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).

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.

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

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.

The in- and out-of-hospital management of HF patients: results from a nationwide Belgian survey.

BACKGROUND: We conducted a nationwide survey to describe the in-and out-of-hospital flow (diagnosis, treatment and follow-up) of patients with heart failure with reduced ejection fraction (HFrEF). METHOD: A survey was developed with five dedicated HF cardiologists. The data are all self-reported by cardiologists. RESULTS: The response rate was 84%. Presence of a dedicated HF cardiologist or HF nurse was indicated by 49% and 46% of the hospitals respectively. Devices (p < .05), angiotensin receptor neprilysin inhibitors, and rehabilitation are considered more standard of care therapy by dedicated compared to non-dedicated HF cardiologists. Most cardiologists indicated that target dosages of HF drugs can be reached in 25‒75% of patients. Achieving >75% of the target dose seems easier for angiotensin converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB) (22%) and mineralocorticoid receptor antagonists (25%), compared to ß-blockers (10%) and angiotensin receptor neprilysin inhibitors (7%). 62%, 49% and 4% of the cardiologists indicated to use subtypes of angiotensin converting enzyme inhibitors, angiotensin receptor blockers and ß-blockers respectively not validated in the HF population. In the acute setting, dedicated HF cardiologists (23%) are less influenced by blood parameters for decongestion compared to non-dedicated HF cardiologists (39%). They tend to change patients more to guideline-recommended drugs (60% vs 47%). Six minutes walk test and ergospirometry are significantly more used by dedicated compared to non-dedicated HF cardiologists for HF drug change (17% and 29% vs 2% and 4%). CONCLUSION: This survey showed that a minority of hospitals have HF care. Those that do, report a higher implementation of guideline-recommended diagnosis, treatment and follow-up of HF patients. Competent authorities could use this survey as a tool to improve HF care.

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.

Diagnosis, treatment, and follow-up of heart failure patients by general practitioners: A Delphi consensus statement.

AIMS: Creation of an algorithm that includes the most important parameters (history, clinical parameters, and anamnesis) that can be linked to heart failure, helping general practitioners in recognizing heart failure in an early stage and in a better follow-up of the patients. METHODS AND RESULTS: The algorithm was created using a consensus-based Delphi panel technique with fifteen general practitioners and seven cardiologists from Belgium. The method comprises three iterations with general statements on diagnosis, referral and treatment, and follow-up. Consensus was obtained for the majority of statements related to diagnosis, referral, and follow-up, whereas a lack of consensus was seen for treatment statements. Based on the statements with good and perfect consensus, an algorithm for general practitioners was assembled, helping them in diagnoses and follow-up of heart failure patients. The diagnosis should be based on three essential pillars, i.e. medical history, anamnesis and clinical examination. In case of suspected heart failure, blood analysis, including the measurement of NT-proBNP levels, can already be performed by the general practitioner followed by referral to the cardiologist who is then responsible for proper diagnosis and initiation of treatment. Afterwards, a multidisciplinary health care process between the cardiologist and the general practitioner is crucial with an important role for the general practitioner who has a key role in the up-titration of heart failure medication, down-titration of the dose of diuretics and to assure drug compliance. CONCLUSIONS: Based on the consensus levels of statements in a Delphi panel setting, an algorithm is created to help general practitioners in the diagnosis and follow-up of heart failure patients.

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.

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.

Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience.

Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

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.

Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial.

BACKGROUND: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting. METHODS: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412. FINDINGS: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary. INTERPRETATION: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center. FUNDING: National Institutes of Health.

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.

Effectiveness and Tolerability of Vildagliptin and the Single Pill Combination of Vildagliptin and Metformin in "Real-World" Management of Type 2 Diabetes Mellitus: The G-FORCE Study.

INTRODUCTION: Randomized clinical trials showed that vildagliptin is well tolerated and leads to clinically meaningful decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) both in monotherapy and as add-on therapy in inadequately controlled type 2 diabetes mellitus (T2DM) patients. Nevertheless, there is an increased interest for real-life studies to confirm the clinical trial findings in the setting of a daily clinical practice. The aim of this study was to evaluate the effectiveness and tolerability of vildagliptin in a real-life clinical setting and to explore factors determining drug adherence and T2DM management. METHODS: G-FORCE was a prospective, observational, open-label, multi-center study in which T2DM patients were prescribed de novo vildagliptin. Clinical effectiveness was determined by changes in HbA1c and FPG and by the proportion of patients reaching glycemic goal. Data were collected at baseline, after 105 ± 15 days and after 180 ± 15 days. RESULTS: A total of 1230 patients were included in this analysis. Mean age was 63.9 ± 10.8 years, and mean HbA1c and FPG levels were 8.2 ± 1.3% and 171.0 ± 53.3 mg/dL, respectively. At 180 days of treatment, HbA1c and FPG levels decreased to 7.2 ± 1.0% and 141.1 ± 44.0 mg/dL, respectively, while the proportion of patients reaching HbA1c and FPG goals rose from 8.6 to 44.6% and from 14.2 to 42.8%, respectively. CONCLUSION: In this real-world study, vildagliptin was an effective and safe treatment for T2DM patients already treated with metformin, while the single pill combination of vildagliptin and metformin provides a convenient alternative while ensuring comparable effectiveness and tolerability. FUNDING: Novartis Pharma.

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.

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.

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.