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Donor-specific HLA antibodies are associated with graft failure and delayed hematologic recovery after unrelated donor hematopoietic cell transplantation
Lima, A. C. M., Getz, J., do Amaral, G. B., Loth, G., Funke, V. A. M., Nabhan, S. K., Petterle, R. R., de Marco, R., Gerbase-DeLima, M., Pereira, N. F., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND 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. OBJECTIVE We sought to validate the presence of DSAs as a risk factor for GF and hematologic recovery in the unrelated donor allo-HCT setting. STUDY DESIGN 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. RESULTS 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). CONCLUSIONS 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.
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Untreated donor-specific HLA antibodies are associated with graft failure and poor survival following haploidentical transplantation with post-transplant cyclophosphamide in pediatric patients with nonmalignant disorders: DSAs in pediatric haplo-PTCy
Lima, A. C. M., Bonfim, C., Getz, J., do Amaral, G. B., Petterle, R. R., Loth, G., Nabhan, S. K., de Marco, R., Gerbase-DeLima, M., Pereira, N. F., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Donor-specific HLA antibodies (DSAs) have been recognized as a major risk factor for graft failure (GF) in adult patients with malignancies undergoing haploidentical transplantation with post-transplant cyclophosphamide (haplo-PTCy). However, the impact of DSAs after pediatric haplo-PTCy for nonmalignant disorders (NMDs) has been poorly reported. OBJECTIVE We sought to investigate whether preexisting DSAs adversely affect pediatric haplo-PTCy outcomes. STUDY DESIGN We retrospectively analyzed 59 pediatric patients (≤21 years) who received their first haplo-PTCy for NMDs from January 2008 to December 2017. DSA testing was performed using single antigen beads, and mean fluorescence intensity (MFI) >1000 was considered positive and MFI <1000 and >500 was considered potentially positive, based on HLA epitope reactivity patterns. Primary endpoints were neutrophil and platelet recovery and GF, whereas secondary endpoints included event-free and overall survival. Multivariable analyses were performed using Fine-Gray competing risk regression or Cox proportional hazards regression models. RESULTS The median age was 10 years, and 66.1% were male. Main indications for haplo-PTCy were Fanconi anemia (n=33) and severe aplastic anemia (n=11). All patients received bone marrow as the graft source, and most patients (91.5%) received fludarabine-based conditioning. Overall, 15 patients (25.4%) had DSAs >500 MFI. Four patients had false-positive DSAs with median MFI of 1762. Of the 11 patients with true-positive DSA reactivity, 5 had 1 DSA, 5 had 2 DSAs, and one had 3 DSAs, with median MFI of 2372 (range, 527-24200). Four patients received desensitization therapy with rituximab and plasmapheresis, whereas 7 patients were untreated. All patients with treated DSAs achieved donor engraftment. In the multivariable analyses, untreated DSAs were associated with lower neutrophil recovery (SHR=0.15; 95% CI, 0.03-0.63; P=.001), increased GF (SHR=11.90; 95% CI, 3.56-39.81; P<.001), inferior event-free survival (HR=10.09; 95%CI, 3.37-30.22; P<.001), and poor overall survival (HR 5.56; 95% CI, 1.92-16.12; P=.002). Both treated DSAs (SHR=0.26; 95% CI, 0.10-0.68; P=.006) and untreated DSAs (SHR=0.13; 95% CI, 0.04-0.37; P<.001) adversely affected platelet recovery. CONCLUSIONS Our results indicate that the presence of DSAs is an independent predictor of poor outcomes following pediatric haplo-PTCy for NMDs. Therefore, DSA-positive donors should be avoided whenever possible, and when a DSA-negative donor is unavailable, desensitization therapy must be performed to enhance the likelihood of donor engraftment and improve transplant outcomes.
PICO Summary
Population
Children under 21 years with non-malignant disorders undergoing haploidentical transplantation (n=59)
Intervention
Children with donor specific antibodies (DSAs) either treated (n=4) or untreated (n=7)
Comparison
Children without DSAs (n=48)
Outcome
All patients with treated DSAs achieved donor engraftment. In the multivariable analyses, untreated DSAs were associated with lower neutrophil recovery (SHR=0.15; 95% CI, 0.03-0.63), increased GF (SHR=11.90; 95% CI, 3.56-39.81), inferior event-free survival (HR=10.09; 95% CI, 3.37-30.22), and poor overall survival (HR 5.56; 95% CI, 1.92-16.12). Both treated DSAs (SHR=0.26; 95% CI, 0.10-0.68) and untreated DSAs (SHR=0.13; 95% CI, 0.04-0.37) adversely affected platelet recovery.
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Incidence and risk factors for graft failure in the modern era of cord blood transplantation
Chakrabarty, J. H., Glover, J., Schmidt, S., Phan, M., Bycko, M., Duong, Q., Vesely, S. K., O'Neal, C., Robertson, C., Davis, C., et al
Vox sanguinis. 2022
Abstract
BACKGROUND AND OBJECTIVES Graft failure (GF) after cord blood transplant (CBT) has decreased with improved supportive care and cord selection strategies. We aimed to evaluate cord blood selection and factors associated with retransplantation on the incidence of GF, determine risk factors for GF including host antibodies to Kell antigen and evaluate survival after GF. MATERIALS AND METHODS We retrospectively reviewed 84 patients who underwent CBT at the University of Oklahoma between 2000 and 2016 and compared outcomes in patients with/without engraftment by Day 28. The nonengraftment cohort was further divided into patients who underwent retransplantation. Kaplan-Meier curves with log-rank tests were calculated to assess the association between mortality and engraftment. RESULTS Engraftment following CBT was high at 81%, with 52% engrafting by Day 28 and an additional 29% engrafting by a median of 36 days. Retransplantation led to 88% engraftment at a median of 53 days. Overall, 75% of the 40 patients who did not engraft by Day 28 died. Female sex and total nucleated cell count < 3.5/kg were significantly associated with lack of engraftment and higher mortality. Antibodies to Kell fetal antigen were not identified. Retransplantation by Day 28 for primary GF conferred a survival advantage. CONCLUSION This study demonstrates that failure to engraft by 28 days was associated with increased mortality, and risk was mitigated with early retransplantation. Female sex and low total cell dose were associated with increased mortality. Early identification of GF coupled with early retransplantation can reduce mortality in CBT.
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Evaluation of risk factors for and subsequent mortality from poor graft function (PGF) post allogeneic stem cell transplantation
Prabahran, A., Koldej, R., Chee, L., Wong, E., Ritchie, D.
Leukemia & lymphoma. 2021;:1-13
Abstract
Poor Graft Function (PGF) is defined by multi-lineage cytopenias with complete donor chimerism post allogeneic transplantation, Risk factors for and subsequent mortality from PGF were assessed in our transplant cohort. Non-sibling donor [OR 1.97; 95% CI 1.02-3.70], ICU admission [OR 5.28; 95% CI 2.29-11.88] or blood culture positivity within the first 30?days [OR 1.67; 95% CI 1.07-2.62], grade III-IV acute graft vs host disease (GVHD) [OR 4.082; 95% CI 2.31-7.16] and CMV viremia [OR 2.43; 95% CI 1.53-3.88] and were significantly associated with development of PGF. PGF patients without count recovery had a 2?year OS of 6%. Severe GVHD, thrombocytopenia and anemia portended inferior survival and were used to develop a prognostic score for mortality from PGF. This analysis identifies risk factors predictive of PGF and poor survival in those without recovery.
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Donor-specific antibodies and primary graft failure in allo-hematopoietic stem cell transplant: a systematic review and meta-analysis: DSA and primary graft failure in allo-HSCT
Xie, Y., Parekh, J., Tang, Z., Wu, D., Wu, X.
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND With increase in the number of non-matched hematopoietic stem cell transplants (HSCT), there has been growth in evidence regarding factors affecting graft outcomes. One of the factors affecting graft outcomes that are currently being evaluated is anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs). OBJECTIVE We designed our study to analyze the clinical relevance of anti-HLA DSAs in patients who have undergone hematopoietic stem cell transplant at a population level by conducting a systematic review of existing literature. STUDY DESIGN A comprehensive search was conducted through PUBMED, Embase, Cochrane library and Web of Science from inception to January 1, 2021. A meta-analysis was performed of the association between anti-HLA DSAs and primary graft failure with further subgroup analyses. It was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS A total of 920 eligible citations were identified out of which 15 studies were included in the final meta-analyses after application of rigorous selection criteria and independent review. A total of 2436 patients were included. Patients with anti-HLA DSAs prior to HSCT had a 7.47-fold increased risk of primary graft failure compared to patients without DSA (OR 7.47, 95%CI 4.54-12.28, p<0.001; I2= 28.91%, P?=?0.1315). In subgroup and meta-regression analyses, areas, NOS, mean fluorescence intensity (MFI) cut off, primary diseases, HSCT types, graft sources, and pre-transplant desensitization did not affect the impact of anti-HLA DSAs on primary graft failure (PGF). There was no significant difference between the impact of HLA class I and II on PGF as well. CONCLUSION We conclude that prior presence of anti-HLA DSAs had negative impact on graft outcomes in patients with haploidentical and umbilical cord blood hematopoietic stem cell transplants.
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Graft failure after "ex-vivo" T-cell depleted haploidentical transplantation in pediatric patients with high-risk hematological malignancies. A risk factors and outcomes analysis
Diaz, M. A., Lopez, I., Molina, B., Pereto, A., Zubicaray, J., Sevilla, J., Castillo, A., Alenda, R., Moreno, M. A., Vicario, J. L., et al
Leukemia & lymphoma. 2021;:1-8
Abstract
Risk factors and outcomes of GF after TCD haploidentical transplantation in children with hematological malignancies were analyzed. 148 TCD transplants were included. 78 patients were diagnosed of ALL and 70 patients of AML. 22 out of 148 patients developed GF. MVA showed that patient <9?years (HR: 5.0; 95% CI: 1.1-23.0; p?=?0.03) and pre-transplant CD8+ =150/µL (HR: 12.0; 95% CI: 1.6-95.3; p?=?0.01) were associated with GF. A score was assigned to each patient. The cumulative incidence of GF for patients with CD8+ =150/µL (2 points) was 6?±?4% and 3?±?2% for patients <9?years (1 point) while for patients with 3 points was 24?±?6%, With a median follow-up of 48?months (range; 4-180?months), 14 (64%) of 22 patients with GF are alive and disease-free. DFS for GF patients was 53?±?12%. In conclusion, patient age and pre-transplant CD3+/CD8+ are associated with GF in children undergoing TCD haploidentical transplantation.
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Primary graft failure, but not relapse, may be identified by early chimerism following double cord unit transplantation
Hough, R. E., Lopes, A., Patrick, P., Russell, N. H., Raj, K., Tholouli, E., Snowden, J. A., Collin, M., El-Mahidi, N., Lawrie, A., et al
Blood advances. 2021
Abstract
Umbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism following RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage specific chimerism following DUCBT in adult patients with haematological malignancies in the UK. Fifty-eight patients with a median age of 52 years were recruited, with an overall and progression free survival of 59% (95%CI 45% to 71%) and 52% (95%CI 39% to 64%) respectively at 2 years. Nonrelapse mortality was 4% (95% CI 1% to 13%) at day 100 and the relapse rate was 31% (95%CI 21% to 45%) at 1 year. Peripheral blood lineage specific chimerism was feasible from day 7 post-transplant onwards. Five patterns of chimerism were observed including i) complete single unit dominance (39 patients), ii) sustained donor-donor mixed chimerism (3 patients), iii) sustained donor-recipient mixed chimerism (5 patients), iv) dominance reversion (1 patient) and v) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematological malignancies to safely access UCBT in the UK and provided novel insights into the kinetics of donor and recipient chimerism following RIC DUCBT which are clinically relevant. (Clinical Trials.gov identifier: NCT00959231; EudraCT identifier: 2004-003845-41).
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Haploidentical donor transplant is associated with secondary poor graft function after allogeneic stem cell transplantation: A single-center retrospective study
Lv, W. R., Zhou, Y., Xu, J., Fan, Z. P., Huang, F., Xu, N., Xuan, L., Shi, P. C., Liu, H., Wang, Z. X., et al
Cancer medicine. 2021;10(23):8497-8506
Abstract
BACKGROUND Secondary poor graft function (sPGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) related to poor outcome. We aimed to retrospectively evaluate the morbidity and hazard elements of sPGF after allo-HSCT. METHODS Eight hundred and sixty-three patients who achieved initial engraftment of both neutrophils and platelets were retrospectively reviewed in this study. RESULTS Fifty-two patients developed sPGF within 180 days post-transplants, with the median onset time was 62 days (range, 34-121 days) post-transplants. The overall cumulative incidence of sPGF within 180 days post-transplantation was 6.0%, with 3.4%, 3.4%, and 10.1%, respectively, in matched sibling donor (MSD), matched unrelated donor (MUD), and haploidentical donor (HID) transplant (p < 0.0001). Multivariable analysis showed that HID (HID vs. MSD: hazard ratio [HR] 2.525, p = 0.004; HID vs. MUD: [HR] 3.531, p = 0.017), acute graft versus host disease (aGVHD) within +30 days ([HR] 2.323, p = 0.003), and cytomegalovirus (CMV) reactivation ([HR] 8.915, p < 0.0001) within +30 days post-transplants were hazard elements of sPGF. The patients with sPGF had poorer survival than good graft function (51.7±8.1% vs. 62.9±1.9%, p < 0.0001). Our results also showed that only CMV reactivation was the hazard element for the development of PGF in HID transplant ([HR] 12.521 p < 0.0001). CONCLUSION HID transplant is also an independent hazard element of sPGF except for aGVHD and CMV reactivation.
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9.
Prognostic factors in salvage transplantation for graft failure following allogeneic hematopoietic stem cell transplantation
Harada, K., Kimura, S. I., Fuji, S., Najima, Y., Yakushijin, K., Uchida, N., Onizuka, M., Ikegame, K., Yano, S., Shingai, N., et al
Bone marrow transplantation. 2021
Abstract
Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor's hazard ratio, weighted scores of 1-3 were assigned to these factors. Using the summed scores (0-8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0-2, n?=?122), intermediate (3-4, n?=?209), and high score (5-8, n?=?110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P?0.001), whereas the 1-year NRM was 24.1%, 43.9%, and 72.7%, respectively (P?0.001). The prognostic value of the scoring system was confirmed in the validation cohort (n?=?470). Our scoring system is useful for predicting survival after salvage SCT.
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10.
Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation
Park, J. H., Lee, J. H., Lee, J. H., Park, H. S., Choi, E. J., Kang, Y. A., Kang, H., Woo, J. M., Lee, Y. S., Jeon, M., et al
Journal of Korean medical science. 2021;36(23):e151
Abstract
BACKGROUND This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). METHODS We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000-September 2017) at our center. RESULTS Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97-28.0, P < 0.001) and lower CD34? cell dose (RR, 2.44-2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. CONCLUSION Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis.