5-year Cumulative Incidence Of Relapse Research Articles

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Negative MRD at Day 100 after Allogenic Hematopoietic Stem Cell Transplant (HSCT): The Grail to Reach in Acute Myeloid Leukemia (AML)

INTRODUCTIONHSCT remains the best curative treatment in eligible AML patients with adverse or intermediate cytogenetics according to the ELN classification, and for those with unfavorable molecular markers at diagnostic or with a positive measurable residual disease (MRD) after intensive chemotherapy. MRD-positivity after HSCT confers an inferior outcome and a recently published study demonstrated that the evaluation of WT1 MRD before HSCT or 3 months after HSCT is highly predictive of post-transplant relapse. Besides, the impact and the kinetics of MRD positivity on prognosis are still unclear. Here we assess the impact of both pre- and post-transplant MRD on long term survival and incidence of relapse among a real-life cohort of 117 AML patients who underwent HSCT. PATIENTS AND METHODFrom November 7, 2012 to December 17, 2019, 117 patients diagnosed with AML and aged over 18 years underwent HSCT in Amiens University Hospital Center. MRD status was assessed using RQ-PCR (sensitivity 10 -4 to 10 -5) or multiparametric flow cytometry (sensitivity 10 -3 to 10 -4) before HSCT, depending on the markers available at diagnosis, at day 30, day 100 and a year after HSCT. Overall survival (OS) and cumulative incidence of relapse (CIR) were evaluated at the same time-points in landmark analysis for patients surviving beyond d100 to reduce the impact of early death on CIR. Statistical analyses were performed with SPSS Statistics 20 (IBM). RESULTSMedian age was 55 years (range 18-72) with 67/117 males. 85% patients had de novo AML. Cytogenetic ELN risk stratification was favorable for 15 (13%), intermediate for 72 (62%) and adverse for 28 (25%). At the time of HSCT, 76% were in complete remission (CR) after intensive chemotherapy. 30 patients (25%) had myeloablative conditioning (MAC) or toxicities-reduced regimens (TRC), 34 patients (30%) had reduced-intensity regimens (RIC) and 53 patients (45%) underwent sequential-based conditioning regimens (Seq). For the 100 patients who survived beyond d100, median time follow-up was 23.5 months (3.0-85.0). OS at 1 and 3 years was respectively 80% (75.9-84.1) and 61.7% (56.1-67.3) and CIR at same time-points was 19,3% (15.2-23.4) and 29,8% (24.6-35.0). No OS and CIR differences were observed according to the conditioning regimen, stem cell source and ELN score. A progressive disease before HSCT increased the risk of relapse but didn't worsen the OS. Before HSCT, MRD was positive in 48 patients (58.5%) with analyzable markers, either at molecular or flow cytometry level. OS and CIR were not impacted by the pre-HSCT MRD. Strikingly, performing HSCT resulted in MRD negativation at day 100 for 85.4% of patients with previous positive MRD, significantly improving OS and CIR (p<.001 for both, Figure 1A and B). Beyond day 100, achieving a negative MRD limited the 5-year CIR to 20%. In multivariate analysis, OS was significantly inferior, in patients with acute GVHD > grade 2 (HR=5.4, 95CI=1.8-16.1; p=.002) and positive MRD at day 100 (HR=19.2, 95CI=6.0-61.1; p<.001). Positive MRD at day 100 was the only significant predictor of adverse CIR (HR=17.5, 95CI=5.6-55.3; p<.001).DISCUSSION/CONCLUSIONIn this real-life cohort of patients diagnosed with AML, we show that HSCT procedure consistently allows MRD negativation, subsequently improving the outcome of patients surviving beyond d100. Persistence of positive MRD after HSCT was the main predictor of long-term adverse outcome after transplant. Our data highlight the importance of MRD negativation at day 100 regardless of pre-transplant status, conditioning regimen or initial ELN classification. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience

IntroductionMutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. Patients and MethodsIn this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. ResultsPatients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). ConclusionAmong patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).

Development of a Nomogram for Predicting the Cumulative Incidence of Disease Recurrence of AML After Allo-HSCT.

Using targeted exome sequencing, we studied correlations between mutations at diagnosis and transplant outcomes in 332 subjects with acute myeloid leukemia (AML) receiving allotransplantation. A total of 299 patients (299/332, 90.1%) had at least one oncogenic point mutation. In multivariable analyses, pretransplant disease status, minimal residual disease (MRD) before transplantation (pre-MRD), cytogenetic risk classification, and TP53 and FLT3-ITD high ratio mutations were independent risk factors for AML recurrence after allotransplantation (p < 0.05). A nomogram for the cumulative incidence of relapse (CIR) that integrated all the predictors in the multivariable model was then constructed, and the concordance index (C-index) values at 6, 12, 18, and 24 months for CIR prediction were 0.754, 0.730, 0.715, and 0.690, respectively. Moreover, calibration plots showed good agreements between the actual observation and the nomogram prediction for the 6, 12, 18, and 24 months posttransplantation CIR in the internal validation. The integrated calibration index (ICI) values were 0.008, 0.055, 0.094, and 0.136 at 6, 12, 18, and 24 months posttransplantation, respectively. With a median cutoff score of 9.73 from the nomogram, all patients could be divided into two groups, and the differences in 2-year CIR, disease-free survival (DFS), and overall survival (OS) between these two groups were significant (p < 0.05). Taken together, the results of our study indicate that gene mutations could help to predict the outcomes of patients with AML receiving allotransplantation.

Long-term outcome of hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse

AbstractBurkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long‐term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥60 years old), 73% had bone marrow (BM) involvement, and 28% had CNS involvement. The complete response rate was 91% (BL 96%; HGBCL 79%; P = .16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, P = .06) and was associated with baseline BM (27% vs 0%; P = .02) and CNS (42% vs 12%; P < .01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%; P = .31); 16% with baseline CNS involvement (P = .03). Our data support the use of hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Prognostic significance of TIM-3 expression pattern at diagnosis in patients with t(8;21) acute myeloid leukemia

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK − TIM-3+ and CD34+CD38−TIM-3+ cells were significantly associated with a high 2-year cumulative incidence of relapse (CIR) (p = 0.028, 0.016). Further, concurrent high frequencies of T + NK-TIM-3+ and CD34+CD38-TIM-3+ cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, [95% confidence interval (CI), 1.1–6.0], p = 0.04; HR = 46.5, [95% CI, 2.7–811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML.

Risk Stratification of Cytogenetically Normal Acute Myeloid Leukemia With Biallelic CEBPA Mutations Based on a Multi-Gene Panel and Nomogram Model.

BackgroundApproximately 30% of Chinese individuals with cytogenetically normal acute myeloid leukemia (CN-AML) have biallelic CEBPA (biCEBPA) mutations. The prognosis and optimal therapy for these patients are controversial in clinical practice.MethodsIn this study, we performed targeted region sequencing of 236 genes in 158 individuals with this genotype and constructed a nomogram model based on leukemia-free survival (LFS). Patients were randomly assigned to a training cohort (N =111) and a validation cohort (N =47) at a ratio of 7:3. Risk stratification was performed by the prognostic factors to investigate the risk-adapted post-remission therapy by Kaplan–Meier method.ResultsAt least 1 mutated gene other than CEBPA was identified in patients and mutation number was associated with LFS (61.6% vs. 39.0%, P =0.033), survival (85.6% vs. 62.9%, P =0.030) and cumulative incidence of relapse (CIR) (38.4% vs. 59.5%, P =0.0496). White blood cell count, mutations in CFS3R, KMT2A and DNA methylation related genes were weighted to construct a nomogram model and differentiate two risk subgroups. Regarding LFS, low-risk patients were superior to the high-risk (89.3% vs. 33.8%, P <0.001 in training cohort; 87.5% vs. 18.2%, P =0.009 in validation cohort). Compared with chemotherapy, allogenic hematopoietic stem cell transplantation (allo-HSCT) improved 5-year LFS (89.6% vs. 32.6%, P <0.001), survival (96.9% vs. 63.6%, P =0.001) and CIR (7.2% vs. 65.8%, P <0.001) in high-risk patients but not low-risk patients (LFS, 77.4% vs. 88.9%, P =0.424; survival, 83.9% vs. 95.5%, P =0.173; CIR, 11.7% vs. 11.1%, P =0.901).ConclusionsOur study indicated that biCEBPA mutant-positive CN-AML patients could be further classified into two risk subgroups by four factors and allo-HSCT should be recommended for high-risk patients as post-remission therapy. These data will help physicians refine treatment decision-making in biCEBPA mutant-positive CN-AML patients.

Association Between Measurable Residual Disease in Patients With Intermediate-Risk Acute Myeloid Leukemia and First Remission, Treatment, and Outcomes

Measurable residual disease (MRD) is widely used as a therapy-stratification factor for acute myeloid leukemia (AML), but the association of dynamic MRD with postremission treatment (PRT) in patients with intermediate-risk AML (IR-AML) has not been well investigated. To investigate PRT choices based on dynamic MRD in patients with IR-AML. This cohort study examined 549 younger patients with de novo IR-AML in the South China Hematology Alliance database during the period from January 1, 2012, to June 30, 2016, including 154 who received chemotherapy, 116 who received an autologous stem cell transplant (auto-SCT), and 279 who received an allogeneic SCT (allo-SCT). Subgroup analyses were performed according to dynamic MRD after the first, second, and third courses of chemotherapy. The end point of the last follow-up was August 31, 2020. Statistical analysis was performed from December 1, 2019, to September 30, 2020. Receipt of chemotherapy, auto-SCT, or allo-SCT. The primary end points were 5-year cumulative incidence of relapse and leukemia-free survival. Subgroup analyses were performed for 549 participants (314 male participants [57.2%]; median age, 37 years [range, 14-60 years]) according to the dynamics of MRD after 1, 2, or 3 courses of chemotherapy. Comparable cumulative incidences of relapse, leukemia-free survival, and overall survival were observed among participants who had no MRD after 1, 2, or 3 courses of chemotherapy. Participants who underwent chemotherapy and those who underwent auto-SCT had better graft-vs-host disease-free, relapse-free survival (GRFS) than those who underwent allo-SCT (chemotherapy: hazard ratio [HR], 0.35 [95% CI, 0.14-0.90]; P = .03; auto-SCT: HR, 0.07 [95% CI, 0.01-0.58]; P = .01). Among participants with MRD after 1 course of chemotherapy but no MRD after 2 or 3 courses, those who underwent auto-SCT and allo-SCT showed lower cumulative incidence of relapse (auto-SCT: HR, 0.25 [95% CI, 0.08-0.78]; P = .01; allo-SCT: HR, 0.08 [95% CI, 0.02-0.24]; P < .001), better leukemia-free survival (auto-SCT: HR, 0.26 [95% CI, 0.10-0.64]; P = .004; allo-SCT: HR, 0.21 [95% CI, 0.09-0.46]; P < .001), and overall survival (auto-SCT: HR, 0.22 [95% CI, 0.08-0.64]; P = .005; allo-SCT: HR, 0.25 [95% CI, 0.11-0.59]; P = .001) vs chemotherapy. In addition, auto-SCT showed better GRFS than allo-SCT (HR, 0.45 [95% CI, 0.21-0.98]; P = .04) in this group. Among participants with MRD after 1 or 2 courses of chemotherapy but no MRD after 3 courses, allo-SCT had superior cumulative incidence of relapse (HR, 0.10 [95% CI, 0.06-0.94]; P = .04) and leukemia-free survival (HR, 0.18 [95% CI, 0.05-0.68]; P = .01) compared with chemotherapy, but no advantageous cumulative incidence of relapse (HR, 0.15 [95% CI, 0.02-1.42]; P = .10) and leukemia-free survival (HR, 0.23 [95% CI, 0.05-1.08]; P = .06) compared with auto-SCT. Among participants with MRD after 3 courses of chemotherapy, allo-SCT had superior cumulative incidences of relapse, leukemia-free survival, and overall survival compared with chemotherapy (relapse: HR, 0.16 [95% CI, 0.08-0.33]; P < .001; leukemia-free survival: HR, 0.19 [95% CI, 0.10-0.35]; P < .001; overall survival: HR, 0.29 [95% CI, 0.15-0.55]; P < .001) and auto-SCT (relapse: HR, 0.25 [95% CI, 0.12-0.53]; P < .001; leukemia-free survival: HR, 0.35 [95% CI, 0.18-0.73]; P = .004; overall survival: HR, 0.54 [95% CI, 0.26-0.94]; P = .04). Among participants with recurrent MRD, allo-SCT was also associated with advantageous cumulative incidence of relapse, leukemia-free survival, and overall survival compared with chemotherapy (relapse: HR, 0.12 [95% CI, 0.04-0.33]; P < .001; leukemia-free survival: HR, 0.24 [95% CI, 0.10-0.56]; P = .001; overall survival: HR, 0.31 [95% CI, 0.13-0.75]; P = .01) and auto-SCT (relapse: HR, 0.28 [95% CI, 0.09-0.81]; P = .02; leukemia-free survival: HR, 0.30 [95% CI, 0.12-0.76]; P = .01; overall survival: HR, 0.26 [95% CI, 0.10-0.70]; P = .007). This study suggests that clinical decisions based on dynamic MRD might be associated with improved therapy stratification and optimized PRT for patients with IR-AML. Prospective multicenter trials are needed to further validate these findings.

Unrelated cord blood stem cell transplantation for high-risk/refractory childhood acute myeloid leukemia: a clinical analysis of 160 cases

目的探讨单份非血缘脐血干细胞移植（UCBT）治疗高危/难治儿童急性髓系白血病（AML）的疗效。方法对2008年6月至2018年12月期间接受UCBT的160例高危/难治AML（不含急性早幼粒细胞白血病）患儿进行回顾性分析。全部病例均采用清髓性预处理方案，应用环孢素A（CsA）联合短程霉酚酸酯（MMF）预防移植物抗宿主病（GVHD）。结果160例AML患儿中男103例、女57例，中位年龄7（1～14）岁，中位体重23（8～77）kg。移植后42 d中性粒细胞累积植入率为95.0％（95％CI 90.0％～97.5％），移植后120 d血小板累积植入率为85.5％（95％CI 83.3％～93.4％），中性粒细胞、血小板植入中位时间分别为移植后16（11～38）d、35（13～158）d。Ⅱ～Ⅳ、Ⅲ～Ⅳ度急性GVHD发生率分别为37.3％（95％CI 29.3％～45.2％）、27.3％（95％CI 20.0％～35.0％），慢性GVHD发生率为22.4％（95％CI 15.5％～28.7％）。可评估的移植后360 d移植相关死亡率（TRM）为13.1％（95％CI 8.4％～18.9％）。移植后5年累积复发率为13.8％（95％CI 8.5％～20.3％），无病生存（DFS）率为71.7％（95％CI 62.7％～77.8％）、总生存（OS）率为72.2％（95％CI 64.1％～78.7％），无GVHD无复发生存（GRFS）率为56.1％（95％CI 46.1％～64.9％）。移植前处于第1次完全缓解（CR1）期（95例）、第2次完全缓解（CR2）期（28例）、未缓解患者（37例）的移植后5年累积复发率分别为5.3％（95％CI 1.9％～11.1％）、19.9％（95％CI 6.9％～37.7％）、30.9％（95％CI 14.3％～49.2％）（P＝0.001），移植后5年OS率分别为79.9％（95％CI 70.3％～86.7％）、71.1％（95％CI 50.4％～84.4％）、52.9％（95％CI 33.0％～69.3％）（χ2＝7.552，P＝0.020）。结论UCBT是治愈高危/难治儿童AML安全、有效的治疗方法。第1次完全缓解期进行UCBT有利于改善预后。

Pre-Transplant Minimal Residual Disease Determined By Multiparameter Flow Cytometry Is Better Than RQ-PCR to Predict the Outcomes of Ph+ALL Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

▪Acute lymphoblastic leukemia with the Philadelphia (Ph) chromosome (Ph+ALL) occurs in about 25-30% adult patient ALL. Though the appearance of tyrosine kinase inhibitors (TKIs) greatly improved the outcomes of this kind of leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a radical approach for this kind of leukemia. Several previous studies had demonstrated that minimal residual disease prior to transplantation (pre-MRD) could predict the transplant outcomes, especially leukemia relapse. For Ph+ALL, multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RQ-PCR) were used to monitor MRD. In this study, we compared the impact of pre-MRD determined by MFC and BCR/ABL expression on the outcomes of Ph+ALL who underwent allo-HSCT. Total 155 patients who received HLA-matched sibling donor transplantation (MSDT, n=49) and unmanipulated haploidentical HSCT (haplo-HSCT, n=106) were enrolled. Pre-MRD was determined using MFC (pre-MFC) and RQ-PCR-based BCR/ABL expression (pre-BCR/ABL). The results showed that patients received MSDT and haplo-HSCT could have the comparable clinical outcomes. When pre-MRD was evaluated by RQ-PCR, the patients with or without BCR/ABL expression in both MSDT and haplo-HSCT groups didn't show any significant difference in cumulative incidence of relapse (CIR), transplantation related mortality (TRM), leukemia-free survival (LFS) and overall survival (OS). In addition, we also divided patients into 5 groups based on pre-BCR/ABL level: group 1, BCR/ABL=0; group 2, 0<BCR/ABL<0.1%; group 3, 0.1%<BCR/ABL<1%; group 4, 1%<BCR/ABL<10%; group 5, BCR/ABL>10%. Through kaplan-meier analysis, it showed that only patients of group 5 would show the extremely higher CIR (75.0%) while there was no significant difference among the other four groups (group 1 vs. 2 vs. 3 vs. 4, 14.5% vs. 10.2% vs. 20.6% vs. 10.0%, P>0.05). However, when pre-MRD was determined by MFC, patients with negative pre-MFC had a lower 2-year CIR and a slight higher 2-year leukemia-free survival (LFS) than those with positive pre-MFC in whole crowd (CIR: 7.5% vs. 40.0%, P<0.001; LFS: 74.4% vs. 61.2%,P=0.119). For those pre-BCR/ABL positive patients, they were further stratified by pre-MFC in both MSDT and haplo-HSCT groups. Patients with pre-MFC prior to MSDT showed a higher 2-year CIR and lower 2-year LFS compared to those with negative MRD (CIR: 44.4% vs. 6.6%, P=0.002; LFS: 44.4% vs. 85.7%, P=0.019). In patients undergoing haplo-HSCT, the 2-year CIR in pre-MFC positive group was higher than that of pre-MFC negative group (32.4% vs. 5.9%, P=0.014), while the 2-year LFS was comparable between above two groups (62.9% vs. 73.8%, P=0.513). Multivariate analysis indicated that prolonged neutrophil engraftment (HR, 1.243; 95% CI, 1.073-1.440, P=0.004) and positive pre-MFC (HR, 5.492; 95% CI, 1.574-19.161; P=0.008) was associated with a higher CIR. The results indicated that, pre-transplant MRD determined by MFC was better than RQ-PCR-based BCR/ABL expression in predicting outcomes of Ph+ALL patients receiving allo-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Adoptive Cellular Therapy with Donor Lymphocyte Infusion Versus a Second Allogeneic Hematopoietic Cell Transplant for Post-Allograft Relapsed Acute Myeloid Leukemia: An Intent-to-Treat Analysis on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

▪Background: We have previously reported that in patients with acute myeloid leukemia (AML) relapsing after allogeneic hematopoietic cell transplant (allo-HCT) outcome was highly dependent on the use of donor lymphocyte infusion (DLI) or second transplant for consolidation. Despite response to chemotherapy without cellular therapy to consolidate, most of the patients relapsed and died (Schmid C, et al. JCO 2007;25: 4938-4945).There are no randomized controlled trials comparing DLI vs. second allo-HCT (allo-HCT2) for patients with AML relapsing after a first allo-HCT. The decision to offer DLI or an allo-HCT2 is based on several factors including remission status, donor availability, performance status, and center or physician preference. Methods: We conducted a retrospective comparative analysis of 418 patients with post-transplant relapsed AML treated with either DLI (n=281) or an allo-HCT2 (n=137) at 61 EBMT participating centers between 1992 and 2014. Primary endpoint was overall survival (OS). All analyses were performed on an intent-to-treat basis. Results: Patients treated with DLI (n=281) were older (median age 49 vs. 43 years, p<0.001), had shorter median time from first allo-HCT to relapse (211 vs. 348 days, p=0.004), received the intended treatment faster (30 vs. 71 days, p<0.001), but were less likely to be in complete hematologic remission (CHR) at the time of intervention (18% vs. 39%, p<0.001) (Table 1). For patients in the DLI or allo-HCT2 groups the median follow-up for survivors was 64 (1-157) months and 61 (15-110) months, respectively. There were no differences in 5-year OS between treatments [DLI=15% (95% confidence interval (CI):10-19%) vs. allo-HCT2=19% (95%CI:12-25%), p=0.86)]. An analysis of patients who were in complete hematologic remission (CHR) at the time of intervention showed similar 5-year cumulative incidence of relapse [DLI=64% (95%CI:47-77%) vs. allo-HCT2=56% (95%CI:41-68%), p=0.64] and non-relapse mortality (NRM) [DLI=16% (95%CI:7-28%) vs. allo-HCT2=27% (95%CI:16-39%), p=0.08]; and comparable 5-year leukemia-free survival (LFS) [DLI=21% (95%CI:8-33%) vs. allo-HCT2=18% (95%CI:7-28%), p=0.17] and OS [DLI=33% (95%CI:19-48%) vs. allo-HCT2=29% (95%CI:17-42%), p=0.22]. Results in patients with active disease at time of cellular therapy were very poor with 5-year cumulative incidence of relapse being [82% (95%CI:76-86%) vs. 63% (95%CI:52-73%), p=0.02], after DLI or allo-HCT2, respectively. The very high relapse rate resulted in poor 5-year LFS [DLI=10% (95%CI:6-13%) vs. allo-HCT2=6% (95%CI:0-13%), p=0.03], and OS with DLI [DLI=11% (95%CI:7-15%) vs. allo-HCT2=11% (95%CI:4-18%), p=0.59]. NRM was significantly lower with DLI [DLI=9% (95%CI:6-13%) vs. allo-HCT2=31% (95%CI:20-42%), p<0.0001]. Conclusions: There is no difference in 5-year OS when offering DLI versus allo-HCT2 in post-allograft relapsed AML patients. The most important prognostic factor is disease status at time of cellular therapy (whether DLI or allo-HCT2). Best results are achieved in patients who can attain CHR prior to intervention. In patients with active disease results are disappointing with 5-year LFS and OS in only 10% of cases. New therapeutic strategies and novel therapies are needed to improve outcomes in these patients. [Display omitted] DisclosuresKharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Schmid:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; MoilMed: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Mohty:Sanofi: Honoraria, Speakers Bureau.

Durable Outcomes of a Prospective Double Cord Blood Transplantation Trial in Adults with Acute Lymphoblastic Leukemia: Different Outcomes According to the Presence of Philadelphia Chromosome

▪Background: Alternative donor hematopoietic cell transplantation (HCT) is an emerging topic in acute leukemia for patients without matched sibling donors (MSD) or unrelated donors (MUD). Cord blood transplantation (CBT) has been tried for several years in adult acute lymphoblastic leukemia (ALL), and the long-term survival outcomes were comparable to those treated with conventional donor HCT.Aim : We have conducted double CBT (DCBT) in patients without both MSD and MUD for final step, and here, we report our phase 2 study results of clinical outcomes for adult ALL patients treated with DCBT.Methods: During the period between 2005 and 2016, 67 patients (median age, 37 years [range, 16-59 years]; 34 Ph-negative ALL and 33 Ph-positive ALL) were treated with DCBT in CR1 (n=48), CR2 (n=15), and in advanced status (n=4). The indications for DCBT were unavailability of MSD and MUD, agreement for conduction of the transplantation procedure, and proper performance status and organ function to undertake transplantation. The median time to transplant was 198 days (range, 97-1751 days). All patients received DCBT following total body irradiation (TBI) 12.0 Gy plus cytarabine 9.0 g/m2 plus fludarabine 150 mg/m2, and graft versus host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 25 days (23 days [range, 12-109] for Ph-negative ALL and 26 days [range, 9-59] for Ph-positive ALL, P=0.336) and 34 days (27.5 days [range, 8-123] for Ph-negative ALL and 40 days [range, 9-185] for Ph-positive ALL, P=0.022), respectively. The median CD34+ cell count was 1.21 x 105/kg (range, 0.4-5.85) and TNC was 4.04 x 107/kg (range, 1.58-7.88). In our data, extramedullary involvements were more frequently observed in Ph-negative ALL, while hyperleukocytosis was frequently observed in Ph-positive ALL. Except for 5 patients who died in aplasia, 28 developed acute GVHD (grade II in 23 and grade III in 5), and the cumulative incidence of acute GVHD at 1-year was 41.8%, and the incidence was 9.0% for acute GVHD with grade III-IV. Except for 11 patients with early deaths within 100 days, 17 developed chronic GVHD (11 mild, 4 moderate, 2 severe), resulting in a 4-year cumulative incidence of 23.0% (3.0% for severe chronic GVHD). After a median follow-up duration of 43.7 months (range: 6.5 - 135.3), the 4-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 15.6% and 29.6% (7.2% and 29.2% for CR1), respectively, and the 4-year disease-free survival (DFS) and overall survival (OS) rates were 52.5% and 53.9% (62.9% and 65.6% for CR1), respectively. The 4-year CIR, NRM and DFS for Ph-negative and Ph-positive subgroup was 9.6% and 21.6% (P=0.140), 21.0% and 38.9% (P=0.107), and 66.5% and 37.7% (P=0.017). The results of Ph-negative and Ph-positive subgroup in CR1 were 4.8% and 9.9% (P=0.357), 19.1% and 43.0% (P=0.088), and 76.1% and 45.0% (P=0.029), respectively. In multivariate analysis, advanced disease status≥CR2 (HR, 5.61; 95% CI, 1.4-22.2; P=0.014) was related with higher CIR rate, and older age (HR, 3.75; 95% CI, 1.5-9.3; P=0.004) and lower CD34+ cell count (HR, 4.96; 95% CI, 1.1-22.3; P=0.037) were related with higher NRM rates. Overall, Ph-chromosome (HR, 2.65; 95% CI, 1.2-5.8; P=0.016), longer time to transplant (HR, 4.18; 95% CI, 1.9-8.9; P <0.001), lower CD34+ cell count (HR, 3.66; 95% CI, 1.4-9.5; P=0.008) and the absence of acute GVHD (HR, 3.19; 95% CI, 1.4-7.4; P=0.006) were related to poorer DFS.Conclusion: Our data showed that DCBT can be a good alternative choice for providing a long-term disease control for adult ALL patients especially in Ph-negative subgroup. Since Ph-positive subgroup was related with poorer DFS and higher NRM rate in our data, another alternative haploidentical HCT should be considered. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No Association between Relapse Risk and Thiopurine Methyltransferase Activity By Either Geno- or Phenotype in the NOPHO ALL-2008 Protocol

Background6-mercaptopurine/methotrexate (6MP/MTX) maintenance therapy is essential for high cure rates of childhood acute lymphoblastic leukemia (ALL). 6MP exerts its cytotoxicity through conversion into thioguanine nucleotides (TGN) that are substrates for DNA polymerase and compete with normal guanine for DNA incorporation. DNA-TGN occasionally mismatches to thymidine causing cell death due to futile attempts of repetitive mismatch repair. We recently showed that higher levels of DNA-incorporated TGN were associated with a reduced relapse risk in non-high risk ALL (Nielsen, Lancet Oncol 2017). Common germline variants in TPMT that codes for thiopurine methyltransferase (TPMT) lead to reduced TPMT activity and higher levels of cytosol TGN when measured in erythrocytes. Thus, low TPMT activity could theoretically lead to higher DNA-TGN and a lower relapse rate. Low TPMT activity (phenotype) has been associated with a lower relapse risk in the NOPHO ALL92 protocol (Schmiegelow, Leukemia 2009). We explored if TPMT status evaluated by either geno- or phenotype was related to DNA-TGN levels and relapse rate in the NOPHO ALL2008 protocol.MethodTPMTgenotype and repeated phenotyping (2141 measurements in total), and levels of DNA-TGN (10830 measurements in total) during maintenance therapy were determined for 918 children treated for non-high risk ALL (89% of all eligible patients). On a subset (N=204) TPMT phenotype was available both at diagnosis and during maintenance therapy. 6MP was started at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients, respectively, and subsequently adjusted to a target WBC of 1.5-3.0 x109/L. Cox analyses were adjusted by age, sex and WBC at diagnosis.Results78 of the 918 non-high risk patients were TPMT heterozygous (none homozygous deficient). TPMT activities were significantly higher during maintenance therapy than at diagnosis for both TPMT wildtype and heterozygous children (N=204; wildtype: 16.6 vs. 11.3 U/mL ery., p <0.001; heterozygous: 9.9 vs. 6.8 U/mL ery., p=0.047). Mean DNA-TGN levels were higher for TPMT heterozygous than wildtype children (N=523, children in remission at end of therapy with Maintenance II measurements, median 760.9 fmol/µg, range 125.7−1255.0 vs. 494.9, range 44.0−1559.0, p <0.001; Figure). The 5-year cumulative incidence of relapse was 4.2% (95% CI: 0-8.7%) for TPMT heterozygous and 5.7% (95% CI: 3.8-7.5%) forwildtype children (hazard ratio =0.87, 95% CI: 0.27−2.83, p=0.81). No association between mean TPMT activity during maintenance therapy (as a time-dependent covariate) and relapse-specific hazard was seen (N=812; hazard ratio =0.98 per one unit increase in TPMT activity (U/mL ery.), 95% CI: 0.89−1.08, p=0.63). In patients with positive MRD at end of induction (d29) results were similar (N=476; hazard ratio =1.04 per one unit increase in TPMT activity (U/mL ery.), 95% CI: 0.93−1.16, p=0.50).ConclusionAlthough mean DNA-TGN levels were higher in TPMT heterozygous than wildtype children, variability was high in both groups and DNA-TGN levels were largely overlapping, and no association with relapse hazard was seen for neither TPMT geno- nor phenotype. In accordance with previously published data TPMT phenotype determinations done in erythrocytes present at ALL diagnosis can lead to TPMT misclassification.FIGUREa) Mean DNA-TGN levels (N=523) during Maintenance II of children in clinical remission with completed therapy and at least one measurement.b) Cumulative incidence curves of relapse of children carrying TPMT wildtype vs. heterozygous. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Determinants of Early Death and Outcomes for Acute Promyelocytic Leukemia in the Arsenic Era: A Real World Study

ObjectiveEarly death (ED) persists as the main obstacle to cure all the patients with acute promyelocytic leukemia (APL) in all-trans retinoic acid (ATRA) era. Uncertainty remains as to whether ED rate can reduce and which markers are independent predictors for ED and outcomes in arsenic era. We conducted a real world study of APL patients to assess ED, outcomes and predictors in arsenic era.MethodsThis study includes consecutive 309 APL patients in our center between 2005 and 2013. Three treatment protocols using arsenic and ATRA as first-line treatment were adopted in our center. Protocol A was used from 2005 to 2007.Patients received oral tetra-arsenic tetra-sulfide (As4S4) (60mg/kg/day) or intravenous ATO (10 mg/day) daily with ATRA (25 mg/m2/day), until complete remission (CR) for induction therapy, whereas additional minimal chemotherapy was administered to control hyperleukocytosis (mitoxantrone 1.4 mg/m2/day for 5-10 days or daunorubicin 40 mg/m2/day for 2-3 days was added if peripheral WBC was greater than 10 × 109/L or on the second day in patients with high risk). After achieving CR, most patients were administered 3 courses of consolidation chemotherapy including mitoxantrone (6-8 mg/m2/day for 3 days), daunorubicin (40mg/m2 for 3 days) ,idarubicin (6-8 mg/m2 for 3 days). Maintenance treatment included inter-mittent oral As4S4 and ATRA for 2-3 years. Protocol B was used from 2008 to 2012, which is described in our previous report (Zhu HH, et al. JCO 2013; 31:4215-4221 ).Protocol C was used since 2013, which only included non high-risk patients and was described in our previous report (Zhu HH, et al. NEJM 2014; 371:2239-41).ResultsThe ED (death within 30 days of diagnosis) rate was 4.8% (n=15) and showed a trend of decrease after 2008 (3.8% vs, 8.5% p=0.053). Using multivariate Cox proportional hazards regression, the hazard ratio of ED was 19.89 (95% CI, 4.49-88) for white blood cell (WBC) count of >10×109/L vs ≤10×109/L (P<0.0001) and 8.70 (95% CI, 1.15-66.67) for platelet count of ≤40×109/L vs >40×109/L(P=0.037). Estimated 10 year cumulative incidence of relapse (CIR), disease-free survival and overall survival (OS) was 6.32% (95% CI: 3.03%-9.61%), 93.0% (95% CI: 88.7%-95.7%) and 92.0% (95% CI: 88.3%-94.6%). WBC count was only independent predictor for OS (HR 5.34, 95% CI, 2.36-12 for >10×109/L vs ≤10×109/L, P<0.0001) in multivariate analysis.ConclusionsIn this large cohort of APL patients under a ‘real world’ setting, a relative low ED and high OS could be achieved and high WBC count emerged as an independent predictor of ED and OS in arsenic era. DisclosuresNo relevant conflicts of interest to declare.

Flow Cytometric Minimal Residual Disease As Risk Stratification Tool in Younger Adults with NPM1 Wild Type Standard Risk Acute Myeloid Leukemia

Response to induction therapy is a powerful prognostic indicator in acute myeloid leukemia (AML). Measurable/minimal residual disease (MRD) assays are being increasingly incorporated into response assessment; however, their value as a surrogate for long-term outcome remains unclear because of assay limitations and the effect of post remission therapies. This is particularly the case for the molecularly heterogeneous NPM1 wild type standard risk patients for whom treatment decisions, including predicting the benefit of allogeneic stem cell transplantation (SCT), are particularly challenging. We investigated the effect on outcome of MRD status compared to other response criteria after each cycle of induction for NPM1 wild type (wt) standard risk patients and other risk groups in a cohort of younger AML patients.Patients and MethodsAs part of the UK NCRI AML17 trial (ISRCTN55675535) for patients with AML or high risk MDS up to the age of 60, prospective flow cytometric MRD (MFC-MRD) monitoring was performed after each course of induction. Any level of MRD detected was considered MRD+ (sensitivity thresholds: ~0.02% by tracking diagnostic leukemic aberrant phenotypes/LAIP, ~0.05-0.1% by “different-from normal” blast LAIP). Clinicians were not informed of MFC-MRD results. Following cycle 1 of induction with daunorubicin/ara-C based therapy, patients were allocated a risk group by a validated score (comprising cytogenetics, WBC, age, secondary disease, blast response to cycle 1 and mutation status). Standard risk patients including ITD wt/ NPM1 wt received a second daunorubicin/ara-C induction with some proceeding to SCT after 1 or 2 consolidation cycles (high dose ara-C).Results2450 non APML patients, median age 51, randomised 4/09 to 12/14, contributed data. For the total cohort, 5 year overall survival (OS) excluding early deaths was 52% for those achieving CR/CRi vs 31% for those not in CR (p<.001).Post cycle 1 (C1) responses were categorised as resistant disease (RD), partial remission (PR) and CR/CRi by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. RD vs PR vs MRD+ vs MRD- frequencies were 15% vs 14% vs 40% vs 31% for all patients with response data (n=1443), 5% vs 7% vs 45% vs 43% for good / standard risk (n=785), 10% vs 8% vs 47% vs 35% NPM1 wt standard risk (n=320).Post C1 response was prognostic for survival: OS for RD vs PR vs MRD+ vs MRD- were 25% vs 36% vs 43% vs 63% all patients; 33% vs 49% vs 51% vs 70% good/standard risk and 28% vs 38% vs 47% vs 59% NPM1 wt standard risk. (p<.0001 throughout). For NPM1 wt standard risk as well as good/standard risk patients adjusted analyses confirmed significant OS differences between C1 RD vs PR or MRD+ but not PR vs MRD+. Results were similar when censored at SCT.Post C1 best response was CRi for 39/446 MRD- vs 49/575 MRD+ overall (11/111 vs 8/149 for NPM1 wt standard risk). C1 CRi was associated with reduced OS overall (39% vs 53% CR, p=.002) and in MRD+ (19% vs 45% CR, p=.001) but not for MRD- patients. OS for NPM1 wt standard risk MRD+ was 25% CRi vs 43% CR (p=0.4). No significant difference was detected for 5 year cumulative incidence of relapse (CIR).The effect on outcomes of MRD status post cycle 2 (C2) for the 806 patients in CR/CRi with MFC-MRD data appeared greater (relapse HR 1.88(1.50- 2.36), p<0.001; OS HR 1.77(1.41-2.22) p<0.001)than C1 (relapse HR 1.70(1.40- 2.06), p<0.001; OS HR 1.50(1.23-1.84) p<0.001). MRD+ levels of ≥0.1% predicted highest CIR in NPM1 wt standard risk patients at C1 (CIR 71%) and C2 (CIR 89%) but any MRD+ at C2 reduced OS (32% vs 63% MRD-, p=0.003) and OS censored at any SCT (35% vs 88%). The effect of CR vs CRi was smaller post C2 although outcomes were still worst in CRi/MRD+ve patients.Of 204 NPM1 wt standard risk patients with C2 MRD data 83 had an allograft (44 in CR1: 29 MRD-, 15 MRD+). In Mantel-Byar analyses, although numbers were small, there was a suggestion that transplant could be considered in MRD +ve (HR 0.72 (0.31-1.69)) but not MRD -ve patients (HR 1.68 (0.75-3.85); p-value for interaction p=0.16).ConclusionMRD status by MFC refines response criteria at induction time-points to differentiate NPM1 wild type standard risk patients with poor outcome and helps define a group of patients who may benefit from SCT in CR1. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylactic Modified Donor Lymphocyte Infusion after Allogeneic Peripheral Blood Stem Cell Transplantation for Very High-Risk Hematological Malignancies: Low Incidence of Relapse without Increasing the Risk of Graft-Versus-Host Disease

Introduction The prognosis of patients with very high-risk hematologic malignancies who have relapsed/refractory diseases or carrying very poor-risk gene mutations were dismal even after allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion (DLI) is a promising prophylactic strategy for reducing relapse after transplant. However, DLI-associated graft-versus-host disease (GVHD) and non-relapse mortality (NRM) were still concerned, especially after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Therefore, prophylactic DLI should be safe with tolerable DLI-associated GVHD and NRM except for its anti-leukemia effect. To evaluate the safety and efficacy of prophylactic DLI for the very high-risk hematologic malignancies after allo-PBSCT, we performed a cohort study in 160 consecutive patients with hematological malignancies who received unmanipulated allo-PBSCT. DLI procedure was modified to use G-CSF mobilized peripheral progenitors instead of steady state lymphocytes and 4 to 6 weeks of immunosuppressant for prevention of DLI-associated GVHD. The outcomes of those very high-risk patients (group A: DLI group; group B: non-DLI group) and the patients without the very high-risk features (group C) who were not planned for prophylactic DLI were compared.Patients and Methods The underlying diseases consist of acute myeloid leukemia (n = 78), myelodysplastic syndrome (n = 22), acute lymphoblastic leukemia/lymphoma (n = 45), chronic myeloid leukemia (n = 7), non-Hodgkin's lymphoma (n = 7), and plasma cell leukemia (n = 1). Sixty five patients (41.2%) received allo-PBSCT from HLA-matched sibling donors, 7 patients (4.4%) from matched unrelated donors, and 87 patients (54.4%) from haploidentical donors (Table 1). The very high-risk features were defined as 1) disease in non-remission state at time of transplant; 2) acute leukemia achieving complete remission (CR1) with 3 or more cycles of induction chemotherapy; 3) leukemia in CR1/CR2 carrying TP53, TET2 or DNMT3A gene mutation. Patients in CR with FLT3/ITD or BCR/ABL T315I gene mutation were enrolled due to the unavailability of effective targeted drugs. Prophylactic modified DLI was planned at 30 to 60 days post-transplant for all very high-risk patients with the absence of GVHD. The infusion was G-CSF mobilized peripheral progenitors from cryopreserved cell aliquots of the original graft. The trough concentration of CSA was maintained at 180 to 250 ng/mL for at least 4 to 6 weeks post-DLI and then discontinued within 2 weeks when no GVHD occurred. All the patients were followed-up for a median of 11.1 (0.5 - 29.7) months after transplant.Results Prophylactic DLI was administered for 29 very high-risk patients (group A) at a median of 63 (25 - 176) days after transplant. The median numbers of mononuclear cells and CD3+ lymphocytes infused were 0.7 (0.1 - 1.4) × 108/kg and 18.5 (5.4 - 69.2) × 106/kg with a single dose. Nineteen patients (39.6%) with very high-risk features did not receive prophylactic DLI (group B) for the reasons of early relapse (n = 8), occurrence of GVHD (n = 8), and uncontrolled infections (n = 3). The cumulative incidence (CI) of grade II-IV acute GVHD at day 100 after transplant was 33.2% in group A, 38.0% in group B (p= 0.318), and 28.2% in group C (p= 0.746). The 2-year CI of chronic GVHD was 29.9% in group A, 15.8% in group B (p= 0.428), and 54.6% in group C (p= 0.255). The 2-year CI of relapse was 54.6% in group A, which was significantly lower than that in group B (68.4%, p= 0.019). The relapse-free survival in group A was superior to that in group B (37.3% vs . 24.6%, p = 0.032). In the very high-risk group of patients (group A and B), prophylactic DLI was correlated with a lower risk of relapse (p= 0.043, hazard ratio = 0.45). The 2-year CI of NRM in group A was not significantly different from that in group B (22.4% vs . 15.8%, p= 0.461) or group C (22.4% vs . 23.2%, p= 0.949). In addition, there was no significant difference in overall survival between group A and group B (48.6% vs . 35.1%, p = 0.134). The 6-month CI of CMV/EBV reactivations in group A was not significantly different from that in group B (p= 0.107 and p= 0.668) or group C (p= 0.130 and p= 0.596).Conclusions This study showed that the prophylactic DLI after unmanipulated allo-PBSCT was well tolerated and effective for the patients with very high-risk hematologic malignancies in decreasing relapse without increasing the risks of GVHD and NRM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia with Monosomy 7 or Deletion 7q: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

▪ INTRODUCTIONMonosomy 7 or deletion 7q (-7/7q-) is the most frequent high-risk cytogenetic feature reported in acute myeloid leukemia (AML) and is associated with a dismal outcome after chemotherapy alone. Allogeneic stem cell transplantation (SCT) appears to be the best consolidation strategy in these patients (pts), thereby significantly improving outcomes. Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion/translocation of chromosome 3q26 (inv(3)). The presence of such abnormalities may further influence the outcomes of SCT in pts with -7/7q-. The purpose of this study was to evaluate the role of SCT in AML with -7/7q- in the context of additional cytogenetic abnormalities. METHODSWe selected adult pts with AML and -7/7q- reported to the EBMT registry with a complete cytogenetic report. We included only first SCT from a sibling or unrelated donor (UD) performed between 2000 and 2016. RESULTSA total of 1109 pts were identified. Median age at SCT was 52 year-old (range, 18-76) and median follow-up was 34 months (range, 0.7-193). A diagnosis of secondary AML was reported in 213 pts (19%). At the time of SCT, 702 patients (63%) were in first remission (CR1), 58 (5%) in subsequent remission and 349 (32%) had active disease. Four hundred ninety-six pts received SCT from a sibling donor (45%). Most pts had a Karnofsky's performance status (KPS) of more than 80% at the time of SCT (93%). A myeloablative conditioning regimen was administered in 50% of the pts. In vivo T-cell depletion was part of the regimen in 56% of the pts.The 2-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. The 2-year probability of non-relapse mortality (NRM) was 20% and the 2-year cumulative incidence of relapse (RI) was 50%. The cumulative incidence of acute graft-versus-host disease (GvHD) was 31% and the 2-year cumulative incidence of chronic GvHD was 31%. The 2-year probability of GvHD and relapse-free survival (GRFS) was 21%. In multivariate analysis, age was not associated with any outcomes. Active disease was significantly associated with increased NRM and RI, which translated into worse LFS, OS and GRFS. Significant higher NRM was associated with UD. Secondary AML was associated with higher NRM and decreased OS. Better KPS correlated significantly with less NRM and better LFS, OS and GRFS.To evaluate the impact of additional cytogenetic abnormalities, we have been able to sort out 5 different groups within the entire cohort. The first group included 523 pts with -7/7q- with or without CK, but without any of the following chromosomal abnormalities: MK, -5/5q-, abn(17p) or inv(3). One hundred ninety-nine pts belonged to the second group that included pts with -7/7q- within MK but without -5/5q-, abn(17p) or inv(3). The third group included 151 pts with -7/7q- in association with -5/5q- but no abn(17p) or inv(3). Group 4 included 125 pts with -7/7q- and abn(17p) but without inv(3). Finally, 111 pts had inv(3) in addition to 7/7q- and were assigned to the fifth group. NRM was similar across all groups. The 2-year probability of LFS was 39.7% for group 1, 28.5% for group 2, 22.5% for group 3, 16.4% for group 4 and 13.7% for group 5 (p<0.001) (see figure). The 2-year probabilities of OS in the 5 groups were 47.7%, 34.9%, 28.2%, 15.9% and 19.7%, respectively (p<0.001). The corresponding 2-year probability of GRFS was 29.7% for group 1, 16.6% for group 2, 14.5% for group 3, 8.1% for group 4 and 8.9% for group 5 (p<0.001). Multivariate analysis confirmed those significant differences across groups. We observed comparable results when the analysis was focused on CR1 pts. CONCLUSIONSSCT in AML pts with -7/7q- provides durable response in one third of the pts. Disease status at the time of transplantation remains the strongest prognostic factor for poor outcomes. The presence of -7/7q- with or without CK in the absence of MK, -5/5q-, abn(17p) or inv(3) was associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of pts that benefits less from SCT. In these pts, future efforts should focus on prevention of relapse by therapeutic modalities like early withdrawal of immunosuppression, administration of hypomethylating agents, donor lymphocytes infusion or others. [Display omitted] DisclosuresSocié:Alexion Pharmaceuticals, Inc.: Consultancy. Mohty:Sanofi: Honoraria, Speakers Bureau.

Systemic ALK-Positive Anaplastic Large-Cell Lymphoma (ALCL): Final Analysis of an International, Individual Patient Data Study of 263 Adults

Abstract Introduction: ALK-positive ALCL comprises 0.5% of adult lymphomas. Because of disease rarity, prospective trials specifically dedicated to adult ALK-positive ALCL are lacking. In published adult studies, mainly retrospective, ALK-positive ALCLs were most often pooled with ALK-negative ALCLs and/or other PTCLs, which are distinct entities, preventing a correct assessment of specific prognostic factors and impact of different treatments for ALK-positive ALCL. A retrospective study from the DSHNHL and a population-based study from the Nordic lymphoma registries have suggested a possible benefit of etoposide use, but definitive conclusions are lacking and the role of etoposide is still a matter of debate. Moreover, the respective impact of upfront HDT-ASCT or consolidative radiotherapy (RT) is unknown. A pooled analysis of individual patient data (IPD) would provide greater statistical power to identify prognostic factors and treatment effects. Therefore, we conducted a pooled analysis of IPD from studies of first-line therapy in adult ALK-positive ALCL. Methods: Eligibility criteria were as follows: study including patients (pts) with a diagnosis of systemic ALK-positive ALCL after initial centralized pathologic review, age ≥ 18 years, HIV-negative serology, first-line treatment including at least one cycle of systemic chemotherapy, sufficient sample size (at least 10 cases of ALK-positive ALCL) and publication between 2000 and 2015. A minimum dataset was required, comprising characteristics at diagnosis (individual IPI and PIT factors), and first-line chemotherapy regimen. We assessed PFS, OS, EFS24, cumulative incidence (CI) of relapse, and the associations between patient characteristics or treatment type (etoposide, upfront HDT-ASCT and consolidative RT) and PFS or OS. These associations were analyzed by Cox survival models stratified by cohort and assessed by Log-Likelihood Ratio (LLR) tests with predictive C-index measurement. Results: IPD of 263 pts diagnosed between 1985 and 2008 were collected and pooled from six published studies: 2 from the LYSA, 1 from the DSHNHL, 1 from Japan, 1 from the IPTCLP and 1 from the Mayo Clinic. Median follow-up was 4.9 years. Median age was 34 years (18-76). Overall, 261 (99%) pts received an anthracycline-based regimen and 92 (35%) received an etoposide-based induction. Thirty-four (13%) pts underwent planned upfront HDT-ASCT, and 54 (21%) received consolidative RT. The respective CR/CRu, PR and SD/PD rates to first-line therapy were 85%, 5% and 10%. The 5-year PFS and OS rates were 69% (95% CI, 64% to 75%) and 81% (95% CI, 76% to 86%), respectively. The respective 1-, 2- and 5-year CI of relapse were 22%, 25% and 30%. For the 82 pts with a first relapse, the respective 1-, 2- and 5-year OS rates from this event were 38%, 35% and 28%, with a median OS of only 3.2 months. Pts achieving EFS24 had a 5-year OS from this time point of 95% (Fig 1). The IPI identified different risk groups; 5-year PFS was 80% for IPI 0 to 1, 63% for IPI 2, 54% for IPI 3, and 40% for IPI 4 to 5 (p Pts who received an etoposide-based induction chemotherapy had significantly improved 5-year PFS (83% vs 62%, p=0.001) and OS (93% vs 74%, p=0.001, Fig 3), independent of IPI, age and cohort. Etoposide did not increase significantly the response rate at the end of treatment, but significantly decreased the 5-y CI of relapse (17% vs 37%, p=0.001). Finally, CHOEP (n=38), compared to CHOP (n=98), significantly improved 5-year PFS (89% vs 57%, p=0.017) and OS (97% vs 69%, p=0.049, Fig 4). In stratified Cox models, there was no independent impact of upfront HDT-ASCT or consolidative RT on PFS or OS. Conclusion: To our knowledge, this is the largest analysis of patients with ALK-positive ALCL. IPI, CD3 positivity and anemia are strong independent predictors of outcome. Etoposide use in induction is associated with important improvement of PFS and OS independent of IPI and age, whereas upfront HDT-ASCT and consolidative RT have no independent impact. Download : Download high-res image (99KB) Download : Download full-size image Disclosures Suzuki: Novartis: Honoraria; MSD: Honoraria; Kyowa-Hakko Kirin: Honoraria; Celgene: Honoraria; Takeda Pharmaceuticals: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical: Honoraria; MundiPharma: Consultancy; Shionogi: Honoraria; Jazz Pharmaceuticals: Consultancy; Mochida Pharmaceutical: Honoraria; Meiji Seika Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Ohtsuka: Honoraria; Sawai Pharmaceutical: Honoraria; Gilead Sciences: Consultancy. Tilly: Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Honoraria; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria. Savage: Roche: Research Funding.

The Effect of Sorafenib Therapy on the Outcome of Acute Myeloid Leukemia with FLT3-ITD Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutation has been reported in about 25% patients with acute myeloid leukemia (AML). AML with FLT3-ITD mutations have an inferior survival, primarily due to shorter remission durations and higher relapse rates. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves the survival for FLT3-ITD AML, the rate of leukemia relapse remains high. Sorafenib, a multi-kinase inhibitor, has shown promising activity in AML with FLT3-ITD. A growing body of studies have suggested that sorafenib monotherapy or in combination with chemotherapy are effective in attaining complete remission (CR) for untreated and refractory relapsed FLT3-ITD AML. Sorafenib maintenance after allo-HSCT has been proved to be safe for FLT3-ITD AML, but whether it could improve survival remains uncertain. The aim of this study is to evaluate the effect of sorafenib therapy on the outcome of FLT3-ITD AML undergoing allo-HSCT.Methods A total of 118 AML with FLT3-ITD undergoing allo-HSCT were enrolled in this retrospective study between January 2012 and December 2015 at Nanfang Hospital, Peking University People's Hospital and Zhujiang Hospital. Patients with HLA-matched sibling or unrelated donors received BuCY conditioning (busulfan 3.2 mg/kg/day, on days -7 to -4; cyclophosphamide 60 mg/kg/day, on days -3, -2), and patients with HLA-haploidentical related donors received modified BuCY conditioning (cytarabine4g/m2/day, on days -10, -9; busulfan 3.2 mg/kg/day, on days -8 to -6; cyclophosphamide 1.8g/m2/day, on days -5, -4). Sorafenib therapy pre-HSCT was initiated at the time of induction, post-remission maintenance or relapse, and continued until one week prior to the start of the conditioning regimen. Sorafenib maintenance post-HSCT was started from day 30 to 180 post-transplantation. Either before or after transplantation, the initial dose of sorafenib was 400 mg twice daily and was adjusted on the basis of suspected toxicity or emerging drug resistance (dose range, 200-800 mg daily).Results Of the 118 patients, 90 were in CR, 8 in partial remission and 20 in non-remission at the time of transplantation. The 118 patients all achieved hematopoietic reconstitution and achieved CR by day +30 post-transplantation. Depending on whether patients received sorafenib pre-HSCT and sorafenib maintenance post-HSCT, the 118 patients were divided into 4 groups. Thirty-two patients only received sorafenib pre-HSCT (Group A), 29 only maintenance post-HSCT (Group B), 23 both pre-HSCT and maintenance post-HSCT (Group C), and 34 did not receive sorafenib pre-HSCT or maintenance post-HSCT (Group D). There were no significant differences in disease status pre-transplantation, donor source or HLA typing among four groups. Thirty-three patients relapsed at a median time of 137 (range, 44 to 589) days post-transplantation. Six abandoned treatment and 27 received salvage therapy of sorafenib combined with chemotherapy and DLI. Thirteen of the 27 patients achieved CR after salvage treatment. The 5-year cumulative incidence of relapse were 20.6%±9.4%, 20.7%±3.4%, 17.4%±4.3% and 50.2%±18.6% in Group A, B, C and D (P=0.006). With a median follow up of 670 (range, 63-1898) days post-transplantation, 85 patients survived and 33 died. The 5-year overall survival (OS) and disease-free survival (DFS) were 75.0%±8.8% and 70.0%±8.6%, 75.9%±8.0% and 75.9%±8.0%, 82.6%±7.9% and 78.3%±8.6%, 51.6%±9.6% and 31.2%±8.9% in Group A, B, C and D (P=0.093, P <0.001). Multivariate analysis revealed that sorafenib therapy pre-HSCT and sorafenib maintenance post-HSCT were the protective factors for lower relapse and longer OS; the nCR (not in CR) status pre-HSCT was the only risk factor for longer OS.Conclusions Sorafenib therapy pre-HSCT and sorafenib maintenance post-HSCT could reduce relapse and improve survival for AML with FLT3-ITD. DisclosuresNo relevant conflicts of interest to declare.

Genetic Ontogeny Defines Distinct Prognostic Subgroups in AML Patients Age 60 and Older Following Hematopoietic Stem Cell Transplantation

▪BackgroundThe prognosis for older adults diagnosed with acute myeloid leukemia (AML) is poor. The response to conventional chemotherapy in these patients is frequently brief, and long-term survival is largely limited to those who undergo allogeneic hematopoietic stem cell transplantation (HSCT). However, mortality after transplantation HSCT is also high, with deaths attributable both to relapsed AML and to transplant-related complications. There is thus a critical need for strategies that can reliably discern older AML patients who are most likely to benefit from current transplantation approaches and those for whom novel approaches should be developed.We have previously shown that genetic characteristics can divide AML patients into three clinically distinct categories: (1) TP53 -mutated AML; (2) “secondary-type” AML, defined by mutations in any of eight genes with high specificity for the presence of antecedent myelodysplastic syndrome; and (3) “de novo” type AML, defined by absence of TP53 and secondary-type mutations. We showed that older patients with de novo-type AML have improved response to standard induction chemotherapy and significantly superior event-free survival than those with either secondary-type or TP53- mutated AML. Since disease burden prior to HSCT has been linked to post-HSCT outcomes, we hypothesized that diagnostic ontogeny classification would be associated with relapse and survival among older AML patients receiving HSCT in first complete remission.MethodsWe identified AML patients age 60 or older who underwent HSCT at Dana-Farber Cancer Institute (DFCI; Boston, MA) in first complete remission between 2012-2016, for whom next-generation sequencing of the diagnostic AML sample was available. Based on targeted gene panel sequencing of recurrent myeloid driver alterations, we classified AML as TP53 -mutated, secondary-type (SRSF2, SF3B1, U2AF1, ZRSR2, BCOR, ASXL1, EZH2, or STAG2 mutations), or de novo type (neither TP53 mutation nor secondary-type mutations). We extracted data on clinical outcomes from the medical record and assessed the impact of diagnostic AML genetics on overall survival and cumulative incidence of relapse following HSCT.ResultsFifty-five patients met inclusion criteria, with a median age of 67 (range 60-76). All had received intensive induction chemotherapy; nine (16.4%) received myeloablative conditioning regimens, while the remainder received reduced intensity regimens. Of the 55 patients, 13% (n=7) had TP53 mutations, 40% (n=22) had secondary-type mutations, and 47% (n=26) had de-novo type mutations. Patients with de-novo type mutations had significantly superior 2-year overall survival than those with secondary-type mutations, who in turn had significantly superior survival than those with TP53 mutations (82.2% versus 48.1% versus 14%, p<0.001 for all comparisons, Figure 1A). These differences reflected a significant difference in the 2-year cumulative incidence of relapse following HSCT (100% for TP53 versus 56.7% for secondary-type versus 33.4% for de-novo type mutations, p<0.001 for all comparisons, Figure 1B).ConclusionIn our cohort of older AML patients who underwent HSCT in first complete remission after intensive induction chemotherapy, genetic ontogeny classification at the time of diagnosis was significantly associated with overall survival and rate of relapse after HSCT. Our findings, which merit further evaluation in a larger cohort, suggest that genetic classification of ontogeny can form the basis of a robust prognostic model that accurately predicts post-HSCT outcomes in older AML patients. [Display omitted] DisclosuresKoreth:Amgen Inc.: Consultancy; Millennium Pharmaceuticals: Research Funding; Prometheus Labs: Research Funding; Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Nikiforow:Kite Therapeutics: Membership on an entity's Board of Directors or advisory committees. Armand:Sigma Tau: Research Funding; Sequenta/Adaptive: Research Funding; Affimed: Research Funding; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Genmab: Consultancy; Roche: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Tensha: Research Funding; Otsuka: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lindsley:MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy.