Reduced-intensity Regimen Research Articles

Better Outcome in Children Compared to AYAs and Young Adults after Allogeneic HSCT for AML: A Multicenter Retrospective Study from the Societe Francophone De Greffe De Moelle Et De Therapie Cellulaire (SFGM -TC)

The two first authors contributed equally.IntroductionThere is currently little data on the outcome of AML in adolescents and young adults (AyAs) after allogeneic HSCT. In this retrospective study from the SFGM-TC registry, we analyzed the outcome of AML patients classified in 3 groups according to the age at transplantation: children (<15 years), AyAs (15-25 years) and adults (26-40 years) in the goal to determine factors influencing survival and NRM differences.Patients and MethodThis study included 2240 patients from 43 centers among France, Belgium, Switzerland, Lebanon and Algeria, of whom 481 children (21.5%), 545 AyAs (24.3%) and 1214 adults (54.2%). All patients received a first allogeneic HSCT for AML between 2005 and 2015. Five-years OS, NRM, GRFS and EFS and cumulative incidence of relapse were compared between the three groups of patients.ResultsThe median follow-up of the study was 7 years (range, 4-9.6). According to the 2016 WHO classification, children had the highest rate (31.8%) of adverse risk disease, followed by AyAs (25.2%) and adults (21.3%) (p=0.0001). Extramedullary disease was observed in 42.8%, 24% and 21.4 % of children, AyAs and adults (p=0.0001). Among patients in complete remission (CR), younger age was associated more frequently with advanced disease (29.9% ≥ CR2 for children, 23% for AyAs and 18.2% for adults) (p=0.0001). Donors were matched siblings in 36.4% of children, 36.7% of AyAs and 40.3% of adults, and matched unrelated in 29.1%, 33.4% and 35.7% respectively. Children had more mismatched unrelated donors (31.6%), compared to AyAs (25.3%), and adults (19.5%) (p=0.0001). Stem cell source was different between the 3 groups (p=0.0001): bone marrow (BM) was the main source for children (60.9 % of grafts) followed by cord blood (CB) (28.9%), whereas peripheral blood stem cells (PBSC) was the main source for adults (60 %), followed by BM (29.7%) and CB (10.2%). AyAs were transplanted with BM in 44.4% of cases, PBSC in 40.4% or CB in 15.2%. The intensity of the conditioning was myeloablative (MAC) in 93% of children, 79% of AYAs and 77.7% of adults, while a reduced-intensity regimen was used in 4% of children, 12.3% of AyAs and 14.1 % of adults (p=0.0001).The 5y-overall survival (OS) was higher in children (64%), compared to AyAs (54%) and adults (52%) (p=0.001) (figure). One-year cumulative incidence (CI) of relapse was comparable in the 3 groups: 27 % for children, 33% for AYAs and 28% for adults (p=0.19) (figure). The 5y-CI of EFS and the 5y-CI of NRM were better for children (56%) compared to AyAs (49%) and adults (47%) (p=0.017) respectively and 11%, 18% and 27% for NRM in each group respectively (p=0.0001).Regarding causes of deaths, GvHD related mortality was significantly higher in AyAs and adults with 3.1%, 5.1% and 7.7% in each group respectively. There was no difference in the CI of grade II-IV acute GvHD at day +100 between the 3 groups: 37.7%, 35.8% and 35% respectively (p=0.58) while the one-year CI of chronic GvHD was higher in adults (37%) and AyAs (31%) compared to children (17%) (p=0.0001) (Figure).AyAs had a significantly lower 5y-OS and 5y-EFS than children and AyAs had a greater risk of NRM than children in this study. Moreover the GRFS is significantly better in children with 5y-survival 26% for children, 18% for AyAs and 17% for adults (p=0.011) (figure).In univariate and multivariate analysis, independent factors associated with OS were age, TBI, cytogenetics and status of disease, HLA matching and donor age.ConclusionAyAs patients seem to have greater risk of NRM and cGvHD after HSCT than children. This study suggests that AyAs should be treated more like children and that donor age and HLA compatibility should be considered in the treatment strategy. [Display omitted] DisclosuresChalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Beguin:Kiadis Pharma: Consultancy. Peffault De Latour:Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Recovery of Specific Subsets of Natural Killer and T Cells Highly Associated with Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in Acute Leukemia

Background In the allogeneic hematopoietic stem cell transplantation, recent studies showed that T cell and natural killer (NK) cells recovery are implicated in the graft-versus-host disease (GVHD) and graft versus leukemia (GVL) effects. However, the significance of specific subsets of NK and T cell recovery in relation to transplantation outcomes remains to be elucidated in the haploidentical stem cell transplantation (haploSCT).Methods Clinical data of patients with acute myeloid leukemia (n = 21) and acute lymphoblastic leukemia (n = 24) who underwent their first haploSCT between September 2009 and December 2017 were analyzed. Peripheral blood mononuclear cells obtained from 27 patients were examined by multiparametric flow cytometric analysis. PD-1 and Tim-3 expression were examined in CD4+ and CD8+ T-cells and NK cell receptor (NKG2D, NKG2A, NKG2C, DNAM1 and NKp46) expression were analyzed in NK cells, respectively, at the 3 determined times (immediate prior to conditioning therapy, 28 and 90 days after haploSCT).Results Median age at haploSCT was 38 years (range, 21-62) and median follow-up duration was 31.6 months. Myeloablative conditioning was used for 32% and reduced intensity regimen for 68% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide for 8 (18%) or on anti-thymocyte-globulin for 36 (82%) plus standard prophylaxis. Incidence of grade II-IV acute GVHD was 50%, gastrointestinal tract (GIT) GVHD was 55.6%, non-GIT acute GVHD 35.7%, and chronic GVHD was 52.4%. Longitudinal analysis of immune reconstitution after haploSCT showed that the incidence of acute GVHD was associated with a delayed expansion of the NK cell population and incidence of chronic GVHD was associated with the extent of CD4+ T cell reconstitution. The incidence of acute GVHD was significantly higher in patients with lower counts of CD56bright CD16neg cell (100% for patients with less than 30 cells/uL at day 28 vs 50% for patients with higher counts, P = 0.026), particularly in NKG2A (P = 0.002) and DNAM1 (P = 0.027)-positive NK cell subsets. In univariate analysis, early CMV replication (P < 0.001), chronic GVHD (P = 0.001), donor age ≥ 28years (P = 0.018), CD4/CD8 ratio of product ≥ 2.4 (P = 0.033), and dose of infused T cells ≥ 3.91 x 108 /kg (P = 0.022) were significantly associated with lower 3-year cumulative incidence of relapse after haploSCT. Donor age ≥ 28years was significantly associated with high incidence of chronic GVHD (P = 0.002). Dose of infused T cells ≥ 3.91 x 108 /kg (HR, 0.088; CI, 0.009 to 0.823; P = 0.033) were independent factors for reducing leukemia relapse after adjustment in multivariate analysis. Chronic GVHD was an independent prognostic factor for higher leukemia-free survival rate (72.7% versus 20.1%, P = 0.008). Longitudinal analysis of T cell reconstitution after haploSCT showed that the high dose of infused T cells was associated with the increased expansion of CD4+PD-1- T cells (P = 0.031 at day 28 and P = 0.017 at day 90). Of note, The incidence of chronic GVHD was significantly higher in patients with higher counts of CD4+ T cell at day 28 (100% for patients with over than 150 cells/uL at day 28 vs 38.8% for patients with lower counts, P = 0.008), particularly in CD4+PD-1- subsets (P = 0.008). Among CD4+ T cell, PD-1-/PD-1+ ratio over than 4.5 was significantly associated with increased chronic GVHD (P = 0.005). In 22 patients with chronic GVHD, GIT GVHD was adverse prognostic factor for overall survival (59.5 % in GIT GHVD vs 100% in patients without GIT GVHD, P = 0.063). The incidence of GIT GVHD was significantly higher in patients with lower CD4/CD8 ratio at day 28 (77.8% for patients with less than 1.5 vs 0% for patients with higher ratio, P = 0.045).Conclusions Our findings suggest that high CD56brightCD16neg NK cell count at day 28 after hasploSCT was significantly associated with decreased incidence of acute GVHD. High dose of infused T cells was associated with increased reconstitution of CD4+ PD-1- T cells and high CD4+ T cell counts, particularly in PD-1- subset, are associated with increased development of chronic GVHD. These findings should be further validated for elucidating the roles of these immune effectors cells in the development of GVHD and GVL effect in haploSCT for acute leukemia. DisclosuresKim:Novartis Korea: Honoraria.

Alternative-Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Pediatric Patients: A Systematic Review and Meta-Analysis

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched sibling donor for patients with sickle cell disease (SCD) provides excellent curative potential with acceptable rates of graft rejection and other common post transplant complications. However, in the United States, only 18% of patients with SCD have an HLA-matched sibling donor. Hence, multiple studies adopted various strategies to figure out alternative donors with favorable outcomes. Poor engraftment, graft versus host disease (GVHD) and regimen related toxicities are the main obstacles following alternative-donor transplant. To overcome these complications, different modalities had been experimented targeting the source of the stem cell, CD34 and TNC cell counts, pre-transplant conditioning regimens and adding immunosuppressive drugs pre/post transplant. However, so far there is no worldwide consensus about robust strategy for alternative donor HSCT.AimThe aim of this review is to systematically evaluate the outcomes of alternative-donor HSCT in patients with SCD in pediatric population, and correlate the outcomes with experimented interventional regimens.MethodsWe searched PubMed, SCOPUS, Embase, Cochrane and Clinical trials.gov from 2000 till February 2018. We utilized the Systematic Reviews and Meta-Analyses guidelines for Preferred Reporting Results (PRISMA). Two reviewers independently screened titles/abstracts, assessed full-text articles, extracted data from included articles, and assessed their quality. Risk of bias in the included studies was assessed using ROBINS-I tool. Data of platelet/neutrophil recovery, acute/chronic GvHD incidence and overall survival were pooled in a single-arm meta-analysis approach.ResultsOf the 2886 records examined, 19 met predefined criteria. 16 studies were included in the meta-analysis. 12 clinical trials, 5 cohort observational studies and 2 case reports. All studies had a sample size <50. The pooled times of platelet and neutrophil recovery were 31.55 and 20.15 days, respectively. The pooled incidences of acute and chronic GvHD were 36.1% and 21.7, respectively (Figure 1). The pooled one-year overall survival was 90.3% and two-years was 88.3%. Neutrophil engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 16 days (7-32) compared to 23 days (12-42) after Myelo-ablative Conditioning, (P=0.013). Platelet engraftment was earlier and more sustained after using Reduced Intensity Conditioning, 29 days (15-204) in comparison to 62 days (18-123) after Myelo-ablative Conditioning, (P=0.026). The median duration of neutrophil engraftment after mismatched related donors was 14 days (14-17), after unrelated donors was 14 days (9-25) , after haplo-identical transplantation was 14 days (12-16), after umbilical cord blood transplantation (UCBT) was 23 days (7-42), (P=0.001). The median duration of platelet engraftment after haplo-identical and mismatched related transplantation was 19 days, after matched unrelated donors was 19 days (18-24), after mismatched unrelated donors was 22 day (19-37) and after UCBT was 47 days (15-204), (P=.001). There was no significant difference in acute/chronic GvHD between different types of alternative donors but acute GvHD was significantly less in Myelo-ablative Conditioning compared to Reduced Intensity Conditioning (P=.036)ConclusionOur systematic review showed better outcomes with using Myelo-ablative Conditioning and post transplant cyclophosphamide in haplo-identical transplantation compared to using Reduced Intensity Conditioning. Adding pre-transplant immunosuppressive drugs in haplo-identical transplantation didn't significantly improve the outcomes. In unrelated donor no significant difference between Myelo-ablative Conditioning and Reduced Intensity Conditioning but adding Mesenchymal Stem Cell to the reduced intensity regimen improved the outcomes. In UCBT and mismatched related donors, Reduced Intensity Conditioning had better outcomes especially with high doses of TNC and CD34 cell counts and with applying Mesenchymal Stem Cell or adequate dose of Alemtuzumab. Randomized controlled trials are mandated to generate standardized regimen in the setting of alternative-donor HSCT. DisclosuresNo relevant conflicts of interest to declare.

Impact of Early Immune Reconstitution after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction:Immune reconstitution (IR) has a significant impact in HSCT outcome with a role against opportunistic infections and in disease control. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infection related mortality (IM).The aim of this study was to evaluate the impact of early IR on different HSCT outcomes in patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution.Patients and methods:Eighty-eight patients received a Haplo-HSCT from 2011 to 2016. Thirty-six percent of the patients received myeloablative conditioning regimen and 64% received reduced intensity regimen. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil. Early IR was assessed through the analysis of different lymphocyte subpopulations at days +30 and +90 after transplantation, including ALC30 (cellular analyzer DXH, Beckman Coulter®); CD3+ lymphocyte count and their different subpopulations (CD4+ and CD8+ lymphocytes, naive and memory T cells) and NK cells count. Lymphocytes subpopulations were determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®). ROC curves were used to determine the optimal cut-off values for each of the studied variables.Results:Eighty-one patients were studied, excluding 7 who died before day +30. Median follow-up was 26 months (10-43). Patient´s characteristics are shown in Table 1.CMV reactivation was documented in 76% (62) of the patients, 4% (3) developed a proven invasive fungal infection, and 31% (25) presented hemorrhagic cystitis. Median OS and DFS were 26 months (10-43) and 24 months (9-39), respectively. IM rate and NRM rate were 10% and 24%, respectively, at the end of follow up.Median lymphocyte populations counts at day +30 are shown in Table2.ALC30 below 100 cells/uL (p= 0.027) and CD4+ naïve lymphocytes below 12 cells/uL (p=0.033) (both corresponding to the 25 percentile) were associated with lower OS compared to patients with higher counts at day +30 (Figure 1).Patients with ALC30 lower than 300 cells/uL (p=0.026) showed significantly higher NRM; CD8+ count lower than 20 cells/uL (p=0.022) also showed higher NRM.NK cells counts at day +30 lower than 14 cells/uL (p=0.014), near to percentile 25, predicted higher IM (62.5% vs 37.5%).We did not identify any lymphocyte subpopulation that could predict DFS. Patients with acute GVHD grades II-IV showed values of ALC30 lower than 200 cells/uL (p=0.051), although non-statistically significant. No relationship was found between lymphocytes subpopulations at day +90 and HaploSCT outcomes.Conclusions:Our study supports the prognostic significance of early IR after unmanipulated haploidentical transplantation with PTCy, as previously described by other groups. ALC30, CD4+ naïve lymphocytes, and CD8+ lymphocyte count at day +30 may be good early predictors for OS and NRM in this setting. On the other hand, low NK cells counts (lower than percentile 25) predicted higher IM. Patients with very low lymphocyte counts should be monitored closely as they are at high risk for infectious complications, NRM and OS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Cytokine Release Syndrome on Outcomes after T-Cell Replete Peripheral Blood Haploidentical Donor Transplantation

Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) is an advancing and potentially curative therapy for patients with hematologic malignancies when the availability of HLA-matched donors are limited. The common source for haplo-HCT is donor bone marrow, but peripheral blood (PB) haplo-HCT is an emerging and less invasive option with similar survival outcomes. However, multiple series showed an increased incidence of culture negative fever early after haplo-HCT, which has been attributed to cytokine release syndrome (CRS) and more commonly observed with PB haplo-HCT. In this study, we investigated the incidence and impact of CRS on clinical outcomes and financial toxicity in PB haplo-HCT patients treated at a single center.Methods: A total of 40 patients who underwent PB haplo-HCT in the Ohio State University between Jan 2015 - Dec 2017 were included. CRS was defined and graded based on the criteria proposed by Lee, et al (Blood, 2014). Symptoms occurring before day +14 were included, patients with a documented infection (e.g. positive culture data) and clinical suspicion of sepsis were excluded. Overall survival (OS) was defined as the time from transplantation until death. Transplant-related mortality (TRM) was defined as death before day +28 from any cause and patients who died after day +28 with no evidence of disease.Results:. The median age at HCT was 53 years (range, 19 to 74), 63% were male. The most common diagnosis was acute myeloid leukemia (47.5%), followed by lymphoma (22.5%), acute lymphoblastic leukemia (7.5%) and myelodysplastic syndrome (7.5%). Two patients had undergone previous autologous HCT. At the time of haplo-HCT, 62% of patients were in complete remission, 38% had relapsed/refractory disease. Donor was the child in 58%, sibling in 24% and parent in 18% with an antigen match ratio of 5/10 in 50%, 6/10 in 30%, 7/10 in 12.5%, 8/10 in 7.5%. Mismatch for sex and ABO blood group were seen in 50% and 45%, respectively. Twenty percent of patients received myeloablative conditioning with fludarabine/busulfan/thiotepa, while 80% received reduced-intensity regimen with fludarabine/cyclophosphamide/total body irradiation. The incidence of CRS was 85%, including grade 1-2 CRS in 77.5% and grade 3-4 CRS in 7.5%. Time to the onset of CRS was <4 days in all cases, with 82% showing evidence of CRS within the first 48 hours. The incidence and severity of CRS did not differ by patient age, sex, remission status at the time of HCT, sex mismatch, ABO mismatch, degree of HLA matching, type of conditioning, or total nucleated cell dose. In 34 patients with CRS, most common symptoms were fever (88.2%), hypotension (15%), and worsening oxygen requirement (12%). Two patients (6%) experienced grade 2 creatinine elevation and another 2 (6%) experienced grade 1-2 transaminitis. Among 3 patients with severe CRS, 1 received tocilizumab and 1 received methylprednisolone after the onset of CRS. Patients with mild CRS (n= 31) had significantly better OS than the patients with severe CRS and no CRS (n=9) (median OS not reached, 11 months, 10.5 months, respectively, p= 0.005). Similarly, relapse-free survival (RFS) was longer in the mild CRS group than the patients with severe CRS and no CRS (p= 0.02). TRM was 20% in patients with mild CRS, when compared to 66% (2/3) in severe CRS and 33% (2/6) in patients without CRS. The duration of hospitalization was significantly longer in patients who experienced severe CRS as compared to patients with mild CRS or without CRS (40 vs 27.6 vs 27.4 days, p= 0.01). Concomitantly, inpatient cost of admission for HCT was significantly higher in patients with severe CRS (mean, $849,571) as compared to patients with mild CRS ($543,074) and without CRS ($574,632) (p= 0.04).Conclusions: CRS is commonly observed after PB haplo-HCT and usually manifests with fever within 48 hours of cell infusion. We observed favorable survival outcomes in patients who experienced mild CRS, which may suggest an association between mild CRS and graft-versus-leukemia effect. A minority of patients developed severe CRS requiring intensive care unit support, which was associated with poor OS, high TRM, prolonged hospital stay and increased financial toxicity. Further studies investigating biomarkers that can predict the development of severe CRS might enable the incorporation of CRS prophylaxis (e.g. with tocilizumab) into standard conditioning regimens for PB haplo-HCT. DisclosuresVasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Mims:Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Devine:Kiadis Pharma: Consultancy. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy.

Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan

Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare BCR-ABL1 fusion gene-negative myeloid neoplasms with a predominance of neutrophils. Since no standard therapeutic strategy currently exists for these diseases, we retrospectively evaluated the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aCML and CNL. Data from 14 aCML and 5 CNL patients as their diagnoses were collected using a nationwide survey. Allo-HSCT was performed between 2003 and 2014. Preconditioning regimens included myeloablative (n = 15), reduced-intensity (n = 3), and non-myeloablative (n = 1) regimens. Transplanted stem cells were obtained from HLA-matched related donors (n = 5) and alternative donors (n = 14). Neutrophil engraftment was successfully achieved in 17 patients. One-year overall survival rates (OS) were 54.4% (95% confidence interval [CI], 24.8 to 76.7%) and 40.0% (95% CI, 5.2 to 75.3%) in patients with aCML and CNL, respectively. Among aCML patients, 1-year OS were 76.2% (95% CI, 33.2 to 93.5%) and 20.0% (95% CI, 0.8 to 58.2%) in patients with <5% myeloblasts (n = 9) and ≥5% myeloblasts (n = 5) in peripheral blood before allo-HSCT, respectively. These results suggest that allo-HSCT achieves long-term survival in patients with aCML and CNL. Better pre-transplant management is required to improve the outcomes of aCML patients with ≥5% blasts in peripheral blood.

Alemtuzumab vs anti-thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning.

Relapse and graft-vs-host disease (GVHD) are still the main complications after allogeneic hematopoietic stem cell transplantation, especially in the setting of reduced intensity regimen (RIC) and unrelated donor. We compared here anti-thymocyte globulin (ATG) or alemtuzumab as GVHD prophylaxis in patients with myeloid disease transplanted after RIC and from an unrelated donor. ATG and alemtuzumab patients have been matched by age, gender, HLA matching, comorbidities and cytogenetics risk (119 patients in each group). After matching, we found that ATG decreased the risk of relapse (HR: 0.55, P=.0049) and improved relapse-free survival (RFS, HR: 0.70, P=.042). The improved RFS with ATG was more pronounced in CMV-positive patients but was not influenced by disease risk. Regarding overall survival, GVHD-free relapse-free survival and transplant-related mortality, the risk was similar using ATG or alemtuzumab. Even if GVHD risk is lowered by alemtuzumab use, it does not translate in better outcome due to higher risk of relapse.

Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity

AbstractIn this study, we sought to identify specific individual high-intensity or reduced-intensity conditioning regimens with the best relapse-free survival (RFS) rather than the global high- vs reduced-intensity regimen comparison. Patients (median age, 58 years) with acute myeloid leukemia (AML; n = 1258), who were in first or subsequent remission, or with MDS (n = 951) who had refractory anemia with unilineage or multilineage dysplasia, 5q− syndrome, or refractory anemia with excess blasts received nonirradiation-containing regimens and were transplanted between 2009 and 2014 in the United States. Three-year RFS with high-intensity busulfan/cyclophosphamide (Bu4/Cy; 44%) was comparable to conditioning with high-intensity fludarabine/busulfan (Flu/Bu4; 44%), reduced-intensity fludarabine/melphalan (Flu/Mel; 52%; P = .53), and Flu/Mel + anti-thymocyte globulin (ATG; 44%; P = .38). RFS was lower with reduced-intensity Flu/Bu2 + ATG (31%; P = .0006). RFS was also lower with high-intensity Flu/Bu4 + ATG (38%; P = .05) and reduced-intensity Flu/Bu2 (38%; P = .02), although the difference did not reach the level of significance set for these analysis. RFS with Flu/Mel was superior to RFS with Flu/Bu2 (P = .01) and Flu/Bu2 + ATG (P = .0006). The 3-year incidence of relapse was 22% with Flu/Mel compared with 46% with Flu/Bu2 and 56% with Flu/Bu2 + ATG. With only a modest reduction in nonrelapse mortality with the Flu/Bu2 regimens, the higher relapse incidence resulted in lower RFS. The data support optimal RFS with Bu4/Cy, Flu/Bu4, and Flu/Mel regimens for AML in remission or MDS. The low relapse rate with reduced-intensity Flu/Mel resulted in RFS comparable to that after the higher-intensity regimens.

Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34+-Selected to CD3/CD19-Depleted Grafts in a Retrospective Multicenter Study.

Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.

Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission.

BackgroundA preparatory regimen consisting of thiotepa-busulfan-fludarabine (TBF) has been associated with reduced relapse in patients with haematological malignancies after haploidentical and cord blood transplants; however, few data exist regarding TBF conditioning in sibling (MSD) and unrelated donor (URD) transplants for AML.ResultsAmong patients receiving a myeloablative (MAC) regimen, TBF-MAC was associated with significantly lower relapse (HR 0.47, p = 0.005) however higher non-relapse mortality (NRM, HR 2.69, p < 10–4) as compared to BF. This led to similar leukemia-free (LFS) and overall survival (OS) between the two regimens (LFS: p = 0.6; OS: p = 0.27). When we selected TBF-MAC patients receiving busulfan 9.6 mg/kg, NRM resulted still higher but no more significantly different as compared to BF-MAC with busulfan 12.8 mg/kg (HR 1.53, p = 0.12); despite the lower busulfan dose, relapse remained inferior with TBF-MAC (HR 0.45, p = 0.01), however no difference in survival could be demonstrated (LFS: p = 0.31; OS: 0.82). Among patients receiving a reduced-intensity (RIC) regimen, similar outcome was observed with TBF-RIC and BF-RIC (LFS: p = 0.77; OS: p = 0.88).ConclusionsTBF-MAC as conditioning regimen for transplant from MSD and URD in AML patients in first remission provided stronger anti-leukemic activity but higher NRM as compared to BF-MAC, thus leading to similar survival. TBF-MAC with busulfan 9.6 mg/kg was associated with low relapse and acceptable NRM, however again with no survival benefit. TBF-RIC and BF-RIC resulted in comparable outcome.MethodsWe conducted a registry-based study comparing outcomes of patients with AML in first remission undergoing transplant from MSD or URD prepared with either TBF (n = 212) or BF (n = 2698) conditioning.

Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia

Different conditioning regimens have been evaluated in matched-related donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acquired severe aplastic anemia (SAA) with varying results. In this manuscript, we report our experience with fludarabine (120mg/m2), very low dose cyclophosphamide (1200mg/m2) and antithymocyte globulin (7.5mg/kg). Low dose total body irradiation (2Gy) was added to the conditioning regimen for patients older than 15 years. Nineteen patients (median age 23years) underwent transplant between 2008 and 2015. The majority (89%) were younger than 40 years. Stem cell source was BM (n=11) or PBSC (n=8). GvHD prophylaxis consisted of cyclosporine and either a short course of methotrexate (n=9) or mycophenolate mofetil (n=10). Eighteen (94.7%) patients achieved sustained engraftment. The median times to neutrophil and platelet engraftments were 19 (range: 14–34) and 17.1 (range: 12–25) days, respectively. The day-30 cumulative incidence of neutrophil and platelet engraftment was 89.4% and 94.7%, respectively. No secondary graft rejection was observed. The 1-year cumulative incidence of aGvHD (grade II–IV) and cGvHD was 11.7% and 0%, respectively. The 2-year GvHD-free survival rate was 78.6% (95% CI: 52.5–91.4%). Fludarabine-based reduced intensity regimen for MRD allo-HSCT in SAA compares favorably to other available regimens. This regimen deserves further investigations with larger cohort of patients.

Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT

BackgroundAllogenic hematopoietic stem cell transplantation (allo-SCT) is the most effective post-remission treatment for adults with high-risk acute lymphoblastic leukemia (ALL). The aim of the study was to analyze results of unmanipulated haploidentical allo-SCT (haplo-SCT) for adults with ALL and to identify prognostic factors.MethodsWe performed a retrospective analysis on 208 adults transplanted in EBMT centers from 2007 to 2014.ResultsMedian age at haplo-SCT was 32 years and median follow-up, 31 months. Forty-four percent of the patients were in first complete remission (CR1). Stem cell source was the bone marrow (BM) for 43% and peripheral blood (PB) for 57% of patients. Myeloablative conditioning (MAC) was used for 66% and reduced intensity regimen (RIC) for 34% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide (PT-Cy) for 118 (57%) or on anti-thymocyte-globulin (ATG) for 90 (43%) plus standard prophylaxis. One hundred eighty-four (92%) patients achieved engraftment. Cumulative incidence (CI) of grade II–IV acute-graft-versus-host-disease (GVHD) was 31%, grade III–IV 11%, and chronic GVHD 29%. Non-relapse mortality (NRM) and relapse-incidence (RI) were 32 and 37%, respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free-survival (GRFS) at 3 years were 33, 31, and 26%. For patients in CR1, OS, LFS, and GRFS were 52, 47, and 40%, respectively. Disease status was the main factor associated with transplant outcomes. Use of BM was independently associated with improvement in NRM, acute GVHD, GRFS, LFS, and OS.ConclusionsUnmanipulated haplo-SCT may be considered a valid option for adult patients with high-risk ALL lacking HLA identical donor preferably in early disease status.

Umbilical Cord Blood Transplantation: Challenges and Future Directions.

SummarySince the first successful allogeneic transplants performed in Seattle 50 years ago, the field of transplantation has evolved considerably, with improvements in human leukocyte antigen typing, patient selection, reduced intensity regimens, and graft‐versus‐host disease prophylaxis. A major breakthrough has been the availability of more donor options, first via the National Marrow Donor Program—Be the Match [Biol Blood Marrow Transplant 2008;14:2–7]. Then, in the 1990s, unrelated umbilical cord blood transplantation became available, first for children and then for adults [New Engl J Med 1996;35:157–166]. More recently mismatched unrelated transplants and haploidentical donor options became available [Blood 2011;118:282–288]. In 2017, there is a donor for almost every patient who needs a transplant. In this review, we will discuss the state of the science (and art) of cord blood transplant, focusing on successes, challenges, and future directions. Stem Cells Translational Medicine 2017;6:1312–1315

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m2. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m2 in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m2 of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.

Is myeloablative dose intensity necessary in allogeneic hematopoietic cell transplantation for lymphomas?

The advent of novel immunotherapy and tyrosine kinase inhibitors has ushered a new era in the treatment of Hodgkin and non-Hodgkin lymphomas. Allogeneic hematopoietic cell transplantation remains, however, a vital component in the management and potential cure of lymphomas, especially in the relapsed setting. Considering the biological and clinical heterogeneity of various subtypes of lymphomas, the optimal intensity of conditioning regimens remains controversial. Reduced intensity conditioning regimens have broadened applicability of the procedure to older and frail patients. Observational studies suggest that although reduced intensity allografting is associated with higher risk of relapse, overall survival is comparable and in some cases even better, than observed with myeloablative regimens. Here, we review the available published data pertaining to allogeneic hematopoietic cell transplantation using reduced intensity or myeloablative conditioning for various lymphoma histologies. Owing to the lack of randomized prospective trials, recommendations are mainly based on registry and single-institution studies. Special emphasis must be given to implementing strategies to prevent relapse when using reduced intensity regimens. Identifying particular patients who may benefit from myeloablative regimens in lymphomas remains to be better defined.

The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL.

Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert anti-neoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations. Likewise, givinostat killed primary cells, but not their normal hematopoietic counterparts, from patients carrying CRLF2 rearrangements. At low doses, givinostat downregulated the expression of genes belonging to the JAK/STAT pathway and inhibited STAT5 phosphorylation. In vivo, givinostat significantly reduced engraftment of human blasts in patient-derived xenograft models of CRLF2-positive BCP-ALL. Importantly, givinostat killed ruxolitinib-resistant cells and potentiated the effect of current chemotherapy. Thus, givinostat in combination with conventional chemotherapy may represent an effective therapeutic option for these difficult-to-treat subsets of ALL. Lastly, the selective killing of cancer cells by givinostat may allow the design of reduced intensity regimens in CRLF2-rearranged Down syndrome-associated BCP-ALL patients with an overall benefit in terms of both toxicity and related complications.

Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency.

Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor—a healthy heterozygous LRBA mutant carrier—was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

Circulating Microparticles As Predictive Biomarkers of Acute Graft Versus Host Disease

Background Graft-versus-host disease (GvHD) remains a leading cause of morbidity and mortality among allogeneic stem cell transplantation (SCT) patients. New research focusing on diagnostic methods and therapeutic interventions is required. Microparticles (MP) are structures ranging from 0.1 to 1 µm that are derived from the cell membranes of different cellular subtypes. The majority of circulating microparticles are derived from megakaryocytes (platelets) and erythrocytes. These structures have been described as biomarkers of cellular damage, activation, and intercellular signaling in in several autoimmune and vascular diseases. Whether the biologic events that characterize GvHD can alter the shedding of microparticles has not been described.Methods Patients who underwent allogeneic stem cell transplantation between august 2012 and September 2014 at the Hospital Sirio Libanes (Sao Paulo, Brazil) were included. Adult and pediatric patients were consecutively enrolled if neutrophil engraftment was achieved. Circulating MP were isolated and quantified by flow citometry. Annexin V-positive (total microparticles - TMP), CD61+ platelet-derived microparticles (PMP) and CD235+ erythrocyte-derived microparticles (EMP) were measured at neutrophil engraftment.Results MP were studied in the plasma of 48 patients. The levels of PMP were not associated with the risk of acute GvHD. However, the cumulative incidence (CI) of aGVHD was significantly increased among the patients with EMP counts above 360/µL at engraftment (59% vs. 26%, P=0.04). Higher EMP counts were associated with increased incidence of skin aGVHD (53% vs. 17%,P=0.02) and liver aGVHD (33% vs. 0%, P=0.002). There was no significant association between higher EMP count and incidence of gastrointestinal (GI) aGVHD (42% vs. 20%, P=0.10). The microparticles counts at engraftment were influenced by the intensity of the conditioning regimen. When compared with reduced intensity regimens, myeloablative regimens were associated with significantly higher EMP counts (152 vs. 349/µL, P=0.03). In patients exposed to reduced intensity conditioning regimens, a stronger association of a high EMP count and acute GvHD was observed (89% vs. 23%; p=0.002). A high EMP count was predictive of skin aGVHD (78% vs. 14%, P=0.002), liver aGVHD (67% vs. 0%, P<0.001), and GI aGVHD (72% vs. 20%, P=0.006).Conclusion Our data suggest that higher counts of erythrocyte-derived microparticles at engraftment may be associated with a greater risk of acute GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Immune Reconstitution Impact on Overall Survival after Hematopoietic Haploidentical Stem Cell Transplantation

Introduction:Early immune reconstitution (EIR) is clinically relevant for the outcome of allogeneic hematopoietic stem cell transplantation. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infectious mortality (IM).The aim of this study was to evaluate the impact of EIR on OS, DFS and IM among patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution.Patients and methods:Sixty-six patients received a Haplo-HSCT at our institution from July 2011 to February 2016. Conditioning regimen consisted of fludarabine, cyclophosphamide and busulfan. Forty-five percent of the patients received a myeloablative regimen, including busulfan for 3 or 4 days, while 55% were conditioned using a reduced intensity regimen with 1 or 2 days of busulfan. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil.EIR was assessed by means of ALC30 (cellular analyzer DXH, Beckman Coulter®), CD3+ lymphocyte count on day +30 (CD3-30) and NK-lymphocyte count on day +30 (NK30), both determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®).The Kaplan-Meier method was used to evaluate OS rate and DFS rate. Differences in survival rate were assessed using the log-rank test. P values <0.05 were considered statistically significant.Results:We analyzed 66 patients, with a median follow-up of 17 months (8-31). The median age of the patients was 43 years (range 30-57), 77% were men. The diagnosis were: acute myeloid leukemia 33%, acute lymphoid leukemia 8%, chronic myeloid leukemia 6%, Hodgkin lymphoma 21%, non-Hodgkin lymphoma 17%, myelodysplastic syndrome 8%, myelofibrosis (MF) 4%, others 3%. Most patients were in complete remission at the time of the transplant (56%), while 21% were in partial remission and 23% with overt disease.CMV reactivation was documented in 74% of the patients, 8% developed a proven invasive fungal infection and 36% suffered from hemorrhagic cystitis. Median OS and DFS were 17 (8-31) and 13 months (7-26), respectively. IM rate was 27% at the end of follow up.ROC curves were used to determine the optimal cut-off values for each of the studied variables: 300 cells/µL for ALC30, 120 cells/µL for CD3-30 and 40 cells/µL for NK30 were chosen.Those patients with an ALC30 ≥ 300/µL had longer OS (p=0.001) and DFS (p=0.005). Median OS and DFS were 25 months vs. not reached (NR) and 13 months vs. NR respectively.Patients with CD3-30 ≥120/µL had better OS (p=0.07, non-significant) and similar DFS than those with CD3-30 <120/µL. No differences were observed for the NK30 in terms of OS and DFS. Cumulative incidence of IM was significantly lower in patients with an ALC30≥300 (p=0.001). Cumulative incidence of relapse was not affected by ALC30. Patients with CD3-30>120/µL had a lower incidence of relapse than patients with CD3-30<120/µL (p=0.06, non-significant).Conclusions:Our study supports the independent prognostic significance of early immune reconstitution after unmanipulated haploidentical transplantation with postransplant cyclophosphamide, previously described by other groups. Patients with an ALC30 count over 300 cells/µL have a statistically significant better overall survival, disease free survival and a lower cumulative incidence of infectious mortality. However, ALC30 seems to have no correlation with relapse rate. CD3+ and NK-cell total counts on day 30 seem to have less prognostic impact, according to our study. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Feasibility of Sorafenib As a Maintenance Agent after Allogeneic Hematopoietic Stem Cell Transplantation for Fms-like Tyrosine Kinase 3 Mutated Acute Myeloid Leukemia

Introduction: Despite allogeneic hematopoietic stem cell transplantation (HSCT), prognosis of fms-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML) remains poor due to the high risk of relapse. Sorafenib, a multikinase inhibitor active on FLT3, has shown encouraging results in these patients.Patients and methods: Here, we report the use of sorafenib as a maintenance agent after HSCT in 28 adults with FLT3 positive AML treated in three hematologic departments.Results: A total of 18 males and 10 females were included. All but one patient (pt) underwent their first HSCT between 2012-2016. Median age at HSCT was 45 years (range 16-57). A normal karyotype was detected in all but 5 pts. Ten pts showed FLT3-ITD as sole molecular abnormality, thirteen with concomitant NPM-1 mutation, associated to WT1 overexpression in 1 case and to CEBP-α double mutated in two. Association of FLT3 and WT1 overexpression was observed in 3 pts. Two more pts presented a FLT3-TKD with concomitant NPM-1 mutation.At time of HSCT, all but 1 pt were in complete remission (CR; CR1, n=23; CR2=3; CR3=1). Thirteen pts in CR had a detectable minimal residual disease (MRD) before HSCT. Median interval from CR to HSCT was 74 days (d, range 6-220). The majority of the pts (n=26) received peripheral blood as stem cell source, 19 from a matched sibling, 4 from a matched unrelated, 3 from a haploidentical donor. A bone marrow unit was used in 2 pts, one matched sibling and one haploidentical donor. Conditioning regimen was myeloablative in 21 pts, while reduced intensity regimen was used in 5 pts, and 2 receiving a sequential regimen. All pts achieved neutrophil engraftment in a median of 16 d.Median time to sorafenib introduction as a maintenance agent after HSCT was 70 d (range 17-645). Seven pts were out of immunosuppressive treatment (IST) without graft-versus host disease (GVHD) at time of sorafenib start. Sorafenib was started at a dose of 400 mg twice a d (n=13), 200 mg twice a d (n=14) or 200 mg once a d (n=1).Sorafenib was used as primary prophylaxis in 25 pts, or as secondary prophylaxis in three relapsed pts who received it first in combination with salvage chemotherapy and then, after obtaining subsequent CR, as a maintenance treatment.Median duration of treatment was 179 d (range 4-1219).Dose reduction or withdrawal due to toxicities was needed in 5 and 3 pts, respectively. These included gastrointestinal (GI, n=3), cardiac (n=1), skin (n=3, 1 with GI), biochemical (n=1) and hematological toxicities (n=2, 1 with GI). Despite dose reduction, persistence of toxicities prompted to treatment withdrawal in 1 pt.Disease relapse occurred in 2 pts: in both sorafenib was withdrawn and then resumed after salvage chemotherapy. One pt died for disease progression, the other from non-relapse mortality.Twelve pts experienced GVHD (limited, n=6; extensive, n=6), resulting in dose reduction in 5 pts, followed by withdrawal in 1 pt. Nine pts required systemic IST. Dose reduction was made in 1 pt due to financial reasons. Three pts received donor lymphocyte infusion (DLI), without experiencing GVHD. Leukemia-free (LFS) and overall survival at one year were 91±6% and 89±7%, respectively. Probability of LFS with undetectable MRD at one year was 87±7%.With a median follow-up of 15 months (range 4-44), all but 2 pts are alive, all in CR. Sorafenib treatment is ongoing in 18 pts (with 7 at reduced doses) with a median of 15 months (range 1-41).Conclusion: Our findings suggest that a post-transplant prophylactic strategy is safe and may markedly improve the poor outcome of FLT3 positive AML. A large prospective randomized clinical trial is warranted in order to confirm our results and to determine the optimal treatment modalities. Although the optimal starting dose still remains unclear, dose individualization according to patient tolerability might be considered. Further analysis is needed to evaluate the immunomodulating role of sorafenib post HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.