scholarly journals The Effect of Fedratinib, a Selective Inhibitor of Janus Kinase 2 (JAK2), on Weight and Metabolic Parameters in Patients with Intermediate (INT)- or High-risk Myelofibrosis (MF)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Douglas Tremblay ◽  
Lara Cavalli ◽  
Sibabrata Raja Banerjee ◽  
Shelonitda Rose ◽  
John Mascarenhas
Keyword(s):  
Weight Gain ◽  
High Risk ◽  
Fasting Glucose ◽  
Albumin Level ◽  
Metabolic Parameters ◽  
Phase Iii ◽  
Spleen Volume ◽  
Publicly Traded ◽  
Starting Dose ◽  
Previously Treated

BACKGROUND: MF is characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, marrow fibrosis, splenomegaly, and shortened survival. Fedratinib (FEDR) is an oral, selective JAK2 inhibitor approved in the United States (US) for treatment (Tx) of INT-2 or high-risk MF. Ruxolitinib (RUX) is a JAK1/2 inhibitor approved in the US and European Union for Tx of INT- or high-risk MF. Clinical experience indicates that weight gain during RUX Tx is both common and substantial (mean increase ~4 kg from baseline [BL] in the COMFORT-I and COMFORT-II studies); begins during early Tx (~6-8 weeks from initiation) and continues throughout the course of Tx; and cannot be solely attributable to resolution of MF symptoms (eg, early satiety, abdominal discomfort) or splenomegaly (Mesa 2015; Sapre 2019; Molle 2020). The impact of FEDR on weight and metabolic parameters is of interest. FEDR was investigated in the randomized, placebo (PBO)-controlled, phase III JAKARTA trial in patients (pts) with JAK-inhibitor-naïve MF, and in the single-arm, phase II JAKARTA2 trial in pts with MF previously treated with RUX. OBJECTIVE: Evaluate changes in weight, BMI, and metabolic parameters in pts treated with FEDR 400 mg/day. METHODS: JAKARTA enrolled pts with INT-2 or high-risk primary or post-ET/post-PV MF, platelet counts ≥ 50 ×109/L, palpable splenomegaly (≥ 5 cm below LCM), and ECOG PS ≤ 2. Pts were randomized 1:1:1 to FEDR 400 mg, FEDR 500 mg, or PBO, administered once-daily for at least 6 continuous 28-day Tx cycles (ie, 24 weeks). This analysis focuses on pts randomized to FEDR 400 mg/day (approved starting dose) or PBO. We assessed changes from BL in weight, BMI, albumin, fasting glucose, and systolic and diastolic blood pressure (SBP and DBP) at the end of cycle 6 (EOC6; PBO pts could crossover to FEDR after EOC6). Reported changes from BL at EOC6 are for pts who completed 6 Tx cycles. As a supporting analysis, we assessed changes in these parameters for pts in JAKARTA2, who all received FEDR 400 mg/day (starting dose). RESULTS: In JAKARTA, 96 pts received FEDR 400 mg and 95 pts received PBO. Median age at BL was 63 years (range 39-86) in the FEDR arm and 66 (27-85) in the PBO arm, and mean [±SD] spleen volumes were 2755 [1353] mL and 2928 [1484] mL, respectively. In the FEDR arm, mean weight at BL was 69.4 kg, and remained relatively unchanged during FEDR Tx, increasing by 0.8 kg from BL to EOC6 (Figure). In the PBO arm, mean weight decreased by 0.1 kg from BL (68.6 kg) to EOC6. Mean BMI increased nominally by 0.3 in the FEDR arm (BL 24.0) and was unchanged from BL (24.3) in the PBO arm. In the FEDR arm, mean albumin level increased slightly by 0.24 g/dL from BL (4.14 g/dL) to EOC6, and fasting glucose was unchanged from BL (5.5 mmol/L). No clinically significant changes were observed in SBP or DBP during FEDR Tx, which were 124.5 and 70.6 mmHg at BL, respectively, and increased nominally at EOC6 by 1.7 and 0.1 mmHg. In the PBO arm, mean albumin level was 4.07 g/dL at BL and decreased by 0.09 g/dL at EOC6, fasting glucose was 5.6 mmol/L and decreased by 0.1 mmol/L, SBP was 124.3 mmHg and increased by 1.3 mmHg, and DBP was 70.6 mmHg and decreased by 1.3 mmHg. JAKARTA2 included 97 pts with advanced MF previously treated with RUX. Median age at study entry was 67 years (range 38-83) and mean [±SD] spleen volume was 3095 [1459] mL. At BL, mean weight was 73.5 kg and BMI was 25.5; these decreased by 0.6 kg and 0.2, respectively, by EOC6. From BL to EOC6, mean albumin, fasting glucose, SBP, and DBP changed by +0.39 g/dL (BL 3.94 g/dL), -0.6 mmol/L (BL 6.6 mmol/L), +3.8 mmHg (BL 124.1 mmHg), and +2.9 mmHg (BL 66.7 mmHg), respectively. Median spleen volume change from BL to EOC6 with FEDR 400 mg was -40% in JAKARTA and -34% in JAKARTA2. There was no apparent correlation between changes in weight and spleen volume in pts treated with FEDR 400 mg in either trial. CONCLUSIONS: Disproportionate weight gain not correlating with MF symptom resolution is a concern with long-term RUX Tx. In JAKARTA, FEDR did not meaningfully increase pts' weight or BMI after 6 Tx cycles. Modest increases in albumin compared with BL suggest improved nutritional status during FEDR Tx, and there were no clinically relevant changes in fasting glucose or BP after 6 FEDR Tx cycles. Changes in weight and metabolic parameters in JAKARTA2 support findings with FEDR 400 mg from JAKARTA. Unlike observations in pts treated with RUX (Mesa 2015), spleen volume reductions during FEDR Tx were not associated with weight increases. Disclosures Cavalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Banerjee:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.

scholarly journals A Prognostic Model Incorporating Tumor Lesion Morphology and Texture Features Identifies High-Risk Patient Subpopulations in De Novo DLBCL and FL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Xiao Li ◽  
Skander Jemaa ◽  
Richard AD Carano ◽  
Thomas Bengtsson ◽  
Joseph N Paulson ◽  
...  
Keyword(s):  
High Risk ◽  
Fdg Pet ◽  
De Novo ◽  
Risk Group ◽  
Low Risk ◽  
Phase Iii ◽  
Publicly Traded ◽  
Prognostic Performance ◽  
Pet Scans ◽  
Worse Prognosis

Background: Despite effective first-line (1L) treatment options for patients with NHL almost 40% of patients with diffuse large B cell lymphoma (DLBCL) will have a poor response or disease progression after 1L treatment. In follicular lymphoma (FL) 15-20% of patients experience early relapse, and almost 8% may develop transformation to more aggressive forms of the disease (such as DLBCL) after 1L treatment. More accurate identification of patients at high-risk for a poor prognosis with the standard of care could lead to improved outcomes. Although the International Prognostic Index (IPI) and its FL extension (FLIPI) are often used to stratify patients by prognosis, they have relatively modest sensitivity and specificity for predicting individualized risk. Radiomics is a promising approach to improve upon existing prognostic models because it provides a comprehensive quantification of tumor lesion morphology and texture derived from FDG-PET scans and may provide new and important information about disease biology and progression risk on an individual level. Methods: A collection of 107 radiomics features [pyradiomics v2.20] that describe shape, size or volume and texture of tumor lesions, including complex features that are believed to reflect the underlying biological tumor phenotype and microenvironment, were derived for n=1093 de novo DLBCL patients with available baseline FDG-PET scans from the Phase III GOYA study (NCT01287741) evaluating obinutuzumab plus CHOP chemotherapy (G-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) (Vitolo, et al. J Clin Oncol 2017). The same set of features were also extracted from n=451 de novo FL patients with available baseline FDG-PET scans from the Phase III GALLIUM study (NCT01332968) comparing obinutuzumab plus chemotherapy with rituximab plus chemotherapy [Marcus, et al. N Engl J Med 2017]. To investigate the association between the derived radiomics features along with baseline clinical variables and progression-free survival (PFS), a Cox proportional hazard model with L1 regularization was trained and internally validated using the GOYA study. We used a nested Monte Carlo Cross Validation (nMCCV) strategy to train our model and provide high- and low-risk group predictions on held-out samples of data. This modeling strategy allows us to make a group prediction on all GOYA patients while reducing overfitting. To evaluate prognostic performance, we ported the final model trained using the GOYA study (called the Li prognostic model) to the fully independent GALLIUM study. Results: Using our nMCCV approach we identified 11 factors, with an inclusion probability of >50%, that are associated with PFS of DLBCL patients (Figure A). Included within the top features are several image-derived morphometric (i.e. metabolic tumor volume, surface area) and radiomics features (i.e. tumor elongation, NGTDM contrast, GLCM inverse variance). When stratifying patients on the predicted (via majority vote) low-risk vs high-risk groupings we found that our high-risk group had significantly worse prognosis vs the low-risk group (Figure B). In comparison, the high-risk group from the IPI model (defined as IPI > 2) had significantly worse prognosis vs the low-risk group, but the performance was slightly worse than our model (Figure C). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 72.7% [70.0-76.6] and 59.8% [54.8-65.2] (vs 74% [70.0-78.2] and 60.4% [55.1-66.2] for the IPI model). After training and testing in the DLBCL population, we evaluated the prognostic performance of our model in an independent set of FL patients. We found that high-risk FL patients had a significantly worse prognosis than the low-risk group (Figure D). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 77.4% [69.8-85.8] and 48.9% [39.5-60.5] (vs. 80% [0.748-0.856] and 58.3% [51.6-65.9] in the full group). Conclusions: Radiomics features are prognostic in DLBCL and provide a modest improvement in prognostic performance when combined with traditional IPI scores, clinical features, and lab values (vs IPI alone). Our prognostic signature, developed in DLBCL, has significant prognostic performance in an independent dataset of patients with FL. While these results are promising, our FL validation dataset was relatively small and further evidence is required to confirm our findings. Disclosures Li: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jemaa:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Carano:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bengtsson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Paulson:F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jansen:F. Hoffmann-La Roche: Current Employment; Molecular Health GmbH: Ended employment in the past 24 months; F. Hoffmann-La Roche, Abbvie, Alphabet, other (non-healthcare), indexed funds and ETFs: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hibar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

Efficacy, Safety, and Confirmation of the Recommended Phase 2 Dose of Ruxolitinib Plus Panobinostat in Patients with Intermediate or High-Risk Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 711-711 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Florian H Heidel ◽  
Alessandro M. Vannucchi ◽  
Vincent Ribrag ◽  
Francesco Passamonti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Spleen Volume ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Marrow Fibrosis

Abstract Background: Myelofibrosis (MF) is a clonal neoplastic disease resulting in bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. The Janus kinase (JAK) pathway is often dysregulated in MF, and agents targeting this pathway have demonstrated efficacy in this disease. Ruxolitinib (RUX), a potent JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume reduction, symptom improvement, and survival compared with the control arm in the phase III COMFORT-I and COMFORT-II studies. Panobinostat (PAN), a potent pan-deacetylase inhibitor (pan-DACi), inhibits JAK signaling through disruption of the interaction of JAK2 with the protein chaperone heat shock protein 90. In phase I/II studies, PAN has shown splenomegaly reduction and improvement of bone marrow fibrosis. The combination of RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. These preliminary results led to the initiation of a phase Ib study evaluating the combination of RUX and PAN in patients (pts) with MF. The updated results from the expansion phase of this trial are presented here. Methods: Eligible pts had intermediate-1, -2, or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF by International Prognostic Scoring System criteria, with palpable splenomegaly (≥ 5 cm below the costal margin). The primary objective was determination of the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID). Secondary objectives included safety, efficacy, and pharmacokinetics. Exploratory endpoints included assessment of improvement in bone marrow fibrosis and reduction of JAK2 V617F allele burden. The treatment schedule was RUX (5-15 mg) twice daily (bid) every day and PAN (10-25 mg) once daily 3 times per week (tiw; days 2, 4, and 6) every other week (qow) in a 28-day cycle. Following dose escalation and identification of the potential RPIID, additional pts were enrolled into the expansion phase and treated at this dose. Results: As of March 14, 2014, a total of 61 pts were enrolled (38 escalation phase and 23 expansion phase). The median duration of exposure to PAN and to RUX was 24.6 weeks and 24.0 weeks, respectively, for pts treated in the expansion phase. Three DLTs were observed in the escalation phase (grade 4 thrombocytopenia [n = 2], grade 3 nausea [n = 1]). No MTD was reached. The RPIID was confirmed to be RUX 15 mg bid and PAN 25 mg tiw qow in May 2014. Among the 34 pts treated at the RPIID, grade 3/4 adverse events (AEs) regardless of causality included anemia (32%), thrombocytopenia (24%), diarrhea (12%), asthenia (9%), and fatigue (9%). AEs led to discontinuation in 6% of pts treated at the RPIID. Two pts treated at the RPIID died due to causes unrelated to study treatment (1 due to myocardial infarction and 1 due to progression of myelofibrosis). Among the pts treated at the RPIID, 79% showed a >50% decrease in palpable spleen length, with 100% decrease (non-palpable spleen) being observed in 53% of pts. Additionally, 48% of pts treated at the RPIID in the expansion phase achieved ≥35% reduction in spleen volume (Figure). These results are similar to those observed for spleen volume response at 24 weeks among pts who received single-agent RUX on the phase III COMFORT-I (41.9%) and COMFORT-II (32%) studies. Conclusions: The combination of the JAK1/JAK2 inhibitor RUX and the pan-DACi PAN was well tolerated and resulted in high rates of reductions in splenomegaly in pts with intermediate- and high-risk MF. Although a relatively larger proportion of patients experienced spleen volume reductions at week 24 as compared to the COMFORT studies, the smaller sample size, shorter follow up times and potential differences in the patient populations preclude definitive comparisons. Similar to COMFORT-I and II trials, hematological AEs, specifically anemia and thrombocytopenia, were the most common AEs observed in pts treated with the combination therapy. Pts continue to be treated in the expansion phase at the RPIID. Updated safety, efficacy, and exploratory analyses on bone marrow fibrosis, JAK V617F allele burden, and biomarkers, including cytokines, will be presented. Figure Change in Spleen Volume in Expansion Phase Figure. Change in Spleen Volume in Expansion Phase Disclosures Kiladjian: Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Research Funding. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ribrag:Celgene: Consultancy; Pharmamar: Consultancy; Epizyme: Research Funding; Bayer: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Conneally:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kindler:Novartis: Consultancy. Acharyya:Novartis: Employment. Gopalakrishna:Novartis: Employment. Ide:Novartis: Employment, Equity Ownership. Loechner:Novartis: Employment. Mu:Novartis: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Honoraria; SBio: Consultancy; Shire: Speakers Bureau.

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1625-1625
Author(s):  
Keita Kirito ◽  
Norio Komatsu ◽  
Kazuya Shimoda ◽  
Hikaru Okada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Spleen Size ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Starting Dose ◽  
Grade 3 ◽  
Eortc Qlq

Abstract BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study. METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued. RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid. Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study. At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure). CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L. Disclosures Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Indirect Treatment Comparisons of the Effect of Fedratinib Versus Navitoclax Plus Ruxolitinib on Spleen Volume and Symptoms in Patients with Myelofibrosis and Prior Ruxolitinib Treatment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4626-4626
Author(s):  
Pranav Abraham ◽  
Xiaomeng Liao ◽  
Manoj Chevli ◽  
Sarah Smith
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Sample Size ◽  
Response Rates ◽  
Janus Kinase ◽  
Spleen Volume ◽  
Treatment Comparison ◽  
Previously Treated ◽  
Indirect Treatment ◽  
Ecog Ps

Abstract Introduction: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm that is characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor, was the first US Food and Drug Administration (FDA)-approved therapy for intermediate- and high-risk MF. However, there remains a high unmet need for alternative treatment options for patients who discontinue (41.1%-60.9% of patients discontinue after 3 months and 48.4%-73.0% after 6 months) (Fonseca E, et al. Blood 2013;122. Abstract 2833) or are no longer responding to ruxolitinib therapy (Bose P, Verstovsek S. Leuk Lymphoma 2020;61:1797-1809). The efficacy and safety of fedratinib, a JAK2 inhibitor approved by the FDA in 2019, was investigated post ruxolitinib in the single-arm trial JAKARTA-2 (NCT01523171) (Harrison CN, et al. Lancet Haematol 2017;4:e317-324; Harrison CN, et al. Am J Hematol 2020;95:594-603). New clinical evidence for treating a similar population with navitoclax plus ruxolitinib was presented at the American Society of Hematology Annual Meeting in 2020 (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50). The efficacy of fedratinib relative to navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib has not yet been evaluated. Objective: To explore the comparative efficacy of fedratinib versus navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib for the 2 binary endpoints of ≥ 35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥ 50% reduction in total symptom score (TSS) from baseline to the EOC6. Methods: Evidence for fedratinib was informed by JAKARTA-2 patient-level data, and evidence for navitoclax plus ruxolitinib was informed by known reported evidence from the REFINE study (NCT03222609) (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50; Harrison CN, et al. J Clin Oncol 2019;37 (suppl 15). Abstract 7057). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all reported Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria were considered. Where sample size was too small, response rates (number of responders divided by total number of patients) were compared naively. Results: A subgroup of 58 JAKARTA-2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population was used in the analyses. Baseline mean platelet count was similar between subgroups. Across the analyses performed, results suggested fedratinib consistently increased the odds/risk of a spleen response compared with navitoclax plus ruxolitinib (Table). The MAIC, matching on ECOG PS, suggested that the odds of having an SVR for patients in the fedratinib group was 2.19 times (95% confidence interval [CI], 1.26 to 3.66) that of the navitoclax plus ruxolitinib group, and the risk of having an SVR for patients in the fedratinib group was 17.59% higher (95% CI, −2.14 to 36.97). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N = 20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the fedratinib group and 30% [6/20] in the navitoclax plus ruxolitinib group). Conclusion: In the population of patients with MF previously treated with ruxolitinib, these analyses suggest treatment with fedratinib was associated with a greater proportion of patients achieving a spleen response compared with navitoclax plus ruxolitinib. Limited data were available for comparison of TSS. Figure 1 Figure 1. Disclosures Abraham: Bristol Myers Squibb: Current Employment. Liao: BMS: Consultancy. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Smith: Sarah Smith is an employee of BresMed. BresMed received consultancy fees from BMS/Celgene for the reasearch in this abstract. She did not receive direct payment as a result of this work outside of her normal salary payments.: Consultancy.

scholarly journals Trial in Progress: The Phase III, Randomized, Open-Label, Multicenter COMMODORE 2 Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria Not Previously Treated with Complement Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Austin Kulasekararaj ◽  
Guangsheng He ◽  
Talha Munir ◽  
Jeffrey Pu ◽  
Antonio Risitano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Medical Writing ◽  
Third Party ◽  
Phase Iii ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Complement Inhibitors ◽  
Previously Treated

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody engineered to significantly extend half-life and enable subcutaneous (SC) administration once every 4 weeks in C5-mediated diseases. Based on the promising results of the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab is currently under investigation as a potential therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations include breakthrough hemolysis due to unsustained C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the treatment burden of regular intravenous (IV) infusions. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 2 study (NCT04434092) is evaluating the efficacy and safety of crovalimab compared with eculizumab in patients aged ≥ 12 years with PNH not previously treated with complement inhibitors. Patients are randomized 2:1 to receive crovalimab or eculizumab (Figure 1). Two hundred patients in the crovalimab arm will receive a loading series of crovalimab (IV dose on Day 1, followed by weekly SC doses for 4 weeks starting on Day 2). This is followed by SC maintenance dosing every 4 weeks starting at Week 5. Patients in the eculizumab arm receive a weekly IV loading dose of eculizumab for the first 4 weeks, followed by IV maintenance dosing starting at Week 5 and then once every 2 weeks for 24 weeks. After 24 weeks of treatment, patients can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective of COMMODORE 2 is to evaluate the noninferiority of crovalimab compared with eculizumab based on the co-primary endpoints of (1) the proportion of patients who achieve transfusion avoidance and (2) the proportion of patients with hemolysis control. Secondary efficacy objectives are to evaluate the noninferiority of crovalimab compared with eculizumab in regard to the (1) proportion of patients who experience breakthrough hemolysis, (2) proportion of patients who achieve stabilization of hemoglobin, and (3) mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, and adverse events leading to study drug discontinuation. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pu:SUNY Upstate Medical University: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; RA pharma: Research Funding. Röth:Roche: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Sima:F. Hoffmann-La Roche Ltd/Genentech: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Treatment of High Risk MDS and AML Post-MDS with Azacytidine (AZA): Preliminary Results of the French ATU Program.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2664-2664 ◽  
Author(s):  
Claire Fabre ◽  
Fatsiha Chermat ◽  
Laurence Legros ◽  
Sophie Park ◽  
François Dreyfus ◽  
...  
Keyword(s):  
High Risk ◽  
Response Duration ◽  
Response Rates ◽  
Phase Iii ◽  
Monosomy 7 ◽  
Phase Iii Trial ◽  
Early Evaluation ◽  
Fda Approval ◽  
Previously Treated ◽  
Patient Refusal

Abstract Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial. Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks. Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16]. Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p<0.1); 75%, 56% and 59% for fav, int and unfav karyotype, resp (p=NS). 4/6 pts with monosomy 7 responded (1 CR+3 PR), 2/4 pts with + 8 (1 PR+1 HI) and 13/23 pts with complex karyotype (5 CR+6 PR+2 HI). OR was 56%, 77% and 56% for IPSS high, int-2 and int-1 pts, resp (p=NS) and 50%, 76% in pts previously treated or not by cytoreductive agents resp (p<0.05). Median survival from inclusion was 7 months [range 3–17]. AZA induced myelosuppression lead to dose reduction in 17% pts and hospitalization in 13% pts but was not responsible for any death. Other side effects included frequent local reactions (reversible with local NSAID) (32%), grade I-II gastro-intestinal disorders (39%), unexpected cardiac arythmias (3%). Conclusion : AZA, in this population with overall unfavorable features, gave response rates at least similar to those of CALGB studies, that may have been higher if treatment had not been stopped in some of the pts stable after 2 courses. Pts with unfavorable karyotype (− 7, complex) or + 8 had about 50% response rates. Accrual in this program is continuing. Data on response duration will be presented.

Progression to and Prevention of Diabetes: Disparity of Impaired Fasting Glucose and Impaired Glucose Tolerance - Review Article

2020 ◽  
Vol 103 (8) ◽  
pp. 829-836
Keyword(s):  
High Risk ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Lifestyle Intervention ◽  
Impaired Fasting Glucose ◽  
Diabetes Prevention ◽  
Lifestyle Modification ◽  
Fasting Glucose ◽  
World Health ◽  
Risk Of Progression

It is well established that individuals who have prediabetes either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) have high risk to develop diabetes. However, it is unclear whether the rate of progression to diabetes is different between these two categories. Lifestyle modification has been recommended for diabetes prevention in these high-risk groups. However, given the differences in their pathophysiology, it is possible that these subtypes of prediabetes condition may have different responses to lifestyle modification. The present review was to summarize the risk of progression to diabetes and the effectiveness of lifestyle intervention for diabetes prevention in individuals who have isolated IGT or isolated IFG or combined. The risk of progression to diabetes is highest in combined IFG and IGT subtype. Individuals who have isolated IFG by the American Diabetes Association criteria (100 to 125 mg/dl) has lower risk of progression to diabetes than those with World Health Organization criteria (110 to 125 mg/dl) and the latter has similar or higher risk of incident diabetes than those with isolated IGT. Lifestyle modification is most effective in individuals with IGT (with or without IFG) but is less effective in those with isolated IFG. In conclusion, The risk of progression to diabetes and the effectiveness of lifestyle intervention for diabetes prevention are disparate between prediabetes subtypes. Given the paucity of diabetes prevention data in individuals with isolated IFG, more studies dedicated to this subtype is required. Keywords: Impaired fasting glucose, Impaired glucose tolerance, Prediabetes, Type 2 diabetes, Lifestyle intervention, Diabetes prevention

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