Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Research Articles

Real-World Impact of Routine Addition of Antithymocyte Globulin to Standard GVHD Prophylaxis in Myeloablative Unrelated Donor Transplants: Important Gains in Graft-versus-Host Disease Prevention though No Difference in Overall Survival

Introduction: Antithymocyte globulin (ATG) has been demonstrated to reduce the incidence of graft-versus-host disease (GVHD); however, it remains controversial whether these gains are offset by an increase in relapse. Methods: We conducted a retrospective historical control study consisting of patients (n = 210) who underwent myeloablative allogeneic hematopoietic stem-cell transplantation (HSCT) from 2014 to 2020. Results: The incidence of acute GVHD was lower in the ATG group (51.4%) than the non-ATG group (control) (70.0%, p = 0.010). The incidence of chronic GVHD was also lower in the ATG group at 1-year (36.4% vs. 62.9%, p < 0.001) and 2-year (40.0% vs. 65.7%, p < 0.001) post-HSCT. The mortality due to GVHD was higher in the control (18.5%) than the ATG group (4.3%; p = 0.024). The severe GVHD-relapse-free survival was higher in the ATG group (36.4%) than the control (12.9%; p < 0.001). Nevertheless, the 2-year overall survival was similar. Conclusion: Our results confirm the effectiveness of ATG in prevention of GVHD in the real-world setting and enhanced GVHD-free survival. An important result is the equalization of overall survival between the ATG and control groups at 1- and 2-year post-HSCT and implies that earlier GVHD-associated mortality may be offset by later relapse mortality producing similar overall survival over time.

Rapid Immune Reconstitution and Elevated Regulatory T Cell Frequencies in Patients Treated with Orca-T

BACKGROUND Immune reconstitution following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) is significantly delayed for T cell depleted allografts when compared to T-cell replete allografts, a feature that has been implicated in higher rates and grades of infection, less GVT, and worse overall survival. Orca-T is a high precision cell therapy currently being investigated for the treatment of certain hematological malignancies otherwise treated with MA-alloHSCT. The cellular drug products of Orca-T (HSPCs, Tregs, and Tcons) are administered at high purity, in controlled doses, and on an established schedule with the intent to reconstitute the blood and immune system while controlling GVHD. Here, we present data on the immune reconstitution in 100 adult patients who received Orca-T. METHODS In the context of an ongoing multicenter Phase Ib clinical trial of Orca-T in recipients with hematologic malignancies (NCT04013685), we performed longitudinal measurements (days -28, 28, 56, 100, 180, and 365 post-transplant) of immune reconstitution in the first 100 consecutive patients. With fresh whole blood, clinical 5-part leukocyte differentials were performed at clinical sites, and lymphocyte subset frequencies were measured by flow cytometry in a central lab. Principal component analysis (PCA) was performed to investigate potential associations with recipient sex (male vs. female) and donor relation (related vs. unrelated). RESULTS Longitudinal peripheral blood counts of platelets, WBCs, neutrophils, lymphocytes, monocytes, T cells, B cells, and NK cells are presented in Table 1. T cell and B cell counts were readily observed at days 28 and 56 respectively, and increased with each subsequent time point. Median NK cell levels were observed to be in the normal range at all post-transplant time points. CD4+ T cell and Treg cell counts exhibited similar post-transplant patterns with both being appreciably present at d28 and increasing with each subsequent time point. Strikingly, relative to the level measured in 75 corresponding PBSC donors, the Treg frequency among CD4+ T cells was significantly elevated at all time points post-transplant (Figure 1). Median CD8+ T cell counts increased for the first 6 months post-transplant and then plateaued in the normal range. Upon PCA, very few significant differences were observed in 2-group comparisons of recipient sex and donor relation. CONCLUSIONS Orca-T patients exhibit early immune reconstitution of each of the major leukocyte and lymphocyte subsets hypothesized to control relapse and infection. Concomitantly, elevated Treg frequencies were also observed. This feature of immune reconstitution profiles of Orca-T recipients may be correlated to the reduced occurrence and severity of acute and chronic GVHD in these patients (Meyer et al., EHA 2022, #S237). Similar immune reconstitution profiles were observed in patients of disparate sex and regardless of donor relation. Prospective comparisons of immune reconstitution between Orca-T and standard-of-care patients will be performed in our ongoing phase 3 clinical trial (NCT05316701). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-524 Orca-T, A Precision Engineered Allograft, Results in High GVHD-Free and Relapse-Free Survival Following Myeloablative Conditioning for Hematological Malignancies

Rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) remain unacceptably high. Orca-T is a high-precision, allogeneic investigational cell therapy product comprised of stem and immune cells that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses, reducing the need for pharmacologic GVHD prophylaxis. Orca-T is produced in a central GMP facility and has been successfully scaled to clinical centers throughout the U.S. The aim of these studies was to evaluate the safety and efficacy of Orca-T in patients with hematologic malignancies. Data are reported for 138 patients with high-risk hematologic malignancies who received Orca-T in a single-center Phase 1/2 study (n=41) and a multicenter Phase 1b study (n=97) and had ≥ 100 days of follow-up as of 2/28/22. Orca-T was produced from G-CSF-mobilized peripheral blood (PB) from MRD (n=72), MUD (n=62), or MMUD (n=4). Median follow-up for recipients was 300 days (range: 27-1941). Median age was 49 years, and diagnoses included AML (43%), ALL (27%), MDS (10%), myelofibrosis (7%), and CML (6%). Patients received MAC (busulfan-based, n=109; TBI-based, n=27; BCNU, n=2) followed by GVHD prophylaxis with either single-agent tacrolimus (n=127), sirolimus (n=7), or tacrolimus plus mycophenolate (n=4, MMUD). A contemporaneous CIBMTR-based control arm was obtained that consisted of patients with similar diagnoses who received MA-alloHSCT from a PB source followed by tacrolimus/methotrexate prophylaxis. Orca-T was successfully manufactured, distributed, and infused for all patients. Overall time from donor centers to recipient centers was under 60 hours in all cases. Median time to neutrophil engraftment was 13 days. Rates of grade ≥ 3 acute GVHD in the first 180 days and moderate to severe chronic GVHD through 1 year were low at 4% and 5%, respectively. NRM was infrequent at 4% through 1 year. Orca-T exhibited GVHD-free relapse-free survival (GRFS) of 71% & OS of 90% at 1 year. No formal comparison to CIBMTR cohort was performed. Results from patients treated with Orca-T, a high-precision Treg-engineered donor product, suggest a reduction in cGVHD, improved GRFS, and low toxicity relative to historic data. A multicenter randomized-control phase 3 trial comparing Orca-T to SOC is enrolling.

S237: ORCA-T, AN ENGINEERED ALLOGRAFT, RESULTS IN HIGH GVHD-FREE AND RELAPSE-FREE SURVIVAL FOLLOWING MYELOABLATIVE CONDITIONING FOR HEMATOLOGICAL MALIGNANCIES

Background: Rates of graft versus host disease (GVHD) and non-relapse mortality (NRM) following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) remain unacceptably high. Strategies to reduce GVHD and NRM have been compromised by limited efficacy or increased risk of infection and relapse, emphasizing the need for new approaches that holistically improve outcomes. Orca-T is a high-precision, allogeneic investigational cell therapy product comprised of stem and immune cells that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses, reducing the need for pharmacologic GVHD prophylaxis. Orca-T is produced in a central GMP facility and has been successfully scaled to clinical centers throughout the U.S. Aims: The aim of these studies was to evaluate the safety and efficacy of Orca-T in patients with hematologic malignancies. Methods: As of 28 February 2022, 138 patients with high-risk hematologic malignancies have received Orca-T in a single-center Phase 1-2 study (NCT01660607, n=41) and a multicenter Phase 1b study (NCT04013685, n=97) and have ≥ 100 days of follow-up. Informed consent was obtained from all transplant recipients and donors, and the studies received IRB approval from participating institutions. Orca-T was produced from G-CSF-mobilized peripheral blood (PB) from matched related donors (n=72), matched unrelated donors (n=62), or mismatched unrelated donors (MMUD, n=4). Median follow-up for recipients was 300 days (range: 27-1941). Median age was 49 years, and diagnoses included AML (43%), ALL (27%), MDS (10%), myelofibrosis (7%), and CML (6%). Patients received myeloablative conditioning (busulfan-based, n=109; TBI-based, n=27; BCNU, n=2) followed by GVHD prophylaxis with either single-agent tacrolimus (tac, n=127), sirolimus (n=7), or tac plus mycophenolate (n=4, MMUD). A contemporaneous CIBMTR-based control arm was obtained that consisted of patients with similar diagnoses who received myeloablative alloHSCT from a PB source followed by tac/methotrexate PPX. Results: Orca-T was successfully manufactured, distributed, and infused for all patients enrolled. Overall time from donor centers to recipient centers was under 60 hours in all cases. Median time to neutrophil engraftment was 13 days. The rates of grade ≥ 3 acute GVHD in the first 180 days and moderate to severe chronic GVHD through 1 year were low with Orca-T at 4% and 5%, respectively. NRM was infrequent at 4% through 1 year. Orca-T exhibited GRFS of 71% & OS of 90% at 1 year. No formal comparison to the CIBMTR cohort was performed, and a Phase 3 study has been initiated to confirm these findings. Longitudinal immune reconstitution data was collected and will be presented. Clinical data is summarized in Table 1. *MAGIC Criteria **NIH Consensus Grading Image:Summary/Conclusion: Results from patients treated with Orca-T, a high-precision Treg-engineered donor product, suggest a reduction in cGVHD, improved GRFS, and low toxicity relative to historic data. Orca-T manufacturing was accomplished with consistent and reliable cell manufacturing and distribution across a wide geographic area. A multicenter randomized-control trial phase 3 trial comparing Orca-T to SOC has been initiated.

Oral Mucositis Association with Periodontal Status: A Retrospective Analysis of 496 Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) can induce serious oral complications, including oral mucositis (OM). The presence of periodontal inflammation before HSCT is believed to be associated with OM. The aim of our study was to determine the prevalence and severity of OM in patients undergoing HSCT and its relation to periodontal status. Patients and methods: This is a retrospective study of patients who underwent HSCT and a detailed dental examination between 2007 and 2015. The dental and periodontal status of all patients was evaluated by clinical and radiographic examination prior to HSCT. Oral health was assessed with the gingival index, the the community periodontal index, presence of plaque-related gingivitis, and marginal periodontitis. During the HSCT period, patients were examined daily for the presence of OM, which was graded according to World Health Organization (WHO) classification if present. The patients were assigned to the groups according to type of transplantation: autologous HSCT, myeloablative allogeneic HSCT, and non-myeloablative allogeneic HSCT. Results: A total of 496 patients were included in the study. OM was present in 314 of 496 patients (63.3%): 184/251 (73.3%) in the autologous group, 100/151 (66.2%) in the myeloablative allogeneic group, and 30/94 (31.9%) in the nonmyeloablative allogeneic group. Significantly more patients suffered from OM in the autologous and myeloablative groups versus the nonmyeloablative conditioning group (p < 0.001). The presence of periodontal inflammation did not significantly differ among the groups. There was only a borderline trend for the higher prevalence of OM in the non-myeloablative allogeneic nonmyeloablative group when periodontal inflammation was present (0.073939). Conclusions: Oral mucositis prevalence and severity after stem cell transplantation is not widely affected by the oral hygiene and periodontal disease presence before HSCT. We confirmed the wide-known connection of the conditioning regimen intensity to the prevalence of OM.

The Prognostic Value of Early Detection of Minimal Residual Disease as Defined by Flow Cytometry and Gene Mutation Clearance for Myelodysplastic Syndrome Patients After Myeloablative Allogeneic Hematopoietic Stem-Cell Transplantation.

High relapse incidence remains a major problem for myelodysplastic syndrome (MDS) patients who have received an allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We retrospectively analyzed the correlations between clinical outcomes and minimal residual disease (MRD) by using mutations (MUT) and flow cytometry (FCM) analysis of 115 MDS patients with allo-HSCT. We divided 115 MDS patients into four groups based on molecular genetics and FCM MRD results at day 30 post-HSCT. There were significant differences in the 2-year progression-free survival (PFS) between the FCMhigh MUTpos and FCMlow MUTneg groups (20% vs 79%, P < 0.001). In addition, by univariate analysis, we found that an IPSS-R score ≥4 pre-HSCT (HR, 5.061; P=0.007), DNMT3A mutations (HR, 2.291; P=0.052), TP53 mutations (HR, 3.946; P=0.011), and poor and very poor revised International Prognostic Scoring System (IPSS-R) cytogenetic risk (HR, 4.906; P < 0.001) were poor risk factors for PFS. In multivariate analysis, we found that an IPSS-R score ≥ 4 pre-HSCT (HR, 4.488; P=0.015), DNMT3A mutations (HR, 2.385; P=0.049), positive FCM MRD combined with persistence gene mutations at day 30 (HR, 5.198; P=0.013) were independent risk factors for disease progression. In conclusion, our data indicated that monitoring MRD by FCM combined with gene mutation clearance at day 30 could help in the prediction of disease progression for MDS patients after transplantation.

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease

BackgroundDipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.MethodsWe conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.ResultsA total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.ConclusionsIn this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.)

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant. This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant. We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT. Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.

CD34+ Cell Dose Effects on Clinical Outcomes of Patients with Acute Myeloid Leukemia after T-Replete Haploidentical Allogeneic Hematopoietic Stemcell Transplantation Using Peripheral Blood Stem Cells. a Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

The absolute number of infused CD34+ donor cells represents a critical step towards the achievement of a meaningful marrow engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Previous observations have reported controversial conclusions regarding the impact of CD34+ donor cell doses and post-transplant clinical end-points. The vast majority of analysis conducted so far have considered myeloablative and reduced-intensity conditioning allogeneic HSCT setting, with HLA-matched sibling and/or unrelated donors. The T-cell replete haploidentical setting has not been extensively studied yet. We conducted a retrospective analysis on 414 adult patients (median age 54 years; range, 18-74) with acute myeloid leukemia (AML) in first (70%) and second (30%) complete remission who had received a T-cell replete allogeneic HSCT from a haploidentical donor, using peripheral blood stem cells (PBSC), between 2006-2018, based on ALWP-EBMT registry data. Median donor age was 37 years (range, 20-71). Time from disease diagnosis to HSCT was 6.3 months (range, 1.3-97.9). Seventy-three (18%) patients had secondary-AML. Eighty-seven patients (21%) had unfavorable cytogenetics. Karnofsky performance-status at the time of HSCT was ≥ 90 in 318 (77%) patients. Graft vs. host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PT-Cy)-based in 293 (71%) patients and anti-lymphocyte serum (ATG)-based in 121 (29%) patients. Conditioning was myeloablative in 179 (43%) patients and reduced-intensity in 235 (57%) patients. Median number of infused CD34+ cells was 6.58 x 106/kg (range, 2.2-31.2). Thirteen patients (3.2%) experienced graft failure while the remaining 399 (96.8%) engrafted uneventfully. Neutrophils engraftment at day 30 was 91.2% (95% Confidence interval [CI]: 88 - 93.6) while sustained platelets engraftment (&gt;20.000/uL at 6-months) was observed in 83.7% (95% CI: 79.6 - 87). Median time to neutrophils and platelets engraftment were 20 (range, 10-79) and 21 days (range, 1-37) respectively. After a median follow-up of 23.3 months (range, 12.1-41.8) 2-year overall survival (OS) was 64.5 % (95% CI 59.3-69.7) with a leukemia-free survival (LFS) of 57.3 % (95% CI 51.8-62.7) and non-relapse mortality (NRM) of 23.3 % (95% CI: 19.0-27.7). The cumulative incidence of grade II-IV and III-IV acute GVHD at day-100 were 32.3 % (95% CI: 27.8 - 36.9) and 14.6 % (95% CI: 11.3 - 18.2), respectively. Incidence of 2-years chronic GVHD overall and extensive were 36.3 % (95% CI: 30.9 - 41.6) and 14.4 % (95% CI: 10.7 - 18.6), respectively. GVHD-free/relapse-free survival was 43.5 % (95% CI: 38 - 48.9) at 2-years. We found the optimal CD34+/kg threshold defining high-dose (n= 334) versus low-dose (n= 80)to be 4.96 x 106, using the Hothorn and Zeileis method (Hothorn, T. and Zeileis, A. Generalized maximally selected statistics. Biometrics 2008;64(4):1263-1269). Patients in the high-dose group experienced higher rates of engraftment compared to those in the low-dose group both for neutrophils (92.1% vs. 87.3%, p= 0.005) and platelets (86% vs. 73.3%, p= 0.001) while median time to neutrophils engraftment was 19 days (range, 10-79) in the high-dose group and 22 days (range, 14-46) in the low-dose group (p= 0.0001). Recipients of &gt; 4.96 x 106/kg CD34+ cells experienced lower NRM (hazard ratio [HR] 0.48; 95% CI:0.29-0.75) and prolonged LFS (HR 0.62; 95% CI 0.43-0.90) and OS (HR 0.59; 95% CI:0.40-0.87) than recipients of ≤ 4.96 x 106/kg CD34+cell dose. Patients who received ATG as GVHD prophylaxis experienced less grades II-IV acute GVHD respect those in the PT-Cy cohort (HR 0.56; 95% CI: 0.36-0.87) without any differences in grades III-IV acute GVHD incidence at day 100 between the two groups. On Cox analysis, a female donor to male recipient combination was associated with higher extensive chronic GVHD incidence compared to other donor-recipient sex combinations, with CD34+ categorized according to the optimal threshold of 4.96 x 106 (HR 2.21; 95% CI:1.23-3.97; p= 0.008). AML patients who underwent a PBSC T-cell replete HSCT from haploidentical donors receiving ≥ 4.96 x 106CD34+/kg cells experienced a lower NRM and extended survival rates compared to those receiving ≤ 4.96 x 106/kg CD34+. The latter findings may have a significant practical impact and can guide prospective approaches. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Cost-effectiveness of antifungal prophylaxis, preemptive therapy, or empiric treatment following allogeneic hematopoietic stem cell transplant.

Invasive fungal infection (IFI) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is also associated with excess healthcare costs. Current approaches include universal antifungal prophylaxis, preemptive therapy based on biomarker surveillance, and empiric treatment initiated in response to clinical signs/symptoms. However, no study has directly compared the cost-effectiveness of these treatment strategies for an allogeneic HSCT patient population. We developed a state transition model to study the impact of treatment strategies on outcomes associated with IFIs in the first 100days following myeloablative allogeneic HSCT. We compared three treatment strategies: empiric voriconazole, preemptive voriconazole (200mg), or prophylactic posaconazole (300mg) for the management of IFIs. Preemptive treatment was guided by scheduled laboratory surveillance with galactomannan (GM) testing. Endpoints were cost and survival at 100days post-HSCT. Empiric treatment was the least costly ($147482) and was equally effective (85.2% survival at 100days) as the preemptive treatment strategies. Preemptive treatments were slightly more costly than empiric treatment (GM cutoff≥1.0 $147910 and GM cutoff≥0.5 $148108). Preemptive therapy with GM cutoff≥1.0 reduced anti-mold therapy by 5% when compared to empiric therapy. Posaconazole prophylaxis was the most effective (86.6% survival at 100days) and costly ($152240) treatment strategy with a cost of $352415 per life saved when compared to empiric therapy. One preemptive treatment strategy reduced overall anti-mold drug exposure but did not reduce overall costs. Prevention of IFI using posaconazole prophylaxis was the most effective treatment strategy and may be cost-effective, depending upon the willingness to pay per life saved.

The Impact of Total Body Irradiation-Based Regimens on Outcomes in Children and Young Adults with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Total body irradiation (TBI)-based conditioning regimens are utilized frequently in preparing children and adults with acute lymphoblastic leukemia (ALL) for allogeneic hematopoietic stem cell transplantation (HSCT). However, the late effects of TBI are significant, and therefore, non-TBI regimens have also been developed, with several studies demonstrating excellent disease control and low toxicity. Prior studies that have compared the outcomes of these differing regimens are difficult to interpret in the era of minimal residual disease testing and targeted busulfan. Therefore, we aimed to compare transplant outcomes for patients that received both conditioning regimens at our institution, including the impact of deep sequencing-minimal residual disease (DS-MRD) positivity prior to undergoing allogeneic HSCT. This retrospective analysis included 54 pediatric and young adult patients with a history of ALL, who underwent their first myeloablative allogeneic HSCT between January 2012 and October 2017 at UCSF. TBI-based regimens included >1200 cGy while non-TBI regimens consisted of busulfan, fludarabine, +/- clofarabine, or melphalan, fludarabine, and thiotepa. Most patients received serotherapy. Our primary endpoint was the cumulative incidence of relapse at 3 years post-transplant. The median age of the study population was 11 years (range 1-25 years). 52% of patients received a non-TBI regimen. With a median follow-up time of 2.3 years (range 0.1-6.5 years), the cumulative incidence of relapse at 3 years was 20% in the TBI group and 36% in the non-TBI group (p=0.17). Overall survival, event-free survival, and treatment-related mortality were 70%, 63%, and 12% at 3 years, respectively. The overall rate of acute graft-versus-host disease (GVHD) was 35%, more common in the TBI group (46%) than the non-TBI group (25%) (p=0.10). When patients suffered acute GVHD, the cumulative incidence of relapse was less frequent in the TBI group (8%) than the non-TBI group (36%), while relapse was similarly high in both groups when patients did not experience GVHD (37% vs. 29%) (Figure 1). In subanalysis, patients with DS-MRD positivity prior to transplant had a significantly higher cumulative incidence of relapse (50%) compared to patients who were DS-MRD negative (0%) (p=0.002). DS-MRD positive patients had nonsignificantly lower rates of relapse when they experienced acute GVHD (25% vs. 60%, p=0.24), while DS-MRD negative patients had higher rates of acute GVHD following TBI compared to non-TBI regimens (86% vs. 33%, p=0.02), with no clinical benefit. Our results suggest that TBI-based regimens may be advantageous for patients who are DS-MRD positive prior to transplant while non-TBI regimens appear preferable for DS-MRD negative patients. Prospective trials should better delineate when a non-TBI regimen would be most appropriate to use as a preparative regimen in patients with ALL.

Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Introduction:Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT.Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients.To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS.Patients and methods:We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS.Results:A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002).SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively).In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone.Conclusion:Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. DisclosuresNakane:Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

Myeloablative Allogeneic Stem Cell Transplantation after Cytoreductive Therapies for Adult Patients with RAEB-2

Background:The prognosis of refractory anemia with excess blasts (RAEB)-2 is poor and allogeneic hematopoietic stem cell transplantation (HSCT) is believed to be the only curative treatment. New strategies are under active investigation to further advance the efficacy after HSCT. Here, we report on the outcome of 35 adults with RAEB-2 using cytoreductive therapies as a bridge to subsequent myeloablative allogeneic HSCT.Patients and Methods:A total of 35 adult patients (19 males and 16 females) with RAEB-2 who received cytoreductive therapies before allogeneic HSCT at our institution between January 2011 and April 2016 were analyzed. The median age was 41 years (range, 12 - 54 years). The IPSS scores at diagnosis were INT-1 in 3 (8%), INT-2 in 24 (69%) and high risk in 8 (23%). Prior to transplantation, 8 patients had been treated with only hypomethylating agents (HMAs), 4 with only chemotherapy, and 23 with HMAs in combination with chemotherapy. The median time from diagnosis to transplantation is 3 months (range, 2 - 9 months). Graft source was HLA-identical sibling in 8 (23%), unrelated donor in 10 (29%), and haploidentical related donor in 17 (48%). 7 (20%) recipients received bone marrow (BM), 14 (40%) received peripheral blood stem cells (PBSCs), and 14 (40%) received BM plus PBSCs. The median number of CD34-positive cells was 3.97 × 106 cells per kg (range, 1.69 - 12.17 × 106 cells per kg). All patients received a myeloablative conditioning regimen consisting of busulfan and cyclophosphamide, while rabbit antithymocyte globulin was given as an additional immunosuppressive measure in patients transplanted from non-HLA-identical sibling donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and short-term methotrexate. Recipients of non-HLA-identical sibling transplants also received mycophenolate mofetil.Results:22 patients received 1course, 9 received 2 courses and 4 received more cycles of cytoreductive treatment. In general, treatment was well tolerated and infection (63%) was the most frequent adverse events. Transplantation was postponed for about two months in 2 patients due to pneumonia. At time of transplantation, 11 (31%) achieved marrow complete remission (CR) and hematologic improvement, 11 (31%) had marrow blasts decreased more than 50% (including 1 patient showed CR response after induction, but relapsed prior to HSCT), and 13 (37%) had persistent or progressive disease before HSCT. All patients showed primary eneutrophil engraftment after a median of 12 days (range, 10 - 20 days). For patients achieving platelet engraftment (34/35), the median time to platelet recovery was 14 days (range 11-193 days). Acute graft-versus-host disease (GVHD) grade II-IV developed in 30%, and extensive chronic GVHD in 18% of the patients. After a median follow-up of 25 months, the 2-year overall and disease-free survival estimates were 61% and 57%, respectively. The 2-year cumulative incidences of relapse and non-relapse mortality were 3% and 32%, respectively. Refractory to cytoreductive therapies was the only prognostic factor for poor overall survival after HSCT.Conclusion:This study indicates that the safety and high response rate of 1-2 courses of HMA-containing cytoreductive therapies before HSCT and a high probability of survival for adult patients with RAEB-2 after a myeloablative allogeneic HSCT. DisclosuresNo relevant conflicts of interest to declare.

A pilot study comparing the neutropenic diet to a non-neutropenic diet in the allogeneic hematopoietic stem cell transplantation population.

Historically, dietary restrictions imposed on patients undergoing hematopoietic stem cell transplantation (HSCT) were severe and limited to prevent exposure to foodborne organisms. With improvements in supportive care and anti-infective agents, the necessity of the neutropenic diet for this population has been in question. This study aimed to determine whether the incidence of infection differs and to analyze the nutritional status in patients undergoing myeloablative allogeneic HSCT with a neutropenic diet as compared to those with a diet without restrictions. This study was a randomized, controlled prospective pilot study beginning within the first 24 hours of the start of the conditioning regimen. Patients were randomized to receive a neutropenic diet or a diet without restrictions. All patients received care in a high-efficiency particulate air-filtered room on the inpatient adult blood and marrow transplantation unit (ABMTU). All patients received antibacterial and antifungal prophylaxis. Patients were followed until the end of neutropenia (defined as absolute neutrophil count of greater than 500 for three days) or until discharge from the inpatient ABMTU. In 46 evaluable patients, no significant difference was found between infection rates or nutritional status. The neutropenic diet did not offer a protective effect against infection in patients undergoing myeloablative allogeneic HSCT. No differences were found in nutritional status between the two groups.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL)

▪ PurposeThe pediatric-inspired intensified GRAALL protocol yielded a marked improvement in the outcome of adults with Ph-negative acute lymphoblastic leukemia (ALL) (Huguet et al,JCO 2009), raising the issue of the place of allogeneic HSCT in this new context. We report here the results associated with HSCT in first complete remission (CR) in younger adults treated in the GRAALL-2003/2005 trials. Patients and methodsIn these trials, HSCT was offered in first CR to patients aged 15-55 years with ALL at higher risk of relapse. High-risk factors included white blood count >30 x 109/L for B-lineage ALL, central nervous system (CNS) involvement, t(4;11)/MLL anomalies, t(1;19), low hypodiploidy/near triploidy, complex karyotype, early resistance to the steroid prephase (CsR), early resistance to chemotherapy (ChR) as assessed by poor bone marrow blast clearance at day 8, and late CR. Per protocol, HSC donor should be a matched sibling or an unrelated donor (10/10 or eventually 9/10 HLA matched) and conditioning regimen should include single fraction 10-Gy or fractionated 12-Gy total body irradiation (TBI) and high-dose cyclophosphamide. The role of HSCT was evaluated by HSCT versus no-HSCT cohort comparison (Mantel-Byar time-dependent analysis). ResultsAmong the 522 high-risk patients eligible, 283 (54%) actually received HSCT in first CR (185 B-lineage and 98 T-lineage ALL; median age, 31 years). There were no significant differences in baseline characteristics and early response between HSCT and no-HSCT cohorts, except more HSCT patients with t(4;11)/MLL anomalies. Among the 283 HSCT patients, 46 had t(4;11)/MLL anomalies, 13 had CNS disease, 116 had CsR and 176 had ChR ALL. Origin of HSC was 140 sibling and 143 unrelated donors, including 47 unrelated donors with 1 HLA mismatch. The following HSCT protocol violations were observed: a) conditioning did not include TBI in 17 patients; b) 10 patients received reduced-intensity conditioning (RIC); and c) 13 patients received cord blood HSCT. These patients remained in the HSCT cohort for the analysis. With a median post-transplant follow-up of 3.5 years, post-HSCT cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and relapse-free survival (RFS) were estimated respectively at 19% (95% CI, 15-25), 16% (95% CI, 12-21) and 64% (95% CI, 58-70) at 3 years, without any RFS difference between sibling and unrelated donors. A marked trend for a higher NRM was observed in patients aged 45 years or more (26% versus 13% at 3 years; HR, 1.6; p=0.059), while post-transplant CIR was similar in older and younger patients. Mantel-Byar RFS estimations showed no significant difference between both HSCT and no-HSCT cohorts (HR, 0.80; p=0.13), meaning that the risk factors used in these protocols failed to identify patients who could significantly benefit from HSCT in first CR. As minimal residual disease (MRD) had a major prognostic impact, we retrospectively analyzed the effect of HSCT in the 278/522 patients evaluated for 6-week Ig/TCR MRD level (154 HSCT and 124 no-HSCT patients, including 92 and 62 patients with MRD >=10-4, respectively). Mantel-Byar RFS estimations showed that HSCT did not benefit to patients with MRD <10-4 (HR, 1.2; p=0.67) as opposed to those with MRD >=10-4 (HR, 0.6; p=0.02), with a positive HSCT-by-MRD interaction (p=0.04) (Figure 1). [Display omitted] ConclusionIn adult patients with high-risk ALL in first CR treated in the GRAALL-2003/2005 trials, myeloablative allogeneic HSCT from sibling and unrelated donors was associated with a 64% RFS at 3 years. The 26% NRM observed at 3 years in patients aged 45 years or more suggests considering RIC-HSCT in these patients. MRD response appears to be a powerful tool to select patients who might benefit from HSCT. This selection tool will be prospectively evaluated in the next GRAALL-2013 trial.ND and AH contributed equally to the work. Disclosures:No relevant conflicts of interest to declare.

The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation

Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury. This study examined the associations between red blood cell (RBC) and platelet (PLT) transfusions and idiopathic pneumonia syndrome (IPS) among 914 individuals who underwent myeloablative allogeneic HSCT between 1997 and 2001. Patients received allogeneic blood transfusions at their physicians' discretion. RBCs, PLTs, and a composite of "other" transfusions were quantified as the sum of units received each 7-day period from 6 days before transplant until IPS onset, death, or Posttransplant Day 120. RBC and PLT transfusions were modeled as separate time-varying exposures in proportional hazards models adjusted for IPS risk factors (age, baseline disease, irradiation dose) and other transfusions. Timing of PLT transfusion relative to myeloid engraftment and PLT ABO blood group (match vs. mismatch) were included as potential interaction terms. Patients received a median of 9 PLT and 10 RBC units. There were 77 IPS cases (8.4%). Each additional PLT unit transfused in the prior week was associated with 16% higher IPS risk (hazard ratio, 1.16; 95% confidence interval, 1.09-1.23; p < 0.001). Recent RBC and PLT transfusions were each significantly associated with greater risk of IPS when examined without the other; only PLT transfusions retained significance when both exposures were included in the model. The PLT association was not modified by engraftment or ABO mismatch. PLT transfusions are associated with greater risk of IPS after myeloablative HSCT. RBCs may also contribute; however, these findings need confirmation.

Clinical Significance of Pulmonary Function Tests in Long-Term Survivors after Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation

We retrospectively assessed long-term pulmonary function in adults surviving for ≥5 years after myeloablative allogeneic hematopoietic stem cell transplantation and identified risk factors for late-onset noninfectious pulmonary complications. Among 174 patients undergoing transplantation for hematologic malignancies between May 1994 and December 2004, 81 long-term survivors were evaluated. Pulmonary function tests (PFTs) were performed before conditioning, 3 months and 1 year after transplantation, and then annually. Eight patients (10%) had abnormal pulmonary function before transplantation, but this was not associated with late changes in PFTs. Patients with chronic graft-versus-host disease (GVHD) showed a significant decline of lung function after 3 years when compared with patients without chronic GVHD. Abnormal pretransplantation lung function was associated with pulmonary chronic GVHD according to National Institutes of Health criteria (score 0, n = 58; score 1, n = 14; score 2, n = 6; score 3, n = 3). Five patients with late-onset noninfectious pulmonary complications showed a decline of lung function at 1 year after transplantation. Only chronic GVHD was significantly related to late-onset noninfectious pulmonary complications. In conclusion, abnormal lung function before transplantation may be associated with a decline in pulmonary function within 1 year after transplantation, but late-onset noninfectious pulmonary complications could not be predicted from pretransplantation lung function.

Hypersensitivity Reaction to Intravenous but Not Oral Tacrolimus

Overcoming drug hypersensitivity reactions can improve transplant patient care, especially when specific medications are integral to treatment protocols. Our allergy service was consulted on a 40-year-old female hematopoietic stem cell transplantation (HSCT) patient for a hypersensitivity reaction during intravenous (IV) tacrolimus infusion. The patient was recently diagnosed with AML M5a and was status-post induction chemotherapy in her first complete remission. She was admitted for a myeloablative allogeneic HSCT and was under a randomized transplant protocol that included tacrolimus to prevent graft versus host disease (GVHD). The patient had never received tacrolimus. Within five minutes of her first IV dose, she developed pruritus, nausea, vomiting, and diffuse urticaria. She had no other symptoms. Her pulse increased to 102/min, but her blood pressure and oxygen saturation remained stable. The infusion was stopped within 15 minutes. She had not received any other medications. She was administered 50 mg of IV diphenhydramine with resolution of her symptoms. We were consulted for recommendations regarding future dosing of tacrolimus. Tacrolimus intravenous infusion contains anhydrous tacrolimus, polyoxyl 60 hydrogenated castor oil (HCO-60), and dehydrated alcohol (Table 1). Polyoxyl 60 hydrogenated castor oil (HCO-60) is a form of polyoxyethylated castor oil solubilizer similar to Cremophor. Cremophor is a nonionic surfactant obtained by polyethoxylation of castor oil expressed from the seed of R. communis, and it is used as a solubilizer in several medications (1). It has been associated with hypersensitivity reactions with medications including vitamin K, cyclosporine, paclitaxel, diazepam, propanidid and multivitamin hydrosol (2, 3). Oral tacrolimus does not require a solubilizer and consequently does not contain polyoxyethylated castor oil (Table 1). Table 1 Components of tacrolimus and cyclosporine formulations Our patient’s symptoms were consistent with a hypersensitivity reaction. Our suspicion was that her reaction was to the intravenous carrier polyoxyethylated castor oil and not to tacrolimus itself. Since the oral form of tacrolimus does not contain polyoxyethylated castor oil, we recommended a two step graded challenge with oral tacrolimus. The patient tolerated oral tacrolimus without reaction and was maintained on oral tacrolimus without any complications. The intravenous forms of both tacrolimus and cyclosporine contain polyoxyethylated castor oil (Table 1). Both have oral counterparts that do not. There are case reports describing patients who react to intravenous cyclosporine but tolerate the corn-oil based soft gelatin capsule formulation of cyclosporine (Sandimmune soft gelatin capsule formulation, Novartis)(2, 3). Takamatsu et al(3) describe a patient with T cell lymphoma status post allogeneic HSCT who developed diffuse urticaria and tachycardia within minutes of receiving a first lifetime dose of intravenous cyclosporine. Intravenous tacrolimus was then tried which also resulted in diffuse urticaria. The patient was then started on the oral soft gelatin capsule cyclosporine formulation and had no reaction. Volcheck at el(2) report a patient with AML status post HSCT who developed urticaria, angioedema, vomiting, and throat tightness with his first lifetime dose of intravenous cyclosporine, but who later tolerated the oral soft gelatin capsule formulation of cyclosporine. They also performed a literature search which revealed 22 cases of IV cyclosporine hypersensitivity reaction. Seven of these patients were subsequently given oral formulations of cyclosporine which they tolerated. The common chemotherapy agent paclitaxel is another example of a drug that contains a carrier that is thought to be responsible for hypersensitivity reactions rather than the drug itself. Consequently, Abraxane (nab-paclitaxel), a Cremophor-free formulation of paclitaxel, has been developed and five patients with hypersensitivity reactions to paclitaxel tolerated Abraxane without incident (4). Proposed mechanisms underlying hypersensitivity reactions to polyoxyethylated castor oil include IgE-mediated (2), complement activation (5) or direct histamine release (6). IgE mediated reactions typically require prior exposure for sensitization. Though our patient had never received intravenous tacrolimus, polyoxyethylated castor oil is used as a vehicle in several medications and she may have been exposed to the carrier previously. While a method to investigate IgE mediated reaction is to perform a skin test to the suspected allergen, this was not appropriate in our patient’s clinical situation, and there is no validated skin test for polyoxyethylated castor oil allergy. To our knowledge, this is the first report of tolerance to oral tacrolimus following a hypersensitivity reaction to IV tacrolimus. Our experience suggests that polyoxyl 60 hydrogenated castor oil was the culprit agent. Oral tacrolimus formulations should therefore be considered as an alternative in patients who have reacted to IV tacrolimus. This is especially important in the transplant population who require immunosuppression. Of note, Jina Pharmaceuticals manufactures an intravenous tacrolimus formulation (Nanosomal Tacrolimus) that does not contain polyoxyethylated castor oil, but it is not currently available for clinical use(7).

Prognostic Impact of Posttransplantation Iron Overload after Allogeneic Stem Cell Transplantation

In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT.