A phase II study of ibrutinib in combination with ixazomib in patients with Waldenström macroglobulinaemia.

This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.

BACKGROUND: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. METHODS: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. RESULTS: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. CONCLUSIONS: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

The digital divide: Racial disparities in adoption and utilization of health information technology among patients with lymphoid cancers.

INTRODUCTION: Health information technology (HIT) has the potential to improve healthcare delivery and engagement. Studying racial-ethnic disparities in HIT engagement will help understand and overcome challenges to healthcare utilization. METHODS: We undertook a patient-reported survey among patients with lymphoid malignancies at two campuses of Mayo Clinic, Florida to explore HIT-related disparities. Variables between Whites and non-Whites, and non-Whites from the two campuses were compared. RESULTS: The survey was completed by 1004 respondents, with 71% whites, 27% non-Whites (race-ethnicity not reported by 2%). Non-Whites included 30% responders at the main campus and 64% at an inner-city campus. Whites were significantly older and had higher education, while non-Whites had lesser access to a computer. Only 51% of non-Whites were registered to use electronic medical records (EMR) as compared to 72% Whites (p < 0.001) and significantly lesser number of non-Whites even knew that EMR existed (81% vs. 92%, p < 0.001). Encouragingly, a higher number of non-Whites wanted to engage in EMR. Non-Whites from the main campus were older, more educated and had more access to a computer as compared to those from the inner-city campus. Similar disparate factors were noted among minorities from the two campuses, suggesting impact of socioeconomic backgrounds on EMR usage among non-Whites. Linguistic barriers were more striking among inner-city campus non-Whites. CONCLUSIONS: Non-Whites continue to struggle with suboptimal utilization of the healthcare system and barriers related to integration in HIT, including disparities representing socioeconomic differences. Efforts need to be made at several levels to help racial-ethnic minorities overcome awareness, access, and linguistic barriers to HIT utilization.

AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma.

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia's. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.

Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy.

PURPOSE: Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575). EXPERIMENTAL DESIGN: Computational modeling was used to design "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models. RESULTS: Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo. CONCLUSIONS: These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.

Trends in Early Mortality From Multiple Myeloma: A Population-Based Analysis.

INTRODUCTION: Despite significant improvements in multiple myeloma (MM) treatment modalities, patient mortality early in the course of disease has been identified as a persistent phenomenon with variable reported rates and causes. Trends in early mortality over time have not been clearly defined. PATIENTS AND METHODS: The Surveillance Epidemiology and End Results (SEER) database was used to identify adult patients with MM between 1975 and 2015. Association of available sociodemographic factors with all-cause and MM-specific early mortality (death within 6 months after the diagnosis of MM) was conducted by multivariate analysis. Trends in early mortality were studied by joinpoint regression analysis. RESULTS: Of the 90,975 MM cases included in this analysis, early mortality was noted in 21%. Median age was 68 years overall, and 75 years for the early mortality cohort (P < .01). The most common causes of death for early mortality were MM itself, followed by cardiovascular, infections, and renal failure. Male gender, "other" race/ethnicity group, advancing age, and West, Midwest or South regions (reference Northeast) were associated with increased risk of both all-cause and MM-specific early mortality. Joinpoint regression analysis of trends data resulted in 1 joinpoint for all-cause 6-month mortality (2006-2015), while 2 joinpoints were noticed for myeloma-specific 6-month mortality (1975-1987 and 2003-2015). CONCLUSION: Early mortality remains a significant unmet need for MM patient care, despite improving trends in recent years. Understanding the factors associated with early mortality can help develop individualized plans of patient care and mitigate circumstances that may contribute to early mortality among MM patients.

Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses.

Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]-like CLL cells) produce high amounts of IL-10 and transforming growth factor ß (TGF-ß) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-ß-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL-patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.