Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL.

The Bcl-2 inhibitor venetoclax has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional proapoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling antiapoptotic proteins using flow cytometry, we find that leukemic B cells that recently emigrated from the lymph node (CD69+/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple antiapoptotic proteins (Mcl-1High/Bcl-xLHigh/Bcl-2High) in both treated and treatment-naive CLL patients. These cells exhibited antiapoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry-based functional assay. Antiapoptotic multidrug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving "persister" cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally induced multidrug resistance. Overcoming this resistance required simultaneous inhibition of multiple antiapoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient peripheral blood mononuclear cells cultured in an ex vivo microenvironment model, we identify novel venetoclax drug combinations that induce selective cytotoxicity in multidrug-resistant CLL cells. Thus, we demonstrate that antiapoptotic multidrug-resistant CLL cells exist in patients de novo and show that these cells persist during proapoptotic treatment, such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.

Barriers to Access to Hematopoietic Cell Transplantation among Patients with Acute Myeloid Leukemia in Virginia.

Allogeneic hematopoietic cell transplantation (HCT) is a standard therapy for patients with intermediate to high-risk acute myeloid leukemia (AML) and is associated with improved long-term disease-free survival. Disparity exists in access to HCT among different patient populations and requires further study. In this study, we compared HCT rates for AML among different regions in the state of Virginia and identified geographic and socioeconomic factors associated with the likelihood of receiving HCT. We conducted a retrospective, cohort study of patients 18 to 74 years of age diagnosed with AML in Virginia from 2013 to 2017 as reported to the Virginia Cancer Registry (VCR); the VCR was further linked with the Center for International Blood and Marrow Transplant Research database for identification of patients who had undergone HCT within 2 years of diagnosis. Socioeconomic data were generated from the VCR and the American Community Survey. Univariate and multivariable logistic regression models were used to examine selected socioeconomic factors of interest, including patient-level information such as sex, age, race, marital status, and primary insurance payer, as well as factors associated with geography, including the Social Vulnerability Index (SVI) and percentage of African Americans residing in the region. In Virginia, 818 patients were diagnosed with AML from 2013 to 2017, and, of these, 168 patients (21%) underwent HCT within 2 years of diagnosis. Median age was lower in the HCT cohort (55 years) versus the non-HCT cohort (64 years) (P < .001). There was a higher proportion of married patients in the HCT cohort (67%) versus the non-HCT cohort (53%) (P = .005). The rate of HCT varied by geographic region (P = .004). The multivariable analyses (without including SVI) showed decreased likelihood of HCT with increasing age (odds ratio [OR], .96; 95% confidence interval [CI], .95 to .98). Patients from regions that had a greater than 25% African American population were less likely to undergo HCT (OR, .58; 95% CI, .38 to .89). Patients who were not married were less likely to undergo HCT compared with married patients (OR, .56; 95% CI, .36 to .88). Patients with government-sponsored insurance as the primary payer were less likely to undergo HCT compared with patients with private insurance (OR, .49; 95% CI, .32 to .77). Patients living in Zip Code areas with a greater percentage of population with a bachelor's or graduate degree were more likely to undergo HCT (OR, 1.02; 95% CI, 1.00 to 1.03). In a separate multivariate model with SVI, patients residing in a Zip Code with higher SVI were less likely to undergo HCT (OR, .37; 95% CI, .16 to .82). From 2013 to 2017, we found that the likelihood of a patient undergoing HCT in Virginia for AML within 2 years of diagnosis was negatively associated with increasing age, percent of African Americans residing in the region, not-married relationship status, government-sponsored insurance as primary payer, higher SVI, and decreased percent of population with a bachelor's or graduate degree. Resources should be directed toward at-risk patient populations to remove barriers to improve access to HCT. The SVI can be used to identify communities at risk nationwide.

Severe combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series.

BACKGROUND: Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner. Cardiac and neurologic complications are rare, but can result in serious clinical consequences. METHODS: We describe the presentation, management, and outcomes of eight sequential cases of combined cardiac and neurologic toxicities resulting in severe illness and demonstrating lack of rapid response to immunosuppression. RESULTS: Our cohort consisted of six males and two females with an average age of 73.5 years (61-89 years). There were four patients with melanoma, and one patient each with urothelial carcinoma, renal cell carcinoma, breast cancer, and non-small cell lung cancer. Four patients received combination immunotherapy and four patients received monotherapy. The median time to presentation from treatment initiation was 27 days (11-132 days). All patients had a cardiovascular and neurologic toxicity, and most had hepatitis and myositis. The cardiac signs and symptoms were the prominent initial features of the clinical presentation. Each patient was managed by a multidisciplinary team and received a range of immunosuppressive agents. All patients died as a consequence of the immune related adverse events. CONCLUSIONS: The evaluation of patients with cardiac adverse events from immunotherapy, should include assessment of overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.

Novel therapies for relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma is an aggressive Non-Hodgkin's lymphoma that is considered incurable with standard therapies. Most patients treated with frontline immunochemotherapy relapse within a few years and do not usually respond to salvage chemotherapy. Persistent activation of the B-cell receptor pathway is critical to the pathogenesis of mantle cell lymphoma. Inhibition of Bruton's tyrosine kinase, an essential B-cell receptor pathway component with ibrutinib has shown clinical activity and has changed how MCL is treated in the relapsed/refractory setting. However, resistance to ibrutinib is common and response is limited. Novel agents targeting the B-cell receptor pathway along with therapies outside of the pathway will be reviewed in this article. Ongoing and future studies will better define how these agents should be utilized in the ever-changing treatment landscape of mantle cell lymphoma.