Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further.

SARS-CoV-2 Vaccination IgG Antibody Responses in Patients with Hematologic Malignancies in a Myeloid Enriched Cohort: A Single Center Observation.

OBJECTIVE: Patients diagnosed with hematologic malignancies are at increased risk for severe SARS-CoV-2 infection. We evaluated the serological IgG response following two doses of the SARS-CoV-2 vaccine in patients with hematologic malignancies. METHODS: Patients treated at UT Southwestern Medical Center with a diagnosis of a myeloid or lymphoid neoplasm were included. SARS-CoV-2 vaccination response was defined as a positive quantifiable spike IgG antibody titer. RESULTS: Sixty patients were included in the study and 60% were diagnosed with a myeloid neoplasm. The majority (85%) of the patients with a myeloid malignancy and 50% of the patients with a lymphoid malignancy mounted a serological response after receiving two doses of the vaccine. CONCLUSION: Vaccination should be offered irrespective of ongoing treatment or active disease. Findings require validation in a larger cohort of patients.

Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study.

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma.

PURPOSE: Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models. PATIENTS AND METHODS: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791). RESULTS: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01-3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29-86) and the median prior lines of therapies was 3 (1-16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%. CONCLUSIONS: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.

Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease. OBJECTIVE: We investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT. STUDY DESIGN: This retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90-120 post allo-HSCT. RESULTS: A total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients. CONCLUSION: Our study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.

Cost-Effectiveness Analysis of CAR T-Cell Therapies vs Antibody Drug Conjugates for Patients with Advanced Multiple Myeloma.

OBJECTIVES: Among advanced multiple myeloma (MM) patients, B-cell maturation antigen (BCMA) specific targets like Belantamab Mafodotin (belamaf) and CAR T-cell therapies have been shown to improve clinical outcomes, but at significant costs. To compare the expected costs per quality-adjusted life years (QALYs) gained among a hypothetical cohort of triple refractory MM patients treated with one of three BCMA-directed therapies: (1) idecabtagene vicleucel (ide-cel), (2) ciltacabtagene autoleucel (cilta-cel), and (3) belamaf for up to 20 months. METHODS: In this cost-effectiveness analysis, we built a Monte Carlo Markov Chain microsimulation model using estimates and parameters from the evidence on MM treatment for 10 000 hypothetical patients between the ages for 40 and 80. We assigned expected years of life remaining and made varying assumptions about survival beyond 5 years. RESULTS: We predicted total cost of treatment for CAR-T therapy to be six times greater than for belamaf, but the QALYs gained from treatment are 6 to 8 times greater. Ide-cel was weakly dominated by cilta-cel and our base-case incremental cost effectiveness ratio (ICER) comparing cilta-cel with belamaf was $109,497 per QALY gained, averaging $123,618 in probabilistic sensitivity analyses. CONCLUSIONS: These findings hinge on the assumption of longer-term survival but suggest that the use of CAR-T therapy is approaching standard ICER thresholds.

Clinical and molecular characteristics associated with Vitamin C deficiency in myeloid malignancies; real world data from a prospective cohort.

Vitamin C is an essential vitamin that acts as a co-factor for many enzymes involved in epigenetic regulation in humans. Low vitamin C levels in hematopoietic stem cells (HSC) promote self-renewal and vitamin C supplementation retards leukaemogenesis in vitamin C-deficient mouse models. Studies on vitamin C levels in patients with myeloid malignancies are limited. We thus conducted a retrospective analysis on a prospective cohort of patients with myeloid malignancies on whom plasma vitamin C levels were measured serially at diagnosis and during treatment. Baseline characteristics including hematological indices, cytogenetics, and molecular mutations are described in this cohort. Among 64 patients included in our study, 11 patients (17%) had low vitamin C levels. We noted a younger age at diagnosis for patients with myeloid malignancies who had low plasma vitamin C levels. Patients with low plasma vitamin C levels were more likely to have acute myeloid leukemia compared to other myeloid malignancies. Low vitamin C levels were associated with ASXL1 mutations. Our study calls for further multi-institutional studies to understand the relevance of low plasma vitamin C level in myeloid neoplasms, the role of vitamin C deficiency in leukemogenesis, and the potential benefit of vitamin C supplementation.

Optimizing Palliative Focal Radiation Therapy Dose in Cutaneous T-Cell Lymphoma: How Low Can You Go?

PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) are radiosensitive tumors with variable and often relapsing courses. Local disease can be treated with low-dose focal palliative radiation therapy (RT), though little data supports the use of a specific dose. This study assesses clinical outcomes after focal RT to a total dose of 4 Gy, 8 Gy, or 12 Gy. METHODS AND MATERIALS: An International Review Board-approved, retrospective, single-institution study was performed of 225 lesions in 41 patients with primary CTCL treated with low-dose focal RT from 2015 to 2020. Patient, tumor, and treatment characteristics were reviewed. The primary outcome was freedom from treatment failure (FFTF), defined as time to requiring local retreatment, and secondary outcomes included response rates and toxicities. RESULTS: Of the 225 lesions, 90 received 4 Gy, 106 received 8 Gy, and 29 received 12 Gy. Lesions treated with 12 Gy (96%) or 8 Gy (92%) had a significantly higher 1-year FFTF compared with 4 Gy (77%) (P = .034). Overall response rate and complete response rate were not significantly different between different doses (P = .117), though there was a trend toward higher overall response rate at initial assessment with 8 Gy versus 4 Gy (91.5% vs 82.2%, P = .057). Toxicity was low, with 7.1% of lesions having grade 2 or higher radiation dermatitis. CONCLUSIONS: In primary CTCL lesions treated with focal palliative RT, a dose response was noted favoring 8 to 12 Gy, with 1-year FFTF rates over 90%. However, 4 Gy resulted in substantially better outcomes than previously reported, with 77% requiring no further treatment at 1 year and comparable response rates to higher doses. While our data substantiates 8 to 12 Gy as the standard of care, it also suggests that 4 Gy should be considered an acceptable alternative in situations with concern for radiation toxicities, such as with fragile or heavily pretreated skin.

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma.

Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Balancing Quality, Cost, and Access During Delivery of Newer Cellular and Immunotherapy Treatments.

PURPOSE OF REVIEW: The chimeric antigen receptor (CAR) T-cell therapy is currently changing the landscape of hematologic malignancies with multiple FDA-approved cell therapy products in the USA. The current administration process of the CAR T-cell therapy is complicated, labor-intensive, and expensive. RECENT FINDINGS: The chimeric antigen receptor (CAR) T-cell therapy is currently changing the landscape of hematologic malignancies with multiple FDA-approved cell therapy products in the USA. The current administration process of the CAR T-cell therapy is complicated, labor-intensive, and expensive. This review article addresses the present-day challenges and discusses opportunities to optimize the access and affordability of the CAR T-cell therapy. The field of cellular immunotherapy is going to change the future of solid tumors and non-oncological diseases. However, this promising therapy poses challenges in the administration and management of quality in the current field of healthcare. We describe various novel approaches to manage challenges in improving access and improving widescale implementation of cellular therapies.

Evaluation of SARS-CoV-2 Serological Testing in Patients with Multiple Myeloma and Other Hematologic Malignancies on Monoclonal Antibody Therapies.

BACKGROUND: Patients with hematological malignancies (HM), including multiple myeloma (MM), frequently suffer from immune deficiency-associated infectious complications because of both the disease and the treatment. Alarming results from China and the UK confirm the vulnerability of HM patients to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven coronavirus disease 2019 (COVID-19). Given that the immunoassay interference from the endogenous monoclonal immunoglobulin (M paraprotein) and treatment antibodies continually challenges the MM management, it is critical to evaluate the SARS-CoV-2 serology tests for suspected interference/cross-reactivity. METHODS: We compared the degree of interference in three SARS-CoV-2 serology assay platforms in HM patients with and without COVID-19 and on various therapeutic monoclonal antibody (t-mAb) treatments. Further, we confirmed the cross-reactivity in pooled samples from normal and COVID-19 + samples spiked with respective antibodies in vitro. RESULTS: None of the 93 HM patient samples with or without t-MAbs showed cross-reactivity on any of the three serology platforms tested. CONCLUSIONS: The tested three serologic assays for SARS-CoV-2 are specific and do not have cross-reactivity with M-components or t-MAbs indicating that they can be used safely in oncology practice and in research exploring the immunologic response to COVID-19 in patients with HM.

An evaluation of zanubrutinib, a BTK inhibitor, for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Recent years have seen a tremendous increase in the availability of therapeutic options for the management of patients with chronic lymphocytic leukemia (CLL). Notable among those are Bruton's tyrosine kinase (BTK) and b-cell lymphoma-2 (bcl-2) inhibitors. AREAS COVERED: The authors provide a brief overview of the BTK signaling pathway as well as available, approved BTK inhibitors for CLL. In addition, they review pre-clinical and clinical data related to zanubrutinib and its use and CLL and other lymphoid malignancies. EXPERT OPINION: Two BTK inhibitors are currently Food and Drug Administration (FDA) approved for use in CLL, and multiple additional agents are in development. Zanubrutinib is currently approved for the treatment of patients with relapsed mantle cell lymphoma and has demonstrated an impressive safety and efficacy profile. The choice of a specific BTK inhibitor for clinical use is dependent on its efficacy and relative toxicity profile. In addition, drug interactions also influence this decision. Zanubrutinib therefore provides an exciting option to utilize a specific BTK inhibitor with potentially limited toxicities. Additional comparative studies are currently underway to establish its advantage over currently available BTK inhibitors. Combination strategies are also being pursued to increase the depth and durability of remissions.

Complement inhibition with eculizumab for thrombotic microangiopathy rescues a living-donor kidney transplant in a patient with antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome (APS) is an enigmatic heterogeneous disorder despite several revelations in its pathobiology. Renal transplantation in patients with APS has been notoriously difficult due to the high risk of development of thrombotic microangiopathy (TMA), which is often refractory to conventional treatment modalities such as aggressive anticoagulation and plasmapheresis. We describe a case of a 58-year-old male with secondary APS undergoing living unrelated renal transplantation for end-stage renal disease from lupus nephritis. Shortly after transplantation, he developed graft dysfunction from APS related TMA that was refractory to systemic anticoagulation and plasmapheresis. After becoming hemodialysis dependent, the patient was started on eculizumab, a humanized monoclonal antibody against complement factor 5, as salvage therapy. We show that this intervention successfully rescued his renal allograft and that the patient has remained dialysis free for over 20 months. Our experience adds to the limited body of literature suggesting the role of complement inhibition in facilitating renal transplantation in patients with APS spectrum of disorders, thus adding a new tool to the therapeutic armamentarium for this difficult disease. The optimal treatment schedule and long term safety data for eculizumab in complement mediated TMA is still unclear. The search for an optimal biomarker to help guide treatment duration is an area of active research.

The Evolving Biology of Castration-Resistant Prostate Cancer: Review of Recommendations From the Prostate Cancer Clinical Trials Working Group 3.

In 2008, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) developed consensus guidelines for clinical trial design and conduct that redefined trial endpoints, with a dual-objective paradigm: to (1) controlling, relieving, or eliminating disease manifestations at the start of treatment; and (2) preventing or delaying further disease manifestations. Clinical and translational research in prostate cancer has expanded our current-day understanding of the mechanisms of its pathogenesis, as well as the different clinicopathologic and molecular subtypes of the disease, and has improved the therapeutic armamentarium for the management of metastatic castration-resistant prostate cancer (CRPC). These new advances led to the development of the updated PCWG3 guidelines in 2015. In this review, we analyze our evolving understanding of the biology of CRPC, acquired resistance mechanisms, and emerging therapeutic targets in light of the updated PCWG3 guidelines. We present a joint perspective from the medical oncology and urologic disciplines on the ongoing efforts to advance clinical trial performance in order to discover new therapies for this fatal disease.

"The Immune Conundrum": Acquired Hemophilia A, Immune Thrombocytopenia, and Neutropenia in a Patient with Pancreatic Cancer.

Background: Malignancy-associated bleeding can pose diagnostic dilemmas. We report a unique case of paraneoplastic acquired hemophilia A (AHA), immune thrombocytopenia (ITP), and immune neutropenia in a patient with pancreatic adenocarcinoma. Case Presentation: A 66-year-old male with newly diagnosed pancreatic cancer and normal preoperative hematological evaluation was taken to the operating room for pancreaticoduodenectomy. The operation was aborted due to empyema of the gall bladder, cholangitis, and local extent of disease. Postoperatively, the patient developed bleeding diatheses with mucocutaneous and intra-abdominal bleeding and a prolonged activated partial thromboplastin time. Evaluation revealed high-titer factor VIII inhibitor confirming AHA. Management with bypassing agents such as recombinant activated factor VII, factor VIII inhibitor bypassing activity, and immunosuppression with steroids, cyclophosphamide, and rituximab achieved remission in 2 months. ITP developed after achieving normal factor VIII levels, which was managed with intravenous immunoglobulin. Neutropenia was detected before initiation of chemotherapy and was managed with granulocyte-colony stimulating factor. Conclusion: These unique challenges posed by paraneoplastic hematological syndromes warrant the need for astute clinical judgment and multidisciplinary collaboration for effective management.

Increasing colon cancer screening in primary care among African Americans.

BACKGROUND: The study aimed to determine the effect of preference-based tailored navigation on colorectal cancer (CRC) screening adherence and related outcomes among African Americans (AAs). METHODS: We conducted a randomized controlled trial that included 764 AA patients who were age 50 to 75 years, were eligible for CRC screening, and had received care through primary care practices in Philadelphia. Consented patients completed a baseline telephone survey and were randomized to either a Standard Intervention (SI) group (n = 380) or a Tailored Navigation Intervention (TNI) group (n = 384). The SI group received a mailed stool blood test kit plus colonoscopy instructions, and a reminder. The TNI group received tailored navigation (a mailed stool blood test kit or colonoscopy instructions based on preference, plus telephone navigation) and a reminder. A six-month survey and a 12-month medical records review were completed to assess screening adherence, change in overall screening preference, and perceptions about screening. Multivariable analyses were performed to assess intervention impact on outcomes. RESULTS: At six months, adherence in the TNI group was statistically significantly higher than in the SI group (OR = 2.1, 95% CI = 1.5 to 2.9). Positive change in overall screening preference was also statistically significantly greater in the TNI group compared with the SI group (OR = 1.5, 95% CI = 1.0 to 2.3). There were no statistically significant differences in perceptions about screening between the study groups. CONCLUSIONS: Tailored navigation in primary care is a promising approach for increasing CRC screening among AAs. Research is needed to determine how to maximize intervention effects and to test intervention impact on race-related disparities in mortality and survival.