Phase 2 Study of Dasatinib in Chinese Patients (Pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) or Advanced Phase Who Are Resistant to or Intolerant of Imatinib (IM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4434-4434
Author(s):  
Jianxiang Wang ◽  
Xiaojun Huang ◽  
Jianda Hu ◽  
Jianyong Li ◽  
Jie Jin ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Median Time ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
First Line ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 4434 Background: CML has a lower incidence in China than in Western countries and appears to affect a younger population (Au, Int J Hematol 2009). In recent years, IM has become the first-line standard of care across Asia for pts with newly diagnosed CML. In a cohort of Chinese pts, >25% of evaluable pts in CP failed to achieve a CCyR with first-line IM, and response rates were significantly lower in pts with accelerated-phase (AP) or blast-phase (BP) CML (Wang, J Exp Clin Cancer Res 2010). Dasatinib is a highly potent second-generation BCR-ABL inhibitor that has established efficacy and safety in pts with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after prior imatinib therapy. Dasatinib is approved by various regulatory authorities worldwide for first-line treatment of Philadelphia chromosome-positive (Ph+) CML in CP. Limited efficacy and safety data are available for second-generation BCR-ABL inhibitors in Chinese pts with CML or Ph+ ALL after imatinib therapy. Methods: In an open-label, single-arm phase 2 study, Chinese pts aged ≥18 years with IM resistant/intolerant CML or Ph+ ALL received dasatinib 100 mg once daily (CP) or 70 mg twice daily for AP/BP or Ph+ ALL. Bone marrow cytogenetic evaluation was performed at months 3 and 6, then every 6 months in CP pts, and was optional for pts with AP/BP or Ph+ ALL. Primary study objectives were to assess rates of major cytogenetic response (MCyR) in CP pts and complete and overall hematologic response (CHR and OHR) in pts with AP/BP or Ph+ ALL. OHR was defined as CHR, no evidence of leukemia, or return to CP. Treatment continued until disease progression or intolerable toxicity. Results: Of 140 enrolled pts, 121 pts had received ≥1 dose of dasatinib and were evaluable (59 with CP, 25 with AP, 35 with BP, and 2 with Ph+ ALL). Of pts with CML-CP or AP/BP/Ph+ ALL, 52 (88%) and 53 (85%) were IM resistant, 4 (7%) and 5 (8%) were IM intolerant, and 3 (5%) and 4 (6%) were both IM resistant and intolerant. Median time from original CML diagnosis to first dasatinib dose was 46.3 months (CP) and 50.2 months (AP/BP/Ph+ ALL). More than half of pts had received prior interferon therapy. At last follow-up, dasatinib therapy had been discontinued by 7 pts (12%) with CP and 43 pts (69%) with AP/BP/Ph+ ALL, due to disease progression or loss of response in 2% and 35%, study drug toxicity in 2% and 11%, stem-cell transplant in 0% and 5%, death in 2% and 2%, and other reasons in 7% and 16%, respectively. After a minimum of 12 months follow-up, MCyR was achieved by 30 pts with CP (51%), 10 pts with AP (40%), and 8 pts with BP/Ph+ ALL (22%). In pts with CP, median time to MCyR was 12 weeks and no patient lost MCyR. Complete cytogenetic response was achieved by 25 pts with CP (44%), 7 pts with AP (28%), and 6 pts with BP/Ph+ ALL (16%). CHR was achieved by 54 pts with CP (92%), 13 pts with AP (52%), and 6 pts (16%) with BP/Ph+ ALL. In CP pts, most (51/54) who achieved CHR did so within 2 months. Median times to CHR were 16 and 12 weeks for pts with AP and BP/Ph+ ALL, respectively. After 12 months, 3 pts in CP, 2 pts in AP, and 1 pt in BP had lost their CHR. OHR was achieved by 23 and 13 pts (92% and 35%) with AP and BP/Ph+ ALL, respectively. In safety assessments (Table), grade 3/4 cytopenia was frequent but managed by dose interruption/reduction or supportive care, with 1 pt discontinued for cytopenia. Pleural effusion of any grade occurred in 15%, 20%, and 22% of pts with CP, AP, and BP/Ph+ ALL, respectively. Grade 3/4 pleural effusion occurred in 1 pt with CML-CP (2%) and 5 pts with AP/BP/Ph+ ALL (8%). Conclusions: The current study confirms the efficacy and safety of dasatinib in Chinese pts with CML or Ph+ ALL that is resistant or intolerant to IM. Results were consistent with data from global trial populations. Disclosures: No relevant conflicts of interest to declare.

Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3229-3229 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Francis Giles ◽  
Andreas Hochhaus ◽  
Jane F. Apperley ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Time To Progression ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3866-3866 ◽  
Author(s):  
Maria Teresa Petrucci ◽  
Igor W. Blau ◽  
Paolo Corradini ◽  
Meletios A. Dimopoulos ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Bortezomib Treatment ◽  
Best Response ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3785-3785 ◽  
Author(s):  
H. Jean Khoury ◽  
Carlo Gambacorti-Passerini ◽  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
David Marin ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115     CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110     MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41)     CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119     PFS at 2 yc 70% 81% 79% 38% 75%     OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

scholarly journals Efficacy and Safety of Pomalidomide in Combination with Prednisone in Patients with Myelofibrosis and Anemia — Final Results of a Prospective Phase 2 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1764-1764
Author(s):  
Lucia Masarova ◽  
Naval G. Daver ◽  
Tapan M. Kadia ◽  
Naveen Pemmaraju ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Hemorrhagic Stroke ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Prospective Phase

Abstract INTRODUCTION: Pomalidomide (POM) is a potent second-generation immunomodulatory agent that has been suggested to have a better toxicity and safety profile than thalidomide and lenalidomide. In patients with myelofibrosis (MF) and anemia, the combination of POM plus prednisone showed up to 36% responses per International Working Group for Myelofibrosis Research and Treatment criteria (IWG-MRT). OBJECTIVE: We present an efficacy and safety data of a prospective phase 2 study of POM in MF patients with anemia after a median follow up of 37.5 months (range, 2-98 months). This report substantiate on previously published results (Daver et al., Leuk Res, 2014; Daver et al., Leuk Res, 2013) and represents final analysis of the study. METHODS: Newly diagnosed or previously treated patients ≥ 18 years with MF and anemia (hemoglobin < 10 g/dL or transfusion [PRBC] dependency) in a need for therapy were eligible. Patients were treated with single POM 3 mg / daily (3 weeks on / 1 week off) or POM 0.5 mg daily continuously with prednisone taper for first 3 months. Responses were re-assessed according to IWG-MRT 2013 criteria. RESULTS: Seventy patients with MF (primary MF, n = 64) of median age of 68 years were enrolled between 07/2009 - 03/2013. Cohort with POM 3 mg (n=21) was closed after 3 months due to excessive toxicity (Daver et al, Leuk Res, 2013). Nine patients who remained on the therapy continued on POM 0.5 mg daily along with 49 additionally enrolled patients, accounting for 58 patients included in this analysis (Table 1). The median time on therapy was 7 months (range, 2-97 months); with 19 patients (33%) treated with more than 12 cycles. Median follow-up from enrollment to data cut-off (May 2018) was 32.5 months (range, 1-99). In total, IWG-MRT responses were identified in 9 patients (16%); only one of them was originally treated with POM 3 mg. The median time on study for responding patients was 16 months (range, 8-71 months). Responses included Clinical Improvement (CI) in hemoglobin in 3 patients (5%); PRBC independence in 6 (10% all, 26% of PRBC dependent patients), and CI spleen in 2 patients (3% all, 20% of patients with splenomegaly). Two patients achieved combined responses; CI spleen with CI hemoglobin and CI spleen with PRBC independence (1 each). Overall median response duration was 8.4 months (range, 3.7-30.3); and it was longer for PRBC independence (30.3 months; range, 8-30.3), and CI spleen (14 months; range, 13-15). Additional 13 patients (without achievement of IWG-MRT response) derived clinical benefit while on study and continued on therapy for a median of 24.5 months (range, 12-93). Observed benefit in these patients included improvement of thrombocytopenia [1], improvement of performance status and/or reduced frequency of PRBC [11], and disease stabilization [1]. One patient progressed to acute leukemia (AML) on a study after 7 cycles of therapy. The treatment was well tolerated with 26 patients (45%) experiencing at least one adverse event (AE) regardless of causality. The most frequent AE were neutropenia (12%); rash (10%); fatigue (10%); and gastrointestinal symptoms (diarrhea/constipation, nausea; 9%). Grade 3/4 AE occurred in 12 patients (21%). All enrolled patients discontinued study due to the following reasons: no response / loss of response [42]; progression to AML [1]; toxicity [4]; stem cell transplantation (SCT) [2]; patient's preference [4]; death [2]; unrelated medical conditions [3]. Reasons for treatment discontinuation due to drug related AE were thrombocytopenia in 2 patients, pneumonitis in 1 patient and allergic reaction in 1 patient. By the time of data cut-off, 43 patients (74%) died with 20 known causes of death: MF progression [4]; AML [2], other medical conditions [7], sepsis [3], myocardial infarction and hemorrhagic stroke [2 each], SCT complications and mesenteric artery ischemia [1 each]). Two of these deaths occurred while on a study; one due to hemorrhagic stroke and one of unknown cause after 31 and 42 months on study, respectively. CONCLUSION: Pomalidomide with prednisone is safe therapy with good anti-anemia activity in patients with MF. It could lead to transfusion independence in one third of patients for a median duration of about 30 months. ClinicalTrials.gov Identifier: NCT00946270. Table 1. Disclosures Daver: Alexion: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; ARIAD: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Karyopharm: Consultancy; Novartis: Research Funding. Kadia:BMS: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Pemmaraju:plexxikon: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; cellectis: Research Funding; novartis: Research Funding; daiichi sankyo: Research Funding. Cortes:novartis: Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy.

scholarly journals Updated Results of Phase 2 Study of Ruxolitinib in Combination with 5-Azacitidine in Patients with Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 352-352 ◽  
Author(s):  
Lucia Masarova ◽  
Srdan Verstovsek ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
Prithviraj Bose ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 2 ◽  
Bone Marrow Fibrosis ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: JAK1/2 inhibitor ruxolitinib (RUX) abrogates symptoms and organomegaly in patients with myelofibrosis (MF). Combination with azacitidine (AZA) may further improve its efficacy. Methods: We initiated a single institutional, single arm, prospective, phase 2 study of RUX AZA combination in adult patients with MF and < 20% blasts. Previous therapy with RUX or AZA was not allowed. RUX 5 - 20 mg orally twice daily was given continuously since cycle 1. AZA 25 - 75 mg/m2 on days 1 - 5 of each 28-day cycle was added starting cycle 4. Responses were assessed per International Working Group for Myelofibrosis Research and Treatment 2013 criteria (IWG-MRT). Enrollment cut-off for this analysis was December 31st, 2017 to allow > 6 months of follow-up for all enrolled patients. We plan to present updated results with additional 5 months of enrollment at the meeting. Results: Fifty two pts were enrolled on study between 03/2013-12/2017, and were evaluable for responses. Forty seven pts (84%) were treated with both agents (RUX and AZA), with a median of 25 cycles (range, 1-55). Median age was 66 years (range, 48-87). Thirty four pts (65%) had int-2/high DIPSS score, 40 pts (77%) had spleen ≥5 cm. Thirty pts (58%) were JAK2V617F positive. Among 36 pts tested for non-driver mutations (28-gene panel); 7 pts had ASXL1, 6 had TET2, 3 had IDH1/2 and 2 had EZH2 and TP53. After a median follow-up of 22+ months (range, 1-59+); 21 pts (40%) are on therapy with a median overall follow-up of 30+ months. The most common reasons for therapy discontinuation were elective stem cell transplantation (n=12), and uncontrolled disease (n=8), including progression to acute leukemia (n=4). Four pts (8%) primarily discontinued therapy due to drug related toxicity (cytopenias). Three treatment unrelated deaths occurred on study; one each due to sepsis, meningitis and metastatic melanoma. Thirty eight pts (73%) had objective response on a study (Table). Median time to response was 1.8 months (range, 0.7-19). Seven responses (21% of responders) occurred after the addition of AZA with a median time to response of 2 months. These responses included spleen and symptom clinical improvements in 26% and 16% of pts, respectively. In total, 26 (65%), and 23 (58%) pts had palpable spleen reduction by > 50% at any time on study, and at week 24, respectively. JAK2V617F allele reduction was noted in 13 (81%) of 16 evaluable pts. Thirty one pts (60%) had available bone marrow for sequential evaluation. Nineteen pts (61%) had a documented improvement in bone marrow fibrosis, collagen or osteosclerosis, with a median time to first response of 12 months (range, 6-18). The most common grade ≥3 non-hematologic toxicity on a study was infection (34%), constipation (21%), and nausea (14%). New onset of grade ≥3 anemia, thrombocytopenia and neutropenia occurred in 33%, 30% and 16% of pts, respectively. Conclusion: Concomitant RUX with AZA was feasible with overall IWG-MRT response rate of 73%, including >50% spleen reduction in 65% of pts. Moreover, 61% of pts achieved improvement in bone marrow fibrosis, collagen or osteosclerosis. ClinicalTrials.gov Identifier: NCT01787487. Table. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; 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. Cortes:novartis: Research Funding. Pemmaraju:novartis: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; SagerStrong Foundation: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding. Daver:Pfizer: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; Sunesis: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; ARIAD: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

A phase 2 study of s-1 plus leucovorin in patients with untreated advanced cholangiocarcinoma (CCA).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 467-467
Author(s):  
Suebpong Tanasanvimon ◽  
Teerapat Ungtrakul ◽  
Nattaya Poovorawan ◽  
Napa Parinyanitikul ◽  
Chanida Vinayanuwattikun ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Primary Endpoints ◽  
Phase 2 Study ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Grade 3

467 Background: Patients with CCA usually present with advanced disease leading to the grave prognosis. Currently, cisplatin and gemcitabine is the standard treatment in advanced CCA. However, the CCA treatment outcomes are still poor and the options of treatment are quite limited. This study aimed to explore the efficacy and safety of S-1 plus leucovorin in patients with untreated advanced CCA. Methods: This single-arm two-center phase 2 study evaluated the efficacy and safety of S-1 40, 50 and 60 mg according to body surface area and leucovorin 15 mg , both given orally twice daily for one week, repeated every two weeks. Treatment was continued until complete 12 cycles, disease progression or unacceptable toxicity. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST version 1.1. The secondary endpoints were progression free survival (PFS), overall survival (OS) and toxicity. Results: Of total 32 patients and a median follow up time of 9.5 months, the ORR was 25% (95%CI 9.1-40.9) and the DCR was 62.5% (95% CI 44.8-80.2). In 25 response evaluable patients, the ORR was 32% (95% CI 12.4-51.7). The PFS was 8.0 (95%CI 5.59-10.4) months. The OS was 11.0 (95%CI 9.47-12.53). The most common grade 3 or 4 toxicities were anemia, mucositis and diarrhea. There was one patient discontinuing treatment due to treatment related toxicity. Conclusions: S-1 plus leucovorin was active and tolerable in patients with advanced CCA. Clinical trial information: TCTR20160313001.

Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CMLCP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3238-3238 ◽  
Author(s):  
Hagop M Kantarjian ◽  
Francis Giles ◽  
Kapil N. Bhalla ◽  
Richard A. Larson ◽  
Norbert Gattermann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Prior Therapy ◽  
Imatinib Resistant ◽  
Phase 2 Study ◽  
Biochemical Laboratory ◽  
Grade 3

Abstract Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR, survival, and safety. Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151–1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinibintolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.

scholarly journals Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Wee-Joo Chng ◽  
Xinhua Li ◽  
Cindy Lin ◽  
Jin Seok Kim ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Prior Exposure ◽  
Phase 2 ◽  
Asian Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Bortezomib-Dexamethasone Alone or Plus Cyclophosphamide or Lenalidomide As Second-Line Treatment for Patients with Multiple Myeloma: Final Results From a Phase 2 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1861-1861
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Meral Beksac ◽  
Lotfi Benboubker ◽  
Huw Roddie ◽  
Nathalie Allietta ◽  
...  
Keyword(s):  
Response Rate ◽  
Stage Migration ◽  
Second Line ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Line Of Therapy

Abstract Abstract 1861 Background: Bortezomib plus dexamethasone (VD) has been shown to be effective and well tolerated in patients (pts) with multiple myeloma (MM) as frontline induction therapy and in relapsed pts; however, no studies have prospectively assessed VD as second-line therapy. The addition to VD of cyclophosphamide (VDC) or lenalidomide (VDR) may improve efficacy, but with increased toxicities. This phase 2 study evaluated the efficacy and safety of VD, with the addition of C or R for pts with stable disease (SD) after 4 cycles, in pts with relapsed or refractory MM following 1 prior line of therapy. This is the first prospective study of VD as second-line therapy for MM. Methods: Bortezomib-naïve pts aged ≥18 years with measurable MM and no grade ≥2 peripheral neuropathy (PN) who had relapsed/progressed after 1 previous line of therapy received four 21-day cycles of VD (bortezomib 1.3 mg/m2, days 1, 4, 8, 11; Dex 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12). Pts achieving at least partial response (PR) then received a further 4 cycles of VD. Pts with SD were randomized to a further 4 cycles of VD, or 4 cycles of VDC (VD + C 500 mg, days 1, 8, 15), or VDR (VD + R 10 mg, days 1–14) for Cycles 5–8. Pts with progressive disease (PD) discontinued treatment. The primary end point was response rate; secondary end points included time to response, duration of response (DOR), safety, and improvement in renal function (defined by the Cockcroft-Gault glomerular function rate [GFR], assessed prior to treatment on day 1, Cycles 1–5). Results: A total of 189 pts were enrolled; 26 did not receive therapy and were excluded from the safety/ITT population (N=163). Median age was 63 years (range 34–86), 53% were male, 20% had KPS ≤70; median time from prior therapy was 13.9 months. In the ITT population, 52% of pts (84/163) experienced an OR by Cycle 4 as validated by IDMC. Discontinuations were due to toxicity (N=10), death, PD, and other reasons (6 each). Of 135 remaining pts who started Cycle 4 treatment, 120 pts had a response assessment at Cycle 4; according to investigators, 82% of these pts experienced an overall response (OR) and 2.5% had PD; median time to first and best response was 49 and 85 days, respectively. Nineteen pts had SD and were randomized: 7 to VD, 8 to VDC (1 did not continue treatment), 4 to VDR. Only 11 pts received a third drug, C or R, in addition to VD. Due to the high response rate for the first four cycles, the second randomization arm was not completed. 47% (77/163) had continued treatment up to Cycle 8. Based on IDMC response validation as of June 2011, 122 patients had a Best Confirmed Response: 75% OR, 20% SD, and 4% PD. GFR results at Cycle 8 are shown in the Table. In pts who had baseline and on-study assessments, median GFR was 62.2 mL/min at baseline and increased after Cycles 1, 2, 3, 4, 5, 6, 7, and up to Cycle 8 by 4.5, 5.7, 9.4, 8.7, 6.0, 9.6, 8.9, and 5.5 mL/min, respectively. Of the 26 pts with stage migration from baseline GFR to best GFR at Cycle 4, 12 had a renal response (MR renal). Of the 24 pts with baseline GFR <50 ml/min and renal response with stage migration from baseline GFR to best GFR at Cycle 8, 13 had CR renal, 11 had MR renal. Grade 3/4 adverse events (AEs) occurred in 64% of pts; the most common were thrombocytopenia (17%), anemia (10%), and constipation (6%). 40% of pts had serious AEs, and 46%/29%/12% had AEs resulting in dose reductions/discontinuation/death. Overall rates of sensory PN, polyneuropathy, PN (neuropathy peripheral), and motor PN in Cycles 1–8 were 20%, 18%, 13%,and 1% respectively, including 5%, 5%, 4%, and 1% grade 3/4, respectively; 55% of PN events were reversible, with resolution in 43%. Conclusions: This is the first prospective trial which assessed VD as second-line treatment in MM. VD is effective and well tolerated with less than 10% of pts receiving subsequent C or R added to VD. Overall renal function was shown to improve with treatment. PN was manageable with good reversal rates. VD represents a feasible, active treatment option for pts with relapsed MM. Final efficacy and safety data will be presented. Disclosures: Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Beksac:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Allietta:Covance for Janssen-Cilag: Employment. Broer:Janssen-Cilag: Employment. Couturier:Janssen-Cilag: Employment. Angermund:Janssen-Cilag: Employment. Facon:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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