BACKGROUND:The GOSSAMER phase 2 study assessed the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib as maintenance therapy in patients with FLT3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) in first complete remission without previous hematopoietic stem cell transplantation (HSCT). METHODS:Patients had to be within 2 months of their last consolidation cycle and have completed the recommended number of cycles per local practice. FLT3 inhibitors were allowed only during induction and/or consolidation. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS), event-free survival, and measurable residual disease (MRD). RESULTS:In total, 98 patients were randomized (gilteritinib, n = 63; placebo, n = 35). RFS was not significantly different between the arms (hazard ratio, 0.74; 95% confidence interval, 0.41-1.34; p = .16). RFS rates for the gilteritinib and placebo arms were 68.5% and 55.3% at 1 year, 51.8% and 44.9% at 2 years, and 41.2% and 40.8% at 3 years, respectively. OS was not significantly different between the arms but may have been affected by subsequent AML therapies after discontinuation. In patients who received subsequent therapy (gilteritinib, 46.8%; placebo, 60.0%), a higher percentage of placebo-treated (57.1%) versus gilteritinib-treated patients (27.6%) underwent HSCT. At the end of treatment, 96.4% of gilteritinib-treated and 85.7% of placebo-treated patients had undetectable MRD. Relapsed placebo-treated (86.7%) versus gilteritinib-treated patients (34.8%) had a greater FLT3 mutational burden. No new significant safety concerns were noted. CONCLUSIONS:The primary end point was not achieved; however, an observed trend toward potential benefit was noted in patients with FLT3-ITD AML who had not undergone prior HSCT.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Background: Patients with acute myeloid leukemia (AML) in remission are at high risk of relapse, warranting remission-prolonging therapy. Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) inhibitor approved as monotherapy in FLT3-mutated relapsed/refractory AML. The aim of the study was to compare relapse-free survival (RFS) in patients with FLT3/internal tandem duplication AML in first complete remission who received gilteritinib or placebo. Method: In this phase 2, double-blind trial, patients were randomized 2:1 to gilteritinib (120 mg) or placebo once daily for up to 2 years, beginning after completion of induction/consolidation (I/C) therapy. RFS, defined as time from randomization date until the date of documented relapse or death from any cause was assessed via independent review committee adjudication (primary efficacy endpoint). Overall survival (OS) was defined as the time from date of randomization until date of death from any cause. Survival and treatment-emergent adverse events (TEAEs) were assessed 30 days after treatment discontinuation, and every 3 months thereafter. Due to a slow accrual rate, this trial (NCT02927262) was changed from a planned phase 3 to phase 2 based on the reduction in sample size. Results: 124 patients were screened and 98 were randomized (gilteritinib 63, placebo 35) and are included in the full analysis set (FAS), of whom 32 (gilteritinib 20, placebo 12) completed 2 years of treatment. The safety analysis set (SAF) comprised 97 patients (gilteritinib 62, placebo 35) who had received ≥1 dose of study drug. In the FAS, relapse occurred in 31/63 (49.2%) gilteritinib- and 20/35 (57.1%) placebo-treated patients; 3/63 (4.8%) gilteritinib-treated patients died without relapse. RFS was not significantly improved with gilteritinib vs placebo (hazard ratio [HR] 0.738, 95% confidence interval [CI] 0.407-1.336; 1-sided stratified log-rank p-value 0.163). Median RFS was 24.02 months for gilteritinib and 15.84 months for placebo. OS in the FAS was not significantly different between treatments (gilteritinib 21/63, [33.3%], placebo 11/35 [31.4%]; HR 1.130, 95% CI 0.540-2.364; 1-sided stratified log-rank p-value 0.627). Median OS was not reached in either arm. TEAEs in the SAF occurred in 58/62 (93.5%) gilteritinib- and 33/35 (94.3%) placebo-treated patients including, respectively, 51/62 (82.3%) and 20/35 (57.1%) drug-related TEAEs and 10/62 (16.1%) and 3/35 (8.6%) serious drug-related TEAEs. The most common TEAEs were increased blood creatine phosphokinase (gilteritinib 18/62 [29.0%], placebo 1/35 [2.9%]) and thrombocytopenia (gilteritinib 12/62 [19.4%], placebo 4/35 [11.4%]). Conclusion: Gilteritinib showed improved RFS versus placebo, but the difference was not statistically significant. There were no new safety findings in the gilteritinib arm. Citation Format: Mark D. Minden, Jacob M. Rowe, Emmanuel Gyan, Kohmei Kubo, Nahla Hasabou, David Delgado, Wensheng He, Stanley C. Gill, Jason E. Hill, Ramon Tiu. A phase 2, multicenter, randomized, double-blind trial of maintenance therapy with FLT3 inhibitor gilteritinib (ASP2215) in patients with FLT3/ITD AML (GOSSAMER study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT537.

Background: Acute myeloid leukemia (AML) accounts for ~18% of all childhood leukemias (Puumala SE, et al. Pediatr Blood Cancer. 2013;60(5):728-733). Gilteritinib, an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, has demonstrated efficacy with favorable tolerability in clinical trials of adults with FLT3-mutated relapsed or refractory (R/R) AML, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations (Perl AE, et al. N Engl J Med. 2019;381(18):1728-1740), leading to approval for the treatment of adults with R/R AML in the United States and many other countries/regions. Since the clinical progression of FLT3 ITD AML appears to be similar in children and adults, it is expected that the clinical benefit of gilteritinib in pediatric patients with FLT3 ITD R/R AML should be similar to that demonstrated in adults. We describe an ongoing phase 1, multicenter, open-label, single-arm, dose-escalation study (ClinicalTrials.gov identifier: NCT04240002) investigating the combination of gilteritinib with chemotherapy in children, adolescents, and young adults with FLT3 ITD R/R AML, which will inform the dose for the phase 2 dose-expansion portion of the study.

Chemotherapy-associated cardiotoxicity may delay or impair the ability to administer fully myeloablative chemotherapy for stem cell transplant in those with reduced left ventricular ejection fraction. Studies in adults have been inconsistent regarding the value of ejection fraction in predicting cardiotoxicity in the posttransplant period. Recent publications, however, have demonstrated successful stem cell transplantation in adults despite low ejection fractions. This case series highlights 2 pediatric patients who were successfully treated with stem cell transplantation without posttransplant cardiac complications, despite pretransplant ejection fractions of 38% and 29%.

PurposeThe current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) is a combination of an anthracycline with cytarabine resulting in significant short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the introduction of innovative medicines into the therapy, yet drug development continues to be adult-focused. Furthermore, there are major differences, including differing profiles of genetic abnormalities, making clinical development of adult AML drugs in children problematic. The large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.MethodsTo address these issues, the fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.ResultsEight classes of medicinal products were discussed at the Forum: FLT3, IDH1&2, checkpoint, cell signalling and HDAC inhibitors, monoclonal antibodies, bispecific T cell engagers and ADCs as well as other cytotoxics. CD123 is a high priority target for immunotherapies, and the paediatric development of CD123-targeted drugs should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. The studies of FLT3 inhibitors included in agreed paediatric investigation plans (PIPs) present challenges to be completed because they would require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials, which could be included in PIPs. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated from adolescent and adult data to younger children. There is also an important need to standardise internationally and validate methodologies and definitions of minimal residual disease, so that it can be used as a new response criterion. Industry supported, academic sponsored platform trials with compounds from different pharmaceutical companies could identify products to be further developed in paediatric AML. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative may fulfil these requirements and has the potential to be a major advance in the field.ConclusionThe initiatives created during the Forums will be continued as part of an ongoing process, aiming to accelerate drug development for children with AML and ultimately improve clinical outcomes.

PURPOSE:The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS:The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS:CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION:These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18–60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

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/m(2)/day (BSA <= .5 m(2)), 12 g/m(2)/day (BSA > .5 to 1.0 m(2)), or 14 g/m(2)/day (BSA > 1.0 m(2)) on days -6 to -4; fludarabine 30 mg/m(2)/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. (C) 2018 American Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, ,6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n =1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further. (C) 2018 American Society for Blood and Marrow Transplantation.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia <50x109/L (26% and 57% after 2 and 3 days of collection, respectively). RD age 18-40 had a higher risk of grade 2-4 pain and symptoms peri-collection, burrt donors above age 40 had more persistent pain at 1, 6, and 12 months (OR1.7, p=0.02) and a higher rate of non-recovery to pre-donation levels (OR 1.7, p=0.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by NMDP unrelated donor standards had an increased risk for persistent grade 2-4 pain (OR=2.41, p<0.001) and failure to recover to pre-donation baseline for other symptoms (OR=2.34, p=0.004). Conclusion: This information should be used in counseling RD regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals. Funding Statement: This study was funded by R01 HL085707 through the NHLBI. Additional funding for MAP was provided by 2UG1HL069254 (NHLBI/NCI) and the Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant. Conflict of Interests: None of the authors has any conflict of interest to declare. Ethical Approval Statement: If approved for donation, RD were approached for consent for this IRB approved study if they were willing and able to complete symptom reviews at 1, 6 and 12 months after donation administered by the CIBMTR Survey Research Group.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

Hematopoietic stem cell transplantation from HLA-matched sibling donors results in disease-free survival of >90% in patients with sickle cell disease (SCD); however, only approximately 18% of these patients have suitable donors available. Unrelated cord blood transplantation (UCBT) is one way to expand donor options for patients with severe SCD, but historically has been associated with high graft rejection rates (50% to 62%). We hypothesized that the addition of thiotepa to a previously tested reduced-intensity conditioning (RIC) regimen would support engraftment after UCBT in patients with SCD. Nine children (age 3 to 10 years) with cerebrovascular complications of SCD underwent 5-6/6 HLA-matched (A, B, and DRB1 loci) UCBT after conditioning with hydroxyurea, alemtuzumab, fludarabine, thiotepa, and melphalan. A calcineurin inhibitor and mycophenolate mofetil were used for graft-versus-host-disease (GVHD) prophylaxis. With median follow up of 2.1 years (range, 1 to 4.2 years), 7 patients had sustained donor cell engraftment and are free of SCD, and 2 patients had autologous recovery. Acute GVHD (grade II-IV) and mild and moderate chronic GVHD developed in 3 patients, 2 patients, and 1 patient, respectively. At >2 years post-UCBT, 4 of 5 patients discontinued systemic immunosuppression. Seven patients had viral infections (cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, or adenovirus) and recovered. The 1-year overall survival and disease-free survival rates were 100% and 78%, respectively. Thus, this RIC regimen was able to achieve donor engraftment in the majority of patients. Future efforts will focus on further reducing rates of acute GVHD and viral infection.

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft versus -host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) Ha. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR],.42; 95% confidence interval [CI],.26 to.70; P=.0008), grade II-IV aGVHD (HR,.24; 95% CI,.10 to.56;.001), and cGVHD (HR,.32; 95% CI,.19 to.54; P <.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.36; 95% CI,.20 to.65; P=.0007) and in 20092013 (HR,.24; 95% Cl..11 to.53; P=.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR,.23; 95% CI,.08 to.65; P=.0056) and 2009-2013 (HR,.16; 95% CI,.04 to.67; P=.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis. (C) 2017 American Society for Blood and Marrow Transplantation.

Introduction: HLA-matched sibling donor (MSD) hematopoietic stem cell transplant is curative in >92% of patients with sickle cell disease (SCD) but only 18% have MSD. Unrelated cord blood transplantation (UCBT) expands donor options but is associated with high graft rejection rates (50–62%). We hypothesized that a previously used reduced intensity conditioning (RIC) regimen when combined with thiotepa would have acceptable toxicity and support donor engraftment after UCBT for SCD.