Transplantation For Acute Leukemia Research Articles

DIFFERENTIAL IMPACT OF CD34+ CELL DOSE FOR DIFFERENT AGE GROUPS IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR ACUTE LEUKEMIA: A MACHINE LEARNING-BASED DISCOVERY

Allogeneic hematopoietic cell transplantation (allo-HCT) presents a potentially curative treatment for hematologic malignancies, yet carries associated risks and complications. Continuous research focuses on predicting outcomes and identifying risk factors. Notably, the influence of CD34+ cell dose on overall survival (OS) has been the subject of numerous studies yielding contradictory results. We developed machine learning (ML) models to predict allo-HCT outcomes and through the application of SHAP (SHapley Additive exPlanations), an explainable artificial intelligence (XAI) technique, enabled the identification of new and clinically relevant feature-outcome relationships. In particular, we identified clear interaction between CD34+ cell dose of peripheral blood stem cell (PBSC) grafts and patient age at allo-HCT for acute leukemia patients. Results of multivariable analysis validated the interaction effect: On young acute leukemia patients (≤45-year-old), low dose of CD34+ cells (<4.3 × 106 CD34+/kg) was associated with better OS against high dose (≥7 × 106 CD34+/kg) (hazard ratio [HR] 0.38, p=0.019), while for older acute leukemia patients (>45-year-old), low CD34+ cell dose (<3.8 × 106 CD34+/kg) was associated with worse OS against high dose (≥6.1 × 106 CD34+/kg) (HR 1.58, P = 0.033). In conclusion, our findings suggest that tailoring CD34+ cell dose by patient age may benefit acute leukemia patients undergoing allo-HCT, while XAI showcases excellent proficiency in revealing such interactions.

Donor cytomegalovirus serology impacts overall survival in children receiving first unrelated hematopoietic stem cell transplant for acute leukemia: European Society of Bone Marrow Transplantation Pediatric Diseases Working Party Study.

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Sociodemographic and Patient-Related Determinants of Outcomes after Allogeneic Hematopoietic Cell Transplantation in Acute Leukemia and Myelodysplastic Syndromes

Background: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a curative therapy for several high-risk hematologic disorders. Sociodemographic determinants (age, gender, and ethnicity) and patient-related factors (frailty and comorbidities) significantly impact post-transplant outcomes. We aimed to investigate the impact of sociodemographic and patient-related factors on allo-HCT outcomes. Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant (CIBMTR) registry from 2013 to 2018 using P5646 data by Ramathan et al. Cox regression was performed to compare overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), and platelet and neutrophil engraftment. Multivariate analyses were performed for recipient age, gender, ethnicity, Karnofsky's performance status (KPS), and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and adjusted for significant variables identified in the univariate analysis. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. SPSS version 28 and R version 4.16 were used for data analysis. Statistical significance was considered at p &amp;lt;0.05. Results: We included 7545 allo-HCT recipients. The median age at the time of transplant was 56 years, and 58% were men. Ethnicities were Caucasian (76%), Hispanic (8%), African American (6%), Asian (5%), and others (5%). The primary disorders included acute myeloid leukemia (47.2%), myelodysplastic syndrome (34.4%), and acute lymphoblastic leukemia (18.4%). Myeloablative conditioning was used in 53% of patients. Donor types were matched unrelated (49.5%), matched related (34.1%), and cord blood (16.4%). Graft sources were peripheral blood stem cells (68%), umbilical cord blood (16%), and bone marrow (16%). GVHD prophylaxis regimens included tacrolimus or cyclosporine-based (87%), post-transplant cyclophosphamide-based (9%), CD34 selection (2%), and others (2%). The KPS was 90% or higher (57%), 80-89 (29%), and &amp;lt;80 (14%). The HCT-CI was 0 (20%), 1-2 (30%), 3-4 (31%), and five or higher (19%). In the multivariate analyses adjusted for all significant predictors identified in the univariate analyses, significant predictors of outcomes included - inferior OSwas predicted by older age (HR 1.01, 95% CI 1.01-1.10, p&amp;lt;0.001), male gender (HR 1.08, 95% CI 1.00-1.15, p=0.030), lower KPS (HR 1.33, 95% CI 1.20-1.46, p&amp;lt;0.001), and higher HCT-CI (HR 1.71, 95% CI 1.53-1.92, p&amp;lt;0.001); lower DFSwas predicted by older age (HR 1.013, 95% CI 1.010-1.016 p&amp;lt;0.001), lower KPS (HR 1.30,95% CI 1.12-1.50, p&amp;lt;0.00), and higher HCT-CI (HR 1.66, 95% CI 1.41-1.95, p&amp;lt;0.001); higher NRMwas predicted by older age (HR 1.01, 95% CI 1.01-1.02, p&amp;lt;0.001), male gender (HR 1.13, 95% CI 1.00-1.28), lower KPS (HR 1.23, 95% CI 1.04-1.46, p=0.018), and higher HCT-CI (HR 2.17, 95% CI 1.77-2.65, p&amp;lt;0.001); higher rate of relapsewas predicted by older age (HR 1.01, 95% CI 1.01-1.01, p&amp;lt;0.001), lower KPS (HR 1.23, 95% CI 1.10-1.38, p&amp;lt;0.001), and higher HCT-CI (HR 1.15, 95% CI 1.02-1.30, p=0.020); higher incidence of chronic GVHD was predicted by older age (p&amp;lt;0.001, HR 1.01, 95% CI=1.0008-1.012), male gender (HR 1.12, 95% CI 1.04-1.20, p=0.003), and lower KPS (HR 1.134, 95% CI 1.01-1.27, p=0.028); and delayed neutrophil engraftment was predicted by older age (HR 1.01, 95% CI 1.01-1.01, p&amp;lt;0.001). No other significant associations were observed between these factors and post-transplant outcomes. Conclusion: The analyses identified sociodemographic factors (older age, male gender), frailty, and higher comorbidities as predictors of post-transplant outcomes, including inferior overall and disease-free survival, higher risk of relapse and non-relapse mortality, and increased incidence of chronic graft-versus-host disease in patients with acute leukemia and myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation. Our findings highlight the relevance of developing patient-centered interventions and a tailored selection of disease- and transplant-related factors to improve post-transplant outcomes.

Prognostic Factors Affecting Day+100 Survival in Patients Undergoing Allogeneic Haematopoietic Stem Cell Transplantation for Acute Leukaemia - A Single Centre Experience.

To determine the factors affecting the first 100 days of survival in acute leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Descriptive study. Place and Duration of the Study: Bone Marrow Transplant Centre, Rawalpindi, Pakistan, from March 2016 to February 2022. Patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in complete remission (CR) undergoing Allo-HSCT were included. Data were collected on patient demographics, diagnosis, remission status, pre-transplant analysis, donor compatibility, conditioning regimen, GVHD prophylaxis, engraftment times, post-transplant complications, mortality causes, and overall survival (OS) at 100 days. Among 101 transplant recipients (mean age of 24 ± 11.05 years; n = 76 males, n = 25 females), 41 had AML and 60 had ALL. Ninety patients underwent matched sibling donor (MSD)-HSCT, while 11 had haplo-identical sibling-HSCT. Patients ≤13 years had higher survival rates than older patients (94.4% vs. 67.5%, p = 0.03). High pre-transplant serum ferritin levels (>2500 mg/dl) predicted lower OS (48.9% vs. 100% in ferritin <1000 mg/dl, p <0.01). AML patients had a survival advantage over ALL patients (82.9% vs. 65%, p = 0.05). Early neutrophil engraftment within 14 days correlated with better survival (96.4% vs. 54.3%, p <0.01). Lastly, severe mucositis also adversely affected survival (60% in Grade III vs. 9.5% in Grade IV, p <0.01). Identifying modifiable factors can improve long-term support and follow-up, enhancing the patient outcomes in underdeveloped nations. Haematopoietic stem cell transplant, Day + 100 survival, Acute leukaemia, Pakistan.

Prognostic Factors Affecting Day+100 Survival in Patients Undergoing Allogeneic Haematopoietic Stem Cell Transplantation for Acute Leukaemia - A Single Centre Experience.

To determine the factors affecting the first 100 days of survival in acute leukaemia patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Descriptive study. Place and Duration of the Study: Bone Marrow Transplant Centre, Rawalpindi, Pakistan, from March 2016 to February 2022. Patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in complete remission (CR) undergoing Allo-HSCT were included. Data were collected on patient demographics, diagnosis, remission status, pre-transplant analysis, donor compatibility, conditioning regimen, GVHD prophylaxis, engraftment times, post-transplant complications, mortality causes, and overall survival (OS) at 100 days. Among 101 transplant recipients (mean age of 24 ± 11.05 years; n = 76 males, n = 25 females), 41 had AML and 60 had ALL. Ninety patients underwent matched sibling donor (MSD)-HSCT, while 11 had haplo-identical sibling-HSCT. Patients ≤13 years had higher survival rates than older patients (94.4% vs. 67.5%, p = 0.03). High pre-transplant serum ferritin levels (>2500 mg/dl) predicted lower OS (48.9% vs. 100% in ferritin <1000 mg/dl, p <0.01). AML patients had a survival advantage over ALL patients (82.9% vs. 65%, p = 0.05). Early neutrophil engraftment within 14 days correlated with better survival (96.4% vs. 54.3%, p <0.01). Lastly, severe mucositis also adversely affected survival (60% in Grade III vs. 9.5% in Grade IV, p <0.01). Identifying modifiable factors can improve long-term support and follow-up, enhancing the patient outcomes in underdeveloped nations. Haematopoietic stem cell transplant, Day + 100 survival, Acute leukaemia, Pakistan.

Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia.

Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.

Early Post-Transplant Serum Ferritin Levels as Predictive Biomarkers for Severe Acute Graft-Versus-Host Disease in Pediatric Umbilical Cord Blood Transplantation for Acute Leukemia.

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) using umbilical cord blood is a valuable therapy option for patients with acute leukemia (AL). Acute graft-versus-host disease (aGVHD) remains the most frequently encountered complication. This study investigated risk factors for aGVHD and assessed whether post-transplant serum ferritin (SF) within 2 weeks is a potential biomarker for aGVHD in pediatric patients with AL undergoing umbilical cord blood transplantation (UCBT). MATERIAL AND METHODS We conducted a retrospective cohort study of 71 patients with AL who underwent UCBT at the Children's Hospital of Soochow University between 2017 and 2022. We evaluated several factors related to aGVHD. Univariate and multivariate analyses were performed using the proportional subdistribution hazard regression model of Fine and Gray. Analyses of overall survival (OS) were performed using the Kaplan-Meier method, and differences were compared using log-rank tests. RESULTS Of the 71 patients, 23 (32.4%) experienced grade II-IV aGVHD, of whom 18 (25.4%) developed grade III-IV aGVHD. Patients with grade II-IV and III-IV aGVHD had worse 5-year OS (69.4±10%, p=0.01; and 60.6±11.6, P=0.007, respectively). Conditioning intensity was a risk factor for grade III-IV aGVHD (HR: 0.34, 95% CI: 0.13-0.89, P=0.027). An SF level >1650 ng/mL within 2 weeks post-transplant was associated with an increased risk of severe aGVHD (HR: 3.61, 95% CI: 1.09-11.97, P=0.036). CONCLUSIONS Post-transplant SF within 2 weeks was a potential biomarker for developing severe aGVHD. Higher levels of post-transplant SF are associated with a higher incidence of grade II-IV aGVHD and grade III-IV aGVHD.

Persistent or New Cytopenias Predict Relapse Better than Routine Bone Marrow Aspirate Evaluations After Hematopoietic Cell Transplantation for Acute Leukemia or Myelodysplastic Syndrome in Children and Young Adult Patients

The clinical value of serial routine bone marrow aspirates (rBMAs) in the first year after allogeneic hematopoietic cell transplantation (alloHCT) to detect or predict relapse of acute leukemia (AL) and myelodysplastic syndrome (MDS) in pediatric and young adult patients is unclear. The purpose of this analysis was to determine if assessment of minimal residual disease (MRD) by multiparameter flow cytometry (MFC, MFC-MRD) or donor chimerism (DC) in rBMAs or serial complete blood counts (CBCs) done in the year after alloHCT predicted relapse of AL or MDS in pediatric and young adult patients. We completed a retrospective analysis of patients with AL or MDS who had rBMAs performed after alloHCT between January 2012 and June 2018. Bone marrow (BM) was evaluated at approximately 3, 6, and 12 months for disease recurrence by morphology, MFC-MRD, and percent DC by short tandem repeat molecular testing. CBCs were performed at every clinic visit. The main outcome of interest was an assessment of whether MFC-MRD or DC in rBMAs or serial CBCs done in the year after alloHCT predicted relapse in AL or MDS pediatric and young adult patients. A total of 121 recipients with a median age of 13 years (range 1 to 32) were included: 108 with AL and, 13 with MDS. A total of 423 rBMAs (median 3; 0 to 13) were performed. Relapse at 2 years was 23% (95% CI: 16% to 31%) and at 5 years 25% (95% CI: 18% to 33%). One hundred fifty-four of 157 (98%) rBMAs evaluated for MRD by MFC were negative and did not preclude subsequent relapse. Additionally, low DC (<95%) did not predict relapse and high DC (≥95%) did not preclude relapse. For patients alive without relapse at 1 year, BM DC (P = .74) and peripheral T-cell DC (P = .93) did not predict relapse. Six patients with low-level T-cell and/or BM DC had a total of 8 to 20 BM evaluations, none of these patients relapsed. However, CBC results were informative for relapse; 28 of 31 (90%) relapse patients presented with an abnormal CBC with peripheral blood (PB) blasts (16 patients), cytopenias (9 patients), or extramedullary disease (EMD, 3 patients). Two patients with BM blasts >5% on rBMA had circulating blasts within 5 weeks of rBMA. Neutropenia (ANC <1.5 K/mcl) at 1 year was predictive of relapse (P = .01). Neutropenia and thrombocytopenia (<160 K/mcl) were predictive of disease-free survival (DFS) with inferior DFS for ANC <1.5 K/mcl, P = .001, or platelet count <160 K/mcl (P = .04). These results demonstrate rBMAs after alloHCT assessed for MRD by MFC and/or for level of DC are poor predictors for relapse in pediatric and young adult patients with AL or MDS. Relapse in these patients presents with PB blasts, cytopenias, or EMD. ANC and platelet count at 1-year were highly predictive for DFS.

How adoptive transfer of components of the donor immune system boosts GvL and prevents GvHD in HLA-haploidentical hematopoietic transplantation for acute leukemia.

Why a new Perspective in allogeneic hematopoietic transplantation? A summary. Nowadays, for high-risk acute leukemia patients without an HLA-matched donor (sibling or volunteer), hematopoietic transplants that use HLA-haploidentical grafts combined with enhanced post transplant immune suppression (i.e., high-dose cyclophosphamide) are widely used. They are associated with low TRM rates. However, they are also associated with significant chronic GvHD while they only partially abrogate leukemia relapse rates. One may speculate that post-transplant immune suppression, required for GvHD prophylaxis, weakens the anti-leukemic potential of the graft. Historically, haploidentical transplants became feasible for the first time through transplantation of T cell-depleted peripheral blood hematopoietic progenitor cells. Lack of post-transplant immune suppression allowed the emergence of donor-versus-recipient NK-cell alloreactions that eradicated AML. In an attempt to improve these results we recently combined an age-adapted, irradiation-based conditioning regimen with transplant of T-cell-depleted grafts and infusion of regulatory and conventional T cells, without any post transplant immune suppression. With the obvious limitations of a single center experience, this protocol resulted in extremely low relapse and chronic GvHD rates and, consequently, in a remarkable 75% chronic GvHD/relapse-free survival in over 50 AML patients up to the age of 65 many of whom at high risk of relapse.

The Outcomes and Risk Factors for Late-Onset Haemorrhagic Cystitis after Allogeneic Haematopoietic Transplantation for Acute Leukaemia: A Retrospective, Single-Centre Observational Study

The Outcomes and Risk Factors for Late-Onset Haemorrhagic Cystitis after Allogeneic Haematopoietic Transplantation for Acute Leukaemia: A Retrospective, Single-Centre Observational Study

T-Cell Depletion with Both Reduced Dose Anti-Thymocyte Globulin and Reduced Dose Post-Transplant Cyclophosphamide in Haploidentical Peripheral Blood Stem Cell Transplantation for Acute Leukemia and Myelodysplatic Syndrome

Graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation from HLA haplo-identical familial donor (haplo-HSCT) is based on in vivo T-cell depletion with either anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). ATG has made significant contributions to enabling haplo-HSCT. However, the benefit of ATG may be often mitigated by higher risk of viral reactivation, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV) due to a slower immune reconstitution. PTCy revolutionized HLA-mismatched HSCT and rapidly became the standard-of-care. However, it also has problems due to a cytokine release syndrome (CRS) -like symptoms and excessive cytotoxicity leading to the risk of acute cardiotoxicity and the possibility of alleviated graft-versus-leukemia effect. Considering a demand for more optimal in vivo T-cell depletion, we tried to combine both ‘lower-dose’ ATG and ‘lower-dose’ PTCy before and after stem cell infusion, respectively, hoping they can mitigate their individual limitations while maintaining the effectiveness of in vivo T-cell depletion. We retrospectively included 60 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT following busulfan (3.2 mg/kg/day for 4 days as myeloablative and for 2 days as reduced intensity conditioning) and fludarabine (a total of 160 mg/m 2) between January 2019 and June 2023. Among them, 32 received a novel combination of ATG (a total of 3.0, 3.5, or 4.0 mg/kg depending on the absolute lymphocyte count level on days -3) and PTCy (50mg/kg on day +3 and 30mg/kg on day +4) compared to 28 patients who received ATG only (2.5 mg/kg/day from days -3 to -1, a total of 7.5 mg/kg) as in vivo T-cell depletion. Most patients received cyclosporine and mycophenolate mofetil as GVHD prophylaxis. The median follow-up duration for all patients was 8 months (median 9 months in the ATG/PTCy group and 7.5 months in the ATG group, respectively; P = 0.744). Baseline characteristics including age, sex, disease status, modified EBMT score, and the intensity of conditioning, were well-balanced except slightly higher infused CD34+ cells in the ATG/PTCy group (median 5.2 vs. 4.7 x 10 6/kg, P = 0.042). The cumulative incidence of acute GVHD at day +100 and moderate to severe chronic GVHD at 1 year were significantly lower in the ATG/PTCy group compared to the ATG group, respectively [grades II-IV acute GVHD: 20.4% (95% confidence interval [CI], 4.3-33.8%) vs. 48.4% (95% CI, 25.2-64.4%), P = 0.014; grades III-IV acute GVHD: 7.5% (95% CI, 0-17.1%) vs 31.1% (95% CI, 10.5-46.9%), P = 0.019; and moderate to severe chronic GVHD: 9.5% (95% CI, 0-21.2%) vs. 60% (95% CI, 23.3-79.1%), P = 0.007]. The ATG/PTCy group had a tendency of less incidence and severity of the haplo-fever. Multivariate analysis showed a significantly higher GRFS (hazard ratio 0.35, P = 0.002) and OS (hazard ratio 0.4, P = 0.014) for an ATG/PTCy group. The use of dual T-cell depletion with the reduced dose ATG in combination with the reduced dose PTCy showed a significantly superior early transplant outcome over with ATG of 7.5 mg/kg in terms of both GVHD and survival outcomes.

Outcomes of Attenuated Dose Fludarabine and Melphalan Based Conditioning Regimen in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant for Acute Leukemia and Myelodysplastic Syndrome

Introduction: Fludarabine combined with melphalan 140 mg/m2 (FluMel140) is a commonly used reduced-intensity conditioning (RIC) regimen in patients undergoing matched related (MRD) and unrelated donor (MUD) allogeneic stem cell transplant (alloSCT). Ciurea et al Blood 2020, described outcomes of Flu 160 mg/m2 and Mel 100 mg/m2. In this study, we describe our experience of attenuated melphalan dosing 100-120 mg/m2 versus 140 mg/m2 with fludarabine 125 mg/m2 (attenuated FluMel versus regular dose FluMel). Methods: We retrospectively reviewed patients from November 2016 to April 2023 with AML, ALL or MDS undergoing alloSCT who received fludarabine and melphalan. Patients who received the lower dose of melphalan were considered to be the attenuated FluMel cohort, whereas patients receiving the melphalan 140 mg/m2 were considered to be the control cohort. Kaplan-Meier and log-rank tests were used to estimate OS. NRM and relapse incidence (RI) was calculated using competing risk analysis. R 4.2.0 (R Foundation for Statistical Computing) was used for statistical analyses. Results: A total of 134 patients [92 (68.7%) males] were evaluated. Thirty-seven (27.6%) patients received attenuated FluMel and 97 (72.4%) patients received regular dose FluMel (controls). Among the patients in the attenuated FluMel cohort, 5 (13.5%) patients also received fludarabine at doses less than 125 mg/m 2 [median 20 mg/m 2 (range 87.5-112.5 mg/m 2]. Median age at transplant was 65 years (range 30 - 76 years). The most common disease was AML [75 (56.0%) patients] ( Table 1). Patients in the attenuated FluMel group had comparable iothalamate clearance compared to control cohort (clearance &amp;lt;65 ml/min/1.73 m2: 18.9% vs. 12.4%, P = 0.52). Patients in the attenuated FluMel group had comparable rates of high/very high DRI to those in control cohort (51.4% vs. 43.3%, P = 0.91). Compared to the control cohort, patients in the attenuated FluMel group were less likely to have a matched related donor (21.6% vs. 45.4%, P = 0.02) and were more likely to receive PTCy for GVHD prophylaxis (37.8% vs. 16.5%, P = 0.02). Among the patients receiving attenuated FluMel, the median melphalan dose administered was 100 mg/m2. The median time to neutrophil engraftment was 19 days (IQR 16-21 days), and median time to platelet engraftment was 18 days (range 12-25 days). Eleven (29.7%) patients developed post-alloSCT mucositis, and 3 (8.1%) patients developed grade 3-4 mucositis. All the patients in the attenuated FluMel group achieved 100% CD33 donor chimerism at day +30 (n=35) and day +100 (n=28) after alloSCT. Similarly, 26 (74.3%, n = 35) patients achieved ≥ 95% CD3 donor chimerism at day +30 after alloSCT and 23 (82.1%, n = 28) patients achieved ≥ 95% CD3 donor chimerism at day +100 after alloSCT. Median follow-up of the entire cohort after alloSCT was 2.3 years (95% CI 2.1-2.5 years). Median follow-up was 1.5 years in the attenuated FluMel cohort and 2.5 years for the control cohort ( P&amp;lt;0.001) . Survival was similar among patients receiving attenuated FluMel vs. control cohort (2-year OS 74.7% vs. 65.0%, P = 0.28). At 2 years post-alloSCT, the attenuated FluMel and control cohort had similar non-relapse mortality (19.9% vs. 24.4%, P=0.58) and relapse (22% vs. 15.2%, P=0.51). The attenuated FluMel was not associated with an increased incidence of relapse (HR 1.36, 95% CI 0.50-3.73, P=0.55) or NRM (HR 0.74, 95% CI 0.28-1.95, P = 0.55). GVHD-free relapse free (GRFS) survival was also similar among the attenuated Flu/Mel and control cohort (1-year GRFS rate 41.1% vs. 45.6%, P = 0.8). Among the patients receiving PTCy for GVHD prophylaxis, the 2-year OS in patients receiving attenuated FluMel was higher than the control group, but it was not statistically significant (2-year OS rate: 90% vs. 55%, P=0.37, Figure 1). Compared to the control group, the attenuated FluMel group had similar rates of NRM at 100 days (10% vs. 12.5%), 1 year (NA vs. 25%) and at 2 years after alloSCT (NA vs. 25%, P=0.54). GRFS at 1 year was also similar between the attenuated FluMel and control group (68.6% vs. 43.8%, P = 0.69). Conclusion: The attenuated dosed FluMel conditioning is a safe and effective regimen for elderly patients with acute leukemia and MDS, and is non-inferior to regular dose FluMel. Among patients receiving PTCy for GVHD prophylaxis, the lower dose of melphalan was non-inferior to regular dose FluMel for survival outcomes. Larger studies are needed to confirm our findings.

Second Allogeneic Stem Cell Transplantation in Acute Leukemia with Post-Transplantation Relapse

Aim: It is known that the prognosis of acute leukemia patients who relapse after the first allogeneic stem cell transplantation (ASCT) is dismal. Our goal was to assess the value of a second allogeneic stem cell transplant in acute leukemia patients who experienced post-transplant recurrence.&#x0D; Material and Methods: We retrospectively reviewed data from 29 patients with relapsing acute leukemia who underwent a second ASCT. Nineteen patients with acute myeloid leukemia and ten patients with acute lymphoblastic leukemia were included in the study.&#x0D; Results: Ten AML patients and 10 ALL patients were included in the study. Most patients (62%) were in remission before the second transplantation. The median time between the first and second ASCT was 11.9 months (3.1-42 months). Complete remission (CR) was achieved after the second ASCT in 21 (72%) patients, and 11 (52%) patients relapsed after the second ASCT. During this analysis, six patients (21%) were alive and in remission. Relapse of the disease was the leading cause of mortality. After the second ASCT, overall survival (OS) was 6.34 months, and leukemia-free survival (LFS) was 13.8 months.&#x0D; Conclusion: For patients with acute leukemia who relapsed after the first ASCT, a second ASCT is a good option and can keep patients alive.

Immunology of cord blood T-cells favors augmented disease response during clinical pediatric stem cell transplantation for acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been an important and efficacious treatment for acute leukemia in children for over 60 years. It works primarily through the graft-vs.-leukemia (GVL) effect, in which donor T-cells and other immune cells act to eliminate residual leukemia. Cord blood is an alternative source of stem cells for transplantation, with distinct biological and immunological characteristics. Retrospective clinical studies report superior relapse rates with cord blood transplantation (CBT), when compared to other stem cell sources, particularly for patients with high-risk leukemia. Xenograft models also support the superiority of cord blood T-cells in eradicating malignancy, when compared to those derived from peripheral blood. Conversely, CBT has historically been associated with an increased risk of transplant-related mortality (TRM) and morbidity, particularly from infection. Here we discuss clinical aspects of CBT, the unique immunology of cord blood T-cells, their role in the GVL effect and future methods to maximize their utility in cellular therapies for leukemia, honing and harnessing their antitumor properties whilst managing the risks of TRM.

Myeloablative fractionated busulfan for allogeneic stem cell transplant in older patients or patients with comorbidities

AbstractTraditional conditioning regimens for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce nonrelapse mortality (NRM) while retaining antileukemic effects. Here, we performed a phase 2 trial for adults with hematological malignancies receiving matched related or unrelated allo-HCT. Participants received busulfan 80 mg/m2 as outpatients on days −20 and −13 before transplant. Fludarabine 40 mg/m2 was administered on days −6 to −3, followed by busulfan dosed to achieve a target area under the curve of 20 000 mol/min for the whole course. The primary end point was day-100 NRM. Seventy-eight patients were included, with a median age of 61 years (range, 39-70 years), who received transplantation for acute leukemia (24%), myelodysplastic syndrome (27%), or myeloproliferative disease/chronic myeloid leukemia (44%). HCT-specific comorbidity index (HCT-CI) was ≥3 in 34 (44%). With a median follow-up of 36.4 months (range, 2.9-51.5), the 100-day, 1-year, and 3-year NRM rates were 3.8%, 8%, and 9.3%, respectively, without a significant difference in age or HCT-CI score. The 1-year and 3-year relapse incidence was 10% and 18%, respectively. The 3-year overall survival was 80%, without a significant difference in age or HCT-CI score and was similar for patients aged >60 years and those aged <60 years as well as for those with HCT-CI ≥3 and HCT-CI <3. Overall, a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities. This trial was registered at www.clinicaltrials.gov as #NCT02861417.

Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT.

Graft failure has remained a limitation of umbilical cord blood transplantation (CBT). Here, we assessed the outcomes of patients who experienced graft failure after CBT. Inclusion criteria were patients (age ≥ 18 years) experiencing graft failure after unrelated CBT (single or double) between 2005 and 2016, for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), no prior allogeneic or autologous transplantation, no other stem cell product. The study included 87 patients. At 1-year, cumulative incidence of relapse and nonrelapse mortality (NRM) was 35% and 37%, respectively. One-year overall survival (OS) and progression-free survival (PFS) was 40% and 29%, respectively. Forty-six patients underwent a salvage second transplantation with 1-year and 2-year OS and PFS from second transplantation 41% and 34% for OS, and 37% and 34% for PFS, respectively. In multivariate analysis, complete remission (CR) at CBT (HR = 0.45, 95% CI 0.25-0.83, P = 0.01) and reduced-intensity conditioning (HR = 0.51, 95% CI 0.29-0.91, P = 0.023) were associated with better OS. In conclusion, in this retrospective study, we observed that approximately one-quarter of patients experiencing graft failure after CBT remained alive without relapse 2 years later.

Refining eligibility criteria of unit selection for myeloablative cord blood transplantation in acute leukemia: Real-world experience of a referral center.

The algorithm for cord blood (CB) unit selection is still somewhat ambiguous. We retrospectively analyzed 620 cases of acute leukemia between 2015 and 2020, who were treated with myeloablative single-unit umbilical CB transplantation (UCBT). We found that, when human leukocyte antigen (HLA) mismatch was ≤3/10, CD34+ cell dosage<0.83 × 105/kg-considerably lower than prevalent guidelines-was permissible without affecting survival. Moreover, synergy between donor killer-cell immunoglobulin-like receptors (KIR) haplotypes-B and donor-recipient HLA-C mismatch protected against relapse-related mortality. We submit that minimum required CD34+ cell dosage can possibly be relaxed to broaden access to UCBT, and donor KIR genotyping should be considered during unit selection.

HIV-1 remission and possible cure in a woman after haplo-cord blood transplant

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) invitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC

Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010 and December 31, 2016, considering data from the French national retrospective register ProMISe (SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy)). We included patients presenting LR, defined as a relapse occurring at least two years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, 7,582 AHSCT were performed in 29 centers and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered as LR, representing an incidence of 4.2% from the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia, and 40 (13.8%) with acute lymphoid leukemia. Median delay from AHSCT to LR was 38.2 months (29.2-49.7) and 27.2% of patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (5.6-46.4). The most common salvage therapy was induction regimen (55.5%), with complete remission being obtained for 50.7%. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (7.1-49.1). Non-relapse mortality after second AHSCT was 18.2%. We identified in the Cox model some of the associated factors with delay of LR: the disease status not in first complete remission at first HSCT (odds ratio (OR) 1.31, 1.04-1.64, p=0.02) and the use of post-transplant cyclophosphamide (OR 2.23, 1.21-4.14, p=0.01). Chronic GVHD appeared to be a protective factor (OR 0.64, 0.42-0.96, p=0.04). Prognosis of LR is better than early relapses, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity.

Association of ABO mismatch with the outcomes of allogeneic hematopoietic cell transplantation for acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p=0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.