Time Of Study Entry Research Articles

A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), a Novel Inhibitor of Aurora Kinase a, in Myelofibrosis

Background: Primary/Post-Essential/Post-Polycythemic Myelofibrosis (MF) is characterized by impaired maturation of GATA1 deficient megakaryocytes, which we hypothesize directly contribute to disease. (J Clin Invest 2017). The selective AURKA inhibitor alisertib (MLN8237) was shown to promote megakaryocytic maturation, amelioration of bone marrow fibrosis and lessen disease in animal models (Nat Med 2015).Methods: In an investigator sponsored multi-center pilot study (clinical trials.gov Identifier NCT 02530619), alisertib was administered to MF patients with at least DIPSS intermediate 1 risk who were in need of treatment, and were intolerant/refractory to or unlikely to benefit from JAK inhibitor therapy. Eligibility criteria also included an absolute neutrophil count ≥ 1 x109/L and platelet count ≥ 50 x109/L. Alisertib was provided by Takeda and administered at a dose of 50 mg by mouth twice daily for 7 days every three weeks. Adverse events (AEs) were monitored by common terminology criteria (Version 4.0). Laboratory correlative studies included assessment of the effects of alisertib and ruxolitinib on diagnostic samples and evaluation of changes in megakaryocytes and GATA1 expression in the bone marrow with therapy.Results:i) Patient characteristicsAs of June 2017, 19 patients (63% males; median age 72 years) have been enrolled, including 68% primary MF and 32% post PV/ET MF; 26% were DIPSS high and 74% intermediate-risk.11 (89%) patients had abnormal karyotype, including 7(64%) with unfavorable risk. Driver mutational frequencies were JAK2 58%, CALR 32%, and MPL 10%. Prior treatments included JAK inhibitors in 68% of patients.13 (68%) patients remain on treatment (median number of cycles=4; range 1-16). Median follow up of patients that were alive was 5 months (range; 1-10 months).ii) Safety dataTreatment related grade 4 hematological AEs included neutropenia, lymphopenia and thrombocytopenia seen in one patient each (5%). Grade 3 related hematological AEs included lymphopenia (n=4; 21%), anemia (n=3, 16%), febrile neutropenia (n=2, 11%), thrombocytopenia (n=1; 5%). The incidence of grade 3 related non- hematological AEs was as follows- vertigo (n=1; 5%), diarrhea (n=1; 5%); elevated lipase, alanine aminotransferase, and creatinine in one patient (5%) each. There was one unrelated grade 5 event -pneumonia with renal failure.iii)Preliminary efficacy dataa) Spleen response : 11(58%) patients had palpable splenomegaly ≥ 5 cm at time of study entry; 3 (27%) achieved ≥ 50% reduction in palpable spleen size.b) Erythroid response: 8 (62%) patients were transfusion dependent at baseline, of which none achieved transfusion independence. One patient displayed a durable rise in hemoglobin of ≥ 1g/dl.c) Leukocytosis/Thrombocytosis/Leukoerythroblastosis/LDH responses: 6 (32%) patients presented with leukocytosis and all (100%) had resolution of leukocytosis with treatment. Two patients (11%) had baseline thrombocytosis and both displayed ≥ 50% reduction in platelet count. Ten patients (53%) demonstrated leukoerythroblastosis and 2 (20%) displayed ≥ 50% improvement. All 19 patients had increased serum lactate dehydrogenase levels at time of study entry and 6 (32%) displayed ≥ 50% reduction with treatment.d) Symptom response: Of the 9 patients with constitutional symptoms at presentation, 5 (56%) reported improvement/resolution of symptoms. Moreover, 4 of 16 (25%) patients with at least moderate symptom burden achieved ≥ 50% reduction in the MF-SAF score.iv) Correlative studies: Alisertib, but not ruxolitinib, robustly promoted polyploidization and apoptosis of megakaryocytes derived from patient CD34+ cells at diagnosis. Morphological analysis of bone marrow revealed that alisertib led to improved megakaryocyte morphology and restoration of GATA1 staining (Figure 1).Conclusions: In this study we have reproduced, in the setting of a clinical trial, our previous preclinical observations that alisertib appears to normalize megakaryopoiesis in the MPNs. The reduction in peripheral counts is consistent with studies that suggest atypical MF megakaryocytes promote expansion of leukocytes. Although Alisertib had limited activity beyond demonstrated myelosuppressive activity in patients treated an average of four cycles, it was relatively safe. Updated results including overall response assessment and bone marrow review will be presented. [Display omitted] DisclosuresWatts:Jazz Pharmaceuticals: Consultancy, Speakers Bureau. Altman:Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Giles:Novartis: Consultancy, Research Funding.

Health-Related Quality of Life and Symptom Burden in Chronic Myeloid Leukemia Patients Treated with First Line with Imatinib Versus Those Treated with Dasatinib: First Results of the Leonidas Study

Health-Related Quality of Life and Symptom Burden in Chronic Myeloid Leukemia Patients Treated with First Line with Imatinib Versus Those Treated with Dasatinib: First Results of the Leonidas Study

Intra-patient dose escalation (IPDE) of ripretinib after disease progression in patients with advanced gastrointestinal stromal tumor (GIST): Analyses from the phase 3 INVICTUS study.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p <0.0001). In an earlier phase 1 dose escalation study, the maximum tolerated dose was not reached with doses up to 200 mg twice daily (BID). Here, we report efficacy, safety, and pharmacokinetic data for IPDE patients initially randomized to ripretinib from the phase 3 INVICTUS study based on data as of 10 Aug 2020. Methods: A total of 129 patients were randomized 2:1 to ripretinib 150 mg once daily (QD; n = 85) or placebo (n = 44). Patients receiving ripretinib 150 mg QD who had progressive disease (PD) as assessed by blinded independent central review (BICR) using mRECIST were given the option for IPDE to 150 mg BID. Tumor response assessments were performed every 28 days for 4 cycles and every 56 days thereafter (including after IPDE). The primary endpoint was PFS. For this exploratory analysis, PFS1 for IPDE patients was defined as the time from randomization to PD; PFS2 for IPDE patients was the time from the first dose of ripretinib 150 mg BID to PD or death. PFS1 and PFS2 were based on BICR. Results: Of 85 patients treated with ripretinib 150 mg QD, 43 patients with BICR PD dose escalated to 150 mg BID. Baseline characteristics of IPDE patients at time of study entry were similar to those observed in the original ripretinib QD arm and similar to the 22 patients with BICR PD who either remained on 150 mg QD or discontinued treatment. IPDE patients had a mPFS1 of 4.6 months (95% CI, 2.7–6.4) and a mPFS2 of 3.7 months (95% CI, 3.1–5.3); mPFS2/mPFS1=80%. The IPDE dosing period was well tolerated without the emergence of new safety concerns. The most common new or worsening (unchanged or improving grades not included) treatment-emergent adverse event (TEAE) for IPDE patients during the BID period was abdominal pain (30.2% all grades and 7% Grade 3–4 vs 41.9% and 4.7% in QD period, respectively). The most common Grade 3–4 TEAE in the BID period was anemia (14% vs 2.3% in QD period). IPDE from QD to BID resulted in an approximately 2-fold increase in the steady state trough concentration. Conclusions: Similar to the phase 1 study wherein IPDE to 150 mg BID following PD provided clinical benefit with a mPFS1 of 5.5 months and mPFS2 of 4.6 months (mPFS2/mPFS1=84%) for patients with ≥4th-line GIST, these analyses from INVICTUS indicate that IPDE to ripretinib 150 mg BID can also provide additional meaningful clinical benefit and a similar tolerability profile to the 150 mg QD regimen for patients with ≥4th-line GIST that progressed following treatment with ripretinib 150 mg QD. Clinical trial information: NCT03353753.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small cell lung cancer.

9009 Background: The effectiveness of circulating tumor DNA (ctDNA) at matching patients to life prolonging therapy has been studied mostly in small cohorts with limited follow up. The prognostic value of ctDNA alterations, particularly those absent on tissue, is also unclear. To address these questions, we studied survival outcomes in a prospective cohort of patients (N = 1002) with non-small cell lung cancer (NSCLC). Methods: Adults with metastatic or recurrent NSCLC were eligible if they had no known driver mutation or a known driver with progression following targeted therapy. Patients were enrolled at Memorial Sloan Kettering Cancer Center (New York, NY) starting October 21, 2016; analysis here is from a snapshot November 1, 2020. All patients had ctDNA sequenced via the Resolution ctDx Lung platform. To reduce inclusion of incidental germline mutations, we excluded non-functionally significant mutations with an allele frequency 35-65% that were present in gnomAD. Patients could also receive, at their provider’s discretion, tissue sequencing with MSK-IMPACT, which filters germline and clonal hematopoietic (CH) mutations with matched white blood cell sequencing. We performed survival analyses using Cox proportional hazards models from time of diagnosis of advanced disease to death, left truncating at time of study entry. Results: Of 1002 patients, 348 (35%) were treated with targeted therapy; in 181 of these (52%) the targetable alteration was detected in ctDNA. Patients treated with targeted therapy had prolonged survival whether matched by tissue-based methods (HR 0.39, 95%CI 0.30-0.51) or ctDNA (HR 0.47, 95%CI 0.37-0.61). These benefits persisted across multiple subgroups. ctDNA alterations themselves were associated with worse survival (HR 2.2, 95%CI 1.8-2.8), in a manner that scaled with allele fraction and burden. Of 401 patients with time-matched tissue sampling, 62 (15%) had ctDNA alterations that were absent on IMPACT (“unique” ctDNA alterations). Three such patients had unique ctDNA EGFR T790M mutations leading to changes in therapy. However, unique ctDNA alterations were generally associated with worse survival than no ctDNA alterations (HR 2.5, 95%CI 1.7-3.7) and even tissue-matched ctDNA alterations (HR 1.7, 95%CI 1.1-2.4). Of 98 unique ctDNA mutations, 48 (49%) were detectable in tissue at subthreshold levels, 12 (12%) were filtered by IMPACT as CH or germline, and 38 mutations (39%) were absent even at subthreshold levels. ctDNA alteration burden correlated with radiographic disease extent. In multivariate models with radiographic disease extent and other clinical variables, ctDNA alterations were the strongest independent predictor of worse survival. Conclusions: Our results show that ctDNA may match patients to life-prolonging targeted therapy and have prognostic importance. ctDNA may provide data about a patient’s cancer missed by spatially restricted tissue sequencing. Clinical trial information: NCT01775072.

Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST).

3073 Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (>5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]

The Longitudinal Effects of Moderate Alcohol Use on Mood and Cognition in Late Life Depression

<h3>Introduction</h3> Alcohol use disorder interferes with antidepressant treatment in older adults with major depression (LLD) and is associated with suicidal ideation. Less is known about the effects of moderate alcohol use in LLD on mood and cognitive outcomes over time. Much of the evidence on alcohol use and cognition and mood stems from epidemiological research and not clinical studies of depressed older adults. The purported benefits of moderate alcohol use on older adults' cognitive functioning have often been reported. Yet, not all studies report a positive association between moderate alcohol use and cognitive functioning, and there is also other evidence to suggest moderate alcohol use is correlated with markers of poorer brain health in older adults (e.g., atrophy). In respect to mood, epidemiological research suggests little to no association between moderate alcohol use and depression in older adults or even an inverse association with increased social interactions as a mediator. Given the times at conflicting evidence and the lack of longitudinal studies in well-defined clinical samples, we hypothesized that depressed older adults who were moderate drinkers would experience greater cognitive decline compared to depressed non-drinkers. We also hypothesized that moderate alcohol use would have a detrimental effect on depression illness course in older adults with LLD. <h3>Methods</h3> This study used data from Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. NCODE participants underwent annual neuropsychological evaluations with the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) cognitive battery as well as other tests of executive functioning and processing speed (e.g., Trail Making Test). Participants also underwent annual depression severity ratings with a geriatric psychiatrist using the Montgomery Asberg Depression Rating Scale (MADRS). We used patients self-reported alcohol use at the time of study entry and characterized them as either abstainers (n=81) and moderate drinkers (n=30). We were also able to define a small sample of risky drinkers (n=10) and included this group for exploratory reasons. Alcohol use was based upon NIAAA guidelines for older adult alcohol consumption. Risky alcohol use exceeded NIAAA alcohol consumption guidelines for older adults (meaning >=3 drinks per day or >=8 drinks per week) and moderate alcohol use was defined as <= 2 drinks per day or <=7 drinkers per week). We used mixed linear modeling to investigate change in depression and cognition among groups over time. These analyses included NCODE subjects who were followed for up to 5 years and adjusted for relevant demographics. <h3>Results</h3> In terms of cognition, we found that the total CERAD score of moderate and heavy drinkers significantly declined compared to no alcohol use patients (e.g.,moderate alcohol use x time interaction term estimate = -.00410, DF = 898, t = -5.02, <i>p</i> < .001) . We also found significant declines in Trails A performance among moderate alcohol users compared to the other groups. The MADRS score of moderate alcohol users was also found to decrease at a significantly higher rate compared to other patient groups. <h3>Conclusions</h3> Moderate alcohol consumption appears to have a beneficial impact on depression severity and a detrimental impact on cognitive functioning in LLD patients followed for upwards of five years. Larger samples are needed to confirm the findings in this small and exploratory study.

Influence of aspirin on prevention of colorectal cancer: an updated systematic review and meta-analysis of randomized controlled trials.

Colorectal cancer is the second most common cause of cancer death worldwide. Aspirin, due to its antineoplastic effects, has been suggested to have chemopreventive effects on colorectal cancer based on recent trials. We conducted this systematic review and meta-analysis to provide an updated evidence about the long-term efficacy of daily aspirin use in the prevention of colorectal cancer. We searched Medline/PubMed, Ovid, Web of Science, and Cochrane Library. We included randomized controlled trials (RCTs) that compared the efficacy of daily aspirin use to placebo in healthy individuals at the time of study entry. The desired outcomes of this review were the incidence of advanced lesions (i.e., adenomas with villous component, adenomas ≥1cm in diameter, adenomas with high-grade dysplasia, and/or invasive cancer) and colorectal adenomas. A total of 15 articles representing 11 RCTs were included. Overall, the results indicated that aspirin significantly reduced the risk of developing colorectal adenomas but not advanced lesions at 3years (risk ratio (RR) = 0.84, P < 0.05 and risk ratio = 0.82, P = 0.10, respectively). At 5years, the risk of advanced lesions but not adenomas was reduced by aspirin (RR = 0.68, P < 0.05 and RR = 0.87, P = 0.22, respectively). Aspirin was not found to have an effect on the risk of advanced lesions or adenomas beyond 5years (hazard ratio (HR) = 0.82, P = 0.07 and HR = 0.99, P = 0.82, respectively). Overall, aspirin (particularly high dose) only reduced the risk of advanced lesions up to 5years.

Abstract PD12-06: Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial

Abstract Background: Cytotoxic chemotherapy (CT) in combination with trastuzumab and pertuzumab (HP) is standard of care for patients (pts) diagnosed with HER2-positive early breast cancer (EBC). While highly effective, the toxicity associated with CT is challenging. In KRISTINE/TRIO-021, neoadjuvant T-DM1 was combined with pertuzumab (KP) and compared to standard TCHP. Pts. received six cycles of neoadjuvant treatment followed by adjuvant therapy (KP or HP). Pts. in the KP arm were allowed to receive standard adjuvant CT. Pathologic complete response (pCR) rate was significantly lower with KP versus TCHP and more pts. had disease progression prior to surgery with KP, resulting in a meaningfully lower event-free survival rate vs. the control (85.3% vs 94.2%). However, 3-year invasive disease-free survival was numerically similar in both arms. Neoadjuvant KP demonstrated less toxicity than standard CT, although treatment discontinuation was higher post-surgery. Association of KP and TCHP with treatment-related amenorrhea (TRA) in premenopausal EBC pts. has not been ascertained. Methods: All pts. with premenopausal status at study entry (those not meeting the menopause definition based on National Comprehensive Cancer Network Guidelines v3, 2012) and with menstrual period documented within 3 months of randomization, were independently evaluated for presence or absence of TRA by two reviewers. TRA, a prespecified exploratory endpoint of KRISTINE, was defined as cessation of menstruation for &amp;gt;12 months in the absence of treatment with ovarian suppression or other interventions that can induce amenorrhea. Pts. were followed from the time of study entry through the 3-year follow up period after surgery. For cases with inconsistent determination between the two reviewers, a third reviewer adjudicated. TRA rates were calculated per arm, hormone-receptor (HR) status, adjuvant CT and age group. Proportions were compared by estimating the odds ratio (OR) and the 95% confidence interval. Results: Of 444 pts. enrolled, 205 were excluded based on being post-menopausal per NCCN guidelines. Of 239 pts. remaining, 56 were excluded due to insufficient data. The median age of pts. included was 40 years (range: 22-53) for TCHP and 42.5 (range: 23-52) for KP. TRA was observed in 55% (50/91) of pts. treated with TCHP compared to 30% (28/92) treated with KP (OR=2.79; 95% CI 1.52-5.12). In pts. with HR-positive EBC, TRA occurred in 62% with TCHP vs 35% for KP (OR=2.998; 95% CI 1.44-6.25). In those with HR-negative EBC, TRA was observed in 42% with TCHP vs. 21% with KP (OR=2.77; 95% CI 0.88-8.72). In the KP arm, TRA was observed in 38% (8/21) of pts. treated with standard adjuvant CT vs. 28% (20/71) of those that did not (OR 1.57; 95% CI 0.57-4.36). For women age ≤ 40, the rate of TRA was 38% with TCHP vs. 17% with KP (OR=3.00; 95% CI 1.05-8.60). For those &amp;gt; 40 years, TRA was observed in 74% treated with TCHP vs. 39% of those with KP (OR=4.50; 95% CI 1.88-10.73). Conclusion: The rate of TRA with standard TCHP is nearly double that observed with KP, suggesting that targeted CT with an antibody-drug conjugate regimen is associated with less gonadal toxicity. Rates of TRA are higher in women over the age of 40 for each treatment arm however KP is associated with lower rate of TRA in each age group. Association of TRA with efficacy outcomes (pCR, iDFS) will be presented. Citation Format: Sara A Hurvitz, Rodrigo Fresco, Karen Afenjar, Daniil Stroyakovskiy, Chiun-Sheng Huang, Hans Wildiers, Kyung Hae Jung, Jean-François Boileau, Mario Campone, Miguel Martín, Vicente Valero, Joseph A. Sparano, W. Fraser Symmans, Peter A. Fasching, Alastair M. Thompson, Nadia Harbeck, Vanesa López-Valverde, Chunyan Song, Thomas Boulet, Eleonora Restuccia, Dennis J. Slamon. Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-06.

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma

Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. We performed a dual center single-arm Phase II study to expand on the safety and efficacy of Evo plus bevacizumab in bevacizumab refractory glioblastoma. 33 patients with bevacizumab refractory GBM received Evo 670 mg/m2 in combination with Bevacizumab 10 mg/kg IV every 2 weeks. Assessments included adverse events, response, and survival. Median age of patients was 47 (range 19–76) and 24 (69%) were male. At the time of study entry, 9 (26%) had ongoing corticosteroid use. ECOG performance status was 0 or 1 in 83% of patients. Patients were mostly heavily pretreated with 77% have three or more prior regimens. A total of 12 patients (36%) suffered grade 3–4 drug associated adverse event (AE); no grade 5 AE were reported. Of the 33 evaluable patients, best response was PR in 3 (9%), SD in 14 (43%), and PD in 16 (48%) with responses confirmed by a second reviewer. Median time to progression of disease was 53 days (95% CI 42–113) and Median time to death was 129 days (95% CI 86–199 days). Progression free survival at 4 months (PFS-4) on Evo-Bev was 31%, which was a statistically significant improvement over the historical rate of 3%. The median overall survival of patients receiving Evo-Bevacizumab was 4.6 months (95% CI 2.9–6.6). The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation.

The Association of Clinical Characteristics and Lifestyle Habits with Poor Glycemic Control in Patients with Type 2 Diabetes Mellitus

Background: The goal of this paper is to explore clinical characteristics and lifestyle habits in patients with type 2 diabetes mellitus and their association with poor glycemic control.&#x0D; Material and Methods: Total of 541 subjects of over 40 years of age with type 2 diabetes mellitus of both genders were included in the study. Anthropometric measurement, glucose level in plasma, HbA1c, triglycerides, AST, ALT, creatinine and eGFR were collected at the time of study entry and patients were asked to fill out the questionnaire on lifestyle habits.&#x0D; Results: Patients with elevated triglyceride and LDL cholesterol levels, alcohol consumers and smokers were more likely to have poorly controlled glycaemia.&#x0D; Conclusions: Our study showed a significant impact of patient characteristics to poor glycemic control. Physician activities to reduce cholesterol, triglyceride levels and improve lifestyle habits in patients with type 2 diabetes mellitus will result in better glycemic control.

A Prospective Trial of Radiation Therapy Efficacy and Toxicity for Localized Mucosa-associated Lymphoid Tissue (MALT) Lymphoma

We report the long-term results of a prospective trial conducted to determine the efficacy and safety of radiation therapy (RT) alone in treating localized mucosa-associated lymphoid tissue (MALT) lymphoma. Patients with localized MALT lymphoma were eligible and treated with involved field RT to doses of 24 to 39.6 Gy. Relapse-free survival (RFS) was the primary endpoint. Kaplan-Meier analysis was used to estimate RFS, progression-free survival (PFS), and overall survival (OS) defined from time of study entry. Preplanned subgroup analyses were performed based on site of involvement. From 2000 to 2012, 75 patients were accrued; 73 received protocol-specified RT. Median follow-up was 9.8 years. Thirty-four patients had gastric MALT, 17 orbital, 13 head and neck nonorbit, 4 skin, and 5 disease of other sites. Thirteen of 34 patients with gastric MALT were Helicobacter pylori positive at the time of initial diagnosis and underwent 1 to 3 courses of triple antibiotic therapy. All gastric MALT patients had documented persistent MALT without H. pylori on endoscopy before enrollment in the study. All patients achieved a complete response with a median time of 3 months. Eleven patients (15%) had disease relapse, 9 of which were at sites outside the RT field with median time to progression of 38.3 months. Median PFS was 17.5 years, and median RFS and OS were not reached. The 10-year relapse-free rate was 83% (95% confidence interval [CI], 74%-93%). The 10-year PFS rate was 71% (95% CI, 60%-84%). The 10-year OS rate was 86% (95% CI, 77%-96%). RFS, PFS, and OS did not differ by disease site (P = .17, .43, and .50, respectively). All relapses were successfully salvaged. One patient developed metastatic gastric adenocarcinoma and was found to also have recurrent MALT on biopsy. Otherwise, all relapsed patients were alive without evidence of disease at last follow-up, and no patient died of MALT lymphoma. Sixty-seven patients (92%) experienced acute toxicity during radiation, all of which were grade 1 and 2, with only 1 grade 3 toxicity. Twenty-two patients (30%) experienced late toxicity, with only 1 grade 3 toxicity. This prospective study confirms that RT for MALT lymphoma provides excellent long-term RFS with acceptable rates of toxicity. Current efforts are focused on RT de-escalation in an effort to further avoid treatment-related morbidity. CLINICALTRIALS.GOV: NCT04465162.

COVID-19 in-hospital mortality and mode of death in a dynamic and non-restricted tertiary care model in Germany.

Reported mortality of hospitalised Coronavirus Disease-2019 (COVID-19) patients varies substantially, particularly in critically ill patients. So far COVID-19 in-hospital mortality and modes of death under state of the art care have not been systematically studied. This retrospective observational monocenter cohort study was performed after implementation of a non-restricted, dynamic tertiary care model at the University Medical Center Freiburg, an experienced acute respiratory distress syndrome (ARDS) and extracorporeal membrane-oxygenation (ECMO) referral center. All hospitalised patients with PCR-confirmed SARS-CoV-2 infection were included. The primary endpoint was in-hospital mortality, secondary endpoints included major complications and modes of death. A multistate analysis and a Cox regression analysis for competing risk models were performed. Modes of death were determined by two independent reviewers. Between February 25, and May 8, 213 patients were included in the analysis. The median age was 65 years, 129 patients (61%) were male. 70 patients (33%) were admitted to the intensive care unit (ICU), of which 57 patients (81%) received mechanical ventilation and 23 patients (33%) ECMO support. Using multistate methodology, the estimated probability to die within 90 days after COVID-19 onset was 24% in the whole cohort. If the levels of care at time of study entry were accounted for, the probabilities to die were 16% if the patient was initially on a regular ward, 47% if in the intensive care unit (ICU) and 57% if mechanical ventilation was required at study entry. Age ≥65 years and male sex were predictors for in-hospital death. Predominant complications-as judged by two independent reviewers-determining modes of death were multi-organ failure, septic shock and thromboembolic and hemorrhagic complications. In a dynamic care model COVID-19-related in-hospital mortality remained very high. In the absence of potent antiviral agents, strategies to alleviate or prevent the identified complications should be investigated. In this context, multistate analyses enable comparison of models-of-care and treatment strategies and allow estimation and allocation of health care resources.

Immune Senescence and Exhaustion Correlate with Response to Flotetuzumab, an Investigational CD123×CD3 Bispecific Dart® Molecule, in Acute Myeloid Leukemia

Immune Senescence and Exhaustion Correlate with Response to Flotetuzumab, an Investigational CD123×CD3 Bispecific Dart® Molecule, in Acute Myeloid Leukemia

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

The Addition of Venetoclax to Ibrutinib Achieves a High Rate of Undetectable Minimal Residual Disease in Patients with High-Risk CLL

The Addition of Venetoclax to Ibrutinib Achieves a High Rate of Undetectable Minimal Residual Disease in Patients with High-Risk CLL

A Prospective Trial of Radiation Therapy Efficacy and Toxicity for Localized Mucosa-associated Lymphoid Tissue (MALT) Lymphoma

Radiation therapy is an effective therapy for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). We report the long-term results of a prospective trial conducted to determine the efficacy and toxicity of radiation therapy (RT) alone in treating MALT lymphoma. Patients with stage I or II MALT lymphoma or with stage IV disease due to bilateral parotid, ocular/ocular adnexal involvement, or from multiple sites within Waldeyer’s ring were eligible. Radiation treatment consisted of involved field RT starting with 39.6 Gray (Gy) later amended down to 24 Gy. Relapse-free survival was the primary endpoint. Clinical, radiographic and/or endoscopic response was assessed beginning 3 months after treatment. Acute and late toxicities were evaluated per Radiation Therapy Oncology Group (RTOG) criteria v3.0. Kaplan-Meier analysis was used to estimate time to progression (TTP), relapse free survival (PFS), progression free survival (PFS) and overall survival (OS) defined from the time of study entry. Preplanned subgroup analyses of outcome were performed based on site of involvement. From 2000-2012, 75 patients were accrued; 73 received protocol-specified RT. Median follow-up was 9.8 years for the 62 alive patients. Sixty-nine patients (95%) had a complete response at time of first restaging and the remaining 4 achieved CR with additional observation. Eleven patients (15%) had disease relapse, 9 of which were at sites outside of the radiation treatment field with median time to progression of 37.5 months. The two local relapses were in the stomach, 13.7 and 84.9 months after completion of RT. Median PFS was 17.5 years and median RFS and OS were not reached. 10-year relapse-free rate was 83% (95% CI 74-93%). 10-year PFS rate was 71% (95% CI 60-84%). 10-year OS rate was 86% (95% CI 77-96%). TTP, PFS, and OS did not differ by site of involvement (P = 0.18, 0.43, 0.50). All relapses were successfully salvaged most commonly with rituximab alone (n = 3), RT (n = 3), or chemotherapy (n = 2). One patient developed metastatic gastric adenocarcinoma and was found to also have recurrent MALT on biopsy. Otherwise, all relapsed patients were alive without evidence of disease at last follow up, and no patient died due to MALT lymphoma. Sixty-seven patients (92%) experienced acute toxicity during radiation, all of which were grade 1 and 2 with only 1 grade 3 toxicity of the eye (retinal detachment). Twenty-two patients (30%) experienced late toxicity, with only one Grade 3 toxicity (eye) in the same patient with G3 acute eye toxicity. No patients had subsequent disease transformation to aggressive lymphoma. This prospective study confirms that RT for MALT lymphoma provides excellent long-term relapse free survival with acceptable rates of toxicity. Current efforts are focused on RT de-escalation in an effort to further reduce toxicity risk.

Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients. We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events. In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM.

Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial.

Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. Trial participation required a recent embolic stroke of undetermined source. Patients' history of cancer was recorded at the time of study entry. During a mean follow-up of 11months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78-1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71-2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67-9.96; P for interaction 0.95). All-cause mortality was similar in both groups. Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).

Dimensions of Poststroke Depression and Neuropsychological Deficits in Older Adults

ObjectivePoststroke depression (PSD) has a heterogeneous presentation and is often accompanied by cognitive impairment. This study aimed to identify distinct dimensions of depressive symptoms in older adults with PSD and to evaluate their relationship to cognitive functioning. DesignCross-sectional factor and correlational analyses of patients with poststroke depression. SettingPatients were recruited from the community and from acute inpatient stroke rehabilitation hospitals. ParticipantsParticipants had suffered a stroke and met DSM-IV criteria for major depression (≥18 Montgomery Åsberg Depression Scale; MADRS). InterventionNone. MeasurementsMADRS was used to quantify depression severity at study entry. Neuropsychological assessment at the time of study entry consisted of measures of Global Cognition, Attention, Executive Function, Processing Speed, Immediate Memory, Delayed Memory, and Language. ResultsThere were 135 (age ≥50) older adult participants with PSD and varying degrees of cognitive impairment (MMSE Total ≥20). Factor analysis of the MADRS identified three factors, that is sadness, distress, and apathy. Items comprising each factor were totaled and correlated with neuropsychological domain z-score averages. Symptoms of the apathy factor (lassitude, inability to feel) were significantly associated with greater impairment in executive function, memory, and global cognition. Symptoms of the sadness and distress factors had no relationship to cognitive impairment. ConclusionPSD consists of three correlated dimensions of depressive symptoms. Apathy symptoms are associated with cognitive impairment across several neuropsychological domains. PSD patients with prominent apathy may benefit from careful attention to cognitive functions and by interventions that address both psychopathology and behavioral deficits resulting from cognitive impairment.

Engaging hematopoietic cell transplantation patients and caregivers in the design of print and mobile application individualized survivorship care plan tools.

INSPIRE (INteractive Survivorship Program with Information and REsources) is an online health program that includes a mobile app, website, health action plan, and individualized survivorship care plans for adult hematopoietic cell transplant (HCT) survivors. The INSPIRE program integrates two previously effective randomized control trials that tested an internet-based program and patient-centered survivorship care plans for HCT survivors. Three focus groups were conducted with a total of 22 participants (20 patients, 2 caregivers/patient advocates) to explore patient and caregiver preferences and to optimize the patient-centered emphasis of INSPIRE. Adult (age > 18 years at the time of study entry) HCT recipients had to be at least 1-year post-HCT to participate; caregivers/patient advocates were also eligible. Participants had to be able to communicate in English, could have any diagnosis, transplant type, or donor source, and could have had multiple transplants. All patient participants received an allogeneic HCT; average time since HCT was 8 years (range 2-22 years). The majority of participants were female (77.3%). Overall, the tools were well received by participants in this study, particularly the personalized features of all the tools. Major themes included interest in having the ability to tailor features to individual needs, and an interest in tracking information over time. Engaging patients and caregivers is invaluable to optimize tools designed to improve HCT survivorship care. Print, online, and mobile-based tools, tailored to individual patients' treatment history and requisite follow-up care, can provide otherwise unavailable expertise and guidelines for care.