Luspatercept Increases Hemoglobin, Decreases Transfusion Burden and Improves Iron Overload in Adults with Beta-Thalassemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 851-851 ◽  
Author(s):  
Antonio G. Piga ◽  
Immacolata Tartaglione ◽  
Rita Gamberini ◽  
Ersi Voskaridou ◽  
Angela Melpignano ◽  
...  
Keyword(s):  
Study Data ◽  
Extension Study ◽  
Beta Thalassemia ◽  
Employment Equity ◽  
Base Extension ◽  
Base Study ◽  
Duration Of Response ◽  
Equity Ownership

Abstract Background.Luspatercept (ACE-536) is a modified activin receptor type IIB fusion protein that promotes late-stage erythroid differentiation. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors causes ineffective erythropoiesis (IE) leading to anemia and dysregulated iron homeostasis. In a mouse model of beta-thalassemia, luspatercept corrected the effects of ineffective erythropoiesis and in a phase 1 clinical study with healthy volunteers, was well tolerated and increased hemoglobin (Suragani R, Nat Med, 2014; Suragani R, Blood, 2014; Attie K, Am J Hematol, 2014). Aims.This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia with the following key endpoints: erythroid response (including Hgb increase) and patient-reported quality-of-life (QoL) measures in NTD patients, and reductions in RBC transfusion burden in TD patients. Methods.Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥ 4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as < 4 RBC units transfused in the 8 weeks prior to first dose with baseline Hgb < 10.0 g/dL). Luspatercept was administered subcutaneously every 3 weeks for up to 5 doses over 12 weeks with an 8 week follow-up (20 weeks total). Six cohorts (n=35) were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort (n=29) and all pts who rolled over to the extension study (n=51) were treated at ≥ 0.8 mg/kg with escalation up to 1.25 mg/kg. Results. A total of 30 TD pts enrolled in the base study and, of those, 24 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 38 yr (range 22-55 yr), 67% had prior splenectomy. At baseline, median transfusion burden was 8 units/12 weeks (range 4-15 units) and mean (SD) liver iron concentration (LIC) was 5.1 (5.3) mg/g dw. A total of 20/24 (83%) and 16/24 (67%) TD pts achieved a ≥ 33% and ≥ 50% decrease in transfusion burden over any 12-week period compared to baseline, respectively. Duration of response ranged from 12 to 48+ weeks. A total of 34 NTD pts enrolled in the base study and, of those, 27 enrolled in the extension study (data as of 11 March 2016). Data summarized are for the long-term extension study. Median age was 37 yr (range 23-62 yr); 67% had prior splenectomy. At baseline, median Hgb was 8.7 g/dL (range 7.6-9.8 g/dL) and mean (SD) LIC was 4.9 (3.4) mg/g dw. A total of 21/27 (78%) and 15/27 (56%) NTD pts achieved ≥ 1.0 g/dL and ≥ 1.5 g/dL increases, respectively, in mean Hgb over any 12-week period compared to baseline. Duration of response ranged from 16 to 72+ weeks, with no trend for lower Hgb response over time. Increases in mean hemoglobin over a 12-week period correlated with increases in a pt-reported QoL questionnaire, FACIT-F (r=0.67, p=0.001). 3/5 (60%) pts with baseline LIC ≥ 5 mg/g dw had a decrease in LIC ≥ 2 mg/g dw after at least 6 months of treatment; 8/9 (89%) patients with baseline LIC < 5 mg/g dw maintained LIC < 5 mg/g dw. Luspatercept was generally well tolerated, with no related SAEs. AEs were mostly mild-moderate. The most frequent related AEs (≥ 10% in base + extension studies) in TD pts were bone pain, myalgia, arthralgia, headache, asthenia, and musculoskeletal pain. The most frequent related AEs (≥ 10% in base + extension studies) in NTD pts were bone pain, headache, musculoskeletal pain, and arthralgia. Conclusions: Luspatercept treatment in pts with beta-thalassemia had a favorable safety profile. Efficacy was clinically relevant in both NTD pts (increased Hgb levels, decreased LIC, and improved quality of life) and TD pts (decreased RBC transfusions). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with beta-thalassemia is ongoing (NCT02604433). Disclosures Zhang: Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Leneus:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership.

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.

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.

Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results from Phase 2 PACE-MDS Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3168-3168 ◽  
Author(s):  
Uwe Platzbecker ◽  
Ulrich Germing ◽  
Katharina Götze ◽  
Philipp Kiewe ◽  
Thomas Wolff ◽  
...  
Keyword(s):  
Lower Risk ◽  
Extension Study ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Employment Equity ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Equity Ownership ◽  
Rbc Transfusion

Abstract Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014). Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, and pt-reported QoL. Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), ESA refractory or EPO > 500 U/L, no prior HMA, and no current lenalidomide or ESA. Luspatercept was administered SC every 3 wks for up to 5 doses in the base study (NCT01749514), including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max 1.75 mg/kg). A 2-year extension study (n=32) is ongoing (NCT02268383). Results: Data (as of 4 Mar 2016) were available for the 32 extension study pts. Of these, 13 pts received < 4U RBC/8 weeks pretreatment (low transfusion burden, LTB) and 19 pts received ≥ 4U RBC/8 weeks (high transfusion burden, HTB). Median age was 72 yr (range 29-90 yr), 59% had prior ESA. Median Hgb for LTB pts was 8.5 g/dL (range 6.4-10.1 g/dL) and median RBC transfusion burden for HTB pts was 6 U/8 weeks (range 4-14 units). 91% pts were RS+ (≥ 15% RS in bone marrow). IWG HI-E was achieved in 11/13 (85%) LTB pts and 15/19 (79%) HTB pts. 11/22 (50%) pts with at least 2 units transfused in 8 weeks prior to dosing with luspatercept achieved RBC transfusion independence for at least 8 weeks. The range of transfusion independence was 9 to 80+ weeks, with most responders still receiving treatment. IWG HI-E response rates were 83% for RS+ pts, 90% for EPO < 200 U/L, 86% for EPO 200-500 U/L, and 50% for EPO > 500 U/L; 85% for ESA-naïve and 79% for those who had prior ESA treatment. RBC transfusion independence was achieved in 58% for EPO < 200 U/L, 50% for EPO 200-500 U/L, and 33% for EPO > 500 U/L. Luspatercept was well tolerated, with 3 related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common related AEs (≥ 2 pts in both base and extension studies) were fatigue, bone pain, diarrhea, myalgia, headache, hypertension, and injection site erythema. Conclusions: Long-term treatment with luspatercept was well tolerated and led to erythroid response in 81% of low-intermediate risk MDS pts who enrolled into the extension study. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). Disclosures Platzbecker: Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Donovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Risk-Benefit Trade-Off of Pediatric-Inspired Versus Hyper-CVAD Protocols for Philadelphia Negative Acute Lymphocytic Leukemia (ALL) in Adolescents and Young Adults: A Modeling Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1281-1281
Author(s):  
Gregory F. Guzauskas ◽  
Kathleen F. Villa ◽  
Trudy F. Vanhove ◽  
David L. Veenstra
Keyword(s):  
Quality Of Life ◽  
Acute Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Free Survival ◽  
Life Years ◽  
Equity Ownership

Abstract Background Although treatment outcomes for childhood acute lymphocytic leukemia (ALL) have dramatically improved in recent years, treatment outcomes in adolescents and young adults (AYA, ages 16-39) have remained inferior due to unfavorable cytogenetic features associated with increasing age and differences in treatment for this population. Pediatric-inspired protocols include L-asparaginase for induction and intensification phases, which are thought to be less tolerable and to lead to increased adverse events in adults. As a result, they are not widely used in the AYA population. Although non-comparative studies suggest improved survival in AYA patients treated with pediatric-inspired protocols, the long-term risk-benefit profile of treating AYAs with a pediatric-inspired ALL protocol is unknown. We utilized an exploratory decision-analytic approach to model the survival and quality-adjusted survival of a pediatric-inspired protocol versus hyper-CVAD, a widely utilized adult protocol, in AYA patients with Philadelphia negative ALL. Methods Patient outcomes were simulated using a 6-state Markov model including complete response (CR), no CR, first relapse, second CR, second relapse, and death. Hyper-CVAD protocol outcomes were modeled by fitting a Weibull distribution to the progression free survival curve of AYA patients from a single-center study of 288 patientsa; we utilized comparable patient data from a retrospective study of 85 patients treated with a pediatric-inspired regimenb to estimate a relative progression difference (HR = 0.51), and used this estimate to model survival for pediatric-inspired protocol patients. We estimated health state utilities (quality of life) based on treatment stage, and assumed the pediatric protocol had a 0.10 disutility compared to hyper-CVAD prior to the maintenance phase of treatment. Our analysis compared total life years and quality-adjusted life years (QALYs) between treatment protocols at 1 year, 5 years, and 10 years. Figure 1 Figure 1. Results Treatment with the pediatric-inspired protocol led to a 0.04 increase in life years but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increases in life years and 0.25 and 0.32 increases in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was largely offset by more favorable progression-free survival and overall survival in comparison to hyper-CVAD. Table Outcome Pediatric Hyper-CVAD Difference 1 Year Life Years 0.815 0.774 0.041 QALYs 0.507 0.513 -0.006 5 Years Life Years 1.882 1.633 0.250 QALYs 1.362 1.179 0.182 10 Years Life Years 2.120 1.802 0.318 QALYs 1.564 1.324 0.241 Conclusions Our exploratory analysis suggests Philadelphia negative AYA patients treated with a pediatric-inspired protocol experience a decrease in QALYs versus hyper-CVAD during the initial stages of treatment for ALL. However, the pediatric protocol leads to an increase in life years throughout all treatment stages and an increase in QALYs in the long-term following the initial stages of treatment. Ongoing work will incorporate treatment and adverse event costs to estimate the cost-effectiveness of pediatric-inspired versus hyper-CVAD protocols. a Kantarjian H. et al. Cancer 2004; 2788-801. b Storring JM, et al. BJH 2009; 76-85. Analysis support: This analysis was supported by Jazz Pharmaceuticals. Disclosures Guzauskas: Jazz Pharmaceuticals: Consultancy. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States.. Vanhove:Jazz Pharmaceuticals: Employment, Equity Ownership. Veenstra:Jazz Pharmaceuticals: Consultancy.

Ahead Study: A 3 Year Follow-up of 522 Severe and Moderate Hemophilia a Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3786-3786
Author(s):  
Johannes Oldenburg ◽  
Dimitrios Tsakiris ◽  
Cedric R. Hermans ◽  
RI Liesner ◽  
Kate Khair ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prophylaxis Group ◽  
Equity Ownership

Abstract Introduction: Long-term, real-world data on natural history of hemophilia A patients, safety and treatment outcome are still insufficient, particularly as far as the impact of bleeding on patient lives is concerned, as most of clinical trials and PASS studies are limited in study population size and length of follow-up, often no longer than 12 months. Methods: The AHEAD study is a non-interventional, prospective long-term cohort study including severe and moderate hemophilia A patients treated with ADVATE. Study endpoints include long-term joint health outcomes, annualized (joint) bleeding rates (ABR/AJBR), factor consumption, quality of life and safety data. Globally, AHEAD aims to evaluate data on approximately 1,000 patients, with a maximum follow-up period of up to 8 years. This interim data report includes 3 years of follow-up after study start. Results: The interim data report includes 522 patients from 21 countries (German study arm is not included in this analysis), for overall 1160 patient years. Of these, 334 completed year 1, 238 year 2 and 136 year 3 study visits. Median age at screening was 17 years (min-max: 0 - 78) and 57% of patients had severe HA (FVIII<1%); 78% were on prophylaxis, 21% were on demand (OD) and 1% on ITI treatment. The median ABRs in year 1, 2 and 3 were 1.2/1.2/1.9 respectively in patients on prophylaxis and 8.4/10.0/7.2, respectively in patients on OD. Median AJBRs were 0.9/0.9/1.0 in the prophylaxis group and 6.4/5.5/5.9 for patients on OD in the first three years of observation. Very similar data were reported taking only severe hemophilia A patients on prophylaxis into account (ABR: 1.9/1.7/2.5 and AJBR: 1.0/1.0/1.1) Overall, 56% of patients on prophylaxis and 32% of patients OD had an AJBR <1 in the first year, 54% and 33% in the second year and 52% and 22% in the third year. In the OD group about half of the patients had an AJBR ≥ 6, in the 3 years of follow up, while only 10% of patients in the prophylaxis group. Median annualized total dose in the prophylaxis group was consistently approximately 245,000IU while the FVIII consumption in the OD group was ranging from 26,000 to 47,000. Effectiveness of prophylaxis assessed by investigators was excellent/good in 93-96% of cases in the three years of observation. Functionality assessment using the hemophilia activity level (HAL) questionnaire showed a median summary score of 77.3-86.7 for patients on prophylaxis and 67.9-71.3 in patients OD over the 3 year follow up period. Differences of health related quality of life (HRQoL) as assessed by the SF-12 were found in the domain physical functioning (median score of 75-100 vs. 50-75 in patients on prophylaxis and OD, respectively) and role physical (median scores of 75 vs. 62.5-75 in patients on prophylaxis and OD, respectively). There were 7 treatment-related adverse events (AEs): 6 serious AEs (5 transient low titer inhibitors and 1 transient high titer inhibitor). The remaining non serious treatment-related adverse event was a mild allergic cutaneous reaction with rhinitis. All patients continued to receive ADVATE. Conclusion: Interim read-out of 3 year follow-up of patients enrolled in the AHEAD study show a clinically meaningful difference in ABR/AJBR, HAL, HRQoL of patients on prophylaxis or OD treatment. This study represents the largest cohort of hemophilia patients with the longest follow-up period. Disclosures Tsakiris: Baxalta, now part of Shire: Consultancy, Honoraria, Research Funding; Bayer Switzerland GmbH: Consultancy, Honoraria, Research Funding. Hermans:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Liesner:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Research Funding; Cangene: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Khair:Pfizer: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Investigator, Research Funding; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Investigator, Patents & Royalties, Research Funding, Speakers Bureau; Sobi/Biogen: Research Funding. Mazzucconi:Baxalta, now part of Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Speakers Bureau; NovoNordisk: Speakers Bureau; Pfizer: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Shire: Speakers Bureau. Steinitz-Trost:Baxalta, now part of Shire: Employment. Spotts:Shire: Employment. Reininger:Baxalta, now part of Shire: Employment, Equity Ownership. Gringeri:Shire: Employment, Equity Ownership.

An Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim in Thrombocytopenic Patients (Pts) with Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2765-2765 ◽  
Author(s):  
Pierre Fenaux ◽  
Hagop Kantarjian ◽  
Roger Lyons ◽  
Richard A. Larson ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Research Funding ◽  
Extension Study ◽  
Platelet Response ◽  
Bleeding Events ◽  
Open Label ◽  
Employment Equity ◽  
Open Label Extension ◽  
Equity Ownership

Abstract Abstract 2765 Poster Board II-741 Background: Romiplostim is a peptibody protein that increases platelet production by binding to and activating the thrombopoietin receptor. Currently, platelet transfusion is the only supportive treatment for thrombocytopenia in MDS. In a phase 1/2 study of romiplostim in lower-risk thrombocytopenic MDS pts receiving supportive care only, about half achieved a platelet response (Sekeres et al., ASCO 2009, Kantarjian et al, JCO 2009, in press). We report results from an interim analysis of the subsequent ongoing open-label extension study evaluating the long-term safety and efficacy of romiplostim in MDS pts. Methods: MDS pts who, after completing the parent study, had platelets '50×109/L and no evidence of disease progression were eligible to enroll in this extension. The primary endpoint of this extension was adverse event (AE) incidence with long-term use of romiplostim; incidence of bleeding events was a secondary endpoint. Pts received romiplostim at a dose of 250, 500, 750, 1000, or 1500 μg weekly or every two weeks based on previous dosing, with subsequent adjustment between 250 and 1000 μg. If after 4 weeks at the increased dose there was an inadequate platelet response (using IWG 2006 criteria), the dose could be further escalated (with 4 weeks at each dose) up to a maximum of 1000 μg/week. If no response was observed after 4 weeks at 1000 μg/week, treatment was discontinued. Results: At the reference date of Feb 18, 2009, 28 pts had enrolled in this open-label extension study: 68% male, median age 71.5 y [interquartile range (Q1-Q3): 63.5-76.5 y], median baseline platelets 31×109/L (Q1-Q3: 20–41×109/L), 32% with platelets <20×109/L. During the parent study, 24 of the 28 pts had a platelet response. At the end of the parent study, there was a 4-week washout period. At initiation of the open-label extension study, IPSS status was low (13 pts), int-1 (12), int-2 (1), or missing (2), and MDS subtypes were RA (11 pts), RCMD (7), MDS-U (4), RAEB-1 (2), RCMD-RS (1), RARS (1), or missing (2). Ten pts (36%) had bleeding events in the previous year. Median duration of treatment in the extension study was 41 weeks (Q1-Q3: 23–58 weeks), with a median weekly dose of 748 μg (Q1-Q3: 493–821 μg). All 28 pts received μ8 weeks of romiplostim. Most AEs were mild-to-moderate; the most common being epistaxis (36%), arthralgia (29%), anemia (21%), and cough (21%). No neutralizing antibodies to romiplostim or TPO were observed. Nine pts withdrew from the study, 6 of these due to AEs. By investigator assessment, five of these AEs were related to romiplostim: 3 pts with increased blast cells, 1 pt with early-stage chronic myeloid leukemia (CML) diagnosed 519 days after romiplostim initiation, with bcr-abl first detected 1 year after romiplostim initiation (negative at baseline), and 1 pt with a history of chronic obstructive pulmonary disease and congestive heart failure who subsequently experienced the acute and rapid development of fatal pulmonary fibrosis after treatment with romiplostim. Two of these AEs were severe (pulmonary fibrosis and CML). For the increased blast cells, in cases 1 and 2, peripheral blasts were detected: in case 1 bone marrow (bm) blasts of 7% fell to <1% after drug discontinuation, while in case 2, bm blasts were 3% (no follow-up blast count). In both cases 1 and 2, peripheral blasts disappeared after drug discontinuation. In case 3, increase in blasts was reported by the investigator, with no peripheral blasts detected (follow-up bm biopsy was not evaluable). One AE leading to study withdrawal was not related to romiplostim (follicular B-cell lymphoma). As of the reference date, no progression to AML was reported. Eighteen pts (64%) reported ≥1 bleeding events, with 6 pts (21%) reporting ≥1 clinically significant bleeding events (i.e., CTCAE grade ≥3, serious AE, or any bleeding AE requiring intervention). Eight pts (29%) received platelet transfusions. From Study Week 4 on, the median platelet count was ≥50×109/L. Twenty-three pts (82%) had a platelet response (per IWG 2006 guidelines), including 6 of 9 pts with baseline platelet counts <20×109/L. The median platelet response lasted 30 weeks (Q1-Q3: 16–52 weeks). Over half of pts (54%) demonstrated an initial platelet response by Study Week 3. Conclusion: In this long-term, follow-up, open-label extension study in thrombocytopenic MDS pts, romiplostim demonstrated an acceptable toxicity profile, with the majority of pts achieving a durable platelet response. Disclosures: Fenaux: Cephalon: Research Funding; Amgen Inc.: Research Funding; Merck: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: Nplate (romiplostim) is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Kantarjian:Amgen Inc.: Research Funding. Lyons:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau. Larson:Amgen Inc.: Equity Ownership, Research Funding. Sekeres:Celgene: Honoraria, Research Funding, Speakers Bureau. Becker:Amgen Inc.: Research Funding, Speakers Bureau. Muus:Amgen Inc.: Speakers Bureau. Hu:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership.

scholarly journals Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3512-3512
Author(s):  
Rachael F. Grace ◽  
D. Mark Layton ◽  
Frédéric Galactéros ◽  
Wilma Barcellini ◽  
Eduard J. van Beers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
The Core ◽  
Equity Ownership ◽  
Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses &gt;25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Melphalan, Prednisone and Lenalidomide Followed by Lenalidomide Maintenance Displays Treatment Characteristics Favourable to Global Quality of Life in Newly Diagnosed Multiple Myeloma (NDMM) Patients ≥ 65 Years,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3988-3988 ◽  
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Antonio Palumbo ◽  
Roman Hajek ◽  
Martin Kropff ◽  
Maria Teresa Petrucci ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Progressive Disease ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Risk Of Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3988 Background: Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance (MPR-R) demonstrated higher response rates (ORR; 77% vs. 50%, p <.001; VGPR or better: 32% vs. 12%, p <.001) and significantly reduced the risk of disease progression (hazard ratio [HR] = 0.423, p <.001) vs. MP alone [Palumbo, 2010]. Alongside efficacy considerations, analyses on health-related quality of life (HRQoL) may help more fully establish a regimen's overall treatment profile. HRQoL improvements with MPR-R were observed during MPR induction as well as lenalidomide maintenance, documenting a well-balanced profile in terms of efficacy, tolerability and HRQoL [Dimopoulos, 2011]. Alternative findings on novel NDMM treatment have shown efficacy of melphalan, prednisone and bortezomib (VMP) treatment to be associated with an intermittent deterioration in patients' HRQoL [Dhawan, 2009]. Methods: A mixed effects model was developed based on parameters pre-selected as potentially clinically relevant in impacting HRQoL. Models were run on six domains pre-selected based on clinical relevance: Global QoL, Physical Functioning, Fatigue and Pain (from EORTC QLQ-C30), and Disease Symptoms and Side Effects of Treatment (from EORTC MY20). Cycle 16 was determined as the last observation time point with a statistically meaningful sample size at time of follow-up (May 2010). Following explanatory variables were included: time-dependant covariates at individual HRQoL measurement time points (i.e. cycle 4, 7, 10, 13 and 16), treatment group (MPR-R vs. MP), gender (Female vs. Male), age, baseline QoL, Partial Response (PR) vs. Stable Disease (SD) and Very Good Partial Response or better (≥VGPR) vs. SD, Progressive Disease (PD) and Discontinuation (DC). Neutropenia and anemia, both Grade 3 or 4, were considered the clinically most relevant safety parameters. Main results for Global QoL are reported, with results from other domains found to be comparable. Results: Across all time-dependant covariates, a statistically significant reduction on Global QoL (−4.63; p=.004) was observed at Cycle 4. Being female vs. male significantly reduced Global QoL by -−.07 (p=.026). Each additional life year was found to lower Global QoL b− −0.40 points (p=.034). Baseline Global QoL was also significant, each additional score point leading to +0.30 (p <.001). A response level of ≥VGPR vs. SD increased Global QoL by 9.11 (p=.023); Progressive Disease (PD) reduced Global QoL by -−.34 score points (p <.001). All other pre-defined variables did not significantly impact Global QoL. Clinically meaningful changes for Global QoL in the underlying patient population have been determined to constitute at least a 7-point change [Dimopoulos, 2011]. Progressive disease (reducing Global QoL), respectively ≥VGPR (increasing Global QoL) exerted clinically meaningful changes, as did anemia grade 3–4, which had a clinically meaningful, but not statistically significant negative impact (−9.85; p=.057). Although no significant direct effect of MPR-R over MP on Global QoL was detected in the underlying model, MPR-R displays properties which favor an improved HRQoL profile, including a stronger delay in PD and higher % of VGPR vs. MP patients. Furthermore, certain properties more frequently observed with MPR-R than MP (neutropenia grade 3 or 4 and discontinuation, DC) were shown not to have a significant impact on HRQoL. Anemia grade 3 or 4, exerted a clinically meaningful negative effect but was not significantly more often observed with MPR-R compared to MP (24% vs. 17%, p= 0.091). Conclusions: More patients achieved ≥VGPR when receiving continuous MPR-R treatment than those receiving MP. In the above pooled analysis, ≥VGPR was shown to improve Global QoL in a clinically meaningful and statistically significant way. Furthermore, progression was also shown to negatively impact Global QoL (−8.34; p <.001), with MPR-R significantly reducing the risk of disease progression over MP. Delaying progression with continuous MPR-R therefore helps to maintain a high Global QoL. Disclosures: Dimopoulos: Celgene: Consultancy, Honoraria. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Ortho-Biotech: Honoraria. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria. Petrucci:Celgene: Honoraria. Lewis:Celgene: Employment, Equity Ownership. Millar:Celgene: Consultancy. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Health Related Quality of Life of Bosutinib in Imatinib-Resistant or Imatinib-Intolerant Patients with Advanced Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4448-4448 ◽  
Author(s):  
Jennifer Whiteley ◽  
Arlene Reisman ◽  
Virginia Kelly ◽  
Jorge E Cortes ◽  
David Cella
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Well Being ◽  
Health Related Quality ◽  
Employment Equity ◽  
Blast Phase ◽  
Related Quality ◽  
Health Related ◽  
Equity Ownership

Abstract Abstract 4448 Purpose: Bosutinib is a dual Src/Abl tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in a phase I/II study of patients with Advanced Phase Chronic Myeloid Leukemia (CML). The objective was to evaluate the effect of bosutinib on health -related quality of life (HRQoL) in patients with advanced CML after failure with imatinib. Methods: Patient reported HRQoL was an exploratory objective in the clinical trial and measured using the 44-item Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). The FACT-Leu is a modular approach to assess patient HRQoL using a core set of general cancer questions as well as a cancer site specific leukemia subscale with 5 domains: Social Well-being (SWB), Emotional Well-being (EWB), Physical Well-being (PWB), Functional Well-being (FWB) and Leukemia Subscale (LeuS); and 3 summary scales: FACT-General, FACT Trial Outcome Index (TOI) and FACT-Leu Total. The item responses for each scale are summed to provide scores; higher scores indicate better HRQoL. The FACT-Leu was completed at weeks 4, 8, 12 and every 12 weeks thereafter, as well as treatment completion. Within cohort comparisons were assessed using paired t-tests. Results: Of the 164 patients with advanced leukemia included in the trial, 76 had accelerated phase (AP) CML and 64 blast phase (BP) CML. At 24 weeks, AP patients reported statistically significant improvements in PWB (p=0.02), EWB (p<0.001), LeuS (p<0.001), FACT-G (p<0.001), FACT-Leu (p<0.001) and FACT-TOI (p<0.001) with the PWB, FACT-G, LeuS, TOI and FACT-Leu exceeding minimally important differences (MID) at 24 weeks. Blast phase patients reported significant improvements in PWB (p=0.02), EWB (p=0.02), FWB (p=0.04), LeuS (p=0.01), FACT-G (p<0.001), FACT-Leu (p<0.001) and FACT-TOI (p=0.01) at 24-weeks with all scales exceeding MID except the SWB. At 48-weeks the AP patients continued to have statistically significant improvements in PWB (p=0.05), EWB (p=0.02), and FACT-G (p=0.03) and PWB, FACT-G, TOI and FACT-Leu exceeded the MID at 48 weeks. There were no statistically significant deteriorations in HRQoL through week 48 (Figure 1) Conclusions: These data suggest that CML patients treated with bosutinib demonstrate improved HRQoL. Confirmation in a controlled study is needed. Disclosures: Whiteley: Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Kelly:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Cella:Pfizer Inc: Honoraria, Research Funding.

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