Conditioning Regimen For Hematopoietic Cell Transplantation Research Articles

Reproductive health assessment and reports of fertility counseling in pediatric and adolescent patients with sickle cell disease after hematopoietic cell transplantation

Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. This was a secondary analysis of gonadal hormone production, future infertility risk assessment and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (IQR) or percentages. There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 - 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3,388mg/m2 to 9,706mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥ 40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent-proxies (for patients < 18 years old) and patients ≥ 18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty five percent of parent-proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. There are high rates of gonadal dysfunction post-HCT, but many parent-proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

Optimization of Radiolabeling of a [90Y]Y-Anti-CD66-Antibody for Radioimmunotherapy before Allogeneic Hematopoietic Cell Transplantation.

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of 90Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [90Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%–60.8%) and 32.2% (95% CI, 22.4–42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30–3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Renal Dysfunction in Pediatric Acute Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation with Total Body Irradiation-Containing Conditioning Regimen

<h3>Purpose/Objective(s)</h3> Renal dysfunction after hematopoietic cell transplantation (HCT) is a multi-factorial disorder. Studies have linked dose and fractionation with the incidence of late renal dysfunction in patients who underwent total body irradiation (TBI)-based myeloablative conditioning, but the effect of dose rate remains under studied. We conducted a single-institution retrospective study to elucidate the effect of TBI parameters and peri-HCT factors on late renal dysfunction among pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) after allogeneic HCT. <h3>Materials/Methods</h3> 123 patients (age 1-22) with acute leukemia (38 AML, 85 ALL) underwent HCT using a TBI-based regimen at our institution from 2006-2019. HCT conditioning regimen included cyclophosphamide with or without fludarabine followed by TBI (13.2 Gy in 8 twice-daily fractions over 4 days). TBI dose rate was limited to < 20 cGy/min but ranged from 8.7-19.2 cGy/min depending on Linac availability. TBI parameters and peri-HCT factors were recorded and stratified by recipient of high-dose-rate (HDR; > 15 cGy/min; 35%) or low-dose-rate (LDR; ≤15 cGy/min; 65%) TBI. All patients received a calcineurin inhibitor to prevent graft-versus-host disease (GVHD). Serum creatinine (Cr) was recorded at baseline and trended post-HCT. Late renal dysfunction was defined as persistent increase of Cr > 1.2 mg/dL or ≥ 1.25 times the upper limit of age-dependent normal, onset ≥ 3 months after HCT. Using a statistical software, dichotomous variables were tested using Chi-square or Fisher's exact test; and continuous variables using Wilcoxon rank-sum test. Univariate and multivariate analyses were used to examine the association of these variables with late renal dysfunction. <h3>Results</h3> A total of 14 patients developed late renal dysfunction (11%): 6/38 patients in HDR group (14%) vs. 8/79 patients in LDR group (10%, <i>P</i> = 0.03). Comparison between HDR and LDR groups found no difference in age, sex, remission status, HCT comorbidity index (HCT-CI, predictive of late organ dysfunctions, factoring in baseline Cr) or baseline Cr. More patients in the HDR group were cord blood recipients taking cyclosporine/mycophenolate mofetil (37% vs. 19% in LDR, <i>P</i> < 0.01), and fewer were sibling recipients taking tacrolimus/methotrexate (0% vs. 10%, <i>P</i> < 0.01). More patients in HDR group developed acute GVHD (35% vs. 27%, <i>P</i> = 0.05). In univariate analysis, incidence of late renal dysfunction was associated with patient's age ≤12 at HCT (22% vs. 5% > 12), intermediate-high HCT-CI (22% vs. 6% low HCT-CI) and HDR (24% vs. 8% in LDR). On multivariate regression, late renal dysfunction remained associated with age, HCT-CI, and HDR (<i>P</i> = 0.01, 0.02, and < 0.01 respectively). <h3>Conclusion</h3> Patient's age ≤12 at HCT, intermediate-high HCT-CI, and HDR were associated with late renal dysfunction post-HCT. Since dose rate is the only modifiable factor, adoption of LDR TBI is recommended.

Comparison of hematopoietic cell transplant conditioning regimens for hemophagocytic lymphohistiocytosis disorders

Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders. We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models. Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P< .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P< .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P= .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P= .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P< .001). Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

A Prospective Cohort Study Comparing Long-Term Outcomes with and without Palifermin in Patients Receiving Hematopoietic Cell Transplantation for Hematologic Malignancies

The incidence of debilitating oral mucositis (OM) can be as high as 99% after myeloablative conditioning regimens preparing patients with hematologic malignancies for hematopoietic cell transplantation (HCT). Palifermin (KGF) is a recombinant human keratinocyte growth factor that reduces the incidence and duration of severe OM. The long-term safety of KGF has not been well established, however. In this long-term prospective matched-cohort study, patients who received KGF (cases) and underwent autologous or allogeneic HCT for hematologic malignancies between 2006 and 2013 were matched 1:1 to patients who did not receive KGF (controls). The primary outcome was overall survival (OS). Other outcomes were disease relapse, new malignancies, pancreatitis, renal failure requiring dialysis, pulmonary complications, cataract surgery, and acute and chronic graft-versus-host disease (GVHD). The analysis population comprised 2191 matched pairs with a wide range of diseases and donor types that received diverse conditioning and GVHD preventive regimens, representing contemporary practice patterns. The median duration of follow-up was 8 years (range, 1 to 12.5 years). In multivariate analyses, the probabilities of OS (relative risk [RR], 1.01; 95% confidence interval [CI], 0.91 to 1.12), relapse (RR, 1.06; 95% CI, 0.94 to 1.18), new malignancies (RR, 0.89; 95% CI, 0.67 to 1.18), and cataract surgery (RR, 1.05; 95% CI, 0.74 to 1.50) were not statistically significantly different between cases and controls. In univariate analyses, no increased risks were observed for renal failure requiring dialysis, pancreatitis, acute GVHD, chronic GVHD, interstitial pneumonitis/acute respiratory distress syndrome/idiopathic pneumonia syndrome, or bronchiolitis obliterans/cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia among cases compared with controls. This long-term prospective safety cohort study demonstrates that the KGF group had no increased risk of overall mortality, relapse, new malignancies, or any other key outcome. The broad inclusion criteria allow the results to be generalized to contemporary practice for patients with a wide range of diseases and receiving a wide range of HCT conditioning regimens and graft sources from diverse donor types.

Intravenous Busulfan-Based Conditioning Regimens in Allogeneic Hematopoietic Cell Transplantation for Patients with Acute Lymphoblastic Leukemia

Introduction: Intravenous busulfan is a common component of high-dose conditioning regimens for hematopoietic cell transplantation (HCT), but it has not been well investigated in acute lymphoblastic leukemia (ALL). We retrospectively evaluated intravenous busulfan-based conditioning regimens for allogeneic HCT for adult patients with ALL.Methods: This study included 195 patients with ALL who were in first complete remission (CR) at the time of allogeneic HCT. All patients received intravenous busulfan-based conditioning regimens: 4-day busulfan (3.2 mg/kg x 4d) plus cyclosphosphamide (n=80), 4-day busulfan plus fludarabine (n=20), and 2-day busulfan (3.2 mg/kg x 2d) plus fludarabine (n=95). Antithymocyte globulin was added at doses between 3.75 and 12 mg/kg in 104 patients.Results: The hematopoietic cell donor was an HLA matched sibling for 82 patients, an unrelated matched volunteer for 79, and a mismatched family member for 34. All but two patients achieved an absolute neutrophil count > 500/μL on median day 12. Acute graft-versus-host disease (GVHD) occurred in 61 patients (31%): grade I in 27, grade II in 17, and grade III/V in 17, while 100 (52%) of 192 assessable patients developed chronic GVHD: mild in 17, moderate in 33, and severe in 50. After a median follow-up of 4.9 years, 72 patients relapsed, and 85 died. Twenty-five deaths were nonrelapse deaths. The probabilities of overall survival, relapse-free survival, and nonrelapse mortality at 2 years were 68%, 66%, and 10%, respectively. Post-transplant outcomes were not significantly different between 4-d busulfan and 2-d busulfan. Patients with chronic GVHD had superior outcomes compared with those without chronic GVHD, mainly because of lower incidence of relapse.Conclusion: Our study results demonstrate that intravenous busulfan-based conditioning regimens provide effective disease control for ALL with relatively low nonrelapse mortality, and graft-versus-leukemia effects are present after allogeneic HCT for patients with ALL. DisclosuresKo:Boehringer Ingelheim: Research Funding. Lee:Boehringer Ingelheim: Research Funding. Park:Boehringer Ingelheim: Research Funding. Choi:Boehringer Ingelheim: Research Funding. Lee:Boehringer Ingelheim: Research Funding.

A comparative study of porcine antihuman lymphocyte globulin versus antithymocyte globulin-fresenius in an allogeneic hematopoietic cell transplantation conditioning regimen for severe aplastic anemia

ABSTRACT Objectives To compare the outcomes of antihuman T lymphocyte globulin (ATG-F) and porcine antihuman lymphocyte globulin (p-ALG) as part of a conditioning regimen in hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA). Methods we performed a retrospective analysis, evaluating the outcome of patients with SAA who received ATG-F based conditioning (n = 26) with those receiving p-ALG conditioning (n = 34). Results The median time to neutrophil engraftment was 11 days (range, 8 − 38) and 11 days (range, 9 − 24) in the p-ALG and ATG-F groups (P = 0.857); the median platelet engraftment time was 15 (range, 9 − 330) days and 13 (range, 10 − 56) days (P = 0.155). There were no significant differences in grades II − IV acute graft-versus-host disease (aGVHD), grades III − IV aGVHD, chronic GVHD (cGVHD), and the moderate-severe cGVHD between the ATG-F and p-ALG groups (P>0.05). Discussion Patients in the ATG-F group functioned significantly better on role-physical (P = 0.006), general health (P = 0.029), and physical component summary (P = 0.009). The estimated overall survival and failure free survival rates at 5 years were 88.5% ± 6.3% vs. 82.4% ± 6.5% (P = 0.515), 84.6% ± 7.1% vs. 79.4% ± 6.9%, respectively (P = 0.579). The infection rates were 61.53% and 47.05%, respectively (P = 0.265). Conclusion As part of the conditioning regimen, p-ALG achieved a similar efficacy as ATG-F without increasing the incidence of transplantation complications in SAA patients.

A Multi-Center Case Series, Systematic Review and Meta-Analysis of Neonatal Hemophagocytic Lymphohistiocytosis

Background Hemophagocytic lymphohistiocytosis (HLH) is an increasingly recognized life-threatening syndrome characterized by excessive inflammation and immune dysregulation. However, little is known about HLH presenting in neonates. Methods To describe the phenotype, etiology, and efficacy of therapy for infants presenting within 28 days of birth and diagnosed with HLH prior to 90 days of life, a retrospective multi-center study was conducted identifying 13 previously unreported cases from 8 centers. A systematic literature review identified 58 additional cases that were sufficiently similar to allow pooling for meta-analysis (n=71). Results Presenting symptoms and laboratory findings of HLH were non-specific and indistinguishable from other neonatal critical illnesses. More than 85% of patients demonstrated hepatomegaly, splenomegaly, hyperferritinemia, transaminitis, hypoalbuminemia, and severe thrombocytopenia. Notably, liver dysfunction appears more common in neonatal HLH compared to published reviews of HLH cases across the age spectrum. Genetic testing was pursued in 60% of the cohort with pathogenic variants identified in a third of patients (PRF1 in 15, UNC13D in 8). Ten additional cases occurred with a family history of HLH, for a total of 46% (33/71) of cases of presumed familial HLH. Seventeen cases (24%) represented secondary HLH with an identified trigger for immune dysregulation (e.g. infection or non-HLH disease) in the absence of an HLH-associated genetic mutation or family history. Twenty-one (30%) neonatal HLH cases were of unknown etiology. Two-year survival from presentation was low at 27%, with a trend toward superior 2-year overall survival for those with secondary HLH at 65% (unknown etiology 21%, familial HLH 18%, p=0.06; Figure). Ten patients (n=6 familial HLH, n=4 unknown etiology) underwent allogeneic hematopoietic cell transplantation (HCT) at a median of 4.8 months of age. HCT was associated with improved 2-year overall survival (OS) from HLH diagnosis (78% with HCT versus 11% without HCT, p&amp;lt;0.01). Infants proceeding to HCT trended toward older age at diagnosis with less severe lung and liver disease. Suspecting disease severity and/or lethality to confound treatment choice and prohibit proceeding to HCT, a landmark analysis of survival was conducted including only those surviving to 100 days of life. While this landmark analysis attenuated the survival benefit of HCT (78% with HCT versus 28% without HCT, p=0.09), the attenuation was driven by inclusion of secondary HLH cases (2-year OS 78% with HCT versus 0% without HCT when secondary HLH excluded, p&amp;lt;0.01). Conclusion Liver dysfunction in a severely ill neonate should prompt consideration of HLH as an etiology. Our study supports consideration of HCT for any neonate with HLH, except those with an identified trigger and absence of an HLH-associated gene mutation prompting classification as secondary HLH. Early lethality combined with superior HCT outcomes when HLH is well-controlled additionally highlight the need for novel HLH therapies to bridge to HCT. Further studies to better elucidate details of pre-HCT therapy, HCT conditioning regimens and how best to navigate multi-organ failure at HLH presentation are needed. Figure Disclosures No relevant conflicts of interest to declare.

Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation: Analysis of a Multinational, Prospective, Observational Registry Study

Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation: Analysis of a Multinational, Prospective, Observational Registry Study

Chromosomal Aberrations in Pre-HCT Blood Samples and Outcomes after Transplantation in Patients with Myelofibrosis

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for myelofibrosis (MF). However, prognosis post HCT is variable. Identifying subsets of patients who can greatly benefit from HCT is important for clinical decision-making and patient counseling. The Dynamic International Prognostic Scoring System (DIPSS) score includes cytogenetic abnormalities provides important prognostic information. Here, we used high-resolution single nucleotide polymorphism (SNP) arrays to characterize chromosomal aberrations in pre-HCT blood samples from patients with MF and evaluated their added value in patient risk stratification for post HCT survival. Methods: We used the Illumina Global Screening Array to detect somatic copy number alterations (SCNAs) sized ≥2Mb (by calculating the log2 R ratio and B allele frequency and leveraging haplotype information) in pre-HCT blood samples (collected 2-4 weeks prior to HCT conditioning regimen administration) from 923 MF patients who underwent HCT between 2000-2016. Clinical data and blood samples were obtained from the Center for International Blood and Marrow Transplant Research. We used Kaplan-Meier survival analysis and multivariable Cox regression to evaluate the prognostic significance of observed SCNAs on survival after HCT. Results: Median age at HCT was 58 years (range=0.7-76). About 58% were males (N=536), 85% received unrelated donor HCT (N=787), 90% received peripheral blood stem cell grafts (N=826), 47% (N=429) received myeloablative conditioning (MAC), 34% (N=312) received HCT within 1 year from diagnosis, and 537 patients (58%) had known DIPSS score at HCT (47% of them were intermediate II or high). A high frequency of SCNAs were noted in MF (N=623; 67.5%), most commonly on chromosome (chr) 9p (N=224, 24%), chr13q (N=104, 11%), and chr20q (N=102, 11%) (Figure 1). Aberrations noted on chromosomal regions harboring the known MF genes (MPL, DNMT3A, TET2, EZH2, JAK2, SRSF2, CALR, ASXL1, U2AF1) accounted for 28% of all detected (40% of the patients), including JAK2 (9p24.1, N=253, 27%), MPL (1p34.2, N=30, 3.3%) and CALR (19p13.13, N=23, 2.5%). Multivariable models including all MF genes (adjusted for DIPSS score, KPS, year of HCT, hemoglobin count, splenectomy, age, sex, time from diagnosis to HCT, and stratified on CMV match, graft type and conditioning regimen) showed an association between SCNAs on TET2 or SRSF2 regions and poor survival (HR for TET2 =2.40, 95% CI=1.33-4.32, p=0.004; and HR for SRSF2= 2.22, 95% CI=1.26-3.89, p=0.006). TET2 region aberrations were associated with an increased risk of transplant-related mortality (TRM) (HR=2.97, 95% CI=1.53-5.78, p=0.001), worse disease-free survival (DFS; HR=2.22, 95% CI=1.33-3.69, p=0.002), but not the risk of relapse (p=0.12). SRSF2 region aberrations were associated with DFS (HR=1.94, 95% CI=1.11-3.37, p=0.02); no statistically significant association was noted with the risk of relapse (p=0.07) or TRM (p=0.44). These associations were predominant in patients receiving reduced intensity (RIC) or non-myeloablative regimens (Figure 2). Further univariate analyses focusing on all frequently affected chromosomes (affecting ≥10 patients) showed poor OS with SCNAs on chr17p (log-rank p&amp;lt;0.0001), 12p (p&amp;lt;0.0001), 5q (p&amp;lt;0.0001), 13q (&amp;lt;0.001), 8q (p=0.004), 18q (p=0.02) and 4q (p=0.03). In multivariable models stratified on conditioning regimens, chr17p aberrations showed a significant association with excess risk of relapse independent of regimen intensity (HR=5.31, p=0.01 in MAC, and HR=2.70, p=0.02 in RIC). The HR for OS was 2.55, p=0.09, and 2.86, p=0.002, respectively. Other chromosomal aberrations that showed significant associations with inferior OS in patients receiving RIC were SCNAs on chr8q (HR=5.55, p&amp;lt;0.001) (Figure 3), with excess risk of TRM (HR=5.09, p=0.002) but not relapse (p=0.34). In patients that received MAC, elevated risk of mortality was noted with chr5q SCNAs (HR=2.83, p=0.02) with a suggestive association with relapse (HR=2.72, p=0.08) but not with TRM (p=0.59). Conclusion: This study highlights the prognostic ability of pre-HCT detected SCNAs in patients with myelofibrosis, independent on DIPSS score. Relapse risk in patients with aberrations affecting TP53 region was not eliminated by MAC. Follow-up studies to confirm the poor prognosis of those chromosomal changes are warranted. Disclosures Lee: Incyte: Consultancy, Research Funding; Syndax: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Research Funding; Novartis: Research Funding.

Novel Approach for Bone Marrow Transplantation Conditioning in Acute Myelogenous Leukemia not Responding to the Induction Therapy Using Etoposide Carried in Lipid Core Nanoparticles: A Pilot Clinical Study

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for acute myelogenous leukemia (AML) not responding to induction therapy. It is a therapeutic choice for the blast phase of chronic myelogenous leukemia (CML-BP) in patients failing to respond to tyrosine kinase inhibitors (TKIs). Lipid core nanoparticles (LDEs) concentrate severalfold more in blast cells than in corresponding normal cells. Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity. We tested a drug-targeting system, LDE-etoposide plus total body irradiation (TBI; 1200 cGy dose), in 13 patients with AML not responding to the induction therapy and in 2 patients with CML-BP refractory to second-generation TKIs. The mean patient age was 46.7 years (range, 22 to 66 years). The LDE-etoposide dose was escalated at 20, 30, 40, 50, and 60 mg/kg. No patients developed grade 4 or 5 toxicity; however, mucositis grade 3 occurred in 6 patients, 3 patients experienced diarrhea, and 1 patient had an elevated total bilirubin level. No deaths were related to conditioning. All patients were successfully engrafted. The median times to neutrophil and platelet engraftment were 20 ± 5 days and 16 ± 4 days, respectively. Five patients (33.4%) had acute graft-versus-host-disease (GVHD), including 4 grade I, and 1 with grade II, and 8 patients (57.1%) had moderate-to-severe chronic GVHD. This pilot study shows the potential of LDE-etoposide plus TBI as an HCT conditioning regimen in AML patients not responding to the induction and refractory therapies for CML-BP patient. These findings pave the way for subsequent larger clinical trials.

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged &gt;1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) &gt;2 × the upper limit of normal, thrombocytopenia (platelet count &lt;50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase &gt;50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was &lt;50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as &lt;25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

A Phase II Trial to Compare Allogeneic Transplant Vs. Standard of Care for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1503

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for sickle cell disease (SCD). A pilot trial confirmed the suitability of a myeloablative conditioning regimen (busulfan/fludarabine/r-ATG) for HLA-matched sibling and unrelated donor HCT for severe SCD. This led to the current phase II trial funded by the NHLBI. The primary aim is to determine the efficacy of treatment options (HCT vs. standard of care) for adolescents and young adults with severe SCD (NCT02766465). Study design and Treatment: This is a "biologic assignment" trial in which subjects with an HLA-matched sibling or HLA-matched unrelated donor are assigned to a donor arm (expected to receive HCT). Those without a suitable donor are assigned to a no-donor arm and expected to receive current therapies for SCD at the discretion of their provider. Although randomization is the gold standard for comparing treatments, such an approach for a rare disease is not feasible for the following reasons: 1) timely completion of the trial (~30% expected to identify a matched sibling and ~20%, a matched unrelated donor) and 2) accrual is challenging when the two arms of a randomized trial have markedly disparate treatments (i.e., one arm is an intervention with about 10-20% upfront mortality vs. the other arm also expected to have mortality risks but accepted as a consequence of disease). While we expect some to decline HCT (donor arm) or proceed to a mismatched related or unrelated donor HCT (no-donor arm), through education /counselling prior to consent, we anticipate &lt;5% cross-over. Major Inclusion Criteria: Age 15 - 40 years with SCD (stroke or neurologic deficit, recurrent vaso-occlusive crisis, acute chest syndrome, high impact chronic pain or tricuspid regurgitant jet velocity ≥2.7m/second. Subjects who already have a suitable donor are excluded. Statistical Methods: Subjects are screened for eligibility and enrolled without knowing their biological assignment. HLA typing of the subject and donor search can be undertaken only after enrollment. Treatment arm assignment, (donor or no-donor arm) has to occur within 6 months of enrollment. We hypothesize that subjects on the donor arm will exert an early impact on survival and that survival will plateau by 1-year. Those on the no-donor arm are expected to follow the natural history of their disease with risk of premature mortality. A non-inferiority framework was chosen to test the non-inferiority of the donor arm compared to the no donor arm. The non-inferiority margin of 0.20 was chosen to establish that the difference in the proportion of subjects surviving at 2 years between the donor arm is no more than 0.20 worse than the no donor arm. If we reject the non-inferiority null hypothesis with a one-sided test, we will declare that the non-inferiority margin is met and that the difference in the probability of 2-year survival between the donor and no-donor arm is no more than 20%. Endpoints: The primary endpoint is the estimate of overall survival at 2-years after enrollment. Regardless of treatment received subjects will remain in their assigned treatment arm for analysis of survival (intent-to-treat principle). Secondary endpoints include comparison of occurrence of sickle related events in both treatment groups over 2 years (pulmonary hypertension, cerebrovascular, renal, avascular necrosis, leg ulcer), and functional assessment (6-minute walk distance test, 28-day e-pain diary [mean pain intensity] and HRQoL. Exact logistic regression will be used to estimate an odds ratio of such events, assuming that at least one such event occurs on study in each of the treatment arms, controlling for other patient-related characteristics and individual history of the event of interest. The trial is on-going and has met ~55% of projected accrual. Obstacles to accrual include: physician bias, subjects were not aware of a curative option for their disease, payment for HCT on a clinical trial in some US states despite meeting the Center for Medicare/Medicaid Services (CMS) requirement for coverage with evidence determination (CED), prior HLA typing and knowledge regarding donor availability, competing treatment options and the fact that substantial numbers of potentially eligible subjects are followed in the community and lack access to academic sites. Overcoming obstacles took ~2 years. The trial is now at "steady state accrual" and expected to complete accrual in ~18-24 months. Disclosures Neuberg: Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership. Stevenson:Celgene: Research Funding. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Walters:Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy.

The Result of a Phase 1 Study of Selinexor in Combination with High-Dose Melphalan and Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: High-dose melphalan and autologous hematopoietic cell transplantation (HCT) remains a crucial treatment modality for patients with multiple myeloma (MM). Strategies to improve the conditioning regimen have been explored with addition of novel targeted therapies previously with limited success. Selinexor, an orally available selective inhibitor of nuclear export (SINE), targeting Exportin-1 (XPO-1), was recently approved by the Food and Drug Administration (FDA) for relapsed/refractory MM. Our pre-clinical data show synergy between selinexor and bifunctional alkylating agents in several MM models. Therefore, we hypothesized that the addition of selinexor to high-dose melaphalan would be safe and improve outcomes of autologous HCT in MM. Methods: We designed a single institution, standard 3+3 dose escalation phase 1 study to evaluate the combination of selinexor (given at 40 mg po (dose level 1); 60 mg (dose level 2); and 80 mg (dose level 3) on days -3 and -2 before melphalan) and high-dose melphalan (100 mg/m2 IV on days -3 and -2) as a conditioning regimen for autologous HCT in patients with MM achieving either partial response (PR) or very good partial response (VGPR) after less than 4 lines of systemic anti-myeloma chemotherapy (NCT02780609). The primary objective was to establish a maximum tolerated dose (MTD) and identify a recommended phase 2 dose (RP2D). Results: From 08/2017 to 03/2019, a total of 12 MM patients (pts) received autologous HCT under the phase 1 protocol at Moffitt Cancer Center. Baseline characteristics included: a median age of 57 (range, 43-69); M:F = 7:5; IgG subtype=9, light chain type=2, IgD subtype=1; 92% with Durie-Salmon stage 3; 22% with high-risk disease based on del17p/t(4;14) (2/9, n=3 with unknown risk); a median number of induction=1 (range, 1-2); all received bortezomib-based induction, 83% received immunomodulatory agent, 17% received daratumumab. Pre-HCT responses were PR=4; VGPR=8. Pts received a median of 4.16 (range, 2.16-5.73) million CD34+ cells/kg. Neutrophil engraftment occurred with a median of 11 (range 11-12) days, and a platelet engraftment with a median of 15 (range, 10-36) days. Three pts each entered in dose level 1 and 2; and 6 pts at dose level 3. One pt in dose level 2 did not receive dexamethasone on day -1 due to grade (G) 3 hyperglycemia. One pt in dose level 3 (80 mg selinexor) did not receive day -2 dose of selinexor due to liver function test (LFT) abnormality (ALT &gt; 2x ULN) which was considered as dose-limiting toxicity (DLT) as second dose of selinexor was not given. LFTs normalized after HCT. Dose level 3 was expanded to 3 additional pts and no additional DLTs were observed. Treatment-related serious adverse events (SAEs) included: G3 febrile neutropenia=3, G3 diarrhea=1, G3 nausea=1, G3 small bowel obstruction=1, G3 acute kidney injury=1, G3 lung infection=1. Post-HCT responses at day +90 were complete response (CR)=2, VGPR=6, PR=3, and progression=1. CR conversion rate was 16.7% though phase 1 portion of the study was not powered to evaluate the CR rate. Therefore, RP2D was established as selinexor 80 mg on days -3 and -2. The study is proceeding to the phase 2 portion to assess the efficacy of this combination. Conclusions: The combination with selinexor 80 mg po with high-dose melphalan at 100 mg/m2 on days -3 and -2 (dose level 3) was well tolerated and engraftment kinetics were not altered. A phase 2 study of selinexor 80 mg with high-dose melphalan and autologous HCT is ongoing (NCT02780609). Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Alsina:Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau. Baz:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding. Shain:Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Sullivan:Karyopharm: Research Funding. OffLabel Disclosure: Selinexor in combination with high-dose melphalan

Mobilization of Leukemic Cells Using Plerixafor as Part of a Myeloablative Preparative Regimen for Patients with Acute Myelogenous Leukemia Undergoing Allografting: Assessment of Safety and Tolerability.

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease relapse. The purpose of this single-center Phase I study was to determine the safety and tolerability of administration of the CXCR4 inhibitor plerixafor (Mozobil; Sanofi Genzyme) along with myeloablative conditioning in patients with AML undergoing allogeneic HCT. The rationale was that plerixafor may mobilize leukemic stem cells, making them more susceptible to the conditioning chemotherapy (registered at ClinicalTrials.gov; identifier NCT01141543). Three patients were enrolled into each of 4 sequential cohorts (12 patients total). Patients in the first cohort received 1 dose of plerixafor (240 μg/kg s.c.) before the first dose of fludarabine and busulfan, and subsequent cohorts received injections before 2, 3, and 4 days of conditioning chemotherapy. The median age at HCT was 49 years (range, 38 to 58 years). All patients engrafted following HCT, with an absolute neutrophil count ≥.5 × 109/L observed at a median of 14 days (range, 11 to 18 days). Adverse events possibly related to plerixafor were transient and not severe. Main adverse events following the injection were nausea and dizziness in 4 patients (33%) and fatigue in 4 patients (33%). Among the 12 patients, 2 patients (17%) relapsed post-HCT and 6 (50%) were alive at the last follow-up. The median follow-up of survivors was 67 months (range, 53 to 82 months). In conclusion, plerixafor administration is safe and well tolerated when included in a myeloablative conditioning regimen for allogeneic HCT for AML. Further study in a larger cohort is warranted for the investigation of the impact of plerixafor on post-allogeneic HCT outcomes.

Fludarabine/Melphalan 100 mg/m2 Conditioning Therapy Followed by Allogeneic Hematopoietic Cell Transplantation for Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Our previous research indicated that a reduced-intensity conditioning regimen (fludarabine and melphalan at 100 mg/m2) was useful in allogeneic hematopoietic cell transplantation (HCT) for patients with lymphoma. This retrospective study evaluated the reduced-intensity conditioning regimen in allogeneic HCT for adult patients with hemophagocytic lymphohistiocytosis (HLH). Sixteen patients with HLH were evaluated, including 6 patients who were enrolled in a prospective clinical trial (NCT00772811) and 10 patients who received the same conditioning regimen (fludarabine at 30 mg/m2/day on days -6 to -2 and melphalan at 100 mg/m2 on day -2). The median age was 42 years (range, 18 to 64), and 12 patients had Epstein-Barr virus (EBV)-associated HLH. Donors were an HLA matched sibling for 10 patients, an unrelated matched volunteer for 4 patients, and a mismatched family member for 2 patients. After excluding 3 patients who died soon after HCT, 12 patients achieved an engraftment (neutrophil median, day 12; platelet median, day 16). Five patients experienced acute graft-versus-host disease (GVHD), including 1 case of grade II and 4 cases of grades III to IV. Chronic GVHD occurred in 3 patients (moderate, 1 case; severe, 2 cases). After a median follow-up of 33.8 months 1 patient progressed, 3 patients relapsed, and 9 patients died. Five deaths were unrelated to relapse or progression and were caused by infection (n = 3), bleeding (n = 1), and GVHD (n = 1). No deaths or relapses were observed at >124 days post-transplant. The overall survival rate was 48.6%, and significant differences were observed according to pretransplant ferritin level (P = .007) and cytopenia lineage (P = .021). Before allogeneic HCT 10 of 12 patients still tested positive for EBV DNA: 6 patients tested negative for EBV DNA after HCT, 2 patients had persistent EBV DNA, and 2 patients were unassessable because of early death. Conditioning therapy using a lower dose of melphalan combined with fludarabine appears to be promising in allogeneic HCT for adults with HLH. However, strategies are needed to reduce the risk of early death.

Bendamustine with Total Body Irradiation Limits Murine Graft-Versus-Host Disease in Part Via Myeloid-Derived Suppressor Cells

BackgroundGvHD remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An under-investigated strategy to reduce GvHD is the modification of the preparative conditioning regimen. Cyclophosphamide (CY) and total body irradiation (TBI) is a commonly utilized myeloablative conditioning regimen, but is associated with GvHD. Bendamustine (BEN) is an alkylating agent that has been applied recently in nonmyeloablative chemotherapy-based conditioning regimens, demonstrating reduced myelosuppression, transplant related mortality, and acute graft versus host disease (GvHD). We have recently published that BEN can effectively replace CY when given following murine haploidentical bone marrow transplantation. We therefore hypothesized that BEN can also have advantages over CY when given in conjunction with TBI as a myeloablative preparative regimen.MethodsWe used a major histocompatibility mismatched murine BMT model to evaluate GvHD following BEN-TBI and CY-TBI conditioning. BALB/c (H-2d) mice received equivalent doses of BEN or CY (based on maximum tolerated dose), followed by TBI (400 cGy) and infusion of bone marrow (BM) cells with splenocytes (SC) or purified T-cells from C57BL/6 (H-2b) mice. GvHD morbidity and mortality and engraftment were monitored and MDSC frequencies were assessed by flow cytometry and immunofluorescence.ResultsWe demonstrate that BEN-TBI conditioning, while facilitating complete donor chimerism, results in significantly less GvHD and improved survival compared to CY-TBI. In BEN-TBI conditioned mice, suppressive CD11b+Gr-1high myeloid cells are increased in the blood, bone marrow (BM), and spleen, with no evident differences in suppressive function. The ratio of Gr-1+ cells to T-cells is significantly increased in BEN-TBI mice in the intestines. When Gr-1high cells are depleted prior to transplant, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of G-CSF, which promotes CD11b+Gr-1+ myeloid cell expansion, trends towards an increase in survival in BEN-TBI mice.ConclusionsThese findings indicate a potential role of granulocytic myeloid-derived suppressor cells (MDSCs) in the mechanism by which BEN allows engraftment with reduced GvHD. BEN-TBI conditioning reduces GvHD morbidity and mortality compared to CY-TBI and may present a safer alternative to CY-TBI as a myeloablative conditioning regimen in allogeneic HCT. DisclosuresNo relevant conflicts of interest to declare.

Advances in Transplantation for Lymphomas Resulting from CIBMTR Lymphoma Working Committee's Research Portfolio: A Five-Year Report (2013-2018).

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin (MCW). The CIBMTR collaborates with the global scientific community to advance hematopoietic cell transplantation (HCT) and cellular therapy worldwide to increase survival and enrich quality of life for patients. The observation research program within CIBMTR is organized into 15 working committees. This review is aiming to highlight the observational research studies published by the CIBMTR Lymphoma Working committee over the last five years (2013-18) and to summarize how these studies have impacted the field by helping inform clinical practice in scenarios where prospective data from high quality randomized trials were not available or where owing to the rarity of a particular transplant indication such data were unlikely to be generated, outside the setting of a large observational research database. The salient findings reviewed include; (a) studies supporting role of autologous HCT in diffuse large B-cell lymphoma (DLBCL) patients with sensitive relapse of disease within one year of diagnosis, (b) role of autologous HCT vs allogeneic HCT in follicular lymphoma patients with early therapy failure, (c) prognostic scoring system development for classical Hodgkin lymphoma and DLBCL patients with prior autograft failure, (d) defining the role of alternative donor transplantation in lymphomas, (e) evaluating appropriate conditioning regimens for HCT in lymphoma, and (f) outcomes of HCT in rare lymphoid malignancies.

Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation.

Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.