scholarly journals Quality-Adjusted Survival for Low-Dose Cytarabine (LDAC) Versus Glasdegib+LDAC Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Not Candidates for Intensive Chemotherapy: A Q-TWiST Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2610-2610 ◽  
Author(s):  
Youngmin Kwon ◽  
Timothy J Bell ◽  
Caitlyn Solem ◽  
Joseph C Cappelleri ◽  
Courtney Johnson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
Relative Gains ◽  
Mean Time ◽  
Low Dose Cytarabine

Introduction: The efficacy and safety of glasdegib (a selective oral inhibitor of hedgehog signaling pathway) in combination with low-dose cytarabine (LDAC) was evaluated in a randomized, phase 2 trial of newly diagnosed acute myeloid leukemia (AML) patients (BRIGHT AML 1003; NCT01546038). Patients receiving glasdegib+LDAC experienced statistically significant and meaningful gains in overall survival (OS) compared with patients receiving LDAC alone (median OS [95% CI]): 8.3 months [4.7-12.2] vs 4.3 months [1.9-5.7]). This analysis examined whether quality-adjusted survival improvements were similarly observed using a quality-adjusted time without symptoms of disease progression or toxicities (Q-TWiST) approach to evaluate possible trade-offs between time with adverse events (toxicities), time in relapse/progression (i.e., with symptoms of disease), and 'good' survival (i.e., time without toxicities or symptoms of progression [TWiST]) when comparing regimens. Methods: OS in BRIGHT AML 1003 data, restricted to a follow-up of 20 months, was partitioned into time with toxicity (TOX: grade 3+ adverse events prior to progression), TWiST, and time post-progression (REL). Progression was defined as treatment discontinuation due to insufficient clinical response or death; patients who discontinued for other reasons (including adverse events) were censored at the date of discontinuation unless death occurred within 28 days of discontinuation. Q-TWiST was calculated by multiplying restricted mean time in each state by respective utilities (U) and then summing up the utility-adjusted time. Base case analysis used U(TOX)=U(REL)=0.5 and U(TWiST)=1.0; threshold analyses were performed varying U(TOX) and U(REL) jointly each from 0 to 1. Relative gains in Q-TWiST (i.e., Q-TWiST difference (combination vs LDAC) / OS in LDAC arm) of ≥15% were considered clearly clinically meaningful per the clinical literature. Sensitivity analysis varied the length of follow-up and AE definitions; subgroup analyses were also performed. 95% confidence intervals were obtained using the bootstrap procedure. Results: At 20 months of follow-up, the survival rate for glasdegib+LDAC and LDAC arm was 28.2% and 7.9%, respectively. Glasdegib+LDAC patients (n=78) compared with LDAC patients (n=38) had significantly longer mean time in TWiST (+3.4 [95% confidence interval: 1.8, 5.2] months) and TOX (+0.8 [0.1, 1.6] months), and longer but non-significant REL (+0.3 [-1.9, 2.3] months). Q-TWiST was 4.0 [2.1, 5.8] months longer for glasdegib+LDAC, translating into a 75% relative improvement in quality-adjusted survival relative to LDAC alone. In threshold analyses, absolute and relative Q-TWiST gains ranged from 3.5 to 4.5 months and 66% to 85%, respectively (Table 1). They exceeded the clinically meaningful threshold for gains in Q-TWiST and were statistically significant across all combinations of U(TOX) and U(REL). Results were robust to length of follow-up 6 to 24 month and remained significant when including all adverse events regardless of grade. Discussions/Conclusions: Glasdegib+LDAC is an add-on therapy that has demonstrated significant survival benefits for newly diagnosed AML patients who are unable to receive intensive chemotherapy. While patients can experience a longer time with toxicities from receiving glasdegib+LDAC (as expected since it is given as an add-on therapy), the trade-off can still be favorable as the treatment provides added time spent in 'good' health (i.e., a significantly longer time in TWiST). In the BRIGHT AML 1003 cohort, the relative gains in OS greatly exceeded previously established thresholds for being clearly clinically meaningful, which suggests that the benefits of glasdegib+LDAC vs LDAC alone outweigh the risks. Table 1 Disclosures Kwon: Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Solem:Pharmerit International: Employment; Pfizer Inc.: Research Funding. Cappelleri:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Hoang:Pfizer Inc.: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

scholarly journals Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 890-890
Author(s):  
Andrew Wei ◽  
Stephen A. Strickland ◽  
Gail J. Roboz ◽  
Jing-Zhou Hou ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Equity Ownership ◽  
Low Dose Cytarabine

Abstract Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, <1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

Efficacy and Tolerability of Bosutinib and Imatinib in Older Versus Younger Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia–BELA Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4442-4442 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H Brümmendorf ◽  
Dong-Wook Kim ◽  
Irina Dyagil ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Kaplan Meier ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4442 Bosutinib (BOS) is an orally active, dual Src/Abl kinase inhibitor with activity and manageable toxicity in the phase 3 BELA trial of patients (pts) with newly diagnosed (≤6 mo) chronic phase (CP) chronic myeloid leukemia (CML). The current analysis of the BELA trial summarizes the activity and tolerability of BOS 500 mg/d and imatinib (IM) 400 mg/d among older (≥65 y; BOS n = 30; IM n = 27) versus younger pts (<65 y; BOS n = 220; IM n = 225). Sokal risk scores were balanced between treatment arms but, as expected, higher among older pts (4% low; 72% intermediate; 25% high) versus younger pts (39% low; 44% intermediate; 17% high). Minimum follow-up duration was 24 mo. BOS was discontinued by 37% of pts (57% older vs 35% younger; P = 0.023); difference between age groups was primarily due to adverse events (AEs; 39% vs 22%; most commonly increased alanine aminotransferase [ALT]). IM was discontinued by 27% of pts (35% older vs 28% younger; P= 0.496); disease progression was the primary reason. In the intent-to-treat population, cumulative rate of complete cytogenetic response (CCyR) by 24 mo in older/younger pts was 70%/80% on BOS and 78%/80% on IM. Median time to CCyR was 24.0 wk for older versus 12.7 wk for younger pts on BOS and 24.4 wk versus 24.7 wk on IM; in younger pts CCyR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a CCyR, 57%/79% on BOS and 76%/85% on IM were still on treatment and retained their CCyR as of the data cutoff. Cumulative rates of major molecular response (MMR) by 24 mo in older/younger pts were 53%/60% on BOS and 48%/49% on IM. Median time to MMR was 48.1 wk for older versus 48.0 wk for younger pts on BOS and 60.6 wk versus 84.1 wks on IM; for younger pts MMR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a MMR, 63%/84% on BOS and 92%/89% on IM were still on treatment and retained their MMR as of the data cutoff. Kaplan-Meier event-free survival in older/younger pts at 2 y was 100%/91% on BOS and 81%/88% on IM. Kaplan-Meier on-treatment transformation to accelerated/blast phase CML by 2 y was 0% for older and 2% (4 transformations) for younger pts on BOS (4 total), and 9% (2 transformations) for older and 5% (11 transformations) for younger pts on IM (13 total). Kaplan-Meier overall survival in older/younger pts at 2 y was 100%/97% on BOS and 92%/95% on IM. The majority of deaths were due to disease progression (BOS, n = 6; IM, n = 10); few deaths due to AEs on BOS (n = 1) or IM (n = 2) were reported, none treatment related. BOS was associated with higher rates of gastrointestinal TEAEs, elevated ALT and aspartate aminotransferase (AST), and pyrexia; IM was associated with higher rates of musculoskeletal TEAEs and edema (Table). Rates of common TEAEs were generally similar or higher among older pts. Pleural/pericardial effusion occurred in 6 (21%) older pts (3/6 with treatment-related events; median event duration, 36.5 d) versus 5 (2%) younger pts (all with treatment-related events) on BOS, and in no IM pts. Overall grade 3/4 TEAEs were more frequent among older pts on both BOS and IM, as was dose modification (Table). Grade 3/4 lab abnormalities of elevated ALT (BOS, 18% older/24% younger; IM, 4% each) and AST (BOS, 7%/12%; IM, 4% each) were more frequent with BOS versus IM, but similar between age groups. Grade 3/4 lab abnormalities of neutropenia were more frequent with IM (23% older/22% younger) versus BOS (11% each) regardless of age; grade 3/4 anemia (6%-14%) and thrombocytopenia (14%-23%) were generally similar regardless of age or treatment arm. In conclusion, BOS demonstrated activity in both older and younger pts with newly diagnosed CP CML. Although the frequency of certain toxicities as well as treatment discontinuations due to TEAEs was higher among older pts, the toxicity profile of BOS remained manageable and distinct from that of IM regardless of age. Event, % BOS IM ≥65 y (n = 28) <65 y (n = 220) ≥65 y (n = 26) <65 y (n = 225) Non-hematologic TEAEsa     Diarrhea 86 68 46 22     Rash 36 22 27 18     Nausea 36 32 31 37     Vomiting 32 32 19 15     Dyspnea 32 5 12 3     Pyrexia 29 17 4 13     Elevated ALT 29 32 15 8     Elevated AST 25 27 15 8     Elevated lipase 25 12 19 10     Headache 21 12 8 12     Asthenia 21 5 4 7     Dyspepsia 14 6 23 5     Muscle spasms 14 3 35 21     Periorbital edema 7 <1 35 12 Any grade 3/4 TEAE 89 65 73 56 Dose reduction due to AE 64 40 42 18 Dose interruption due to AE 89 63 69 42 Treatment discontinuation due to AE 39 22 8 9 All treated pts were included in the safety analyses. a Includes TEAEs reported for ≥20% of older or younger pts. Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4229-4229
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Mohit Narang ◽  
Jayesh Mehta ◽  
Howard R. Terebelo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Equity Ownership ◽  
Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 99-99 ◽  
Author(s):  
Jorge E. Cortes ◽  
Florian H. Heidel ◽  
Michael Heuser ◽  
Walter Fiedler ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
P Value ◽  
Employment Equity ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

An Ongoing Phase 3 Study of Bosutinib (SKI-606) Versus Imatinib In Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 208-208 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brummendorf ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 208 Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor (TKI), with minimal inhibitory activity against PDGFR or c-kit. In a phase 2 study, bosutinib demonstrated activity in patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) in the second- and third-line treatment settings (Cortes JE, et al. ASCO 2010, Abstract #6502; Khoury JH, et al. ASCO 2010, Abstract #6514), as well as in patients with advanced Ph+ leukemias (Gambacorti-Passerini C, et al. ASCO 2010, Abstract #6509) following resistance or intolerance to imatinib and other TKIs. The current randomized, open-label, phase 3 study compared the activity and safety of bosutinib with that of imatinib in newly diagnosed patients with CP CML. The study enrolled adults aged 318 years with cytogenetic diagnosis of Ph+ CP CML within 6 months, adequate hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomized to daily oral treatment with 500 mg bosutinib or 400 mg imatinib. Adverse events were graded using the National Cancer Institute Common Terminology Criteria, version 3.0. The primary efficacy endpoint was the rate of complete cytogenetic response (CCyR) at 1 year; the rates of hematologic response, molecular response, and progression and transformation to accelerated or blast phase were also evaluated. The study randomized 502 patients: 56.6% male, median age of 48 years (range, 18–91 years), and median time since diagnosis of 0.7 months (range, -0.3-7.9 months; the range minimum is negative due to CML diagnosis during the study screening period, and the range maximum is >6 months because of 1 patient considered a major protocol violator). The median duration of treatment was 11.1 months (range, 0.03–24.8 months). At Week 48 (approximately 11 months), 71.5% and 74.8% of patients (both treatment arms combined) were in CCyR and complete hematologic response (CHR), respectively. During the study, 81.4% of patients achieved a CCyR at or before Week 48, with a median time to CCyR of 24 weeks; 82.6% of patients achieved a CHR, with a median time to CHR of 8 weeks; and 40.6% of patients achieved a major molecular response (MMR), with a median time to MMR of 49 to 61 weeks for the 2 treatment arms. For the combined treatment arms, common treatment-emergent adverse events included diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). The only grade 33 treatment-emergent adverse event observed in 32% of patients was diarrhea (5.2%), which was usually limited to the first weeks of treatment. Grade 33 hematologic laboratory abnormalities included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%). Other grade 33 laboratory abnormalities (35% of patients) included alanine aminotransferase elevation (11.6%), phosphatemia (7.6%), and aspartate aminotransferase elevation (6.4%). Overall, 22.2% patients discontinued therapy; adverse events led to discontinuation or death in 12.8% of patients, and 4.2% of patients discontinued due to disease progression. The high combined percentage of patients achieving MMR, CCyR, and CHR and the relatively low incidence of generally manageable grade 33 events observed suggest good efficacy and an overall favorable safety profile. Data for individual treatment arms will be unblinded by the end of August 2010, and will be presented at the meeting. Disclosures: Gambacorti-Passerini: Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; BMS, Pfizer: Research Funding. Brummendorf:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Griskevicius:Pfizer Inc: Research Funding. Goh:Novartis and Janssen Ciliag: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Cortes:Pfizer Inc: Consultancy, Research Funding.

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 452-452 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp D. LeCoutre ◽  
Ricardo Pasquini ◽  
Saengsuree Jootar ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Safety Data ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Comparison of Splenectomy and Treatment Failure Incidence in Nonsplenectomized Patients with Immune Thrombocytopenia (ITP) Receiving Romiplostim or Medical Standard of Care: 1-Year Treatment and 6-Month Safety Follow-up.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 679-679 ◽  
Author(s):  
David J Kuter ◽  
Mathias J Rummel ◽  
Ralph Vincent Boccia ◽  
B. Gail Macik ◽  
Ingrid Pabinger ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Treatment Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Actual Incidence

Abstract Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count <50 × 109/L. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. Patients received romiplostim or SOC for 52 weeks, and those who did not subsequently transfer to another romiplostim study completed a 6-month off-treatment safety follow-up. Co-primary endpoints of the study were: the incidence of splenectomy and the incidence of treatment failure (defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms). Patients who discontinued study during the treatment period were counted as having had splenectomy or treatment failure. To assess the impact of treatment discontinuation on the primary endpoints, a sensitivity analysis was conducted to determine the actual incidence of splenectomy or treatment failure. A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p<0.0001), and the incidence of treatment failure was 12% (18/157) in the romiplostim group compared to 30% (23/77) in the SOC group (OR, 0.31; 0.15, 0.61; p=0.0005). Sensitivity analyses confirmed the primary endpoint analyses: the actual incidence of splenectomy was significantly lower in the romiplostim group (2/157, 1%) than the SOC group (15/77, 20%) [p<0.0001], and the actual incidence of treatment failure was significantly lower in the romiplostim group (6/157, 4%) than the SOC group (10/77, 13%) [p=0.009]. The incidence of bleeding events with a worst grade score ≥3 appeared lower for patients in the romiplostim group (3%) than the SOC group (7%). Safety analyses included only patients who received ≥1 dose of romiplostim or 1 type of SOC. During the 52-week treatment period, adverse events occurred in 96% (147/154) of patients receiving romiplostim and 92% (69/75) of patients receiving SOC. Serious adverse events occurred in 23% (35/154) of romiplostim and 37% (28/75) of SOC patients; serious adverse events were considered treatment-related in 5% (7/154) of romiplostim and 8% (6/75) of SOC patients. During the 6-month safety follow-up period, 36% (11/31) of romiplostim and 43% (18/42) of SOC patients experienced an adverse event; treatment-related adverse events occurred in none of the romiplostim patients and 2 of the SOC patients. Overall, 6 patients died: 1 (1%) in the romiplostim group and 5 (7%) in the SOC group. None of the deaths were considered related to study treatment or the underlying ITP. No patients tested positive for neutralizing antibodies to romiplostim or TPO. One romiplostim-treated patient showed an increase in bone marrow reticulin that was still within the normal range (Grade 2). In summary, romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to SOC. The safety profile of romiplostim was similar to SOC. Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2768-2768 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Francois Guilhot ◽  
Chao Zhu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Response Rates ◽  
Similar Response ◽  
Medical Procedure ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Reductions

Abstract Abstract 2768 Background: 24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP. Methods: Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses. Results: 134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose. Conclusions: Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3768-3768 ◽  
Author(s):  
Richard A. Larson ◽  
Udomsak Bunworasate ◽  
Anna G. Turkina ◽  
Stuart L. Goldberg ◽  
Pedro Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Durable Responses Following Treatment with the PI3K-Delta Inhibitor Idelalisib in Combination with Rituximab, Bendamustine, or Both, in Recurrent Indolent Non-Hodgkin Lymphoma: Phase I/II Results

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3063-3063 ◽  
Author(s):  
Sven de Vos ◽  
Nina D. Wagner-Johnston ◽  
Steven E. Coutre ◽  
Ian Flinn ◽  
Marshall T. Schreeder ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Stable Disease ◽  
Research Funding ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Grade 3 ◽  
Systemic Therapies

Abstract Introduction: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity as monotherapy in recurrent (Flinn, Blood 2014) or refractory iNHL subjects (Gopal, NEJM 2014). FDA granted accelerated approval for Idelalisib (ZYDELIG®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. This study evaluated Idelalisib in combination with rituximab, bendamustine, or both. We now present mature safety and response data with up to 4 years of follow up. Methods: Eligible patients had relapsed/refractory indolent NHL. Idelalisib (Z) was administered continuously with rituximab (R) (375 mg/m2 given weekly for 8 doses) (R/Z regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2, for 6 cycles) (B/Z regimen), or in combination with R (375 mg/m2, on Day 1) and B (90 mg/m2 given on Days 1 and 2 of each cycle, for 6 cycles (BR/Z regimen). Initial subjects in the R/Z and B/Z groups (n=8 each), received Idelalisib 100 mg/dose BID. Thereafter, all patients received an Idelalisib dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). The cutoff date for this analysis was June 2014, 26 months after the last patient enrolled. Results: Between April 2010 and May 2012, 79 subjects with iNHL were enrolled (including 59 with FL, 15 with SLL, and 5 with MZL). Median [range] age was 61 [37-84] years. At baseline patients had elevated beta-2 microglobulin (59%), stage IV disease (58%), bulky adenopathy (> 5cm) (48%), anemia (Hgb <12gm/dL) (41%), and elevated LDH (28%). Patients had a median number of 3 prior therapies (range 1 -11). Most patients had received a rituximab-containing regimen (98%), an alkylating agent (86%), or an anthracycline (53%). Approximately 46% of patients were refractory to their last pre-study therapy and 58% of patients were refractory to rituximab. Frequent adverse events (all grade %/grade 3-4 %) included pyrexia (54/3), nausea (44/0), fatigue (43/4), diarrhea (39/15), rash (38/9), cough (35/0), pneumonia (22/19), pneumonitis (4/3), and febrile neutropenia (3/3). Laboratory abnormalities included lymphopenia (75/62), neutropenia (56/41), anemia (47/10), thrombocytopenia (42/8), and serum transaminase elevations (56/17). Drug was temporarily held for Grade 3/4 ALT/AST elevations, and 8/13 pts (62%) were re-treated without recurrence of ALT/AST elevation. 27% of pts have discontinued therapy due to adverse events. Of the 79 subjects enrolled, 64 had an objective response with an ORR of 81% (95% CI: 70.6-89.0). Complete responses were demonstrated in 26 patients (33%), and partial responses in 38 patients (48%). In addition, 7 patients had stable disease (9%), and 4 patients had progressive disease (5%) as best response on-study. Four patients were non-evaluable, as they did not have follow up CT scans. By treatment subgroup, the ORR were (n=24/32) 75% (95% CI: 57-89) for R/Z, (n=29/33) 88% (95% CI: 72-97) for B/Z, and (n=11/14) 79% (95% CI: 49-95) BR/Z. The CR rates were 25% (n=8/32), 36% (n=12/33), and 43% (n=6/14) respectively; stable disease was noted in 4/32 patients (13%), 3/33 patients (9%), and 0/14 patients in the three groups respectively. ORR/CR by iNHL subtype is: FL (81%/39%), SLL (73%/13%), and MZL (100%/20%). The median progression-free survival is 32.8 months. Median PFS for R/Z group is 29.7 months, B/Z group 32.8 months, and BR/Z group 37.1 months. The PFS at 24 months was 55%, 64%, and 71% for the R/Z, B/Z, and BR/Z groups respectively. The median duration of response has not yet been reached. Median DOR for the R/Z group is 28.6 months, for the B/Z, and BR/Z groups it is not yet reached. The DOR at 24 months was 65%, 67%, and 64% for the R/Z, B/Z, and BR/Z groups respectively. Figure 1: Median overall survival is not yet reached. Conclusions: Idelalisib in combination therapy was well tolerated, had an acceptable safety profile, and was highly effective in this recurrent iNHL population with an ORR of 81%, and CR rate of 33%. Responses are durable beyond 2 years, supporting further evaluation of these combination regimens. Phase 3 trials evaluating the efficacy of Idelalisib in combination with R or BR in iNHL are ongoing (NCT01732913, NCT01732929). Figure 1 Figure 1. Disclosures de Vos: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Wagner-Johnston:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Leonard:Gilead Sciences: Research Funding.

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