Hematopoietic Cell Transplantation For Acute Myeloid Leukemia Research Articles

Systematic evaluation of donor-KIR/recipient-HLA interactions in HLA-matched hematopoietic cell transplantation for AML

AbstractIn acute myeloid leukemia (AML), donor natural killer cell killer immunoglobulin–like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions, however, have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult patients with AML (n = 2025) who received HCT with MUD grafts in complete remission reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67-0.93; P = .006) compared with donor-2DL2–/recipient-HLA-C1+ pair. However, no association was found when comparing HLA-C groups among KIR-2DL2+–graft recipients. We identified 9 prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype 5 (G5) in all recipients and G3 in Bw4+ recipients were associated with decreased relapse risk (HR, 0.52; 95% CI, 0.35-0.78; P = .002; and HR, 0.32; 95% CI, 0.14-0.72; P = .006; respectively) and G2 (HR 1.63, 95% CI, 1.15-2.29; P = .005) with increased relapse risk in C1-homozygous recipients, compared with other patients with the same ligand. However, we could not validate these findings in an external data set of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations; therefore, these data do not support these KIR-driven strategies for MUD selection in AML.

Application of the CIBMTR One Year Survival Outcomes Calculator as a tool for retrospective analysis.

The Web-based One Year Survival Outcomes Calculator developed by the Center for International Blood and Marrow Transplant Research (CIBMTR) applies large-scale registry data to generate individualized estimates of overall survival (OS) probability 1 year after first allogeneic hematopoietic cell transplant (HCT) and can therefore provide a data-driven foundation for personalized patient counseling. We assessed the calibration of the CIBMTR One Year Survival Outcomes Calculator when applied to retrospective data among adult recipients of first allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) with peripheral blood stem cell transplant (PBSCT) from a 7/8- or 8/8-matched donor from 2000 through 2015 at a single center. Predicted 1 year OS was estimated for each patient using the CIBMTR Calculator. Corresponding observed 1 year OS was estimated for each group by the Kaplan-Meier method. A weighted Kaplan-Meier estimator was used to visually display the average of observed 1 year survival estimates over the continuous range of predicted OS. In the first analysis of its kind, we demonstrated that the CIBMTR One Year Survival Outcomes Calculator could be applied to larger patient cohorts and predicted 1 year prognosis with general agreement between predicted and observed survival.

Selected Articles from This Issue

Highlights| June 01 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (11): 2013. https://doi.org/10.1158/1078-0432.CCR-29-11-HI Related Content A commentary has been published: Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia A commentary has been published: A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma A commentary has been published: A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy View more A commentary has been published: A Tumor-suppressive Molecular Axis EP300/circRERE/miR-6837-3p/MAVS Activates Type I IFN Pathway and Antitumor Immunity to Suppress Colorectal Cancer View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record June 1 2023 Citation Selected Articles from This Issue. Clin Cancer Res 1 June 2023; 29 (11): 2013. https://doi.org/10.1158/1078-0432.CCR-29-11-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Outcomes for acute myeloid leukemia (AML) remain suboptimal. The curative approach is hematopoietic cell transplantation (HCT) for most patients, although subsequent relapse is common. IDH inhibitors have revealed tolerability and activity in relapsed/refractory patients and have been approved for use. Despite this, maintenance therapy with the IDH1 inhibitor ivosidenib has not been adequately studied. In this phase I study, Fathi and colleagues evaluated ivosidenib as maintenance following HCT for AML and found the agent to be well tolerated. At the recommended phase II dose of 500 mg daily, progression-free and overall survival compared favorably to historical data. The authors also assessed IDH1 allelic burden prior to transplant and prior to maintenance, and, due to the small number of patients in this phase II study, could not conclude a definitive predictive trend for outcomes. The results from this trial have substantial value in promoting a rationale to pursue more advanced-phase, larger... You do not currently have access to this content.

Multiplex proteomics using proximity extension assay for the identification of protein biomarkers predictive of acute graft-vs.-host disease in allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is associated with acute graft-vs.-host disease (aGVHD). The presented study applied a novel multiplex antibody-based proximity extension assay (PEA) proteomic platform that can detect thousands of serum proteins simultaneously for the identification of potential biomarkers of aGVHD. Serum samples from 28 patients who underwent allogeneic HCT for acute myeloid leukemia (AML) were analyzed; 17 were diagnosed with grade II-IV aGVHD while 11 patients were not. Samples collected on day-6, day 0, +14, +30, +60 and +90 post-HCT were analyzed for the relative concentrations of 552 proteins. The concentration of each protein from baseline to the closest time point before onset of aGVHD, or to the latest time point in control patients, was documented. Individualized analysis identified 26 proteins demonstrating≥3-fold increase at aGVHD onset compared to baseline, eliminating proteins with a similar increase in controls. Another approach used paired t-testing and logistic regression that identified a four-marker panel, including SLAMF7, IL-1ra, BTN3A2 and DAB2, where individual log-likelihood ratios ranged from 3.99 to 8.15 (logistic regression, p=0.004-0.046). When combined, the four-marker panel demonstrated an area under the curve (AUC) of 0.90 (95% CI: 0.78-1.00; p=0.0006) with high negative predictive value of 81.8% and positive predictive value of 86.7%. All four markers play a physiological role in immune regulation. Among these, three were also present in the individualized analysis (SLAMF7, IL-1ra and BTN3A2). We conclude that serum proteins identified using multiplex proteomics, particularly SLAMF7, IL-1ra, BTN3A2 and DAB2, may potentially predict aGVHD.

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard Gvhd Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS

Similar Risk of Relapse and Survival with Post-Transplant Cyclophosphamide Compared to Standard GVHD Prophylaxis after Allogeneic Hematopoietic Cell Transplantation for AML and MDS Background: Post-transplant cyclophosphamide (PTCy) is frequently used after allogeneic hematopoietic cell transplant (HCT) as it results in lower rates of graft versus host disease (GVHD). In addition to its predominant use in haploidentical and HLA mismatched donor HCT, PTCy showed potential to become the standard of care GVHD prophylaxis in a setting of HLA matched related and unrelated donor HCT as well (Bolaños-Meade, Lancet 2019). However, recent registry study reported higher risk of relapse after PTCy-based vs.calcineurin inhibitor (CNI) and methotrexate (MTX) GVHD prophylaxis in patients with acute myeloid leukemia (AML) receiving matched sibling donor HCT (Nagler, Transplant Cell Ther 2022). Thus, additional studies are needed to determine whether the benefit of GVHD prevention with PTCy comes at the cost of compromising the graft versus leukemia effect yielding higher relapse of AML and myelodysplastic syndromes (MDS) after HCT. In this retrospective study, we compared the HCT outcomes of PTCy-based vs. CNI-based GVHD prophylaxis in patients with AML and MDS. Methods: We included patients with AML and MDS who received an allogeneic HCT in first or second complete remission at our institution from 1/1/2014 to 12/31/2019. Patients received either a PTCy-based or a CNI-based GVHD prophylaxis regimen. CNI-based regimen consisted of either CNI/sirolimus +/- other (CNI/Siro group) or CNI/MTX +/- other (CNI/MTX group). The graft source in all the patients was peripheral blood (n=582) or bone marrow (n=23). Results: Total of 605 patients were identified: 442 with AML and 163 with MDS (Table 1.). GVHD prophylaxis with PTCy was used in 137 (23%), CNI/Siro in 402 (66%) and CNI/MTX in 66 (11%) patients. The PTCy group had higher proportion of patients who were Caucasian, received haploidentical donor HCT, reduced intensity (RIC) or non-myeloablative (NMA) conditioning or a bone marrow graft. Otherwise, baseline characteristics were similar between the GVHD prophylaxis groups. With a median follow up of 47 months, 149 (25%) patients relapsed, and 265 (44%) patients died. The probability of relapse at 2 years after HCT was similar between the GVHD prophylaxis groups: 23% in PTCy, 26% in CNI/Siro and 23% in CNI/MTX (p=0.94) (Figure 1). Similarly, there were no significant differences in 2-year overall survival (OS) between the groups: 58% in PTCy, 62% in CNI/Siro and 69% in CNI/MTX (p=0.33). We also observed no differences in non-relapsed mortality (NRM) between the groups. Median time to post-HCT relapse was 175 days in PTCy group, 180 days in CNI/Siro group and 131 days in CNI/MTX group. Management for post-HCT relapse included chemotherapy alone (n=58), chemotherapy +/- targeted therapy (n=53), chemotherapy + donor lymphocyte infusion (n=6), second HCT (n=3) and supportive care (n=29). GVHD prophylaxis groups did not differ by type of treatment used for relapse. Post-relapse OS at 2 years was 6% in PTCy, 20% in CNI/Siro and 31% in CNI/MTX groups (p=0.34). In multivariable analysis, the type of GVHD prophylaxis regimen did not significantly influence the post-HCT relapse, NRM, OS or post-relapse survival. Relapse was affected by DRI (p<0.001) and by type of conditioning regimen (p=0.002). NRM was influenced by HCT-CI (p=0.007) and by type of conditioning regimen (p=0.006). OS was inferior with high/very high risk DRI (p<0.001) and HCT-CI ≥ 3 (p<0.001). Survival after post-HCT relapse was better in patients relapsing >12 months after receiving HCT (p=0.003) and in those receiving treatment other than supportive care (p<0.001). Conclusion: In patients with AML and MDS receiving allogeneic HCT, we found similar risk of relapse and survival with PTCy-based and standard GVHD prophylaxis regimens. Survival after post-HCT relapse was also similar between the GVHD prophylaxis groups. The findings of this study support the use of PTCy-based regimen as GVHD prophylaxis after allogeneic HCT in patients with AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Specific Cytogenetic Abnormalities at Diagnosis Predict Survival after Hematopoietic Cell Transplant in Poor-Risk Pediatric Acute Myeloid Leukemia: A PDWP/EBMT Study

Introduction: Cytogenetic abnormalities are an important prognostic factor for predicting overall survival (OS) and relapse incidence (RI) in children with acute myeloid leukemia (AML). Although allogeneic hematopoietic cell transplant (HCT) is generally recommended for patients with AML in first complete remission (CR1) and poor-risk (PR) cytogenetics, whether these cytogenetic and molecular features retain their prognostic value after HCT is unknown. Additionally, PR AML is a heterogeneous category that includes several distinct cytogenetic abnormalities, some of which might have a worse prognosis than others. In this study, we evaluated whether the cytogenetic risk classification at diagnosis of AML was predictive of post-HCT outcomes in pediatric patients. Methods: All patients <18 years of age at the time of HCT reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, who had received their first allogeneic HCT for AML in CR1 between 2005 and 2020, and who had their karyotype evaluation at diagnosis available were included in this analysis. Patients were subgrouped as (a) monosomy 7/del7q or monosomy 5/del5q, (b) 11q23 abnormality excluding t(9;11), (c) complex or monosomal karyotype, or (d) other. A complex karyotype was defined as one with three or more structural abnormalities, and a monosomal karyotype was defined as a monosomy with one or more structural abnormalities, excluding WHO-designated recurring translocations or inversions based on 2017 ELN recommendations. Other cytogenetic abnormality subgroup included t(6;9), t(3;5), t(9;22), t(8;16), inv(3) or t(3;3), t(16;21), abn(11p15), and del(12p) or abn(12p13). Cytogenetic subgroup, age at HCT, whether HCT was from a female donor to a male recipient, patient/donor CMV status, time from AML diagnosis to HCT, and year of HCT were included as predictors for OS, RI and non-relapse mortality (NRM) in the multivariate analysis. Results: We included 744 pediatric patients (42.2% female; median age at HCT: 8.6 years [range: 0.3-18 years]) from 139 participating centers in the study. Median follow-up after HCT was 4.4 years. Thirty-seven percent had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 15% met the criteria for other PR cytogenetic abnormalities. Only 7% had secondary AML. Pre-HCT minimal residual disease (MRD) data were available for 346 patients, 86% of whom were MRD negative at the time of HCT. Patients received grafts from a matched related donor (27%), a mismatched related donor (11%), an unrelated donor (46%), or a cord blood donor (16%). Of the total patients, 55% received bone marrow, 29% received peripheral blood-derived stem cells and the rest (16%) received cord blood as the stem cell source. Myeloablative conditioning was used in 97% of the patients. The OS and leukemia free survival for the entire cohort was 76% and 70% respectively at 2 years. In a multivariate model, 11q23 (hazard ratio [HR] = 0.59, P = 0.01) and other poor-risk cytogenetic abnormalities (HR = 0.49, P < 0.01) were associated with significantly better OS when compared with monosomy 7/del7q or monosomy 5/del5q. The "other PR cytogenetic abnormalities" category was also associated with a lower risk of disease relapse after HCT (HR = 0.4, P = 0.01). Receiving an HCT from an unrelated donor, as compared with a matched related donor, was associated with lower RI (HR = 0.58, P = 0.03). Additionally, older age at HCT (12-18 years) was associated with the highest risk of NRM (HR = 1.95, P = 0.02) and with worse OS (HR = 1.71, P < 0.01) than seen in younger patients (aged 4-12 years). Conclusion: PR cytogenetic abnormalities at diagnosis remain predictive of OS after HCT for AML in pediatric patients. Monosomy 7/del7q or monosomy 5/del5q confer a poor prognosis even after HCT, whereas 11q23 abnormality and other PR cytogenetic abnormalities predict a favorable outcome after HCT. Our data also suggest that an HCT from an unrelated donor may offer greater protection against relapse than an HCT from a matched related donor, but this requires further validation. Efforts for improving conditioning regimens and transplant techniques should focus on reducing NRM and reducing RI in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm patients with AML

AbstractWe designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

ATG in HLA-Matched, Peripheral Blood, Hematopoietic Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Secondary Analysis of a CIBMTR Database

w?>Peripheral blood stem cells (PBSC) are the preferred grafts for hematopoietic cell transplantation (HCT), according to the CIBMTR. Donor recovery is faster with PBSC harvest, but PBSC is associated with higher chronic graft-versus-host disease (GVHD) and poorer quality of life. Anti-T-cell globulin (ATG) is polyclonal IgG from rabbits or horses immunized with human thymocytes or a human T-cell line, which may reduce GVHD in HCT and improve outcomes. The objective of this study was to analyze the impact of ATG in HLA-matched related (MRD) and matched (HLA 8/8) unrelated donor (MUD) HCT. We used a freely available CIBMTR database published online for secondary analyses. The database included patients ≥ 40 years old who have undergone their first PBSC MRD or MUD HCT for acute myeloid leukemia or myelodysplastic syndrome with or without ATG between 2008 and 2017. Patients who received posttransplant cyclophosphamide or alemtuzumab were excluded. Overall survival was not different with ATG (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.00-1.19; P = .06) compared with no ATG. Relapse rate was higher with ATG (HR = 1.29; 95% CI, 1.17-1.43; P < .001) and non-relapse mortality was lower with ATG (HR = 0.84; 95% CI, 0.72-0.98; P = .03). Grades II-IV acute GVHD was significantly lower with ATG (HR = 0.77; 95% CI, 0.69-0.87; P < .001) but not grades III-IV acute GVHD (HR = 0.85; 95% CI, 0.69-1.04; P = .11). Both chronic GVHD (HR = 0.54; 95% CI, 0.48-0.60; P < .001) and moderate/severe chronic GVHD (HR = 0.45; 95% CI, 0.38-0.52; P < .001) were lower with ATG. There was an interaction between ATG and conditioning regimen for relapse rate and overall survival. Relapse rate was higher in those who received reduced-intensity (RIC) or non-myeloablative (NMA) conditioning regimens and ATG, compared with MAC ± ATG or RIC without ATG (interaction test, P = .003). Overall survival was also poorer with ATG and RIC or NMA conditioning regimens (interaction test, P = .03). Our results show that ATG can mitigate the more severe forms of chronic GVHD without impairing overall survival in HLA-matched HCT with PBSC grafts and myeloablative conditioning regimen. ATG should be standard in this population.© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Argentina: Results Comparing Matched Related, Unrelated or Haploidentical Donors. a Grupo Argentino De Trasplante De Medula Osea (GATMO) Experience

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many Acute Myeloid Leukemia (AML) patients. There are not direct comparisons of results of HCT according to donor type in our region.Objective: To evaluate the impact of donor type in different outcomes as overall survival (OS), non relapse mortality (NRM), relapse (Rel) and disease free survival (DFS) in HCT for AML patients. Secondary objective was to evaluate early variables like engraftment, Acute Graft versus Host Disease (aGVHD), CMV reactivations, fungal infections and bacteriemias.Materials and Methods: A retrospective analysis of 250 medical records was conducted, addressing all patients who received an HCT for AML in seven Argentinian centers performing all three types of transplants, between January 2012 and December 2016. Mean patient´s age was 37 years; mean donors age 34 years; forty one percent (41%) of patients and 51% of donors were male; 89 patients (36%) received a matched related Allo-SCT (Sib), 78 (31%) an unrelated Allo-SCT (UD) and 83 (33%) a haploidentical Allo-SCT (Haplo). Pretrasplant HCT-CI score was low risk in 51% of the patients, 48% of the population were in CR 1 A myeloablative-conditioning (MAC) was used in 81% of the general population, peripheral blood stem cells were used in 85%.OS and DFS were tested with Kaplan Meier and NRM and Rel with cumulative incidence. Dichotomic variables were tested with Chi2. We conducted a multivariate analysis (MVA) for time dependent variables with Cox Regression.Results: Median follow up were 1.59 years. Patient and donor gender, age, HCT-CI and MAC were similar between the three type of donors., Haplo and UD groups were more likely to be in late stage compared to Sib (64% and 62% vs. 36%; p<0.001). BM source was more frequently used in Haplo (27% vs. 8% Sib and 6% UD ; p=0.001). Engraftment was slower in the Haplo group than in Sib and UD (≥15 days) (85% vs. 35% vs. 40% respectively; p=0.001). Graft failure rates were higher in Haplo than Sib and UD (16% vs. 1% and 4%; p=0.001). CMV reactivation was also more frequent in the Haplo and UD setting (53% and 56% vs.34%; p=0.02). There was a trend to a higher aGVHD incidence in UD group (60% vs. 43% Sib vs 42% Haplo; p=0.06), with no differences in GII-IV (41% vs. 27% vs 33%; p=0.19) or cGVHD (27% vs. 22% vs. 25%; p=0.65).Early NRM (day 100) was lower in Sib (4% Sib vs 13% UD vs 12% Haplo) as well as NRM at 1-3 years, (12-15% vs 21-25% vs 27-29% respectively; p=0.04) (Figure 1). Relapse rates (1-3 years) were higher among Sib and Haplo (39-44% Sib vs 40-40% Haplo vs 21-29% UD; p=0.05) (Figure 2). DFS (1-3 years) was higher in Sib and UD compared to Haplo (50-42% vs 57-46% vs 32-31% respectively; p=0.03) (Figure 3) as was OS (1-3 years 61-51% Sib vs 65-51% UD vs 44-34% Haplo; p=0.01) (Figure 4). This difference remained significant in the early stage disease (p=0.04) but no for late stageMultivariate analysis (expressed as Hazard Ratios with 95% confidence interval) showed that pretrasplant intermediate or high risk HCT-CI score were associated with poorer OS (HR 2.40, 1.34 - 4.30) and (2.67, 1.20 - 5.95). No association was seen with the type of donor used. Late stage disease at diagnosis was associated with higher relapse rates, independent of the type of donor and type of conditioning regime used (HR 2.05, 1.16-3.64). No factor affected negatively NRM after adjustment in MVA.Conclusion: Although early toxicity was similar in both Haplo and UD when expressed as NRM (day 100), worse 1 y and 3 y NRM and higher rates of relapse were observed in Haplo, resulting in a negative impact in OS. This experience shows that Haplo HCT is a complex procedure in the real world. Larger number of patients and prospective trials are needed to establish firm conclusions regarding the best strategy for patients with AML requiring a HCT [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pretransplant bone marrow cellularity and blood count recovery are not associated with relapse or survival risk following allogeneic stem cell transplant for AML in CR.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. Median follow-up was 33months. Overall survival (OS) for the whole cohort was 55.8% at 2years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P<2.6e-8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II-IV GvHD, and moderate-severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. Neither ELNr status nor pretransplant BMC influenced relapse post-HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post-HCT outcomes of AML.

Hematopoietic Stem Cell Transplant Recipients Surviving at Least 2 Years from Transplant Have Survival Rates Approaching Population Levels in the Modern Era of Transplantation.

The health and outcomes of long-term survivors after hematopoietic cell transplant (HCT) are areas of evolving interest as short-term transplant outcomes improve. Because recent changes in transplant practice have likely changed the survivor population, we sought to assess the survival of a contemporary cohort of patients who were alive and free of disease 2 years after HCT. Data were extracted from first transplants documented between 2002 and 2011 in the Australasian Bone Marrow Transplant Recipient Registry on patients who received an allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia (CML), non-Hodgkin lymphoma, and myelodysplastic syndromes or an autologous HCT for myeloma or lymphoma. Patients were included if they had survived at least 2 years without disease relapse or progression. Mortality rates were compared with standard Australian and New Zealand populations using relative-survival analysis. A total of 1562 allogeneic and 3822 autologous HCT patients were included, with a median follow-up of 5.6 years. Compared with a matched group of patients from our previous study from 1992 to 2001, the contemporary cohort of allogeneic HCT recipients was older and more likely to receive peripheral blood stem cells and from unrelated donors. Allogeneic HCT for AML increased, wheresa transplants for CML fell from 32% to 8%. Increasing use of reduced-intensity conditioning and unrelated donors was also seen. Long-term survival after allogeneic and autologous HCT were very similar to the previous 1992 to 2001 cohort despite changes in practice over time. Recipients of autologous HCT for myeloma demonstrated substantially lower overall survival than HCT for other indications with no clear plateau. Annual relative survival for survivors of allogeneic HCT was 96% to 99% of the general population but only 89% to 96% of the general population for recipients of autologous HCT. Late deaths were primarily due to nonrelapse causes after allogeneic HCT, but relapse or disease progression remained prominent for recipients of autologous HCT, particularly for myeloma. The management of late HCT effects is important to improve long-term survival of transplant recipients but should be tailored to the risks specific to the primary disease and transplant type. Future planning should account for the impact of the expected increase in transplant activity and number of survivors on resource utilization.

[Importance of gene mutation analysis as prognostic factor of acute myeloid leukemia].

In acute myeloid leukemia (AML), a number of chromosomal abnormalities and gene mutations associated with onset and recurrence were discovered by the recent progress of genome analysis technology. The founding did not only have clinical application as prognostic factors and minimal residual disease markers but also contributed to novel molecular targeted drug development. Many new drugs, such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor, have been developed in Europe and the United States. In addition, the second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, which significantly improved the treatment outcome of AML. However, there is still a large disparity in drug availability between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to practical use in Japan. This paper presents an outline of the prognosis stratification and indication of allogenic hematopoietic cell transplantation for AML by gene diagnosis in Japan.

Postremission Consolidation by Autologous Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia in First Complete Remission (CR) and Negative Implications for Subsequent Allogeneic HCT in Second CR: A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n=417) or without (n=2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P=.01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P=.03 and 1.18 (1.03 to 1.35), P=.02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P= .1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

Myeloablative Conditioning Is Preferred for Allogeneic Transplantation of Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate but Not High Disease Risk Index

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p&lt;0.001) but significantly higher risk of relapse (HR=1.54, 95% CI 1.35-1.76; p&lt;0.001). As a result, RFS in this cohort was significantly worse with RIC (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/ very high risk DRI cohort, RIC resulted in similar TRM (HR=0.83, 95% CI 0.68-1.00; p=0.051) but again significantly higher risk of relapse (HR=1.23, 95% CI 1.08-1.41; p=0.002). RFS in high/ very high risk DRI cohort was similar between RIC and MAC. Adjusted outcome curves for the 3 endpoints are shown in the Figure. In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM. In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group. Disclosures Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Utilizing Data to Modify Standard Operating Procedures and Improve Outcomes: Evaluating Complications after Donor Lymphocyte Infusions in Allogeneic Stem Cell Transplant Recipients

Introduction Despite major advances in hematopoietic cell transplant (HCT), 10-50% of patients relapse following allogeneic HCT. Donor lymphocyte infusion (DLI) is one treatment strategy for relapse that potentially provides a graft versus malignancy therapeutic effect. A major complication of DLI is graft versus host disease (GVHD), with incidences ranging from 40-60%. Risk of developing GVHD is related to multiple factors with DLI cell dose speculated to have the strongest correlation. Conversely, too small of a dose can allow disease progression. The literature is quite heterogeneous regarding dosing and consensus data are lacking. The University of North Carolina Bone Marrow Transplant and Cellular Therapy Program (BMT CTP) has a standard operating policy surrounding DLI dosing and timing. As part of our quality audit, we evaluated policy compliance and outcomes to determine if policy changes were needed. Methods We evaluated HCT recipients with Acute Myeloid Leukemia (AML) and myelodysplastic syndrome (MDS) who received at least one DLI between 2001 and 2016. During these 15 years, 282 patients received an allogeneic HCT for AML and MDS. 42 patients with AML (15%) received at least 1 DLI for a total of 59 DLIs and 14 patients with MDS (5%) received at least 1 DLI for a total of 21 DLIs. 4 patients with AML and 1 with MDS received a DLI for reasons not included in the policy and were excluded. The final population included 38 AML patients receiving 54 DLIs and 13 MDS patients receiving 15 DLIs for a total of 51 patients receiving 69 DLIs. The BMT CTP DLI policy outlines the recommended cell dose to be administered (Figure 1). Data collected included disease, donor type, recipient age, graft, reason for DLI, cell dose infused, survival, cause of death, GVHD occurrence after DLI, and if DLI algorithm was followed. Results Figure 2 shows patient characteristics and outcomes following DLI. Time from HCT to first DLI for AML patients was a median of 176.5 days (range 71 days – 10 years) and for MDS, 137 days (range 78 days - > 3 years). DLI dosing ranged from 1 × 106 to 5 × 107 CD3 cells/kg for AML and 1 × 106 to 1.2 × 107 CD3 cells/kg for MDS. For those with follow-up data, 50% (25/50) developed GVHD following DLI and 28.6% (14/49) were alive at a median of 6.2 years after last DLI. For both cohorts, dosing algorithm was followed about 50% of the time. Conclusion While our GVHD occurrence following DLI is within published data range, AML relapse remains high. Heterogeneity in dose and disease precludes precise identification of prognostic factors for successful outcomes, yet these data support the role of DLI in contributing to the survival of a subset of patients following HCT. However, improved uniformity in dosing may aid in understanding appropriate dosing. We have recently made modifications to our current algorithm with a goal that increased consistency will allow systematic evaluation of outcomes and improved care.

Upfront allogeneic hematopoietic cell transplantation (HCT) versus remission induction chemotherapy followed by allogeneic HCT for acute myeloid leukemia with multilineage dysplasia: A propensity score matched analysis.

The efficacy of induction chemotherapy before allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia with multilineage dysplasia (AML-MLD) is unclear. Some patients with AML-MLD have received upfront HCT without prior induction chemotherapy. To compare the transplant outcomes between patients who received upfront HCT and those who received induction chemotherapy followed by allogeneic HCT for AML-MLD, we retrospectively analyzed the Japanese registration data of 1445 adult patients who had received allogeneic HCT between 2007 and 2016. Propensity score matching identified 269 patients in each cohort. There were no significant differences in overall survival between the two groups. The cumulative incidence of leukemia-related mortality was significantly lower in patients who received upfront HCT than those who received induction chemotherapy before HCT. In the subgroup analyses, upfront HCT had a significantly reduced incidence of leukemia-related mortality among patients aged between 60 and 70 years, those with a lower white blood cell count at diagnosis (<3000/μL), and poor cytogenetic risk, and those who received myeloablative conditioning and cord blood transplantation. Our results suggested that induction chemotherapy before HCT did not have any benefits of survival after HCT for AML-MLD. Upfront HCT contributed to the reduced incidence of leukemia-related mortality after HCT. Upfront HCT should be considered for patients with AML-MLD who are eligible for allogeneic HCT.

Complete Remission with Incomplete Count Recovery (CRi) Prior to Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia Is Associated with a High Non-Relapse Mortality without Increased Relapse Risk

Abstract Background: For the majority of patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) offers the best prospect of long-term survival. However both the risk of relapse and non-relapse mortality remain stubborn barriers to successful outcome. Remission status is one of the strongest predictors of outcome, and while conventional risk stratification models account for this, complete remission with incomplete count recovery (CRi) is typically ascribed the same predictive value as complete remission (CR). Methods: In this single center retrospective study we assessed the impact of incomplete count recovery on outcome of allogeneic HCT for AML. Patients' disease status was classified immediately prior to HCT as complete remission (CR), complete remission with incomplete count recovery (CRi) or no complete remission (no CR/CRi). The conventional definition of complete remission (&amp;lt;5% marrow blasts by morphology) was employed and incomplete count recovery was defined as platelet count &amp;lt;100 x 109/L and/or absolute neutrophil count &amp;lt; 1 x 109/L. Measurable residual disease (MRD) was defined by detectable disease by a contemporaneously accepted standard methodology at the time of transplant (e.g. PCR or immunophenotyping). The primary outcome measure was overall survival, and secondary endpoint of non-relapse mortality and relapse were also assessed. Results: Between January 2005 and December 2017, 155 patients underwent allogeneic HCT for AML in our institution. Disease status was defined as CR in 82 (53%), CRi in 54 (35%) and no CR/CRi in 19 (12%). No significant demographic or transplant characteristics were observed between the groups. With a median follow-up of 3.4 [0.1 - 12.8] years, survival at 3 years was 42.5% for the whole cohort with significant differences between the three groups: 54.3% for CR, 34.8% for CRi and 13.4% for no CR/CRi (p&amp;lt;0.001; fig 1A; HR 1.94 for CRi, and 3.4 for no CR). These differences remained after corrections for standard transplant risk factors. The significant differences in overall survival between CR and CRi groups were accounted for by increased non-relapse mortality (7.5% vs. 24.2% at 100 days and 28.7 vs 44.9% at 3 years (p=0.003), fig 1B). The overall cumulative incidence (CI) of relapse at 3 years was 32.4%, and while those patients transplanted not in CR/CRi has a significantly increased CI of relapse (55.3%, p=0.006), there were no significant differences between the CR and CRi groups (25.1 and 36.7% respectively (p=0.441; fig 1C). Patients without MRD (n=107) had a lower incidence of relapse compared to those with MRD (n=48, 21.9% vs. 48.1%, p=0.009), however MRD negative patients with incomplete recovery still had a significantly worse 3-year survival than those with complete recovery (37.5 vs 56.7, p=0.006) resulting from higher NRM (46.4% vs 30.4%%, p=0.003, fig 1D). Discussion: CRi patients have a poorer survival and higher NRM than CR patients with full marrow recovery, without evidence of increased relapse. While death from NRM is a competing risk for relapse, the increased incidence of relapse remains overtly demonstrable in those patients transplanted not in CR/CRi, despite an equally high NRM. Additionally, the persistently increased NRM in CRi patients without MRD, suggests that the poorer survival may result from poor fitness for transplant and increased susceptibility to transplant related complications rather than an imminent relapse. With the advent of increasingly sensitive MRD technologies, these data may suggest that further pre-transplant optimization to promote marrow recovery may be permissible in order to minimize NRM without risking increased risk of relapse in CRi patients. Figure 1. Figure 1. Disclosures Apperley: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Speakers Bureau.

It's Not All in the Conditioning or the Perils of Early Trial Cessation

Reduced-intensity conditioning (RIC) regimens were initially developed in an effort to offer a potential curative treatment to patients who were historically not considered candidates for allogeneic transplantation either because of age or advanced comorbidities. The lower treatment-related mortality (TRM) of these regimens led to an interest in exploring RIC in healthier and younger patients. Many retrospective studies showed no difference in overall survival (OS) compared with higher intensity conditioning regimens referred to as myeloablative conditioning (MAC) [1.Martino R. Iacobelli S. Brand R. et al.Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.Blood. 2006; 108: 836-846Crossref PubMed Scopus (294) Google Scholar, 2.Scott B.L. Sandmaier B.M. Storer B. et al.Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis.Leukemia. 2006; 20: 128-135Crossref PubMed Scopus (211) Google Scholar, 3.Alyea E.P. Kim H.T. Ho V. et al.Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome.Biol Blood Marrow Transplant. 2006; 12: 1047-1055Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]. However, the cause of death was different. It was observed that relapse was a more frequent cause of death in patients who received RIC, whereas TRM was a more frequent cause of death in patients who received MAC. Most retrospective studies included many different hematologic malignancies with different risks of underlying relapse. In addition, a significant selection bias that goes beyond age and patient health when selecting the most appropriate conditioning intensity for a given patient is widely acknowledged. Additional retrospective studies showed no difference in OS and perhaps a survival benefit in patients with myeloid malignancies who were in remission at time of transplant [4.Shimoni A. Hardan I. Shem-Tov N. et al.Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.Leukemia. 2006; 20: 322-328Crossref PubMed Scopus (260) Google Scholar]. This led many to question whether conditioning intensity was an important component of allogeneic transplant in patients who were in remission at the time of transplant. Perhaps these were patients who could be spared the potential morbidity and increased TRM observed with MAC. Several randomized trials have been performed to answer this question but with mixed results. The BMT CTN 0901 trial enrolled patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who were in morphologic remission and randomized them to either RIC or MAC regimens primarily consisting of either 2-day or 4-day busulfan [5.Scott B.L. Pasquini M.C. Logan B.R. et al.Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes.J Clin Oncol. 2017; 35: 1154-1161Crossref PubMed Scopus (383) Google Scholar]. There were 272 patients randomized in total, and the trial was stopped early by an independent Data and Safety Monitoring Board because of a higher than expected relapse rate in the RIC arm. There was no significant difference in OS, but there was a significantly higher relapse-free survival (RFS) for the MAC regimen. The principal endpoint of the trial was 18-month OS. A similar trial was conducted by the German transplant group comparing total body irradiation–based RIC (8 Gy) with total body irradiation–based MAC (12 Gy) for patients with AML in first complete remission [6.Bornhauser M. Kienast J. Trenschel R. et al.Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial.Lancet Oncol. 2012; 13: 1035-1044Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar]. There were a total of 195 patients enrolled, and the trial was stopped early because of slow accrual. The authors found no significant difference in OS, RFS, or TRM. Longer term follow-up of these patients again showed no difference in OS, RFS, or TRM [7.Fasslrinner F. Schetelig J. Burchert A. et al.Long-term efficacy of reduced-intensity versus myeloablative conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: retrospective follow-up of an open-label, randomised phase 3 trial.Lancet Haematol. 2018; 5: e161-e169Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. The European Society for Blood and Marrow Transplantation RICMAC trial randomized 129 patients with secondary AML or MDS to receive either a MAC of 4-day busulfan or a RIC of 2-day busulfan [8.Kroger N. Iacobelli S. Franke G.N. et al.Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC Trial).J Clin Oncol. 2017; 35: 2157-2164Crossref PubMed Scopus (144) Google Scholar]. The principal endpoint of this trial was to show a difference in TRM; however, this trial was also stopped early because of slow accrual. Not surprisingly, this study also failed to show a significant difference in OS, RFS, or TRM. The different regimens used in these trials highlight a difficult aspect of evaluating conditioning intensity, which is that truthfully it is a continuous spectrum of intensity rather than a solid rigid line that defines RIC versus MAC [9.Giralt S. Ballen K. Rizzo D. et al.Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant Research.Biol Blood Marrow Transplant. 2009; 15: 367-369Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar, 10.Bacigalupo A. Ballen K. Rizzo D. et al.Defining the intensity of conditioning regimens: working definitions.Biol Blood Marrow Transplant. 2009; 15: 1628-1633Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar]. Also, it has become increasingly apparent that minimal residual disease and minimal identifiable disease are significant predictors of relapse post-transplant, and these data were not available in these randomized trials [11.Walter R.B. Buckley S.A. Pagel J.M. et al.Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission.Blood. 2013; 122: 1813-1821Crossref PubMed Scopus (270) Google Scholar, 12.Festuccia M. Deeg H.J. Gooley T.A. et al.Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia evolving from myelodysplastic syndrome.Biol Blood Marrow Transplant. 2016; 22: 1227-1233Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. Additionally, most patients enrolled into these trials received matched sibling or matched unrelated donor stem cell grafts. Therefore, the impact of donor selection was not easily assessed in these studies. In this issue Huselton et al. [13.Huselton E. Slade M. Trinkaus K.M. DiPersio J.F. Westervelt P. Romee R. Propensity score analysis of conditioning intensity in peripheral blood haploidentical hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2018; 24: 2047-2055Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] take us a step further by evaluating the impact of conditioning intensity in the setting of haploidentical (haplo) donors. There are certainly many reasons to suspect that the use of haplo donors would affect the choice of conditioning regimens; perhaps with an enhanced graft-versus-leukemic effect the use of MAC has less importance. The authors performed a retrospective analysis comparing 61 patients who received haplo MAC withto 87 patients who received haplo RIC. A variety of hematologic malignancies was included in this analysis, but most patients had AML. The authors found no significant differences in RFS or OS between MAC and RIC; however, patients who received MAC were less likely to have relapsed and more likely to have TRM. Besides the unique inclusion of haplo donors, another interesting aspect of this article is the use of a propensity score to adjust for selection bias that would be inherent in any retrospective study evaluating the choice of conditioning intensity. As the authors state, several factors were included in the propensity score adjustment such as age, diagnosis, de novo versus secondary, and disease stage at time of transplant. As the authors state, not all variables known to account for selection bias were included in the propensity score, and there may, of course, be unknown variables that lead to bias in selection of conditioning regimens. Therefore, there are limitations to this approach. However, the authors make an excellent first step in evaluating the impact of conditioning intensity in the setting of haplo donors. One hopes this will be addressed by future large randomized trials that are not stopped too early.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days −6 to −4; fludarabine 30 mg/m2/day on days −6 to −2; and a single fraction of 200 cGy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.