Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 279-279 ◽  
Author(s):  
Claire N. Harrison ◽  
Jean-Jacques Kiladjian ◽  
Heinz Gisslinger ◽  
Dietger Niederwieser ◽  
Francesco Passamonti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Response Rate ◽  
Response Rates ◽  
Risk Category ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Starting Dose ◽  
Secondary Endpoints ◽  
Equity Ownership

Abstract Abstract 279 Background: COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P <.0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P <.0001), respectively. Subgroup analysis was performed on both the 48- and 24-week endpoints. Methods: In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator's choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895–2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression. Results: The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48 is shown below (Figure). BL, baseline; HU, hydroxyurea. The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48. Conclusions: Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose. Disclosures: Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Waltzman:Novartis: Employment. Hollaender:Novartis Pharma AG: Employment. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Knoops:Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Efficacy of Ruxolitinib By Baseline Spleen Volume in Patients with Polycythemia Vera Resistant to or Intolerant of Hydroxyurea

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1840-1840 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Srdan Verstovsek ◽  
Mark M Jones ◽  
Shui He ◽  
Jingjin Li ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Linear Regression ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume. Methods : Patients with PV ≥18 years of age who were resistant to or intolerant of HU with palpable spleen (confirmed by MRI/CT to be ≥450 cm3) and phlebotomy requirement were randomized 1:1 to receive open-label RUX 10 mg BID or BAT. The primary endpoint was a composite that required a ≥35% reduction in spleen volume at Week 32 and hematocrit (HCT) control. HCT control was defined as lack of phlebotomy eligibility (based on HCT values) between Weeks 8–32 with no more than 1 phlebotomy eligibility between randomization and Week 8. A linear regression was conducted to determine the effect of baseline spleen volume on the percent change in spleen volume at Week 32. A logistic regression was conducted to determine the effect of baseline spleen volume on HCT control through Week 32. Spleen volume was measured by MRI at screening and Weeks 16 and 32. Hematocrit was assessed at screening, prerandomization, and every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32. Results :The RESPONSE trial enrolled 222 patients (RUX, 110; BAT, 112). Median (range) spleen volume at baseline was 1195 cm3 (396–4631 cm3) in the RUX arm and 1322 cm3 (254–5147 cm3) in the BAT arm. Baseline median (range) spleen length by palpation was 7.0 cm (0.0–24.0 cm) in the RUX arm and 7.0 cm (0.0–25.0 cm) in the BAT arm. In the 24 weeks prior to screening, most patients in both arms had ≥2 phlebotomy procedures (RUX, 87%; BAT, 80%). There was no correlation between the percentage change in spleen volume at Week 32 and baseline spleen volume; linear regression showed no significant effect of baseline spleen volume on the percentage change in spleen volume at Week 32 (P=0.40). No significant effect of baseline spleen volume on HCT control through Week 32 was identified based on logistic regression analysis (P=0.37). Conclusion : In PV patients with inadequate response to or intolerant of HU, the degree of splenomegaly at baseline did not influence achievement of HCT control or reduction in spleen volume with RUX therapy. Disclosures Vannucchi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2883-2883
Author(s):  
Matthew S. Davids ◽  
Andrew W. Roberts ◽  
William G. Wierda ◽  
Kathryn Humphrey ◽  
Debbie J Alter ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Study Drug ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Equity Ownership

Abstract Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up. Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018. Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years. The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy. The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug. Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). Disclosures Davids: Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

Bortezomib, Thalidomide, and Dexamethasone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT: A Randomized Phase 2 Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2312-2312 ◽  
Author(s):  
Heinz Ludwig ◽  
Luisa Viterbo ◽  
Richard Greil ◽  
Tamas Masszi ◽  
Ivan Spicka ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2312 Poster Board II-289 Bortezomib (Velcade®) has shown substantial activity and manageable toxicity in newly diagnosed multiple myeloma (MM) in combination with thalidomide (Thalomid®) and dexamethasone (VTD) in a phase 3 study (Cavo et al, ASH 2008), and with cyclophosphamide and dexamethasone (VCD) in a phase 2 study (Knop et al, ASCO 2009). Four-drug combinations may be more effective than 3-drug regimens, but may also be associated with increased toxicity. This randomized, non-comparative, open-label, multicenter, phase 2 study was designed to evaluate the efficacy and safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy prior to high-dose therapy plus autologous stem cell transplant (HDT-ASCT). A total of 98 previously untreated MM patients with measurable disease who were candidates for HDT-ASCT were enrolled. Additional eligibility criteria included: age 18–70 years, Karnofsky Performance Status (KPS) ≥60%, adequate hematologic, hepatic, and renal function, and no grade ≥2 peripheral neuropathy (PN)/neuropathic pain. Patients were randomized (1:1), stratified by International Staging System (ISS) disease stage (I / II / III), to receive four 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, thalidomide 100 mg daily, and dexamethasone 40 mg on days 1–4 and 9–12 (VTD), or VTD plus cyclophosphamide 400 mg/m2 IV on days 1 and 8, as induction therapy prior to HDT-ASCT. All patients received antithrombotic prophylaxis. Patients who became ineligible for HDT-ASCT or had a complete response (CR) after induction therapy could receive an additional 4 cycles of treatment. Responses were categorized using modified IMWG Uniform Response Criteria (stringent CR [sCR] were unconfirmed by immunohistochemistry) through blinded review by the principal investigator and medical monitor, using central laboratory M-protein data and local bone marrow data. The primary efficacy endpoint was combined CR rate (sCR + CR + near-CR) following induction therapy. Secondary objectives included combined CR rate post-HDT-ASCT, overall response rate (ORR: ≥partial response) post-induction and post-HDT-ASCT, time to progression (TTP), overall survival (OS), and safety. Adverse events (AEs) were graded using NCI CTCAE v3.0. Forty nine patients were randomized to each arm; median age was 57 and 58 years in the VTD and VTDC arms, respectively, 53% and 51% of patients were male, 49% and 43% had KPS ≤80%, and 24 / 45 / 31% and 18 / 47 / 35% had ISS stage I / II / III MM. All but 7 patients completed induction; these patients discontinued due to AEs (3 [6%] each arm) and disease progression (1 [2%] VTDC). Four VTDC patients received additional cycles of treatment. One patient (VTDC arm) was not evaluable for response. Response rates following induction are shown in the table. Median CD34+ stem cell yields were 8.16 (VTD; n=48) and 8.13 (VTDC; n=40) x 106/kg. At data cut-off (April 10, 2009), 47 VTD and 35 VTDC patients had undergone HDT-ASCT; response rates post-HDT-ASCT in 38 and 27 evaluable patients are shown in the table. Time-to-event data are not mature (median follow-up: 9.8 months). The 1-year survival rate was estimated to be 94% in each arm. At least one AE was reported in 98% and 96% of patients on the VTD and VTDC arms, with at least one grade ≥3 AE reported in 47% and 59%, respectively. The most common non-hematologic grade 3/4 AEs included fatigue (2% and 8%) and constipation (6% and 2%); analyses of hematology laboratory values indicated grade 3/4 AEs of lymphopenia (39% and 77%), anemia (8% and 18%), neutropenia (14% and 18%), and thrombocytopenia (6% each). PN was reported in 35% (VTD) and 29% (VTDC) of patients, including 8% grade 3 in each arm and 2% grade 4 in the VTD arm. Two patients (1 [2%] each arm) had deep vein thrombosis; one (VTDC arm) was a grade 3 SAE. At least one serious AE (SAE) was reported in 22% (VTD) and 41% (VTDC) of patients, including 6% and 14% with SAEs of infections (MedDRA SOC), and 2% and 14% with musculoskeletal-related pain. In conclusion, both VTD and VTDC are highly active induction regimens, with CR rates and ORRs among the highest reported; the efficacy profiles were similar between the arms, but there were higher rates of toxicity in the VTDC arm compared with the VTD arm. Table. Response rates following induction and post-HDT-ASCT. Post-induction n=49 n=48 Combined CR*, % 51 44 sCR†, % 27 27 ORR, % 100 96 Post-HDT-ASCT n=38 n=27 Combined CR*, % 76 78 sCR, % 39 33 ORR, % 100 100 * sCR + CR + near-CR † unconfirmed Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen-Cilag: Honoraria. Dmoszynska:Milllennium: Research Funding. Cakana:Janssen Cilag: Employment, Equity Ownership. Enny:Johnson & Johnson: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership.

The Use of Erythropoietic-Stimulating Agents (ESAs) with Ruxolitinib in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), and Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2838-2838 ◽  
Author(s):  
Mary Frances McMullin ◽  
Claire N Harrison ◽  
Dietger Niederwieser ◽  
Hilde Demuynck ◽  
Nadja Jakel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Spleen Size ◽  
Epoetin Alfa ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2838 Background: Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 COMFORT studies in MF patients (pts). Consistent with rux's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable leading to discontinuation in only 1 pt. In clinical practice, anemia can be managed with ESAs, which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of rux in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of rux. This post hoc analysis evaluated the safety and efficacy of rux in pts receiving concomitant ESA in COMFORT-II. Methods: COMFORT-II is an open-label, randomized, multicenter study. Pts were randomized (2:1) to receive rux 15 or 20 mg bid or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa, epoetin nos), although not prohibited, was discouraged for pts randomized to rux because ESAs can increase spleen size, which could confound efficacy analyses. Spleen volume was assessed by MRI or CT every 12 wk. The rate of transfusions was calculated as the number of units transfused per exposure duration (typically 12 wk). Results: Concomitant use of ESA was reported for 13 (PMF, n = 10; PET-MF, n = 2; PPV-MF, n = 1) of the 146 pts who were treated with rux (darbepoetin alfa, 2% [n = 3]; epoetin alfa, 6% [n = 9]; epoetin nos, < 1% [n = 1]). The median exposure to rux was similar for pts who received an ESA (+ESA group; 500 d) vs those who did not receive ESA (468 d), and the median dose intensity of rux was the same for each group (30 mg/d). As shown in the table, 8 pts (62%) had no change, 2 pts (15%) had a decrease, and 3 pts (23%) had an increase in the rate of packed red blood cell (PRBC) transfusions per mo after the first administration of ESA compared with 12 wk before ESA use. Six wk prior to the first administration of ESA, 10/13 pts (77%) had grade 3/4 hemoglobin abnormalities; however, 6 wk after the administration of ESA, most pts' conditions improved to grade 2 (7/13 [54%]). The majority of pts (77%) did not have any change in their reticulocyte counts within the 6 wk before and after the administration of ESA; 1 pt (8%) had a marked increase; for 2 pts (15%), the data were not available. The AEs reported in pts who received ESA were similar to those previously reported with rux. Serious AEs were reported for 8 pts in the +ESA group (3 events in 2 pts that were possibly related to study drug). Within the last assessment prior to and the first assessment after the first administration of ESA, 7/9 evaluable pts (78%) had spleen volume reductions. Conclusions: In this analysis, although the sample size is small, rux was generally well tolerated in pts who received ESA, and the tolerability profile of rux was similar to that reported in previous studies. Rux-treated pts who received ESA generally did not have any change in their transfusion rates, but the rate of grade 3/4 hemoglobin abnormalities decreased within 6 wk of the first administration of ESA, suggesting that the use of ESA in combination with rux was beneficial in some pts. ESA did not appear to affect the efficacy of rux concerning spleen size reduction. The use of ESA for the treatment of anemia is common in clinical practice, and further analyses in combination with rux in this pt population are warranted. Disclosures: McMullin: Bristol Myers Squibb: Honoraria; Shire: Honoraria; Novartis: Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. Recher:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, travel to ASH, travel to ASH Other; sunesis: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Al- Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

scholarly journals Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. LBA-6-LBA-6 ◽  
Author(s):  
Franco Locatelli ◽  
Michael B. Jordan ◽  
Carl E. Allen ◽  
Simone Cesaro ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Diagnostic Criteria ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Null Hypothesis ◽  
Research Funding ◽  
Response Rate ◽  
Study Entry ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, genetic life-threatening syndrome characterized by hyper-inflammation that is mainly driven by high production of interferon (IFN)-𝛾, leading to the development of fever, splenomegaly, cytopenias and coagulopathy. There are currently no approved treatments for HLH, and recent attempts to improve the dexamethasone/etoposide-based regimen (HLH-94) did not show a significant improvement in overall probability of survival. Emapalumab (NI-0501) is a fully human, anti-IFN-𝛾 monoclonal antibody that binds to and neutralizes IFN-𝛾 and is in development for treatment of HLH. Methods: This open-label pivotal study (NCT01818492) includes patients ≤18 years with a diagnosis of pHLH based on genetic confirmation, family history, or the presence of ≥5 of the 8 HLH-2004 diagnostic criteria. Patients were either treatment-naïve or had failed previous conventional HLH therapy prior to study entry. The emapalumab initial dose was 1 mg/kg given intravenously every 3-4 days. Subsequent doses could be increased up to 10 mg/kg based on the evolution of clinical and laboratory response parameters. Emapalumab was administered concomitantly with 5 to10 mg/m2/day of dexamethasone which could be tapered during the study. Treatment duration was 8 weeks (with possible shortening to a minimum of 4 weeks). Treatment could be extended up to allogeneic hematopoietic stem cell transplantation (HSCT) whenever needed. The primary efficacy endpoint of the study was overall response at end of treatment assessed by pre-defined objective parameters. Overall Response Rate (ORR) was assessed as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen and/or D-Dimer levels, central nervous system (CNS) abnormalities, with no sustained worsening of sCD25 serum levels. The primary analysis used an exact binomial test to evaluate the null hypothesis that ORR be at most 40% at a one-sided 0.025 significance level. Data presented are from 34 patients of whom 27 entered the study after failing conventional HLH therapy. Following completion of the main study patients entered into an extension phase (NCT02069899). The data cut-off applied is July 20 2017. Results: Patient characteristics are summarized in Table 1. Disease presentation at study entry was consistent with the broad spectrum of pHLH abnormalities, both in terms of HLH-2004 diagnostic criteria and other known HLH features; over 30% of patients had signs and/or symptoms of CNS disease. Efficacy results are summarized in Table 2. ORR was significantly higher than the pre-specified null hypothesis of 40%; thus the primary endpoint was met. The response rate based on investigator's clinical judgement was 70.6% and 70.4% in the two groups. Emapalumab infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. The observed safety events pre-HSCT conditioning mostly included HLH manifestations, infections or toxicities due to other administered drugs. Infections caused by pathogens potentially favored by IFN-𝛾 neutralization occurred in 1 patient during emapalumab treatment (Disseminated histoplasmosis), and resolved with appropriate treatment. No off-target effects were observed. Conclusions: This is the first prospective HLH study that reports response rates based on pre-defined objective criteria. Our results indicate that emapalumab should be considered as a new therapeutic option in pHLH thanks to its targeted mode of action. Treatment with emapalumab was able to control HLH activity with a favorable safety and tolerability profile in a very fragile population. The majority of patients proceeded to HSCT with favorable outcome. Disclosures Jordan: Novimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allen:Novimmune: Membership on an entity's Board of Directors or advisory committees. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties; Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years . Grom:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AB2Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; NovImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Benedetti:Novartis: Consultancy, Research Funding; SOBI: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; UCB: Consultancy; Eli-Lylli: Consultancy; Abbvie: Research Funding; Novimmune: Research Funding; Pfizer: Research Funding. Ferlin:Novimmune: Employment, Equity Ownership, Patents & Royalties. Ballabio:Novimmune: Employment, Equity Ownership. De Min:Novimmune: Employment, Equity Ownership.

scholarly journals Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4471-4471 ◽  
Author(s):  
Michael Wang ◽  
Andre Goy ◽  
Peter Martin ◽  
Rod Ramchandren ◽  
Julia Alexeeva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 2 Study of the Safety and Efficacy of INCB050465, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 353-353 ◽  
Author(s):  
Naval G. Daver ◽  
Marina Kremyanskaya ◽  
Casey O'Connell ◽  
Kim-Hien Dao ◽  
Stephen T Oh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Percent Change ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Median Percent Change

Abstract Introduction: Despite the demonstrated efficacy of ruxolitinib (Rux) in patients (pts) with myelofibrosis (MF), suboptimal or declining responses to Rux occur, possibly due to persistent PI3K/AKT activation with chronic JAK inhibitor therapy. We evaluated the combination of INCB050465, a potent and highly selective PI3Kδ inhibitor (≥19,000-fold selectivity for PI3Kδ vs other isoforms) and Rux in pts with MF with suboptimal response to chronic Rux monotherapy. Methods: Pts with primary, post-polycythemia vera or post-essential thrombocythemia MF with suboptimal response or loss of response (palpable spleen >10 cm below left subcostal margin [LSM], or splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the Screening Symptom Form) after ≥6 months of Rux monotherapy (5-25 mg twice daily, stable dose for ≥8 weeks [wks]), and ECOG performance status ≤2 were eligible for this phase 2 study (NCT02718300). All pts in Part 1 (safety run-in) and Part 2 (expansion) received oral INCB050465 once-daily (QD) for 8 wks followed by once-weekly (QW) at the same dose plus Rux (existing stable dose for ≥8 wks). Part 1 assessed up to 3 dose levels of INCB050465 (5, 10, and 20 mg). In Part 2, pts were randomized to treatment groups (TGs) in a 1:1 ratio between two doses of INCB050465 determined in Part 1. Primary endpoints were to identify tolerated INCB050465 dose in combination with Rux (Part 1) and percent change in spleen volume from baseline through wk 12 (Part 2). Results: At data cutoff (May 01, 2018), 10 and 18 pts were enrolled in Parts 1 and 2, respectively. INCB050465 doses of 10 mg (TG10, n=3) followed by 20 mg (TG20, n=7) were explored in Part 1. No DLTs were observed, thus the 5 mg dose was not assessed, and the 10 mg (TG10, n=11) and 20 mg (TG20, n=7) doses were expanded in Part 2. In Part 1 (n=10) (median age, 69 years [60-79]; males, 60%), median spleen volume (cm3) was 3058 (996-5324) at baseline. Five pts (50%) discontinued treatment due to progressive disease (n=1, TG10), physician decision (n=1; TG20), adverse event (AE; n=1; TG20, blood bilirubin increased), consent withdrawal (n=1; TG10), and decision to proceed to transplant (n=1; TG10). Median percent change in spleen volume was +4.3% and -2.0% at wks 12 and 24, respectively (Figure). By wk 16, 40% of pts reported that their MF-related symptoms were much improved on the Patient Global Impression of Change (PGIC) form. In Part 2 (n=18) (median age, 63.5 years [41-89]; males, 38.9%), median spleen volume (cm3) was 2201 (327-3569) and median total symptom score (TSS; by the Myeloproliferative Neoplasms Symptom Assessment Form [MPN-SAF]) was 30 (3-61) at baseline. One pt in TG20 discontinued treatment due to physician decision. Median percent change in spleen volume was -0.3% and -5.2% at wks 12 and 24, respectively (Figure). By wk 16, 33.3% of pts reported that their MF-related symptoms were much or very much improved on the PGIC. Median percent change in TSS by the MPN-SAF was -21.9% and -27.8% at wks 12 and 24, respectively. MPN-SAF TSS was a planned longitudinal endpoint only for Part 2 and updated data for Part 2 pts will be presented. In both Parts 1 and 2, nonhematologic treatment-emergent AEs (TEAEs) occurring in ≥3 pts were primarily grade (Gr) 1/2 (Table). Most common new or worsening Gr 3/4 hematologic AEs were thrombocytopenia (Gr 3: 4 pts [14.3%]; Gr 4: 4 pts [14.3%]) and neutropenia (Gr 3: 2 pts [7.1%]; both pts had Gr 2 neutropenia at baseline). No serious TEAEs of interest were reported. TEAEs led to INCB050465 dose interruption in 11 pts (thrombocytopenia [n=8 events], pyrexia [n=2 events], and abdominal pain, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased [n=1 event each]), and to Rux dose interruption in 3 pts (pyrexia [n=2 events] and thrombocytopenia [n=1 event]). Conclusion: The add-on strategy of INCB050465 plus Rux demonstrated preliminary efficacy in MF pts with suboptimal spleen and/or symptom response to chronic Rux monotherapy. The dosing regimen (QD for 8 wks followed by QW) of INCB050465 in this study seemed to mitigate AEs observed with other PI3K inhibitors (limited Gr 3/4 TEAEs and no TEAEs of colitis or rash reported). Long term dosing strategies will be explored in Part 3 of the study, and additional trials are underway to identify optimal dosing of INCB050465 for enhanced safety and efficacy in combination with other agents. Disclosures Daver: Karyopharm: Research Funding; Novartis: Consultancy; Alexion: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; ImmunoGen: Consultancy; ARIAD: Research Funding; Sunesis: Consultancy; BMS: Research Funding; Incyte: Consultancy; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy. Kremyanskaya:Incyte: Research Funding. O'Connell:Incyte: Research Funding. Dao:Incyte: Consultancy. Oh:Takeda: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Zhou:Incyte: Employment, Equity Ownership. Assad:Incyte Corporation: Employment, Equity Ownership. Yacoub:Seattle Genetics: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals Clinical Outcomes with Ruxolitinib (RUX) in Patients with Myelofibrosis (MF) Stratified By Transfusion Status: A Pooled Analysis of the COMFORT-I and -II Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3118-3118 ◽  
Author(s):  
Vikas Gupta ◽  
Srdan Verstovsek ◽  
Ronald Paquette ◽  
Jason R. Gotlib ◽  
Alessandro M. Vannucchi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Control Group ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
First Occurrence ◽  
Equity Ownership

Abstract Background: The phase 3 COMFORT trials demonstrated that the Janus kinase (JAK)1/JAK2 inhibitor RUX reduces spleen volume, prolongs overall survival (OS), and improves MF−related symptoms and measures of quality of life in patients with intermediate-2 or high-risk MF, compared with either placebo (COMFORT-I) or best available treatment (BAT; COMFORT-II). Many patients with MF are anemic or transfusion-dependent; the impact of these features on clinical outcomes is unknown. We evaluated the relationship between transfusion requirement and clinical outcomes in patients treated with RUX in the COMFORT studies. Methods: Analyses of data pooled from COMFORT-I and -II were stratified by baseline anemia status (defined as receiving ≥2 units of red blood cells [RBCs] within the 12 weeks before baseline or baseline hemoglobin [Hb] <10 g/dL). Transfusion independence was defined as the absence of RBC transfusions and maintenance of Hb levels ≥8 g/dL for ≥12 weeks; transfusion dependence was defined as a requirement for ≥4 units of RBCs or Hb levels <8 g/dL during an 8-week interval (Gupta V, et al. JCO [ASCO Abstracts]. 2015;33[s15]:abstract TPS7102). Patients achieving transfusion independence during Weeks 13-24 were considered responders for independence by Week 24; those developing transfusion dependence during Weeks 17-24 were considered dependent by Week 24. Effects of transfusion status at Week 24 on MF Symptom Assessment Form total symptom scores (TSS), spleen volume, and body weight were assessed descriptively. The effect on OS was evaluated using the landmark approach (including patients completing ≥24 weeks of study treatment) with stratified log-rank tests for responder vs nonresponder comparisons. Times to first occurrence of transfusion independence and first occurrence of transfusion dependence in the ITT population (censored at last clinical visit), and time to discontinuation among patients in the RUX group who were anemic at baseline (censored at Week 240) were analyzed using the Kaplan-Meier method. Results: Overall, 301 patients were randomized to RUX (baseline anemia, n=138 [45.8%]) and 227 to the control group (placebo or BAT; baseline anemia, n=113 [49.8%]). In the RUX group, a greater proportion of patients who were nonanemic at baseline (range, 73.4%-73.8%) achieved transfusion independence compared with those who had anemia at baseline (range, 15.5%-22.4%). Week 24 transfusion independence vs nonindependence status did not significantly affect OS in the RUX group (P=0.1322; Figure A), whereas it was significant (P=0.0004; Figure B) in the control group. Similarly, Week 24 transfusion dependence vs nondependence status did not significantly affect OS in the RUX group (P=0.4547; Figure C), whereas it was significant (P=0.0323; Figure D) in the control group. Median OS was significantly longer in the RUX vs control group for patients who were not transfusion independent (baseline anemia, 200 vs 137 weeks; nonanemic, 271 vs 166 weeks; overall P=0.002) or became transfusion dependent (baseline anemia, 210 vs 127 weeks; nonanemic, 292 vs 90 weeks; overall P=0.0323). Changes from baseline in spleen volume, body weight, and TSS at Week 24 were not affected by transfusion or anemia status in the RUX group; however, TSS worsened in the control group among patients who did not achieve transfusion independence vs those who did. Risk of transfusion dependence decreased after Week 24 in the RUX group. The probability of becoming transfusion independent after 1 year of treatment was similar in both treatment groups (approximately 0.75); median time to transfusion independence for the RUX and control groups was 16.6 and 12.0 weeks, respectively. For patients in the RUX group who became transfusion dependent, the mean monthly units of RBCs peaked at Week 20 (2.82 units), decreasing thereafter to 0.52 units at Week 240. Transfusion dependence did not affect RUX discontinuation rates or dosage. Conclusion: Transfusion requirement had little impact on clinical outcomes or treatment discontinuation within the RUX group but was associated with reduced OS and worsened TSS in the control group. The risk of becoming transfusion dependent, units of RBCs administered, and the monthly proportion of patients requiring transfusions decreased rapidly after 24 weeks of RUX treatment. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Verstovsek:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Geron: Research Funding; Lilly Oncology: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Langmuir:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau.

A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp le Coutre ◽  
Ron Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Treatment Options ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

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