The Transplantation Ecosystem: A New Concept to Improve Access and Outcomes for Older Allogeneic Hematopoietic Cell Transplantation Patients.

Allogeneic hematopoietic cell transplantation (HCT) is increasingly offered to older adults with hematologic malignancies, even though nonrelapse mortality remains a major concern in older patients owing to more comorbidities and greater frailty compared with their younger counterparts. The importance of patient fitness, a well-matched donor, and disease control to the success of allogeneic HCT have been well documented; however, these factors fail to account for the impact of the complex transplantation ecosystem (TE) that older adult HCT candidates must navigate. We propose a definition of the TE modeled after the social determinants of health. Furthermore, we outline a research agenda aimed at increasing understanding of the roles of individual social determinants of transplantation health in the larger ecosystem and how they may benefit or harm older adult HCT candidates. Herein we define the TE and its individual tenets, the social determinants of transplantation health. We review the available literature while incorporating the expertise of the membership of the American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Group for Aging. The membership of the ASTCT Special Interest Group for Aging identify knowledge gaps and strategies to address them for each of the described social determinants of transplantation health. The ecosystem is an essential but underappreciated pillar for transplant access and success. We put forth this novel research agenda seeking to gain a better understanding of the complexity of HCT in older adults and develop strategies to improve access to HCT, survival, and quality of life.

Impact of autologous hematopoietic cell transplantation on disease burden quantified by next-generation sequencing in multiple myeloma treated with quadruplet therapy.

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.

International harmonization in performing and reporting minimal residual disease assessment in multiple myeloma trials.

Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.

Utilization and Cost Implications of Hematopoietic Progenitor Cells Stored for a Future Salvage Autologous Transplantation or Stem Cell Boost in Myeloma Patients.

Autologous hematopoietic cell transplantation (autoHCT) is a standard initial treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells (HPCs) for 2 autoHCTs in all eligible patients. Despite a lack of published data on the utilization of HPCs stored for future use, it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients. In this single-center retrospective study, we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM, along with the cost implications of HPC collection targets sufficient for 2 transplantations. In a cohort of 400 patients (median age, 63 years; range, 22 to 79 years), after a median follow-up of 50.4 months, 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT (n = 29) and/or HPC boost (n = 8). In this cohort, a median CD34+ cell dose of 4.3 × 106/kg (range, 1.1 to 12.94.3 × 106/kg) was used for first autoHCT, and a median of 4.4 × 106/kg (range, 1.0 to 20.2× 106/kg) CD34+ cells were stored for future use. At 6 years after the first autoHCT, the estimated cumulative incidence of salvage autoHCT was 12.0% without HPC boost and 13.9% with HPC boost. HPC utilization was significantly higher in the 60- to 64-year age group, whereas no patients who were age ≥70 years at the time of first autoHCT received salvage autoHCT. Using the CD34+ cell dose infused during the first autoHCT as the cutoff for individual patients, the estimated mean additional cost of HPC collection intended for subsequent use (over and above the HPCs used for first autoHCT) was $10,795 ($4.32 million for the entire cohort), an estimated 14% of which (ie, $583,600) was actually used up in salvage autoHCT by 6 years from first autoHCT. In conclusion, our results suggest the need for reappraisal of HPC collection targets for salvage autoHCT and argue against HPC collection and storage for salvage autoHCT in patients age ≥70 years at the time of first autoHCT.

Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta-analysis of phase 3 randomized controlled trials.

BACKGROUND: Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). METHODS: Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). RESULTS: Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). CONCLUSIONS: The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

Factors Associated With Unplanned 30-Day Readmissions After Hematopoietic Cell Transplantation Among US Hospitals.

Importance: Hematopoietic cell transplantation (HCT) is a therapeutic strategy in the management of several hematological cancers. Limited data exist on the incidence and predictors of 30-day readmission after HCT. Objective: To measure the incidence of and risk factors associated with 30-day readmission following HCT in the United States. Design, Setting, and Participants: This cohort study examined patient data from the US population-based Nationwide Readmissions Database. All adults (age ≥18 years) who underwent autologous (auto-) or allogenic (allo-) HCT in US hospitals between January 1, 2012, and November 30, 2014, were included. The analysis was performed from June 2018 to February 2019. Main Outcomes and Measures: The main outcome was 30-day readmission rates for auto-HCT and allo-HCT. Factors associated with readmission, including baseline demographic characteristics and disease- and hospital-related characteristics (including annual case volume), were measured. Results: A total of 28 356 index admissions for auto-HCT in 244 centers (191 low-volume, 38 medium-volume, and 15 high-volume centers) and 17 217 index admissions for allo-HCT in 211 centers (161 low-volume, 37 medium-volume, and 13 high-volume centers) were identified during the study period. The overall 30-day readmission rates were 11.6% for auto-HCT and 24.4% for allo-HCT. The odds of readmission were significantly higher in low-volume hospitals compared with high-volume hospitals (adjusted odds ratio [aOR], 1.69; 95% CI, 1.08-2.64 for auto-HCT and aOR, 1.41; 95% CI, 1.09-1.82 for allo-HCT) but comparable to medium-volume hospitals (aOR, 1.06; 95% CI, 0.62-1.83 for auto-HCT and aOR, 1.19; 95% CI, 0.90-1.57 for allo-HCT). Other factors associated with readmission for auto-HCT included younger age (aOR for age ≥50 vs <49 years, 0.82; 95% CI, 0.68-0.98), female sex (aOR, 1.21; 95% CI, 1.06-1.36), disease type (aOR for other vs myeloma, 1.37; 95% CI, 1.06-1.77), and Elixhauser comorbidity index score (aOR for ≥20 vs 0, 1.5; 95% CI, 1.17-1.93). For allo-HCT, factors associated with readmission included disease type (aOR for acute lymphoblastic leukemia vs acute myelogenous leukemia, 1.30; 95% CI, 1.04-1.62), insurance (aOR for Medicare vs private, 1.18; 95% CI, 1.02-1.36), and Elixhauser comorbidity index score (aOR for 1-9 vs 0, 1.2; 95% CI, 1.04-1.39). Infections, neutropenic fever, and gastrointestinal symptoms were the most common reasons for readmission for both types of HCT. Conclusions and Relevance: This study found substantial rates of readmission for both types of HCT and an inverse association between hospital HCT volume and 30-day readmission. These results may provide guidance when developing quality indicators and policies penalizing hospitals for HCT readmission.

Comparison of Graft Acquisition and Early Direct Charges of Haploidentical Related Donor Transplantation versus Umbilical Cord Blood Transplantation.

Alternative donor allogeneic hematopoietic cell transplants (HCTs), such as double umbilical cord blood transplants (dUCBT) and haploidentical related donor transplants (haplo-HCT), have been shown to be safe and effective in adult patients who do not have an HLA-identical sibling or unrelated donor available. Most transplant centers have committed to 1 of the 2 alternative donor sources, even with a lack of published randomized data directly comparing outcomes and comparative data on the cost-effectiveness of dUCBT versus haplo-HCT. We conducted a retrospective study to evaluate and compare the early costs and charges of haplo-HCT and dUCBT in the first 100 days at 2 US transplant centers. Forty-nine recipients of haplo-HCT (at 1 center) and 37 with dUCBT (at another center) were included in the analysis. We compared graft acquisition, inpatient/outpatient, and total charges in the first 100 days. The results of the analysis showed a significantly lower cost of graft acquisition and lower total charges (for 100-day HCT survivors) in favor of haplo-HCT. Importantly, to control for the obvious shortcomings of comparing costs at 2 different transplant centers, adjustments were made based on the current (2018) local wage index and inflation rate. In the absence of further guidance from a prospective study, the cost analysis in this study suggests that haplo-HCT may result in early cost savings over dUCBT and may be preferred by transplant centers and for patients with more limited resources.

Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation.

BACKGROUND: Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. METHODS: We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18-75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. RESULTS: One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. CONCLUSIONS: Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. TRIAL REGISTRATION: This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.