Impact of payment source, referral site, and place of residence on outcomes after allogeneic transplantation in Mexico.

BACKGROUND: The impact of social determinants of health in allogeneic transplant recipients in low- and middle-income countries is poorly described. This observational study analyzes the impact of place of residence, referring institution, and transplant cost coverage (out-of-pocket vs government-funded vs private insurance) on outcomes after allogeneic hematopoietic stem cell transplantation (alloHSCT) in two of Mexico's largest public and private institutions. AIM: To evaluate the impact of social determinants of health and their relationship with outcomes among allogeneic transplant recipients in Mexico. METHODS: In this retrospective cohort study, we included adolescents and adults ≥ 16 years who received a matched sibling or haploidentical transplant from 2015-2022. Participants were selected without regard to their diagnosis and were sourced from both a private clinic and a public University Hospital in Mexico. Three payment groups were compared: Out-of-pocket (OOP), private insurance, and a federal Universal healthcare program "Seguro Popular". Outcomes were compared between referred and institution-diagnosed patients, and between residents of Nuevo Leon and out-of-state. Primary outcomes included overall survival (OS), categorized by residence, referral, and payment source. Secondary outcomes encompassed early mortality, event-free-survival, graft-versus-host-relapse-free survival, and non-relapse-mortality (NRM). Statistical analyses employed appropriate tests, Kaplan-Meier method, and Cox proportional hazard regression modeling. Statistical software included SPSS and R with tidycmprsk library. RESULTS: Our primary outcome was overall survival. We included 287 patients, n = 164 who lived out of state (57.1%), and n = 129 referred from another institution (44.9%). The most frequent payment source was OOP (n = 139, 48.4%), followed by private insurance (n = 75, 26.1%) and universal coverage (n = 73, 25.4%). No differences in OS, event-free-survival, NRM, or graft-versus-host-relapse-free survival were observed for patients diagnosed locally vs in another institution, nor patients who lived in-state vs out-of-state. Patients who covered transplant costs through private insurance had the best outcomes with improved OS (median not reached) and 2-year cumulative incidence of NRM of 14% than patients who covered costs OOP (Median OS and 2-year NRM of 32%) or through a universal healthcare program active during the study period (OS and 2-year NRM of 19%) (P = 0.024 and P = 0.002, respectively). In a multivariate analysis, payment source and disease risk index were the only factors associated with overall survival. CONCLUSION: In this Latin-American multicenter study, the site of residence or referral for alloHSCT did not impact outcomes. However, access to healthcare coverage for alloHSCT was associated with improved OS and reduced NRM.

Increasing access to transplantation through telemedicine and patient navigation.

BACKGROUND: Hematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. AIM: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. METHODS: In this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. RESULTS: One hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. CONCLUSION: Our pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study.

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1-21, itraconazole 100 mg twice daily from days 1-21, and azacytidine 100 mg subcutaneously, once daily from days 1-7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25-73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Treatment of Ph-Negative Acute Lymphoblastic Leukemia in Adolescents and Young Adults with an Affordable Outpatient Pediatric Regimen.

BACKGROUND: B-cell acute lymphoblastic leukemia is frequent in Hispanic adolescents and young adults. Outcomes of implementation of pediatric-inspired regimens in low-and middle-income countries are not well known. METHODS: In this study we treated 94 adolescents and young adults with a local BFM regimen designed to be affordable with the use of native L-asparaginase and mitoxantrone administered in an outpatient fashion, and the of BCR/ABL and measurable residual disease (MRD) determined by high sensitivity flow cytometry for risk stratification. RESULTS: Induction mortality was 11%; 25% of patients had to abandon treatment or be transferred to another health system. Two-year overall (OS) and event free survival (EFS) were 61.5% and 49.8%, MRD-negative patients had a 24-month OS of 85.6% vs. 69.6% (p = .024) and EFS of 76% vs. 45.5% (p = .004). Patients older than 40 years and those who abandoned treatment had worse EFS. Overall drug costs in our regimen were 52% lower than those of CALGB10403. CONCLUSION: The treatment of AYAs with ALL with an outpatient focus was implemented successfully at a reduced cost. Genetic risk assessment, treatment abandonment and lack of access to novel therapies remain major barriers for improving outcomes.

Protein interaction networks define the genetic architecture of preterm birth.

The likely genetic architecture of complex diseases is that subgroups of patients share variants in genes in specific networks sufficient to express a shared phenotype. We combined high throughput sequencing with advanced bioinformatic approaches to identify such subgroups of patients with variants in shared networks. We performed targeted sequencing of patients with 2 or 3 generations of preterm birth on genes, gene sets and haplotype blocks that were highly associated with preterm birth. We analyzed the data using a multi-sample, protein-protein interaction (PPI) tool to identify significant clusters of patients associated with preterm birth. We identified shared protein interaction networks among preterm cases in two statistically significant clusters, p < 0.001. We also found two small control-dominated clusters. We replicated these data on an independent, large birth cohort. Separation testing showed significant similarity scores between the clusters from the two independent cohorts of patients. Canonical pathway analysis of the unique genes defining these clusters demonstrated enrichment in inflammatory signaling pathways, the glucocorticoid receptor, the insulin receptor, EGF and B-cell signaling, These results support a genetic architecture defined by subgroups of patients that share variants in genes in specific networks and pathways which are sufficient to give rise to the disease phenotype.

Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy, which complicates up to 15% of US deliveries. It is an idiopathic disorder associated with several different phenotypes. We sought to determine if the genetic architecture of preeclampsia can be described by clusters of patients with variants in genes in shared protein interaction networks. We performed a case-control study using whole exome sequencing on early onset preeclamptic mothers with severe clinical features and control mothers with uncomplicated pregnancies between 2016 and 2020. A total of 143 patients were enrolled, 61 women with early onset preeclampsia with severe features based on ACOG criteria, and 82 control women at term, matched for race and ethnicity. A network analysis and visualization tool, Proteinarium, was used to confirm there are clusters of patients with shared gene networks associated with severe preeclampsia. The majority of the sequenced patients appear in two significant clusters. We identified one case dominant and one control dominant cluster. Thirteen genes were unique to the case dominated cluster. Among these genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia. Using bioinformatic analysis, we were able to identify subsets of patients with shared protein interaction networks, thus confirming our hypothesis about the genetic architecture of preeclampsia.