Bone Marrow Transplant Registry Research Articles

Age, Gvhd Prophylaxis, and Timing Matter in Thrombotic Microangiopathy after Hematopoietic Cell Therapy- a Secondary CIBMTR Analysis

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) is associated with significant morbidity and mortality. Risk factors for developing TA-TMA and impact of TA-TMA on survival were published from a large Center for International Bone Marrow Transplantation Registry (CIBMTR) (Epperla et al, BJH. 2020). We used this published database to investigate whether there were different risk factors for developing TA-TMA in children and adults and identify prognostic factors, including timing of TA-TMA diagnosis. Methods: All first allogenic HCT recipients with malignant or non-malignant diseases between 2008-2016 were included in this retrospective secondary analysis of an existing CIBMTR dataset. Measures of association were generated using sub-distribution cox proportional hazard models, treating death as a competing risk. Significant risk factors for developing TA-TMA in univariable models were then tested in a multivariable model. SAS 9.4 (Cary, NC) was used for analysis, and statistical significance was set at 0.05. Results: The incidence of TA-TMA in children and adults was similar, 2.9% (n=138/4818) and 2.8% (n=514/18249) respectively. Significant adjusted risk factors for developing TA-TMA shared in both children and adults included an unrelated donor, and grade 2-4 acute graft versus host disease (aGVHD) (Table 1a). Female sex, black race, peripheral blood and umbilical cord versus bone marrow, and HLA mismatch were risk factors for developing TA-TMA in adults, but not children in a multivariable analysis (Table 1b). AGVHD prophylaxis withpost-transplant cyclophosphamide (PT-CY) compared to calcineurin inhibitor and mycophenolate mofetil (CNI + MMF) was associated with a decreased risk of developing TA-TMA in children, and an adjusted decreased risk in adults. Compared to black adults, black children had a significantly higher proportion of bone marrow as a stem cell source, non-malignant disease as HCT indication, PFS >90, and lower rates of grade 2-4 acute GVHD (p <0.0001). Among all patients with TA-TMA (n=652), features associated an adjusted increased risk of death included age >18 years old, onset of TA-TMA diagnosis ≤ 6 months post HCT, unrelated donor, peripheral blood stem cell source, grade 3-4 acute GVHD, and a performance score of <90 prior to HCT (Table 1c). The estimated 2-year survival in patients with an early HCT-TMA diagnosis (<6 months post HCT, n= 468) was 34.2 ± 8.8% versus 55.9 ± 15.6% in those with a later diagnosis (n= 171), p<0.0001, Figure 1a). The early HCT-TMA cohort had significantly more black patients, CNI + MTX, performance score <90 (P<0.05), though there were no significant differences in the severity of acute GVHD compared to late HCT-TMA. Children with HCT-TMA had a significantly higher estimated 2-year survival compared to adults (49.85 ±17.5 vs 36.73 ±8.8, p= 0.002, Figure 1b); after adjusting for significant differences in the cohorts, the HR of death remained lower in children than adults (0.73, p=0.045) Discussion: Our data add to the prior publication that showed the association of moderate and severe aGVHD and TA-TMA by demonstrating that the incidence of TA-TMA is similar between children and adults though outcomes are better in children and the time of onset post HCT impacted survival. Acute GVHD prophylaxis with PT-CY versus CNI+ MMF was associated with a decreased risk of developing TA-TMA in unadjusted and adjusted models in adults. As there were no differences in proportions of severe aGVHD in the prophylaxis cohorts, additional studies are needed to understand this association. Female sex was not a risk factor for TA-TMA in children, but was for adults, and may be related to the impact of hormones on vascular endothelium, though additional studies are needed. Black race was a risk factor for disease in adults and not children and may be due to lower rates of aGVHD in this adults or smaller numbers limiting power. Our data highlight that early onset TA-TMA was associated with significantly lower survival than TA-TMA diagnosed >6 months post HCT, and that pediatric recipients had higher 2-year OS compared to adults. While this study is limited by the lack of consistent screening among centers, the large sample size, diversity in age, race, HCT indication and transplant approaches, support that expedited and novel interventions for TA-TMA should be considered for children and adults with early onset TA-TMA.

Developing an Allogeneic Hematopoietic Progenitor Cell Transplant Service in a Resource-Limited Country: Challenges and Outcomes.

Introduction Allogeneic stem cell transplant has curative potential for many hematological disorders. Building an allogeneic hematopoietic progenitor cell transplant (HPCT) unit requires huge investment, infrastructure, equipment, medical supplies, and training of health care professionals. The key objective of this study is to share our experience of developing an allogeneic HPCT service at our tertiary care cancer hospital in a low-middle-income country. In addition, this study presents the outcomes of the first 30 allogeneic HPCTs done at our center. Methods This retrospective observational study included adult patients 18 years old or older with hematological malignancies who underwent allogeneic HPCT between July 2019 and April 2023 at Shaukat Khanum Memorial Cancer Hospital and Research Centre. Result Of the 30 patients, 24 underwent matched sibling donor (MSD) transplants in which a myeloablative-conditioning regimen (MAC) was used in 19, and a reduced conditioning regimen (RIC) was used in one. Of the six haploidentical-related donor transplants, four received MAC, and two received RIC. The median recipient age at HPCT was 23 and 21 years for MSD and Haplo-related donor transplants, respectively. The median follow-up duration was 12 months (Range: 10 days - 33 months). The overall survival rate at one yearwas 71.3% among all allogeneic stem cell transplant patients, whereas the disease-free survival rate at one yearwas 63.7%. In the acute lymphoblastic leukemia group, the disease-free survival rate at one year post allograft was 51.5%, while in the acute myeloid leukemia group, it was 78.7%. Conclusion This study demonstrates the successful development of an allogeneic bone marrow transplant unit at our hospital despite significant financial constraints. This has allowed us to provide a potentially curative and life-saving treatment to a substantial number of cancer patients. The bone marrow transplant outcomes of this study are comparable to those reported by international bone marrow transplant registries.

U-Statistics for left truncated and right censored data

The analysis of left truncated and right censored data is very common in survival and reliability analysis. In lifetime studies patients are often subject to left truncation in addition to right censoring. For example, in bone marrow transplant studies based on International Bone Marrow Transplant Registry (IBMTR), the patients who die while waiting for the transplants will not be reported to the IBMTR. In this paper, we develop novel U-statistics under left truncation and right censoring. We prove the n -consistency of the proposed U-statistics. We derive the asymptotic distribution of the U-statistics using the counting process technique. As an application of the U-statistics, we develop a simple non-parametric test for testing the independence between time to failure and cause of failure in competing risks when the observations are subject to left truncation and right censoring. The finite sample performance of the proposed test is evaluated through a Monte Carlo simulation study. Finally, we illustrate our test procedure using the lifetime data of transformers.

Incidence of cutaneous graft-versus-host disease in a Singapore academic medical centre - A retrospective cohort study.

Cutaneous graft-versus-host disease (GVHD) is common in allogeneic haematopoietic stem cell transplantation. HLA mismatch is the most significant determinant of GVHD. Our study aimed to compare the incidence of cutaneous GVHD haploidentical (Haplo) and matched donors in an Asian population. Retrospective cohort study of the 2015-2019 bone marrow transplant registry was conducted in a transplant centre. We compared the incidence of cutaneous GVHD in Haplo with allogeneic matched unrelated donor (MUD) and matched-sibling donor (MSD) transplant recipients. Secondary objectives include acute and chronic GVHD incidence, dermatology referrals, and histological findings. One hundred and seventy-nine out of 203 cases were reviewed; 17 (9.5%) Haplo, 80 (44.7%) MUDs and 82 (45.8%) MSDs. The median follow-up for Haplo, MUD and MSD was 15.2, 34.2 and 35.7months, respectively. Haplo had a higher cumulative incidence of cutaneous GVHD than MUD and MSD (p=0.053). Chronic GVHD was only reported in MSD. The most common histology was vacuolar interface changes (13 [44.8%]) with a wide range of onset post-transplant (19-456 days). Haplo donors may have a higher GVHD incidence than MUD and MSD in our predominantly Asian cohort. This information may be helpful when counselling patients pre-transplant. Further prospective studies are required.

Utility of eGVHD App for bedside GVHD assessment in a high-volume BMT center.

Assessing acute and chronic graft-versus-host disease (GVHD) is challenging because there are several classification systems. The European Society for Blood and Marrow Transplantation and the Center for International Bone Marrow Transplantation Registry task force recommends using the eGVHD application (App) to score acute GVHD according to the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria and chronic GVHD according to the National Institutes of Health 2014 criteria. We prospectively used the eGVHD App at each follow-up visit in a large-volume bone-marrow transplant center in India from 2017 to 2021. We retrospectively evaluated the discrepancy in scoring GVHD severity by physicians not using the App from the same patient charts. The App user satisfaction and experience were recorded using the technology acceptance model (TAM) and the Post-Study System Usability Questionnaire (PSSUQ). In 100 consecutive allogeneic hematopoietic cell transplantation recipients, there was more discrepancy in scoring the severity of chronic GVHD (38%) than acute GVHD (9%) without using the App. The median TAM and PSSUQ scores were six (IQR:1) and two (IQR:1), respectively, indicating high perceived usefulness and user satisfaction. The eGVHD App is an excellent learning tool for hematology/BMT fellows and helps manage GVHD in high-volume BMT centers.

Multiple Myeloma Transplant: Examining the Intersection of Access, Age and Race

Introduction: Autologous Stem Cell Transplant (ASCT) is standard frontline therapy for patients newly diagnosed with Multiple myeloma (MM). Receipt of ASCT is influenced by factors such as race, age, socioeconomic status (SES), and geographic location. The degree to which these factors collectively influence MM transplant access and jointly impact overall survival is not well established. Our study aimed to assess the impact of age, race, rurality, and area-level SES on ASCT transplant receipt and overall survival following MM diagnosis. Methods: An IRB approved retrospective analysis was conducted of adult MM patients diagnosed in 1992-2020 from The Ohio State University Comprehensive Cancer Center (OSUCCC). Patients included were previously consented to the Buckeye Surveillance, Contact, and Research for Multiple Myeloma and Amyloidosis Protocol (NCT01408225); a registry database for patients with suspected plasma cell dyscrasia pursuing care at OSUCCC; and the Bone Marrow Transplant (BMT) registry, an internal database compiled of demographic and transplant-specific data. Area-level SES was measured by census tract-level (2008-2017) Yost indices (a composite of education-, income-, and occupation-related variables.)1, 2 Rural-urban status was measured by census tract-level 2010 Rural-Urban Commuting Area (RUCA) codes.3 Yost were categorized into quartiles where higher quartiles represented higher SES, and RUCA codes were grouped by metropolitan (Primary RUCA 1-3) v. non-metropolitan (Primary RUCA 4-10). Poisson regression models with robust variance were used to evaluate the associations between patient characteristics and receipt of transplant. Overall survival (OS) from diagnosis was analyzed and median OS was estimated using the Kaplan-Meier method. Cox proportional hazard models were used to estimate the hazard ratios of risk of death. Results: In the combined MM registries, a total of 1,799 MM patients were included in this analysis, 1,169 (65%) received a transplant. MM patients median age at diagnosis was 61 (17-87), race was self-identified as White (85.6%), Black (13.1%) other (1.3%). In multivariable analysis, patients who were 65 years or older were less likely to undergo a transplant (age 65-70: IRR=0.80, 95% CI: 0.72-0.89, p<0.001; age > 70: IRR 0.23, 95% CI: 0.18-0.30, p<0.001). When assessed by race, relative to White patients, Black patients were less likely to receive a MM transplant (IRR=0.85, 95% CI: 0.74-0.97, p=0.018). RUCA code showed no significant difference in receiving a transplant between the non-metropolitan v. metropolitan groupings (IRR 1.06, 95% CI: 0.97-1.16, p=0.186). Residence in higher SES areas (quartiles 2-4) was associated with higher rate of ASCT receipt compared to those in quartile 1 (IRR 1.16, 95% CI: 1.05-1.29, p=0.038). Among all MM patients median OS for age <65 was 9.0 years (95%CI 8.4-9.7); age 65-70, 7.0 years (95%CI 6.3-7.9); age>70, 4.7 years (95%CI 4.0-5.3). In multivariable analysis, hazard of death was lower for those who received a transplant (vs. no transplant, HR= 0.63, 95%CI 0.53-0.74, p<0.001), patients identified as Black (vs. White, HR=0.66, 95%CI 0.51-0.85, p=0.001), and those residing in higher SES areas (quartile 2-4 vs. quartile 1, HR=0.69, 95%CI 0.58-0.83, p<0.001). Advancing age was associated with higher hazard of death, age 65-70 HR=1.45 (95%CI 1.18-1.78, p<0.001); age >70 HR=2.03 (95%CI 1.65-2.49, p<0.001). Rurality was not associated with OS (HR 1.14, 95% CI 0.96-1.35, p=0.134). Conclusions: In a large MM population, age, race, and area-level socioeconomic status impact both the receipt of transplant and overall survival following MM diagnosis. Area-level SES could be an important driver of MM survival independent of transplant access.

Oxidative stress indicators during the course of acute graft versus host disease

Aim: This prospective study aimed to observe the changes in oxidative stress indicators, including total anti-oxidant status (TAS), total oxidant status (TOS), paraoxanase-1 (PON1), total thiol (TT), native thiol (NT), disulphide (DS) and nitric oxide (NO) levels from sequential blood samples obtained during a de-novo episode of acute graft versus host disease (aGvHD) and evaluate their association with disease severity and the risk of steroid resistant disease.&#x0D; Material and Method: Sequential patients who underwent an allogeneic stem cell transplantation (ASCT) in our unit and subsequently developed a de-novo episode of aGvHD between January 2022 and May 2022 were included in case they gave informed consent. All patients were started high dose (2 mg/kg/day) methylprednisolone as institutional standard first-line treatment of aGvHD as soon as the clinical diagnosis is evident. All episodes were confirmed simultaneously with gastrointestinal (GI) endoscopy and/or skin biopsies. TAS, TOS, PON1, TT, NT, DS and NO were studied from blood samples collected on days 0, +3 and +7 of steroid treatment. Demographic characteristics, diagnoses, donor type, GvHD prophylaxis, stage and grade of aGvHD, performance status (PS), the presence of cytomegalovirus (CMV) reactivation and response to steroid therapy were also noted.&#x0D; Results: A total of 15 cases was included. The median age was 49 (23-77). Males constituted 60.0% (n=9). The most frequent diagnosis and donor type were acute leukemia (53.3%, n=8) and matched related donor (46.7%, n=7), respectively. High grade aGvHD with Glucksberg grading and International Bone Marrow Transplant Registry severity index (IBMTR-SI) included 53,3% (n=8) and 86.7% (n=10) of cases, respectively. Non-responders (20.0%, n=3) significantly had advanced stage GI involvement, higher grade of aGvHD with Glucksberg grading and IBMTR-SI, and lower PS (p=0.005, p=0.04, p=0.006, and p=0.02, respectively). The changes in TAS, TOS, PON1, TT, NT, DS and NO levels on days 0, +3 and +7 of steroid treatment were not significant. Median PON1 levels on days 0, +3 and +7 of steroid treatment were significantly lower among non-responders (p

Chronic gvhd dictionary—eurograft cost action initiative consensus report

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology—COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators.

Stem cell transplant for mantle cell lymphoma in Taiwan

Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization.

Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia: Why Do Adolescents and Young Adults Outcomes Differ from Those of Children? a Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

Introduction:Adolescents and Young Adults (AYA) represent a specific population in the Acute Lymphoblastic Leukemia (ALL) landscape, often presenting high-risk diseases and increased chemotherapy-related toxicities. Indications of Hematopoietic Stem Cell Transplantation for pediatric patients (HSCT) have been restricted to those with early poor response to chemotherapy. The same trend has led to a decrease of HSCT indications in AYAs, which are nevertheless still more frequent than in younger counterpart. Outcomes of AYAs after HSCT seemed to be worse than the ones of children in two previous studies published in 2013 and 2014. In Minneapolis, the decrease of overall survival in AYA was attributed to an excess of Treatment Related mortality (TRM) (28% versus 14%; p=0.04), but because of small numbers, factors influencing TRM were not identified. Our study aimed to compare, in a large cohort, the outcomes of children and AYA with ALL after HSCT and to determine factors influencing potential differences.Material and Methods:All patients aged between 1 and 25 years, reported in the SFGM-TC (Francophone Society of bone marrow transplantation and cellular therapy) registry, who received a first HSCT in treatment for ALL between 2005 and 2012 were included. The AYA group was defined by age range between 15 and 25 years old, according to European studies and the SFGM-TC. Data about diagnosis and transplantation procedure were prospectively collected in the registry. Before transplant procedure, patients or their parents/guardians provide a signed consent in order to be included in the registry.Results:891 patients were included, 494 children and 397 AYA. Median time of follow up was 45.6 months (0 to 114). HSCT was performed in first CR for 56.8% of the AYAs, whereas 57.5% of children received HSCT in second CR or more advanced phase (p<0.001). HSCT procedures mainly included a Myelo-Ablative Conditioning (MAC) regimen. TBI was used more frequently in AYAs than in children (90.1% versus 83.1%, p=0.003). Bone Marrow (BM) or Cord-Blood (CB) were often used in children 60.2% and 29.4% versus 55.6% and 16.4% in AYA group respectively (p < 0.0001) . Peripheral Blood Stem Cells (PBSC) were more frequently used for AYA (28%) than for children 10.3% (p < 0.0001). Moreover, when being transplanted in an adult center, PBSC were more commonly used for AYA (30% of AYA's HSCT in adult centers versus 21.2% of AYA's HSCT in pediatric centers, p=0.051). BM and PBSC cells were provided by a match sibling donor (MSD) in 40.2% of children and 43.4% of AYAs and from a MUD in 57.2% and 55.1% of cases respectively (p = 0.474). Anti-thymoglobulins (ATG) were used for 336 patients (48% of children and 26% of AYA patients, p<0.001). See patient's characteristics in Table.Five-year OS was lower in AYA 53.1% versus 64% (p = 0.0012) and we confirmed higher 5-years TRM in AYA 19% versus 13% (p=0.04). TRM incidence markedly rose after 10 years of age (from 9% before 10 years old to 20% between 10 and 15 years, and 17% after 15 years).Graft versus host disease and Relapse Free Survival probability (GRFS) was lower in AYA: 36% versus 47% (p=0.007), while Cumulative Incidence of Relapse (CIR) and acute Graft versus Host Disease (GvHD) incidence were both similar in our two groups: 32% and 61% in AYAs versus 27% and 59% in children, (p=0.19 and p=0.62), respectively. Thus, chronic GvHD, which occurred more frequently in AYA than in children (32% versus 19%, p<0.001), mainly impact post-HSCT morbi-mortality in AYA (Figure 1 and 2).In our multivariate analysis, two factors were associated with higher risk of cGvHD: use of PBSC as stem cell source (HR 1.41 [0.96-2.07], p=0.083), and absence of ATG use (HR associated with use of ATG: 0.62 [0.42-0.92], p=0.017) (Figure 3). Of note a subgroup analysis in patients who received a bone marrow transplant after a MAC, showed no TRM difference between AYA and children.Conclusion:AYA or patients aged more than 10 years, compared to ones aged less than 10 years have a worse outcome after HSCT for ALL. Excess of death in this specific population is mainly due cGvHD. Transplantation practices in those patients, particularly choice of stem cells source and GvHD prophylaxis, should be discussed. Their treatment adherence should also be questioned and reinforced by development of multidisciplinary teams. [Display omitted] DisclosuresPeffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Forcade: Novartis: Other: travel grant.

Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database.

We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.

Transplant Outcome for Patients with Acquired Aplastic Anemia over the Age of 40: Mortality HAS NOT Been Reduced in 2015

Mortality following HSCT in pts with SAA over the age of 40 is reported to be in the order of 50%; international guidelines recommend first line immunosuppressive therapy above the age of 40. The aim of this study is to assess whether this is still true in 2015.We used the Working Party for SAA (WPSAA) of the European Blood and Bone Marrow Transplantation Registry (EBMT), and identified 768 patients, aged 40 years or more, with acquired SAA , who underwent an allogeneic HSCT between 2001 and 2015.. Pts were divided in two transplant eras: 2001-2009 (n=329) and 2010-2015 (n=439). In the 2010-2015 period pts were older (52 vs 50 years, p<0.01), were more often grafted from alternative donors (ALT) (52% vs 28%, p<0.01), with a greater use of BM (53% vs 42%, p<0.01), and more often received a fludarabine containing regimen (60% vs 42%, p<0.01), and ATG or Campath (87% vs 67%, p<0.001).The 5 year OS of patients grafted in 2001-2009 was 61% , compared with 58% for pts grafted in 2010-2015 (p= 0.9). In multivariate analysis including the interval between diagnosis and transplant, the patient's age, donor type, stem cell source , the use of fludarabine and ATG or Campath, the lack of improved survival in 2010-2015 was confirmed (RR 0.9, 95%CI 0.7-1.19; p=0.5). A very strong age effect was shown both in univariate and multivariate analysis: 5 year OS of patients aged 40-49 years, 50-59 years and >60 years , was respectively 66%, 57%, 40% (p<0.0001). The second favorable predictive factor was the use of either ATG or Campath (RR 0,58- 95%CI 0.43-0.76, p=0.002)Regarding HSCT from HLA identical siblings, we could show identical 5 year survival for pts aged 40-49 years in 2010-2015 as compared to 2001-2009 (67% vs 70% p=0.8); for patients aged 50-59 years (59% vs 60%, p=0.9) and patients over 60 (47% vs 50%, p=0.9). For UD the 5 year survival in pts aged 40-49 was 64% in 2010-2015, vs 56% in the earlier period (p=0.1), and 53% vs 58% (p=0.6) for pts aged 50-59. The numbers were too small for comparison in patients over 60, with only 8 patients grafted in the 2001-2009 period; 61 patients were grafted in 2010-2015 with a 47% actuarial 5 year survival. (Figure 1).Combined primary and secondary graft failure was reduced from 16% to 12% in the two time periods (p=0.02), acute GvHD grade II-IV was reduced from 15% to 11% (p=0.1) and chronic GvHD was also reduced from 31% to 25% (p=0.01). Infections remain the leading cause of death in both transplant eras (18% and 22% respectively), followed by GvHD (5% and 4%) and graft failure (5% and 2%),whereas PTLD have been reduced from 3% to 0,5%.HSCT in pts with acquired SAA over the age of 40 years, continues to carry a significant risk of mortality , also in 2015, ranging from 30% in younger SIB transplants to over 50% in older pts. This study gives further support to current guidelines , suggesting first line therapy with ATG+CsA , in patients over the age of 40. Tailored protocols need to be devised to reduce transplant mortality in older SAA patients. [Display omitted] DisclosuresPeffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Idarubicin Intensified Bucy Regimen in Allogeneic Peripheral Blood Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia: A Multicenter, Randomized Study (NCT 01766375)

▪AbstractBackground: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a potentially curative treatment in patients with acute myeloid leukemia (AML). The results of conventional BUCY regimen for high-risk acute myeloid leukemia (AML) are unsatisfactory because of higher relapse. Recent studies suggested survival advantage with idarubicin intensified BUCY regimen in Allo-HSCT for patients with high-risk AML.Methods: This study was a multi-center, open, randomized-control study on the effects and safety of idarubicin 60mg/m2 combined with BUCY pretreatment program or BUCY pretreatment program on the overall survival (OS) rate and disease-free survival (DFS) rate of AML in high-risk group over a period of 2 years, where 118 high-risk AML patients underwent allogeneic peripheral blood stem cell transplantation (Allo-PBSCT) were enrolled between December 2012 and March 2017, from sibling or unrelated donors with well-matched human leukocyte antigens. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR) and ClinicalTrials.gov (NCT 01766375). The conditioning regimen of experimental group (IDA-BUCY group, n=61) were: 1) Idarubicin 20mg/m2 given intravenously (IV) for 3 days (day -12 to day -10); 2) Busulphan (BU) 0.8mg/kg given intravenously (IV) four times per day for 4 days (day -7 to day -4); 3) cyclophosphamide (CTX) (60 mg/kg/day) given IV for 2 days (day -3 to day -2). The conditioning regimen of active comparator (BUCY group, n=57) were: 1) Busulphan (BU) 0.8mg/kg given intravenously (IV) four times per day for 4 days (day -7 to day -4); 2) cyclophosphamide (CTX) (60 mg/kg/day) given IV for 2 days (day -3 to day -2). GVHD prophylaxis of sibling Allo-PBSCT consisted of a combination of cyclosporin A (CSA), methotrexate(MTX) and mycophenolate mofetil(MMF) regimen [BMT 2009; 43(1):61-67]. Unrelated Allo-PBSCT used CSA, MMF, MTX, and anti-thymocytes globulin (ATG, 2.5 mg/kg/day given IV for 4 days,days -4 to day -1) for the prevention of GVHD.Results: The two groups were well balanced according to disease status, cytogenetic risk, and other variables. Data cut off for survival follow-up was June 30, 2017. The median follow-up time was 19 months (range, 4 months to 54 months). Six patients (9.8%) in the IDA+BUCY group and 15 (26.3%) in the BUCY group relapsed. Thirty-eight patients (IDA+BUCY group n=13, BUCY group n=25) died during the conduct of this study. The cumulative rates of transplant related mortality (TRM) of IDA+BUCY group and BUCY group were 12.7% (95% confidence interval [CI], 6.3 to 25.7) and 28.6% (95% CI, 16.8 to 51.7) (P=0.186), respectively. The cumulative rates of relapse was lower for the IDA+BUCY group (13.7%, 95% CI, 6.2 to 30.2) than for the BUCY group (28.1%, 95% CI, 17.8 to 44.3) (P=0.030). The OS and DFS of IDA+BUCY group at 2 years were 75.2% (95% CI, 63.0 to 87.4) and 74.9% (95% CI, 58.4 to 84.9), respectively. The OS and DFS of BUCY group at 2 years were 51.2% (95% CI, 36.5 to 65.9) and 50.1% (95% CI, 34.0 to 63.9), respectively. (Fig 1)Conclusion: Our results demonstrate that Idarubicin intensified BUCY regimen could dramatically improve the survival of high-risk AML with low relapse and acceptable transplantation-related mortality. This strategy could be of great benefit for the treatment of patient with high-risk AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Differential Impact of Conditioning Intensity on Post-Transplant Outcome of FLT3 -Mutated and FLT3 Wild Type AML in First Remission, a Report from Taiwan Bone Marrow Transplant Registry (TBMTR)

AML with FLT3 -internal tandem duplication mutation (FLT3-ITD) has a very high relapse rate when patients were treated with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible once remission is achieved is generally recommended. Nevertheless, the best conditioning regimen, specifically the myeloablative (MAC) or reduced intensity conditioning (RIC), for FLT3-ITD AML remains unknown. Of the two largest series reported so far, vast majority of the patients received myeloablative regimen (100% in EBMT report, 87% in CIBMTR report). In this study, we utilize the Taiwan Bone Marrow Transplant Registry (TBMTR) database to analyze the impact of conditioning intensity on the post-transplant outcome of FLT3 -mutated and FLT3 wild type AML.TBMTR is a research collaboration affiliated to the Taiwan Society of Blood and Bone Marrow Transplantation. It comprises all the 14 transplantation centers in Taiwan that contribute detailed information on HSCT. In this study, only adults aged ≥ 18 years with a diagnosis of de novo AML who received allogeneic peripheral blood stem cell transplantation (PBSCT) at the first complete remission (CR1) and with known FLT-ITD mutation status in the registry were included. Patient characteristics and transplant outcome following MAC or RIC allogeneic PBSCT were compared. Kaplan-Meier estimates were used to calculate the probability of LFS and overall survival (OS). Cumulative incidence of relapse and non-relapse mortality (NRM) was calculated from the time of transplant to the time of event. NRM was considered a competing risk for relapse and vice versa. Multivariable analyses for LFS and OS were performed using Cox proportional hazards model.146 patients who met the eligibility criteria were enrolled for analysis. The median follow-up of survivors was 21 months (range, 1-73 months). Of the 146 patients, 49 (33.6%) were positive and 97 (66.4%) were negative for FLT3-ITD mutation. 32.7% and 35.1% of FLT3-ITD mutated and FLT3 WT AML received RIC regimen respectively. FLT3-ITD mutated patients had significantly higher WBC count (51.7 x 109/L) and more normal (64.9%) karyotype at diagnosis comparing to patients without FLT3 mutation (11.8 x 109/L WBC count and 42% normal karyotype). Patients who received RIC regimen were significantly older than patients who received MAC regimen (53.196±12.107 vs 38.327±11.788, p<0.001, for FLT3-ITD mutated AML; 52.084±12.533 vs 39.181±10.704, p<0.001, for FLT3 WT AML).In multivariable analysis, FLT3 mutation status did not negatively impact the transplant outcome in term of both overall survival (OS) and leukemia free survival (LFS). However, RIC regimen is associated with a significant poor LFS (HR 1.754, p=0.0476) and higher relapse rate (HR 2.184, p=0.015). The impact of conditioning intensity is even more prominent in patients of FLT3 WT AML (Figure 1, left, p=0.0468 for LFS, log rank test). For FLT3-ITD mutated AML, the LFS and relapse rate were almost the same after either MAC or RIC conditioning (Figure 1, right, p=0.768 for LFS, log rank test). For NRM and cumulative incidence of acute and chronic GVHD, the differential impact of conditioning intensity was not seen in FLT3-ITD mutated AML and FLT3 WT AML.In conclusion, conditioning intensity has a differential impact on post-transplant outcome of FLT3-ITD mutated AML and FLT3 WT AML. Reduced intensity conditioning is associated with a lower LFS and higher relapse rate for FLT3 WT AML. For patients of FLT3-ITD mutated AML, RIC is just as good as MAC, even though patients who received RIC were almost 15 years older than patients who received MAC. RIC allogeneic HSCT should be a viable option for elderly or unfit AML with FLT3-ITD mutation. [Display omitted] DisclosuresYao:Celgene International Sàrl: Research Funding. Tang:Celgene International Sàrl: Research Funding.

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Thalassaemia: A Single Institution Experience of 53 Patients

AbstractBackground: Thalassemia major (TM) is a fatal genetic disease currently only curable with allogeneic stem cell transplantation, which is limited by the lack of suitable donors. For patients lacking matched related donors, unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) is increasingly being utilized. Despite this success in leukemia patients, UD-PBSCT is not widely practiced in thalassemia patients because of higher graft-versus-host disease (GVHD) risk and increased transplant-related mortality (TRM).Methods: The purpose of the study is to assess the safety and efficacy of UD-PBSCT for patients with thalassemia major. The trial was designed as a prospective, open-label, single-center clinical protocol, where 53 TM patients were enrolled between March 2013 and April 2017 and transplanted with peripheral blood stem cell (PBSC), from an HLA-matched unrelated donor. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR). The primary end point was 2-year thalassemia free survival (TFS). Secondary end points included 2-year overall survival (OS), the cumulative incidence of GVHD, transplant related mortality (TRM), graft rejection (GF). The conditioning regimen were: 1) busulphan (BU) 1mg/kg given intravenously (IV) four times per day for 4 days (day -9 to day -6); 2) fludarabine (FLU) (50mg/m2/day) given IV for 3 days (day -12 to day -11); 3) cyclophosphamide (CTX) (50 mg/kg/day) given IV for 4 days (day -5 to day -4); 4) anti-thymocytes globulin (ATG, Genzyme ) (2.5 mg/kg/day) given IV for 4 days (days -4 and day -1). All patients were placed on 30 mg/kg hydroxyurea orally once daily for 2-3 months before transplantation. GVHD prophylaxis consisted of a combination of cyclosporin A, methotrexate and mycophenolate mofetil regimen.Results: Data cut off for survival follow-up was June 30, 2017. The median follow-up time was 22 months (range, 4 months -58 months). The median age of patients was 5 years (range, 2-13 years). The median numbers of MNCs and CD34 cells infused per graft were 17.6 ×108/kg (range, 10.0 to 34.6)and 9.2×106/kg (range, 3.5 to 32.9), respectively. A total of 52 (98.1%) patients achieved sustained myeloid engraftment. The median time of absolute neutrophil count engraftment was 11(range 9-15) days. The median time of platelet engraftment was 13(range, 9 to 35) days. The rate of Graft rejection was 1.9%. The cumulative incidence of acute (a)GVHD and grade II-IV aGVHD were 41.5% (95% confidence interval [CI], 29.1 to 56.2) and 32.0% (95% CI, 21.1 to 48.6) , respectively . The chronic (c)GVHD and extensive cGVHD were 6.2% (95% confidence interval [CI], 2.1 to 16.6) and 2.2% (95% CI, 0.3 to 15.1), respectively. The cumulative incidence of TRM at 2 years was 8.0% (95% CI, 3.1 to 20.4). The OS and TFS at 2 years were 92.0% (95% CI, 87.8 to 100) and 90.1% (95% CI, 85.0 to 99.6), respectively. (Figure 1)Conclusion: Our results demonstrate that MUD-PBSCT in TM yields excellent engraftment rate and TFS when the protocol consisted of busulphan, cyclophosphamide, fludarabine and antithymocyte globulin was used, and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for MUD-PBSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia

AbstractAllogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 × 109/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell–depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Survival With Bone Marrow Transplantation Versus Hydroxyurea or Interferon for Chronic Myelogenous Leukemia

AbstractHydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.

Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia

AbstractThe impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 × 108 nucleated cells/kg (median, 3.0 × 108cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 × 108 cells/kg) versus low (less than or equal to 3 × 108 cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23% to 52%), respectively. In multivariate analysis, among patients surviving in remission at least 9 months after transplantation, those receiving high cell doses were at significantly lower risk for treatment failure (relapse or death) than those receiving low cell doses (RR, 0.27; 95% CI, 0.12 to 0.6;P = .001). Lower treatment failure resulted from fewer relapses in the high cell dose group (RR for relapse, 0.28; 95% CI, 1.2 to 0.66; P = .003). These findings suggest that outcomes after syngeneic bone marrow transplantation could be improved by transplanting more than 3 × 108 nucleated cells per kilogram. The benefit of high cell dose on relapse may represent a delayed graft-versus-leukemia effect.

Allogeneic Bone Marrow Transplantation for Low-Grade Lymphoma

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS ≥90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.© 1998 by The American Society of Hematology.

Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the International Bone Marrow Transplant Registry

Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)