23 research outputs found
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Safety and Efficacy Results of a Phase I, Open-Label Study of Concurrent and Delayed Nivolumab in Combination With nab-Paclitaxel and Carboplatin in Advanced Non-small Cell Lung Cancer.
Introduction: Multicenter, phase I study of concurrent and delayed nivolumab plus nab-paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received nab-paclitaxel 100 mg/m2 (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. Results: All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. Conclusions: The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with nab-paclitaxel/carboplatin for the treatment of advanced NSCLC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02309177
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Factors Associated with Early Therapy Initiation in Patients (pts) with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry
Abstract
Introduction: In prior studies, only 13-22% of lower-risk (LR) MDS pts and 11-69% of higher-risk (HR) MDS pts received potentially disease-modifying therapy despite the proven benefits of reduced blood transfusions and prolonged survival. Pt age, frailty, and comorbidities are commonly assumed to influence therapy choice; however, this has not been proven and other factors may govern treatment (tx) decisions. To identify factors associated with receiving first-line tx for MDS, health services data from the Connect® MDS/AML Registry, which includes MDS pts treated in US academic, community, and government-based centers, were analyzed.
Methods: The Connect MDS/AML Registry (NCT01688011) is an ongoing, prospective observational cohort study of pts with newly diagnosed acute myeloid leukemia (AML) (aged ≥ 55 years) or MDS (aged ≥ 18 years). Local AML and MDS diagnoses are confirmed by an independent central review of all available diagnostic reports. Baseline demographics, disease characteristics, laboratory parameters, and ZIP-code-level per capita income were collected at enrollment on MDS pts from December 2013 to March 2018. Analyses were performed separately for LR-MDS pts, defined as having Low- or Intermediate (Int)-1-risk MDS according to the International Prognostic Scoring System (IPSS), and HR-MDS pts, defined as having Int-2- or High-risk MDS.
Uni- and multivariable logistic regression analyses were used to identify factors associated with early use of first-line tx in MDS pts, defined as chemotherapy or biotherapy initiated ≤ 45 days after diagnosis. Univariable testing was performed for each potential predictor; those with an association of P < 0.15 were included in multivariable analysis. The final multivariable model was derived using a score-based selection method. Pts receiving first-line tx (regardless of intensity) were compared with a combined group of pts receiving best supportive care (BSC) or no tx.
Results: As of March 8, 2018, data from 536 MDS pts (232 HR-MDS and 304 LR-MDS) from 130 institutions (20 academic and 110 community/government) were available for analysis. In the LR-MDS group, median age was 76 years (range 28-95), with 65% male, and 89% white; 19% had private insurance, and the average median ZIP-code-level per capita income was 10,000-26,000 (range 83,000).
In LR-MDS pts, univariable predictors of early first-line therapy initiation included baseline transfusion dependency (defined as ≥ 1 transfusion episode in the 8 weeks prior to diagnosis), comorbidities (higher Adult Comorbidity Evaluation 27 [ACE-27] score), having fluorescence in situ hybridization (FISH) or molecular analyses performed, Int-1 IPSS risk score, primary vs secondary MDS, and higher bone marrow (BM) blast percentage. Multivariable logistic regression analysis identified transfusion dependency (P = 0.001), Int-1 IPSS risk score (P = 0.026), BM blast percentage ≥ 5% (P = 0.002), and having both FISH and molecular genetic testing performed at diagnosis (P = 0.022) as factors significantly associated with early initiation of first-line tx (Table 1).
Univariable analysis of HR-MDS pts showed insurance status, comorbidities (ACE-27 score ≤ 2), High IPSS risk score, primary vs secondary MDS, having flow cytometry analysis performed, lower baseline frailty, and BM blast percentage as univariable correlates associated with early tx. Multivariable logistic regression analysis identified private insurance coverage (P = 0.031) and BM blast percentage ≥ 10% (P = 0.021) as factors significantly associated with early initiation of first-line tx (Table 2).
Conclusions: Early first-line tx in MDS pts was significantly associated with disease severity as indicated by transfusion dependency, higher IPSS risk score, and higher BM blast percentage. However, counter to common assumptions, age, frailty, and comorbidities were not associated with receiving early tx in MDS. Access to care may be an important factor in the tx of MDS pts, as having private health insurance and undergoing genetic testing were also significantly associated with receiving early tx. Additional pt-centered research with prescribing MDS physicians as stakeholders is needed to verify and extend these findings.
Disclosures
Cogle: Celgene: Other: Steering Committee Member of Connect MDS/AML Registry. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; AbbVie: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Scott:Celgene: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Louis:Cellmedica: Patents & Royalties; Celgene: Employment. Flick:Celgene: Employment. Nifenecker:Celgene: Employment. Kiselev:Celgene: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Steensma:Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy
Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy
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Diagnostic Testing Patterns and Concordance with World Health Organization (WHO) Criteria for Patients (Pts) with Newly Diagnosed (ND) Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Registry
Background: Diagnosing and risk stratifying MDS requires an integrated approach including morphologic, cytogenetic, and molecular genetic assessments to inform treatment decisions and aid prognostication. The WHO classification criteria for diagnosis of MDS were updated in 2016 (Arber DA, et al. Blood. 2016;127:2391-405) with specific recommendations; however, the impact of these updates on clinical practice patterns is unclear. We investigated testing patterns for pts with ND MDS treated in predominantly community- and government-based centers in the Connect® MDS/AML Registry and compared these practices with the WHO 2016 criteria.
Methods: The Connect® MDS/AML Disease Registry (NCT01688011) is a large, US, multicenter, prospective observational cohort study of pts with ND acute myeloid leukemia (AML; aged ≥ 55 years) or MDS (aged ≥ 18 years). Baseline demographics, disease characteristics, and laboratory testing parameters were collected on MDS pts at enrollment to the Registry from December 2013 to March 2019. Pts were classified according to the International Prognostic Scoring System (IPSS) as having lower-risk MDS (LR-MDS; IPSS Low- or Intermediate-1-risk MDS) or higher-risk MDS (HR-MDS; IPSS Intermediate-2- or High-risk MDS). Differences in testing rates at enrollment between LR- and HR-MDS pts were assessed using a chi-square test with P < 0.05 considered statistically significant. Concordance with the recommendations of the WHO 2016 criteria, including frequency of SF3B1 testing, was assessed.
Results: As of March 8, 2019, 694 pts with MDS were enrolled in the Registry; 392 (56.5%) with LR-MDS and 302 (43.5%) with HR-MDS. Median age was 75.0 vs 73.0 years, 66.3% vs 64.9% were male, and 70.6% vs 75.6% were insured by Medicare/Medicaid. There was a significant difference in bone marrow blast enumeration method between LR- and HR-MDS pts; the most common method was manual differential (75.9% vs 72.1%), followed by immunohistochemistry (IHC) (11.5% vs 21.5%) (P = 0.002). The mean (standard deviation) number of cells counted on manual differential was 361.7 (151.3) in LR-MDS pts and 348.2 (163.6) in HR-MDS pts. This was not significantly different between pt groups, but was below the recommended 500 cells. Presence of ring sideroblasts (RS) was more common in LR- than HR-MDS pts (39.8% vs 34.1%; P = 0.02); median percentage of RS was also higher in LR- than HR-MDS pts (25.0% vs 7.5%; P < 0.0001). The majority of pts underwent complete cytogenetic analysis at baseline; 97.4% of LR- and 95.7% of HR-MDS pts. Flow cytometry testing to assess cell lineage was widely done; 97.0% of HR-MDS pts and 93.6% of LR-MDS pts.
To assess changes in diagnostic testing patterns following publication of the WHO 2016 criteria, LR- and HR-MDS pts were grouped based on their date of enrollment: pts enrolled prior to January 1, 2017, and pts enrolled from January 1, 2017 onward. Molecular testing rates increased in pts enrolled after January 1, 2017, from testing rates seen prior to 2017, in LR- and HR-MDS pts; however, testing rates remained < 40% (Table). Testing rates for specific mutations were higher in pts enrolled after January 1, 2017 than in those enrolled prior to 2017. In parallel with overall testing rates, testing rates for SF3B1 were also higher in pts enrolled after January 1, 2017; however, they remained at approximately 50% in these pts. During this time, rates of fluorescence in situ hybridization testing decreased by 36.1% and 26.0% in HR- and LR-MDS pts, respectively.
Conclusions: In this analysis from the Connect® MDS/AML Registry, increased SF3B1 testing rates were observed following the publication of the WHO 2016 criteria, suggesting uptake of this recommendation by physicians. The increase in testing rates for other specific mutations associated with targeted therapies coincides with the approval of these new therapies by the US FDA. However, further education to increase molecular testing rates for specific mutations, improve prognostication, as well as to ensure the appropriate use of targeted therapies is required. The use of IHC rather than manual differential for blast enumeration, as recommended by the WHO, and the significant difference in enumeration method between LR- and HR-MDS pts, may be due to higher levels of fibrosis in HR pts and poor-quality aspirates rather than a lack of awareness of the recommendations; however, the recommended counting of 500 cells was not performed in all pts.
Disclosures
George: Novartis: Honoraria; Blueprint Medicines: Consultancy; Deciphera: Consultancy; Allakos: Consultancy. Garcia-Manero:Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Komrokji:Incyte: Consultancy; DSI: Consultancy; Celgene: Consultancy; Agios: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau. Savona:Boehringer Ingelheim: Patents & Royalties; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees. Scott:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Steensma:Stemline: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Arrowhead: Equity Ownership; H3 Biosciences: Other: Research funding to institution, not investigator.; Astex: Consultancy; Summer Road: Consultancy; Pfizer: Consultancy. Flick:Celgene Corporation: Employment. Kiselev:Celgene Corporation: Employment, Equity Ownership. Louis:Celgene Corporation: Employment, Equity Ownership. Nifenecker:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Foucar:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees
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Health-related quality of life (HRQoL) in patients (pts) with myelodysplastic syndromes (MDS) in the Connect Myeloid Disease Registry
7040
Background: At diagnosis, disease risk and transfusion burden (TB) can impact HRQoL in pts with MDS. The impact of disease status and higher transfusion requirements on HRQoL has not been well studied. We used data from the Connect Myeloid Disease Registry, an ongoing, prospective, observational cohort study that includes adult pts with lower-risk (LR) and higher-risk (HR) MDS, to investigate factors influencing baseline (BL) and subsequent HRQoL. Methods: BL and Month 6 (M6) data from pts enrolled from Dec 12, 2013 to Mar 6, 2020 (data cutoff) were analyzed. Pts were stratified by International Prognostic Scoring System (IPSS) risk (LR, HR), treatment (Tx) within 45 days post-enrollment (no Tx, best supportive care [BSC], active Tx), and TB 16 weeks post-BL (non-transfusion dependent [NTD], low TB [LTB]; 1−3 transfusions, high TB [HTB]: ≥4 transfusions). Pts completed EQ-5D, FACT-An trial outcome index (TOI), and FACT-Fatigue (FACT-F) questionnaires at BL and quarterly thereafter. Clinically meaningful change, based on minimally important differences, was defined as a change of ±0.07 for EQ-5D, ±6 for FACT-An TOI, and ±3 for FACT-F. Results: At data cutoff, 830 (489 LR, 341 HR) pts were enrolled. Median age was 74 years. 278 pts received no initial Tx, 161 BSC, and 378 active Tx. At BL, 470 were NTD, 197 LTB, and 163 HTB. Of 670 pts still on-study at M6, 462 completed the questionnaires at both BL and M6. At BL , clinically meaningful differences were observed in FACT-An TOI and FACT-F scores, but not EQ-5D, between LR- and HR-MDS and the Tx subgroups . From BL to M6, no clinically meaningful changes were observed in mean scores for each questionnaire. For the TB subgroups, meaningful differences were observed at BL in FACT-An TOI and FACT-F scores, but not EQ-5D (Table). From BL to M6, meaningful decreases in scores were reported by 26%, 30%, and 35% of NTD, LTB, and HTB pts in EQ-5D, 41%, 43%, and 48% for FACT-An TOI, and 40%, 42%, and 48% for FACT-F; increases were reported by 19%, 19%, and 20% pts for EQ-5D, 31%, 32%, and 39% for FACT-An TOI, and 30%, 39%, and 40% for FACT-F. Conclusions: This preliminary analysis suggests that pts with HR-MDS, and transfusion-dependent pts, generally had worse HRQoL at BL, providing further support to initiating active Tx in pts with TB. Possible limitations of the analysis are lower completion rates in pts with more severe disease, and EQ-5D may not capture changes in these subgroups at M6. A longer follow-up may help delineate the impact of Tx on HRQoL assessments in pts with MDS. Clinical trial information: NCT01688011. [Table: see text
Factors Associated with Early Therapy Initiation in Patients (pts) with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry
Radiation Therapy to the Primary and Postinduction Chemotherapy MIBG-Avid Sites in High-Risk Neuroblastoma
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MDS-280: Longer-Term RBC Transfusion Reduction in the Phase 3 MEDALIST Study of Luspatercept in Patients with Lower-Risk MDS (LR-MDS) with Ring Sideroblasts (RS)
MEDALIST (NCT02631070) is a randomized, placebo-controlled, phase 3 trial evaluating efficacy and safety of luspatercept in patients with anemia due to LR-MDS with RS.
To evaluate long-term transfusion burden reduction with luspatercept in MEDALIST trial patients.
Patients were aged ≥18 years; had IPSS-R-defined LR-MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥2 units/8 weeks in the 16 weeks before randomization). Two hundred twenty-nine patients were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo subcutaneously every 3 weeks.
As of 1 July 2019, 77/153 (50.3%) and 11/76 (14.5%) patients receiving luspatercept and placebo, respectively, achieved ≥50% RBC transfusion burden reduction over at least 24 weeks versus baseline (P < 0.0001). Median longest single response episode was 131.6 weeks with luspatercept and not estimable with placebo due to patients stopping treatment. Mean change from baseline in RBC units transfused in Weeks 9–24, was −3.0 (95% CI −3.9, −2.1) versus +0.4 (95% CI −0.6, 1.4) in the luspatercept versus placebo arms; in Weeks 33–48, mean change was −4.9 (95% CI −5.9, −3.9) with luspatercept. Mean transfusion visits in Weeks 1–24 was 5.9 versus 9.5 in the luspatercept versus placebo arms. Mean number (least squares mean [LSM]) of RBC units transfused/48 weeks during Weeks 1–48 was 22.89 (23.28) versus 35.98 (35.20) in the luspatercept versus placebo arms (LSM difference −11.92 [95% CI −15.55, −8.28]; P < 0.0001). Mean (LSM) RBC transfusion events/48 weeks was 12.95 (13.14) versus 19.54 (19.15) in the luspatercept versus placebo arms (LSM difference −6.00 [95% CI −8.16, −3.85]; P < 0.0001). Serum ferritin LSM change from baseline was −2.7 μg/L versus +226.5 μg/L in luspatercept versus placebo arms (LSM difference −229.1 μg/L; P=0.0024) in Weeks 9–24; −72.0 μg/L versus +247.4 μg/L in Weeks 33–48 (LSM difference −319.5 μg/L; P=0.0294). In Weeks 1–24, 38/127 (29.9%) versus 5/65 (7.7%) patients (P=0.0005) achieved major hematologic improvement-erythroid response (per IWG 2018) in the luspatercept versus placebo arms.
Luspatercept demonstrated clinical efficacy in patients with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥50%) and serum ferritin