Safety of Lenalidomide (LEN) 10mg in Non-Del(5q) Versus Del(5q) in the Treatment of Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS): Pooled Analysis of Treatment-Emergent Adverse Events (TEAEs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2880-2880 ◽  
Author(s):  
Antonio Almeida ◽  
Valeria Santini ◽  
Stefanie Gröpper ◽  
Anna Jonasova ◽  
Norbert Vey ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lower Risk ◽  
Research Funding ◽  
Pooled Analysis ◽  
Employment Equity ◽  
Pooled Data ◽  
Starting Dose ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg. Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%. Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies. Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. Disclosures Almeida: Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

scholarly journals Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1708-1708 ◽  
Author(s):  
Ajay K. Gopal ◽  
Brad S. Kahl ◽  
Sven de Vos ◽  
Nina D. Wagner-Johnston ◽  
Stephen J. Schuster ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes “double-refractory” to both rituximab + alkylating agents, there are limited options to induce durable remissions. 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 in double-refractory iNHL (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. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: 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.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

scholarly journals Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1949-1949 ◽  
Author(s):  
Hans Michael Kvasnicka ◽  
Juergen Thiele ◽  
Carlos E. Bueso-Ramos ◽  
William Sun ◽  
Ahmad Naim ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Rank Test ◽  
Employment Equity ◽  
Advisory Committees ◽  
Signed Rank ◽  
Signed Rank Test ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-Term Safety and Durability Of Response In Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients In An Open-Label Extension Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4163-4163 ◽  
Author(s):  
Susan O'Brien ◽  
Richard R. Furman ◽  
Nathan Fowler ◽  
Steven E. Coutre ◽  
Jeff P. Sharman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Extension Study ◽  
First Year ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background Bruton’s Tyrosine Kinase (BTK) plays a critical role in chronic lymphocytic leukemia (CLL) cell survival by modulating B-cell receptor signaling. Ibrutinib (PCI-32765), a first-in-class oral inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells. A total of 148 patients with CLL/SLL received ibrutinib monotherapy in a Phase 1 multiple ascending dose study (PCYC-04753) or Phase 1b/2 continuous dosing study (PCYC-1102-CA), after which a long-term extension study was available for continued follow-up for safety and efficacy with daily orally-administered ibrutinib monotherapy. The studies included patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL/SLL. The aims of the present analysis were to evaluate safety based on time on ibrutinib therapy (≤ 1 year and > 1 year), summarize safety findings in the TN and RR patient populations, and assess duration of response (DOR). Methods Demographics and baseline characteristics were summarized according to parent study, comprising either TN patients or RR CLL/SLL patients who had received at least one dose of ibrutinib monotherapy. Patient disposition, treatment-emergent adverse events (AEs), best response, overall response rate (ORR), and DOR were determined for the time treated (beginning in the parent studies and extending into the long-term extension study). Results At a median treatment duration of 21.5 months, 109 out of 148 patients continued treatment with ibrutinib for over a year. The percentage of patients who had a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. With respect to side effects determined to be related to study drug, the number of grade 3 AEs and SAEs also declined from within the first year of treatment (24% and 8%, respectively) to after the first year of treatment (7% and 0%, respectively). AEs leading to ibrutinib discontinuation occurred in 12 patients within the first year of treatment for all 148 patients and in 6 out of 109 patients after the first year of treatment. Overall, the most frequent AEs grade 3 or higher were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%), and diarrhea (5.4%), regardless of relationship to study drug. Grade 3 or higher SAEs were reported in RR patients at 62% compared to TN patients at 29%. Pneumonia was reported in TN patients at 6.5% and in RR patients at 19.7%. Within the efficacy population (n = 140), the ORR was 86.2% for TN patients and 88.3% for RR patients who achieved a partial response (PR) or better. The ORR combined with PR with lymphocytosis suggests that 93.1% of TN patients and 93.7% of RR patients achieved an objective response to ibrutinib therapy based on Cheson JCO 2012. After a median follow up of 27.2 months (range 1.9-42 months) for TN and RR responders who achieved PR or better, the median DOR has not been reached. At landmark 30 months, 76.1% of the responders were alive without progression. Conclusions Ibrutinib as a single agent demonstrates long-term safety, tolerability, and durability of response in patients with TN and RR CLL/SLL. Indeed, a decrease in the number of patients experiencing SAEs or AEs grade 3 or higher after 1 year of treatment with ibrutinib resulted in low rates of treatment-related discontinuation after that time point. Grade 3 or higher SAEs were reported at a two-fold higher rate in patients who had received prior therapies, which may be reflective of disease state rather than relationship to ibrutinib. A majority of patients remain on ibrutinib monotherapy with the median DOR not yet reached in the ongoing extension study. Disclosures: O'Brien: Pharmacyclics: Research Funding. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Fowler:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Coutre:Pharmacyclics: Consultancy, Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Jones:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wierda:Abbott Laboratories: Research Funding; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, DSMB, DSMB Other, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Tragara: Research Funding. Flinn:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding; Janssen: Research Funding. Kolibaba:Pharmacyclics: Research Funding. Shaw:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Chu:Pharmacyclics: Employment, Equity Ownership. Byrd:Celgene: Consultancy; Johnson and Johnson: Consultancy; Pharmacyclics: Research Funding.

scholarly journals Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 463-463 ◽  
Author(s):  
David P. Steensma ◽  
Uwe Platzbecker ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership ◽  
Grade 3 ◽  
Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

An Ethnographic Investigation Tracking the Experience of Chronic Myeloid Leukemia (CML) Patients on Tyrosine Kinase Inhibitor (TKI) Therapies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 394-394 ◽  
Author(s):  
François Guilhot ◽  
John Coombs ◽  
Tomasz Szczudlo ◽  
Oleg Zernovak ◽  
Nancy J. Macdonald ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Healthcare Providers ◽  
Work And Family ◽  
Employment Equity ◽  
Study Results ◽  
Equity Ownership ◽  
The Impact

Abstract Abstract 394 Background: The advent and approval of TKIs has dramatically improved the life expectancy of patients with CML. As treatment innovation has transformed CML into a chronically managed disease, we examined the impact of these changes on patients with CML in order to offer recommendations for healthcare providers (HCPs) to better support patients with CML. Method: 50 patients with CML from Brazil, France, Germany, Russia and Spain were included in this ethnographic investigation including: patients within 18 months of diagnosis and on frontline imatinib therapy (n = 20), patients with ongoing frontline treatment (> 18 months to 7 years, n = 20), and patients who were switched to second- or third-line TKI therapies (n = 10). Patients in all 5 countries participated in a 2.5-hour in-home interview, and patients in Brazil and France completed 7-day photo journals and an optional telephone debrief interview. Patients were asked to discuss and write about their perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and their relationship with HCPs. Result: This global ethnographic investigation generated a 5-stage, patient-centered model emphasizing emotions and experiences throughout the diagnosis, treatment and management of their disease: crisis, hope, adaption, normalcy, and uncertainty. Depending upon their circumstances, these experiential stages were found to be abbreviated or prolonged and influenced by patients having differentiating levels of knowledge about their disease, comfort levels with the treatment and/or their HCPs, as well as different degrees of optimism about their treatment and long-term prognosis. In addition, the study results showed that patients cycle through the various stages of the model throughout the course of their disease. The crisis phase occurred at diagnosis and tended to resolve upon HCP reassurance of the availability of successful treatments. Hope followed crisis when patients were educated about their disease and its treatments and responded to initial therapy. Adaption involved patients adjusting to any physical changes wrought by the disease, treatments, and associated adverse events. As well, they began to psychologically come to terms with the long-term nature of their disease and develop their drug-taking routines and compliance pattern. As patients attained stability in their disease and adapted to changes, a ‘new’ normal returned and patients began to refocus their life away from the disease back to social, work, and family matters. The uncertainty stage was found to be associated with drug resistance, disease progression, newly occurring adverse events, or due to limitations around access to therapy because of public health regulations or personal financial issues. While uncertainty arose for multiple reasons and could occur at any time after patients had advanced through the 4 preceding phases, patients who went through stages of uncertainty most often cycled back to phases of adaption or normalcy once the issues were resolved. Conclusions: Here, we have identified 5 common patient experience stages and we provide recommendations based on patient research for the management of CML. This investigation suggests that HCPs can help patients move through the early stages of crisis and hope by providing reassurance, along with information and resources regarding drug efficacy and product differentiation, while explaining the importance of speed and depth of responses. Once in the adaption/normalcy stages, HCPs should set expectations for the risk/benefits of long-term chronic drug therapy and long-term disease monitoring and continue to support patient compliance and adherence programs while helping patients achieve and maintain a normal lifestyle. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Macdonald:Novartis: Consultancy. Shapiro:Novartis: Consultancy.

Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 800-800 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Jason Gotlib ◽  
Richard S. Levy ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Survival Advantage ◽  
Primary Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 800 Background: Ruxolitinib (RUX), an oral JAK1/JAK2 inhibitor, reduced spleen volume (SV), improved myelofibrosis (MF)-associated symptoms and quality of life (QoL), and appeared to exhibit a survival advantage over placebo (PBO) in patients (pts) with MF regardless of JAK2V617F mutation status in the phase III COMFORT-I study. We describe long-term efficacy and safety of RUX from COMFORT-I, with 1 year of additional follow up beyond previously published data. Methods: Eligible pts (N=309) were randomized (1:1) to RUX or PBO. The primary analysis occurred when all pts completed 24 weeks (wks) and when half the pts completed 36 wks of treatment. All pts receiving PBO were eligible for crossover to RUX after the primary analysis; crossover before wk 24 was permitted if pts met protocol-defined criteria for worsening splenomegaly. The proportion of pts with ≥35% SV reduction at 24 wks (primary endpoint) and durability of SV response were assessed. Although symptom burden (measured daily using the modified MF Symptom Assessment Form v2.0) was only measured up to wk 24, QoL continued to be evaluated beyond wk 24 (every 24 wks) using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Overall survival (OS) was assessed according to original randomized treatment. Results: In this updated analysis, median follow-up of pts randomized to RUX was 102 wks. All pts receiving PBO completed crossover or discontinued within 3 months of the primary analysis. Of 134 pts randomized to RUX who remained on treatment after the primary data analysis, 100 continue on study. Mean SV reduction in pts randomized to RUX was 31.6% at wk 24 and has remained stable with additional follow up through wk 96 (Table). In pts who achieved a ≥35% SV reduction, response was durable, with a median response duration of 108 wks. RUX treatment was also associated with durable improvements in the Global Health Status/QoL (Table) and the 5 functional domains of the EORTC QLQ-C30. Twenty-seven (27) pts randomized to RUX and 41 pts randomized to PBO died, representing a continued OS benefit in favor of RUX (HR=0.58; 95% CI: 0.36, 0.95; P = 0.028; Fig 1) similar in magnitude to that previously reported. OS favored RUX across subgroups including starting dose as well as baseline risk status and hemoglobin (Hgb). Of 34 pts randomized to RUX who discontinued after the primary analysis, 4 discontinued for an adverse event (AE). In pts who continued on RUX, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in only 12 and 5 pts, respectively. One pt discontinued for anemia. Overall, among all pts randomized to RUX, Grade 3 and 4 anemia regardless of baseline Hgb was reported in 37.4% and 14.8% of pts, respectively. Similarly, Grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of pts, respectively. These rates were similar to those reported in the primary analysis. By wk 36, the proportion of pts receiving red blood cell transfusions decreased to the level seen with PBO and remained stable thereafter (Fig 2). Rates of nonhematologic AEs adjusted for increased follow-up duration remain similar to those seen at the time of the primary data analysis. No additional cases of acute myeloid leukemia (AML) in pts randomized to RUX were reported. Two pts originally randomized to PBO developed AML, 21 and 178 days after crossover to RUX. There continued to be no reports of a withdrawal syndrome after RUX discontinuation. Conclusions: RUX provides durable reductions in SV and improvements in QoL. Although all pts randomized to PBO crossed over to RUX shortly after the primary analysis, with 1 year of additional follow up, RUX continues to be associated with a survival advantage over PBO. RUX continues to be well tolerated; the AE profile with long-term treatment is consistent with that previously reported. The proportion of pts receiving transfusions decreased over time to rates similar to PBO, and there were no reports of a specific withdrawal syndrome or cytokine rebound phenomenon after RUX discontinuation. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy, travel to congress Other. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofiå]Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Catalano:Incyte: Consultancy. Deininger:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Winton:Incyte: Consultancy, Honoraria. Arcasoy:Incyte: Research Funding. Lyons:Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Telik: Research Funding. Paquette:Incyte: Consultancy. Vaddi:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Kantarjian:Incyte: grant support Other.

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.

Safety and Efficacy of Oral Azacitidine (CC-486) Administered in Extended Treatment Schedules to Patients with Lower-Risk Myelodysplastic Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 424-424 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Suman Kambhampati ◽  
Bart L Scott ◽  
Ayalew Tefferi ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Employment Equity ◽  
Once Daily ◽  
Hematologic Response ◽  
Dosing Regimens ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 424 Background: Azacitidine for injection has been shown to prolong overall survival in patients (pts) with higher-risk myelodysplastic syndromes (MDS) compared with conventional care regimens (CCR) (Lancet Oncol, 2009). An oral formulation of azacitidine (CC-486) is in development. Oral azacitidine may maximize convenience, eliminate injection-site reactions, and if administered in extended dosing schedules, may enhance and prolong the therapeutic effects of azacitidine. Oral azacitidine administered once-daily (QD) for 7 days (d) of repeated 28d cycles has been shown to be bioavailable, biologically and clinically active, and well-tolerated in pts with MDS and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Preliminary evidence suggests that extending oral azacitidine dosing to 14d or 21d of the 28d cycle may enhance pharmacodynamic and epigenetic activity (Laille, Leuk Res, 2011). Purpose: To evaluate hematologic response and safety associated with extended dosing regimens of oral azacitidine in pts with lower-risk MDS. Methods: This ongoing, multicenter, phase 1 study, enrolled pts with lower-risk (IPSS Low or INT-1) MDS who were RBC transfusion dependent (TD) and/or thrombocytopenic (average platelet count ≤50,000 within 56d prior to the first dose) at baseline. Pts were sequentially assigned to receive oral azacitidine 300mg QD for either 14d or 21d of repeated 28d cycles. Hematologic assessments were made every 2 weeks. Hematologic response was assessed using IWG 2006 criteria (Cheson, Blood, 2006). Adverse events (AEs) were graded using NCI-CTCAE version 3.0. Results: At data cut-off (May 18, 2012), 53 pts with lower-risk MDS had enrolled (300mg oral azacitidine QDx14d, n=26; QDx21d, n=27). Demographic and disease characteristics at baseline were similar in the 14d and 21d treatment cohorts (Table 1). Median (range) hematology counts at baseline were Hgb 8.7 g/L (6.0–13.0), ANC 1.6×109/L (0–30.3), and platelets 56.0×109/L (6.0–564.0). At study entry, 40% of pts had received no prior MDS treatment (except transfusions), 45% had received erythropoiesis-stimulating agents, and 15% had received WBC growth factors. The number of oral azacitidine treatment cycles received ranged from 1 to 12 (median numbers of oral azacitidine cycles were 6 in the QDx14d and 4 in the QDx21d cohorts). Four pts in the 21d cohort and 1 pt in the 14d cohort received reduced oral azacitidine doses (200mg QD). Overall, 10 pts discontinued the study, including 6 pts (3 pts in each cohort) who discontinued due to AEs that may have been treatment-related (gastrointestinal [n=2] or intracranial [n=1] hemorrhage, febrile neutropenia [n=1], pneumonia [n=1], thrombocytopenia [n=1]). Overall response rates (ORR), which included complete (CR) and partial remission (PR), any hematologic improvement (HI), and transfusion independence (TI), ranged from 38.5% in the QDx14d cohort to 29.6% in the QDx21d cohort, and RBC TI was achieved by 47% and 33%, respectively, of pts who were RBC TD at baseline (Table 2). For pts who received at least 4 cycles of oral azacitidine (14d, n=19; 21d, n=14), ORR was 47.4% in the 14d and 50.0% in the 21d cohorts, and RBC TI rates in RBC TD pts (n=16) were 67% in the 14d and 57% in the 21d cohorts. The most frequent (≥5%) grade 3/4 hematologic AEs in the QDx14d cohort were anemia (11.5%), thrombocytopenia (11.5%), and neutropenia (7.7%); and in the QDx21d cohort were neutropenia (14.8%), anemia (7.4%), and febrile neutropenia (7.4%). Most frequent grade 3/4 non-hematologic AEs were gastrointestinal, including vomiting (7.7%) in the QDx14d cohort, and diarrhea (11.1%) and vomiting (7.4%) in the QDx21d cohort. Conclusions: Oral azacitidine 300mg QD administered in extended dosing schedules of 14d or 21d of repeated 28d cycles was effective and well-tolerated in these pts with lower-risk MDS. Beside hematologic AEs, the most frequently observed AEs with oral azacitidine were gastrointestinal and were manageable. Efficacy and safety outcomes with 300mg QD oral azacitidine were generally comparable between the 14d and 21d extended dosing regimens. Based on these data, oral azacitidine administered once-daily in extended dosing schedules is active and well-tolerated and warrants further investigation in randomized, controlled trials. Disclosures: Garcia-Manero: Celgene: Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Scott:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Hetzer:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership.

scholarly journals Exploration of Potential Relationships between CD22 and Selected Safety Outcomes in the Inotuzumab Ozogamicin Phase 3 INO-VATE Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4031-4031
Author(s):  
Partow Kebriaei ◽  
Daniel J. DeAngelo ◽  
Anjali S. Advani ◽  
Susan M. O'Brien ◽  
David Marks ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Research Funding ◽  
Post Treatment ◽  
Employment Equity ◽  
Inotuzumab Ozogamicin ◽  
Post Transplant ◽  
Safety Outcomes ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: CD22 is widely expressed on leukemic lymphoblasts in patients with B-cell acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, has shown significantly higher remission rates than standard of care (SC) chemotherapy in relapsed or refractory B-cell (R/R) ALL, independently of CD22 expression level. Here we report safety outcomes by CD22 expression in patients with R/R ALL receiving InO (vs SC) as salvage therapy in the INO-VATE trial (NCT01564784). Methods: Adults with CD22-positive ALL in 1st or 2nd salvage were randomized to InO (n=164; starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or SC (n=162; fludarabine/high-dose (HD) cytarabine (Ara-C)/granulocyte colony-stimulating factor, Ara-C plus mitoxantrone, or HD Ara-C).The InO dose was reduced to 1.5 mg/m2 per cycle in patients who achieved complete remission [CR] or CR with incomplete hematologic recover [CRi]. Last patient visit was January 4, 2017. Central flow cytometry was used to assess CD22 expression, which was quantified as % leukemic blasts CD22-positive and as Molecules of Equivalent Soluble Fluorochrome (a quantitative measure of receptor density on leukemic blasts [MESF]). Outcomes were reported in patients by baseline leukemic blast positivity (≥90% vs <90%), and in quartiles of patients (Q1-Q4) defined by CD22 MESF: Q1=lowest CD22 expression, Q4= highest CD22 expression. Results: At baseline, 142 InO patients and 117 SC patients had an evaluable sample for central-lab CD22 analysis. The majority of patients in both arms had high (≥90%) CD22 positivity (InO, 75.4%; SC, 72.6%), with a smaller proportion of patients exhibiting CD22 positivity <90% (InO, 24.6%; SC, 27.4%). The median number of completed cycles in the InO arm for the CD22 expression quartiles was n=2 for Q1, n=3 for Q2, n=2 for Q3, and n=3 for Q4; respective median overall dose was similar across quartiles: 4.2 mg/m2 (range: 1.3-9.2), 4.5 mg/m2 (range: 0.8-9.2), 4.2 mg/m2 (range: 0.8-9.3), and 4.6 mg/m2 (range: 0.8-9.6). In both arms, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (InO, 47% vs SC, 44%), thrombocytopenia (InO, 40% vs SC, 58%), febrile neutropenia (InO, 28% vs SC, 55%), leukopenia (InO, 29% vs SC, 34%), and anemia (InO, 24% vs SC, 44%), with similar rates between CD22 MESF expression quartiles (Table 1). Grade ≥3 hepatotoxicity occurred more frequently in the InO arm (17%) vs SC (8%), occurring with similar rates in the CD22 expression quartiles (Table 1). In the InO arm, more patients with ≥90% CD22 positivity received post-treatment SCT (60 [56%] vs 12 [34%] patients with CD22 <90%); 9 (8%) patients with ≥90% CD22 positivity and 2 (6%) patients with <90% also had a pre-treatment SCT. The rate of post-treatment SCT in the CD22 MESF expression quartiles is shown in Table 2. Among patients who proceeded to SCT in the InO arm, where VOD risk was higher, post-transplant VOD occurred in 16 (27%) patients with ≥90% CD22 positivity vs 2 (17%) patients with <90%. When assessing CD22 expression by MESF, the rate of post-transplant VOD was similar across CD22 MESF quartiles (Table 2). Conclusions: The risk of developing TEAEs, including hepatic adverse events, which were more common in the InO vs SC arm, was not associated with intensity of CD22 expression in either the InO or SC arm. Among InO patients with post-treatment SCT, there was no apparent relationship between CD22 expression and the risk of developing VOD, when analyzing CD22 by % positivity or by MESF. Disclosures DeAngelo: BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria. Advani:Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. O'Brien:Sunesis: Consultancy, Research Funding; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Astellas: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; Kite Pharma: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; Pharmacyclics: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Wang:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Stelljes:Amgen: Honoraria; MSD: Consultancy; JAZZ: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

Interim Results for the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia (CC-5013-CLL-009 Study)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2859-2859
Author(s):  
Clemens Wendtner ◽  
Graeme Fraser ◽  
Stuart L. Goldberg ◽  
Adrian JC Bloor ◽  
Stephan Stilgenbauer ◽  
...  
Keyword(s):  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
Study Drug ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Tumor Lysis ◽  
Starting Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Double Blinded

Abstract Abstract 2859 Introduction: Patients with chronic lymphocytic leukemia who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These patients have limited therapeutic options and novel agents with alternative mechanisms of action are needed. In phase 1 and 2 trials, escalating dose regimens of the immunomodulatory agent lenalidomide demonstrated promising activity with relapsed/refractory CLL. Of interest, the data indicate that superior efficacy might be achieved by a starting dose above 2.5 mg daily lenalidomide. A phase 2 trial (CLL-009 study) was developed to investigate the safety of different starting doses of lenalidomide followed by a step-wise dose escalation as tolerated in relapsed/refractory CLL. Methods: In this ongoing trial, eligible subjects with relapsed/refractory CLL who have received at least 1 prior treatment regimen are being enrolled. Subjects are randomized 1 :1 :1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral lenalidomide on days 1–28 of each 28-day cycle. The primary objectives are to determine the safety and efficacy of the different lenalidomide starting doses of 5 mg, 10 mg or 15 mg daily, followed by an intra-patient escalation up to a maximum of 25 mg daily using a Bayesian approach. Based on individual patient tolerability, the daily lenalidomide dose can be escalated every 28 days by 5 mg increments. Dose reductions also occur in 5 mg increments; however, dose levels below 5 mg sequentially include 2.5 mg and 1.25 mg daily. Tumor lysis syndrome (TLS) prophylaxis, comprised of oral hydration and allopurinol 300 mg/day is initiated at least 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. This adaptive design trial is considering joint efficacy and toxicity outcomes to stop randomization of less promising arms. Accrual to a starting dose arm will be stopped if unacceptable toxicities and/or high progression rate are observed in that arm. A total of 90 subjects will be enrolled in the study. Results: To date, 51 subjects with a median age of 63 years (range 39–78) have been enrolled. Subjects to date are primarily male (65%) and Caucasian (84%), and slightly more than half (53%) are ≥ 65 years old. Cytogenetic data is available for 42 subjects; 10 have del(11q), 8 have del(17p), and 24 have del(13q). Overall, 31 subjects had at least one cytogenetic deletion. Based on the Binet and Rai staging systems: 3 (6%), 10 (20%) and 15 (29%) of subjects are stage A, B and C, respectively; and, 6 (12%), 7 (14%) and 7 (14%) subjects are low, intermediate or high-risk disease, respectively. For 3 (6%) subjects the Binet/Rai staging is currently unknown. The most common hematological grade 3/4 adverse events (AEs) thus far include neutropenia (41% of patients) and thrombocytopenia (24%). The most common non-hematological grade 3/4 AEs include fatigue (12%) and tumor flare (12%). Only 1 subject (2%) experienced tumor lysis syndrome of grade 1. Over half of the subjects (53%) remain on therapy; 24 (47%) subjects have discontinued treatment. The longest subject has completed 17 cycles, and remains on study medication. The most common reasons for study discontinuation include disease progression (n = 8) and AEs (n = 10). To date, 20 subjects (54% of eligible patients) have successfully dose escalated above their respective starting double blinded dose level, including 3, 3, 2 and 12 subjects undergoing 4, 3, 2, and 1 dose escalations, respectively. As 14 patients are still in the first cycle of the study, a total of 20 subjects have had no dose level reduction or escalations. The average duration of treatment is 4.34 cycles, and the median number of cycles is 3. Efficacy evaluations are completed monthly after 3 months of study drug treatment. By investigator assessment, 34 subjects have been evaluated to date, including 1 (3%) complete response, 12 (35%) partial response, 7 (21%) stable disease, 10 (29%) progressive disease and 4 (12%) not evaluable. Conclusion: The independent Data Monitoring Committee, as of March 24, 2011 (N=41), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were tolerated. To date, the ORR is 38% (13/34 evaluable subjects), and 54% of subjects (20/37) have dose escalated at least once. In this relapsed/refractory CLL population lenalidomide appears active, and completion of accrual will hopefully demonstrate the appropriate starting dose. Disclosures: Wendtner: Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: lenalidomide in cll. Goldberg:Celgene: Honoraria, Research Funding, Speakers Bureau. Bloor:Celgene: Honoraria, Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Research Funding. Cymbalista:Roche: Research Funding; Mundipharma: Honoraria; Genzyme: Honoraria. Kipps:Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Genentech: Research Funding; Gilead Sciences: Consultancy, Research Funding; Igenica: Membership on an entity's Board of Directors or advisory committees. Purse:Celgene: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment.

Sign in / Sign up

Export Citation Format

Share Document