Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1749-1749
Author(s):  
Rupali Roy ◽  
Andrew M Evens ◽  
David P. Patton ◽  
Annette Larsen ◽  
Alfred Rademaker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Induction Therapy ◽  
Research Funding ◽  
Phase I Trial ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1749 Background: Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy. Methods: This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22, rituximab 250 mg/m2 on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m2 weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC> 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation. Results: Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity characterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m2. One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m2. All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months). Conclusions: The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m2. Consolidation with bortezomib at 1.6 mg/m2 was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL. Disclosures: Evens: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.

scholarly journals Dynamo: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1218-1218 ◽  
Author(s):  
Ian W. Flinn ◽  
Carole B. Miller ◽  
Kirit M Ardeshna ◽  
Scott Tetreault ◽  
Sarit E. Assouline ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Clinical Activity ◽  
Phase 2 ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract DYNAMO: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma Introduction: Indolent non-Hodgkin lymphoma (iNHL) is characterized by a relapsing clinical course with shorter responses to therapy after each relapse. Duvelisib is an oral dual inhibitor of PI3K-d,γ in development for the treatment of hematologic malignancies, including previously-treated iNHL. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for previously-treated iNHL, with an acceptable safety profile. DYNAMO is a Phase 2 study designed to evaluate the safety and efficacy of duvelisib in a previously-treated, refractory iNHL population. Methods: DYNAMO is an ongoing, open-label, single-arm, safety and efficacy study that includes adult patients (pts) diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen (containing an alkylator or purine analogue) or radioimmunotherapy. Pts received duvelisib 25 mg twice daily (BID) in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study is overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), time to response (TTR), adverse events (AEs), and changes in safety laboratory values. Pneumocystis jirovecii pneumonia (PJP) prophylaxis was mandated for all patients. Here we present the results from the final analysis, with a data cut-off of 07 April 2016. Results: 129 iNHL pts received at least 1 dose of duvelisib, including 83 pts with FL, 28 with SLL, and 18 with MZL. The median duration of exposure was 6 months (range 0.4 - 23.8). The median age was 65 years, and 68% were male. The median time from initial diagnosis to the first dose of duvelisib was 4.5 years, and from last anticancer therapy was 3.5 months. Pts had received a median of 3 prior regimens (range 1 - 18), with 40% having received ≥ 4 regimens. 77% of patients had disease refractory to ≥ 2 regimens and 96% were refractory to their most recent regimen. 64% of patients previously received bendamustine, 80% of whom were refractory. The ORR was 46% (all PRs, 95% CI 37 - 55), with a median DoR of 9.9 months (95% CI 4.5 - 10.3). The median TTR was 1.9 months (range 1.4 - 11.7). With a median follow-up of 11.5 months, the median PFS was 8.4 months (95% CI 5.8 - 11.3) with a 60% estimated probability of being alive and event-free at 6 months, and the median OS was 18.4 months (95% CI 15.7 - NE) with an estimated probability of survival of 74% at 12 months. 83% of pts experienced a reduction in tumor burden following treatment with duvelisib. The response rate across the disease subtypes was: 41% FL, 68% SLL, and 33% MZL (see Table). AEs were predominantly Grade 1-2. The most common ≥ Grade 3 AEs were transient cytopenias (neutropenia [28%], anemia [12%], and thrombocytopenia [13%]), and diarrhea (15%). 63% of pts had dose modifications (interruptions or reductions) due to AEs and 17% of pts discontinued due to an AE. AEs leading to duvelisib discontinuation in ≥ 2 pts included pneumonitis (n = 3), pneumonia (n = 2), and rash generalized (n = 2). Six pts had an AE with an outcome of death, four assessed as related to duvelisib (suspected viral infection, septic shock, and 2 severe cutaneous reactions [TEN and DRESS]). The incidence of ≥ Grade 3 infection was 20%. The incidence of pneumocystis was 0.8% (1 patient) and the incidence of CMV was 2.3% (3 subjects), none of which were fatal. Conclusions: In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in a heavily pretreated and highly refractory iNHL population. The safety profile was acceptable, with the majority of AEs low grade (≤ Grade 2) and the majority of pts able to remain on duvelisib. These results suggest duvelisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Table 1 Table 1. Disclosures Flinn: Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Miller:Infinity: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Assouline:BMS: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani:Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Pettitt:Roche: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Infinity: Research Funding. Tournilhac:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Honoraria, Research Funding. Crump:Roche: Consultancy; Seattle Genetics: Consultancy; Janssen-Ortho: Consultancy; Celgene: Consultancy. Santabarbara:Infinity: Consultancy. Shi:Infinity: Employment. Steelman:Infinity: Employment. Wagner-Johnston:Pharmacyclics: Speakers Bureau.

Phase 1 Dose-Escalation Study of MLN4924, a Novel NAE Inhibitor, in Patients with Multiple Myeloma and Non-Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1854-1854 ◽  
Author(s):  
Jatin J Shah ◽  
Andrzej J Jakubowiak ◽  
Owen A O’Connor ◽  
Robert Z Orlowski ◽  
Molly Patterson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Whole Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Abstract 1854 Poster Board I-880 Background: MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), an essential component of the NEDD8 conjugation pathway in the ubiquitin-proteasome system. Inhibition of NAE with MLN4924 prevents conjugation of NEDD8 to the Cullin Ring Ligases (CRLs). This subsequently prevents ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell cycle regulation (p27), signal transduction (pIκBá), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. MLN4924 has demonstrated potent antitumor activity in vitro against multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines as well as in mouse xenograft models of NHL. This phase 1 dose-escalation study is the first investigation of MLN4924 in MM or NHL patients (pts). The primary objectives were to determine the maximum tolerated dose (MTD) and safety profile of MLN4924, describe the pharmacokinetics (PK) and pharmacodynamics (PD) in blood (inhibition of NEDD8-Cullin levels in peripheral blood mononuclear cells [PBMCs]; Nrf-2 target gene transcription in whole blood), and investigate PD effects in skin (Cdt-1, Nrf-2 accumulation). Methods: Pts aged ≥18 yrs with relapsed and/or refractory MM or NHL after ≥2 prior lines of therapy were eligible. Pts received escalating doses of MLN4924 by IV infusion on days 1, 2, 8, and 9 of 21-day cycles; once the MTD for this schedule was reached, MTDs for other schedules will be investigated. MTD determination was based on an adaptive approach using a Bayesian continual reassessment method, with the MTD defined as the dose level closest to that predicted to result in a dose-limiting toxicity (DLT) rate of 25%. DLT was defined as: grade 4 neutropenia or thrombocytopenia for >7 days; grade 3 neutropenia with fever/infection or thrombocytopenia with bleeding; grade ≥3 non-hematologic toxicity except arthralgia/myalgia, brief fatigue, or fever without neutropenia; and grade ≥2 MLN4924-related toxicities requiring dose reduction/discontinuation. For PD analysis, PBMCs and whole blood were isolated at screening, baseline, and following MLN4924 administration; skin biopsies for Cdt-1 and Nrf-2 assays were performed at baseline and after the second dose. Results: Among 22 pts enrolled to date, median age was 65 years, 13 were male, 14 had MM, and 8 had NHL (4 FL, 1 MCL, 1 DLBCL, 1 B-cell CLL/SLL, 1 transformed CLL). All MM pts had received prior autologous SCT, and 13, 9, and 9 had prior bortezomib, lenalidomide, and thalidomide, respectively. Seven NHL pts had received prior autologous SCT, 1 had a prior allogeneic SCT, and 8 had prior rituximab. Pts received MLN4924 at 6 dose levels: 25 (n=3), 50 (n=2), 65 (n=3), 83 (n=2), 110 (n=9), and 147 mg/m2 (n=3). Of the 15 (68% of the 22 enrolled) pts who received all 4 scheduled doses or had a DLT in cycle 1 (DLT-evaluable pts), 4 experienced a DLT: 1 grade 4 febrile neutropenia at 65 mg/m2; 1 grade 3 liver function tests at 110 mg/m2, and 1 grade 4 muscle cramps and 1 grade 2 myalgia that was considered dose limiting at 147 mg/m2. Thus, the MTD for this schedule was determined to be 110 mg/m2. The most common adverse events (AEs, NCI CTCAE v3.0) included fatigue, nausea, myalgia, and elevated liver enzymes. With the exception of the grade 4 neutropenia seen at 65 mg/m2, myelosuppression was limited. No infusion-related reactions were noted. Elevated CRP levels appeared transient in most cases. There have been no treatment-related deaths; 1 MM pt died due to progressive disease. MLN4924 displayed a multiexponential PK profile with a half life of 4–9 hours, relatively low PK variability, and approximately dose-proportional increases in total plasma exposure over the 25–147 mg/m2 dose range. NEDD8-Cullin levels in PBMCs were inhibited and Nrf-2 target gene transcripts in whole blood were higher vs baseline after MLN4924 administration, indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the second dose of MLN4924, indicative of NAE inhibition in peripheral tissue. The 110 mg/m2 dose level is being expanded to more fully characterize safety, PK, and PD in MM and NHL. Subsequent pts will be enrolled to receive MLN4924 on 2 other schedules. Conclusions: This early analysis provides evidence of PD inhibition of NAE activity by MLN4924 in blood and skin, and supports continued investigation of MLN4924. Disclosures: Shah: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Elan: Consultancy; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: MLN4924 is not approved for the treatment of multiple myeloma or non-Hodgkin lymphoma.. Jakubowiak:Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Millennium Pharmaceuticals, Inc.: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Petruzzelli:Pfizer: Equity Ownership; Millennium Pharmaceuticals, Inc.: Employment; Amgen: Equity Ownership. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Novartis: Consultancy; Gloucester: Research Funding; BMS: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy.

An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4175-4175
Author(s):  
Christine I. Chen ◽  
Susi Snitzler ◽  
Trina Wang ◽  
Harminder Paul ◽  
Lisa W Le ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Treatment Phase ◽  
Phase 2 ◽  
Akt Inhibitor ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

scholarly journals Ritumixab in Combination with Adapted-Dose of Ifosfamide and Etoposide As Salvage Treatment in Elderly Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for High Dose Therapy: A Retrospective Study of Lyon Hospital University

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4215-4215
Author(s):  
Guillaume Aussedat ◽  
Delphine Maucort-Boulch ◽  
Philippe Rey ◽  
Violaine Safar ◽  
Lionel Karlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
High Dose ◽  
First Line ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

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.

Bortezomib in Combination with Dexamethasone and Pegylated Liposomal Doxorubicin (DoVeD) Breaks Plateau Responses Following Initial Induction Therapy in Multiple Myeloma: Results of a Phase II Pilot Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2311-2311
Author(s):  
Megan C. Manco ◽  
Tomer Mark ◽  
David S Jayabalan ◽  
Faiza Zafar ◽  
Roger Pearse ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
M Protein ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Disease Characteristics ◽  
Grade 3

Abstract Abstract 2311 Poster Board II-288 Improved quality of response to induction therapy has been shown to be associated with improved long-term outcomes, including prolonged progression-free (PFS), event-free, and overall survival (OS), in newly diagnosed multiple myeloma (MM) patients (pts). Induction regimens incorporating the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have demonstrated high overall response rates (ORR), and substantial complete response (CR) and very good partial response (VGPR) rates in MM; however, while a large majority of pts respond, a proportion does not achieve ≥VGPR. Per the Norton–Simon hypothesis, the sequential, dose dense, use of agents or regimens that are not cross-resistant may improve the proportion of pts achieving CR or VGPR to induction therapy, and subsequently improve long-term outcomes. This phase II pilot study investigated the efficacy and safety of bortezomib + dexamethasone ± liposomal doxorubicin (DoVeD) in MM pts who had reached a response plateau (<25% change in M-protein level for three successive assessments) after achieving a partial response (PR) to initial induction with IMiD-containing therapy. All pts proceeded to high-dose therapy and stem cell transplantation. Pts received six 3-week cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, plus dexamethasone 40 mg on days 1–4, 8–11, and 15–18. Pts achieving <PR after two cycles or <CR after four cycles received liposomal doxorubicin 30 mg/m2 on day 4 for the remaining four or two cycles, respectively. Response to DoVeD was assessed relative to baseline prior to start of DoVeD therapy according to IMWG uniform response criteria. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 34 pts were enrolled; baseline demographics and disease characteristics are shown in the Table. Initial induction therapy comprised lenalidomide–dexamethasone in 22 pts, thalidomide–dexamethasone in 5 (followed by VAD in 1), thalidomide in 2, and thalidomide–lenalidomide–dexamethasone in 5. At data cut-off, 3 pts remained on DoVeD therapy and were not evaluated for response. The other 31 pts received a median of 6 cycles of DoVeD; liposomal doxorubicin was added in 22/31 (71%) pts, 11 after cycle 2 and 11 after cycle 4. Best responses to DoVeD were 5 (16%) stringent CR, 2 (6%) CR, 6 (19%) VGPR, and 12 (39%) PR, for a ≥VGPR rate of 42% and an ORR of 81%. Four (13%) pts achieved a minimal response, and 2 (6%) had disease progression. Median PFS was 1,210 days (95% CI: 387–1311) and 3-year PFS was 57% (95% CI: 27%–73%). Four pts died during the follow-up period. Median survival was not reached; 4-year OS was 83% (95% CI: 60%–94%). A Cox proportional hazards model controlling for age, sex, and ISS showed that only a ≥90% reduction in M-protein significantly correlated with reduction in disease progression (p=0.014). Among 33 pts who had completed one cycle of DoVeD and were thus evaluable for safety, all experienced at least one AE, including 23 (70%) who experienced at least one grade 3/4 AE. Hematologic grade 3/4 AEs during DoVeD therapy included 9/3% neutropenia and 9% grade 4 thrombocytopenia; non-hematologic AEs included fatigue, pneumonia, infection (9% each), diarrhea, constipation, irritability, hypotension (6% each), hand–foot syndrome, chest pain, and myopathy (3% each). In total, 23 (70%) pts experienced peripheral neuropathy, including 9 (27%) grade 2 and 3 (9%) grade 3 (no grade 4 PN). In conclusion, DoVeD therapy can result in further substantial reductions in tumor burden, including additional CRs and VGPRs, in MM pts whose response has reached a plateau following PR with prior IMiD-containing induction. The additional cytoreduction and increase in CR/VGPR rates achieved with this tandem approach, plus the potential associated improvement in long-term outcomes, suggest a possible paradigm shift for MM induction therapy in general. Table Patient baseline demographics and disease characteristics Characteristic* N=34 Age, years 60.5 (27-76) Male, n (%) 19 (56) B2-microglobulin, mg/L 2.1 (1.0-10.2) Albumin, g/dL 3.5 (2.0-4.3) Durie-Salmon Stage Ia / IIa / IIIa / IIIb, n 2 / 14 / 17 / 1 ISS Stage I / II / III, n 16 / 15 / 3 Abnormalities by FISH, n (%) del 13q14 13 (38) Trisomy 11 6 (18) Hyperdiploidy 5 (15) t(4;14) 4 (12) p53 3 (9) t(11;14) 2 (6) t(14;16) 2 (6) None 16 (47) * Median (range) shown unless stated Disclosures: Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Crann:Milllennium: Membership on an entity's Board of Directors or advisory committees. Leonard:Milllennium: Consultancy; Johnson & Johnson: Consultancy. Coleman:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau; Immunomedics: Membership on an entity's Board of Directors or advisory committees. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2271-2271
Author(s):  
Andreas L Petzer ◽  
Dominic Fong ◽  
Thomas Lion ◽  
Irina Dyagil ◽  
Zvenyslava Masliak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
De Novo ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 2271 Introduction: Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML. Methods: We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726. Results: From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B. Conclusions: Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients. Disclosures: Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

90Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 594-594 ◽  
Author(s):  
Anton Hagenbeek ◽  
John Radford ◽  
Achiel Van Hoof ◽  
Umberto Vitolo ◽  
Ama Z.S. Rohatiner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Control Group ◽  
Advanced Stage ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees

Abstract Abstract 594 The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39–0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42–0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27–0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30–1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were – for the greater part – rituximab-naïve. Disclosures: Hagenbeek: Roche Global Advisory Board: Consultancy. Radford:Schering (May 2009): Honoraria, Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche Italy: Membership on an entity's Board of Directors or advisory committees; Celgene Italy: Membership on an entity's Board of Directors or advisory committees. Soubeyran:Roche: Honoraria, Research Funding; Cephalon: Research Funding. Bischof Delaloye:Expert Statement (questions of reimbursement in Switzerland): Honoraria. Morschhauser:Roche: Honoraria, Paid expert testimony within the past 2 years; Bayer: Honoraria.

Ofatumumab and Bendamustine in Previously Treated CLL and SLL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4615-4615
Author(s):  
Chaitra S. Ujjani ◽  
Edmund A Gehan ◽  
Pari Ramzi ◽  
Catherine Broome ◽  
Bruce D. Cheson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Brain Mri ◽  
Viral Reactivation ◽  
Multiple Infections ◽  
Advisory Committees ◽  
Richter’S Transformation ◽  
Richter's Transformation ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 4615 Background: Despite response rates of 85–95% with fludarabine and rituximab (R)-based therapies in multicenter trials, patients (pts) with CLL invariably relapse. Ofatumumab (O) and Bendamustine (B) have each shown efficacy in relapsed/refractory CLL with ORRs of 68–78% and 44–58%, respectively. While excellent responses have been seen with BR in CLL (77-91%), the combination of O and B has yet to be investigated. In this phase II study, we are combining O and B in previously treated CLL and SLL in order to investigate the efficacy and tolerability of this regimen. We report our experience with the first 5 pts here. Methods: Pts with relapsed/refractory CLL/SLL with adequate performance status and organ function were eligible as long as they had not received B previously. Pts received O 300 mg IV on D &minus;7, followed by O 1000 mg IV on D1 and B 70 mg/m2 on D1, 2 of each cycle (C). Premedications included acetaminophen 650 mg PO, diphenhydramine 50 mg PO, and hydrocortisone 100 mg IV prior to O and Ondansetron 8 mg IV prior to B. Pts received 6 cycles of OB as long as tolerated or until disease progression. The target enrollment is 40 pts. Results: Of the 5 pts on study, the median age was 62 years, 4 were male, and 3 were Rai Stage III/IV. One pt had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a mean of 2 prior therapies (range, 1–4). The first 3 pts developed Grade 2 infusion-related reactions with O during C1. Thus, the protocol was amended to increase acetaminophen to 1000 mg and hydrocortisone to 200 mg for O premedication. Three patients developed > Grade 3 neutropenia which delayed C2 treatment in 2 pts. Two pts experienced > Grade 3 anemia requiring transfusion. In addition, multiple infections arose on study. Pt 1 had a Grade 1 URI requiring hospitalization during C1. Pt 2 had a Grade 2 pneumonia with Grade 3 NTP during C1 and a Grade 2 UTI during C2. Pt 4 developed a Grade 3 pneumonia, Grade 3 hepatosplenic fungal infection, and Grade 3 bacteremia after C1. Pt 5 had a Grade 2 URI during C1 and Grade 2 sinusitis during C3. The protocol was amended so that pegfilgrastim was to be given with each cycle. After C1, Pts 1 and 4 developed a systemic neurotoxicity, characterized by blunted affect, weakness, fatigue, and failure to thrive requiring hospitalization. Complete infectious, metabolic, psychological, and neurologic evaluation was negative for Pt 1. Due to his ongoing weakness, he was removed from study after C2 and discharged to rehab. At 3 months he was only able to walk 3 blocks and his affect remained blunted. Pt 4 was found to have pneumonia on admission. With antibiotics, his functional status improved, but his affect remained mildly altered. Proposed etiologies for this neurotoxicity included infection such as viral reactivation or cytokine release storm. The protocol was amended to exclude pts with history of neurologic deficit and to perform a thorough neurologic evaluation including brain MRI, lumbar puncture, and serum and CSF viral serologies and cytokines levels at onset of concerning symptoms. Pts received a median of 2 cycles of therapy (range, 1–6). All showed evidence of response after C1. Pt 1 achieved a clinical CR with C1 but was removed from study after C2 and had recurrent disease at 5 months. Pt 2 achieved a CR after C3 and remains progression-free 5 months after completing C6. Pts 3 and 4 initially showed a response after C1 but developed Richter’s transformation during C2. Pt 5 had a response after C1 and is currently in C4. The most common reasons for stopping therapy were toxicity and Richter’s transformation. Conclusion: OB has significant efficacy in pts with multiply-relapsed and highly-refractory CLL/SLL. However, toxicity is considerable, particularly in terms of infection. In addition, despite an initial response, Richter’s transformation has been reported in two patients. As this is a small cohort with multiple confounding factors, further evaluation is needed. Disclosures: Broome: Alexion: Honoraria, Speakers Bureau. Cheson:Cephalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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