Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction. METHODS: ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested. RESULTS: The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity. CONCLUSION: Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.

Donor matters: Donor selection impact on hematopoietic stem cell transplantation outcomes in Hispanic patients with B-cell acute lymphocytic leukemia: Insights from a myeloablative HSCT study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a pivotal treatment for high-risk acute lymphocytic leukemia (ALL), although limited by suitable human leukocyte antigen (HLA)-matched sibling donors (MSD). This study evaluates the impact of donor selection on outcomes in post-HSCT Hispanic B-cell ALL patients. METHODOLOGY: This single-center retrospective study evaluates outcomes in 88 adult Hispanic B-cell ALL patients who underwent haploidentical, MSD, or MUD myeloablative HSCT between 2013 and 2023. RESULTS: Compared to Haploidentical transplants, MSD exhibited worse cumulative incidence of relapse (CIR) (HR = 3.39; P = 0.014) and disease-free survival (DFS) (HR = 2.44; P = 0.048) whereas MUD outcomes did not differ. This effect persisted even when controlling for pre-HSCT stage and Minimal residual disease (MRD) status. In addition, Ph-like was a significant predictor of worse DFS (HR = 3.60; P=0.014) and CIR (HR = 2.97; P=0.035) on multivariate analysis. Older donor age correlated with worse GVHD-free, relapse-free survival (GRFS) in haploidentical transplants (HR = 1.05; P=0.036). CONCLUSION: Our data highlights improved outcomes with younger, haploidentical donors among Hispanic B-cell ALL patients undergoing myeloablative HSCT. This underscores the importance of donor selection in optimizing outcomes for ALL patients.

Hospital healthcare resource utilization and costs for chimeric antigen T-cell therapy and autologous hematopoietic cell transplant in patients with large B-cell lymphoma in the United States.

The efficacy of chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is well-established. This study, using the Premier PINC AI Healthcare Database, assessed hospital costs and healthcare resource utilization (HRU) between CAR T-cell therapy and autologous hematopoietic cell transplant (AHCT) for 733 LBCL patients from 01/01/2017-04/30/2021 (166 CAR T and 567 AHCT from 37 US hospital systems. CAR T-cell therapy had higher index costs but lower non-pharmacy costs, shorter hospital stays, lower ICU utilization than AHCT. The CAR T-cell cohort also presented fewer preparatory costs and HRU. At a 180-day follow-up, AHCT had lower hospitalization rates and costs. Overall, despite higher index costs, CAR T-cell therapy has lower non-pharmacy costs and HRU during the index procedure and requires less preparation time with lower preparation HRUs and costs than AHCT. This has important implications for resource management and informed decision-making for stakeholders.

Healthcare utilization and costs associated with autologous haematopoietic stem cell transplantation in Norwegian patients with relapsing remitting multiple sclerosis.

Multiple sclerosis (MS) patients experience long-term deterioration of neurological function, reduced quality of life, long-lasting treatment cycles, and an increased risk of early workability loss imposing an economic burden to society. Autologous haematopoietic stem cell transplantation (AHSCT) has shown promising treatment effects for relapsing remitting MS (RRMS). This study employs a micro-costing approach to estimate healthcare utilization and costs associated with AHSCT in Norwegian RRMS patients. Patient-level data were extracted from medical journals of 30 RRMS patients receiving AHSCT treatment at Haukeland University Hospital in the period from January 2015 to January 2018. The time horizon for the analysis was from the pretransplant screening until one year after AHSCT. A correlation was found between patient body weight and total healthcare cost. The average total healthcare cost of AHSCT for RRMS patients was estimated to EUR 66 304 (95% CI: EUR 63 598 - EUR 69 010) including costs associated with the pre-AHSCT period, AHSCT treatment phases and one-year follow-up. The majority of the costs, EUR 64 329, occurred during the treatment phase and within the first 100 days after AHSCT. The results indicate that long-term healthcare cost savings may be achieved using AHSCT in selected patients with aggressive RRMS. This is due to the high costs of most used disease modifying treatments. Further research including long-term clinical data is needed to determine the cost-effectiveness of this treatment.

Systemic sclerosis, silica exposure and cellular therapies: The sand in the gears?

Systemic sclerosis (SSc) is a chronic orphan autoimmune disease with the highest mortality rate among rheumatic diseases. SSc-related interstitial-lung disease (ILD) remains among the leading causes of SSc-related mortality with still few therapeutic effective strategies. In patients with crystallin silica exposure, SSc is recognized as an occupational disease according to the French social security system (Table 25A of the general insurance regimen). Lympho-ablative or myeloablative immunosuppression followed by autologous hematopoietic stem-cell transplantation (aHSCT) is the only therapeutic approach with demonstrated efficacy, improved survival with disease modifying effects on SSc-fibrotic manifestations (skin disease and ILD) and quality of life. A documented past and/or present occupational silica exposure, with extensive exposure and/or silica-related ILD and/or with persistent silica content in the broncho-alveolar lavage fluid are contra-indications to aHSCT in SSc patients, due to the risk of silica-related malignancy or of SSc relapse. This article aims to discuss alternative options in SSc patients with a history of silica exposure, and how innovative cellular therapies (mesenchymal stromal cells, CAR cells) could represent new therapeutic options for these patients.

Development of an umbilical cord blood transplantation-specific nonrelapse mortality risk assessment score.

ABSTRACT: Higher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation-specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Cost and effectiveness of autologous haematopoietic stem cell transplantation and high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective one-off treatment for relapsing-remitting multiple sclerosis (RR-MS), potentially representing an optimal front-loading strategy for costs. OBJECTIVE: Exploring cost/effectiveness of AHSCT and high-efficacy disease-modifying treatments (HE-DMTs) in RR-MS, estimating costs at our centre in Italy, where National Health Service (NHS) provides universal health coverage. METHODS: Costs (including drugs, inpatient/outpatient management) for treatment with AHSCT and HE-DMTs were calculated as NHS expenditures over 2- and 5-year periods. Cost-effectiveness for each treatment was estimated as "cost needed to treat" (CNT), i.e. expense to prevent relapses, progression, or disease activity (NEDA) in one patient over n-years, retrieving outcomes from published studies. RESULTS: Costs of AHSCT and HE-DMTs were similar over 2 years, whereas AHSCT was cheaper than most HE-DMTs over 5 years (€46 600 vs €93 800, respectively). When estimating cost-effectiveness of treatments, over 2 years, mean CNT of HE-DMTs for NEDA was twofold that of AHSCT, whereas it was similar for relapses and disability. Differences in CNT were remarkable over 5 years, especially for NEDA, being mean CNT of HE-DMTs €382 800 vs €74 900 for AHSCT. CONCLUSIONS: AHSCT may be highly cost-effective in selected aggressive RR-MS. Besides priceless benefits for treated individuals, cost-savings generated by AHSCT may contribute to improving healthcare assistance at a population level.

Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is increasingly being used in the United States (US) and across the world as a curative therapeutic option for patients with certain high-risk hematologic malignancies and non-malignant diseases. However, racial and ethnic disparities in utilization of the procedure and in outcome following transplant remain major problems. Racial and ethnic minority patients are consistently under-represented in the proportion of patients who undergo allo-HSCT in the US. The transplant outcomes in these patients are also inferior. The interrelated driving forces responsible for the differences in the utilization and transplant outcome of the medical intervention are socioeconomic status, complexity of the procedure, geographical barriers, and the results of differences in the genetics and comorbidities across different races. Bridging the disparity gaps is important not only to provide equity and inclusion in the utilization of this potentially life-saving procedure but also in ensuring that minority groups are well represented for research studies about allo-HSCT. This is required to determine interventions that may be more efficacious in particular racial and ethnic groups. Various strategies at the Federal, State, and Program levels have been designed to bridge the disparity gaps with varying successes. In this review paper, we will examine the disparities and discuss the strategies currently available to address the utilization and outcome gaps between patients of different races in the US.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy.

ABSTRACT: Chimeric antigen receptor (CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia (ALL). Measurable/minimal residual disease (MRD) monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy. Common MRD detection methods include flow cytometry (FCM), polymerase chain reaction (PCR), and next-generation sequencing (NGS), and each method has advantages and limitations. It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse. Thus, how to perform prognostic evaluations, stratify risk based on MRD status, and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice. This review assesses the common and novel MRD assessment methods. In addition, we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as other therapeutic strategies to improve treatment effect. Furthermore, this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Estimating the Cost per Clinical Outcome of Second-Line Liso-Cel Versus Autologous Stem Cell Transplantation in Patients with Transplantation-Intended Relapsed/Refractory Large B Cell Lymphoma.

It is important to consider the total cost of care (TCOC) associated with a therapy and clinical benefit for relapsed or refractory (R/R) large B cell lymphoma (LBCL). We estimated the 1-year TCOC and cost per clinical outcome for patients with R/R LBCL treated with second-line lisocabtagene maraleucel (liso-cel) versus autologous stem cell transplantation (ASCT) using data from the TRANSFORM study (ClinicalTrials.gov NCT03575351). A cost per clinical outcome analysis using a Monte Carlo simulation approach was conducted. Cost inputs were generated from a retrospective microcosting analysis of healthcare resource utilization (HCRU). Patient-level data from an interim analysis (March 2021) were used to derive HCRU and clinical inputs. Clinical inputs included median event-free survival (EFS), median progression-free survival (PFS), objective response rate, and complete response (CR) rate. In the intention-to-treat analysis, the mean (standard deviation) TCOC per patient was $550,864 ($173,087) for liso-cel and $413,200 ($290,802) for ASCT. The cost per clinical outcome model estimated a mean cost for liso-cel versus ASCT per EFS month of $57,295 versus $186,369, per PFS month of $40,949 versus $78,797, per overall responder of $653,965 versus $881,804, and per complete responder of $828,045 versus $1,063,822. This economic model shows reductions in mean estimated TCOC per EFS month, PFS month, overall responder, and complete responder with liso-cel versus ASCT owing to the superior efficacy of liso-cel. Although liso-cel-treated patients incurred greater upfront costs, fewer required subsequent therapy, and they accumulated less downstream costs. These results underscore the importance of considering the durability of response and clinical benefit when assessing total costs.

Assessing Medicaid Coverage for Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy: A Project from the American Society for Transplantation and Cellular Therapy and the National Marrow Donor Program ACCESS Initiative.

The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) to ensure equal access and outcomes for all patients in need. The 3 committees, addressing awareness, poverty, and racial and ethnic inequity, defined pilot projects focusing on addressing relevant barriers to HCT/CT. Because many socioeconomically disadvantaged HCT/CT recipients receive care through state Medicaid programs, the Poverty Committee conducted a Medicaid scan of all 50 US states with the following objectives: to define beneficiary coverage for allogeneic and autologous HCT and chimeric antigen receptor (CAR) T cell therapy; to define support for travel, temporary lodging, and meals for both beneficiaries and caregivers; and to determine search and cell acquisition payment procedures. Here we summarize the results of the Medicaid scan and highlight significant variations and gaps in coverage for HCT/CT recipients. We also provide an initial roadmap for addressing gaps in Medicaid support for HCT and CAR-T therapy recipients.

Cost-Effectiveness of Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Bone Marrow Transplantation: Evidence from BMT CTN 1101.

BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced-intensity conditioning followed by double unrelated umbilical cord blood transplantation (UCBT) versus HLA-haploidentical related donor bone marrow transplantation (haplo-BMT) for patients with high-risk hematologic malignancies. Here we report the results of a parallel cost-effectiveness analysis of these 2 hematopoietic stem cell transplantation (HCT) techniques. In this study, 368 patients were randomized to unrelated UCBT (n = 186) or haplo-BMT (n = 182). We estimated healthcare utilization and costs using propensity score-matched haplo-BMT recipients from the OptumLabs Data Warehouse for trial participants age <65 years and Medicare claims for participants age ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used to estimate quality-adjusted life-years (QALYs). At a 5-year follow-up, survival was 42% for haplo-BMT recipients versus 36% for UCBT recipients (P = .06). Over a 20-year time horizon, haplo-BMT is expected to be more effective (+.63 QALY) and more costly (+$118,953) for persons age <65 years. For those age ≥65 years, haplo-BMT is expected to be more effective and less costly. In one-way uncertainty analyses, for persons age <65, the cost per QALY result was most sensitive to life-years and health state utilities, whereas for those age ≥65, life- years were more influential than costs and health state utilities. Compared to UCBT, haplo-BMT was moderately more cost-effective for patients age <65 years and less costly and more effective for persons age ≥65 years. Haplo-BMT is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BMT is a preferred choice when considering costs and outcomes.

Feasibility of a New Model of Care for Allogeneic Stem Cell Transplantation Recipients Facilitated by eHealth: The MY-Medula Pilot Study.

The use of allogeneic stem cell transplantation (allo-SCT) for the treatment of hematologic diseases is steadily increasing; however, allo-SCT has the downside of causing considerable treatment-related morbidity and mortality. Mobile technology applied to healthcare (mHealth) has proven to be a cost-effective strategy to improve care and offer new services to people with multimorbidity, but there are little data on its usefulness in allo-SCT recipients. Here we describe a new integrated healthcare model facilitated by an mHealth platform, EMMASalud-MY-Medula, and to report the results of a feasibility and usability pilot study. The MY-Medula platform was developed in 4 phases. First, patient and healthcare professional needs were identified, and technological development and pretesting tests were conducted (phases 1 to 3, January 2016 to March 2021). Then a nonrandomized, prospective, observational, single-center pilot study was conducted (October 2021 to January 2022) at the adult SCT unit of a tertiary university hospital. Twenty-eight volunteer allo-SCT recipients were included in the pilot study, of whom one-half were outpatients in the first-year post-SCT and one-half were affected by steroid-dependent graft-versus-host disease (SR-GVHD). All patients used the MY-Medula app during the 2-month follow-up period, with a median number of visits to the app of 143 (range, 6 to 477). A total of 2067 self-monitoring records were created, and 205 text messages were received, most of them related to symptoms description (47%) and doubts about medication (21%). In 3.4% of the cases, drug dosage was adjusted by the pharmacist because of dosing errors or interactions. At the end of the study, a 6-question Likert-type questionnaire for patients and a 22-question test for healthcare professionals showed a high degree of satisfaction (95% and 100%, respectively) with the new healthcare pathway. Reengineering the follow-up of allo-SCT recipients into an integrated, multidisciplinary model of care facilitated by mHealth tools is feasible and has been associated with high usability and a high degree of satisfaction by patients and healthcare professionals. A randomized trial aiming to determine the cost-effectiveness of MY-Medula-based follow-up post-SCT is currently enrolling participants.

Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases.

Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) that has been investigated extensively in the field of hemoglobinopathies but has not been thoroughly characterized after HSCT in pediatric malignancies. Our aim was to assess prevalence, severity, risk factors, and management of IOL, as defined using biochemical (serum ferritin) and radiologic tools (T2*-weighted magnetic resonance imaging [MRI]), in a cohort of pediatric patients who underwent HSCT for either malignant or benign diseases. This monocentric, retrospective, observational study included all the 163 patients alive and in continuous remission at 24 months post-HSCT out of the 219 consecutive children and adolescents who underwent HSCT at our institution between 2012 and 2018, were included in the study. IOL was classified into 4 categories: absent, mild, moderate, and severe. Among the 163 patients, 73% had some degree of IOL (mild in 37%, moderate in 29%, and severe in 7%). Moderate/severe IOL was more frequent among patients diagnosed with a malignant disease versus those with a benign disease (43% versus 19%; P = .0065). Trend lines for serum ferritin showed a "bell-shaped" distribution, with the highest levels recorded during the first 6 months post-HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 ng/mL versus 617 ng/mL; P < .001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL; P < .001) median ferritin levels were statistically higher in the patients with malignancies. Radiologic assessment of IOL confirmed a more severe degree in patients with malignant disorders compared to those with benign disorders (median T2*-MRI, 4.20 msec [interquartile range (IQR), 3.0 to 6.40 msec] versus 7.40 msec [IQR, 4.90 to 11.00 msec]; P = .008). T2* levels were associated with the number of transfusions performed (P = .0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope for subsequent transfusions. T2* and ferritin values showed a statistically significant negative exponential relationship (P < .0001), although a ferritin level ≥1000 ng/mL showed poor specificity (48%) and low positive predictive value (53%) for discriminating moderate-to-severe IOL from absent-mild IOL as assessed by T2*-MRI, but with high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (odds ratio [OR], 4.07; 95% confidence interval [CI], 1.61 to 10.68; P = .003) and higher pre-HSCT ferritin level (P < .001) were associated with the risk of developing moderate-to-severe IOL. Use of a sibling donor (OR, .29; 95% CI, .10 to .77; P = .015) and a nonmalignancy (OR, .27; 95% CI, .08 to .82; P = .026) were protective factors. Phlebotomy (66%), low-dose oral chelators (9%), or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six percent of the patients treated exclusively with phlebotomy (median, 14, significantly higher in patients >40 kg) discontinued phlebotomy owing to poor venous access, lack of compliance, or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects that resolved after tapering or discontinuation. Patients with malignancies showed statistically higher pre-HSCT and post-HSCT ferritin levels and lower T2* values. High ferritin level recorded on T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL; thus, T2*-MRI should be considered a key tool for confirming IOL after HSCT in patients with an elevated serum ferritin level. IOL treatment is feasible after HSCT.

Impact of valproic acid on busulfan pharmacokinetics: In vitro assessment of potential drug-drug interaction.

Busulfan (Bu) is an alkylating agent commonly used at high doses in the preparative regimens of hematopoietic stem cell transplantation (HSCT). It has been shown that such high doses of Bu are associated with generalized seizures which are usually managed by prophylactic antiepileptic drugs (AEDs) such as valproic acid (VPA). Being a strong enzyme inhibitor, VPA may inhibit Bu metabolism and thus increase its potential toxicity. Despite its clinical relevance, the potential interaction between Bu and VPA has not yet been evaluated. The aim of the present study was to assess and evaluate the potential drug-drug interaction (DDI) between Bu and VPA. This study was carried out by incubating Bu in laboratory-prepared rat liver-subcellular fractions including S9, microsomes, and cytosol, alone or in combination with VPA. The liver fractions were prepared by differential centrifugation of the liver homogenate. Analysis of Bu was employed using a fully validated LC-MS/MS method. The validation parameters were within the proposed limits of the international standards guidelines. Bu metabolic stability was assessed by incubating Bu at a concentration of 8 µg/ml in liver fractions at 37°C. There were significant reductions in Bu levels in S9 and cytosolic fractions, whereas these levels were not significantly (P ˃ 0.05) changed in microsomes. However, in presence of VPA, Bu levels in S9 fraction remained unchanged. These results indicated, for the first time, the potential metabolic interaction of Bu and VPA being in S9 only. This could be explained by inhibiting Bu cytosolic metabolism by the interaction with VPA either by sharing the same metabolic enzyme or the required co-factor. In conclusion, the present findings suggest, for the first time, a potential DDI between Bu and VPA in vitro using rat liver fractions. Further investigations are warranted in human-derived liver fractions to confirm such an interaction.

Enhancing Administrative Claims Data: Feasibility, Validation and Application of Linking Medicare Claims Data and National Marrow Donor Program Search Data.

PURPOSE: Administrative claims data provide real-world service utilization of acute myeloid leukemia (AML) treatment, but lacks insight into treatment delays or barriers. The National Marrow Donor Program (NMDP)/Be The Match Search (Search) data contains information on donor search, but lacks information on treatment received if allogeneic hematopoietic cell transplant (HCT) is not performed. We hypothesized that linking these two data sets would create a rich resource to define factors associated with receiving HCT that could not be evaluated with either data set alone. METHODS: A subset of 2010-2016 Medicare administrative claims data was linked with Search data. A total of 5,351 patients with AML age 65-74 years (HCT = 607, no HCT = 4,744) were identified using Medicare. These patients were then linked to 93,800 records with a donor search between 2009 and 2016. Patient date of birth, sex, disease, ZIP code, transplant center/hospital, and diagnosis date were used for matching. Exploratory analysis was conducted to identify predictors associated with receiving HCT for patients with AML who received a search. RESULTS: The data sets were successfully linked, showing high sensitivity and specificity. The final cohort included 5,085 patients with AML (HCT = 533, no HCT = 4,552). Of 97 patients who received HCT without a matched search, more than 85% received a related donor HCT. Of those not receiving HCT, 609 had a matched NMDP search and 3,943 did not have a matched NMDP search. Multivariate analysis showed time to search, age, diagnosis year, race/ethnicity, and neighborhood education status associated with receiving HCT. CONCLUSION: Methods herein demonstrate the feasibility of linking Search and Medicare data. Similar methods may be applied to answer critical questions regarding barriers to HCT, thereby identifying areas to improve access to care.

Trends in Allogeneic Hematopoietic Cell Transplantation Utilization and Estimated Unmet Need Among Medicare Beneficiaries with Acute Myelogenous Leukemia.

Allogeneic hematopoietic cell transplantation (alloHCT) is a resource-intensive procedure and the sole potentially curative treatment available for patients with acute myelogenous leukemia (AML). Although Medicare coverage may help address a major financial barrier to accessing alloHCT, there remains an unmet need for alloHCT owing to sociodemographic disparities. This study examined trends and factors associated with the utilization of alloHCT and the estimated unmet need for alloHCT among Medicare beneficiaries with AML. This retrospective cohort study included patients (age 65 to 74 years) with a diagnosis of AML identified in Medicare claims data from 2010 through 2016. To study trends in utilization, transplantation rates were calculated as the number of patients who underwent alloHCT within 180 days and 1 year of diagnosis (numerator) divided by the total number of patients with AML within each diagnosis year (denominator). A multivariable logistic regression was used to identify factors associated with the likelihood of undergoing alloHCT within 1 year of diagnosis. Two approaches were applied to estimate the unmet need for alloHCT. The first approach used claims data to identify the potential need for alloHCT among patients who achieved complete remission for at least 90 days. The second approach used established National Marrow Donor Program (NMDP) methodology, which considers estimates of risk level, response to treatment, comorbidity, and early mortality, to identify the potential and unmet need for alloHCT. The overall estimated need and unmet need from 2010 to 2015 and over different time periods were evaluated for both approaches. The alloHCT rate within 180 days of diagnosis increased from 8% in 2010 to 15.8% in 2016 (P < .001), and the 1-year alloHCT rate also increased over time, from 11.9% in 2010 to 20.0% in 2015 (P < .001). The likelihood of undergoing alloHCT within 1 year of diagnosis was associated with diagnosis year, age, race, geographic region, Elixhauser Comorbidity Index, and population-level median household income. Between 2010 and 2015, the claims data approach estimated a lower potential need for alloHCT compared with the NMDP methodology estimate (27% versus 36%); both approaches estimated that 43% to 44% of patients with a potential need for alloHCT had an unmet treatment need. Despite the differences in estimated potential need between the 2 approaches, both showed a sustained unmet need but with a downward trend over time. Our data show that utilization of alloHCT has increased over time among Medicare beneficiaries with AML. Two approaches of need analysis were conducted for validation of estimated need and unmet need for alloHCT using claim-identified remission status, given the lack of cytogenetics and molecular information in claims data. Both approaches to estimating the unmet need for alloHCT found a downward trend over time; however, there are differences in utilization of alloHCT by age, race, geographic region, comorbidity, and socioeconomic status, indicating disparities in access to alloHCT among Medicare beneficiaries with AML. This suggests the need for policy efforts, research, and continued education to improve access to alloHCT and to close the gap between the actual utilization of alloHCT and the unmet need.

Incidence, economic burden, and treatment of acute respiratory tract infection in hematopoietic stem cell transplantation recipients using real world data in Japan: a retrospective claims data analysis.

AIMS: Acute respiratory tract infections (ARTIs) are common in hematopoietic stem cell transplantation (HSCT) recipients, however, data is limited regarding epidemiology and economic burden of ARTI in HSCT recipients in Japan. We evaluated the incidence of ARTI in HSCT recipients, associated economic burden, and ARTI-related treatments post-HSCT. MATERIALS AND METHODS: Patients receiving HSCT between July 2017 and December 2018, and those enrolled in the JMDC Claims Database for ≥6 months before index month (month when latest medical procedure code of HSCT recorded) were included. The outcomes included demographics, ARTI incidence, healthcare resource utilization (HCRU), direct costs, and ARTI-related treatments. RESULTS: In 330 analyzed patients, the ARTI incidence rate was 85.5% during total follow-up, consisting of post-HSCT hospitalization of mean 2.1 months and post-discharge periods of mean 17.6 months (post-HSCT hospitalization: 44.8%; post-discharge: 77.6%). For ARTI vs non-ARTI patients during post-HSCT hospitalization, length of hospitalization was significantly longer (mean [SD] months; 2.40 [1.73] vs 1.84 [1.09]; p = 0.0004), and median cost was significantly higher (JPY; 6,250,120.00 vs 4,774,570.00; p = 0.0096). The cost of outpatient visits during post-discharge periods, drug-related and non-drug-related costs of outpatient visits were generally higher for ARTI vs non-ARTI patients. In ARTI vs non-ARTI patients, utilization of any symptom relievers (decongestants, antitussives, and antipyretics), bronchodilators, immunoglobulin G, antibiotics, antivirals, and oxygen supply were numerically higher during post-HSCT hospitalization and post-discharge periods. The proportion of patients and mean prescription days for immunosuppressants during post-HSCT hospitalization were higher in ARTI vs non-ARTI patients. LIMITATIONS: This administrative claims study lacks clinical data and contains only direct medical costs. Patients were retained if they had at least 1 month of enrollment post-HSCT. CONCLUSIONS: In HSCT recipients, ARTI leads to substantial incremental HCRU and direct costs for management in real-world settings in Japan.

People receiving hematopoietic stem cell transplantation (HSCT) commonly suffer from acute respiratory infections (ARTIs). The real-world data on its incidence and economic impact in Japan is limited. In this study, using the JMDC Claims Database 330 HSCT recipients were identified during July 2017 and December 2018. Of these patients, 85.5% developed ARTI either during post-HSCT hospitalization (44.8%, within mean 2.1 months) or post-discharge period (77.6%, within mean 17.6 months). Patients with ARTI had longer hospital stays (2.40 months vs 1.84 months) and higher in-patient treatment costs (6,250,120.00 JPY vs 4,774,570.00 JPY) than those without ARTI. The costs associated with out-patient treatment, both drug-related and non-drug-related, were also higher for ARTI patients than non-ARTI patients. The use of medicines for stuffy nose (decongestants), dry cough (antitussives), and fever (antipyretics), and other medicines to treat respiratory infections (such as bronchodilators, immunoglobulin G, antibiotics, antivirals, and oxygen supply) was generally high with ARTI patients both during post-HSCT hospitalization and during post-discharge periods. The use of immunosuppressants was also more in patients who acquired ARTI as compared with non-ARTI patients during post-HSCT hospitalization. This study demonstrates the significant impact of ARTI in terms of economic and healthcare resource utilization in HSCT recipients in Japan.

Ex Vivo and In Vivo Gene Therapy for Mucopolysaccharidoses: State of the Art.

Enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT) are standard treatments for some mucopolysaccharidoses. Nevertheless, ERT is not curative, and HSCT is associated with significant mortality and morbidity, leaving a substantial disease burden of brain and skeletal manifestations. To overcome these limitations, different gene therapy (GT) strategies are under preclinical and clinical development. Data from ex-vivo GT clinical trials have demonstrated encouraging biochemical and early clinical outcomes. In-vivo GT, based on local brain delivery or systemic intravenous injections, resulted in biochemical and clinical stabilization of the disease.

Assessment of donor cell engraftment after hematopoietic stem cell transplantation for sickle cell disease: A review of current and future methods.

Hematopoietic stem cell transplantation (HSCT) is the only established curative treatment for sickle cell disease (SCD), a debilitating red blood cell (RBC) disorder with significant prevalence worldwide. Accurate assessment of RBC engraftment following HSCT is essential to evaluate the status of the graft and can enable early intervention to treat or prevent graft rejection. Currently, chimerism measurement is performed on whole blood samples, which mainly reflect white blood cell (WBC) chimerism. This approach has limitations in assessing engraftment in patients with SCD because RBCs engraft non-linearly with WBCs. Direct measures of RBC chimerism exist but are not routinely used. In this review, we critically examine the current methodologies for assessing donor engraftment; highlight the limitations of these different methods, and present emerging and novel technologies with the potential to improve clinical monitoring of RBC engraftment post-HSCT for SCD. Promising alternative methodologies include RBC-specific flow cytometry, RBC-specific RNA analysis, and quantification of plasma cell-free DNA derived specifically from nucleated RBCs.