Sex-Specific Cardiovascular Risks of Cancer and Its Therapies.

In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies.

Early infectious complications after autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. METHODS: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007-2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non-relapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS). RESULTS: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), and Clostridium difficile colitis 6% (4-8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100-day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100-day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03-2.30], P = 0.03), although there was no difference in NRM and RFS. CONCLUSIONS: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients.

Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation.

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received ≥2 (n = 109), 1 (n = 93), or 0 cycles (n = 322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving ≥2, 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk, 1.20, 95% confidence interval, .86 to 1.67; P = .28 for no consolidation; RR, 1.18, 95% confidence interval, .79 to 1.76; P = .41 for 1 cycle versus ≥2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1.

The association of histologic grade with acute graft-versus-host disease response and outcomes.

Consensus criteria are routinely used to clinically grade acute graft-versus-host disease (GVHD). A histologic grading system for acute GVHD is available, but there are limited data on its correlation with clinical grade and hematopoietic cell transplantation (HCT) outcomes. Among 503 patients who underwent allogeneic HCT from 2005 to 2013, we identified 300 biopsy episodes of the skin and gastrointestinal (GI) tract in 231 patients. Histologic grade was correlated with clinical grade of GVHD, day 28 treatment response, and outcome. Both skin (R = 0.32) and GI (R = 0.61) histologic grade correlated with clinical grade (P < 0.001). On multivariable analysis, histologic grade (HR 0.87, P = 0.011) and clinical grade (HR 0.86, P = 0.008) were significantly associated with day 28-treatment response. A histologic grade lower than its associated clinical grade predicted for better response (HR 1.26, P = 0.027), while a histologic grade higher than associated clinical grade had no correlation with response (P = 0.89). Both clinical and histologic GVHD grade were significant predictors of non-relapse mortality (HR 1.47, P = 0.04 and HR 1.67, P = 0.002, respectively) and all-cause mortality (HR 1.57, P = 0.001 and HR 1.29, P = 0.046, respectively). Histologic GVHD grade thus is correlated with clinical grading and treatment response, and may play a role in further predicting severity and treatment response of acute GVHD.