Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

RWD-derived response in multiple myeloma.

Real-world data (RWD) are important for understanding the treatment course and response patterns of patients with multiple myeloma. This exploratory pilot study establishes a way to reliably assess response from incomplete laboratory measurements captured in RWD. A rule-based algorithm, adapted from International Myeloma Working Group response criteria, was used to derive response using RWD. This derived response (dR) algorithm was assessed using data from the phase III BELLINI trial, comparing the number of responders and non-responders assigned by independent review committee (IRC) versus the dR algorithm. To simulate a real-world scenario with missing data, a sensitivity analysis was conducted whereby available laboratory measurements in the dataset were artificially reduced. Associations between dR and overall survival were evaluated at 1) individual level and 2) treatment level in a real-world patient cohort obtained from a nationwide electronic health record-derived de-identified database. The algorithm's assignment of responders was highly concordant with that of the IRC (Cohen's Kappa 0.83) using the BELLINI data. The dR replicated the differences in overall response rate between the intervention and placebo arms reported in the trial (odds ratio 2.1 vs. 2.3 for IRC vs. dR assessment, respectively). Simulation of missing data in the sensitivity analysis (-50% of available laboratory measurements and -75% of urine monoclonal protein measurements) resulted in a minor reduction in the algorithm's accuracy (Cohen's Kappa 0.75). In the RWD cohort, dR was significantly associated with overall survival at all landmark times (hazard ratios 0.80-0.81, p<0.001) at the individual level, while the overall association was R2 = 0.67 (p<0.001) at the treatment level. This exploratory pilot study demonstrates the feasibility of deriving accurate response from RWD. With further confirmation in independent cohorts, the dR has the potential to be used as an endpoint in real-world studies and as a comparator in single-arm clinical trials.

The Impact of a Lockdown for the COVID-19 Pandemic on Seasonal HbA1c Variation in Patients with Type 2 Diabetes.

Glycemic control in patients with type 2 diabetes may be disrupted due to restricted medical service access and lifestyle changes during COVID-19 lockdown period. This retrospective cohort study examined changes of HbA1c levels in adults with type 2 diabetes 12 weeks before and after May 19 in 2021, the date that COVID-19 lockdown began in Taiwan. The mean levels of HbA1c-after were significantly lower than HbA1c-before in 2019 (7.27 ± 1.27% vs 7.43 ± 1.38%, p < 0.001), 2020 (7.27 ± 1.28% vs 7.37 ± 1.34%, p < 0.001), and 2021 (7.03 ± 1.22% vs 7.17 ± 1.29%, p < 0.001). Considering the seasonal variation of HbA1c, ΔHbA1c values (HbA1c-after minus HbA1c-before) in 2020 (with sporadic COVID-19 cases and no lockdown) were not significantly different from 2021 (regression coefficient [95% CI] = 0.01% [-0.02%, 0.03%]), while seasonal HbA1c variation in 2019 (no COVID-19) was significantly more obvious than in 2021 (-0.05% [-0.07, -0.02%]). In conclusion, HbA1c level did not deteriorate after a lockdown measure during the COVID-19 pandemic in Taiwan. However, the absolute seasonal reduction in HbA1c was slightly less during the COVID-19 pandemic compared with the year without COVID-19.

Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.

Simultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma.

Background: In patients with multiple myeloma, thrombotic microangiopathy is a rare adverse event associated with proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib. Case Presentation: Two patients with multiple myeloma who presented with carfilzomib-induced thrombotic microangiopathy received eculizumab with subsequent stabilization of renal function. Conclusions: Given the overall rarity of this adverse event, the simultaneous presentation of these 2 cases was unexpected. These cases underscores the need for heightened awareness in clinical practice of thrombotic microangiopathy. The potential role of eculizumab as a therapeutic treatment in the setting of thrombotic microangiopathy requires further investigation.

Treatment patterns and outcomes according to cytogenetic risk stratification in patients with multiple myeloma: a real-world analysis.

A clearer understanding of the prognostic implications of t(11;14) in multiple myeloma (MM) is needed to inform current and future therapeutic options. We utilized real-world data from a US database to examine treatment patterns and outcomes in patients by t(11;14) status compared with high- and standard-risk subgroups across different lines of therapy (LoT). This retrospective, observational cohort study used de-identified patient-level information from adults with MM and first-line treatment initiation between January 2011 and January 2020, followed until February 2020. The high-risk cohort comprised patients with high-risk genetic abnormalities per mSMART criteria (including those with co-occurring t(11;14)). Among 6138 eligible patients, 6137, 3160, and 1654 received first-, second-, and third-line treatments, respectively. Of 645 patients who had t(11;14), 69.1% had t(11;14) alone, while 30.9% had co-occurring high-risk abnormalities. Altogether, 1624 and 2544 patients were classified as high- and standard-risk, respectively. In the absence of biomarker-driven therapy, treatment patterns remain similar across LoT in high-risk, t(11;14)+, and standard-risk subgroups. Across all LoT, patient outcomes in the high-risk subgroup were less favorable than those in the t(11;14)+ and standard-risk subgroups. Thus, there is an opportunity for novel therapeutics targeted to t(11;14) and other defined subgroups to personalize MM therapy and optimize patient outcomes.

Combination of Atezolizumab and Tazemetostat in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results From a Phase Ib Study.

BACKGROUND: The combination of atezolizumab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, and tazemetostat, an EZH2 inhibitor, may lead to selective epigenetic reprogramming, alter the tumor microenvironment, and provide additive or synergistic response to patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: This was an open-label, phase Ib study assessing the safety, tolerability, and preliminary efficacy of atezolizumab plustazemetostat in patients with R/R DLBCL. Atezolizumab (1200 mg) was administered via intravenous (IV) infusion on day 1 of each cycle and tazemetostat (800 mg) was given orally twice daily (BID) on days 1 to 21. Primary endpoints were safety and tolerability, and to identify a recommended phase II dose (RP2D) for atezolizumab. Secondary efficacy endpoints included response rate and duration of response. RESULTS: A total of 43 patients were enrolled, receiving a median of 3 prior lines of treatment (range: 1-9). The RP2D for atezolizumab was 1200 mg IV infusion every 3 weeks in combination with tazemetostat 800 mg BID. At the RP2D, adverse events reported in ≥20% patients were anemia(11 patients [26%]), fatigue (10 patients [23%]), and nausea (10 patients [23%]). Overall response rate was 16% (complete response rate: 7%). Median progression-free survival was 2 months (range: 0-24) and median overall survival was 13 months (range: 1-29). CONCLUSIONS: The combination of atezolizumab and tazemetostat was determined to be safe and tolerable. However, anti-tumor activity of the combination was modest.

Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study.

BACKGROUND: This was an open-label, phase 1b study assessing the safety, tolerability, preliminary efficacy and pharmacokinetics of the combination of atezolizumab and obinutuzumab in patients with relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). There is a mechanistic rationale suggesting that this combination may enhance recruitment of both innate and adaptive immunity and be effective against CD20+ B-cell malignancies. MATERIALS AND METHODS: The study consisted of a safety evaluation stage and an expansion stage. Patients received obinutuzumab 1000 mg intravenously (IV) in cycle (C) 1, obinutuzumab plus atezolizumab 1200 mg IV for C2-8, and atezolizumab only from C9. Primary endpoints were to identify a recommended phase 2 dose (RP2D) for atezolizumab, and safety and tolerability in the safety and expansion stages. RESULTS: A total of 49 patients were enrolled (FL, n = 26; DLBCL, n = 23), with a median of 2 prior lines of treatment. The RP2D for atezolizumab was 1200 mg IV every 3 weeks. Adverse events reported in ≥ 20% of patients were fatigue (15 patients [31%]), nausea (13 patients [27%]), cough, and diarrhea (10 patients [20%] each). Objective response rate was 54% in the FL cohort (complete response [CR] rate: 23%) and 17% in the DLBCL cohort (CR: 4%). Median progression-free survival was 9 months for FL and 3 months for DLBCL. Median overall survival was not estimable for FL and 9 months for DLBCL. CONCLUSION: The combination of obinutuzumab and atezolizumab was determined to be safe and tolerable, with no new toxicities observed.

NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.

Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines. SIGNIFICANCE: CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies.See related commentary by Velasquez and Gottschalk, p. 559. This article is highlighted in the In This Issue feature, p. 549.

Bilateral widespread segmental swelling on nerve sonography in multifocal acquired demyelinating sensory and motor neuropathy: Two case reports.

INTRODUCTION: Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) is an asymmetric immune-related neuropathy with conduction block. We report 2 MADSAM cases with detailed clinical, electrophysiological, and sonography profiles. PATIENT CONCERNS AND DIAGNOSIS: Two cases presented with patchy sensorimotor impairment in both clinical and electrophysiological findings. Notably, nerve ultrasound demonstrated multifocal nerve enlargement not only at sites of conduction blockade but also at the unaffected contralateral sites. Interestingly, in our first case, focal radial nerve enlargement was observed prior to the clinical manifestations, suggesting nerve dynamic pathogenesis with variable clinical significance. INTERVENTIONS AND OUTCOMES: The first patient was initially treated with prednisolone, however, 3 months after steroid therapy, her symptoms progressed. After treatment with intravenous immunoglobulin for 3 months, the symptoms stabilized. The second patient showed improvement after 2 months of prednisolone treatment. CONCLUSION: These observations suggest a more widespread pathomechanism underlying MADSAM, and ultrasound may detect nerve lesions earlier than clinical electrophysiology studies, and is warranted for early detection and thorough documentation of nerve pathology.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Front-line treatment patterns in multiple myeloma: An analysis of U.S.-based electronic health records from 2011 to 2019.

Multiple myeloma (MM) treatment options have evolved rapidly, but how new agents are incorporated into treatment decisions in current practice is not well understood. This study examined prescribing trends of physicians treating newly diagnosed MM and treatment outcomes in the United States. Electronic health record data from 6271 adult patients diagnosed with MM and receiving initial treatment between 1 January 2011 and 31 January 2020 were derived from the Flatiron Health electronic-health record de-identified database. The number/types of agents included in therapy regimens, time to next treatment (TTNT), and overall survival (OS) were assessed. Subgroups were analyzed by the International Staging System (ISS) disease stage at diagnosis, stem cell transplant eligibility and timing, and practice type. Exploratory prognostic models evaluated the association between baseline covariates and time-to-event outcomes. The proportion of patients receiving triplet therapies increased from 2011 (36%) to 2019 (72%) as those receiving initial monotherapy or doublet therapy decreased. Overall, the most prevalent triplet regimen consisted of an immunomodulatory drug (IMiD), a proteasome inhibitor, and a steroid. From 2017 to 2019, median TTNT from front-line to second-line was longer in patients with ISS stage I versus stages II/III, and in those receiving IMiD-containing doublet or triplet therapies versus other combinations. Overall median OS was 56 months and increased from 2011 to 2014, after which median OS was not yet reached. Age, ISS stage, and high-risk status were prognostic for both OS and TTNT, while sex, practice type, and ECOG status were prognostic for OS only.

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings.

BACKGROUND: Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities. METHODS: In this phase 1/2 study (NCT02265731), Japanese patients (≥60 years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400 mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 per 28-day cycle until disease progression or unacceptable toxicity. RESULTS: As of 10 December 2019, six patients were enrolled (median age: 75 years; untreated: n = 5; relapsed/refractory: n = 1); median treatment duration: 10.3 months (range, 0.7-29.4). Most common grade ≥ 3 adverse events were lymphopaenia and febrile neutropaenia (n = 4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n = 3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0 month (range, 0.8-5.5); median overall survival: 15.7 months (95% confidence interval: 6.2, not reached). CONCLUSIONS: Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.

The importance of social media to the academic surgical literature: Relationship between Twitter activity and readership metrics.

BACKGROUND: Social media has an increasing role within professional surgical practice, including the publishing and engagement of academic literature. This study aims to analyze the relationship between social media use and traditional and alternative metrics among academic surgical journals. METHOD: Journals were identified through the InCites Journal Citation Reports 2019, and their impact factor, h-index, and CiteScore were noted. Social media platforms were examined, and Twitter activity interrogated between 1 January to 31 December 2019. Healthcare Social Graph score and an aggregated Altmetric Attention Score were also calculated for each journal. Statistical analysis was carried out to look at the correlation between traditional metrics, Twitter activity, and altmetrics. RESULTS: Journals with a higher impact factor were more likely to use a greater number of social media platforms (R2 = 0.648; P < .0001). Journals with dedicated Twitter profiles had a higher impact factor than journals without (median, 2.96 vs 1.88; Mann-Whitney U = 390; P < .001); however, over a 1-year period (2018-2019) having a Twitter presence did not alter impact factor (Mann-Whitney U = 744.5; P = .885). Increased Twitter activity was positively correlated with impact factor. Longitudinal analysis over 6 years suggested cumulative tweets correlated with an increased impact factor (R2 = 0.324, P = .004). Novel alternative measures including Healthcare Social Graph score (R2 = 0.472, P = .005) and Altmetric Attention Score (R2 = 0.779, P = .001) positively correlated with impact factor. CONCLUSION: Higher impact factor is associated with social media presence and activity, particularly on Twitter, with long-term activity being of particular importance. Modern alternative metrics correlate with impact factor. This relationship is complex, and future studies should look to understand this further.

Glycemic benefits with adherence to testosterone therapy in men with hypogonadism and type 2 diabetes mellitus.

BACKGROUND: While previous studies have demonstrated testosterone's beneficial effects on glycemic control in men with hypogonadism and Type 2 Diabetes, the extent to which these improvements are observed based on the degree of treatment adherence has been unclear. OBJECTIVES: To evaluate the effects of long-term testosterone therapy in A1C levels in men with Type 2 Diabetes Mellitus and hypogonadism, controlling for BMI, pre-treatment A1C, and age among different testosterone therapy adherence groups. MATERIALS AND METHODS: We performed a retrospective analysis of 1737 men with diabetes and hypogonadism on testosterone therapy for 5 years of data from 2008-2018, isolating A1C, lipid panels, and BMI results for analysis. Subjects were categorized into adherence groups based on quartiles of the proportion of days covered (> 75% of days, 51-75% of days, 26-50% of days and 0-25% of days), with >75% of days covered considered adherent to therapy. RESULTS: Pre-treatment median A1C was 6.8%. Post-treatment median A1C was 7.1%. The adherent group, >75%, was the only group notable for a decrease in A1C, with a median decrease of -0.2 (p = 0.0022). BMI improvement was associated with improved post-treatment A1C (p = 0.007). When controlling for BMI, age, and pre-treatment A1C, the >75% adherence group was associated with improved post-treatment A1C (p < 0.001). DISCUSSION: When controlling for all studied variables, testosterone adherence was associated with improved post-treatment A1C. The higher the initial A1C at the initiation of therapy, the higher the potential for lowering the patient's A1C with >75% adherence. Further, all groups showed some reduction in BMI, which may indicate that testosterone therapy may affect A1C independent of weight loss. CONCLUSION: Even when controlling for improved BMI, pre-treatment A1C, and age, testosterone positively impacted glycemic control in diabetes patients with hypogonadism, with the most benefit noted in those most adherent to therapy (>75%).

Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma.

Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open-label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21-day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL-2) and BCL2L1 (BCL-XL ) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R MM.

Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study.

This analysis represents the longest-term follow-up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open-label, non-randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA; 75 mg/m2 ; days 1-7) or decitabine (DEC; 20 mg/m2 ; days 1-5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi]), response duration and overall survival (OS). The median follow-up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.

Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. FINDINGS: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. INTERPRETATION: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. FUNDING: AbbVie and Genentech.