Risk Of Transplant-related Mortality Research Articles

Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study

BackgroundWe previously reported that the “Endothelial Activation and Stress Index” (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as...

Role of Polyomavirus BK and Adenovirus in the Development of Urinary Tract Complications in Pediatric Hematopoietic Stem Cell Transplantation

One of the major challenges in pediatric hematopoietic stem cell transplantation (HSCT) is the susceptibility to viral infections and reactivations that can lead to potentially life-threatening complications and increase the transplant-related mortality (TRM). Polyomavirus BK (BKPyV) and Adenovirus (AdV) represent the predominant causes of urinary tract complications, in particular hemorrhagic cystitis (HC), in HSCT recipients. Treatment options for BKPyV and AdV infections are limited and there is no accepted standard of care for the prevention and treatment of these HSCT complications. The aim of our retrospective study was to analyze the incidence of BKPyV and AdV infection in urinary and plasma samples of pediatric patients undergoing HSCT for both malignant and non-malignant disease at a single pediatric Hematology-Oncology unit. Endpoints were the cumulative incidence of infection, measured on blood and urine samples, in the first 100 days after HSCT, prevalence of asymptomatic and symptomatic infection, and correlation between BKPyV and AdV DNAemia and DNAuria and the development of HC. A total of 79 patients were analyzed. Thirty-seven (47%) patients were positive for BKPyV on urine samples and 20 (30%) on blood samples within the first 30 days after transplantation. As for AdV, 11 (9%) patients were positive on urine samples and 18 (15%) on blood samples. In our pediatric cohort, BKPyV DNAuria was a frequent event after HSCT, while BKPyV DNAemia was observed less frequently, and was accompanied by higher viruria values (p-value <0,001, with a median viral load in the urine of 3.8 x 10 9 copies/mL). Conversely, AdV positivity in urine is rare, while AdV DNAemia was more frequent, due to the modality of BKPyV and AdV distribution (urothelium is the main reservoir for BKPyV, while intestinal lymphocytes represents the main reservoir for AdV). Of the 37 patients with BKPyV DNA on urine samples, 11 (30%) developed a symptomatic infection with grade II (5 patients, 40%) and grade III (6 patients, 60%) HC. We did not observe any correlation between BKPyV DNA urinary levels and the development of HC, as higher viral loads have not been shown to be good predictors of occurrence or severity of HC. Cumulative incidence (CI) of BKPyV infection was higher in haploidentical HSCT (51%) and matched unrelated donors (MUD) (48%) than in HSCT from matched familiar donors (31%). Similarly, CI of AdV reactivation was higher in haploidentical HSCT (16%) than MUD (6%) and matched familiar donors (9%). Choice of donor, the type of immunosuppression used and the intensity of conditioning regimen represented predictors of both blood and urine DNA positivity for both viruses. In our cohort, positivity for BKPyV on blood and/or urine did not increase the risk of transplant-related mortality and did not affect the overall survival after HSCT. On the basis of our data, we now perform screening of BKPyV viruria only in symptomatic patients or in transplant recipients with specific risk factors (type of donor, severity of immunosuppression). Similarly, search for BKPyV DNAemia is reserved to subjects with a high viral load on urine. Likewise, search for AdV on urine samples is performed on symptomatic patients with high-load AdV DNAemia.

Allotransplantation and Gene Therapy Equity for Children with Sickle Cell Disease: Distributional Cost-Effectiveness of Allotransplantation Vs Gene Therapy Vs Standard-of-Care in Pediatric Patients with Sickle Cell Disease in the United States

Introduction: Patients with sickle cell disease (SCD) have reduced quality-adjusted life expectancy due to substantial mortality risks and decreased quality-of-life for every year lived with the disease. Allotransplantation was the first treatment with curative potential, but it carries concomitant risks of transplant-related mortality and graft-versus-host disease (GVHD). Once approved, gene therapy would be the second treatment with the possibility of lifelong cure but unlike allotransplantation, it may do so without the concomitant risks. Prior research has shown that even if gene therapy is conventionally cost-ineffective versus the standard-of-care (SOC), it can be a justifiable treatment option for a historically marginalized patient population in the United States, as demonstrated by equity-weighted cost-effectiveness. For allotransplantation and gene therapy, neither conventional nor distributional (i.e., equity-weighted) cost-effectiveness is known. Accordingly, we conducted the first conventional and distributional cost-effectiveness analyses of allotransplantation therapy for pediatric patients with SCD in the United States. Methods: We built a Markov model of pediatric patients with sickle cell disease to examine the cost-effectiveness of allotransplantation vs gene therapy vs SOC and determine equity weight thresholds. Sex-, age-, and disease-severity-specific annual costs and transition probabilities across disease severities for SOC were informed by 11 years of data from US commercially insured patients with SCD (2007-2017; Optum). Disease severity was defined based on annual number of hospitalizations for vaso-occlusive crises, as defined in clinical trials. SOC included hydroxyurea, opioid therapy, antibiotics, vaccinations, and blood transfusions. Allotransplantation- and GVHD-specific transition probabilities and costs were informed by prior literature and health resource utilization data, originally reported from the Center for International Blood and Marrow Transplant Research and the Pediatric Health Information System. Quality-adjusted life-years (QALYs) were informed by published lifetime simulations of patients living with SCD and matched controls, derived initially from a polynomial fit linking Euroqual-5 Dimensions to the visual analog scale for pain in patients with SCD in several studies. Age-, sex- and disease-specific background mortality probabilities were employed. Conventional cost-effectiveness was quantified using an incremental cost-effectiveness ratio (ICER), at a willingness-to-pay threshold of $100,000/QALY. Given expert clinical experience with optimizing allotransplantation outcomes in SCD, we employed a maximum patient starting age of 12 and assumed that gene therapy cost $2.45 million and was 100% effective. To account for health inequities in SCD, we then conducted a distributional cost-effectiveness analysis (DCEA), which applies an inequality aversion parameter (i.e., how much weight one puts on reducing disparities), to the distribution of outcomes across relevant sub-groups for allotransplantation to be favored over SOC and justify funding per DCEA standards. These were compared to prior estimates for commonly used equity weights in the United States (range 0.5-3.0). Results: In the base-case, allotransplantation, gene therapy, and SOC accrued 22.1, 25.5, 15.7 discounted lifetime QALYs at costs of $1.9, $2.8, $1.0 million, respectively, with all therapies on the cost-effectiveness frontier (Table 1). The ICERs and equity weight thresholds were $138,000/QALY and 0.5, and $253,000/QALY and 4.5, for allotransplantation (vs SOC) and gene therapy (vs allotransplantation), respectively. Conclusion: Similar to findings for gene therapy versus SOC in the first published DCEA in sickle cell disease, allotransplantation also appears to be an equitable therapeutic option for pediatric patients with sickle cell disease, regardless of conventional cost-ineffectiveness and as compared to SOC. The consideration of patient-population-specific equity offers an important opportunity to derive transparent benchmarks for intertwined equity- and value-informed decision making. Quantitative consideration of equity in the context of conventional cost-ineffectiveness can be an important tipping point in justification of funding.

Autologous followed by allogeneic versus tandem-autologous transplantation in high-risk, newly diagnosed multiple myeloma: a systematic review and meta-analysis

ABSTRACTObjectives:High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM.Methods:Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models.Results:Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51–1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67–5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%).Conclusion:Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

The association of intestinal microbiota diversity and outcomes of allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis.

Growing evidence suggests that highly intestinal microbiota diversity modulates host inflammation and promotes immune tolerance. Several studies have reported that patients undergoing allo-HSCT have experienced microbiota disruption that is characterized by expansion of potentially pathogenic bacteria and loss of microbiota diversity. Thus, the primary aim of this meta-analysis was to determine the association of intestinal microbiota diversity and outcomes after allo-HSCT, and the secondary aim was to analyze the associations of some specific microbiota abundances with the outcomes of allo-HSCT. Electronic databases of Pubmed, Embase, Web of Science, and Cochrane Library were searched from inception to August 2023, and 17 studies were found eligible. The pooled estimate suggested that higher intestinal microbiota diversity was significantly associated with overall survival (OS) benefit (HR = 0.66, 95% CI: 0.55-0.78), as well as decreased risk of transplant-related mortality (HR = 0.56, 95% CI: 0.41-0.76), and lower incidence of grade II-IV aGVHD (HR = 0.41, 95% CI: 0.27-0.63). Furthermore, higher abundance of Clostridiales was associated with a superior OS (HR = 0.40, 95% CI: 0.18-0.87), while higher abundance of Enterococcus (HR = 2.03, 95% CI: 1.55-2.65), γ-proteobacteria (HR = 2.82, 95% CI: 1.53-5.20), and Candida (HR = 3.80, 95% CI: 1.32-10.94) was an adverse prognostic factor for OS. Overall, this meta-analysis highlights the protective role of higher intestinal microbiota diversity on outcomes after allo-HSCT during both pre-transplant and post-transplant periods. Some specific microbiota can be useful in the identification of patients at risk of mortality, offering new tools for individualized pre-emptive or therapeutic strategies to improve allo-HSCT outcomes.

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.

Reduced toxicity conditioning and a high CD34+ cell dose can achieve full donor chimerism in DOCK8 deficiency.

Biallelic mutations in the dedicator of cytokinesis 8 (DOCK8) gene were identified as the cause of combined immunodeficiency in 2009. Survival rates without hematopoietic stem cell transplant in patients with DOCK8 deficiency decline from 87% at 10 years to 33% at 30 years. Hematopoietic stem cell transplant is therefore the recommended treatment for cure of DOCK8 deficiency. However, patients with DOCK8 deficiency have multiple infectious comorbidities; hence, they cannot tolerate myeloablative conditioning. Reduced intensity conditioning reduces the risk of transplant-related mortality but increases the possibility of mixed chimerism. Mixed chimerism in children with immunodeficiency increases the risk of autoimmunity and the need for long-term immunoglobulin infusion. Here we have sought to devise a strategy for reducing the possibility of mixed chimerism without increasing the risk of transplant-related mortality. To balance the risk of transplant-related mortality and mixed chimerism, we used treosulfan-based reduced toxicity conditioning with a high CD34+ cell dose and differential T-cell capping for HLA-matched and haploidentical transplants. We are able to report that by using the aforementioned novel strategy, we achieved excellent transplant outcomes in the first cohort of high-risk patients with DOCK8 deficiency from India. High CD34+ cell dose and reduced toxicity conditioning can achieve full donor chimerism in DOCK8 deficiency.

Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT.

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated the ability of this relatively safe transplant modality to eliminate autoimmune T-cell clones in the NOD mouse model which spontaneously develop T1DM. Our results demonstrate that using this approach, marked durable chimerism is attained, without any transplant-related mortality, and with a very high rate of diabetes prevention. TCR sequencing of transplanted mice showed profound changes in the T-cell repertoire and decrease in the prevalence of specific autoimmune T-cell clones directed against pancreatic antigens. This approach could be considered as strategy to treat people destined to develop T1DM but with residual beta cell function, or as a platform for prevention of beta cell destruction after transplantation of allogenic beta cells.

Early Use of Antibiotics and Unfavorable Results after Allogeneic Hematopoietic Stem Cell Transplantation, a Competing Risk Analysis in a Cohort of 274 Patients

The use of empiric broad-spectrum antibiotics for the treatment of febrile episodes during the first weeks of allogeneic transplant has been associated with an increase in the incidence of acute Graft versus Host Disease (aGVHD) and transplant-related mortality (TRM). However, there are several confounding factors; age, donor source, conditioning, GVHD prophylaxis, disease index risk, comorbidities, and the time of initiation of antibiotics that can preclude strong conclusion regarding the importance of this association. We present the outcomes of a cohort of 274 patients whose received or not antibiotics in the early phase of transplant after adjustment for confounding factors and competing risks Methods and patients. Retrospective cohort study from a single cancer center. All consecutive patients older than 15 years and transplanted with bone marrow or peripheral stem cell, from Jan 2003 to Dec 2019, were included. The cohort who was exposed was composed of the patients that received IV antibiotics between day - 7 and + 7 and it was compared with the group that did not. TRM was defined as death due to any transplantation-related cause other than disease relapse from day 0 until + 365, aGVHD was diagnosed and classified according to MAGIC criteria and it was measured until d + 100. For statistical porpoises univariable and multivariate survival analyses were conducted, and Fine-Gray models were fitted to account for competing risks, also, an exploratory subgroups analysis was conducted according to the type of antibiotic received. The study was approved by Institutional Ethic Committee Results. The main characteristics of the patients are summarized in table 1. Briefly: the whole group consisted of 274 patients; median age 36.6 years, 244 had malignancies, 185 acute leukemia. The disease index risk was intermediate or higher in 250, 109 underwent to haplo transplant, and 150 received cyclophosphamide pos transplantation. 154 (56%) received early antibiotic and 119 (44%) did not. The median follow-up for the entire group was 560 days, the cumulative incidence (CI) of TRM at 1 year was 21% in the exposed group vs. 9% in the non-exposed p: 0.007. Without adjustment, early use of antibiotics was associated with a significant increase in the TRM risk (sHR 2.49, 95%CI: 1.26-4.9; p=0.008), and after adjustment, it continued to be an independent risk factor for TRM (sHR 2.48, 95%CI: 1.25-4.90; p=0.009) (table 2). The CI of aGVHD was 24% in the exposed patients vs.15% in the other group; p=0.049). Without adjusting, the early use of antibiotics was associated with an increase in the risk (sHR 1.74, 95%CI: 1.00-3.03; p=0.05), however, after adjusting in multivariate analysis, this effect did not persist (sHR 1.49, 95%CI: 0.818-2.73; p=0.19). Regarding the antibiotic administered it was meropenem in 60% of the cases, cefepime in 30%, and vancomycin was added in 18%. When comparing each antibiotic with the non-early use of them, both, cefepime and meropenem were associated with increased risk of TRM (p=0.008 and p=0.003, respectively) while no differences were found between the use of vancomycin and the non-use of antibiotics (p:0.615) Conclusion. This study shows that, after adjusting for several confounding factors and competing risk, the early use of antibiotics during allogeneic transplant increases the risk of TRM. This result is in concordance with those obtained by other groups which studied the effect of them in late periods of the transplant. However, our finding, in terms of aGVHD, is different from those which have been published, this is difficult to explain, and it is hypothesis generating; we can speculate that the use of post-transplant cyclophosphamide in an important part of our cohort, including sibling donors, and the low incidence of this complication in the whole cohort can be part of the explanation. Understanding whether GVHD is a mediator between antibiotic use and mortality requires further investigation. For a while, the results of this and other studies demand to be cautious with the use of empiric antibiotics during the early period of the allogeneic transplantation Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome after allogeneic hematopoietic stem cell transplantation following Venetoclax-based therapy among AML and MDS patients.

The use of Bcl-2 inhibitor Venetoclax (VEN) combined with hypomethylating agents or chemotherapy has shown efficacy in treating acute myeloid leukemia (AML) as frontline treatment and for relapse, allowing more patients to bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the influence of VEN-based therapy on the prognosis of subsequent allogeneic HSCT remains unknown. We retrospectively collected data from patients who proceeded to allo-HSCT between November 2018 and November 2020 after VEN-based therapy at five transplant centers in Zhejiang Province, China. A total of 39 patients were analyzed. Thirty-one patients were diagnosed with AML (28 de novo, 3 secondary to MDS), 6 with MDS, and 2 with CMML. The majority (74.4%) of patients received VEN-based therapy for the treatment of relapse (38.5%) or refractory disease (35.9%); 5 (12.8%) received it as an initial treatment, and 5 (12.8%) patients who were already in complete remission (CR) received VEN for further consolidation or deep remission before HSCT. Twenty-seven (69.2%) patients were in CR at the time of HSCT. Day + 100 cumulative incidences of grade I-IV acute graft-versus-host disease (aGVHD) and grade II-IV aGVHD were 43.6% and 15.4%, respectively. Of 34 evaluable patients, 6.4% and 25.6% developed chronic GVHD at 1year and 2years. The 100-day cytomegalovirus (CMV) reactivation occurred in 76.3% of patients and Epstein-Barr virus (EBV) reactivation occurred in 29.7% of patients. With a median follow-up of 14.7months, overall survival, progression-free survival, relapse, and non-relapse mortality incidence at 1year were 75.5%, 61.6%, 16.7%, and 21.7%, respectively. Both univariate and multivariate analysis revealed that relapsed/refractory (R/R) disease was associated with inferior PFS (HR 4.849, 95% CI 1.009-23.30; p = 0.049). Prior poor response to VEN was found to be a significant factor predicting higher risk of relapse (HR 4.37, 95% CI 1.130-16.9; p = 0.033). Our results showed that VEN-based regimen therapy followed by allo-HSCT in AML patients is feasible and does not increase the risk of transplant-related mortality and toxicity.

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy.

IntroductionChimeric antigen receptor (CAR) T-cell (CAR-T) therapy followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) markedly improves the long-term survival of patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL).MethodsWe performed a parallel comparison of transplant outcomes in 168 B-ALL patients undergoing haplo-HSCT after achieving minimal residual disease (MRD)-negative complete remission (CR) from CAR-T therapy (n = 28) or chemotherapy (n = 140) between January 2016 and August 2021. We further divided the chemotherapy group into the first CR group (chemo+CR1, n = 118) and a second or more CR group (chemo+≥CR2, n = 22).ResultsWith a median follow-up period of 31.0 months, the 2-year overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), and relapse rates in the CAR-T and chemotherapy groups did not differ significantly (OS, 87.9% vs. 71.5 %; LFS, 72.0% vs. 66.8%; NRM, 3.9% vs. 13.7%; relapse, 24.1% vs. 19.4%). Multivariate analysis confirmed that ≥CR2 at transplantation following chemotherapy was an independent risk factor associated with poor OS (hazard ratio (HR) 4.22 [95% CI, 1.34–13.293], p = 0.014) and LFS (HR 2.57 [95% CI, 1.041–6.343], p = 0.041). The probabilities of OS and LFS at 2 years in the CAR-T group were comparable to those in the chemo+CR1 group but significantly higher than those in the chemo+≥CR2 group (OS, 87.9% vs. 37.8%, p = 0.007; LFS, 72.0% vs. 41.7%, p = 0.043). No significant differences in the incidences of NRM were noted among the three groups.ConclusionsOur results demonstrated that patients with R/R B-ALL receiving haplo-HSCT after CAR-T therapy achieved comparable outcomes to patients transplanted post-chemotherapy-based MRD-negative CR1, without increased risk of transplant-related mortality and toxicity.

Comparable clinical outcomes of haploidentical hematopoietic stem cell transplantation in patients with hepatitis-associated aplastic anemia and non-hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia (HAAA), a rare subtype of aplastic anemia (AA), is defined as bone marrow failure occurring after acute hepatitis. Severe HAAA requires immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) as lifesaving treatment. The outcomes of HAAA patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have not been systematically evaluated. We retrospectively compared the characteristics of 15 patients with HAAA and 60 non-hepatitis-associated aplastic anemia (non-HAAA) patients, all 75 of whom underwent haplo-HSCT in our hospital between January 2006 and October 2021. The median ages of the patients were 18years old (range, 3-36) for HAAA patients and 13years (range, 2-45) for non-HAAA patients (p = 0.693). The median time for neutrophil engraftment was 14days (range, 11-22) in the HAAA group and 12days (range, 10-21) in the non-HAAA group (p = 0.363). At the time of analysis, 15 HAAA patients and 58 non-HAAA patients were alive, and their median follow-up times were 37 (range, 3-87) months and 31 (range, 2-110) months (p = 0.347), respectively. There were no significant differences in the three-year overall survival (OS) rates (100% vs. 96.7 ± 0.33%, P = 0.638) or liver event-free survival (LEFS) (80.0 ± 0.17% vs. 76.7 ± 0.19%, P = 0.747) between the two groups. Despite the small number of HAAA patients due to the rarity of the disease, these results, such as the similar incidence rates of 3-year OS and fewer liver events than expected, suggest that haplo-HSCT is a feasible treatment for HAAA a when there are no human leukocyte antigen (HLA)-matched donors available and has a low risk of transplant-related mortality and complications.

Infusion of Non-HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitors in Patients Undergoing Cord Blood Transplantation: Result of a Phase II Clinical Trial.

Recipients of myeloablative cord blood transplants (CBT) are known to experience delayed hematopoietic recovery and an increased risk of transplant related mortality (TRM). We developed methods for ex vivo expansion and cryopreservation of CB stem and progenitor cells. 15 patients with hematologic malignancies were enrolled in this single center phase II trial between September 2010 and August 2012 to assess the safety of infusing a non-HLA-matched expanded CB product to bolster a conventional CBT. On the day of transplant, an infusion of the expanded CB product followed the primary graft (1 or 2 unmanipulated CB units). All patients engrafted. Median time to neutrophil and platelet recovery was 19 and 35 days, respectively. Early myelomonocytic recovery was almost entirely due to cells arising from the non-HLA-matched expansion product and were no longer detected at day 14 in all but 2 patients. The probability of 3-years disease free survival was 86%. No TRM was observed throughout the study period, and only 2 patients relapsed. All patients presented with grade II acute graft-versus-host disease (aGVHD) at a median time of 32 days, with no grade III-IV aGVHD observed. At 2 years only 2 patients remain on immunosuppressive therapy for mild chronic GVHD. This phase II safety study demonstrate that infusion of an off-the-shelf non-HLA-matched expanded CB product in addition to a conventional CB graft was safe and led to sustained myeloid recovery. Based on these encouraging results, a prospective multicenter randomized trial utilizing this product has been conducted and results will be soon released. ClinicalTrials.gov Identifier: NCT01175785.

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Experience of Low Dose (25mg/Kg) of Cyclophosphamide (Chennai-Chezhian-Kishore PTCy Protocol) As Post Transplant Cyclophosphamide (PTCy) Dose in Haploidentical Bone Marrow Transplant

Introduction:-Haploidentical Bone marrow transplantation has become one of the most commonly employed alternative donor techniques, with many centers applying T-cell-replete strategies developed by the Baltimore group using high-dose post-transplant cyclophosphamide. The usefulness of this technique is to reduce graft acquisition cost, lesser grade of GVHD, and reduction in non-relapse mortality. One problem we face in a country like India is the worry of engraftment delay leading to refractory multi-drug resistant gram-negative sepsis increasing the risk of transplant-related mortality. We took up this pilot study to check for the feasibility of a low dose (50%) 25mg/kg of cyclophosphamide as PTCy and its impact on transplant outcomes especially GVHD.Methodology:-This study was done from January 2016 to June 2019. 41 Haploidentical bone marrow transplants were done for Acute Myeloid leukemia at this time under this protocol. 23 Cases had Busulfan / Fludarabine as conditioning and in 18 cases; we used Treosulfan / Fludarabine-based conditioning regimen. The study protocol PTCy dose was 25mg/kg on Day +3 and Day +4. Cyclosporine / Tacrolimus was used from day -1 in all patients as GVHD prophylaxis. The parameters analyzed are engraftment dynamics, rates of gram-negative sepsis, hemorrhagic cystitis, rates of acute and chronic GVHD, and 2-year Non-relapse mortality.Results:Parents were the haploidentical donors in 22 cases whereas siblings in the rest 19 cases. Peripheral blood stem cell collection was chosen in all cases. The average CD34 dose was 6.8 x 10 6/Kg of the recipient. The mean number of days to achieve engraftment was around day 11. Culture-proven gram-negative sepsis was seen in 11 cases (26.8%). Two patients died within Day +30. Both due to sepsis. The rates of acute GVHD of grade I/2 was 18 (43.9%) and grade 3/4 acute GVHD was seen only in 2 patients (5%). No mortality was due to GVHD. With a median follow-up of two years, chronic skin and liver grade 1/2 GVHD was noted in 29 patients (74.3%) but were manageable with oral and topical medications not needing admission. Three patients had hemorrhagic cystitis. CMV reactivation needing medications was seen in 5(12.2%) patients indicating a higher incidence of post-transplant viral reactivation with PTCy. At data cut-off, we had lost 12 patients due to relapse and there was no non-relapse mortality except for the two sepsis-related death.Conclusion:The results of this pilot study indicate the feasibility of using a low dose PTCy (25mg/kg) in Haploidentical transplant as a methodology for in vivo T cell depletion without increased incidence of GVHD and Non-relapse mortality in Indian patients. This is a small study and it needs further follow-up with drug metabolism analysis and a bigger cohort to make this Chennai-Chezhian-Kishore PTCy Protocol a validated standard in Haplo-identical transplants. This is a pilot study and we are planning to incorporate genetic polymorphism in drug metabolism to validate the proposed protocol more scientifically.Reference:1. Wang, Y et al. Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients. J Hematol Oncol 12, 88 (2019). https://doi.org/10.1186/s13045-019-0781-y2. Shannon R. McCurdy, Leo Luznik How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide Blood (2019) 134 (21): 1802-1810. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Genomic Subgroups Impact Post-Transplant Survival in Patients with Myelodysplastic Syndrome: A CIBMTR Analysis

BackgroundMyelodysplastic syndromes (MDS) are clonal stem cell malignancies characterized by cytopenia, inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages and increased risk of development of acute myeloid leukemia. It has been well appreciated that genomic alterations play a key role in MDS pathogenesis. The Revised International Prognostic Scoring System (IPSS-R) algorithm is commonly used to predict overall survival but may fail to recapitulate reliable prognostic information at the individual patient level, especially at the time of hematopoietic cell transplantation (HCT). Current World Health Organization (WHO) classification includes MDS with isolated 5q deletion as the only genetically defined category. Comprehensive analysis of recurrent genomic features by unsupervised clustering empowers discovery of potential prognostic molecular signatures.MethodsUsing whole blood samples obtained from 494 MDS patients at the time of HCT, we conducted whole-genome sequencing (WGS) and somatic variant processing via a custom analytic pipeline based on OCTOPUS and a set of annotation databases. Multiple filters allowed for selection and fine-tuning of criteria, including removal of variants with Gnomad allele frequency above 10x10 -06, removal of noncoding variants in low complexity and repetitive regions, those with no functional indications from ANNOVAR annotations, CADD conservative score under 15, and absence in HGMD or COSMIC databases. Highly annotated clinical data, including cytogenetic abnormalities at the latest time point prior to HCT, were obtained from CIBMTR forms. K-means clustering was applied to recurrent mutations and cytogenetic abnormalities to identify clinically relevant genomic subtypes. The optimal cluster number was determined by Gap-status algorithm. Statistics of clinical characteristics were compared among different genomic subgroups by Chi-squared test for categorical variables and Mann-Whitney U test for continuous variables. Overall survival association tests were conducted by Cox multivariate models. Relapse and transplant-related risk were performed by competing risk analysis using Fine-Gray models. Models were adjusted for patient-, disease-, and HCT-related factors.ResultsThe somatic genomic landscape in our MDS cohort was examined for the total count of recurrent mutations at the sample level and gene level. Among 53 recurrently mutated genes in 257 of 494 MDS cases, TP53, TET2, RUNX1, DNMT3A, and ASXL1 were the most frequently mutated genes in our MDS cohort. Based on k-means clustering of the recurrent mutational and cytogenetic data, we detected five clusters that stratified our MDS patient cohort, including one reference cluster with no recurrent somatic mutations or cytogenetic abnormalities. Compared to the reference subgroup, significantly higher cytogenetic scores and IPSS-R scores were observed in genomic clusters with TP53 mutations (cytogenetic score: P=3.42E-07*; IPSS-R score: P= 2.38E-10*) and cytogenetic abnormalities del5q, or tri8p (cytogenetic score: P= 2.38E-10*; IPSS-R score: P=0.09) , or mono7 (cytogenetic score: P=3.29E-13*; IPSS-R score: P=1.38E-05*) (data not shown). Cox multivariate models revealed that genomic clusters with TP53 and del5q mutations (P<0.001*) or tri8p (P=0.02*) mutations have strong associations with post-transplant overall survival outcome (Figure 1A). Furthermore, competing risk analysis confirmed significantly higher risk of relapse in genomic subgroups with TP53 and del5q mutations in the reduced intensity conditioning regimen setting (P=0.01) (Figure 1B), while significantly higher risk of transplant-related mortality was found in the genomic subgroup with tri8p in the myeloablative conditioning regimen setting (P=0.03) (Figure 1C).ConclusionOur study suggests that molecular signatures from MDS patient genomes at HCT may provide an independent prognosis of post-transplant survival. Additionally, our data suggests that the choice of regimen intensity could be informed by knowledge of the individual genomic signature of a given MDS patient. [Display omitted] DisclosuresSaber: Govt. COI: Other.

Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis

▪BackgroundAllogeneic hematopoietic stem cell transplantation (SCT) is the only established curative treatment option for patients with sickle cell disease (SCD). Transplantations with an HLA-identical matched sibling donor (MSD) have resulted in excellent disease-free survival of >90% and overall survival (OS) of >95%. However, lack of HLA-identical siblings is a limiting factor. The chance of finding a potential matched unrelated donor is low for patients with a non-Western ethnic background (< 20%). Haploidentical related donors are a promising pool of donors potentially extending SCT as a curative treatment to a larger group of SCD patients with no other meaningful treatment options. Myeloablative conditioning regimens (MAC) are not recommended for adult SCD patients, as cumulative SCD-related organ damage renders these patients susceptible to increased toxicity and higher risk of transplant-related mortality. Using reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMC) in both adult and pediatric patients has resulted in decreased transplant-related toxicity and mortality. However, while successful in hematologic malignancies, NMC has been associated with significant risk of graft failure in hemoglobinopathies. In the present study, we aimed to systematically review (1) the outcomes of haploidentical SCT (Haplo-SCT), (2) the effects of conditioning intensity and modes of T-cell depletion on Haplo-SCT outcomes and (3) comparative outcomes between matched sibling donor SCT (MSD-SCT) and Haplo-SCT in selected studies.MethodsA comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data was extracted by two reviewers independently and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Only studies reporting at least one of the outcomes: graft failure, OS, transplant-related mortality, and acute/chronic graft-versus-host disease (GvHD) were included. Fourteen studies met the inclusion criteria. To have an overview of the results of Haplo-SCT, we divided the included studies in four groups according to the conditioning intensity (MAC versus NMC/RIC) and the T-cell depletion method (in vivo (post-transplant cyclophosphamide (PTCy)) vs. in vitro).ResultsAll included studies were observational cohort studies. A subgroup meta-analysis of the results of Haplo-SCT showed relatively low overall pooled proportions of graft failure (7%, 95% CI: 2 - 20), acute (4%, 95% CI: 2 - 12) and chronic (11%, 95% CI: 7 - 16) GvHD. Overall survival was high (91%, 95% CI: 85 - 94). Graft failure in MAC-in vitro, MAC-in vivo, NMC/RIC-in vitro and NMC/RIC-in vivo groups was 4% (95% CI: 1 - 14), 0% (95% CI: 0 - 100), 25% (95% CI: 10 - 51) and 11% (95% CI: 3 - 36) respectively (Figure 1). OS was 100% and 93% for MAC and NMC/RIC groups with PTCy (in vivo T-cell depletion) respectively. In patients with in vitro T-cell depletion, OS was 87% and 81% in MAC and NMC/RIC groups respectively (Figure 2). Based on a comparative meta-analysis of the three studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio 5.3, 95% CI: 1.0 - 27.6). Overall survival, transplant-related mortality and acute/chronic GvHD were not significantly different between the groups.ConclusionsThis systematic review shows that modifications in the intensity of the conditioning regimen and improved T-cell depletion approaches in Haplo-SCT in SCD have led to reduced transplantation-related toxicity while keeping graft failure rates low. Both in vitro and in vivo (PTCy) T-cell depletions result in very low transplantation-related mortality, though in vitro T-cell depletion is associated with a higher incidence of viral reactivations and other infectious complications.Haploidentical stem cell transplantation is becoming a viable alternative curative option for SCD, extending the availability of allogeneic SCT as a treatment option to many more transplant eligible SCD patients. Novel immunosuppression (immunoablation) and improvement in supportive care have allowed the use of RIC or NMC regimens, resulting in low risk of transplantation-related complications and improvement in engraftment rates. [Display omitted] DisclosuresBiemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria; Sanquin: Research Funding; Novo Nordisk: Honoraria; Celgene: Honoraria. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Treosulphan versus busulphan: pros and cons.

Treosulphan versus busulphan: pros and cons.

Results Of a Phase I Study Of Clofarabine and 2 Gy Total Body Irradiation (TBI) As a Non-Myeloablative Preparative Regimen For Hematopoietic Stem Cell Transplantation (HSCT) In High Risk Children With Hematologic Malignancies: A Multi-Center TACL Study

BackgroundReduced intensity conditioning (RIC) regimens for HSCT in hematologic malignancies are successful in reducing transplant related mortality (TRM) and making HSCT available for a select group of high risk patients. Despite HSCT and its associated graft-versus-leukemia (GVL) effect, the risk of relapse remains high with RIC regimens. Clofarabine is a second generation purine analogue with significant anti-leukemic activity in pediatric patients. We postulated that a non-myeloablative (NMA) preparative regimen with clofarabine and 2 Gy TBI may lead to sustained engraftment with low TRM in high-risk children with hematologic malignancies undergoing related and unrelated HSCT. Patient and MethodsThe primary aim of the Phase I study was to establish the maximum feasible dose (MFD) of clofarabine in conjunction with 2 Gy TBI that leads to durable engraftment with acceptable toxicity in a high-risk pediatric population. Patients between 1-21 years of age with leukemia and undergoing HSCT with significant co-morbidities or any condition that will make them at high risk of TRM with a myeloablative regimen were eligible. Patients had to be in CR or CRp (no morphologic disease, ANC >0.75 x 109/L but without platelet recovery) status prior to HSCT with a PS score of >50 with no active infection, a creatinine clearance of >70 ml/min/1.73m2 and liver enzymes <5X ULN. Patients were stratified according to donor source- related donor (RD) or unrelated donor (UD; 10/10 or 9/10 HLA match) arms. Peripheral blood stem cells (PBSC) were the preferred graft source (BM was allowed for RD only). Cyclosporine and mycophenolate mofetil were used as GVHD prophylaxis. A phase I modified 3+3 design was used with engraftment, severe toxicity and TRM as study end-points. Starting dose of clofarabine was 40 mg/m2 x 5 days with escalation to 52 mg/m2 in case of non-engraftment and acceptable toxicity in the first cohort or de-escalation to 30 mg/m2for dose limiting toxicity (DLT) or TRM. Patients completed the dose evaluation at 100 days post-HSCT, but were followed for 1 year post- transplant and were censored at relapse or death. ResultsSeventeen pediatric patients with a median age of 9 years (range 1-18) enrolled on the study between 7/2010 and 5/2013 and 16 have completed 100-day post-HSCT evaluations. Ten patients had ALL (CR2 =5; CR3 =4 and CR4=1) while 7 had AML (PIF=1; CR1= 1; CR2=3 and secondary AML=3); 9 received UD and 8 received RD grafts. All patients were heavily pre-treated and the indication for the NMA approach was: prior HSCT (n=6), prior liver transplant (n=2), trisomy 21 (n=2) or significant comorbidities (n=7).There was no observed TRM or DLT in the first cohort (clofarabine 40 mg/m2/dose x 5 days) in both the UD and RD strata. The dose was escalated to 52 mg/m2/dose in the next cohorts. All patients tolerated the maximum dose well and no DLT was reported. Significant non-hematologic toxicities (CTC ≥ grade 3) observed were- transient transaminitis (ALT increase in 30% and AST increase in 17%); anorexia (35%) and skin reactions in 16%.PBSC was the stem cell source for all patients, except 3 who had received BM from a RD. Median cell dose was 6.8 x 106 CD34+/kg (range: 2.2-11.5 x 106/kg). All patients achieved neutrophil and platelet engraftment at a median of 19 days (range: 9-25) and 11 days (range: 3-29), respectively. CD3 chimerism analysis at day+30 post-transplant showed donor engraftment in all patients; 15 were full donor (>95%) and 2 showed mixed chimerism (53% and 81% donor).Ten (58%) patients developed acute GVHD, 8 (47%) had ≤ Grade II and 2 (11%) had Grade III acute GVHD. Seven (41%) patients relapsed (4/8 RD and 3/9 in UD arms) at a median time of +106 days (range: 88-190) post-HSCT and all of them died due to disease. Ten patients (58%) are alive and disease free; six have completed 1 year evaluations and 4 are still in follow-up. ConclusionThe MFD of clofarabine in combination with 2 Gy TBI was determined to be 52 mg/m2. This regimen is well tolerated and leads to brisk and sustained donor engraftment in a pediatric population that is at high risk of TRM. Disclosures:Thompson:Sanofi Aventis: Speakers Bureau.