Patients In First Complete Remission Research Articles

Autologous Stem Cell Transplantation (ASCT) for T-Cell Non Hodgkin Lymphoma (T-NHL) Patients Who Achieve Complete Remission with First-Line Treatment: A Systematic Review and Meta-Analysis

Introduction: There is currently no consensus on the optimal frontline therapy for patients with T cell Non-Hodgkin lymphomas (T-NHL). Consolidative autologous stem cell transplant (ASCT) is frequently offered to the patients with chemosensitive disease based on retrospective and prospective studies showing improved progression-free survival (PFS) when compared with historical controls getting chemotherapy alone. However, it remains unclear whether there is a good risk subset of patients who achieve first complete remission (CR1) following induction chemotherapy and who might not benefit from upfront ASCT. To date, no randomized control trials (RCTs) exist and available data is conflicting. We perform a systematic review/meta-analysis of the published literature to address this question. Methods A comprehensive, systematic search (from database inception - 9/2019) of MEDLINE/PubMed, EMBASE and Cochrane databases was performed. PRISMA and Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Studies were selected from a total of 2656, screened based on predefined inclusion/exclusion criteria, and were critically appraised for outcomes of interest [progression free survival (PFS) and overall survival (OS)]. Quality of studies was assessed using Newcastle-Ottawa Scale. Hazard ratios (HRs) and corresponding 95% Cis were calculated, and the meta-analysis was performed using the random-effects model. Test for heterogeneity was performed using I2 statistic. Results Of 2656 unique records, 13 studies (prospective = 3; retrospective = 10) were selected. In 8 studies, upfront ASCT was compared to NO ASCT in patients in first complete remission (CR1), while in 5, comparison was with patients achieving either PR1 (first partial remission) or CR1. 11 (of 13) studies reported PFS. Median follow-up in these studies ranged from 22 months to 7.8 years. Results from the meta-analysis showed that T-NHL patients who underwent ASCT had an improved 5-year PFS compared to those with NO ASCT (HR 1.62, 95% confidence interval (CI) 1.22 to 2.15, I² = 38%) (Figure 1). However, no benefit was observed in 5-year OS when ASCT was compared to NO ASCT (HR 1.32, 95% CI 0.82 to 2.12, I2 = 83%) (Figure 2). A sensitivity analysis including only studies with patients transplanted in CR1 showed similar findings, with a 5-year PFS (HR 1.54, 95% confidence interval (CI) 1.01 to 2.34, I² = 38%) and 5-yr OS (HR 1.11, 95% CI 0.41 to 3.02, I2 = 90%) when compared to No ASCT. Conclusions In the absence of RCTs, the results of this systematic review/meta-analysis represents the best evidence supporting long term PFS benefits of upfront ASCT consolidation in patients with T-NHL in CR1 or CR1/PR1 after frontline chemotherapy. Disclosures No relevant conflicts of interest to declare.

Efficacy of autologous versus allogeneic peripheral blood hematopoietic stem cell transplantation in non-high-risk acute myeloid leukemia patients in first complete remission

Efficacy of autologous versus allogeneic peripheral blood hematopoietic stem cell transplantation in non-high-risk acute myeloid leukemia patients in first complete remission

Cytogenetic risk score maintains its prognostic significance in AML patients with detectable measurable residual disease undergoing transplantation in remission: On behalf of the acute leukemia working party of the European society for blood and marrow transplantation.

While evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Canaani et al. Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD+ patients in first complete remission undergoing allo-SCT from a matched sibling donor or unrelated donor. Seven hundred and seventy-five patients were evaluated with a median follow-up duration of 22 months. Cytogenetic risk score was favorable, intermediate/FLT3wt intermediate/FLT3-ITD3, and adverse in 15%, 28.3%, 37% and 19.7% of the patients, respectively. Favorable and intermediate/FLT3wt risk patients had 2-year leukemia-free survival rates of 78% and 61%, respectively, compared with only 50% and 37% for intermediate/FLT3-ITD3 and adverse risk patients, respectively (P < .001). In multivariate analysis adverse and intermediate/FLT3-ITD3 risk patients were more likely to experience disease relapse compared with favorable risk patients [hazard ratio (HR) = 3.9, 95% confidence interval (CI), 2.1-7.3; P < .001, and HR = 4.4, CI 95%, 2.4-7.8; P < .001, respectively]. The European society for blood and marrow transplantation cytogenetic risk score is a valuable adjunct for risk stratification of MRD+ AML patients.

Outcome of Childhood Acute Myeloid Leukemia With FLT3-ITD Mutation: The Experience of Children’s Cancer Hospital Egypt, 2007-17

IntroductionThe presence of FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutation in pediatric acute myeloid leukemia (AML) is associated with high rates of induction failure and worse survival. Its presence places the patient into a high-risk group. We aimed to describe the outcome of pediatric AML with FLT3-ITD mutation. Patients and MethodsWe performed a retrospective analysis of cases of AML from July 2007 till July 2017 at Children’s Cancer Hospital Egypt. ResultsSeventy-one patients had FLT3 gene mutation out of 687 patients with AML. Sixty-five patients had FLT3 gene mutation with allelic ratio > 0.4; 43 (66.1%) of 65 patients experienced complete remission (CR). Of the 43 patients, 16 patients maintained CR, 18 patients relapsed after first CR, 8 patients died, and 1 patient was lost to follow-up. Patients with relapsing disease died after salvage chemotherapy, except for one patient, who was alive after second CR. Allogeneic bone marrow transplantation (allo-BMT) was performed for 9 (13.8%) of 65 patients in first CR, of whom 8 were alive and in CR, and 1 patient experienced disease relapse and died. Seven patients (10.7%) were alive without allo-BMT. Three years’ overall and event-free survival for patients with FLT3-ITD mutation with high allelic ratio was 26.9% and 22.8%, respectively. Three years’ overall and event-free survival for patients treated with allo-BMT was 77.8% and 78.8%, respectively, versus patients treated without allo-BMT, 16.3% and 12.8%, respectively. ConclusionFLT3-ITD mutation in pediatric AML was associated with poor treatment outcomes, and the survival of relapsing patients was extremely poor. Allo-BMT in first remission was the best treatment option. Alternative donor transplants and FLT3 inhibitors are needed to improve outcome in developing countries.

Outcomes of allogeneic stem cell transplantation for patients with t(6:9) AML- A strong case for allogeneic stem cell transplantation in first complete remission.

Outcomes of allogeneic stem cell transplantation for patients with t(6:9) AML- A strong case for allogeneic stem cell transplantation in first complete remission.

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for T Cell Acute Lymphoblastic Leukemia: A Report from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.

Outcome and Risk Factors of Overall Survival for Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation in First Complete Remission

Objective: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. To investigate how we can improve the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for AML patients in first complete remission (CR1), we analyze the risk factors of overall survival (OS), and depict gene mutation profiles in the patients.

Validation of the Revised AML-Composite Model for the Prediction of Prognosis in Older Patients Receiving Intensive Induction Therapy

Introduction: The prognosis of older patients treated for acute myeloid leukemia (AML) relies on cytogenetic/molecular classifications as well as their ability to tolerate intensive induction therapy for which comorbidities have an important impact. A prognostic model has been elaborated to incorporate these two variables, cytogenetic/molecular risk and comorbidities evaluated by the Hematopoietic Cell Transplantation - Comorbidity Index (HCT-CI) (Sorror et al. 2017). The AML-composite model (AML-CM), which also incorporates hypoalbuminemia and high LDH levels at diagnosis, has been recently updated to incorporate the new European LeukemiaNet (ELN) 2017 classification (Sorror et al. 2019). In this study, we aimed to confirm the predictive impact of the revised AML-CM in an independent cohort and to explore which parameters were the most relevant for predicting early mortality and relapse. Patients and Methods: All patients (pts) older than 60 years diagnosed with AML who received intensive induction therapy in our department between 2004 and 2017 were included. Patients with acute promyelocytic leukemia were excluded. They received induction therapy with idarubicin 8 mg/m2 for 5 days and cytarabine 100 mg/m2 for 7 days with or without lomustine 200 mg/m2 on day 1. Patients in first complete remission (CR1) were to receive six consolidation courses with idarubicin 8 mg/m2 for one day and cytarabine 100 mg/m2 for 5 days and maintenance therapy with oral methotrexate and mercaptopurine. The HCT-CI and the revised AML-CM were calculated as previously described (Sorror et al. 2005; Sorror et al. 2019) using individual patient medical records. Early mortality was defined as death within one month after the start of induction therapy. The ELN 2017 classification, the HCT-CI, and the revised AML-CM were considered to determine which parameters - comorbidities or cytogenetic/molecular risk - were associated with each outcome. Results: Ninety-nine pts were included in the study with a median age of 66 years-old (range: 60 - 82). Twenty-seven pts (27%) had secondary AML (prior solid tumor requiring chemotherapy and/or radiation therapy in 11 pts and prior hematological malignancy in 16 patients). According to the ELN 2017 classification, 24 (24%) were favorable, 53 (54%) were intermediate, and 22 (22%) were adverse. The most frequent comorbidities included liver disease (30 pts, low/moderate, 5 pts, severe), previous cancer (22 pts), and arrythmia (22 pts). Thus, 13 (13%), 25 (25%), 44 (45%), and 17 (17%) pts had a revised AML-CM score of 1-4, 5-6, 7-9, and &amp;gt;10, respectively. 78 pts (79%) achieved CR1, with 10 early deaths (10%) due to toxicity (early mortality) and 11 induction failures (11%). Fifteen pts received allogeneic SCT. 54 (55%) relapsed, and 72 (73%) died with a median follow-up of 18 months (range: 0 - 167). Both the HCT-CI and the AML-CM were associated with increased early mortality (OR: 1.4, 95% CI: 1 - 1.8, p=0.03 for HCT-CI and OR: 1.3, 95% CI: 1-1.7, p=0.03 for AML-CM) whereas the ELN 2017 classification had no impact. The predictive value of the AML-CM for early mortality was not superior to the HCT-CI (area under the curve - AUC: 0.76, p=0.01, and 0.76, p=0.01, respectively). The risk of relapse was only associated with an unfavorable ELN 2017 classification (OR: 8.8, 95% CI: 1.1 - 70, p=0.04). It was the most predictive parameter for relapse, in comparison to the HCT-CI and the revised AML-CM, but this did not reach statistical significance (AUC: 0.62, p=0.08). The AML-CM clearly distinguishes 4 groups with different prognosis (Figure, p&amp;lt;0.001 for log rank test). One-year OS rates were 92%, 68%, 61%, and 29% among pts with a score of 1-4, 5-6, 7-9, and &amp;gt; 10, respectively (OR: 1.4, 95% CI: 1.2 - 1.8, p&amp;lt;0.01). The revised AML-CM (AUC: 0.73, p&amp;lt;0.001) was more reliable for predicting one-year survival than the HCT-CI (AUC: 0.70, p=0.001) or the ELN 2017 classification (AUC: 0.66, p=0.01). Cox analysis confirms the prognostic value of the revised AML-CM on overall survival (HR: 1.2 for each additional point, 95% CI: 1.1 - 1.3, p&amp;lt;0.001). Conclusion: The revised AML-CM is an effective tool for predicting overall survival in older pts with AML receiving intensive induction therapy. It is a better prognostic system compared to the HCT-CI and the ELN 2017 classification as it combines the evaluation of comorbidities, which predicts early mortality, and cytogenetic/molecular risk, which predicts relapse. Figure Disclosures Orvain: Novartis: Honoraria; Incyte: Honoraria.

Impact of Depth of Pretransplant Clinical Response on Outcomes of Acute Myeloid Leukemia Patients in First Complete Remission (AML-CR1) Who Undergo Allogeneic Hematopoietic Cell Transplantation (AlloHCT)

Introduction: AML patients with intermediate or high-risk features often undergo allogeneic hematopoietic cell transplantation (alloHCT) during first complete remission (CR). The 2017 European LeukemiaNet guidelines for AML specify categories of CR: both with and without count recovery (CR vs. CRi) and with and without measurable residual disease (MRD). Previous smaller retrospective studies have suggested poorer survival outcomes after alloHCT for patients with responses less than CR. Methods: Eligible cases were determined using the CIBMTR registry. Each had AML in CR1, was ≥ 18 years, and underwent alloHCT between January 1, 2007 and December 31, 2015. MRD was defined based on the answers to qualitative questions on standard clinical reporting forms that ask if the patient is in either molecular or cytogenetic remission and if disease is detected in marrow by flow cytometry at time of HCT. The primary outcome was overall survival (OS), and secondary outcomes were non-relapse mortality (NRM), relapse and disease-free survival (DFS). The Kaplan-Meier method was used to estimate survival and cumulative incidence function was used to estimate relapse and NRM. Multivariable analysis (MVA) was performed using the Cox proportional hazards model to adjust for patient-, disease-, and transplant-related factors. Adjusted probabilities of DFS and OS, adjusted cumulative incidence curves of NRM and relapse were generated from final Cox regression models stratified on CR vs. CRi and weighted averages of covariate values using pooled sample proportion as weight function. Results: We identified 2492 cases (CR, n=1799; CRi, n=693). The main effect variable (CR vs. CRi) was missing in 262 additional patients; these patients were excluded when univariate analysis confirmed no significant associations, suggesting a random distribution of missing data. Patient characteristics are summarized in Table 1. Compared with patients with CR, patients with CRi were more likely to have a Karnofsky score &lt;90 (38% vs. 31%) and an HCT-CI score 3+ (47% vs. 40%). Other variables were well matched between the groups. MVA demonstrated significantly increased likelihood of mortality in patients with CRi compared to those with CR with hazard ratio (HR) 1.27; 95% confidence interval (CI) (1.13-1.43) (Figure 1A). Other covariates significantly associated with shorter OS included older age, poor-risk cytogenetics, lower Karnofsky score, higher HCT-CI score, and higher white blood cell count at diagnosis. The adjusted OS probabilities at 5 year post-HCT accounted for factors from MVA model are 50% (95%CI 47-52) for patients with CR and 43% (95%CI 39-47) for patients with CRi. CRi was also associated with significantly increased NRM [HR 1.33, 95%CI(1.11-1.59)] with only a trend in increased relapse [HR 1.15, 95% CI(0.99-1.34), p=0.07] resulting in inferior DFS [HR 1.20, 95%CI(1.07-1.35)]. MRD status was available in a subset of 2297 patients, and pairwise comparison demonstrated that presence of MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD (Figure 1B). Pairwise interaction between the main effects (CR vs. CRi) and MRD status were tested with no significant findings at a level of 0.01, demonstrating that the effects of incomplete count recovery and MRD are independent of each other. Conclusions: Analysis of this large CIBMTR cohort demonstrates that survival outcomes differ among AML patients nominally in CR at the time of alloHCT. Patients with CRi and/or MRD have significantly shorter OS after alloHCT compared to those in CR, as well as shorter DFS and higher NRM. Further studies should focus on limiting NRM and reducing relapse to optimize post-alloHCT outcomes for patients with responses less than CR. Disclosures Percival: Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Jazz: Consultancy; Pfizer: Honoraria; Amgen: Research Funding; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy.

Impact of Minimal Residual Disease Detected By Multiparameter Flow Cytometry on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be curative for acute myeloid leukemia (AML) patients. However, the disease relapse after allo-HSCT lead to poor outcomes almost in all cases. Minimal residual disease (MRD) is a strong prognostic marker of increased risk of relapse and reflects overall (OS) and relapse-free survival (RFS) in patients with AML. Immunophenotypic evaluation using multiparameter flow cytometry (MFC) is an important strategy for detecting MRD, because of its simplicity and wide availability. Aim. Determine the impact of MRD detected by MFC before allo-HSCT on clinical outcomes. Patients and methods. To assess the impact of MRD status before transplantation we include 56 AML patients who underwent allo-HSCT in National Research Center for Hematology between July 2016 and June 2019. Patient's characteristics are shown in table 1. All these patients were in first compete morphologic remission at the time of allo-HSCT. MRD was evaluated by MFC. Bone marrow samples were obtained before allo-HSCT and were analyzed by 6-color MFC (BD FACS Canto II, USA). Positive MRD was identified as a cell population deviating from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation for all patients. In addition, for patients with LAIP at diagnosis, positive MRD was also defined as a cell population carrying LAIP markers at diagnosis. The probabilities of OS and RFS were estimated using the Kaplan-Meier method. Results. Among 56 AML patients before allo-HSCT (all were in CR at the time of MRD analysis). Median of follow-up was 9.3 months.11 patients (19,6%) were identified as MRD+ (0,011%-5,08%, mean 1%). And 5 of them relapsed (45,5%). Out of 45 MRD negative patients before HSCT relapse was registered in one (relapse rate 2,2%). Statistical analysis revealed significant differences between MRD- and MRD+ patients: MRD+ had much worse OS (22,9% vs. 85.5%, p=0.0047, Fig.1A) and RFS (26% vs. 97.4%, p&lt;0,0001, Fig.1B). Conclusions. Despite the presence of morphological CR before allo-HSCT, MRD persistence can lead to worse probabilities of OS and RFS, which is comparable to patients who were transplanted in relapse. Because of the association between MRD and relapse risk, it can be assumed, that testing for MRD before allo-HSCT may help to identify a subgroup of patients at high risk of relapse who might benefit from preemptive posttransplantation treatment. Disclosures No relevant conflicts of interest to declare.

Prognostic Factors for Survival after Allogeneic Transplantation in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and treatment guidelines are still evolving. Allogeneic stem cell transplantation (allo-SCT) offers a potentially curative option and is recommended in first relapse and for high-risk patients in first complete remission (CR). Survival after allo-SCT could be substantially improved due to better risk stratification, patient selection and adapted treatment protocols leading to reduced non-relapse mortality (NRM). Prognostic factors for survival after allo-SCT still need to be defined: pheno- and genotype, patients´ age, conditioning regimens and remission status prior to allo-SCT are under discussion. We analyzed the outcome of 180 consecutive ALL patients who received allo-SCT at the Freiburg University Medical Center between 1995 and 2018 with regard to treatment response, survival, adverse reactions, and performed subgroup analyses to identify prognostic factors. The median age in our cohort was 37 years (ys), 19% were older than 55 ys. 27% were diagnosed with Philadelphia (Ph)-positive ALL, 24% with T-ALL. 36% were treated with relapsed/refractory disease. 48% of allo-SCTs were conducted with a HLA-matched, 19% with a HLA-mismatched unrelated and 33% with a related donor. In 61% the conditioning regimen included total body irradiation (TBI). In 48% no minimal residual disease (MRD) was detected prior to allo-SCT, 20% were transplanted in MRD-positive CR. The overall response rate was 86%, with MRD-negativity in 78%. With a median follow up of 10 ys, we observed a median overall survival (OS) of 23 months and a median progression free survival (PFS) of 11 months. The 10ys-OS was 33%, the 10ys-PFS 31%. The cumulative incidence of relapse was 68% at 10 ys, the cumulative incidence of NRM 12%. Acute graft-versus-host disease (GvHD) III-IV° occurred in 17%, severe chronic GvHD in 9%. Survival was significantly better in patients reaching MRD-negative CR before allo-SCT (10ys-OS 48% vs. 19%, p&lt;0.0001; 10ys-PFS 46% vs. 17%, p&lt;0.001) and in thoses receiving TBI (10ys-OS 40% vs. 19%, p&lt;0.01; 10ys-PFS 37% vs. 19%, p&lt;0.001). There was no significant difference in survival between patients younger or older than 55 ys (10ys-OS 37% vs. 21%, p=0.183; 10ys-PFS 34% vs. 21%, p=0.208) and between those diagnosed with T-, Ph-positive or -negative B-ALL (10ys-OS 41% vs. 35% vs. 29%, p=0.298; 10ys-PFS 38% vs. 33%. vs. 27%, p=0.238). Due to lower NRM, survival improved depending on the year of allo-SCT (10ys-OS 1995-2000 22% vs. 2001-2010 32% vs. 2011-2018 n.r., p&lt;0.01; 10ys-PFS 20% vs. 30% vs. n.r., p&lt;0.01). With a very long follow-up and high rate of MRD-assessment, we observed a high response rate and a low rate of severe GvHD. Our data confirm that allo-SCT enables long-term survival in high-risk ALL, suggest that, in certain subgroups, survival may be best in patients transplanted in CR and receiving TBI for conditioning, including the relevant observation that allo-SCT can be performed in carefully selected elderly patients. Disclosures Finke: Medac: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Riemser: Honoraria, Other: research support, Speakers Bureau. Wäsch:Pfizer: Consultancy; Sanofi: Other: Travel, Research Funding; Celgene: Other: travel, Research Funding; Jazz: Other: travel, Research Funding; Amgen: Consultancy; Gilead: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Amgen: Other: travel, Research Funding; Gilead: Other: travel, Research Funding.

S1599 RITUXIMAB MAINTENANCE FOR PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA IN FIRST COMPLETE REMISSION: RESULTS FROM A RANDOMIZED HOVON‐NORDIC LYMPHOMA GROUP PHASE III STUDY

Background:This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R‐CHOP can improve outcome of diffuse large B‐cell lymphoma (DLBCL) patients compared with standard R‐CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R‐CHOP, showing same CR‐rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy.Aims:To assess in a prospective, multicenter, randomized phase III study in patients with DLBCL the efficacy of maintenance treatment with rituximab in comparison to no further treatment on disease free survival.Methods:Patients in CR after R‐CHOP were randomized between 24 months of rituximab maintenance 375 mg/m2 intravenous every 8 weeks (n = 199) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). (www.trialregister.nl NTR1014).Results:Median age was 65 years (range 31–80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high‐intermediate or high aa‐IPI score. After a median follow‐up of 79.9 months (maximum 125.7 months), the 5‐year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57–1.19, p = 0.31, adjusted for age and aa‐IPI). The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients.Summary/Conclusion:Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R‐CHOP.

Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: Results from a randomized HOVON-Nordic Lymphoma Group phase III study.

7507 Background: This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R-CHOP can improve outcome of diffuse large B-cell lymphoma (DLBCL) patients compared with standard R-CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R-CHOP, showing same CR-rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy. Methods: Patients in CR after R-CHOP were randomized between 24 months of rituximab maintenance 375 mg/m2 intravenous every 8 weeks (n = 199 ) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). ( www.trialregister.nl NTR1014). Results: Median age was 65 years (range 31-80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high-intermediate or high aa-IPI score. After a median follow-up of 79.9 months (maximum 125.7 months), the 5-year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57-1.19, p= 0.31, adjusted for age and aa-IPI). The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients. Conclusions: Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R-CHOP. Clinical trial information: www.trialregister.nl NTR1014.

Reduced-Dose Radiation Therapy to the Primary Site is Effective for High-Risk Neuroblastoma: Results From a Prospective Trial

For patients with high-risk neuroblastoma (HR-NB), a dose of 21Gy to the primary tumor site after gross total resection (GTR) provides excellent local control. However, no clinical trial has specifically evaluated the optimal dose of radiation therapy (RT), and RT-related long-term toxicities are of increasing concern. We sought to assess local control, survival outcomes, and toxicity after a reduction in dose to the primary site from 21Gy to 18Gy. After induction chemotherapy and GTR, patients with HR-NB were enrolled and treated on an RT dose-reduction prospective trial with 18Gy hyperfractionated RT given in twice-daily fractions of 1.5Gy each. The 25 study subjects were 1.6 to 9.5 (median, 4.3) years old at enrollment and included 23 (92%) with stage IV and II (8%) with MYCN-amplified stage III disease. Eleven (44%) were in complete remission (CR), and 14 (56%) had persistence of osteomedullary disease postinduction. Three patients (12%) received proton therapy, and the rest received intensity modulated photon therapy. After a follow-up of 1.8 to 4.2 (median, 3.5) years from initiation of RT, no failures occurred within the RT field; 3 patients had marginal recurrences. The respective 3-year progression-free and overall survival rates were 54.5% and 90.9% for patients in first CR and 42.9% and 76.2% for patients not in metastatic CR. Acute toxicity was negligible. Reduced-dose RT with 18Gy did not compromise local control or survival outcomes in our cohort of patients with HR-NB after GTR. These findings support assessing further RT dose reduction and validation on a larger, multi-institutional trial.

Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of the Francophone Society for Stem Cell Transplantation and Cell Therapy

Background: Nowadays acute myeloid leukemia (AML) patients above the age of 60 years are often candidates for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, little is known about the outcomes of HSCT in this particular population, due to the low number of HSCT with robust follow-up, the heterogeneity between centers, as well as reports usually mixing AML and other diseases such as myelodysplastic syndrome. We used the database of the Francophone society for stem cell transplantation and cellular therapy to address this question in a large cohort of patients in a recent time period.Patients and methods: 1167 consecutive patients aged ≥60 years with AML in complete remission (CR), transplanted between January 1st 2006 and January 1st 2016, reported to ProMISe (Project Manager Internet Server), an internet-based system shared by 36 Francophone transplantation centers, were reviewed. Classical post-HSCT endpoints were studied such as engraftment, acute and chronic graft-versus-host disease (GvHD), non-relapse mortality (NRM), relapse rate, leukemia free survival (LFS) as well as overall survival (OS). Cytogenetic risk was assessed according to the European Leukemia Network 2017 for patients in first complete remission. Data were analyzed using proportional hazards models and proportional sub-distribution hazards models in presence of competing risks.Results: Patients' Characteristics are detailed in Table 1. The median age at HSCT was 62.9 years (Interquartile range -IQR 61.9-66.1). Patients aged ≥60 years but less of 65 represented 63.8% of the population with 68.2% of patients transplanted in the recent period (2011-2016). Most patient had de novo AML (91.6%), in first CR (76.9%) with intermediate risk (83.8%) according to ELN-2017 classification. A matched unrelated donor (MUD) was used in 45 % of transplants and the majority of patients received peripheral blood stem cells (83.7%). Half of the patients received fludarabine and 2 days busulfan as conditioning regimen. The majority of patients (70.9%) received anti-thymocyte globuline (ATG). Engraftment occurred in 1089 patients (93.3%; 95%CI, 91.9-94.8). Day 100 cumulative incidence of grade II-IV acute GVHD was 24.6% (15.7% grade II; 5.8% grade III; 3% grade IV). At last follow up, 378 patients had developed chronic GVHD (severe in 37.2% of them; 95%CI, 34.0-40.3). With a median follow-up of 3.5 years (95%CI, 3.1-3.7 years), overall survival (OS) and LFS probabilities at 3 years were 50.7% (95%CI, 47.7-54.0) and 44.8% (95%CI, 41.8-48.1), respectively. In multivariable analysis, the only factor associated with worse OS was the use of a mismatched unrelated donor compare to MUD [Hazard Ratio (HR): 1.35 (95% CI, 1.01 to 1.80), p=0.04]. At 3 years, relapse incidence was 34.4% (95% CI, 31.5-37.4). The use of a sibling donor compared to MUD [Sub-distribution Hazard Ratio (SHR): : 1.49 (95% CI, 1.19 to 1.87), p<0.001], poor risk AML in CR1 according to ELN classification [SHR: 1.49 (95% CI, 1.10 to 2.02), p=0.01], as well as the use of ATG in the conditioning regimen [SHR: 1.57 (95% CI, 1.21 to 2.05), p<0.001] were associated with a higher risk of relapse. During the study, 534 patients died (main causes of death was relapse, 53%); leading to a CI of NRM of 20.7% at 3 years (95%CI, 18.2-23.2). A karnofsky score above 90% [SHR: 0.74 (95% CI, 0.56 to 0.98), p=0.04] and the use of a sibling donor compare to MUD [SHR : 0.43(95% CI, 0.30 to 0.63), p<0.001] were associated with reduced NRM.Conclusion: With more than 3 years follow-up, which is long enough for our results to be considered to be robust, the use of a mismatched unrelated donor was the only factor associated with worse overall survival in this population of AML patients aged of 60 years or more. Relapse appeared as the first cause of death, independently related to AML ELN poor risk classification, but also to the use of a sibling donor and of ATG in the conditioning regimen. This study highlights the major role of alloreactivity in this particular population, where modulation of T-cell alloreactivity as well as donor choice should be urgently addressed in well-designed prospective trials. [Display omitted] DisclosuresPeffault De Latour:Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Outcomes of hematopoietic stem cell transplantation from unmanipulated haploidentical versus matched sibling donor in patients with acute myeloid leukemia in first complete remission with intermediate or high-risk cytogenetics: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic stem cell transplantation is the optimal care for patients with high-risk or intermediate - acute myeloid leukemia. In patients lacking matched sibling donor, haploidentical donors are an option. We compared outcomes of unmanipulated (Haplo) to matched sibling donor transplant in acute myeloid leukemia patients in first complete remission. Included were intermediate and high-risk acute myeloid leukemia in first complete remission undergoing Haplo and matched sibling donor transplant from 2007–2015, and reported to the ALWP of the EBMT. A propensity score technique was used to confirm results of main analysis: 2 matched sibling donors were matched with 1 Haplo. We identified 2654 pts (Haplo =185; matched sibling donor =2469), 2010 with intermediate acute myeloid leukemia (Haplo=122; matched sibling donor =1888) and 644 with high-risk acute myeloid leukemia (Haplo =63; matched sibling donor =581). Median follow up was 30 (range 1–116) months. In multivariate analysis, in intermediate - acute myeloid leukemia patients, Haplo resulted in lower leukemia-free survival (Hazard Ratio 1.74; P<0.01), overall-survival (HR 1.80; P<0.01) and GvHD-free-relapse-free survival (Hazard Ratio 1.32; P<0.05) and higher graft-versus-host disease (GvHD) non-relapse mortality (Hazard Ratio 3.03; P<0.01) as compared to matched sibling donor. In high-risk acute myeloid leukemia, no differences were found in leukemia-free survival, overall-survival, and GvHD-free- relapse-free survival according to donor type. Higher grade II-IV acute GvHD was observed for Haplo in both high-risk (Hazard Ratio 2.20; P<0.01) and intermediate risk (Hazard Ratio 1.84; P<0.01). A trend for a lower Relapse-Incidence was observed in Haplo among high-risk acute myeloid leukemia (Hazard Ratio 0.56; P=0.06). The propensity score analysis confirmed results. Our results underline that matched sibling donor is the first choice for acute myeloid leukemia patients in first complete remission. On the other hand, results of Haplo transplants are similar to matched sibling donor transplants in acute myeloid leukemia patients with high risk cytogenetics.

Comparison of Autologous Stem Cell Transplantation versus Haploidentical Donor Stem Cell Transplantation for Favorable- and Intermediate-Risk Acute Myeloid Leukemia Patients in First Complete Remission

Stem cell transplantation (SCT) is an attractive postremission treatment option for patients with intermediate-risk acute myeloid leukemia (AML) and for some favorable-risk AML patients with additional nongenetic risk factors. Autologous SCT (auto-SCT) and haploidentical donor SCT (haplo-SCT) are the widely used alternatives in cases of a lack of a HLA-matched donor. However, limited data have been published on the direct comparison between these 2 transplant types. Based on the transplant database in our center, we conducted a retrospective study involving patients with favorable- and intermediate-risk AML in first complete remission (CR1), according to the National Comprehensive Cancer Network guideline. Patients with extramedullary disease or those achieving CR by more than 2 cycles were excluded. In total, 195 patients were included in the study, 88 of whom underwent auto-SCT and 107 haplo-SCT. In the entire cohort analyses the impact of high relapse incidence in the auto-SCT group was compensated by low nonrelapse mortality (NRM), which resulted in a comparable overall survival (OS) (79.0% ± 4.6% versus 80.1% ± 5.0%, P = .769) and relapse-free survival (RFS) (66.1% ± 5.2% versus 77.4% ± 4.8%, P = .079) compared with those observed in the haplo-SCT group. However, for patients with intermediate-risk AML, NRM was similar between the groups, and haplo-SCT exhibited superior survival. In case of post-SCT relapse, patients with intermediate-risk AML showed markedly inferior 3-year OS compared with that shown by patients with favorable-risk AML (23.3% ± 9.8% versus 60.8% ± 14.3%, P = .011). In the multivariate analyses, minimal residual disease (MRD) measured by flow cytometry and gene mutation status before transplantation were independent predictors for both OS and RFS. We concluded that both auto-SCT and haplo-SCT were acceptable options for postremission treatment of patients with favorable- and intermediate-risk AML. Haplo-SCT yielded a better outcome in patients with intermediate-risk AML, but the relapse after SCT still led to a poor outcome. Clearance of MRD before SCT could improve the prognosis after transplantation.

Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1

Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8 mg/kg, n = 1265) or a reduced dose (FB2, 6.4 mg/kg, n = 1456) or treosulfan at 42 g/m2 (FT14, n = 403) or 36 g/m2 (FT12, n = 168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P < .0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P = .25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia.

Time-to-Event Ratio to Predict Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation?

• The duration of time (from diagnosis) to transplantation (TTT) for patients in first complete remission (CR1), has been used as a surrogate marker for a disease characteristic for patients with acute myeloid leukemia (AML).