow failure syndromes undergoing matched sibling or well-matched unrelated donor HCT provides a well-tolerated option to achieve sustained engraftment with low incidence of GVHD and toxicities such as SOS. Figure 1 Disclosures Shimano: Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding. Huang:Novartis: Research Funding. Cowan:Homology Medicine: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leadiant: Consultancy; California Institute Of Regenerative Medicine: Research Funding; NIH NIAD: Research Funding; Rocket Pharma: Consultancy; UpToDate: Honoraria; bluebird bio: Consultancy. Dvorak:Alexion Inc: Consultancy; Jazz Pharmaceuticals: Consultancy.

Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Performed in the Inpatient versus Outpatient Setting

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) is commonly performed as an inpatient procedure. The feasibility and outcomes of RIC allo-HCT in the outpatient setting is not known. We performed a single-center retrospective cohort study of patients aged ≥ 18years with hematologic malignancies who underwent RIC allo-HCT either in the inpatient or outpatient setting. Donor types included HLA-matched sibling and well-matched unrelated donors. The objectives were to compare the survival, complications, charges, and incidences of relapse, nonrelapse mortality (NRM), and acute and chronic graft-versus-host disease (GVHD) between the 2 groups. Between 2014 and 2017, 151 eligible patients were included, with 116 undergoing RIC allo-HCT in the inpatient setting and 35 patients undergoing RIC allo-HCT in the outpatient setting. Baseline characteristics were comparable between the 2 groups except for a higher proportion of patients with myeloma in the outpatient cohort (inpatient 15.5% versus outpatient 37.1%). The cumulative incidence of grades II to IV acute GVHD (inpatient 25.2% versus outpatient 25.7%), grades III to IV acute GVHD (inpatient 10.4% versus outpatient 8.5%), chronic GVHD (inpatient 38.3% versus outpatient 51.6%), NRM at 1 year (inpatient 10.8% versus outpatient 3.2%), and relapse (inpatient 24.8% versus outpatient 33.2%) did not significantly differ between the 2 cohorts. One-year progression-free survival (inpatient 64.4% versus outpatient 63.6%, P = .39) and overall survival (inpatient 73.8% versus outpatient 82.8%, P = .93) were also not significantly different between the 2 groups. The proportion of patients who developed neutropenic fever (inpatient 25.8% versus outpatient 8.5%, P = .03) and mucositis (inpatient 50.8% versus outpatient 8.5%, P < .001) and who required total parenteral nutrition (inpatient 20.6% versus outpatient 5.7%, P = .04) were more frequent in the inpatient cohort. About 51.5% of the outpatient cohort never required hospital admission in the first 100days. Outpatient HCT resulted in significantly lower charges than inpatient HCT in the first 100days (median charges: inpatient $339,621 versus outpatient $247,334; P < .001). On multivariate analysis the site of the HCT (outpatient versus inpatient) was not a significant predictor of either overall or progression-free survival. Outpatient RIC allo-HCT is feasible and safe with daily outpatient evaluation and aggressive supportive care resulting in outcomes comparable with those who received the transplant in the inpatient setting.

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants

AbstractOptimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.

Long-term clinical outcomes of hematopoietic cell transplantation for intermediate-to-poor-risk acute myeloid leukemia during first remission according to available donor types

Standard therapy for acute myeloid leukemia (AML) consists of hematopoietic cell transplantation (HCT) including autologous-HCT (AUTO) and allogeneic-HCT from a matched-sibling donor (MSD) or well-matched unrelated donor (WM-URD). When a conventional donor is not available, HCT from a partially-matched (PM)-URD or familial-mismatched donor (FMMD) is typically considered. We analyzed 561 patients with intermediate to poor-risk molecular cytogenetics who underwent transplant from 2002 to 2013 in their first remission. Engraftment was successful in all donor types except five patients who died in aplasia. Disease-free survival (DFS) at 5 years was 61.4% for MSD, 62.1% for WM-URD, 65.3% for FMMD, 44.7% for AUTO and 36.8% for PM-URD. AUTO showed the highest relapse rate (51.0%) compared to MSD (23.5%) and FMMD (18.5%), but showed the lowest 5-year non-relapse mortality (NRM) rate (3.8%). PM-URD showed the highest NRM (29.3%) with more instances of acute graft-vs.-host disease (GVHD) with grade≥III (29.3%), compared to MSD (15.6%) and FMMD (15.7%). In a poor-risk subgroup, the 5-year DFS for FMMD and MSD was 59.8% and 46.7%, respectively, while for AUTO and PM-URD it was 12.6% and 0.0%, respectively, which was caused by a high relapse rate (87.1% in AUTO, 83.3% in PM-URD). In the intermediate-risk subgroup, the 5-year DFS of AUTO (53.9% was not different from the conventional donors in multivariate analysis, presenting a low NRM rate (5.1%). FMMD should be considered prior to PM-URD in intermediate-to-poor-risk AML and GVHD prophylaxis should be intensified when PM-URD is needed. AUTO might be considered for selected patients in the intermediate-risk group.

Transplantation for bone marrow failure: current issues.

The preferred treatment of idiopathic aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-identical sibling donor. Transplantation from a well-matched unrelated donor (MUD) may be considered for patients without a sibling donor after failure of immunosuppressive therapy, as may alternative transplantation (mismatched, cord blood or haplo-identical HSCT) for patients without a MUD. HSCT may also be contemplated for congenital disorders in cases of pancytopenia or severe isolated cytopenia. Currently, HSCT aims are not only to cure patients but also to avoid long-term complications, notably chronic graft-versus-host disease (GVHD), essential for a good quality of life long term. This paper summarizes recent advances in HSCT for idiopathic and inherited AA disorders. The effect of age on current transplantation outcomes, the role of transplantation in paroxysmal nocturnal hemoglobinuria, and the prevention of GVHD are also discussed. Emerging strategies regarding the role of up-front unrelated donor and alternative donor HSCT in idiopathic AA, along with advances in the treatment of clonal evolution in Fanconi anemia, are also examined.

A Stem Cell Donor for Every Adult Requiring an Allograft for Acute Lymphoblastic Leukemia?

A Stem Cell Donor for Every Adult Requiring an Allograft for Acute Lymphoblastic Leukemia?

Allogeneic Hematopoietic Stem Cell Transplantation in Thirty-Four Pediatric Cases of Mucopolysaccharidosis—A Ten-Year Report from the China Children Transplant Group

We investigated the efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric patients with mucopolysaccharidosis (MPS). A retrospective analysis of transplantation data from 34 cases of MPS from the China Children Transplant Group, treated between December 2004 and September 2015, was conducted. Among the 34 cases, 12 cases were type I, 12 were type II, 4 were type IV, 4 were type VI, and 2 were of an unknown type. The median age at transplantation was 3.75 years (range, 1 to 7 years); the median follow-up time was 14 months (range, 2 to 119 months). Eleven patients underwent unrelated cord blood transplantation and 23 underwent peripheral blood stem cell transplantation (4 cases with an HLA-matched sibling donor, 2 cases with an HLA-mismatched related donor, and 17 cases with an unrelated donor). A busulfan-based myeloablative regimen was used as a conditioning regimen. The estimated overall survival at 3 years was 84.8% ± 6.3% and 91.2% of the patients (31 of 34) achieved full donor chimerism. Twenty-seven children were evaluable and all but 1 (carrier sibling donor; enzyme level improved but failed to reach normal) achieved normal enzyme level after transplantation. The incidence of grades II to IV acute graft-versus-host disease (aGVHD) was 41.1% (14 of 34), wherein the incidence of grades III and IV aGVHD was 11.8% (4 of 34). The incidence of moderate-to-severe chronic graft-versus-host disease was 5.9% (2 of 34). There was a significant difference in the survival rate between children who received transplantation before 2009 and those after 2009 (55.6% versus 95.7%, P = .002); the survival rate was lower in patients with pneumonia before transplantation than in those with no active infection before transplantation (66.7% versus 95.5%, P = .019), and no significant differences in survival rates were observed among children with different disease types, ages at transplantation, donor/graft source, and conditioning regimens. After transplantation, upper-airway obstruction, hepatosplenomegaly, and corneal clouding were significantly improved; hearing and motor function were improved to a certain extent; valvular heart disease was improved in some patients but progressed in others; and short stature and speech skills showed little improvement. AlloHSCT may save the lives of patients with MPS I, II, IV or VI and could improve quality of life. Pretransplantation pneumonia affects transplantation outcomes. Advances in transplantation protocols and techniques help to improve patient prognosis. Well-matched unrelated donors can also be an ideal donor source. Standardized follow-up and a multidisciplinary team contribute to accurate evaluation of long-term post-transplantation outcome and further improve the quality of life of MPS patients.

Long Term Clinical Outcome of Hematopoietic Cell Transplantation for Intermediate to High-Risk Adult AML in Complete Remission; Can We Enhance the Survival Outcome Using Alternative Donor Types?

Background: Standard therapy for intermediate to high-risk acute myeloid leukemia (AML) consists of several hematopoietic cell transplantation (HCT) strategies including autologous-HCT (AUTO), allogeneic-HCT from matched-sibling donor (MSD) or well-matched unrelated donor (WM-URD). When a conventional donor is not available, HCT from partially-matched unrelated donor (PM-URD) or familial mismatched/haploidentical transplantation (FMMT) or umbilical cord blood transplantation is also considered for an alternative choice. Although HCT outcomes of those alternative strategies are advancing with optimization of pre-conditioning regimens with immunosuppressive agents, there are still subjects to debate. We tried to analyze the long-term HCT outcomes according to the donor types including FMMT and PM-URD as an alternative choice.Methods: We enrolled 561 AML patients (median 41 years old, range: 16-68) in complete remission (CR) who were transplanted in Catholic BMT Center in Korea from 2002 to 2013. Patients in at least second CR were excluded. All patients presented intermediate to high-risk karyotype according to the NCCN guidelines, and all of the patients received standard 3+7 chemotherapy followed by consolidation chemotherapy. In the absence of MSD and WM-URD, we allocated PM-URD or AUTO as an alternative choice first, and then FMMT was considered. We divided patients according to the 5 donor types (i.e. MSD (n=252), WM-URD (n=112), PM-URD (n=41), AUTO (n=104), and FMMT (n=52)), and survival outcomes with the cumulative incidence of relapse (CIR), non-relapse mortality (NRM), acute/chronic GVHD and CMV reactivation were analyzed.Results: Engraftment was successful and showed similar recovery pattern in all donor types. Our data showed mismatch in ABO, sex, and certain HLA locus was not influential, and stem cell source and conditioning-intensity were not also influential for survival outcome and incidence of GVHD. After median follow-up of 54.3 month (range: 6.6-145.6), MSD, WM-URD and FMMT showed similar 5-year OS around 62% except for AUTO at 47.4% and PM-URD at 36.7%. DFS at 5-years was 59% for MSD, 56% for WM-URD, 62% for FMMT, 44.3% for AUTO, and 33.5% for PM-URD. Five-year CIR rate was highest in AUTO (50.3%) followed by PM-URD (33.1%) and WM-URD (29.8%). Lower CIR-rate was identified in MSD (22.4%) and FMMT (21.4%), and the lowest NRM rate was identified in AUTO subgroup (5.1%) followed by WM-URD (11.4%), FMMT (15.6%) and MSD (18.0%). PM-URD showed the highest NRM rate (33.3%) with higher incidence (26.7%) of Gr°Ã3 acute GVHD compared to 9.3% of MSD. Incidence of chronic GVHD was not significantly different. In adverse-risk subgroup, 5-year OS of MSD, WM-URD, and FMMT was 46%, 47%, and 58% respectively, while AUTO and PM-URD was 11% and 0%, which was caused by significantly higher CIR rate of 79.7% and 83.5%, respectively, compared to 31.1% of MSD. In intermediate-risk subgroup, 5-year OS of AUTO (55.2%) was not inferior to that of MSD (67.2%, p =0.330) or FMMT (64.9%, p =0.451), which showed the highest CIR rate (42.8%) and the lowest NRM (5.4%). PM-URD also showed highest NRM (39.4%) with high incidence (27.3%) of Gr°Ã3 acute GVHD.Conclusions: FMMT should be considered prior to PM-URD in intermediate to adverse-risk AML and GVHD prophylaxis should be intensified when we have to use PM-URD. AUTO might be considered in intermediate-risk AML in selected patients and prospective study should validate the utility of FMMT or AUTO in addition to the conventional donor types. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Relapsed / Refractory (R/R) Follicular Lymphoma (FL). a Joint Study Between the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)

▪Introduction. The definitive management of R/R FL remains controversial due to various treatment options, including chemoimmunotherapy, pathway inhibitors, and autologous stem cell transplantation (auto-SCT). These options can provide prolonged progression-free survival (PFS). Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Herein, we report the long term outcome of the largest sample of allo-SCT for FL ever studied as well as the identification of patient and disease related factors that were significantly associated with treatment failure.Patients. Eligible were adult patients with R/R FL having received a first allo-SCT between 2001 and 2011 from an HLA identical sibling donor (SIB) or a well-matched unrelated donor (MUD). Patients with transformed lymphoma were excluded from the analysis as well as planned second transplants, allotransplants from cord blood, mismatched donors, and transplants with ex vivo T cell depletion (TCD).Results. 1567 patients met the eligibility criteria (EBMT, n = 1115; CIBMTR, n = 452). Demographics separated by data source demonstrate some differences in transplant practices between the two regions. The CIBMTR cohort had a higher proportion of MUD recipients [167 (37%) vs 252 (23%), p < 0.001], more cases with chemoresistant disease [113 (25%) vs 145 (13%), p < 0.001], less patients having received a prior auto-SCT [53 (12%) vs 403 (36%), p < 0.001], more use of myeloablative conditioning (MAC) (145 (32%) vs 220 (20%), p < 0.001) and less use of alemtuzumab in-vivo TCD [29 (6%) vs 201 (18%), p < 0.001] compared to the EBMT cohort. Median (range) follow up of survivors in months was 58 (3 - 130) and 54 (3 - 160) for CIBMTR and EBMT patients, respectively. Cumulative incidence of acute (grades II-IV) graft versus host disease (GVHD) was 20% (18-22) at 100 days and of chronic GVHD 45% (42-48) and 55% (52-58) at 1 and 3 years, respectively for the whole series; this risk was slightly but significantly reduced in the EBMT cohort. All major outcomes [non-relapse mortality (NRM), relapse/progression (R/P), overall survival (OS) and PFS] were comparable between the CIBMTR and EBMT samples (Table 1).Table 1OutcomesCIBMTREBMTp-valueNRMN@ 1 y@ 3 y@ 5 y45021 (17-25)27 (23-32)31 (26-35)108819 (16-21)24 (21-27)28 (25-31)0.3630.1720.114R/PN@ 1 y@ 3 y@ 5 y45013 (10-16)16 (13-20)17 (13-21)108813 (11-15)18 (15-20)21 (18-23)0.8740.4800.114PFSN@ 1 y@ 3 y@ 5 y45066 (62-71)56 (52-61)52 (47-57)108869 (66-72)58 (55-61)52 (48-55)0.3750.4950.792OSN@ 1 y@3 y@ 5 y45274 (70-78)65 (60-69)61 (56-65)110475 (72-78)67 (64-70)62 (59-65)0.5890.4550.695Multivariate analysis indicated that NRM was significantly affected by age (HR 1.04, 1.02-1.05, p < 0.0001), chemoresistant disease (HR 1.61, 1.28-2.03, p < 0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.62, 1.20-2.19, p=0.0015) and Karnofsky performance score (KPS) < 80 (HR 2.05 (1.32-3.19, p=0.0014); R/P was significantly affected by grade 3 histology (HR 1.63, 1.16-2.26, p=0.0049) and chemoresistant disease (HR 1.46 (1.07-1.97), p=0.0156); PFS by grade 3 histology (HR 1.42, 1.15-1.76, p=0.0012), chemoresistant disease (HR 1.54, 1.28-1.86, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.45, 1.13-1.85, p=0.0031), MAC (HR 1.36, 1.14-1.63, p=0.0008) and KPS < 80 (HR 1.78, 1.23-2.58, p =0.0022) and OS by age (HR 1.03, 1.02-1.04, p<0.0001), grade 3 histology (HR 1.44, 1.13-1.83, p=0.0031), chemoresistant disease (HR 1.59, 1.30-1.95, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.63, 1.25-2.13, p=0.0003), MAC (HR 1.42, 1.16-1.73, p=0.0006) and KPS < 80 (HR 2.23, 1.52-3.25, p<0.0001). Of note, outcomes between SIB and MUD were similar (3y OS 68% and 62%, P=0.114). Moreover a significant impact of TCD and prior auto-SCT could not be detected.Conclusions. This study represents an example of a fruitful cooperation between two important scientific transplant societies, the EBMT and CIBMTR. Despite significant differences in patient characteristics and transplant strategies between these 2 hitherto largest samples on allo-SCT for R/R FL, long-term disease control was similar and remarkably good with an R/P risk of about only 20% at 5 years. Chemoresistant disease, higher age, multiple pretreatment lines, poor KPS, and MAC all were predictors for an adverse outcome, whereas MUD, TCD, and prior auto-SCT had no impact on any survival endpoint. DisclosuresSureda:Takeda: Consultancy, Honoraria, Speakers Bureau. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Honoraria. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy.

Haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia.

Severe aplastic anemia (SAA) is a life-threatening disorder for which allogeneic hematopoietic stem cell transplantation (HSCT) is the current available curative treatment. HSCT from matched sibling donors (MSDs) is the preferred therapy for children with acquired SAA. For patients who lack MSDs, immunosuppressive therapy (IST) is widely accepted as a first-line treatment before considering HCT from an unrelated donor (URD). Given the recent progress in HSCT using URDs for childhood SAA, well-matched URDs became a realistic alternative for pediatric patients who have no suitable related donors and who are refractory to IST. However, it is quite challenging to treat patients with refractory SAA who lack suitable related or URDs. Even though haploidentical HSCT from genetically mismatched family members seemed to be an attractive procedure with the amazing benefit of readily available donors for most patients, early attempts were disappointing because of refractory graft-versus-host disease (GVHD) and excessively high transplant-related mortality. Recent advances with effective ex vivo depletion of T cells or unmanipulated in vivo regulation of T cells, better supportive care, and optimal conditioning regimens have significantly improved the outcome of haploidentical transplant. Besides considerable progress in the treatment of malignant diseases, recent emerging evidences for haploidentical HSCT in SAA has provided additional therapeutic options for patients with refractory diseases. Further improvements to decrease the rates of graft failure, GVHD, and infectious complications will facilitate the emergence of haploidentical HSCT as a front-line therapy for treating acquired SAA in children and adolescents who have no suitably matched donors.

Novel Immunosuppressive Approach Attenuates Severe Aplastic Anemia in Mouse Lymphocyte Infusion AA Models

Aplastic Anemia (AA) is an immune-mediated and life-threatening form of acquired bone marrow failure. AA ranges from moderate to severe AA, and is characterized by development and expansion of self-reactive effector T cells, which cause apoptosis of mature blood cells, progenitors and hematopoietic stem cells (HSCs). Current treatments for AA, which are not always effective or feasible, include immunosuppressive therapy (IST) and allogeneic HLA-identical sibling or well-matched unrelated donor BM transplant. Because the self-antigens triggering AA remain to be identified, mouse lymphocyte infusion models of AA with striking similarities to human AA have been developed utilizing alloantigen recognition. The AA in these models is induced by infusing lymph node cells (LNCs) from C57BL/6J mice into MHC partially mismatched F1 hybrid B6D2F1 or CByB6F1 recipients, or into minor-H antigen mismatched C.B10 recipients. The host mice develop SAA without any clinical signs of generalized GVHD, and characterized by BM infiltration and oligoclonal expansion of donor effector T cells, apoptosis of all host BM cells, severe BM aplasia and death within 3-5 weeks after LNC infusion. These preclinical mouse models represent a very useful in vivo system for testing new therapeutic approaches to treat and manage SAA. Activation of self-reactive T cells in human AA and alloreactive donor T cells in mouse AA models involves interaction of T cells with dendritic cells (DCs) as professional APCs. DCs express β2 integrin CD11b/CD18 (Mac-1), which plays an important role in inflammation, cell-mediated killing and cell activation. Notably, Mac-1 expressed on DCs is inactive and is not activated on contact with T cells. More importantly, activation of Mac-1 on DCs by Mg2+ treatment significantly reduces their T cell-activating capacity, and active CD11b represses DC cross-priming of cytotoxic T cells. Thus, activation of Mac-1 on DCs represents a potential new immunosuppressive strategy for reducing pathological T cell responses in AA. Dr. Gupta has identified novel Mac-1 agonists, termed Leukadherins (LAs1-3) that bind to and activate Mac-1. Multiple lines of experimental evidence generated by Dr. Gupta’s and Dr. Jurecic’s groups have shown that LAs have potent anti-inflammatory and immunosuppressive properties. For example, treatment with LA1 is safely and effectively reducing the onset and severity of Experimental Autoimmune Encephalomyelitis (EAE) in mice, induced by Myelin Oligodendrocyte Glycoprotein (MOG). Moreover, in EAE mice LA1 efficiently decreased the activation of myelin-reactive T cells and their IFN-γ production. We hypothesized that by activating Mac-1 on DCs LAs could effectively (a) reduce T cell-activating capacity of DCs and attenuate allo-reactive T cell responses, and (b) reduce severity of AA in mouse models. Indeed, in mixed lymphocyte reaction, which depends on stimulation of allogeneic T cells by DCs, LA1 significantly suppressed proliferation of lymph node T cells from C57BL6/J mice in the presence of irradiated splenocytes from allogeneic DBA/2J mice. SAA was induced in B6D2F1 mice by tail vein injection of 5 x 10e7 LNCs from C57BL/6J mice. The untreated AA mice died within 21 days of LNC infusion and exhibited (a) severe BM aplasia, (b) ~5-fold expansion of CD4+ T cells and >20-fold expansion of CD8+ T cells in comparison to Control B6D2F1 mice, and (c) severe depletion of HSCs (LSK CD150+ CD48- BM cells); Multipotent progenitors (MPPs, LSK CD150- CD48- BM cells); and Hematopoietic progenitors (HPC-1, LSK CD150- CD48+ cells; HPC-2, LSK CD150+ CD48+ cells). In contrast, AA mice treated IP with 1 mg/kg/day of LA1 for 7 or 21 days after LNC infusion exhibited (a) mild BM aplasia and improved BM cellularity, (b) significantly reduced expansion of CD4 (~2-fold) and CD8 (~12-fold) T cells in the BM, and (c) significantly improved frequency and total numbers of HSCs and progenitors in comparison to untreated AA mice. More importantly, treatment of AA mice with LA1 for 21 days resulted in 40-50% of AA mice surviving for more than 7 weeks after LNC infusion. These results demonstrate that treatment with LA1 can safely convert SAA into a moderate disease in preclinical mouse AA models and provide a platform for testing of LAs as new alternative or adjuvant therapy to manage ongoing AA in patients who (1) are not responding to IST and are not candidates for BMT, and/or (2) are undergoing IST and awaiting BMT. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities

Allogeneic BM transplantation from an HLA-identical sibling donor leads to long-term survival in the majority of patients (>80%). Therefore, survival is no longer the sole concern and attention has to be paid to decreasing the incidence and severity of long-term complications. For patients without a sibling donor, transplantation from a well-matched unrelated donor can be considered after failure of a previous course of immunosuppressive therapy. After transplantation from an HLA-identical sibling donor or from an unrelated one, the use of peripheral blood stem cells must be strongly discouraged because they have been systematically associated with an increased incidence of chronic GVHD compared with the use of BM as a stem cell source, leading to an unacceptably higher risk of treatment-related mortality in this setting. For as yet unknown reasons, the age limit after which transplantation results are less satisfactory remains 40 years of age.

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

AbstractWe conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N = 1025; TBI, N = 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval [CI]), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P = .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P = .03) and TBI, respectively. Corresponding incidences of transplant-related mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P = .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P = .08). The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.