Unrelated Research Articles

Should the European Leukemia Net 2022 Adverse Risk Classification of NPM1 mutated Acute Myeloid Leukemia be Revisited? Among Adverse Risk Cytogenetics, Solely Complex Karyotype Is Associated with Worse Post-Transplant Survival: A Study from the EBMT Acute Leukemia Working Party

Introduction The European LeukemiaNet (ELN) 2022 risk classification has identified acute myeloid leukemia (AML) with Nucleophosmin 1 (NPM1) mutation as a distinct entity associated with a favorable prognosis in those with normal cytogenetics (CG) and absent FLT3 ITD. Furthermore, the ELN 2022 reclassified AML patients with mutated NPM1 and high risk CG as adverse risk (AR) regardless of their FLT3 ITD status. We performed this analysis to evaluate the impact of the different AR CG aberrations on post-transplant outcomes in that setting. Methods: In this retrospective registry based analysis from the EBMT, we included adult patients (≥ 18 years) with NPM1 mutated de novo AML, intermediate or AR CG, and known FLT3 ITD mutation status, who received their first allogeneic hematopoietic cell transplantation (HCT) in first complete remission between 2005 and 2021. Multivariate analysis adjusting for differences between the groups (according to CG) was performed using a Cox proportional hazards regression model. Results: We identified a total of 3275 patients (54% females). FLT3 ITD was present in 2377 patients (73%); significantly higher in those with normal CG (75% versus 57%). Normal CG was seen in 2782 patients (85%), while CG aberrations were noted in 493 patients, the most common of which was trisomy 8 (141 patients). Adverse risk CG were seen in 160 patients (4.9%) including complex karyotype (CK) in 72 patients and monosomal karyotype (MK) in 66 patients. The median age was 54 [IQR 45-62]. No significant difference was noted between those with normal and those with abnormal CG with regards to baseline patient and transplant characteristics: HCT comorbidity index (CI) was £2 in 79% of patients in both groups, minimal measurable disease at transplant was positive in 42% and 44%, donor type was matched sibling (MSD) in 32% and 34%, unrelated (UD) in 57% and 58%, or haploidentical in 11% and 9%, stem cell source was peripheral blood in 89% and 89%, conditioning was myeloablative in 52% and 49% respectively. The median follow up for alive patients was 35 months (IQR 33-36). During this follow up a total of 961 patients died (48.3% due to disease relapse). In univariate analysis, post-transplant outcomes were not significantly affected when comparing normal to abnormal CG, or intermediate versus adverse risk CG. Patients with a normal karyotype had a 2-year relapse rate of 23%, NRM of 13%, LFS 63%, OS of 71%, and GRFS of 51%. Conversely, patients with aberrant CG had a 2-year relapse rate of 27%, NRM 12%, LFS 61%, OS of 68%, and GRFS of 48%. On multivariate analysis, CK as well as FLT3 ITD was associated with a worse OS with HR of 1.7 (95% CI 1.13-2.56) and 1.18 (95% CI 1.01-1.39), respectively. When analyzed by subgroup by univariate analysis according to FLT3 ITD status, the impact of CK was maintained for those with FLT3 wild type: 2-year LFS 39.6% vs. 70.5%; p=0.006, and 2-year OS 49% vs. 75.3%, p=0.012. Similarly for patients with FLT3 ITD, CK was associated with a higher risk of relapse (45.7% vs. 26.5%, p=0.021), and worse OS (52.7% vs. 67.4%; p=0.047) with no significant effect on other outcomes. Within patients with chromosomal aberrations, CK was the only significant predictor of worse LFS (HR 1.58 [1.06-2.34]), and OS (HR 1.85 [1.22-2.82]). FLT3 ITD mutation status, CG risk category, as well as the various CG abnormality subgroups had no significant effects (Notably, MK was not associated with a significant impact on LFS [60.9% versus 61.4%; p-value 0.7], OS [67.7% versus 68.2%; p-value 0.97] or GRFS [51.5% versus 47.8%; p-value 0.61]. Conclusion: These data suggest a need to revisit the ELN 2022 risk stratification of AML patients with mutated NPM1 and CG aberrations. In the transplant setting for patients in first remission, only CK among other AR CG appears to predict worse outcomes, although a significant proportion of patients with CK can still achieve long term post-transplant survival.

Outcome of Allogeneic Stem Cell Transplantation in FLT3-TKD-Mutated AML - a Study on Behalf of the Acute Leukemia Working Party of the EBMT

Introduction The overall prognostic impact of point mutations in the tyrosine-kinase domain 1 of FLT3 (FLT3-TKD mut) in patients (pts) with acute myelogenous leukemia (AML) remains controversial. Furthermore, co-occurrence of FLT3-TKD mut and mutated nucleophosmin-1 (NPM1 mut) was shown to have a favorable prognostic impact on AML pts receiving conventional chemotherapy. However, little is known about the outcome of AML pts with FLT3-TKD mut with or without co-occurring NPM1 mut treated with allogeneic stem cell transplantation (alloSCT). Patients and Methods This is a retrospective study of the acute leukemia working party (ALWP) of the European Society for Blood and Marrow transplantation (EBMT) investigating the outcome of adult AML pts with FLT3-TKD mut with or without NPM1 mut after first alloSCT using matched sibling (MSD), unrelated (UD) or haploidentical (haplo) donors between 2005 and 2022. All patients were in first or second complete remission (CR1 of CR2). Information on cytogenetic risk was necessary for inclusion. No ex-vivo T-cell depletion (TCD) was allowed. The primary endpoint was leukemia-free survival (LFS) at two years after alloSCT. Secondary endpoints were overall survival (OS), cumulative incidence of relapse (RI), non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) and GVHD-free, relapse free survival (GRFS). One hundred and eighty-two adult AML pts with FLT3-TKD mut were identified, of which 74 (40.7%) had a co-occurring mutation in NPM1. Median age was 55.1 years (range 18.6-79.1) and 46.7% were male. Median follow-up was 21.4 months [IQR 13.6-28.1]. 78% of the pts were in CR1. Cytogentic risk was favorable, intermediate and adverse in 12.6%, 75.3% and 12.1% of pts, respectively. Additional FLT3 internal tandem duplication (FLT3-ITD) was present in 25.8% of pts. Information on measurable residual disease (MRD) was available for 68.7% of pts, being positive in 48% of these. Karnofsky performance score was < 90% in 21.1%, and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was >=3 in 28.1% of pts. 69.6% of pts were cytomegalovirus (CMV) positive. Conditioning was myeloablative in 52.8% and reduced intensity in 47.2% of pts. Stem cell donors were MSD, UD and haplo in 25.8%, 55.5% and 18.7% of cases. Stem cell source was bone marrow in 10.4%, peripheral blood in 87.4% and both in 2.2%. In-vivo TCD was performed in 59.2% of pts. GVHD prophylaxis was calcineurin inhibitor-based in 92.2% of pts. Results Engraftment was achieved in 99.4% of pts with a day-60 absolute neutrophil count (ANC) >0.5 x 10 9/L of 97.7% [95% CI: 93.7-99.2]. Day-180 rates of acute GVHD (aGVHD) grade II-IV and grade III-IV were 26.2% (95% CI:19.9-32.9) and 8.1% (95% CI:4.6-12.8), respectively. At two years, rates of total chronic GVHD (cGVHD) and extensive cGVHD were 30% (95% CI: 22.5-38) and 16.6% (95% CI:10.6-23.7), respectively. Two-year LFS and OS were 66.1% (95% CI: 57.6-73.2) and 74% (95% CI: 65.4-80.8), respectively. Two-year RI, NRM and GRFS were 22.5% (95% CI:16-29.8), 11.4% (95% CI: 7-17), and 51.1% (95% CI: 42.4-59.1), respectively. Cause of death was original disease in 47.5%, infection in 27.5%, GVHD in 22.5% and non-SCT related in 2.5% of cases. In univariate analysis the only factor with significant impact on LFS was donor type (haplo [n=34] vs. others, p=0.006). For GRFS, patient CMV negativity (p=0.014) and in-vivo TCD (p=0.01) were significant. Interestingly, co-occurring mutations in FLT3 (FLT3-ITD) or NPM1 were not identified as having a significant impact on LFS or GRFS. Moreover, MRD status before alloSCT was also not shown to have a significant impact on these outcomes. In multivariate analysis of LFS and GRFS, only donor type (haplo [n=34] vs. others) was shown to be significant for both endpoints, hazard ratio (HR) 2.54; 95% CI: 1.4-4.6; p=0.002, and HR 2.01; 95% CI: 1.18-3.41; p=0.01, respectively. Conclusion Acknowledging the limitations of our retrospective study in this rare entity results are encouraging given the high-risk population (median age 55.1 years, CR2 in 22%, co-occurring FLT3-ITD in 25.8%, positive MRD in 48%, HCT CI >=3 in 28.1%). LFS, OS and GRFS rates were 66.1%, 74% and 51.1%, respectively, and both RI and NRM were comparably low with rates of 22.5% and 11.4%, respectively. No positive prognostic impact of co-occurring mutations in FLT3-TKD and NPM1 was detected, unlike what was found for conventional chemotherapy.

Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT.

We compared transplants (HSCT) from matched related siblings (MSD) with those from matched 10/10 and mismatched 9/10 unrelated (UD) and T-replete haploidentical (Haplo) donors in acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions, a known poor prognostic factor. One thousand two hundred and ninety-five patients were included: MSD (n = 428), UD 10/10 (n = 554), UD 9/10 (n = 135), and Haplo (n = 178). Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11, p = 0.0002) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13, p = 0.036) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49, p = 0.0009). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03, p = 0.0009) but not in those from UD 10/10 (HR = 1.13, p = 0.22) and Haplo donors (HR = 1.12, p = 0.43) compared to MSD. In conclusion, in AML patients undergoing HSCT in CR1 achieved after two induction courses 10/10 UD and Haplo but not 9/10 UD donors are comparable alternatives to MSD.

Impact of Fourth Methotrexate Dose in ATG-Cyclosporine GvHD Prophylaxis in HLA-Matched Unrelated HSCT: A GITMO Study

Background: Although, post-transplant Cyclophosfamide (PT-Cy) is currently spreading as GvHD prevention, the standard GvHD prophylaxis in unrelated haematopoietic stem cell allogeneic transplant (HSCT) series is still represented by Methotrexate (MTX), a CNI and Anti-thymoglobuline (ATG) combination. The dose of MTX (3 or 4 doses), in association with ATG and CNI remains a matter of debate. Aim: The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari (GITMO) analyzed 568 patients who received unrelated (UD) 10/10 HLA matched HSCT and GvHD prophylaxis based on a combination of cyclosporin (CSA), ATG and Methotrexate. Methods: Patients were grafted in GITMO centers between 2012 to 2015 and GvHD prophylaxis was the same for all patients (ATG-MTX-CSA). The median dose for ATG Fresenius and Thymoglobulin was respectively 30 mg/kg (range 8-60) and 8 mg/Kg (range 4-18); 216 patients received 3 doses of MTX and 352 4 doses. Patient characteristics based on the two groups (MTX 4 and MTX 3 doses) are detailed in table 1. Main differences between the groups concerned conditioning intensity (myeloablative in 75% and 63% for MTX4 and MTX3 respectively, p 0.002), ATG dose (above the median in 59% of MTX4 and in 71% of MTX3 patients, p 0.005), and diagnosis (acute leukemias in 63% of MTX4 and 46% of MTX3, p<0.0001). Statystical analysis: The probabilities of DFS, OS and GRFS were estimated with the Kaplan-Meier method. Cumulative incidence (CI) was estimated for engraftment, GvHD, TRM and relapse to accommodate competing risks. Relapse or progression was a competing risk for TRM, and death from any cause was a competing risk for engraftment and relapse. Relapse or progression and death from any causes were competing risks for GvHD. Univariate comparisons of survival curves were made using the log-rank test and Gray's test was used for univariate comparisons of CI functions. The type I error rate was fixed at 0.05. Statistical analyses were performed with the SPSS (SPSS 22 Inc. IBM, Armonk, NY, USA) and R (R Development Core Team, Vienna, Austria) software. Results In the setting of 10/10 HLA matched unrelated allogeneic HSCT, whose median follow up was 42.5 months (range 3-75), univariate analysis showed that the administration of 3 versus 4 doses of MTX plays a significant favorable impact on the cumulative incidence of engraftment in terms of PMN (94% vs 90%, p=0.04) and PLTS (90% vs 86%, p= 0.04). Moreover, the 3 MTX doses group achieved significant better results in terms of 3-years CI of TRM (15% vs 23%, p=0.03), OS (66% vs 52%, p=0.001), PFS (54% vs 41%, p= 0.001) and GRFS (44% vs 27%, p=0.00001). We built a multivariate Cox model based on the following covariates: patient age (median value), Donor/host gender, Donor/host CMV status, Disease status, HCT-CI Sorror, Karnofsky PS, Conditioning intensity, Source of stem cells (PB vs BM), ATG dose (median value), MTX dose (4 doses vs 3), Center (≥10 transplants/year vs <10 transplants/year), host/donor Italian origin. Multivariate analysis confirmed the significant protective role of 3 MTX doses on grade 3-4 aGvHD (HR 0.41, p=0.03), TRM (HR 0.59, p=0.02), OS (HR 0.59, p=0.001), PFS (HR 0.6, p<0.0001) and GRFS (HR 0.58, p<0.0001). Interestingly, the relapse risk was significantly inferior in patients who received 3 doses of MTX instead of 4 (HR 0.60, p=0.003). Conclusions: A fourth dose of MTX in patients receiving ATG+ CSA may negatively impact on engraftment, aGvHD, TRM, OS, PFS and GRFS. Our data support the need for a prospective investigation of MTX doses in the context of patients receiving unrelated matched HSCT and ATG+a CNI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Easix Application in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Prophylaxis

INTRODUCTION The Endothelial Activation and Stress Index (EASIX) is a biomarker-based laboratory formula applicable in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) which has been proposed to predict non-relapse mortality (NRM), overall survival (OS), and thrombotic microangiopathy (TMA) incidence when measured during the pre-transplant evaluation, and sinusoidal obstruction syndrome (SOS), when measured on day 0. The use of post-transplant cyclophosphamide (PTCY) for graft vs. host disease (GVHD) prevention has become a standard in haploidentical hematopoietic cell transplantation (HCT) and it is increasingly used for allo-HCT performed with unrelated (UD) and matched sibling donors. PTCY-based prophylaxis was incorporated at our Institution between 2014 and 2018. Since then, lower rates of endothelial complications including acute GVHD (aGHVD) have been documented. The predictive ability of EASIX has been validated mainly in patients receiving GVHD prophylaxis that did not contain PTCY. Considering that fewer endothelial complications have been diagnosed at our Institution since the use of PTCY-based prophylaxis, and that EASIX is considered a surrogate parameter of endothelial activation, this study investigates whether the dynamics of EASIX differ between patients receiving PTCY vs. other prophylaxis, and if the predictive ability of EASIX persists in PTCY-based allo-HCT. METHODS Between 2014 and 2020, 328 consecutive adults underwent first allo-HCT at our Institution and were included in the study. EASIX [(creatinine*LDH)/platelets] was calculated based on the information provided at the bloodwork collected at the pre-transplant assessment, on days 0, +7, +21, +28, +100, and +180. EASIX was transformed to a base-2 logarithm to perform the statistical analysis. The ability of EASIX to predict outcomes (OS and NRM) and post-transplant complications (SOS, TMA, and grade 2-4 aGVHD) was explored using landmark and regression analyses. Patients who died or who were diagnosed with the study time-dependent adverse event before each landmark point were excluded from the next time point. RESULTS The study cohort was divided into two groups according to the GVHD prophylaxis (PTCY n=201 vs. others n=127). Median age was 52 years and 81 patients (40.4%) received myeloablative conditioning regimens. One hundred and nine patients (65.2%) received transplants from mismatched donors [68 (44.8%) from mismatched UD and 41 (20.4%) haploidentical]. The dynamics of EASIX, in conjunction to creatinine, LDH, and platelets counts consecutively recorded from day 0 to +180 are depicted in Figure 1. As reported, the values of EASIX differed significantly from day 0 to day +28 between the two groups. These differences were attributed to lower LDH levels from day 0 to day +180, a lower platelet count documented between days +14 and +180 in patients receiving PTCY. The ability of EASIX to predict outcomes and complications was explored in patients receiving PTCY. The cumulative incidence functions of SOS, TMA, and grade 2-4 aGVHD day +100 were 2.0%, 3.5%, and 21.4%, respectively. The 2-years OS and NRM were 69.0% and 16.4%, respectively. As reported in Table 1, higher values of EASIX , measured at the pre-transplant assessment, days 0, +7, +14, +28, and +180 were associated with a higher probability of NRM and lower OS. Moreover, increased values of EASIX, measured at the pre-transplant assessment, days 0, +7, and +14 were predictors for TMA, and higher values of EASIX, measured before allo-HCT, on days +21 and +28 were predictors for grade 2-4 aGVHD. No association was observed between EASIX and SOS prediction. CONCLUSIONS The dynamic of EASIX differs between patients receiving PTCY and those that did not. However, despite this difference, the ability of pre-transplant EASIX to predict NRM and OS persists in patients receiving PTCY. Higher values of EASIX, measured not only at the pre-transplant evaluation, but also on days 0, +7, +21, +28 and +180 were associated with higher NRM and lower OS in patients receiving PTCY. In addition, pre-transplant EASIX was found to be a useful predictor for TMA and grade 2-4 aGVHD in these patients. This analysis validates the predictive ability of EASIX in patients receiving PTCY for GVHD prevention, and enhances the relevance of the assessment of endothelial dysfunction markers for the prognosis of PTCY-based allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Basic characteristics and safety of donation in related and unrelated haematopoietic progenitor cell donors - first 10 years of prospective donor follow-up of Swiss donors.

Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.

Impact of donor-derived CD34 + infused cell dose on outcomes of patients undergoing allo-HCT following reduced intensity regimen for myelofibrosis: a study from the Chronic Malignancies Working Party of the EBMT.

The optimal CD34 + cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34 + cells (>7.0 × 106/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P < 0.001) and platelet engraftment (HR, 1.43; P < 0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34 + dose was associated with improved overall survival (HR, 0.63; P = 0.04) and relapse-free survival (HR, 0.61; P = 0.02), lower risk of non-relapse mortality (HR, 0.57; P = 0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34 + dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0 × 106/kg CD34 + cells.

Individual word activation and word frequency effects during the processing of opaque idiomatic expressions.

Idiom processing studies have paid considerable attention to the relationship between idiomatic expressions as a whole and their constituent words. Although most research focused on the semantic properties of the constituent words, their orthographic form could also play a role in processing. To test this, we assessed both form and meaning activation of individual words during the processing of opaque idioms. In two primed word naming experiments, Dutch native speakers silently read sentences word by word and then named the last word of the sentence. This target word was embedded in either an idiomatic or a literal context and was expected and correct in this context (COR), semantically related (REL) to the expected word, or unrelated (UNREL) to the expected word. The correct target word in the idiomatic context was always part of an opaque idiom. Faster naming latencies for the idiom-final noun than for the unrelated target in the idiomatic context indicated that the idiom was activated as a whole during processing. In addition, semantic facilitation was observed in the literal context (COR < REL < UNREL), but not in the idiomatic context (COR < REL = UNREL). This is evidence that the idiom-final noun was not activated at the meaning level of representation. However, an inhibitory effect of orthographic word frequency of the idiom-final noun indicated that the idiom-final noun was activated at the form level. These results provide evidence in favour of a hybrid model of idiom processing in which the individual words and the idiom as a whole interact on form and meaning levels of representation.

Hematopoietic Cell Transplants (HCT) from HLA-Matched Related (MRD) and Unrelated (URD) Donors for Patients with Hematologic Malignancies Using Low-Dose TBI Conditioning.

Nonmyeloablative conditioning regimens for allogeneic HCT were introduced to reduce the non-relapse mortality and as a therapeutic modality to patients (pts) who otherwise would not be considered candidates for HCT. Here, we present data on 727 pts with hematologic malignancies who received either MRD (n=426) or URD (n=301) HCT using a nonmyeloablative regimen consisting of 2 Gy TBI with or without fludarabine (30 mg/m2/day x 3 days) given before HCT. Mycophenolate mofetil and cyclosporine or, more recently, tacrolimus were administered after HCT for both host and donor cell immunosuppression. Ninety-eight percent of pts received unmodified G-CSF-mobilized peripheral blood cells and 2% received marrow (all URD). Transplants were done between 12/97 and 02/05 on multi-institutional studies with a median follow-up of 2.6 (range 0.3–6.9) years amongst survivors. Pts were ineligible for myeloablative conditioning due to advanced age or co-morbidities. Median pt age was 54 (range 5–74) years (MRD 55; URD 54). Diagnoses included ALL (n=26), AML (n=118), CLL (n=70), CML (n=49), HD (n=45), MDS/MPD (n=120), MM (n=155), and NHL (n=144). Forty-nine percent of pts had aggressive advanced stage diseases (MRD 39%, URD 62%) and 22% had failed previous high-dose autologous or allogeneic HCT (MRD 17%; URD 30%). Sustained engraftment occurred in 93% of pts (MRD 96%; URD 90%). Acute GVHD grades II-IV and III-IV occurred in 51% and 13% of pts, respectively (MRD: 44% and 13%; URD: 60% and 13%). Forty-five percent of pts had chronic extensive GVHD (MRD 46%; URD 43%). Overall, the 3-year Kaplan-Meier estimate of relapse-related mortality was 28% (MRD 26%; URD 30%), and non-relapse mortality was 23% (MRD 20%; URD 27%). The rates of 3-year overall and progression-free survivals were 46% and 36%, respectively (MRD 51%, 38%; URD 39%, 31%). Among pts with measurable disease at HCT (65%), the 3-year overall survival was 49% (MRD 50%; URD 45%). The best outcomes were seen in pts with B-cell malignancies, including MM, CLL and NHL, and with early stage myeloid malignancies. In pts who had failed a previous transplant, 3-year overall survival was 39% (MRD 37%; URD 41%). In summary, nonmyeloablative regimens allowed engraftment of allogeneic hematopoietic cells and the development of graft versus tumor effects. Encouraging outcomes were achieved using nonmyeloablative conditioning for both MRD and URD HCT in pts who otherwise were not eligible for myeloablative conditioning regimens, including those who had failed a myeloablative HCT.

Total Marrow Irradiation for Second Allogeneic Haematopoietic Stem Cell Transplantation in Patients with Advanced Acute Leukemia

Background. Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is associated with very poor outcomes. A myeloablative conditioning regimen for patients with advanced acute leukemia before second allogeneic HSCT is crucial to better control the disease, but the risk of transplant mortality due to toxic complications is very high. Total Marrow Irradiation (TMI) is a novel high precision radiation treatment, alternative to standard Total Body Irradiation (TBI) conditioning regimen, allows to deliver therapeutic radiation doses over extensive selected targets while substantially reducing radiation to vital organs to preserve their functions. Aim of the pilot study. To evaluate the efficacy of high dose per fraction TMI in combination with thiotepa, fludarabine and alkeran as conditioning regimen in 9 patients with acute leukemia relapsed after a first allogeneic HSCT. Patients and Methods. Nine patients relapsed after first allogeneic HSCT received a second allogeneic HSCT, 7 from haploidentical, 1 from unrelated (UD) 10/10 and 1 from HLA-identical sibling (SIB) donor. The conditioning regimen consisted of: TMI 8 Gy in 5 patients on day -8 -7 or TMI 12 Gy in 4 patients on day -9 -8 -7, plus Thiotepa 5 mg/Kg on day -6, Fludarabine 50 mg/mq on day -5 -4 -3, alkeran 140 mg/mq on day -2. TMI was delivered in daily single fraction dose of 4 Gy, instead of the conventional 2 Gy in order to potentially enhance the biological effective dose approximately 20% to 60% (for a total dose of 12 Gy), considering alpha/beta ratio between 10-1.49, while total dose of 8 Gy in 2 fractions schedule is potentially equivalent to six fractions of conventional TBI for low alpha/beta ratio. Graft versus host disease (GvHD) prophylaxis for SIB and UD consisted of cyclosporine methotrexate and ATG, whereas for HAPLO it was high dose post-transplant cyclophosphamide (PT-CY), cyclosporine and mycophenolate. The median age was 45 years (range, 19-70 years); 3 patients were in remission, 6 had active disease at the time of the second allogeneic HSCT. The median number of nucleated cells infused was 4.3 x 10e8/Kg (range 2.6-7.7). Four patients received peripheral blood and 5 patients received unmanipulated bone marrow cells. Results. The median time to neutrophil counts of &amp;gt; 0.5 x 10e9/L was 16 days (range 13-22) and to platelet counts of &amp;gt; 20 x 10e9/L was 19 days (range 11-27) respectively. All the patients showed a full donor chimerism on day 30 after transplant; none of the patients had rejection. Three patients developed acute graft versus-host disease (aGvHD) grade I-II and 1 patient had moderate chronic GvHD. During the neutropenic phase of the transplant one patient developed a sepsis from Pseudomonas Aeruginosa; one patient had pericardial effusion and one patient had mucositis grade II. The median follow up was 528 days (range 227-858). Day +30 and day +100 transplant related mortality were 0. Two patients died of transplant related complications; both died of interstitial pneumonia and received TMI 12 Gy. Two patients died of leukemia and they were not in remission at the time of the transplant. The actuarial 17 months disease free-survival (DFS) is 53%. Conclusions. This is the first report demonstrating the safety and the efficacy of the TMI conditioning regimen in patients with advanced acute leukemia receiving second allogeneic transplantation with encouraging outcome in terms of engraftment, early toxocity, GvHD and relapse. Disclosures No relevant conflicts of interest to declare.

Letermovir Prophylaxis in Patients at High Risk for CMV Disease Following Hematopoietic Cell Transplant

<h3>Objective</h3> Starting January 2018 all adult HCT recipients at Stanford University who were at high risk (HR) for CMV disease received Letermovir prophylaxis (LET PPX). HR included: (1) ATG containing regimen, (2) an umbilical cord blood (UBC) graft, or (3) a haplo-identical, (4) unrelated (URD) (5) mismatched-related donor (misM-RD). We performed a retrospective analysis of the impact of LET PPX on the impact of CMV compared to historical controls. <h3>Methods</h3> 629 adults HCT patients from Jan 2013 - May 2019 were analyzed. 76 of these patients received LET PPX. Plasma CMV PCR was performed weekly through D+100. Prior to 2018, UCB patients received valacyclovir 2000 mg TID. PET was started if viral load (VL) was > 400 copies/ml (2009-2012) or 400 IU/ml (2013-2019). CMV disease was defined by published criteria. <h3>Results</h3> • LET PPX was well-tolerated without hematopoietic/organ toxicity. • CMV viremia occurred during LET PPX in 71 % of patients which was comparable to 74% in the controls; however, 34% LET PPX (34%) were started on a different CMV-active agent compared to 50% of controls. In 52% of LET PPX patients viremia cleared without change of antiviral or disease. (Table 1) • Although median hospital stays were the same in the LET PPX and control groups, there was a trend to greater number of hospitalizations in the control group. • Median Day post-transplant of first detection of CMV viremia for patients who received PET/change in CMV-active agent was later in the LET PPX group (D+45) than in the controls (D+ 18) • 3 of 76 (3.9%) LET PPX developed disease compared with 48 of 553 controls (8.7%). None of 24 ATG patients on LET PPX developed disease compared to 23/235 controls. (Table 2) <h3>Conclusion</h3> • Compared to controls, LET prophylaxis decreased the burden of CMV. • Other analyses not shown: hospitalizations, transfusions, infections, GHVD, relapse, survival

Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL &amp; H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Pharmacokinetic-Guided Busulfan Based Myeloablative Versus Fixed Dose Reduced Intensity Conditioning Regimen in Patients Older Than 55 Years Undergoing Allogeneic Stem Cell Transplantation for High Risk Hematological Malignancies

BACKGROUND Reduced intensity conditioning (RIC) combining fludarabine, busulfan and ATG is commonly used in patients with advanced age and/or comorbid conditions, thus deemed unfit for standard myeloablative conditioning (MAC) regimens (i.e. BuCy or CyTBI12). Although non-relapse mortality (NRM) is dramatically reduced with RIC, relapse remains a major concern. In younger patients, myeloablative doses of busulfan in combination with fludarabine (i.e. myeloablative reduced toxicity conditioning [MA-RTC] regimen) produce similar antitumor effect compared with standard MAC while keeping low NRM. The feasibility of such an approach for older patients is not known. We hypothesized that a pharmacokinetics (PK) guided strategy could improve the safety of busulfan administration, allowing the use of myeloablative doses in older patients. STUDY DESIGN AND METHODS We compared the outcome of patients older than 55 years with hematological malignancies included in a prospective monocentric single arm trial (BxPK: NCT02483325) evaluating the feasibility of PK-guided busulfan doses in myeloablative conditioning regimen (BxPK group: fludarabine 150 mg/m² + IV busulfan targeted AUC 5300 x 4 days + ATG 5 mg/kg) before matched sibling (MSD) or unrelated (URD) donor AlloSCT, with a retrospectively enrolled control cohort of patients with same inclusion criteria, treated during the same period but receiving fixed busulfan dose RIC regimen including fludarabine (150 mg/m²), IV busulfan (260 mg/m²) and ATG (5 mg/kg) [Bx2 group]. The primary objective was 2-year progression-free survival (PFS). Hazard ratio of BxPK vs. Bx2 were adjusted by age, disease risk index (DRI), donor type and hematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS We analyzed 83 consecutive patients (BxPK: n=27; Bx2: n=56) without significant difference in baseline characteristics between both conditioning groups. In the BxPK and Bx2 groups: median age was 65 (range: 57-70) and 63 (range: 55-70) years, respectively (p = 0.552); 10/10 URDs were used for 15 (56%) and 37 (66%) patients, respectively (p = 0.493); HCT-CI was ≥ 3 in 18 (67%) and 28 (50%) patients , respectively (p = 0.232); and DRI was high in 5 (19%) and 5 (9%) patients, respectively (p = 0.369). Based on PK data from day-6 busulfan administration, 22 (81%) patients had dose adjustment (increased and decreased dose in 12 and 10 patients, respectively) in the BxPK group. Median busulfan AUC on day-2 (post adjustment) was 5287 µmol.min (range: 3326-7556). Four patients had AUC &gt; 6000 µmol.min on day-2. Grade 3-4 mucositis (BxPK vs Bx2: 52% vs. 11%, p &lt; 0.001) and nausea (BxPK vs Bx2: 11% vs 0%, p = 0.050) were more frequently observed in the BxPk group. No difference was observed between BxPK and Bx2 patients in grade 3-4 liver (BxPK vs Bx2: 15% vs 11%, p = 0.810), renal (BxPK vs Bx2: 0% vs 1.8%, p = 1) and gastrointestinal tract (BxPK vs Bx2: 11% vs 0%, p = 0.450) toxicities. There was a trend to higher cumulative incidence of grades 2-4 acute graft-versus-host disease (GVHD) at 100 days in the BxPK group (BxPK vs Bx2: 41% vs 29%, p = 0.058) while no difference was observed in 2-year chronic GVHD (BxPK vs Bx2: 41% vs. 36%, p = 0.547). Those trends were confirmed by multivariate analyses (acute GVHD: HR 2.22, 95Cl [1.10-4.48], p = 0.026; chronic GVHD: HR 1.30, 95Cl [0.60-2.80], p=0.502) With a median follow up of 33 months (range: 9-60), 2-year NRM was 19% and 18% (p=0.960) in the BxPK and Bx2 group, respectively. Multivariate analysis confirmed the absence of significant increase in the risk of NRM in the BxPK group (HR 1.11, 95CI [0.36-3.45], p = 0.859). The 2-year cumulative incidence of relapse was 19% and 31% (p=0.269) in the BxPK and Bx2 group, respectively (HR 0.55, 95IC [0.20-1.56], p = 0.264). No significant difference in 2-year PFS (BxPK vs Bx2: 62% vs. 51%, p = 0.391) and OS (BxPK vs Bx2: 70% vs. 61%, p = 0.667) was observed. CONCLUSION In patients older than 55 years who are usually candidates for RIC regimen, the use of PK-guided busulfan myeloablative dose allows delivering higher antitumor intensity without increasing NRM. Beyond the feasibility, we observed low incidence of relapse (19%) and promising OS (70%) suggesting that conditioning intensification may lead to long term disease control. These trends need to be confirmed in a larger comparative study for validating the optimal conditioning intensity in older and/or unfit patients. Disclosures Stoppa: takeda: Other: travel fees; celgene: Other: travel fees, lecture fees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Chabannon:Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees. Blaise:Pierre Fabre medicaments: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Allogeneic stem cell transplantation improves survival in relapsed Hodgkin lymphoma patients achieving complete remission after salvage treatment

Allogeneic stem cell transplant (alloSCT) is a current treatment option for patients with refractory/relapsed classic Hodgkin lymphoma (CHL), including those who have failed an autologous transplantation. We performed a retrospective multicenter analysis of 113 patients (median age 28 years; range 14-56; 54% males) with refractory/relapsed (R/R) CHL who had undergone alloSCT in Argentina. Kaplan-Meier was used to estimate overall (OS) and progression-free survival (PFS). Relapse rate (RR) and non-relapse mortality (NRM) were estimated with cumulative incidence analysis. Disease status at transplant was complete remission (CR) in 39%, partial remission (PR) in 44%, and stable/progressed disease (S/PD) in 17% of the patients. Donor type was matched related (MRD) in 60%, unrelated (URD) in 19%, and haploidentical (HID) in 21% of the patients. OS and PFS at 2 years were 43% and 27%, respectively, for all the cohort. In the univariate analysis, patients in CR showed better OS (p ≤ 0.001) and PFS (p ≤ 0.001), and lower NRM (p = 0.04). HID had better PFS (p = 0.04) and lower RR (p = 0.02). In the multivariate analysis, CR showed a significant impact on OS and PFS, and HID on PFS. AlloSCT is a feasible procedure in patients with CHL. Those in CR at the time of the transplant had better outcomes. Haploidentical transplantation is associated with better PFS in these patients with poor prognosis.

Alternative Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe

Alternative Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe

Inferior Outcome of Allogeneic Stem Cell Transplantation in First Complete Remission for Secondary AML As Compared to De Novo Disease: Results from a Retrospective, Registry-Based Analysis on Behalf of the Acute Leukemia Working Party of the EBMT

Background: Acute myeloid leukemia (AML) secondary to haematological neoplasia or other malignant diseases, defined as secondary AML (sAML), is thought to have an inferior prognosis as compared with de novo AML. However, when corrected for other risk factors such as age and cytogenetic risk, differences are less clear. In particular, it is uncertain whether outcome after allogeneic stem cell transplantation (alloSCT) is different. Thus, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) performed a registry-based analysis to compare results after alloSCT for sAML versus de novo AML.Methods: Inclusion criteria were age >= 18y and alloSCT for de novo or sAML from a matched related, matched unrelated or T-cell replete haploidentical donor between 2000 and 2016. Patients without information on cytogenetics were excluded. 11439 patients with de novo and 1325 with sAML were identified. A multivariate Cox model was performed to account for imbalances of risk factors between the two cohorts; it was stratified for different stages at alloSCT, due to a significant interaction between stage at transplant and diagnosis (de novo or secondary) . In a second approach, a matched pair analysis of secondary versus de novo AML was done, using the following criteria for matching: Age (+/-3 years), stage at alloSCT, Karnofsky performance score, conditioning intensity, in and ex vivo T cell depletion, donor type, donor/recipient sex and CMV-status combination, cytogenetics, and graft source.Results: Median follow up after alloSCT was 36 and 33 months for de novo and sAML, respectively. In a multivariate Cox model focusing on transplants in first complete remission (CR1), sAML was associated with a higher non-relapse mortality (NRM; HR=1.32; p<10-5) and relapse incidence (HR=1.28; p=0.0002), and a lower leukemia-free survival (LFS, HR=1.30;, p<10-5), overall survival (OS, HR=1.32; p<10-5 ) and GvHD/relapse free survival (GRFS, HR=1.20; p<10-5 ), as compared to de novo AML. Other prognostic factors for OS were age (p=<10-5), cytogenetics (intermediate, p=0.002, poor, p=<10-5), patient/donor sex combination (female in male, p=<10-5) KPS (<>80, p=0.003) and donor type (unrelated (UD) 10/10 match, p=0.007; UD 9/10 match, p=10-5; haplo, p=0.002)., Three-year cumulative incidence of relapse and non-relapse mortality after alloSCT in CR1 were 28.5%/16.4% for de novo AML (n=7691), and 35%/23.4% for sAML (n=909), 3-year overall survival (OS), leukemia-free survival (LFS) and GvHD-relapse-free survival (GRFS) were 60.8%, 55.1% and 38.6%for de novo and 46.7%, 41.6% and 28.4% for sAML. (Figure 1). In contrast, when focusing on patients transplanted for primary refractory disease (sAML, n=199, de novo AML, n=607) or for relapsed leukemia (sAML, n=124, de novo AML, n=1009), Cox models did not identify sAML as a relevant factor for outcome. Risk factors for OS in advanced disease stages are presented in Table 1.Using the criteria described above, 877 well-matched pairs were identified. The pair-matched analysis confirmed the above findings: Over all patients, sAML was associated with higher NRM (p=0.004) and lower LFS (p=0.004), OS (p=0.008) and GRFS (0.04). However, when the analysis was stratified by stage at SCT, again differences were only seen among patients transplanted in CR1 (719 pairs, 82%), but not after alloSCT in advanced disease.Conclusion: Our large-scale, registry-based analysis identified sAML as an independent risk factor for outcome after alloSCT in first complete remission. In primary refractory and relapsed AML, other factors such as age, cytogenetics and performance status were of higher relevance. This data may help to improve risk stratification and prognostic estimates after alloSCT for sAML. [Display omitted] DisclosuresSchmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Beelen:Medac: Consultancy, Other: Travel Support. Mohty:MaaT Pharma: Consultancy, Honoraria.

Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors — a Retrospective Study By the EBMT Chronic Malignancies Working Party

Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors.Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis.Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1).Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. [Display omitted] DisclosuresFinke:Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Estimating Genetic Relatedness in Admixed Populations.

Estimating genetic relatedness, and inbreeding coefficients is important to the fields of quantitative genetics, conservation, genome-wide association studies (GWAS), and population genetics. Traditional estimators of genetic relatedness assume an underlying model of population structure. Each individual is assigned to a population, depending on a priori assumptions about geographical location of sampling, proximity, or genetic similarity. But often, this population assignment is unknown and assumptions about assignment can lead to erroneous estimates of genetic relatedness. I develop a generalized method of estimating relatedness in admixed populations, to account for (1) multi-allelic genomic data, (2) including all nine Identity By Descent (IBD) states, and implement a maximum likelihood based estimator of pairwise genetic relatedness in structured populations, part of the software, InRelate. Replicated estimations of genetic relatedness between admixed full sib (FS), half sib (HS), first cousin (FC), parent-offspring (PO) and unrelated (UR) dyads in simulated and empirical data from the HGDP-CEPH panel show considerably low bias and error while using InRelate, compared to several previously developed methods. I also propose a bootstrap scheme, and a series of Wald Tests to assign relatedness categories to pairs of individuals.

Haploidentical T-Repleted Stem Cell Transplantation (SCT) Has Comparable Survival to 10/10 and 9/10 Unrelated SCT in Poor-Cytogenetics Risk Acute Myeloid Leukemia in First Complete Remission: A Study on Behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Allogeneic stem cell transplantation (SCT) is the most powerful therapy to prevent relapse in poor-cytogenetics risk acute myeloid leukemia (poorAML) patients (pts) in first complete remission (CR1). For pts who lack a matched related donor (MRD), SCT from an unrelated (UD) or alternative donor is indicated. Pts with poorAML and thus at high risk of relapse can theoretically benefit the most from SCT from haploidentical donors (HaploSCT), which is an attractive option as the time required to find a well-matched UD could be inacceptable. Several recent reports show comparable outcomes between HaploSCT and transplants from UD (Piemontese S, JHO 2017; Versluis J, Blood Advances 2017). Comparative studies able to include sufficient numbers of pts with poorAML in CR1 are limited; this prompted us to compare the outcomes of HaploSCT to those of 10/10 and 9/10 HLA-matched UD in this disease category.Methods: We retrospectively selected denovo poorAML pts in CR1 receiving T-repleted haplo (n=74), 10/10 UD (n=433) and 9/10 UD SCT (n=123) from 2007 to 2015 who were reported to the ALWP of EBMT Registry. PoorAML was defined as the presence of: complex karyotype (at least 3 structural abnormalities per clone); monosomal karyotype (1 autosomal monosomy plus 1 monosomy or structural abnormality); inv(3)/t(3;3); -5 or del(5q); -7 or abn(7q); t(v;11)(v;q23); abn(17p); t(6;9); t(9;22). Primary endpoints were leukemia-free survival (LFS) and overall survival (OS). Secondary endpoints were acute and chronic GVHD (aGVHD and cGVHD), relapse and nonrelapse mortality (NRM).Results: Main population characteristics are depicted in Table 1. Recipients of haplo-, 10/10 UD- and 9/10 UD-SCT were comparable concerning time from diagnosis to SCT and time from CR1 to SCT. HaploSCT more likely received bone marrow as stem cell source. In-vivo T cell depletion (TCD) with ATG was most likely adopted in UD-SCT, with a conversely increased use of high-dose post-transplant Cyclophosphamide as GvHD prophylaxis backbone in HaploSCT (65% Vs 3% for 10/10 UD and 2% for 9/10 UD, p<10¯³).LFS and OS at 2 years were not significantly different between haploSCT, 10/10 UD SCT and 9/10 UD SCT (53±12% and 59±12%, 43±5% and 50±6%, 44±9% and 50±9%, respectively, p=0.5 and p=0.5, respectively).In Haplo-SCT, the 100-day cumulative incidence (CI) of grade≥2 aGvHD was in line with the one reported for 10/10 and 9/10 UD (33±11% for haplo, 30±4% for 10/10 UD and 34±9% for 9/10 UD, p=0.6). Likewise, the 2-y CI of cGvHD (35±12%) of HaploSCT was similar to those of 10/10 UD (36±4%) and 9/10 UD (36±9%), p=0.8. The 2-y CI of NRM was 19±8% after haploSCT, 18±4% after 10/10 UD SCT and 18±6% after 9/10 UD SCT (p=0.9). Relapse incidence was not significantly affected by donor source, with a 2-y CI of 27±9% for haploSCT, 39±5% for 10/10 UD SCT and 37±9% for 9/10 UD SCT (p=0.3).After adjustment for centre effect, pts age, time from diagnosis to SCT, conditioning intensity, in-vivo TCD, donor/pts gender and CMV serostatus, the multivariable model showed that haploSCT recipients didn't experience worse outcomes compared to 10/10 and 9/10 UD. Indeed, compared to haploSCT (reference) the hazard ratio (HR) for LFS was 1.2 for 10/10 UD (p=0.3) and 1.2 for 9/10 UD (p=0.4). The hazards for OS in 10/10 and 9/10 UD did not differ from haplo-SCT (1.3, p 0.3 and 1.2, p 0.4, respectively). Moreover, compared to haplo, SCT from 10/10 and 9/10 UD was not associated with lower hazards for relapse (HR: 1.4, p=0.2 and 1.4, p=0.3, respectively), NRM (HR: 1, p=0.9 and 1, p=0.9, respectively), grade≥2 aGvHD (HR: 1.2, p=0.6 and 1.4, p=0.3, respectively) and cGvHD (HR: 1.2, p=0.5 and 1.3, p=0.4, respectively). The only factor associated with worse LFS and OS was pts age (for each 10-year interval: HR 1.1, p=0.02 and 1.2, p=0.001, respectively).Conclusions: In the present series of poorAML pts transplanted in CR1, haploSCT recipients experienced comparable outcomes with respect to 10/10 and 9/10 HLA-matched UDs. This suggests that the immunotherapeutic effect of allogeneic SCT is exerted similarly across these different donor sources in this peculiar population. Therefore, in the absence of a MRD, pts with poor risk cytogenetics who have a very high risk of relapse could be allocated to haploSCT in their first remission, especially in the context of the recent improvements, which fostered an abatement of GvHD and NRM rates, historically the main detrimental factors for Haploidentical transplants. [Display omitted] DisclosuresCiceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.

Reduced-Intensity Conditioning with Busulfan, Fludarabine, and Antithymocyte Globulin for Hematopoietic Cell Transplantation from Unrelated or Haploidentical Family Donors in Patients with Acute Myeloid Leukemia in Remission

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.