Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.

Clinical inertia in the treatment of heart failure: a major issue to tackle.

Despite an enormous improvement in heart failure management during the last decades, the hospitalization and mortality rate of heart failure patients still remain very high. Clinical inertia, defined as the lack of treatment intensification in a patient not at evidence-based goals for care, is an important underlying cause. Clinical inertia is extensively described in hypertension and type 2 diabetes mellitus, but increasingly recognized in heart failure as well. Given the well-established guidelines for the management of heart failure, these are still not being reflected in clinical practice. While the absolute majority of patients were treated by guideline-directed heart failure drugs, only a small percentage of these patients reached the correct guideline-recommended target dose of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. This considerable under-treatment leads to a large number of avoidable hospitalizations and deaths. This review discusses clinical inertia in heart failure and explains its major contributing factors (i.e., physician, patient, and system) and touches upon some recommendations to prevent clinical inertia and ameliorate heart failure treatment.

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia.

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy.

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia.

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.

Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes.

BACKGROUND: The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine. METHODS: A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy. RESULTS: Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%). CONCLUSIONS: The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society.

Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality.

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials.

Long-term sustained disease control in patients with mantle cell lymphoma with or without active disease after treatment with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

BACKGROUND: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL). METHODS: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%). RESULTS: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03). CONCLUSIONS: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses.

Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation.

The haematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed in a single centre as a weighted scoring system to predict risks of non-relapse mortality (NRM) following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT-CI in multi-centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen-matched grafts from five different US institutions were analysed. Among all patients, HCT-CI scores of 0 vs. 1-2 vs. ≥3 were associated with 2-year NRM rates of 14%, 23% and 39% (P < 0·0001), respectively, and 2-year overall survival (OS) rates of 74%, 61% and 39%, respectively (P < 0·0001). Using regression models, increasing HCT-CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT-CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C-statistic estimates for the prognostic power of the HCT-CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT-CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia.

This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2)  d 1, 8, 15; B: 72 mg/m(2)  d 1, 8; C: 72 mg/m(2) or 90 mg/m(2)  d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2)  d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia.

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study.

BACKGROUND: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. OBJECTIVE: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. PATIENTS AND METHODS: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. RESULTS: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3-134.2, and 74.8-126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. CONCLUSIONS: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).

Role of the saturated nonesterified fatty acid palmitate in beta cell dysfunction.

Sustained elevated levels of saturated free fatty acids, such as palmitate, contribute to beta cell dysfunction, a phenomenon aggravated by high glucose levels. The aim of this study was to investigate the mechanisms of palmitate-induced beta cell dysfunction and death, combined or not with high glucose. Protein profiling of INS-1E cells, exposed to 0.5 mmol/L palmitate and combined or not with 25 mmol/L glucose, for 24 h was done by 2D-DIGE, both on full cell lysate and on an enriched endoplasmic reticulum (ER) fraction. Eighty-three differentially expressed proteins (P < 0.05) were identified by MALDI-TOF/TOF mass spectrometry and proteomic results were confirmed by functional assays. 2D-DIGE analysis of whole cell lysates and ER enriched samples revealed a high number of proteins compared to previous reports. Palmitate induced beta cell dysfunction and death via ER stress, hampered insulin maturation, generation of harmful metabolites during triglycerides synthesis and altered intracellular trafficking. In combination with high glucose, palmitate induced increased shunting of excess glucose, increased mitochondrial reactive oxygen species production and an elevation in many transcription-related proteins. This study contributes to a better understanding and revealed novel mechanisms of palmitate-induced beta cell dysfunction and death and may provide new targets for drug discovery.

Cardio-renal-metabolic syndrome: clinical features and dapagliflozin eligibility in a real-world heart failure cohort.

AIMS: The Cardiovascular Outcomes Retrospective Data analysIS in Heart Failure (CORDIS-HF) is a single-centre retrospective study aimed to (i) clinically characterize a real-world population with heart failure (HF) with reduced (HFrEF) and mildly reduced ejection fraction (HFmrEF), (ii) evaluate impact of renal-metabolic comorbidities on all-cause mortality and HF readmissions, and (iii) determine patients' eligibility for sodium-glucose cotransporter 2 inhibitors (SGLT2is). METHODS AND RESULTS: Using a natural language processing algorithm, clinical data of patients diagnosed with HFrEF or HFmrEF were retrospectively collected from 2014 to 2018. Mortality and HF readmission events were collected during subsequent 1 and 2 year follow-up periods. The predictive role of patients' baseline characteristics for outcomes of interest was assessed using univariate and multivariate Cox proportional hazard models. Kaplan-Meier analysis was used to determine if type 2 diabetes (T2D) and chronic kidney disease (CKD) impacted mortality and HF readmission rates. The European SGLT2i label criteria were used to assess patients' eligibility. The CORDIS-HF included 1333 HF patients with left ventricular ejection fraction (LVEF) < 50% (413 HFmrEF and 920 HFrEF), who were predominantly male (69%) with a mean [standard deviation (SD)] age of 74.7 (12.3) years. About one-half (57%) of patients presented CKD and 37% T2D. The use of guideline-directed medical therapy (GDMT) was high (76-90%). HFrEF patients presented lower age [mean (SD): 73.8 (12.4) vs. 76.7 (11.6) years, P < 0.05], higher incidence of coronary artery disease (67% vs. 59%, P < 0.05), lower systolic blood pressure [mean (SD): 123 (22.6) vs. 133 (24.0) mmHg, P < 0.05], higher N-terminal pro-hormone brain natriuretic peptide (2720 vs. 1920 pg/mL, P < 0.05), and lower estimated glomerular filtration rate [mean (SD): 51.4 (23.3) vs. 54.1 (22.3) mL/min/1.73 m2 , P < 0.05] than those with HFmrEF. No differences in T2D and CKD were detected. Despite optimal treatment, event rates for the composite endpoint of HF readmission and mortality were 13.7 and 8.4/100 patient years. The presence of T2D and CKD negatively impacted all-cause mortality [T2D: hazard ratio (HR) = 1.49, P < 0.01; CKD: HR = 2.05, P < 0.001] and hospital readmission events in all patients with HF. Eligibility for SGLT2is dapagliflozin and empagliflozin was 86.5% (n = 1153) and 97.9% (n = 1305) of the study population, respectively. CONCLUSIONS: This study identified high residual risk for all-cause mortality and hospital readmission in real-world HF patients with LVEF < 50% despite GDMT. T2D and CKD aggravated the risk for these endpoints, indicating the intertwinement of HF with CKD and T2D. SGLT2i treatment that clinically benefits these different disease conditions can be an important driver to lower mortality and hospitalizations in this HF population.

A Phase I Study of Pelabresib (CPI-0610), a Small-Molecule Inhibitor of BET Proteins, in Patients with Relapsed or Refractory Lymphoma.

Purpose: NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883). Experimental Design: Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule. Results: The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease. Conclusions/Discussion: Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily. Significance: BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis.

Safety and Efficacy of a DNA Oligonucleotide Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: PNT2258 is a liposomal formulation that encapsulates multiple copies of PNT100, a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the B-cell lymphoma 2 (BCL2) gene. METHODS: This phase II, multicenter, single-arm, open-label, 2-stage design study investigated the single-agent activity of PNT2258 in patients with relapsed/refractory DLBCL. Initially, patients had to have a performance status (PS) of ≤2 and prior exposure to CD20-targeted therapy, an alkylating agent, and a steroid with no upper limit. Criteria were modified to PS of 0 or 1 and at least 1 to ≤3 prior therapies (identified as the target population) after observing an initially high frequency of rapid disease progression in patients with extensive prior therapies or poor PS. RESULTS: The study was stopped early following an interim analysis, despite surpassing the protocol predetermined futility boundary, because the ORR was below the expectations of response in an evolving DLBCL treatment landscape. The final analysis included all 45 enrolled patients and demonstrated an ORR of 11%. In the response evaluable subset (n = 26), defined as patients in the target population with exposure to ≥8 doses of PNT2258 within the first 35 days and evaluable baseline/post-baseline scans, the ORR was 19%. The most common adverse events were fatigue (44%), nausea (42%), diarrhea (40%), pyrexia (36%), anemia (32%), and vomiting (27%). CONCLUSIONS: PNT2258 was well-tolerated in a chemotherapy refractory DLBCL population. Despite demonstration of single-agent activity, ORR was lower than acceptable for further new therapy development.