Westervelt, Peter

Abstract Newer approaches to control alloreactivity may produce similar transplant outcomes using HLA-mismatched donors vs HLA-matched unrelated donors (MUD). However, prospective comparisons are lacking. BMT CTN 1702 used a donor search prognosis score to assign patients to an 8/8 HLA MUD or the center’s preference of haploidentical related donors (HAPLO), mismatched unrelated donors (MMUD), or umbilical cord blood (UCB). Outcomes of MUD were compared to HAPLO, MMUD, and UCB transplantation after adjusting for covariates. Patients (n = 1179 [93% adults]) underwent transplantation with MUD (n = 772), HAPLO (n = 254), MMUD (n = 112), and UCB (n = 41) at a median of 3.7, 3.4, 3.9, and 3.8 months from enrollment. Posttransplant cyclophosphamide (PTCy) was used in 23.9%, 83.9%, 65.2%, and 0% of MUD, HAPLO, MMUD, and UCB. In multivariate analyses, compared to MUD, survival was lower for UCB (hazard ratio [HR], 2.65; P< .001) but not statistically different for HAPLO and MMUD (HRs, 1.08 and 1.18, respectively). Relapse risk was not significantly different by donor, but treatment-related mortality (HR, 3.31; P< .001) and disease-free survival (HR, 1.99; P = .002) were inferior for UCB but not different for HAPLO and MMUD than MUD. In patients who received PTCy, HAPLO and MMUD were associated with increased grade 3 or 4 acute graft-versus-host disease (GVHD; HR, 2.39 [P = .017] and 2.53 [P = .038], respectively) and chronic GVHD (HR, 1.71 for both; P = .028 and .080) than MUD, but other outcomes were not different. HAPLO or MMUD may be used to expedite transplantation when finding MUD is unlikely. This study was registered at www.clinicaltrials.gov as NCT03904134.

PURPOSE The likelihood of finding a human leukocyte antigen (HLA)–matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood). METHODS This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups. RESULTS A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation. CONCLUSION Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.

Background: A donor search prognosis score based on HLA type and race/ethnicity can classify patients into 3 groups based on the likelihood of finding an HLA-matched (8/8) unrelated donor (MUD): Very Likely (44% of the population), Likely (41%) and Very Unlikely (15%). Previous studies showed that &gt;90% of Very Likely, 26% of Likely and &lt;10% of Very Unlikely patients used a MUD for their hematopoietic cell transplants (HCT), with the rest using other donor sources (mismatched unrelated donor, cord blood, or haploidentical relative). For some patients, prolonged efforts to identify a MUD might be futile and delay HCT, leading to increased morbidity, greater chance for relapse and disease resistance, and worse HCT outcomes. BMT CTN 1702 (NCT03904134) was the first national study to track the entire donor search identification process. Designed as a biologic assignment study, the goal was to estimate and compare overall survival between two arms: patients who are Very Likely to find a MUD versus those who are Very Unlikely to find a MUD. It tested whether provision of a donor search prognosis score to centers could prevent prolonged futile searches for the Very Unlikely group and improve their transplant rates and outcomes, compared to the Very Likely group. Methods: Eligible diagnoses included acute leukemia, myelodysplastic syndromes, lymphoma, acquired aplastic anemia and sickle cell disease. Patients could be consented at any time after diagnosis until an unrelated donor search was started. Consented patients became evaluable only after it was determined that no appropriate HLA-identical siblings were available. The primary endpoint was survival time after the patient was declared evaluable, regardless of whether HCT occurred, and was compared between the Very Unlikely and Very Likely groups. The target enrollment was 1732 evaluable patients. Because this was a biologic assignment trial and not a randomized trial, formal comparisons of overall survival between the Very Likely and Very Unlikely groups were done using a covariate-adjusted Cox proportional hazards model. The following covariates were a priori specified for adjustment in the model, according to the statistical analysis plan: sex, age, Karnofsky Performance Score (KPS), race/ethnicity, disease, disease status, and interval from consent to evaluability. Results: 1751 evaluable patients were enrolled at 47 centers: 44% female, median age 59.4 years (range 0.6-81.3 years), 73% were non-Hispanic White, 10% Hispanic White, 8% Black, 5% Asian/Native Hawaiian/Pacific Islander, 0.5% American Indian/Alaska Native. Among the evaluable patients, 1181 received a HCT, 827 died, and 924 are still alive with or without HCT, with a median of 25 months of follow up (range=6-54 months [mos], inter-quartile range [IQR]=25-34 mos). The distribution was: 958 Very Likely, 517 Less Likely, and 276 Very Unlikely. Individuals in the Very Unlikely group were younger and were less likely to be non-Hispanic White. The unadjusted cumulative incidences of undergoing HCT by 6 mos and 2 years [yrs], in the Very Unlikely group were 51% and 61% vs. 60% and 69% in the Very Likely Group; after adjustment, there was not a significant difference in the likelihood of undergoing HCT (Dehn et al, submitted). There was no difference in median time from evaluability to HCT: 3.4 mos Very Unlikely and 3.3 mos Very Likely. Unadjusted survival rates from the time of evaluability for the Very Unlikely and the Very Likely groups were: 6 mos (85% vs 84%), 1 yr (69% vs. 69%) and 2 yrs (55% vs. 56%). In the multivariate Cox model, there was no significant difference in the risk of death (HR = 1.07 for Very Unlikely vs. Very Likely, 95% confidence interval 0.86-1.33, p=0.56) adjusting for significant clinical covariates: age, KPS, disease status, and time from consent to evaluability were all significantly associated with overall survival. There was no significant center effect and no interaction between donor search prognosis group and clinical covariates. Conclusion: In this large multicenter BMT CTN study, using the donor selection strategy described, there was no difference in adjusted time to HCT or survival for patients Very Likely versus Very Unlikely to find an 8/8 MUD. These results suggest that patients Very Unlikely to identify a MUD should proceed to HCT using the best available alternative donor rather than delaying HCT to try to identify a MUD.

PURPOSE BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial. METHODS Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen–matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score–matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities. RESULTS Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY. CONCLUSION Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Background: Recent advances in the treatment of myelodysplastic syndrome (MDS) have improved patient survival and quality of life (QOL), while reducing transfusion burden. However, allogeneic hematopoietic cell transplantation (HCT), widely used in younger MDS patients, remains the only curative therapy for MDS. While transplantation outcomes among selected older patients with MDS are similar to younger patients with MDS, early transplantation for older patients is infrequently offered since the relative benefits of HCT over non-HCT therapy in have not been well defined in this patient group. We conducted a multi-center, biologic assignment trial in older individuals with high risk MDS to define the benefit of HCT over non-HCT therapy. Methods: The study was a multicenter, biologic assignment trial in subjects aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT, comparing outcomes of those with a suitable 8/8 HLA-matched donor to those without a donor. The trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102, NCT02016781). Eligible subjects were enrolled prior to a formal donor search, and before or after MDS treatment was initiated. Biological assignment to the Donor or No Donor arm was based on high-resolution HLA typing of eligible family members and a search of the unrelated donor registries. Subjects were initially assigned to the No Donor arm and re-assigned to the Donor arm when a suitable donor was identified. Subjects who died or whose 90-day donor search ended without identifying a suitable donor remained in the No Donor arm. Subjects in the Donor arm were expected to undergo RIC HCT within 6 months of enrollment. Subjects underwent RIC HCT or non-HCT therapy according to institutional standards. The primary analysis compared three-year overall survival (OS) between arms using adjusted survival estimates to account for the potential bias resulting from biological assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year OS. Between January 2014 and November 2018, 384 subjects (Donor n=260, No Donor n=124) were enrolled at 34 centers. The study arms were well balanced for age, gender, KPS, IPSS risk, MDS disease duration and responsiveness to hypomethylating therapy (Table). The median follow-up time for surviving patients was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No Donor arm. Results: In an intent-to-treat analysis, adjusted OS at 3 years from study enrollment in the Donor arm was 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in the No Donor arm (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%)(Figure). A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (Adjusted OS: 48.0% vs. 28.1%, p=0.0004). Leukemia-free survival (LFS) at 3 years was greater in the Donor arm (35.8%, 95% CI: 29.8%-41.8%) compared with the No Donor arm (20.6%, 95% CI: 13.3%-29.1%, p=0.003), with no changes in the sensitivity analysis. An OS and LFS benefit was seen across all subgroups tested (Figure). There were no clinically significant differences in QOL between Donor and No Donor arms as measured by the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score at all time points. The overall non-compliance rate for the trial was 26.3%. Reasons for non-compliance included the use of myeloablative conditioning or failure to proceed to RIC transplant in the Donor arm, and the use of alternative donors in the No Donor arm. In an as-treated analysis, comparison of the HCT and No HCT arms demonstrated a significant advantage in 3-year OS (47.4% vs. 16.0%, p&lt;0.0001) and LFS (39.3% vs. 10.9%, p&lt;0.0001) for subjects who underwent HCT. Conclusions: We observed a significant OS advantage in older patients with Int-2 and High IPSS risk de novo MDS who are RIC HCT candidates and have an HLA-matched donor, when compared with those without a donor. The benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (&gt;65) and below. HCT should be offered to all individuals between the ages of 50-75 with Int-2 and High IPSS risk MDS in whom a suitable donor can be identified. Table Disclosures Nakamura: Magenta Therapeutics: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Celgene: Other: Support on seminar; Viracor: Consultancy. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; Agios, BMS: Honoraria; BMS, Novartis: Research Funding. Oran:ASTEX: Research Funding; Celgene: Consultancy; Arog Pharmaceuticals: Research Funding. Maziarz:Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Athersys: Patents & Royalties; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding. McGuirk:Allo Vir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.