Transplant-related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review.
ABSTRACT: BACKGROUND: Over the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased. PROCEDURE: A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984-31/8/1992, Period 2: 1/9/1992-30/4/2001, Period 3: 1/5/2001-31/12/2009). RESULTS: Despite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6-64.8%, P = 0.0027; OS 41.8-78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time. CONCLUSION: EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post-HSCT are unchanged, and remain the focus for improvement.
Project description:We utilized meta-analysis to compare tandem autologous (TA) hematopoietic SCT (auto-HSCT) or single auto-HSCT followed by reduced intensity conditioning (RIC), allogeneic (AR) hematopoietic SCT in the upfront management of patients with multiple myeloma (MM). A comprehensive search strategy of published and unpublished reports utilized the following entry criteria: newly diagnosed patients, first autologous transplantation in both arms, use of an RIC regimen and assignment to TA or AR based exclusively on the availability of an HLA matched donor. Six trials were identified yielding 1192 subjects in TA and 630 in AR. Patients in AR had higher likelihoods of TRM (relative risk (RR)=3.3, 95% confidence interval (CI)=2.2-4.8) and CR (RR=1.4, 95% CI=1.1-1.8). OS was not different in the first 36 months (hazard ratio (HR)=1.15, 95% CI=0.91-1.45) or after (HR=0.74, 95% CI=0.53-1.04) 36 months from assignment. Similar findings were seen for PFS. When compared with TA in the upfront management of MM, AR is associated with higher TRM and CR without improvement in PFS or OS.
Project description:To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p?=?0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n?=?9) vs unmodified (n?=?6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p?=?0.14), 0% vs 50% [95% CI: 10-90%] (p?=?0.02) and 100% vs 50% [95% CI: 10-90%] (p?=?0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
Project description:The diversity of human leukocyte antigens (HLAs) enables the presentation of immense repertoires of peptides, including tumor-associated antigens (TAAs). As a surrogate for immunopeptidome diversity, the HLA evolutionary divergence (HED) between individual HLA alleles might directly define the ability to present TAAs, a prerequisite for graft-versus-leukemia effects. We therefore analyzed the impact of HED on survival within a cohort of 171 acute myeloid leukemia (AML) patients after matched donor allogeneic hematopoietic stem cell transplantation (HSCT). Low HED (<25th percentile) of HLA class I (HEDclass I) or HLA-DR antigens (HEDDR) was a strong determinant for adverse overall survival after allogeneic HSCT (OS), with a hazard ratio for death of 1.9 (95% CI 1.2-3.2) and 2.1 (95% CI 1.3-3.4), respectively. Defining a cutoff value for the combined HEDtotal (HEDclass I and HEDDR), the respective 5 year OS was 29.7% and 64.9% in patients with low and high HEDtotal (p < 0.001), respectively. Furthermore, the risk of relapse was significantly higher in patients with low HEDtotal (hazard ratio (HR) 2.2, 95% CI 1.3-3.6) and event-free survival (EFS) was significantly reduced (5 year EFS 25.7% versus 54.4%, p < 0.001). We here introduce HED, a fundamental metric of immunopeptidome diversity, as a novel prognostic factor for AML patients undergoing allogeneic HSCT.
Project description:Hematopoietic stem cell transplantation (HSCT) and consolidation chemotherapy have been used to treat intermediate-risk acute myeloid leukemia (AML) patients in first complete remission (CR1). However, it is still unclear which treatments are most effective for these patients. The aim of our study was to analyze the relapse-free survival (RFS) and overall survival (OS) benefit of allogeneic HSCT (alloHSCT) for intermediate-risk AML patients in CR1. A meta-analysis of prospective trials comparing alloHSCT to non-alloHSCT (autologous HSCT [autoHSCT] and/or chemotherapy) was undertaken. We systematically searched PubMed, Embase, and the Cochrane Library though October 2014, using keywords and relative MeSH or Emtree terms, 'allogeneic'; 'acut*' and 'leukem*/aml/leukaem*/leucem*/leucaem*'; and 'nonlympho*' or 'myelo*'. A total of 7053 articles were accessed. The primary outcomes were RFS and OS, while the secondary outcomes were treatment-related mortality (TRM) and relapse rate (RR). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for each outcome. The primary outcomes were RFS and OS, while the secondary outcomes were TRM and RR. We included 9 prospective controlled studies including 1950 adult patients. Patients with intermediate-risk AML in CR1 who received either alloHSCT or non-alloHSCT were considered eligible. AlloHSCT was found to be associated with significantly better RFS, OS, and RR than non-alloHSCT (HR, 0.684 [95% CI: 0.48, 0.95]; HR, 0.76 [95% CI: 0.61, 0.95]; and HR, 0.58 [95% CI: 0.45, 0.75], respectively). TRM was significantly higher following alloHSCT than non-alloHSCT (HR, 3.09 [95% CI: 1.38, 6.92]). However, subgroup analysis showed no OS benefit for alloHSCT over autoHSCT (HR, 0.99 [95% CI: 0.70, 1.39]). In conclusion, alloHSCT is associated with more favorable RFS, OS, and RR benefits (but not TRM outcomes) than non-alloHSCT generally, but does not have an OS advantage over autoHSCT specifically, in patients with intermediate-risk AML in CR1.
Project description:Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.
Project description:B cells are involved in chronic graft-versus-host disease (cGVHD) pathogenesis, and Rituximab may have a therapeutic effect on cGVHD in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. Herein, we retrospectively evaluated the prophylactic effect of Rituximab on cGVHD in a group of Chinese allo-HSCT patients. A total of 102 patients, who suffered Epstein Barr virus (EBV) viremia within 100 days after allo-HSCT, were included in this study. Fifty patients received Rituximab (375 mg/m2 weekly) for EBV viremia, while fifty-two patients did not receive Rituximab. A competing risk model was adopted to compare cumulative incidence of cGVHD, cumulative incidence of relapse (CIR) and transplantation-related mortality (TRM) between two groups. Cumulative incidence of cGVHD in the Rituximab group was lower than in controls (P = 0.0579). Multivariate analyses confirmed that Rituximab was an independent factor for the reduction of cumulative cGVHD incidence (P = 0.0069). No significant difference was observed in CIR (P = 0.39) or TRM (P = 0.48) between two groups and 2-year OS and DFS were comparable (OS, P = 0.667; DFS, P = 0.571). Administration of Rituximab in the early post-transplantation phase may protect against cGVHD in allo-HSCT patients without increasing CIR or TRM.
Project description:Infection, relapse, and GVHD can complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the effect of poor immune recovery on infection risk is well-established, there are limited data on the effect of immune reconstitution on relapse and survival, especially following T-cell depletion (TCD). To characterize the pattern of immune reconstitution in the first year after transplant and its effects on survival and relapse, we performed a retrospective study in 375 recipients of a myeloablative TCD allo-HSCT for hematologic malignancies. We noted that different subsets recover sequentially, CD8?+?T cells first, followed by total CD4?+?and naïve CD4?+?T cells, indicating thymic recovery during the first year after HSCT. In the multivariate model, a fully HLA-matched donor and recovery of T-cell function, assessed by PHA response at 6 months, were the only factors independently associated with OS and EFS. In conclusion, T-cell recovery is an important predictor of outcome after TCD allo-HSCT.
Project description:Overall survival (OS) of pediatric patients with acute myeloid leukemia (AML) increased in recent decades. However, it remained unknown whether advances in first-line treatment, supportive care, or second-line therapy mainly contributed to this improvement. Here, we retrospectively analyzed outcome and clinical data of 1940 pediatric AML patients (younger than 18 years of age), enrolled in the population-based AML-BFM trials between 1987 and 2012. While 5-year probability of OS (pOS) increased from 49?±?3% (1987-1992) to 76?±?4% (2010-2012; p?<?0.0001), probability of event-free survival only improved from 41?±?3% (1987-1992) to 50?±?2% (1993-1998; p?=?0.02) after introduction of high-dose cytarabine/mitoxantrone, but remained stable since then. Non-response and relapse rates stayed constant despite intensified first-line therapy (p?=?0.08 and p?=?0.17). Reduced fatal bleedings and leukostasis translated into fewer early deaths (8.1%vs. 2.2%; p?=?0.001). Strikingly, pOS after non-response (13?±?5% (1987-1992) vs. 43?±?7% (2005-2010); p?<?0.0001) or relapse (19?±?4% vs. 45?±?4%; p?<?0.0001) improved. After 1999, more relapsed or refractory patients underwent hematopoietic stem cell transplantation (HSCT) with increased pOS after HSCT (29?±?5% (1993-1998) vs. 50?±?4% (2005-2010); p?<?0.0001). Since efficacy of salvage therapy mainly contributed to better outcome in pediatric AML, our analysis indicates that a better allocation of patients, who cannot be cured with conventional chemotherapy, to an early "salvage-like" therapy is necessary.
Project description:Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with <CR. We retrospectively analyzed outcomes for 143 patients who underwent RA-SCT with or without consolidation. Melphalan was administered at 100 (14%), 140 (52%) and 200 (34%) mg/m2. The TRM rate at 100 days was 5%. RA-SCT resulted in CR in 24% (3 months) and 48% (12 months) of patients. The CR rate was particularly high (62%) in patients offered bortezomib consolidation. With a median follow-up among survivors of 7.7 years, median event-free survival (EFS) with RA-SCT was 4.04 years (95% confidence interval (CI): 3.41-5.01 years); median OS was 10.4 years (95% CI: 7.3-not achieved). Patients with CR at 12 months after SCT had significantly longer EFS (P=0.01) and OS (P=0.04). In a multivariate analysis, melphalan dose had no impact on EFS (P=0.26) or OS (P=0.11). For selected patients, RA-SCT was safe and was associated with extended long-term survival. With the availability of novel agents for consolidation, RA-SCT remains a very effective and important backbone treatment for AL amyloidosis.
Project description:PURPOSE:Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome. PATIENTS AND METHODS:Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort. RESULTS:Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes. CONCLUSION:Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.