Donor Mismatch Research Articles

Clinical Correlates and Outcomes of Dual Basiliximab and Antithymocyte Globulin Induction in Kidney Transplant Recipients: A National Study.

We used national transplant registry data to study clinical correlates and outcomes of single versus dual induction therapy in adult kidney-only transplant recipients in the United States (2005-2018). The risk of death and graft loss at 1 and 5 y, according to induction therapy type, was assessed using multivariate Cox regression analysis (adjusted hazard ratio with 95% upper and lower confidence limits [LCLaHRUCL]). Of the 157 351 recipients included in the study, 67% were treated with ATG alone, 29% were treated with IL2rAb alone, and 5% were treated with both. Compared with IL2rAb alone, the strongest correlates of dual induction included Black race, calculated panel reactive antibody ≥80%, prednisone-sparing maintenance immunosuppression, more recent transplant eras, longer cold ischemia time, and delayed graft function. Compared with ATG alone, dual induction was associated with an increased 5-y risk of death (aHR 1.071.151.23; P < 0.0001), death-censored graft failure (aHR 1.051.131.22; P < 0.05), and all-cause graft failure (aHR 1.061.121.18; P < 0.0001). Further research is needed to develop risk-prediction tools to further inform optimal, individualized induction protocols for kidney transplant recipients.

Comparison of the clinical outcomes between NIMA-mismatched and NIPA-mismatched haploidentical hematopoietic stem cell transplantation for patients with hematological malignancies.

The objective of this study was to compare clinical outcomes between noninherited maternal antigen (NIMA)-mismatched and noninherited paternal antigen (NIPA)-mismatched haploidentical hematopoietic stem cell transplantation (haplo-HSCT) among patients with hematological malignancies and perform a subgroup analysis. We retrospectively analyzed 378 patients with hematological malignancies who received haplo-HSCT from NIMA-mismatched (n = 201) and NIPA-mismatched (n = 177) donors between January 2012 and December 2017. The cumulative incidence of 100-d grades II-IV acute graft-versus-host disease (aGVHD) (19.2% vs. 32.8%, P = 0.003) was significantly lower in NIMA mismatch. Multivariate analysis showed that NIMA mismatch was associated with lower incidence of grades II-IV aGVHD and better overall survival (OS) and disease-free survival (DFS). According to the subgroup analysis, the clinical outcomes of older and/or female NIMA mismatches were comparable to those of younger and/or male NIPA mismatches with respect to grades II-IV aGVHD, chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse, DFS, and OS. In conclusion, this study confirmed the NIMA effect on aGVHD and demonstrated that NIMA mismatch was associated with better survival. In the NIMA mismatch context, donor age and sex did not seem to influence haplo-HSCT, which provides a basis for the selection of sibling donors.

The correlation between preoperative volumetry and actual graft weight of liver according to the donor age

Liver volume assessment is essential to provide adequate graft volume (GV) to recipients and ensure safety to donors in living donor liver transplantation. This study aims to compare the GV calculated by preoperative liver volumetry and graft weight (GW) measured during surgery according to the donor age and the influence of GRWR mismatch on patient survival. Data from 771 living donors between 2005 to 2020 in Severance hospital were reviewed. We defined GW mismatch as a discrepancy ≥ 10% between preoperatively estimated and actually measured GRWR. Donor groups were divided into 6 groups based on ten year age interval and data were compared according to their age. Recipient survival outcomes were analyzed in accordance with the GRWR mismatch. The proportion of GRWR mismatch donors was not different across the donor age groups (47% vs. 43% vs. 48% vs. 45% vs. 39% vs. 60%; p = 0.778). However, actual GRWR was significantly smaller than estimated GRWR as donor was younger (p = 0.002). Total 29 (3.7%) recipients received liver whose GRWR < 0.8 and 24% of them (n = 7) underwent portal flow modulation (splenic artery ligation, splenectomy, or renal vein ligation) during transplantation surgery. Overall survival did not differ between GRWR < 0.8 and ≥ 0.8 groups. Actual liver GW tends to smaller than estimated GV as donor is younger. GRWR mismatch was not affect overall survival of recipients.

Clofarabine-Based Reduced Intensity Conditioning Regimen with Post-Transplant Cyclophosphamide and Peripheral Stem Cell Graft in Adults with Myeloid Malignancies: Results of the Clo-Baltimore Regimen

Backgound: The Baltimore reduced-intensity conditioning (RIC) regimen using high-dose post-transplant cyclophosphamide (PTCY) is considered as a standard of care for haplo-transplant. However, it is associated with relatively low survivals (OS 46% and EFS 34% at 1 year) and high incidence of relapse (51% at 1 year), especially when considering myeloid malignancies (Luznik, 2008). Here, we have replaced fludarabine by clofarabine, a second-generation purine analogue with high anti-myeloid leukemic activity, as part of the Baltimore regimen (Clo-Baltimore regimen) and we report the results of such an approach in 36 patients with myeloid malignancies.Methods: This retrospective study included 36 adults with a median age of 60.5 (range: 31-70) years who received an allotransplant between March 2014 and March 2017. They were 18 males. Seventeen cases had acute myeloid leukemia (AML), 13 myelodysplastic syndrome (MDS), 3 myelofibrosis (MF), 1 chronic myeloid leukemia (CML), 1 mixed MDS/myeloproliferative syndrome (MPS), and 1 plasmacytoid dendritic cell neoplasm. The status at transplant was as follows: first complete remission (CR) n=16, second CR n=4, third CR n=1, active disease n=15 (MDS n=10, MF n=3; CML n=1, MDS/MPS n=1). Seven patients had already received a first allograft. Twenty-seven patients received a graft from an haploidentical donor (son n=10; daughter n=2; sister n=7; brother n=4; father n=2; nephew n=2) while 8 cases (AML n=1; MDS n=4, myelofibrosis n=2; mixed syndrome n=1) had a matched donor (sibling n=2, mud n=6) and 1 a 9/10 mis-matched unrelated donor. The Clo-Baltimore regimen consisted of Clofarabine 30 mg/m²/day days -6 to -2, cyclophosphamide 14.5 mg/kg day -6, low dose total body irradiation 2 Grays day-1, and PTCY 50 mg/kg/day days +3 and +4. All patients received PBSC as stem cell source at day 0. All patients provided informed consent for data collection before the graft.Results: Except one patient who died during aplasia of multiple organ failure (MOF), all patients engrafted. The median time of neutrophils (>1x109/L) and platelets (>50 x109/L) recoveries were 18 (range: 8-27) and 28.5 (range: 11-111) days, respectively. With a median follow-up of 12.3 months for alive patients (range: 3-39.5), 1-year and 18-month OS were both 74% (0.55-0.86), while 1-year and 18-month DFS were 74% (0.55-0.86) and 62% (0.38-0.78), respectively. At 100 days and 1 year, NRM was 5.5% and 8.3%, respectively. Seven patients have relapsed so far with a median time between graft and relapse of 90 days (range: 66-125). The 1-year relapse incidence was 19.4%. Incidences of grade 2-4 and 3-4 acute GVHD were 48% and 11.4%, respectively, while the incidence of chronic GVHD was 20% (limited 6%, extensive 14%). 1-year and 18-month GRFS were 55% (36-71) and 46% (27-64), respectively. At last follow-up, only 9 patients have died, the causes of death being relapse in 5, dermatomyositis in 1, MOF in 1, sepsis in 1 and grade 4 acute GVHD in 1.In univariate analysis, there were no differences regarding 18-month survivals between patients allografted: 1) in CR vs active disease (OS 65% vs 86%, p=0.13; DFS 56% vs 69%, p=0.18), 2)for AML vs MDS (OS 70% vs 85%, p=0.72; DFS 58% vs 85%, p=0.49), or 3) between haplo-identical vs matched+9/10 mis-matched donors (OS: 69% vs 88%, p=0.29; DFS 59% vs 61%, p=0.57).Conclusion: The Clo-Baltimore regimen has shown very encouraging results in this series for patients with myeloid malignancies, improving OS and DFS at 1 year compared to the Baltimore regimen. A low rate of relapse was observed even although using a RIC regimen, which is suitable for older patients and cases with co-morbidities. An update of the follow up will be provided at the meeting. These data have to be validated prospectively. DisclosuresTouzeau:AbbVie: Research Funding. Moreau:Onyx Pharmaceutical: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria.

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n = 274) or with (n = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p = 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p = 0.03) and HLA mismatch donor (p = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.

ATG and Post-Transplant Cyclophosphamide Do Not Abrogate the Inferior Outcome Risk Conferred By HLA-Α and HLA-B Mismatched Unrelated Donors

Background Donor selection for allogeneic stem cell transplant is a complex process, where several factors are considered for potential impact on transplant outcome. Several publications have suggested that 9/10 mismatched unrelated donors (MMUD) may be equivalent to 10/10 MUDs. However, there is debate as to whether all 9/10 mismatches (MM) are equivalent. We sought to examine this in a single centre retrospective study using ATG followed by post transplant cyclophosphamide (ATG PTCy) as standard GvHD prophylaxis and correlated outcomes in terms of donor MM, donor age and CMV serostatus. Patients and methods A total of 414 patients who received HCT from unrelated donors between Jan 2015 and Dec 2019, at Princess Margaret Cancer Centre, Canada, were enrolled in the retrospective study. Patients and disease characteristics, and outcomes are detailed in Tables 1-3. The probability of overall survival (OS) was calculated using the Kaplan Meier product limit method and heterogeneity of time to event distribution functions was compared by the log rank test. The cumulative incidences of chronic and acute GvHD, relapse, and transplant related mortality (TRM) were estimated using the cumulative incidence method considering competing risk, and groups were compared using Gray's test. Death was considered a competing event for relapse, acute and cGvHD, and relapse was considered a competing event for NRM, acute and cGvHD. GvHD outcomes shown in Table 4. Results Median OS at 5y for the whole cohort (n=414) was 45.8% (38.2-53.0), and relapse free survival was 40.2% (32.9-47.4), with TRM at 1y 23.7% (19.6-28.0), Table 5. Compared to the whole cohort (median OS 38.8mo [21.6-NA]), patients who received grafts from MMUD (n=86) had median OS 9.2mo (6.0-17.3), p&amp;lt;0.001, in particular median OS for HLA-A MM was 8.1mo (5.3-18.4), HLA-B MM 5.9 (2.7-11.8) compared to other 9/10 MMUD (n=32) 18.8mo (5.7-NA), p&amp;lt;0.001. This was due to higher TRM at 1y, MMUD 39.1% (24.0-49.4) vs MUD (n=327) 19.2% (15.0-23.8) p&amp;lt;0.001 primarily due to HLA-A MM 39.6% (24.0-54.9) and HLA-B MM 35.7% (11.7-61.1), p=0.001. GVHD-Free Relapse free Survival (GRFS) at 5y for the whole cohort was 36.8% (29.7-43.9). GRFS At 2y for 9/10 MMUD was 25.2% (16.1-35.4), HLA-A MM 21.6% (9.9-36.2) HLA-B MM 15.4% (2.5-38.8) vs MUD 51.4% (45.3-57.2), p&amp;lt;0.001. Median OS for patients who received ATG PTCY (n=298) was 49.2mo (49.2-NA), for 9/10 (n=58) 10.2mo (6.1-19.6), with HLA-A MMUD (n=26) 9.6 mo (5.8-27.4), HLA-B MMUD (n=9) 4.6mo (1-11.8) (p&amp;lt;0.001), Figure. A number of donor factors significant by univariate analysis (incl. donor age, recipient/donor CMV, CD34 dose, presence of HLA MM, type of MM, female donor to male recipient), were selected to determine correlates with all mortality by multivariable analysis (MVA). The only significant factor was 9/10 MMUD HR 2.27 (1.65-3.14), p&amp;lt;0.0001, specifically HLA-A MM HR 2.69 (1.77-4.08), p&amp;lt;0.00001, HLA-B MM HR 3.14 (1.71-5.78) p=0.0002, Table 6. The same donor factors significant by univariate analysis were examined for correlation with TRM and significance was found for HLA MM HR 2.36 (1.57-3.55) p=0.00004, specifically HLA-A MM HR 2.44 (1.42-4.17), p=0.0012, HLA-B MM HR 2.39 (1.03-5.57) p=0.0034. Graft failure (GF) occurred in 4.6% of patients. Significant donor factors for GF were CD34 dose &amp;lt;4.0x106/kg, HR 5.28 (1.11-24.98) p=0.038; and HLA MM 2.78 (1.27-6.05) p=0.01. Of 414 patients, 395 patients (95.4%) received fresh stem cells and 19 (4.6%) received cryopreserved stem cells. Cryopreserved MUD grafts were associated with GF on MVA, HR 5.56 (1.75-17.4, p=0.0034), which may be due to several possible factors including the travel time prior to cryopreservation. Among AML patients, CMV negative patients in receipt of grafts from CMV negative donors (CMV-/-) (n=64) had worse survival (HR 2.05, 1.03-4.09, p=0.04) compared to recipient/donor pairs where any were CMV positive. There was a significantly higher relapse rate in the CMV-/- (15/64, 23.4%), compared to CMV positive (30/236, 12.2%, any combination), p=0.01 by Chi-squared test. Conclusions These data suggest that HLA-A and HLA-B mismatched donors confer a significantly inferior outcome despite the use of ATG PTCy. Cryopreserved stem cells from unrelated donors were associated with graft failure, and CMV-/- were associated with higher incidence of relapse. Further work is required to develop novel conditioning regimens and GvHD prophylaxis to mitigate these risks. Disclosures Lipton: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Mattsson:Gilead: Honoraria; ITB: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Mallinkrodt: Honoraria.

Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

Human leukocyte antigen disparities reduce relapse after hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A single-center retrospective study from China.

HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). The median follow-up period was 26.0months (range: 1-105months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6±7.7% and 34.8±15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3±10.5% vs 55.5±20.9%, P˂.001), though similar rates of grade II-IV acute GVHD (60.0±22.4% vs 33.3±18.2%, P=.08), grade III-IV acute GVHD (25.0±19.5% vs 7.4±10.1%, P=.08), chronic GVHD (30.0±20.9% vs 34.9±18.8%, P=.85), NRM (20.0±18.0% vs 3.9±7.7%, P=.07), and DFS (74.4±9.9% vs 41.3±10.0%, P=.08). Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01–11.72) years. The 4-year CI of extensive cGvHD was 13 ± 2% and 17 ± 4% (p = NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60 ± 2% vs. 42 ± 5%, p < 0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9 ± 1% vs. 23 ± 4%, p < 0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.

Results of allogeneic hematopoietic stem cell transplantation in patients with chronic granulomatous disease at the Russian Children’s Clinical Hospital

Relevance. Chronic granulomatous disease (CGD) belongs to the group of primary immunodeficiencies. Patients with CGD have an impaired quality of life, severe infections and inflammatory organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment method for CGD. The authors of the article presented the experience of HSCT in patients with CGD in the Russian Children’s Clinical Hospital.Materials and methods. 20 (19 primary and 1 repeated) HSCT during the period from 2009 to 2020 were performed in nineteen patients with CGD. All patients had a long history of infections, three or more foci of chronic infection, 9 patients had a generalized BCG infection. Bone marrow (ВМ) from a related HLA-identical donor was the source of hematopoietic stem cells (HSC) for 4 (21 %) patients, peripheral blood stem cells (PBSC) for 2 (10.5 %). ВМ from a unrelated fully HLA-identical donor was performed in 9 (47.4 %) patients, PBSC – 2 (10.5 %). ВМ from a unrelated 9/10 HLA-compatible donor was performed in one (5.3 %) patient. In one case (5.3 %) the HSC source became PBSC from a unrelated 9/10 HLA-compatible donor after TcRαβ/CD19+ depletion. In 68.5 % (n = 13) cases the conditioning regimen included threosulfan, fludarabine, melphalan, and antithymocyte globulin. In 2 (10.5 %) patients, melphalan was excluded from the conditioning regimen; in 4 (21 %), it was replaced by thiotepa.Results. The overall survival (OS) was 88.9 ± 10.5 %, the event-free survival (EFS) was 88.1 ± 7.9 %, and there was no transplant mortality. Transplant rejections were observed in two patients who received HSC from a unrelated 9/10 HLA-compatible donor with a previous conditioning regimen that included only one alkylating agent. In 4 patients (21 %) there was a prolonged persistence of mixed chimerism after HSCT without clinical and laboratory signs of CGD. After successful transplantation all patients were cured of the infectious and inflammatory diseases characteristic of CGD.Conclusion. Results of HSCT in patients with CGD can be considered satisfactory, the OS and EFS are high. Failure of HSCT is associated with transplant rejection, which is most likely due to the donor and patient mismatch, as well as the use of conditioning modes with reduced intensity.

Hematopoietic cell transplantation for Diamond Blackfan anemia: A report from the Pediatric Group of the Brazilian Bone Marrow Transplantation Society.

The aim of this study was to analyze the outcomes of children with Diamond-Blackfan anemia (DBA) treated in Brazil with hematopoietic cell transplantation (HCT). We performed a retrospective analysis of 44 pediatrics patients transplanted between 1990 and 2018. The median age of patients was 5years, and 57% were male. Twenty-five received their first HCT from an HLA-matched sibling donor (MSD), 12 from a HLA matched unrelated bone marrow donor (MUD 10/10, n=12) and 7 other HLA mismatched donors (MMD). After a median follow-up of 4years, estimate 5-year overall survival (OS) for the entire cohort was 70%, 80% for MSD group, 73% for MUD, and 29% for MMD. Thirty-eight out of the 44 evaluable patients engrafted successfully. Primary and secondary graft failure was observed in five and three patients, respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 25% and 18%, respectively. Nine patients developed chronic GVHD (cGVHD). Overall survival rates observed after HLA matched donors transplant for DBA were comparable to those reported from higher-income countries and international registries.

Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation.

The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors. Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients. In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype. The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.

Prognostic Value of Dobutamine Stress Echocardiography in Heart Transplant Recipients

Dobutamine stress echo (DSE) carries a class IIa recommendation for screening of cardiac allograft vasculopathy (CAV). Positive DSEs have a modest ability to predict development of CAV, but normal DSE has a low negative predictive value for CAV. Ability of a positive DSE to predict outcomes is controversial. Outcomes following a normal DSE have not been assessed in large, modern cohorts. We sought to analyze the prognostic value of DSE in heart transplant recipients. All adult heart transplants performed at our institution from 2000 to 2010 were reviewed. Multi organ, recipients who expired within the first year, and those who did not have a DSE were excluded. Patients were grouped according to their DSE result and CAV grade and survival were analyzed. We also analyzed outcomes in patients with a normal DSE and predictors for CAV in this cohort. Unpaired t-test used for analysis. Kaplan-Meier survival curves generated. P value <0.05 considered significant. 179 (mean age 56.6 yrs, 77.6% male) heart transplant recipients were included. 26 (14.5%) patients had a positive DSE. 143 (79.9%) patients subsequently underwent coronary angiography [median duration 9 (1.1 - 17.2) yrs after transplant]. Positive DSE was associated with development of angiographically significant CAV (40% vs 12.2%, P=0.0015) and higher grade CAV (mean grade 1.2±1.2 vs 0.6±0.8, P=0.0077). Those with a positive DSE had a worse 10 yr survival (45.8% vs 68.7%, P=0.0092). Of those with a normal DSE, 15 (12.2%) developed significant CAV. In the normal DSE cohort, there were no differences in demographics, CMV mismatch status, HLA DR mismatch level or donor age between those who developed significant CAV and those who did not. Following a normal DSE, there was no difference in 10 yr survival (80% vs 77.7%, P=0.88) between those who developed and did not develop CAV. Positive DSE is associated with development of significant CAV and worse survival. Normal DSE is associated with better survival, regardless of development of CAV.

HLA antibodies in haematopoietic stem cell transplantation.

The negative impact of donor specific HLA alloantibodies in solid organ transplantation is well known and understood within the histocompatibility and immunogenetics community. However the influence of donor-specific antibodies in the outcome of haematopoietic stem cell transplantation is less well regarded. As donor choices have evolved from HLA matched siblings and extremely well matched unrelated donors to mismatched cord blood and haplo-identical-related donors, we are now identifying more patients with antibodies reactive against their donor mismatches. The clinical significance of the antibodies that can be detected has not yet been fully elucidated.

Patient Age and Donor HLA Matching Can Stratify Allogeneic Hematopoietic Cell Transplantation (HCT) Patients into Prognostic Groups: A Collaborative Study

BACKGROUND: Allogeneic hematopoeitic cell transplant (HCT) is potentially curative for a variety of hematological diseases. It is however associated with significant morbidity and mortality. Numerous pre-transplant risk scores have been developed to predict outcomes, such as the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). This study assesses the value of the HCT-CI and related scores on a single center population, in comparison with other potential parameters influencing outcomes. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway. METHODS: Two experienced physicians prospectively calculated the HCT-CI score for all patients transplanted at our center. The age-adjusted HCT-CI score and the augmented HCT-CI score were calculated retrospectively. Prospective calculation was performed during the patient's pre-transplant assessment before transplant admission using a pre-prepared form. The HCT-CI/age and the augmented HCT-CI (which includes ferritin, albumin and platelet count) were calculated using additional data retrospectively collected from the electronic patient records (EPR). All other patient and transplant characteristics were retrospectively collected from the EPR. Non-Relapse Mortality (NRM) and Overall survival (OS) were calculated to assess the prognostic power of the scores. We also looked at the impact of major transplant and patient related parameters in our patient population. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway. RESULTS: From August 2014 to April 2017, 299 patients underwent allogeneic HCT at the Princess Margaret Cancer Centre (PMCC), Toronto. A similar analysis was performed in a cohort of 455 patients from Oslo University Hospital who underwent HCT between 2012 and 2018. Comparative patient characteristics are described in Table 1. On univariate analysis, 2-year OS of the PMCC cohort was 51% (95% CI 45-56%). For the HCT-CI scores 0-2 vs ≥3, 2-year OS was 53% vs 46% respectively (p=0.29). For the HCT-CI/age scores 0-2 vs ≥3, it was 56% vs 44% respectively (p=0.03). For the augmented HCT-CI scores 0-2 vs ≥3, it was 55% vs 46% respectively (p=0.05). Among other variables, age group (&lt;50 vs 50-64 vs ≥65, p=0.02) and donor mismatch (p=0.01) were significant for OS. However, age (HR 1.48 and 1.75 for age 50-64 and ≥65 respectively, p=0.047) and donor mismatch (HR 1.60, p=0.02) alone were also prognostically significant in the multivariate analysis as well. We then developed a weighted score that would better reflect risk groups in our population. Age &lt;50 and full HLA matching received 0 point each, age 50-64 and any mismatch (except DQ alone) received 1 point each, while age ≥65 received 2 points. The patients were grouped into 3 groups of 0, 1 and ≥ 2 points. This new simple 3 tier score predicted OS and NRM at 2 years with better accuracy. The 2 yr OS was 62%, 53% and 38% for the 3 groups (p value =0.0004) and 2 year NRM was 24%, 34% and 43% respectively (p value=0.015) (Table 2 and Figure 1). The same scoring system was later applied to an independent cohort of allogeneic HCT patients from the Oslo HCT registry and was found to be similarly significantly predictive of OS and NRM. In the Oslo cohort, the 2 yr OS was 69%, 65% and 35% for the 3 groups according to the new weighted score (p value &lt;0.001) and 2 year NRM was 15%, 20% and 45% respectively (p value=0.015) CONCLUSION: A simple, weighted score involving donor HLA mismatch and age predicts survival and NRM better than the HCT-CI score for patients transplanted at our center with good replicability as shown from Oslo data. Efforts should continue to strive for the development of a widely applicable pre-transplant outcome predictive scoring system. Disclosures Mattsson: Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria. Michelis:CSL Behring: Other: Financial Support.

KIR-Genotype Mismatch, Donor KIR Locus 3DS1 Positive or 2DS3 Negative Facilitates a Positive Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Retrospective Study of 74 Patients

Objection: To investigate the potential influence of donor-recipient KIR genotype matching and KIR alleles on the prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Method :74 cases of AML patients who admitted and treated in the transplantation ward of our hospital from May 2015 to May 2019 were analyzed retrospectively. Binary Logistic regression and k-m survival curve were used to demonstrate the influence of donor age, blood group ABO compatibility, donor-recipient HLA matching, donor-recipient KIR mismatch model and donor KIR gene locus on the transplant outcome. Result :Among the 74 patients with AML, 44 were male (59.5%) and 30 female (40.5%), with the median age of 24 years (1-59 years). 49 cases (66.2%) were in remission at the time of transplantation, and 25 (33.8%) not in remission. aGVHD occurred in 16 patients (21.6%) and recurrence occurred in 11 patients (14.9%). Multivariate analysis revealed that KIR-genotype matching was closely related to the increased risk of aGVHD. The incidence of aGVHD in the KIR mismatching group was significantly lower than that in the matching group (12% vs 31%, P=0.019), but no significant effects on survival and recurrence. Donor KIR 3DS1 negative had an increased risk of aGVHD compared with those with 3DS1 positive (28.2% vs 11.7%, P=0.033). The recurrence rate (RR) of donor KIR 2DS3 negative, even when the recipients with hematologic malignancies were not in remission at the time of HSCT, were much lower than those with 2DS3 positive (10% vs 66.7%, P=0.045). However, donor age, blood group ABO compatibility, donor-recipient HLA matching, and other donor KIR locus had no significant effect on OS, aGVHD and RR. Conclusion: Thus, it is recommended to select the donor with KIR mismatching, KIR locus 3DS1 positive or 2DS3 negative to improve the outcome of allo-HSCT by reducing the risk of aGVHD or recurrence risk, which offer a clinically applicable donor selection strategy. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation in Patients of 65 Years or Older: A Monocenter Analysis on 252 Patients

Advanced hematologic malignancies in older patients are unmet medical needs due to increased incidence in the aging population and the lack of effective treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential curative option for most of hematologic malignancies. However, two main limitations limited this development for a long period of time. High rates of fatal non-relapse morbidities have been progressively addressed using reduced toxicity conditioning approaches and pushing up the age limit of patients considered for transplant. The search for a donor has been also a high limitation in older population, due to the lower incidence of matched sibling donors in this population. The development of allo-HSCT from a familial haplo mismatch donor (Haplo donor) after a reduced intensity (RIC) or non-myeloablative conditioning (NMAC) has allowed for the recent development of allo-HSCT in older population. Here we analyzed a cohort of 252 consecutive patients aged of 65 years or older treated in a single institution. Patients were selected on the following parameters: age of 65 or older on the day of transplant, first allogeneic transplant, no unrelated cord blood HSCT, hematologic malignancies, transplant between 01/01/2004 and 31/12/2018. During this period of time, the search for a one-mismatch haplotype donor (Haplo) has been introduced, the upper limit age for transplant progressively increased, more advanced diseases were considered and patients have gradually benefit from improvement in transplant care. Patient characteristics: Median age: 67,9 (65-77) years; Male patients: 61 %; CMV Positive (70%); Acute leukemia (AL): 43%; Myelodysplastic/myeloproliferative syndromes (MDS/MPS): 35%; Chronic Leukemia: 5%; Lymphoma: 11%; Plasma cell disorders (PCD): 6%. Complete remission (CR) or Chronic phase: 155 (62%) (of whom 81 CR1 AL) Donor characteristics: median age: 62,45 (19-77); Male patients: 63 %; Matched sibling donor (MSD) (24%): 60: Unrelated donor: 75 (29%); Haplo Donor: 118 (47%). Transplant characteristics: % patients per period of time: year range: 2004-2010: 12% (Median age: 67; % Haplo D: 0; No CR/CP: 23%); 2011-2015: 40% (Median age: 68; % Haplo D: 35%; No CR/CP: 39%); 2016-2018: 48% (Median age: 69; % Haplo D: 69%; No CR/CP: 42%); PBSC: 97%; Non Myeloablative/ Reduced toxicity conditioning: 35%/65%; All patients received Post-Transplant (PostT) CSA; PT Cyclophosphamide: 49%; Pre-Transplant ATG: 47%. Median follow-up: 17 (3-112) months; ANC recovery in 96%: 19 (10-44) days; untransfused platelet recovery above 20 in 75%: 17 (7-56) days. In evaluable patients for aGVHD: No: 58%; Grade 1: 13%; Grade 2: 14%; Grade 3: 10%; Grade 4: 4%; 85% patients were evaluable for cGVHD: No: 68%; limited: 17%; extensive:16%; 64 patients (25%) patients died from non-relapse mortality at a median of 122 days (13-3934): 2004-2010: 10/30 (33%); 2011-2015: 36/101 (25%); 2016-2018: 28/121 (23%); 53 patients relapsed/progressed at a median of 252 (30-2764) days. Three year overall and disease-free survivals are respectively of 56% (95% CI: 6.35-7.04) and 47% (95% CI: 7.17-7.55) without any difference according to age or donor type but with an impact of disease status (EFS: CR/CP 51% (95% CI: 8.7-9.5) vs others 38% ((95% CI: 11.9-12.0)) Overall these data show that allo HSCT is a valid option in older patients with high-risk malignancies. They show also that over a long period of time patient typology (more advanced diseases, older patients) and transplant practice (lower number of MSD) show a regular evolution making transplant realization more challenging. This field needs specific approach taking into account comorbidities, performance status and geriatric evaluation, to adapt treatment to every given patient. In this perspective we performed from 2015 in patients older than 65 years systematic and combined evaluation of comorbidities score, performance status and geriatric assessment (instrumental activity of daily living (AIDL); vulnerability assessment). Disclosures Chabannon: Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria.

Similar outcomes of alemtuzumab-based hematopoietic cell transplantation for SAA patients older or younger than 50 years

AbstractSurvival after allogeneic hematopoietic cell transplantation (HSCT) for severe aplastic anemia (SAA) among older patients remains poor and associated with increased risk for graft-versus-host disease (GVHD). In this retrospective study of 65 consecutive patients with acquired SAA who were transplanted using fludarabine, low-dose cyclophosphamide, and alemtuzumab (FCC), outcomes of 27 patients aged at least 50 years were compared with those of 38 patients younger than 50 years. The median age of the older cohort was 61 years (range, 51-71 years); 21 (78%) patients were transplanted from unrelated donors (3 of 21 from HLA 9/10 mismatch donors) and 6 from matched sibling donors. One-year GVHD-free, relapse-free survival (GRFS) was comparable to that of patients younger than 50 years (84% vs 94%, respectively; P = .23). Both groups showed low rates of acute (5% vs 4%) and chronic (18% vs 14%) GVHD, with no cases of severe GVHD among matched donor transplants, and similar 1-year transplant-related mortality (14% vs 5.4%, older vs younger; P = .23). HSCT comorbidity index (HTC-CI) scores were similar between the groups, but overall survival with an HCT-CI of at least 3 was lower compared with a score less than 3 (76% vs 98%; P = .005). Median donor T-cell chimerism among older patients was 64% and 60% at 1 and 3 years, respectively, and was similar to that of younger patients. Increased B regulatory cells potentially contributed to low alloreactivity and mutual donor-recipient tolerance in older patients. Effect of comorbidities rather than age alone may be a more important determinant of suitability for FCC HSCT in older patients.

My jamais vu in post allogeneic hematopoietic cell transplant: a review on secondary hemophagocytosis in adults.

Post allogenic hematopoietic cell transplant (HCT) hemophagocytic lymphohistiocytosis (HLH) is an aggressive disease with unknown etiology. It has a poorly understood pathophysiology and poor outcome if untreated early. It's a state of hypercytokinemia. There are many proposed diagnostic criteria for Post HCT HLH. It usually occurs early in the first 2-6 weeks after allogeneic HCT but can present late. The incidence is highest among cord blood transplant compared with other sources of stem cells with a higher incidence in HLA mismatch donors. Post HCT HLH has a marked low survival rate, when compared with Non-HLH post HCT patients and specifically poor outcome is associated in patients with liver dysfunction, graft failure, and those with endothelial complications. Steroid is the mainstay treatment which can be followed up by cyclosporine and etoposide though an optimal therapy is not known. Intravenous immunoglobulin (IVIg) has been tried in virus associated HLH. Second bone marrow transplant is a rescue procedure in patient with HLH due to graft failure, though a very careful selection of individual patients is mandatory. It has been recently found that etoposide based conditioning regimen may reduce HLH post HCT. A prospective study on post HCT HLH are needed to evaluate this unrecognized condition.

The temporal and long-term impact of donor body mass index on recipient outcomes after kidney transplantation - a retrospective study.

The impact of increasing body mass index (BMI) on development and progression of chronic kidney disease is established. Even implantation kidney biopsies from obese living donors demonstrate subtle histologic changes despite normal function. We hypothesized that kidneys from obese living (LD) and deceased donors (DD) would have inferior long-term allograft outcomes. In a study utilizing US transplant registry, we studied adult kidney transplant recipients from 2000 to 2014. Donors were categorized as BMI <20 (underweight), 20-25 (normal), 25-30 (overweight), 30-35 (mildly obese), and >35kg/m2 (very obese). Our outcome of interest was death censored graft failure (DCGF). Cox proportional hazards model were fitted separately for recipients of DD and LD kidneys, and adjusted for donor, recipient, and transplant characteristics, including donor and recipient size mismatch ratio. Among 118734 DD and 84377 LD transplants recipients, we observed a significant and graded increase in DCGF risk among the overweight (LD:HR=1.06, DD:HR=1.04), mildly obese (LD:HR=1.16, DD:HR=1.10), and very obese (LD:HR=1.22, DD:HR=1.22) compared to normal BMI (P<0.05). The graded effect of donor BMI on outcomes begins early and persists throughout the post-transplant period. Donor obesity status is an independent risk factor for inferior long-term renal allograft outcome despite adjusting for donor and recipient size mismatch and other donor, recipient, and transplant factors.