Probability Of Leukemia-free Survival Research Articles

Score to Guide Donor Choice in Haploidentical Stem Cell Transplant Using Post-Transplant Cyclophosphamide for Patients with Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the EBMT

Introduction: There is paucity of information to guide selection of the most appropriate stem cell donor for haploidentical (Haplo) hematopoietic stem cell transplant (HSCT). Patients and Methods: We retrospectively analyzed the characteristics of haploidentical family donors that may affect transplant outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease (GVHD) prophylaxis with postransplant cyclophosphamide (PTCy) registered in the EBMT database. The primary endpoint was GVHD and relapse-free survival (GRFS). Results: Overall, 2200 patients were included with a median age of 56 years (range, 18-75); 1742 (79%) were in complete remission and 1246 (56.6) received reduced intensity conditioning. Regarding donors, the median age was 37 years (range, 8-71), 820 (37%) were females of which 458 (21%) were used for male recipients, 1252 (57%) had positive CMV serostatus, 1631 (74%) donated peripheral blood (PB) and 1638 (75%) had ≥ 4/8 HLA mismatch with the recipient. 100-day acute GVHD grade II-IV and III-IV and 2-year chronic and chronic extensive GVHD were 28% (95% CI 26-30), 11% (95% CI 10-12), 33% (95% CI 31-35) and 14% (95% CI 12-15), respectively. After median follow-up of 24 months, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS), overall survival (OS) and GRFS were 26% (95% CI 24-28), 22% (95% CI 20-24), 52% (95% CI 50-55), 57% (95% CI 55-60) and 41% (95% CI 39-43), respectively. In multivariable analysis, donor-related risk factors with a negative impact on GRFS were older age (HR 1.1; 95% CI 1.04-1.15), use of PB (HR 1.19; 95% CI 1.04-1.37), and female donors to male recipients (HR 1.25; 95% CI 1.09-1.43). We further developed a score that distinguished 4 groups with 0 (241), 1 (913), 2 (863) or 3 (183) donor-related risk factors. GRFS was 57% (95% CI 50-63), 43% (95% CI 39-46), 37% (95% CI 33-40), and 30% (95% CI 23-38), respectively (P < 0.001) (Figure 1). The score was also able to stratify risk groups for acute and chronic GVHD, NRM, LFS and OS. Conclusion: Donor variables have an important impact on AML patient's outcome after Haplo-HSCT using PTCy. With three simple donor characteristics, age, gender and stem cell source, we were able to generate a score that may help to select the most appropriate donor in clinical practice.

Etoposide plus cytarabine versus cyclophosphamide or melphalan in busulfan-based preparative regimens for autologous stem cell transplantation in adults with acute myeloid leukemia in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.

We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.

More than two courses of pre-transplant consolidation therapy benefits patients with acute myeloid leukemia in the first complete remission who underwent human leukocyte antigen-matched sibling allografts: a multicenter study.

Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial. We retrospectively compared the effect of the number of pre-transplant consolidation chemotherapies on outcomes of human leukocyte antigen-matched sibling stem cell transplantation (MSDT) for patients with AML in CR1 in multicenters across China. In our study, we analyzed data of 373 AML patients in CR1 from three centers across China. With a median follow-up of 969 days, patients with ≥ 3 courses of consolidation chemotherapy had higher probabilities of leukemia-free survival (LFS) (85.6% vs . 67.0%, P < 0.001) and overall survival (89.2% vs . 78.5%, P = 0.007), and better cumulative incidences of relapse (10.5% vs . 19.6%, P = 0.020) and non-relapse mortality (4.2% vs . 14.9%, P = 0.001) than those with ≤ 2 courses of consolidation chemotherapy. Pre-transplantation minimal residual disease-negative patients with AML in CR1 who received MSDT with ≥ 3 courses of consolidation chemotherapy had a higher probability of LFS (85.9% vs . 67.7%, P = 0.003) and a lower cumulative incidence of relapse (9.6% vs . 23.3%, P = 0.013) than those with ≤ 2 courses. Our results indicate that patients with AML in CR1 who received MSDT might benefit from pre-transplant consolidation chemotherapy.

Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.

Total body irradiation plus fludarabine versus busulfan plus fludarabine as a myeloablative conditioning for adults with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation. A study on behalf of the Acute Leukemia Working Party of the EBMT.

Cyclophosphamide is frequently substituted with fludarabine (Flu) in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to compare retrospectively, total body irradiation (12 Gy) plus Flu (FluTBI12) versus busulfan (Bu) plus Flu (FB4) as a myeloablative conditioning before allo-HCT in patients with acute myeloid leukemia (AML). Out of 3203 patients who met the inclusion criteria, 109 patients treated with FluTBI12 and 213 treated with FB4 were included in a final matched-pair analysis. In both groups, median patient age was 41 years, first or second complete remission (CR1/CR2) proportion was 78%/22%, allo-HCT from an unrelated donor was performed in 78% of patients. The probabilities of leukemia-free survival and overall survival at 2 years in FluTBI12 and FB4 groups were 65% vs. 60% (p = 0.64) and 70% vs. 72% (p = 0.87), respectively. The cumulative incidence of relapse was 19% vs. 29% (p = 0.11), while non-relapse mortality was 16% vs. 11%, respectively (p = 0.13). There were no statistical differences in both acute and chronic graft-versus-host disease (GVHD) incidence. The probability of GVHD-free, relapse-free survival (GRFS) was 49% for both groups. FluTBI12 and FB4 are comparable myeloablative regimens before allo-HCT in AML patients transplanted in CR1 and CR2.

Multicenter Pilot Clinical Trial of Enasidenib As Maintenance Therapy after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia (AML) Carrying IDH2 Mutations

Somatic mutations in isocitrate dehydrogenase (IDH) genes are seen in ~20% of adult patients with acute AML, with hotspot mutations in IDH2 (R172, R140) being more common (15%) compared to IDH1 (R132; 5-7%). We previously reported a higher 1-year relapse rate after allogeneic hematopoietic cell transplantation (alloHCT) in AML patients harboring IDH mutations compared to those without IDH mutations. (Salhotra el, Clin Lymphoma Myeloma Leuk. 2019). Similar results were observed by Chen et al in a larger multicenter retrospective study. Enasidenib is a selective inhibitor of mutant IDH2 (mIDH2) enzymes, which has shown single agent activity in patients with relapsed/refractory AML with overall response rate of 40% and a median response duration of 5.8 months. We hypothesized that Enasidenib as post-HCT maintenance therapy is safe, well-tolerated and can improve survival outcomes in AML patients carrying mIDH2. Here, we are reporting results of our multicenter [City of Hope (COH) and Moffitt Cancer Center (MCC)] pilot trial of Enasidenib as maintenance after alloHCT in IDH2 mutated AML patients (NCT03728335). Recipients of alloHCT who had AML (n=15) with IDH2 mutations at the time of diagnosis were prospectively enrolled in this trial. Patients were eligible for maintenance therapy irrespective of conditioning regimen, if in complete remission (CR) at day +30 post-HCT, had ECOG PS ≤2 and adequate marrow function defined as ANC ≥1000/µL; Hemoglobin ≥10gm/dL and platelets ≥ 50,000/µL. Patients with grade ≥2 acute graft-versus-host disease (GVHD) were excluded. Enasidenib was given at the FDA approved dose of 100 mg/day between days 50 and 120 post-HCT for 2 years in 28 days cycles. The primary objective was to evaluate safety and tolerability of enasidenib as post-HCT maintenance therapy. Toxicities were scored by the NCI-CTCAE v5.0. Secondary objectives were to assess overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), relapse, and 1-year chronic GVHD-free and relapse-free survival (CRFS). Sample size of 15 was determined based on modified rule of continuous monitoring for toxicity using Pocock-boundary with desired probability of early stopping of 0.75 if the unacceptable toxicity rate was ≥33%. From August 2020 to July 2021, we enrolled 15 patients (8 at COH and 7 at MCC) who were eligible after day +30 bone marrow biopsy documented remission. The median age was 58 years (range: 24-77); Male: Female ratio was 40:60% and 67% of patients were Caucasian. Pre-transplant remission status was CR1 in 73% (n=7), CR2 in 20% (n=3) and measurable residual disease positive in 6% (n=1). Cytogenetic risk classification was intermediate in 60% (n=9), adverse in 26% (n=4), and favorable risk in 13% (n=2) of patients. Median time to start maintenance post HCT was 104 days (range: 54-119). Donors were 8/8 HLA matched unrelated (53%; n=8), HLA identical related (20%; n=3), or haploidentical (26%; n=4). Most patients (80%; n=12) received reduced intensity conditioning, and mobilized peripheral blood was the graft source used in all study patients. GVHD prophylaxis consisted of post-transplant cyclophosphamide-based (60%; n=9) or tacrolimus-based (40%; n=6) regimens (Tac/Siro= 4 and Tac/MTX= 2). At the data cutoff of June 2022, enrolled patients completed a median of 17 cycles (range: 1-24) of enasidenib maintenance. We collected all grades of adverse effects (AEs) during the first 2 cycles, and grade ≥3 AEs for subsequent cycles. In the first 2 cycles, grade ≥3 AEs were mainly due to hematologic toxicity including: lymphopenia (26%; n=4), anemia (20%; n=3), neutropenia (13%; n=2), and thrombocytopenia (6%; n=1). Non-hematologic AEs were grade 1-2 nausea (60%; n=9), and vomiting/diarrhea (26%; n=4). Table 1 shows the summary of treatment cycles. At median follow up of 17.1 months (range: 7.0-25.9) the 1 and 2-year OS and LFS probabilities were 100%. The cumulative incidence of moderate to severe chronic GVHD at 1-year was 20% and 1-year CRFS was 80% (Figure 1). In conclusion, post-HCT enasidenib maintenance therapy was safe and well-tolerated, resulting in favorable survival outcomes in AML patients carrying IDH2 mutations. While treatment delays and dose reductions were common, the majority of the study patients remained on the protocol therapy. Droplet digital PCR testing on bone marrow was done to study clearance of IDH2 clones post-HCT and these results will be available by December 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Persistence of Mutations in Complete Remission Including DNMT3A, TET2 and ASXL1 Mutations Is Associated with Worse Prognosis in Patients with Acute Myeloid Leukemia Treated in ALFA 0702 Study

Background: Only few studies have validated the use of molecular minimal measurable residual disease evaluation using error-corrected NGS (NGS-MRD). The prognostic relevance of detection of isolated DNMT3A, TET2 or ASXL1 (DTA) mutations post-induction remains controversial. Benchmarking of NGS-MRD with respect to other molecular MRD tools (such as WT1 expression and NPM1 mutation) has yet to be conducted. Material and methods: All patients included in the ALFA-0702 study who reached cytological complete remission (CR) or CR with incomplete platelets recovery after one induction course and with available material were included (n=189). Standard NGS sequencing of 67 genes was performed at diagnosis. Error-corrected NGS was performed on post-induction bone marrow samples using a custom panel including all mutations identified at diagnosis (n=735 mutations in 51 genes). Median sequencing depth in CR was 24695x after UMI deduplication. A threshold of 0.1% VAF was set as cut-off value for NGS-MRD detection for all targets. WT1 expression data in CR were available in 100 patients with initial WT1 over-expression. NPM1-MRD was evaluated in 67 patients by error-corrected NGS. For this evaluation, one alternative read was considered sufficient to define positivity. Leukemia free survival (LFS) and overall survival (OS) probabilities were evaluated since CR. Results: Median age at diagnosis was 46 years. ELN2017 risk was favorable in 52 (27%) patients, intermediate in 75 (40%) and unfavorable in 60 (32%). With a median follow-up from CR of 47 months, median LFS and OS was 35 and 41 months respectively. At diagnosis, gene mutations were detected in 181 (95%) patients. The median number of mutations per patient was 4 (range 1-10). Ninety-one patients had no target detected (NGS-MRD neg) and ninety had at least one target detected (NGS-MRD pos) including 42 patients with detection of DTA mutations only (DTA-MRD). NGS-MRD pos patients were significantly older (p=0.0018) than NGS-MRD neg patients and harbored a higher median number of mutations at diagnosis (4 vs 3, p=0.0021). There were no significant differences in terms of demographics and clinical presentation (age, WBC, number of mutation) between patients with DTA-MRD and non-DTA-MRD patients. In univariable analyses, NGS-MRD pos was associated with a lower probability of LFS (4-years LFS: 44% vs 68%, p= 6e-04) and OS (4-years OS: 57% vs 81%, p= 9e-04). There was no impact of the initial number of mutations on LFS nor OS. There were no significant differences in LFS and OS between DTA-MRD and non-DTA-MRD patients (figure 1). When adjusting analysis on ELN2017 status, MRD-NGS pos remained associated with shorter LFS (HR 2.15[1.34-3.44] , p=0.001) and OS (HR 2.41[1.38-4.20] p=0.002). As a continuous variable, the number of mutations detected in CR was associated with shorter LFS and OS. Specifically, detection of ≥2 mutations predicted poorer LFS (HR, p=3e-05) and OS (HR, p=4 e-05), compared with detection of only 1 mutation (figure 2). Sixteen patients were positive for WT1 MRD evaluation, and 84 were negative (WT1 neg). Among the WT1 neg patients 37 were NGS-MRD pos and 47 were NGS-MRD neg. When adjusting for both ELN17 and WT1 expression in CR, there was no significant impact of MRD-NGS positivity on LFS (HR=1.62 [0.85 - 3.09]) nor OS (HR=1.28 [0.59 - 2.74]) In the 67 patients with NPM1 mutation, 41 patients had NPM1 undetectable MRD (including 21 NGS-MRD pos and 20 NGS-MRD neg) and 26 had detectable NPM1-MRD (including 16 NGS-MRD pos and 10 NGS-MRD neg). When adjusting for both ELN status and NPM1-MRD, NGS-MRD pos was associated with a non-significant trend towards lower LFS (HR=2.34[0.96-5.71] p=0.063). Discussion and conclusions: In the homogeneously treated ALFA-0702 population, MRD-NGS positivity after the first induction course predicts shorter LFS and OS independently of ELN17 risk stratification. Detection of a higher number of mutations in CR is associated with a worse prognosis. Contrary to previous studies accruing older patients treated less intensively persistence of DTA mutations has similar prognostic relevance than non-DTA mutations. Future studies will be necessary to determine the superiority or addivitity of NGS-MRD with respect to available molecular MRD tools. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia

目的探讨单倍型造血干细胞移植（haplo-HSCT）治疗移植前微小残留病（Pre-MRD）阳性急性B淋巴细胞白血病（B-ALL）是否较全相合同胞造血干细胞移植（MSDT）具有生存优势，以及该作用是否受Pre-MRD的影响。方法对2009年6月至2018年6月在北京大学血液病研究所接受异基因造血干细胞移植（allo-HSCT）的998例移植前处于完全缓解（CR）的B-ALL患者进行回顾性分析，其中haplo-HSCT组788例、MSDT组210例，移植前用多参数流式细胞术（MFC）检测MRD水平。结果①全部998例B-ALL患者中，997例获得持续的完全供者嵌合状态，移植后100 d中性粒细胞、血小板植入率分别为99.9％（997/998）、95.3％（951/998），Ⅱ～Ⅳ度急性移植物抗宿主病（GVHD）发生率为26.6％（95％CI 23.8％～29.4％），3年慢性GVHD累积发生率为49.1％（95％CI 45.7％～52.4％），移植后3年白血病累积复发率（CIR）为17.3％（95％CI 15.0％～19.7％），非复发死亡率（NRM）为13.8％（95％ CI 11.6％～16.0％），移植后3年无白血病生存（LFS）率、总生存（OS）率分别为69.1％（95％CI 66.1％～72.1％）、73.0％（95％CI 70.2％～75.8％）。②Pre-MRD阳性组（282例）患者移植后3年CIR高于Pre-MRD阴性组（716例）［31.6％（95％CI 25.8％～37.5％）对14.3％（95％CI 11.4％～17.2％），P<0.001］。③在Pre-MRD阳性组中，haplo-HSCT患者（219例）移植后3年CIR低于MSDT患者（63例）［27.2％（95％CI 21.0％～33.4％）对47.0％（95％CI 33.8％～60.2％），P＝0.002］。④全部998例患者按照Pre-MRD结果分为阴性组（716例）、<0.01％组（46例）、0.01％～<0.1％组（117组）、0.1％～<1％组（87例）、≥1％组（32例）；5组患者中，<0.01％组haplo-HSCT患者（40例）移植后3年CIR低于MSDT患者（6例）［10.0％（95％CI 0.4％～19.6％）对32.3％（95％CI 0％～69.9％），P＝0.017］，0.01％～<0.1％组haplo-HSCT患者（81例）移植后3年CIR也低于MSDT患者（36例）［20.4％（95％CI 10.4％～30.4％）对47.0％（95％CI 29.2％～64.8％），P＝0.004］；其他三组中，haplo-HSCT和MSDT患者移植后3年CIR差异无统计学意义。⑤在Pre-MRD<0.1％组（163例）中，haplo-HSCT患者（121例）移植后3年CIR低于MSDT患者（42例）［16.0％（95％CI 9.4％～22.7％）对40.5％（95％ CI 25.2％～55.8％），P<0.001］，3年LFS率、OS率均高于MSDT组［78.2％（95％CI 70.6％～85.8％）对47.6％（95％CI 32.2％～63.0％），P<0.001；80.5％（95％CI 73.1％～87.9％）对54.6％（95％CI 39.2％～70.0％），P<0.001］，两组3年NRM差异无统计学意义［5.8％（95％CI 1.6％～10.0％）对11.9％（95％CI 2.0％～21.8％），P＝0.188］。多因素分析显示，haplo-HSCT是Pre-MRD<0.1％组移植后低CIR（HR＝0.248，95％CI 0.131～0.472，P<0.001）、高LFS率（HR＝0.275，95％CI 0.157～0.483，P<0.001）和高OS率（HR＝0.286，95％CI 0.159～0.513，P<0.001）的独立影响因素。结论haplo-HSCT治疗Pre-MRD<0.1％的B-ALL患者较MSDT具有生存优势。

Hematopoietic Cell Transplant-Composite Risk (HCT-CR): A Novel Predictor of Prognosis in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curable treatment modality for hematologic disorders. Transplant-related mortality remains high despite prominent scientific and technologic improvements. In consideration with the potential impact of patient- and disease-related factors on transplant outcome, this retrospective study was performed to investigate the predictive role of pretransplant HCT-composite risk (HCT-CR) score in allo-HCT recipients. A total of 313 patients with acute leukemia (male/female: 192/121; median age, 36 [18-71] years) were included in this study. The study cohort was divided into 2 subgroups based on pretransplant HCT-CR categories. The HCT-CRlo group included low-risk patients, and the HCT-CRint-hi group consisted of intermediate-, high-, and very high-risk patients. In the whole cohort, overall survival (OS) and 5-year OS were found to be 32.2% and 45.1%, respectively. Probability of OS was significantly better in the HCT-CRlo group compared with the HCT-CRint-hi group (P < .001). Leukemia-free survival (LFS) and 3-year LFS were 59.5% and 65.1%, respectively. Probability of LFS was better in the HCT-CRlo group compared with the HCT-CRint-hi group (P=.001). Nonrelapse mortality (NRM) and 3-year NRM were estimated to be 38.1% and 27.5%, respectively. Probability of NRM was significantly higher in the HCT-CRint-hi group compared with the HCT-CRlo group (P=.012). In multivariate analysis, HCT-CR was shown to have significant prognostic impact in acute lymphoblastic leukemia patients (P=.023; hazard ratio, 2.613; 95% CI, 1.142-5.982). Pretransplant evaluation of patient- and disease-related factors is essential for the accurate prediction of posttransplant survival. Further efforts to evolve current criteria for pretransplant risk assessment would eventuate in better transplant outcomes.

Post-Transplant Cyclophosphamide (PT-Cy) for Graft Versus Host Disease (GVHD) Prophylaxis in Allogeneic Transplantation from HLA Identical Sibling and Matched Unrelated Donor for Patients with Acute Leukemia, on Behalf of ALWP-EBMT

Background: Post-transplant Cyclophosphamide (PT-Cy) is being used successfully in the setting of unmanipulated haploidentical transplant as graft versus host disease (GVHD) prophylaxis. Experience with the application of PT-Cy for prevention of GVHD post allogeneic stem cell transplantation (HSCT) from matched sibling donors (MSD) or unrelated donor (UD) is rather limited and it involves mainly single center experience and small numbers of patients.Methods: Study aim was to evaluate the yield of PT-Cy as GVHD prophylaxis post HSCT from MSD and UD transplants for acute leukemia. We analyzed 423 patients (pts) with acute leukemia who received PT-CY alone or in combination to other drugs as GVHD prophylaxis and reported to the ALWP of the EBMT. 78 pts received PT-Cy alone (group 1); 204 received PT-CY in combination with one immunosuppressive (IS) drug -cyclosporine A (CSA) or and methotrexate (MTX) or mycophenolate mofetil (MMF)(group 2), while 141 pts received PT-Cy in combination with 2 IS drugs- CSA+MTX or CSA+MMF (group 3). Transplants were performed from 2007-2015 and median follow up is 16 months.Results: There were some differences among groups: pts in group 1 were younger (median age 37 years, p<0.001) were transplanted in more recent year (2014, p<0.001), with a MSD (80%, p<0.001), and CMV positive donor (73%, p=0.008), received more frequently a reduced intensity conditioning (RIC) (56%, p<0.001) and bone marrow (BM) as source of stem cells (74%, p<0.001), with no ATG (100%, p<0.001). Probability of OS at 2 year was 50%, 52.2% and 62.4%, for the 3 groups, respectively, p=0.06.Overall the cumulative incidence (CI) of grade II-IV acute GVHD was 27.9%, and the CI of chronic GVHD was 33.4%, and 16.5% the CI of extensive cGVHD. The CI of relapse at 2 years was 33.5% and non-relapse mortality (NRM) 18.5%, disease recurrence and GVHD were the most common causes of death in the whole cohort.At 2 years the probability of leukemia free survival (LFS) and overall survival (OS) was 48% and 55%.In multivariate analysis, the addition of IS to the PT-CY did not impact the risk of acute GVHD. Diagnosis of ALL (HR 0.57, p<0.001), unrelated donor (HR 1.65, p=0.02), RIC regimen (HR 1.72, p=0.01) and donor CMV positive (HR 1.77, p=0.01) were associated with the risk of grade II-IV acute GVHD. The use of PBSC (HR 2.41, p=0.01) and the absence of ATG (HR 1.69, p=0.03) were independently associated with an higher risk of chronic GVHD (p=0.005). In comparison to PT-Cy alone the addition of 1 or 2 IS drugs as GVHD prophylaxis were associated with reduced risk of extensive chronic GVHD (PT Cy+ 1 drug, HR 0.25, p=0.02, PT Cy+ 2 drugs, HR 0.77, p=0.01) as well the use of BM (HR 0.21, p<0.001) and the use of ATG (HR 0.22, p<0.001). Notably, the addition of 1 or 2 IS drugs to PT-CY did not impact the risk of relapse. Advance disease status (HR 2.42, p<0.001), was the only factor associated with increased risk of relapse. As for NRM addition of CSA+MTX or CSA+MMF to the PT-Cy (HR 0.35, p=0.04), diagnosis of AML (HR 0.35, p=0.001), and disease status at transplant (HR 2.94, p<0.001), and patients CMV serology (HR 2.04, p=0.04), influenced the NRM.Factors associated with increased OS were the use of PT-Cy in combination with CSA+MTX or CSA+MMF (HR 0.49, p=0.02), diagnosis of AML (HR 0.59, p=0.001), and disease status at HSCT ((CR1 vs CR2 HR 0.58, p=0.02), (CR1 vs advanced disease (HR 0.40, p<0.001)).Conclusions: PT-CY is effective GVHD prophylaxis in MSD and MUD HSCT for acute leukemia. The addition of IS drugs CSA+MTX or CSA+MMF to the PT-Cy shapes its effect and further decrease the risk of severe chronic GVHD, reducing transplant related mortality and improving overall survival. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

The Use of Anti-Thymocyte Globulin Is Associated with Decreased Risk of Chronic Graft-Versus-Host Disease without Impact on Survival after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Positive Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUNDAllogeneic hematopoietic stem cell transplantation (allo-SCT) is the standard of care for adults with Philadelphia-positive acute lymphoblastic leukemia (Ph-pos ALL). During the last decade mobilized peripheral blood stem cells (PBSCT) have become predominant source of graft for allo-SCT. However, as compared to bone marrow, PBSCT is associated with increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the cGVHD rate include the addition of anti-thymocyte globulin (ATG) to the conditioning regimen. The goal of this registry-based, retrospective study was to analyze the effect of ATG on results of allo-PBSCT in adults with Ph-pos ALL. PATIENTS AND METHODS1055 patients, aged 18-76 years, with Ph-pos ALL, treated with unmanipulated allo-PBSCT in first complete remission between 1997-2014 were included in the analysis. Conditioning regimen was myeloablative in 769 (72%) cases and based on total body irradiation in 608 (58%) cases. Among 590 transplantations from matched sibling donors, ATG was used in 95 (16%) patients. While, in the 8/8 HLA-matched unrelated setting 304/465 (65%) patients were treated with ATG. RESULTSIn a univariate analysis the use of ATG was associated with decreased incidence of the overall cGVHD (32% vs. 48%, p<0.001) and extensive cGVHD (14% vs. 22%, p=0.002) as well as a tendency to increased probability of survival free from grade III-IV acute GVHD, cGVHD and relapse (GRFS, 43% vs 36%, p=0.07). No significant difference could be demonstrated with regard to the incidence of grade II-IV acute GVHD (34% vs. 33%, p=0.59), grade III-IV acute GVHD (12.5% vs. 13%, p=0.68), relapse (25.5% vs. 27%, p=0.86) and non-relapse mortality (NRM, 19% vs. 18.5%, p=0.21), as well as probability of leukemia-free survival (LFS, 55% vs. 54.5%, p=0.95) and overall survival (OS, 68% vs. 67%, p=0.57). Among patients treated with ATG, original disease was the most frequent cause of death (40%) followed by infections (24%) and GvHD (21%). Respective proportions among those not treated with ATG were 36%, 23%, and 28%.In a multivariate model adjusted for other potential risk factors, the use of ATG was associated with reduced risk of the overall cGVHD (HR=0.53, p<0.001) and extensive cGVHD (HR=0.53, p<0.001) while increased risk of relapse (HR=1.34, p=0.03). No significant effect was found with regard to the risk of NRM (HR=0.78, p=0.15), a chance of LFS (HR=1.01, p=0.49) and OS (HR=0.87, p=0.27). CONCLUSIONSPatients with Ph-pos ALL treated with allo-PBSCT benefit from the use of ATG in terms of reduced risk of cGVHD without impact on survival. Increased risk of relapse, as shown in a multivariate model implicates the need for strict monitoring of minimal residual disease and either prophylactic or pre-emptive use of tyrosine kinase inhibitors after transplantation. Further studies are needed to explore potential role of the ATG brand and dose. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

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

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

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.

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

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

Effect of postremission chemotherapy before human leukocyte antigen–identical sibling transplantation for acute myelogenous leukemia in first complete remission

AbstractAllogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)–identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA–identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction.

Comparison of Reduced Intensity Conditioning - Allogeneic HCT and Autologous HCT for Elderly Patients with Acute Lymphoblastic Leukemia. an Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

BACKGROUND: The outcome of patients with acute lymphoblastic leukemia (ALL) aged above 55 years treated with conventional-dose chemotherapy is poor. Due to the frequent presence of co-morbidities many patients are ineligible for myeloablative allogeneic (allo) hematopoietic cell transplantation (HCT). The role of autologous (auto) HCT and reduced intensity conditioning (RIC)-alloHCT is not well-established. The goal of this study was to analyze results of these transplant options and to identify factors affecting outcome. PATIENTS: Five-hundred and sixty patients with ALL treated in first complete remission (CR1) with RIC-alloHCT (n=418) or autoHSCT (n=142), between 2000-2018, were included in the analysis. Among allogeneic donors, 50% were HLA-matched sibling donors (MSD) and 50% were 8/8 HLA matched unrelated donors (MUD). Median age for RIC-alloHCT and autoHCT was 60 (range 55-76) years and 61 (range 55-76) years, respectively. The proportion of Philadelphia chromosome positive (Ph(+)) ALL was 71% and 63%, respectively. Measurable residual disease (MRD)-positive status at the time of HCT was reported in 35% and 21% patients, respectively (p=0.002). Busulphan and fludarabine (BuFlu) was the most frequently used conditioning regimen in the RIC-alloHCT setting (34%) while a combination of 12 Gy total body irradiation/cyclophosphamide (TBI12Gy/Cy) was most frequent in the autoHCT group (33%). RESULTS: The engraftment rate was 99% after RIC-alloHCT and 96% after autoHCT (p=0.01) while median time to neutrophil recovery was 16 days and 12 days, respectively (p&amp;lt;0.001), respectively. With a median follow-up of 57 months, the probabilities of leukemia-free survival (LFS) and overall survival (OS) at 5 years were 39% versus 34% (p=0.11) and 45% vs. 42% (p=0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) were 41% vs. 51% (p=0.22) and 25% vs. 10% (p=0.001), respectively. In a multivariate model, using autoHCT as reference, the risk of NRM was increased for MSD-HCT (HR=2.1, p=0.02) and MUD-HCT (HR=3.08, p&amp;lt;0.001), which for MUD-HCT translated into a decreased chance of LFS (HR=1.55, p=0.01) and OS (HR=1.62, p=0.008). For MSD-HCT there was a tendency towards decreased LFS (HR=1.31, p=0.11) and OS (1.29, p=0.15) when compared to autoHCT. Among other prognostic factors, the risk of relapse was decreased for Ph(+) ALL compared to Ph(-) B-ALL (HR=0.7, p=0.04) which was accompanied by improved OS (HR=0.74, p=0.04). Finally, the risk of relapse was increased for patients with detectable MRD (HR=1.38, p=0.04) without significant effect on survival. CONCLUSIONS: Results of autoHCT for patients with ALL aged above 55 years in CR1 and with MRD negativity pre-transplant are encouraging. This option may be a valuable alternative to RIC-alloHCT and is associated with an improved OS compared to transplantations from MUD. Our observations require verification in prospective trials in the context of currently available novel agents and technologies, including blinatumomab, inotuzumab ozogamicin and CAR-T cells. Figure. Results of RIC-alloHCT and autoHCT for patients with ALL in CR1 aged &amp;gt;55 years Figure Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Forcade:Novartis: Other: Travel grant for congress; Sanofi: Other: Travel grant for congress; JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau. Yakoub-Agha:Janssen: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Novartis: Honoraria; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Mohty:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Different Effects of Pre-transplantation Measurable Residual Disease on Outcomes According to Transplant Modality in Patients With Philadelphia Chromosome Positive ALL.

Background: This study compared the effects of pre-transplantation measurable residual disease (pre-MRD) on outcomes in Philadelphia chromosome (Ph)-positive ALL patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical SCT (haplo-SCT).Methods: A retrospective study (n = 202) was performed. MRD was detected by RT-PCR and multiparameter flow cytometry.Results: In the total patient group, patients with positive pre-MRD had a higher 4-year cumulative incidence of relapse (CIR) than that in patients with negative pre-MRD (26.1% vs. 12.1%, P = 0.009); however, the cumulative incidence of non-relapse mortality (NRM) (7.4% vs. 15.9%, P = 0.148), probability of leukemia-free survival (LFS) (66.3% vs. 71.4%, P = 0.480), and overall survival (OS) (68.8% vs. 76.5%, P = 0.322) were comparable. In the MSDT group, patients with positive pre-MRD had increased 4-year CIR (56.4% vs. 13.8%, P < 0.001) and decreased 4-year LFS (35.9% vs. 71.0%, P = 0.024) and OS (35.9% vs. 77.6%, P = 0.011) compared with those with negative pre-MRD. In haplo-SCT settings, the 4-year CIR (14.8% vs. 10.7%, P = 0.297), NRM (7.3% vs. 16.3%, P = 0.187) and the 4-year probability of OS (77.7% vs. 72.3%, P = 0.804) and LFS (80.5% vs. 75.7%, P = 0.660) were comparable between pre-MRD positive and negative groups. In subgroup patients with positive pre-MRD, haplo-SCT had a lower 4-year CIR (14.8% vs. 56.4%, P = 0.021) and a higher 4-year LFS (77.7% vs. 35.9%, P = 0.036) and OS (80.5% vs. 35.9%, P = 0.027) than those of MSDT. Multivariate analysis showed that haplo-SCT was associated with lower CIR (HR, 0.288; P = 0.031), superior LFS (HR, 0.283; P = 0.019) and OS (HR, 0.252; P = 0.013) in cases with a positive pre-MRD subgroup.Conclusions: Our results indicate that the effects of positive pre-MRD on the outcomes of patients with Ph-positive ALL are different according to transplant modality. For Ph-positive cases with positive pre-MRD, haplo-SCT might have strong graft-vs.-leukemia (GVL) effects.

Post-Transplant Cyclophosphamide after Matched Sibling, Unrelated and Haploidentical Donor Transplants in Patients with Acute Myeloid Leukemia, a Comparative Study of the ALWP EBMT

Introduction: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. Although PTCy-Haplo has been compared with different transplant platforms, there is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods:We retrospectively analysed outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n=215), MUD (n=235) and Haplo (n=789) donors registered in the EBMT database between 2010 and 2017. The median follow up period of the entire cohort was 2 years. Results: Median age of patients was 52 years (range, 18-76), 693 (56%) were male and 928 (78%) were CMV seropositive. AML was de novo in 1,046 (84%) patients, while 47 (6%),543 (66%) and 239 (29%) had standard, intermediate and high risk cytogenetics, respectively. Peripheral blood (PB) was used as the stem cell source in 814 (66%) patients. Regarding conditioning, 962 (78%) were chemotherapy based regimens and 500 (41%) patients received reduced intensity conditioning (RIC). Preferred conditioning regimens were thiotepa, busulfan, fludarabine for Haplo (n= 371; 47%) and busulfan, fludarabine for MSD (n= 83; 39%) and MUD (n= 102; 43%). Patients received a variety of PTCy containing immune suppressive regimens, the most frequently used being PTCy, calcineurin inhibitor and mycophenolate mofetil in Haplo (n= 684; 87%) and PTCy and calcineurin inhibitor alone in MSD (n= 52; 24%) and MUD (n= 74; 31%). In-vivo T-cell depletion (TCD) was used in 164 (13%) patients. Compared to MSD and MUD, Haplo patients were older and less frequently received RIC, TCD and PB but the distribution of cytogenetic risk group was similar between the donor types. Cumulative incidence of neutrophil recovery at 60 days was 95% (95% CI 94-96). The cumulative incidence of 100 day acute GVHD grade II-IV and III-IV, and 2-year chronic and chronic extensive GVHD were 25% (95% CI 23-28), 9% (95% CI 7-10), 31% (95% CI 28-34) and 12% (95% CI 10-14), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS) and overall survival (OS) were 25% (95% CI 22-28), 19% (95% CI 17-21), 56% (95% CI 53-59) and 63% (95% CI 60-66), respectively. On multivariable analysis, outcomes were not significantly different for MSD and MUD. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) but the risk was not significant for chronic GVHD (HR 1.2; 95% CI 0.8-1.8). Haplo-SCT carried a higher risk of NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no change in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). The most frequent cause of death was relapse for MSD (n= 36, 53%) and MUD (n= 41, 48%) and infection for Haplo (n = 107, 39%). Interestingly, the use of PB was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). Other variables that had an impact on LFS were: poor risk cytogenetics (HR 1.4; 95% CI 1.1-1.7), use of MAC-Chemo (HR 0.7; 95% CI 0.6-0.9), Karnofski performance status &lt;90 (HR 0.8; 95% CI 0.6-0.99), older patient age (HR 1.1 by 10 year increase; 95% CI 1.02-1.2) and CMV seropositivity of recipient (HR 1.3; 95% CI 1.0-1.6). Conclusions:The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD and Haplo is safe and effective and rates of GVHD are low, especially chronic. HLA mismatch in Haplo has a negative impact on acute GVHD and NRM in this setting but also offers increased anti-leukemic efficacy. As seen in other transplant scenarios, PB is associated with more GVHD and less relapse. Figure Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Core binding factor acute myeloid leukemia (AML) comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since long-term response to chemotherapy in these leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at two and five years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2%, respectively. The incidence of relapse and risk of non-relapse mortality at the same time points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality, respectively. The most important adverse factors influencing leukemia-free and overall survival were: leukemia with t(8;21), presence of three or more additional chromosomal abnormalities, and Karnofsky performance score <80. Relapse risk was increased in t(8;21) leukemia and associated with additional cytogenetic abnormalities as well as reduced intensity conditioning. Measurable residual disease in molecular evaluation before transplantation was associated with increased risk of relapse and inferior leukemia-free survival.

Individualized prediction of leukemia-free survival after autologous stem cell transplantation in acute myeloid leukemia.

Autologous stem cell transplantation (ASCT) is a potential consolidation therapy for acute myeloid leukemia (AML). This study was designed to develop a prediction model for leukemia-free survival (LFS) in a cohort of patients with de novo AML treated with ASCT during their first complete remission. This was a registry study of 956 patients reported to the European Society for Blood and Marrow Transplantation. The primary outcome was LFS. Multivariate Cox regression modeling with backward selection was used to select variables for the construction of the nomogram. The nomogram's performance was evaluated with discrimination (the area under the receiver operating characteristic curve [AUC]) and calibration. Age and cytogenetic risk (with or without FMS-like tyrosine kinase 3 internal tandem duplication) were predictive of LFS and were used for the construction of the nomogram. Each factor in the nomogram was ascribed points according to its predictive weight. Through the calculation of the total score, the probability of LFS at 1, 3, and 5years for each patient could be estimated. The discrimination of the nomogram, measured as the AUC, was 0.632 (95% confidence interval [CI], 0.595-0.669), 0.670 (95% CI, 0.635-0.705), and 0.687 (95% CI, 0.650-0.724), respectively. Further validation with bootstrapping showed similar AUCs (0.629 [95% CI, 0.597-0.657], 0.667 [95% CI, 0.633-0.699], and 0.679 [95% CI, 0.647-0.712], respectively), and this suggested that the model was not overfitted. Calibration was excellent. Patients were stratified into 4 incremental 5-year prognostic groups, with the probabilities of LFS and overall survival ranging from 25% to 64% and from 33% to 79%, respectively. The Auto-AML nomogram score is a tool integrating individual prognostic factors to provide a probabilistic estimation of LFS after ASCT for patients with AML.