Primary Graft Failure Research Articles

Has the risk of liver re-transplantation improved over the two decades?

Despite advancements in liver transplantation (LT) over the past two decades, liver re-transplantation (re-LT) presents challenges. This study aimed to assess improvements in re-LT outcomes and contributing factors. Data from the United Network for Organ Sharing database (2002-2021) were analyzed, with recipients categorized into four-year intervals. Trends in re-LT characteristics and postoperative outcomes were evaluated. Of 128,462 LT patients, 7254 received re-LT. Graft survival (GS) for re-LT improved (91.3%, 82.1%, and 70.8% at 30 days, 1 year, and 3 years post-LT from 2018 to 2021). However, hazard ratios (HRs) for GS remained elevated compared to marginal donors including donors after circulatory death (DCD), although the difference in HRs decreased in long-term GS. Changes in re-LT causes included a reduction in hepatitis C recurrence and an increase in graft failure post-primary LT involving DCD. Trends identified included recent decreased cold ischemic time (CIT) and increased distance from donor hospital in re-LT group. Meanwhile, DCD cohort exhibited less significant increase in distance and more marked decrease in CIT. The shortest CIT was recorded in urgent re-LT group. The highest Model for End-Stage Liver Disease score was observed in urgent re-LT group, while the lowest was recorded in DCD group. Analysis revealed shorter time interval between previous LT and re-listing, leading to worse outcomes, and varying primary graft failure causes influencing overall survival post-re-LT. While short-term re-LT outcomes improved, challenges persist compared to DCD. Further enhancements are required, with ongoing research focusing on optimizing risk stratification models and allocation systems for better LT outcomes.

Improving Outcomes with Haploidentical Stem Cell Transplantation [HaploSCT] in Children Using Post-transplant Cyclophosphamide: a Single Center Experience.

Haplo-identical stem cell transplant using post-transplant cyclophosphamide is increasingly being used in children without a matched sibling donor. Between 2010 and June 2021, 127 children underwent 138 transplants with a median age of 7.1years for malignant and non-malignant disorders. Conditioning regimens included both myeloablative and reduced intensity regimens with peripheral blood stem cells as the main graft source. Engraftment occurred in 113 [81.9%] at a median of 16days [range: 10-32] with primary graft failure in 10.2%. Cumulative incidence of grade II-IV acute graft versus host disease (GVHD) was 49.5% and chronic GVHD in 40.7%. Majority [92.7%] had at least one infection with 31% incidence of bacterial infection, 76% incidence of viral and 16% incidence of fungal infection. The 2-year overall survival (OS) is 54.9 ± 4.6% with a lower survival among young children aged 0-5years [28.2 ± 6.4%] compared to 5-10years [71.3 ± 6.8%] and 11-15years [55.7 ± 8.8%] [p = 0.032]. 2-year OS has gradually improved from 25.0 ± 2.1% for 2010-2013 to 47.5 ± 6.2% for 2014-2017 and 67.1 ± 6.6% for 2018-2021 [p = 0.049]. On multivariate analysis, bacterial infection [p = 0.017], invasive fungal disease [p = 0.002] and graft failure [p = 0.029] negatively impacted overall survival. Haplo-identical SCT with post-transplant cyclophosphamide is a reasonable option for children who do not have a matched sibling donor. Strategies to reduce graft failure, infection related mortality and GVHD needs to be explored.

Incidence and risk factors for secondary graft failure in uniformly treated patients with severe aplastic anemia receiving fludarabine and cyclophosphamide for conditioning and matched sibling bone marrow graft as stem cell source

Background aimsGraft failure after allogeneic transplant for aplastic anemia is problematic. The risk of graft failure depends on multiple variables, including the preparative regimen, donor type, stem cell dose and source among other variables. MethodsWe performed a retrospective analysis of patients with aplastic anemia who underwent matched-sibling allogeneic transplant at a single center. ResultsWe identified 82 patients who fit the inclusion criteria. One had primary graft failure and was excluded from this analysis. The recipient median age was 22 years. The donor median age was 23 years. The median time from diagnosis to transplant was 1.6 months. The median number of red cell transfusions before transplant was nine. The median number of platelet transfusions before transplant was 18. Thirteen patients developed secondary graft failure, with a cumulative incidence at 5 years of 16% and median time to develop secondary graft failure of 129 days. All patients engrafted with a median time for neutrophil engraftment of 19 days and a median time for platelet engraftment of 22 days. The survival of patients with or without secondary graft failure was not different. Major or bidirectional ABO incompatibility and older recipient age were statistically significantly associated with greater risk of secondary graft failure. ConclusionsSecondary graft failure is a significant complication after allogeneic transplant for SAA. Identification of recipients at risk and mitigating the potential risks of this complication is warranted.

The effect of cryopreservation on engraftment kinetics in fully matched allogeneic stem cell transplantation: Real-life data and literature review

IntroductionThe standard approach for allogeneic stem cell transplantation (allo-SCT) is to administer donor cells on the same day as a fresh product to a patient who has been given a preparative regimen. The difficulty in collecting and transporting donor cells, especially during the COVID-19 pandemic, has made it essential to collect and cryopreserve the grafts before the recipient begins the transplant preparation regimen. However, the short- and long-term impacts of cryopreservation on transplant outcomes remain controversial. Materials and methodsThis retrospective study included 93 patients who underwent allo-SCT between January 2012 and August 2022 at the Stem Cell Transplant Unit of Bursa Uludag University Faculty of Medicine using frozen and fresh products of peripheral blood stem cells from a fully matched sibling donor. The effect of cryopreservation of donor grafts on engraftment kinetics was investigated. ResultsFrozen and fresh products were used in 37 and 56 patients, respectively. The majority of patients had acute myeloid leukemia and acute lymphoblastic leukemia. The median age at transplantation was 41 years. Neutrophil engraftment time was similar between the two groups (median: 14 vs. 16 days, p = 0.393). Platelet engraftment time was longer in the frozen product group (median: 12 vs. 15 days, p < 0.001). There was no statistically significant difference between freezing time and viability. The acute graft-versus-host disease (GVHD) rate was 37.8 % in the frozen product group and 28.6 % in the fresh product group (p = 0.349). There was no significant difference between the two groups in terms of primary and secondary graft failure, chronic GVHD, 30-day chimerism, relapse, overall survival, progression-free survival, and nonrelapse mortality. ConclusionHaving donor cells ready before transplantation significantly prevents donor-induced adverse events and provides confidence and practicality to both the clinician and the recipient. Allo-SCT with frozen products is a successful method that can be safely applied, especially when disruptions in donor-derived cell collection or transportation are foreseen.

Abstract 2 Results of an Open Label Expanded Access Study of Omidubicel-onlv for Allogeneic Transplantation (allo-HCT) in Patients with Hematologic Malignancies

Abstract Introduction Omidubicel, a nicotinamide expanded allogeneic hematopoietic progenitor cell therapy derived from umbilical cord blood (UCB) was recently FDA approved for use as a sole donor source in allo-HCT based on phase III study results showing improved hematopoietic recovery and decreased infection rate compared to standard UCB. Objectives Open label, single arm expanded access program (EAP) evaluating clinical outcomes for patients with hematologic malignancies following omidubicel allo-HCT. Methods Eligible patients (&amp;gt;12 years) received myeloablative conditioning with supportive care per institutional guidelines. Patients were followed for engraftment, infections, graft versus host disease (GVHD), and two year post-transplantation outcomes. Results Between July 2020 and April 2023, 36 patients were enrolled at 5 US centers, and 29 (18 male, 11 female) were transplanted; median age was 38 years (range: 20-73); 55.2% white, 17.2% Black, 20.7% Asian, 10.3% other. Diagnoses included AML (37.9%), ALL (27.6%), MDS (20.7%) and other (13.8%). Median transplanted CD34+ cell dose was 5.6x106 cells/kg and HLA match was 4/6 in 51.7%, 5/6 in 44.8%, and 6/6 in 3.5%. Median follow-up was 6.25 months (range 0.33-27.7). At 100 and 365 days post-transplant, PFS rates were 95.5% and 82.9%, and OS rates were 96.3% and 84.4%, respectively. No infusion reactions were reported. Median neutrophil (&amp;gt;500/µl x3 days) and platelets (&amp;gt;20,000/µl x7 days) engraftment times were 12 and 33 days, respectively. Primary graft failure occurred in 2 (6.9%) patients, both alive &amp;gt;100 days after second transplant. Incidence of first grade 2 or 3 bacterial, viral, or invasive fungal infections through 100 days post-transplantation were 13.8%, 24.1% and 0%, respectively. Acute GVHD was reported in 13 (44.8%) patients (grade II: 34.5%, grade III: 10.3%) and mild chronic GVHD in 1 (3.5%). There were 4 deaths (13.8%): 2 due to relapse @275 and 381 days, 1 due to infection (day 135) and 1 due to pulmonary failure on day 10. Post-transplant lymphoproliferative disease was reported in one. Discussio In this real-world EAP setting, allo-HCT with omidubicel was well tolerated, and observed engraftment and infections consistent with published Phase 3 data. These data further support the role of omidubicel particularly for patients from diverse racial backgrounds.

Outcomes and Early Complications Using an Endothelium-in Pull-Through Descemet Membrane Endothelial Keratoplasty Technique With Preloaded Versus Surgeon-Loaded Donor Tissue in Fuchs Patients.

This study aimed to compare outcomes and early complications using an endothelium-in pull-through Descemet membrane endothelial keratoplasty (DMEK) technique with preloaded versus surgeon-loaded donor tissue. Data from 163 eyes of 125 patients at the Wilmer Eye Institute diagnosed with Fuchs endothelial corneal dystrophy who underwent DMEK with or without cataract extraction using surgeon-loaded tissue (n = 83) or preloaded tissue (n = 80) were reviewed. Best-corrected visual acuity and early postoperative complications including small graft detachment (less than one third of the graft area), large graft detachment (more than one third), graft failure, and rebubbling were compared. Baseline characteristics including age, sex, and visual acuity were not statistically different between the groups. Small graft detachment was observed in 18.1% of the surgeon-loaded and 22.5% of the preloaded group ( P = 0.48), whereas large detachment occurred in 12.0% and 5.0%, respectively ( P = 0.11). Among these, rebubbling was performed in 18 (21.7%) in the surgeon-loaded compared with 12 (15.0%) in the preloaded group ( P = 0.27). The rebubbling rate of the combined procedure (cataract surgery and DMEK) was 21.8% and of DMEK alone was 7.7% ( P = 0.048). Primary graft failure occurred in 2 surgeon-loaded cases (2.4%) and 1 preloaded case (1.3%) ( P = 0.58). There was no difference in postoperative best-corrected visual acuity at 1 year (logarithm of the minimum angle of resolution 0.21 ± 0.25 for the surgeon-loaded vs. 0.16 ± 0.16 for the preloaded group, P = 0.23). DMEK surgery using preloaded endothelium-in tissue has comparable outcomes with surgeon-loaded endothelium-in tissue. However, there was a trend toward the lower rebubbling rate in DMEK alone compared with combined procedures.

Lung Transplantation Outcomes in Recipients Aged 70 Years or Older and the Impact of Center Volume.

To evaluate trends and outcomes of lung transplants (LTx) in recipients ≥ 70 years. We performed a retrospective analysis of the UNOS database identifying all patients undergoing LTx (May 2005-December 2022). Baseline characteristics and postoperative outcomes were compared by age (<70 years, ≥70 years) and center volume. Kaplan-Meier analyses were performed with pairwise comparisons between subgroups. 34,957 patients underwent LTx, of which 3236 (9.3%) were ≥70 years. The rate of LTx in recipients ≥ 70 has increased over time, particularly in low-volume centers (LVCs); consequently, high-volume centers (HVCs) and LVCs perform similar rates of LTx for recipients ≥ 70. Recipients ≥ 70 had higher rates of receiving from donor after circulatory death lungs and of extended donor criteria. Recipients ≥ 70 were more likely to die of cardiovascular diseases or malignancy, while recipients < 70 of chronic primary graft failure. Survival time was shorter for recipients ≥ 70 compared to recipients < 70 old (hazard ratio (HR): 1.36, 95% confidence interval (CI): 1.28-1.44, p < 0.001). HVCs were associated with a survival advantage in recipients < 70 (HR: 0.91, 95% CI: 0.88-0.94, p < 0.001); however, in recipients ≥ 70, survival was similar between HVCs and LVCs (HR: 1.11, 95% CI: 0.99-1.25, p < 0.08). HVCs were more likely to perform a bilateral LTx (BLT) for obstructive lung diseases compared to LVCs, but there was no difference in BLT and single LTx likelihood for restrictive lung diseases. Careful consideration is needed for recipient ≥ 70 selection, donor assessment, and post-transplant care to improve outcomes. Further research should explore strategies that advance perioperative care in centers with low long-term survival for recipients ≥ 70.

Impact of immunosuppression intensified conditioning regimen for patients with strong positive pre-transplantation donor-specific anti-HLA antibodies (DSAs) undergoing haploidentical hematopoietic stem cell transplantation

Objective: To explore the efficacy of immunosuppression intensified conditioning regimen in patients who have strongly positive donor-specific Anti-HLA antibodies (DSAs) and received a haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: Clinical data of 10 patients with strongly positive pretransplant DSAs (defined as MFI ≥10000) were retrospectively analyzed in this study. All of them received a haplo-HSCT in the Hematology Department of Shanghai Zhaxin Traditional Chinese & Western Medicine Hospital. Results: ① Of all ten patients, three were males, and seven were females, with a median age of 53.5 (36-64) years. Of the 10 patients, three were diagnosed with acute myeloid leukemia, two were myelodysplastic syndromes (MDS), two were chronic myelomonocytic leukemia (CMML), two were in an accelerated phase of chronic myeloid leukemia (CML-AP), and one was primary myelofibrosis (PMF). ② Conditioning regimen consisted of fludarabine (Flu) /busulfan (Bu) combined with whole-body irradiation (TBI) /cyclophosphamide (Cy). ③ On the seventh day after transplantation, the median pretransplant DSA level was MFI 15 999 (10 210-23 417) and 10 787 (0-22 720). ④ Eight patients acquired hematopoietic reconstitution; the median time of neutrophil engraftment was 14 (10-16) days; and 18 (14-20) days for platelet engraftment. After a median follow-up of 12.5 (1.5-27) months, primary graft failure was found in one patient and another with poor graft function. Seven patients remained in a disease remission state, and all were DSA-negative. Conclusions: An intensified immunosuppression conditioning regimen can efficiently decrease the level of donor-specific anti-HLA antibodies (DSAs), leading to good short-term efficacy.

Descemet Stripping Automated Endothelial Keratoplasty versus Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy: A National Registry-Based Comparison

To compare the outcome between posterior lamellar corneal transplant procedures for Fuchs endothelial corneal dystrophy, taking preoperative patient characteristics in consideration. Surgical methods compared were Descemet membrane endothelial keratoplasty (DMEK), Descemet stripping automated endothelial keratoplasty (DSAEK), and DSAEK with concomitant cataract surgery (phacoemulsification plus DSAEK). Registry-based study with propensity score matching. One thousand six hundred seventy-seven patients from all Swedish corneal transplantation units treated from 2012 through2019. All patients undergoing endothelial keratoplasty performed from 2012 through 2019 with completed 2-year follow-up data reported to The Swedish Corneal Transplant Register were included, totaling 1677 patients. Three comparable groups (DMEK, DSAEK, and phacoemulsification plus DSAEK) with 216 patients in each group were generated with propensity score matching based on preoperative visual acuity, age, sex, year of surgery, and preoperative risk factors such as inflammation, vascularization, and glaucoma. Best-corrected visual acuity (BCVA) at the 2-year follow-up, frequency of graft dislocation, graft rejection episodes, and graft failure within 2 years including primary graft failure. The preoperative corneal status was affected more severely in the DSAEK group before matching. In the matched groups, the median BCVA 2 years after surgery was 0.1 logarithm of the minimum angle of resolution (logMAR) in both the DMEK and the phacoemulsification plus DSAEK groups and 0.15 logMAR in the DSAEK group (P= 0.001). The frequency of graft dislocation was higher among the patients undergoing phacoemulsification plus DSAEK, but the frequency of graft failure and primary graft failure was higher in the DMEK group. Visual acuity improved in most patients (90%) with all 3 surgical methods. However, DMEK and phacoemulsification plus DSAEK reached higher levels of visual acuity 2 years after surgery, and phacoemulsification plus DSAEK was superior considering graft survival rate. All 3 surgical procedures showed both strengths and weaknesses, suggesting that the choice of surgical method should be individualized, taking into consideration not only the cornea, but each patient's complete medical status as well as the entire course of postoperative medical care. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Clinical impact of cryopreservation of allogeneic hematopoietic cell grafts during the onset of the COVID-19 pandemic

AbstractAt the onset of the COVID-19 pandemic, the National Marrow Donor Program mandated the cryopreservation of hematopoietic cell grafts from volunteer unrelated donors because of numerous patient and donor safety concerns and logistical hurdles. Using the Center for International Blood and Marrow Transplant Research outcomes database, we report the impact of cryopreservation on overall survival (OS) and other outcomes within 1 year after hematopoietic cell transplantation (HCT). We analyzed 1543 recipients of cryopreserved allografts receiving HCT at US centers during the first 6 months of the pandemic and compared them with 2499 recipients of fresh allografts during a 6-month period in 2019. On multivariable regression analysis, we observed no difference in the OS (P = .09), nonrelapse mortality (P = .89), graft-versus-host disease (GVHD), or GVHD- and relapse-free survival (P = .58) in recipients of cryopreserved vs fresh allografts. Disease-free survival (DFS) was lower in the cryopreserved allograft recipients (P = .006) because of a higher risk of relapse (P = .01) compared with the fresh allograft recipients. Primary graft failure was higher (P = .01), and the risk of chronic GVHD was lower (P = .001) with cryopreservation compared with fresh grafts. In conclusion, although there was no negative impact of cryopreservation on OS, relapse was higher, and DFS was lower than that with no cryopreservation. Fresh grafts are recommended as the pandemic-related logistical hurdles resolve. Cryopreservation should be considered an option for patients when fresh grafts are not feasible.

Posterior Tibial Slope in Patients Undergoing Bilateral Versus Unilateral ACL Reconstruction: MRI and Radiographic Analyses

Background: An increased posterior tibial slope (PTS) is a risk factor for primary anterior cruciate ligament (ACL) tears and graft failure, but the PTS has not been well-defined in those who have experienced bilateral ACL injuries. Purpose: The primary aim was to compare the PTS, as well as the rate of an elevated PTS (>12° on lateral radiography; >7° on magnetic resonance imaging [MRI]), between patients who have undergone bilateral ACL reconstruction (ACLR) versus unilateral ACLR. A secondary purpose was to examine whether these associations remained consistent on both plain radiography and MRI. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We retrospectively identified patients who underwent primary ACLR at our institution from the years 2012 to 2020. Patients who underwent nonsimultaneous bilateral ACLR (n = 53) were matched to those who underwent unilateral ACLR (n = 53) by age, sex, and body mass index. Exclusion criteria were rotated lateral radiographs, MRI scans of inadequate quality, and concomitant ligament injuries or fractures. Those who had undergone unilateral ACLR with <5-year follow-up were further excluded. There were 3 blinded readers who measured the PTS on lateral radiographs, while the medial PTS (MPTS) and lateral PTS (LPTS) were measured on MRI scans. Bivariate regression was performed to determine the correlation between radiographic and MRI measurements. Results: The PTS on radiography (11.26° vs 10.13°, respectively; P = .044) and the LPTS on MRI (7.32° vs 6.08°, respectively; P = .012) in the bilateral ACLR group were significantly greater than those in the unilateral ACLR group but not the MPTS on MRI (4.55° vs 4.17°, respectively; P = .590). The percentage of patients in the bilateral group with a radiographic PTS >12° was 41.0% compared with 13.2% in the unilateral group (P = .012). The bilateral group had a significantly higher rate of an LPTS >7° compared with the unilateral group (53.8% vs 32.1%, respectively; P = .016) but not for an MPTS >7° (P = .190). On MRI, the LPTS (6.90°± 2.73°) was significantly greater than the MPTS (4.41°± 2.92°) (P < .001). There was a weak correlation between MPTS and radiographic PTS measurements (R = 0.24; P = .021), but LPTS and radiographic PTS measurements were not significantly correlated (R = 0.03; P = .810). Conclusion: Patients who underwent bilateral ACLR had a significantly greater PTS on radiography and a significantly greater LPTS on MRI compared with those who underwent unilateral ACLR. The rate of a radiographic PTS >12° was 2.4 times greater among patients undergoing bilateral ACLR compared with those undergoing unilateral ACLR. PTS measurements on radiography demonstrated a weak to negligible correlation with PTS measurements on MRI, suggesting that future normative PTS values should be reported specific to the imaging modality.

Association of Primary Kidney Disease Type and Donor Relatedness With Live Donor Kidney Transplant Outcomes: An Analysis of ANZDATA

There is limited information about the association between primary kidney disease and donor relatedness with transplant outcomes. This study addresses this gap by evaluating clinical outcomes after kidney transplantation in recipients of living donor kidneys as a function of primary kidney disease type and donor relatedness in Australia and New Zealand. Retrospective observational study. Kidney transplant recipients who received allografts from living donors between January 1, 1998, and December 31, 2018, as recorded in the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Primary kidney disease type categorized as majority monogenic, minority monogenic, or other primary kidney disease based on disease heritability as well as donor relatedness. Primary kidney disease recurrence, graft failure. Kaplan-Meier analysis and Cox proportion hazards regression to generate hazard ratios for primary kidney disease recurrence, allograft failure, and mortality. Partial likelihood ratio test was used to examine possible interactions between primary kidney disease type and donor relatedness for both study outcomes. Among 5,500 live donor kidney transplant recipients, majority monogenic (adjusted HR, 0.58, P<0.001) and minority monogenic primary kidney diseases (adjusted HR, 0.64, P<0.001) were associated with reduced primary kidney disease recurrence compared with other primary kidney diseases. Majority monogenic primary kidney disease was also associated with reduced allograft failure (adjusted HR, 0.86, P=0.04) compared with other primary kidney diseases. Donor relatedness was not associated with primary kidney disease recurrence nor graft failure. No interaction was detected between primary kidney disease type and donor relatedness for either study outcome. Potential misclassification of primary kidney disease type, incomplete ascertainment of primary kidney disease recurrence, unmeasured confounding. Monogenic primary kidney disease is associated with lower rates of primary kidney disease recurrence and allograft failure. Donor relatedness was not associated with allograft outcomes. These results may inform pretransplant counseling and live donor selection. There are theoretical concerns that live-donor kidney transplants may be associated with increased risks of kidney disease recurrence and transplant failure due to unmeasurable shared genetic factors between the donor and the recipient. This study analyzed data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry and showed that, although disease type was associated with the risk of disease recurrence and transplant failure, donor relatedness did not impact transplant outcomes. These findings may inform pretransplant counseling and live donor selection.

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: prognostic indicators and the role of JAK2V617F measurable-residual disease monitoring by droplet-digital polymerase chain reaction.

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10-42) days and the median time to platelet engraftment was 26 (12-245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1-223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2-3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).

#6797 EFFICACY OF DESENSITIZATION TREATMENT IN HYPERIMMUNIZED PATIENTS AWAITING A CADAVERIC KIDNEY TRANSPLANTATION

Abstract Background and Aims On all kidney waiting lists, patients who have antibodies against more than 80% of a panel reactive antibody (PRA) are difficult to transplant, even with national or regional programs. Desensitization treatment with high-dose intravenous immunoglobulin and rituximab could be offered to patients with a long waiting time for a cadaveric donor to improve their odds of finding a kidney. Method Retrospective, single-center study including all hyperimmunized patients on the waiting list for a cadaveric kidney donor who received a desensitization treatment between 2010-2020. To be considered to the desensitization protocol, all the patients must have a PRA above 75% and have been on the waiting list more than 3 years, without any offer. Our treatment was based on the modified Cedars-Sinai Medical Center protocol. Eight hyperimmunized patients on the waiting list for a cadaveric donor kidney transplant (50% male with a mean age of 41.5±16.4 years) received desensitization treatment with intravenous immunoglobulin and Rituximab. Six of the 8 patients (75%) were on renal replacement therapy with hemodialysis and two on peritoneal dialysis (mean time on dialysis 48±14 months). 75% had received a previous transplant. The median PRA calculated was 98%. The time between desensitization and kidney transplantation, the percentage of reactivity against panel cells (PRA) before and after therapy, graft and donor survival, as well as episodes of acute rejection and viral infections were analyzed. The mean follow-up time after transplantation was 67 months. Results No patient presented significant side effects to desensitization treatment. Seven of the 8 patients (87.5%) could be transplanted from a cadaveric donor (negative crossmatch test), in a median 8 months after desensitization. No significant changes were observed in the PRA levels. In the immediate post-transplant period, there were 2 graft losses (28.6%) due to non-immunological causes (1 venous thrombosis in a patient with a coagulation disorder and 1 primary graft failure). Creatinine at discharge was 1.6±0.4 mg/dl and 1.4±0.2 a year after the transplant. Five-year censored death graft survival was 100%. Three patients presented viral replication (1 due to cytomegalovirus (CMV), 1 due to polyomavirus (BK) and another CMV+BK), which became negative after switching to m-Tor therapy. There were no episodes of acute rejection. No patient developed cancer during the follow-up. Conclusion Desensitization treatment with immunoglobulin and rituximab on hyperimmunized patients on the cadaveric waiting list is a safe and effective treatment that increases the chances of achieving a kidney transplant in highly sensitized patients.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. To describe the outcome of TBD patients transplanted for marrow failure. This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Second transplantation (HSCT2) is a potential treatment for primary graft failure (pGF). We assessed the outcome of HSCT2, performed between 2000 and 2021, for pGF in 243 patients with acute leukemia. Median age was 44.8 years. Conditioning at first HSCT (HSCT1) was myeloablative (MAC) in 58.4%. Median time from HSCT1 to HSCT2 was 48 days. Donors for HSCT2 were the same as for HSCT1 in 49%. Engraftment post HSCT2 was achieved by 73.7% of patients. The incidence of acute (a) graft versus host disease (GVHD) grades II-IV and III-IV was 23.2 and 8.1%. 5-year total and extensive chronic (c) GVHD was 22.3 and 10.1%. 5-year nonrelapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD free, relapse-free survival (GRFS) was 51.6, 18.8, 29.6, 30.7 and 22.4%, respectively. Infections were the main cause of death. In multivariable analysis, being transplanted at second vs. first remission, lower Karnofsky performance status (KPS; <90) and receiving MAC at HSCT1 were adverse prognostic factors for NRM, LFS, OS, and GRFS, as was increased age for NRM, LFS, OS. We conclude that HSCT2 can rescue about a third of the patients who experienced pGF, but NRM is as high as 50%.

Results of haploidentical transplant in patients with donor-specific antibodies: a survey on behalf of the Spanish Group of Hematopoietic Transplant and Cell Therapy.

Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT. We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes. Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI>10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI>20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF. Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF.

Donor-Specific HLA Antibodies Are Associated with Graft Failure and Delayed Hematologic Recovery after Unrelated Donor Hematopoietic Cell Transplantation

Graft failure (GF) is one of the major concerns after allogeneic hematopoietic cell transplantation (allo-HCT) and remains a significant cause of morbidity and mortality. Although earlier reports have associated the presence of donor-specific HLA antibodies (DSAs) with increased risk of GF after unrelated donor allo-HCT, recent studies have failed to confirm this association. We sought to validate the presence of DSAs as a risk factor for GF and hematologic recovery in the unrelated donor allo-HCT setting. We retrospectively evaluated 303 consecutive patients who underwent their first unrelated donor allo-HCT at our institution from January 2008 to December 2017. DSA evaluation was performed using 2 Single Antigen Beads (SAB) assays, DSA titration with 1:2, 1:8, and 1:32 dilutions, C1q-binding assay, and absorption/elution protocol to assess possible false-positive DSA reactivity. The primary endpoints were neutrophil and platelet recovery and GF, whereas the secondary endpoint was overall survival. Multivariable analyses were performed using Fine-Gray competing risks regression or Cox proportional hazards regression models. The median patient age was 14 years (range, 0-61 years), 56.1% were male, and 52.5% were transplanted for nonmalignant diseases. Eleven patients (3.63%) were DSA-positive. Of them, 10 had preexisting DSAs, and one showed post-transplant de novo DSA. Nine patients had 1 DSA, 1 had 2 DSAs, and 1 had 3 DSAs, with a median MFI of 4334 (range, 588-20,456) and 3581 (range, 227-12,266) in LABScreen and LIFECODES SAB assays, respectively. Overall, 21 patients experienced GF. Of them, 12 had primary graft rejection, 8 had secondary graft rejection, and 1 had primary poor graft function. The cumulative incidences of GF at 28, 100, and 365 days were 4.0% (95% CI, 2.2%-6.6%), 6.6% (95% CI, 4.2%-9.8%), and 6.9% (95% CI, 4.4%-10.2%), respectively. In the multivariable analyses, DSA-positive patients had significantly delayed neutrophil (subdistribution hazard ratio [SHR] = 0.48; 95% CI, 0.29-0.81; P = .006) and platelet recovery (SHR = 0.51; 95% CI, 0.35-0.74; P = .0003) than patients without DSAs. In addition, only DSAs were significant predictors of primary GF at 28 days (SHR = 2.78; 95% CI, 1.65-4.68; P = .0001). The Fine-Gray regression also demonstrated that the presence of DSAs was strongly associated with a higher incidence of overall GF (SHR = 7.60; 95%CI, 2.61-22.14; P = .0002). DSA-positive patients with GF had significantly higher median MFI values than DSA-positive patients who achieved engraftment in LIFECODES SAB assay using neat serum (10,334 vs. 1250; P = .006) and in LABScreen SAB at 1:32 dilution (1627 vs. 61; P = .006). All 3 patients with C1q-positive DSAs failed to engraft. DSAs were not predictive of inferior survival (hazard ratio = 0.50; 95% CI, 0.20-1.26, P = .14). Our results validate the presence of DSAs as a significant risk factor for GF and poor hematologic recovery after unrelated donor allo-HCT. Thus, careful pre-transplant DSA evaluation may optimize unrelated donor selection and improve allo-HCT outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation for Primary Myelofibrosis: A 20-year Experience in a Single Center

Allogeneic hematopoietic stem cell transplantation is a well-established approach for patients diagnosed with primary myelofibrosis and remains the only potentially curative treatment. To present the overall outcome of patients with myelofibrosis treated with allogeneic hematopoietic stem cell transplantation. A retrospective cross-sectional study. This study is a retrospective analysis of 26 consecutive patients with primary myelofibrosis who underwent transplantation at our center between January 2002 and January 2022. Disease and transplant variables contributing to outcomes were analyzed. The median age at the time of transplantation was 52.5 (range, 32-63) years and the median time from diagnosis to allogeneic hematopoietic stem cell transplantation was 25 (range, 3.1-156.8) months. Myeloablative conditioning and reduced-intensity conditioning regimens were used in 8 (30.8%) and 18 (69.2%) transplantations, respectively. Neutrophil and platelet engraftment was achieved in 23 patients at a median follow-up of 21.2 months (range, 12 days to 234.8 months). Primary graft failure occurred in 1 of 23 patients (4.3%). Neutrophil and platelet engraftment occurred at a median of 16 (range, 12-39) days and 20 (range, 11-78) days, respectively. Acute graft-versus-host disease was seen in 11 of 22 patients engrafted allografts, of which 7 (31.8%) were grade 3-4 acute graft-versus-host disease. Eight patients (36.4%) developed chronic graft-versus-host disease, and three cases were extensive. Four patients (19%) relapsed after a median of 5.5 months, and three patients received donor lymphocyte infusion. The 3-year overall survival rate of the entire study population was 46.2%. The median overall survival was not reached in the myeloablative conditioning group; however, it was 11.9 months in the reduced-intensity conditioning group (p =0.3). According to the donor graft source, the median overall survival was 0.73 months in mismatched unrelated graft recipients, 12 months in matched sibling donors, and not reached in matched unrelated graft recipients (p = 0.03). The 3-year progression-free survival rate of patients who survived > 100 days was 74.7%. The effect of JAK-2 status, graft source, conditioning regimen or dynamic international prognostic scoring system on progression-free survival was not statistically significant. Given the poor prognosis of non-transplant recipients and the lack of non-transplant curative approaches, our results support the consideration of allogeneic hematopoietic stem cell transplantation for eligible patients with primary myelofibrosis.

Low-dose post-transplant cyclophosphamide with G-CSF/ATG based haploidentical protocol provides favorable outcomes for SAA patients.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11-20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen.