scholarly journals Idelalisib for Relapsed/Refractory Follicular Lymphoma: Retrospective Study from Spanish Lymphoma Group Geltamo (GELT-IDE-2018-02)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5249-5249
Author(s):  
Juan-Manuel Sancho ◽  
Olga García ◽  
Pablo Mozas ◽  
Santiago Mercadal ◽  
Eva Donato ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Practice ◽  
Retrospective Study ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Advisory Committees ◽  
Biological Variables ◽  
Grade 3

Background and objective. Idelalisib is an oral inhibitor of the p110δ isoform of PI3K (phosphoinositide 3-kinase) approved in Europe and USA as monotherapy in relapsed/refractory follicular lymphoma (FL) after 2 previous lines of therapy based on a phase 2 study (Gopal et al, N Eng J Med 2014). However, there are scarce data on the use of idelalisib in clinical practice (Eyre et al, Br J Haematol 2017). The objective of this study was to analyze the efficacy and toxicity of idelalisib in relapsed/refractory FL patients in clinical practice in Spanish hospitals of GELTAMO group (GELT-IDE-2018-02 Study). Patients and Methods. Retrospective study of relapsed/refractory FL patients treated with idelalisib as salvage therapy in clinical practice. Demographic and clinical and biological variables were analyzed at FL diagnosis and at the time of idelalisib therapy, as well as its efficacy and toxicity. Results. A total of 43 patients from 20 hospitals were included. At time of idelalisib therapy, median age was 63 years (range 44-83), number of previous lines of therapy was 3 (2-7), 42% (n=18) were refractory to last previous treatment and 42% (n=18) had received an autologous stem cell transplantation (SCT); 56% (n=24) had progressed in the first 24 months after FL diagnosis (POD24). Median duration of treatment with idelalisib at time of analysis was 8.1 months (1.1-37.4) and 28/43 patients (65%) discontinued therapy, 13 due to progression, 12 due to adverse events (AE) and 3 due to physician's decision. Overall response rate (ORR) was 73% (32% CR) and median PFS 14.6 months (95% CI 0-32.2), with a trend to be higher in non-POD24 group (median PFS of 9.4 months [95% CI 1.7-16.9] in POD24 vs. 27 months [95% CI NA] in non-PO24 patients, p=0.082); median duration of response to idelalisib was 25.1 months (95% CI 13.1-37.6). Median overall survival (OS) was not reached at the time of analysis, with a 2-year OS of 74% (95% CI 58%-90%) (Figure). In 4 patients, an allogeneic SCT was performed after idelalisib. A total of 86% (n=37) of patients showed any AE, being in 56% (n=24) of grade ≥3 AE. Toxicities of grade ≥3 more frequent were: neutropenia (23% of patients), diarrhea (23%), infections (23%: pneumonia in 4 patients, CMV infection in 2, febrile neutropenia in 1 and other infections in 3 [1 of them died due to Aspergillus infection]), and increased transaminases (9%). Conclusions. In this series of patients with relapsed/refractory FL, several previous lines of therapies and factors associated with poor prognosis, the treatment with idelalisib was associated with efficacy and toxicity similar to published studies. These results support the use of idelalisib as an option for FL patients with multiple or poor risk relapses. Financial support: Gilead Figure. Progression-free survival (PFS) and overall survival (OS) for patients with follicular lymphoma treated with idelalisib. Figure Disclosures Sancho: SERVIER: Honoraria; SANOFI: Honoraria; Novartis: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Martín:Kiowa Kirin: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; iQone: Consultancy; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses. Armando:Roche: Consultancy, Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Chronic Myeloid Leukemia (CML) Patients Who Are Resistant or Intolerant to Two or More Tyrosine Kinase Inhibitors – Results of A Multicenter Phase 2/3 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 861-861 ◽  
Author(s):  
Jorge Cortes-Franco ◽  
Digumarti Raghunadharao ◽  
Purvish Parikh ◽  
Meir Wetzler ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Hematologic Response ◽  
Grade 3

Abstract Abstract 861 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. The development of TKI resistance and intolerance is an emerging problem and patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Study Goals: To evaluate the safety and efficacy of SC omacetaxine in CML Pts who are resistant and/or intolerant to two or more TKIs. Methods: Eligible Pts included adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with resistance and/or intolerance to at least two TKIs. Bcr-Abl mutational analysis was performed at one of 2 central reference laboratories and Pts harboring the T315I Bcr-Abl mutation were enrolled in a separate clinical trial. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 99 Pts have enrolled, with data available for analysis on 65 Pts (30 CP, 20 AP and 15 BP). The median age was 57 yrs (23-78) with 52% male and a median disease duration of 77 mo (1-197). Nearly all (64/65, 99%) Pts failed prior IM therapy and 57% failed 3 or more prior TKIs. Baseline mutations were identified in 21 (32%) Pts with 10 non-P Loop, 7 P Loop and 4 compound mutations. Baseline clonal evolution was evident in 5 (17%) CP, 8 (40%) AP, and 13 (87%) BP Pts. Six CP Pts entered the study in CHR. The median follow-up for all Pts is 4.0 mo (0.3 to 14.7). Efficacy: In CP Pts, CHR was achieved in 18 Pts and maintained for more than 8 weeks in the 6 Pts enrolled with baseline CHR, for an overall CHR rate of 80%; median duration 4.7+ mo (1.4 to 13). Major cytogenetic response (MCyR) was achieved in 6 (20%) CP Pts (1 complete, 5 partial); median duration 1.6+ mo (0.0 to 2.9). Major molecular response was achieved in 10% of CP Pts. In AP Pts, overall hematologic response was achieved in 15 (75%) Pts; 12 CHR and 3 return to chronic phase (RCP); median duration 2.5+ mo (1.8 to 10.5). One (5%) AP Pt achieved a complete CyR, identified immediately prior to data cut-off and ongoing. In BP Pts, overall hematologic response was achieved in 8 (53.3%); 6 CHR and 2 RCP. Three Pts (2 CP, 1 AP) received bone marrow/stem cell transplants after achieving major cytogenetic response, a therapeutic option not available to them at study enrollment. No deaths occurred in CP Pts. The median overall survival for AP Pts has not been reached and 13 Pts were alive at the time of data cut-off. Median overall survival was 14.5 mo for BP Pts. Median time to progression was 11.1, 5.7, and 2.6 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 47/65 (72%) of Pts. The most commonly reported events (>15%) were thrombocytopenia (43%), neutropenia (29%), and anemia (22%). Non-hematologic toxicities were generally grade 1/2 with the most frequently reported; diarrhea (32%), nausea (26%), pyrexia (23%), headache (20%), fatigue (19%), vomiting (17%), and asthenia (17%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and fatigue (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 9 days for all disease phases and cycles (CP=7, AP=11, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Deaths occurred in 6 (9.2%) Pts, including 2 (10%) AP pts and 4 (26.7%) BP Pts. Of the deaths, one occurrence in an AP Pt was considered to be possibly related to omacetaxine treatment (febrile neutropenia). Conclusions: Omacetaxine administered by SC injection produced hematologic and cytogenetic responses with a safety profile primarily consisting of hematologic toxicities. This study demonstrated that omacetaxine may be a potential treatment option for CML Pts who have failed multiple TKIs. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raghunadharao:ChemGenex: Research Funding. Parikh:ChemGenex: Research Funding. Wetzler:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Nicolini:ChemGenex: Research Funding.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

scholarly journals Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 125-125 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Jason R. Westin ◽  
Fredrick B. Hagemeister ◽  
Hun Ju Lee ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Tumor Burden ◽  
Advisory Board ◽  
Advisory Committees ◽  
High Tumor Burden ◽  
Equity Ownership ◽  
Grade 3

Introduction: FL, the most common indolent non-Hodgkin lymphoma, is characterized by a defective immune microenvironment that suppresses normal T-cell and natural-killer (NK)-cell activity. The clinical course is often depicted by high initial response rates coupled with a prolonged natural history and repeated relapses with most patients (pts) succumbing to their disease. Effective, well tolerated therapies are desirable. Obinutuzumab (O) is a humanized, type II anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Lenalidomide (len) is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex resulting in recruitment, ubiquitination, and degradation of transcription factors Aiolos and Ikaros resulting in T-cell and NK-cell activation. Therefore, combining O with len is anticipated to be synergistic in augmenting the innate and adaptive immune response in FL. The combination has been shown to be well tolerated and effective in relapsed FL (Fowler ICML 2017). Therefore, we sought to explore the efficacy and safety of O-len in previously untreated, high tumor burden FL. Methods: We conducted as single-center, phase 2 study in previously untreated, stage II, III, or IV, high tumor burden (defined by GELF) FL (grade 1, 2 or 3A). Pts received 1000mg of O on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and day 1 of even numbered cycles, cycle 8-30. Cycle length was 28 days. Len was administered as 20mg on days 1-21 of cycles 1-6. Pts in a complete response (CR) after 6 cycles received reduced dose len (10mg on days 1-21) for cycles 7-18. Among pts in a partial response (PR) after 6 cycles, len was continued at 20mg for the next 3-6 cycles or until CR, whichever occurred first, len was then dose reduced to 10mg on days 1-21 for the remainder of 18 cycles. The primary endpoint was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria). Secondary endpoints included: safety, CR, PR, overall response (ORR), and overall survival (OS). Results: 90 pts with high tumor burden FL were enrolled. Median age was 58 years (range 33-84), 52% (N=47) were male, 67 (74%) had an ECOG performance status of 0, 9 (10%) had stage II, 23 (26%) stage III, and 58 (64%) had stage IV disease. The majority had grade 1/2 FL (80%). Twenty-one percent had low risk FLIPI scores, 37% intermediate risk, and 42% were high risk. With a median follow-up of 22 months (range 1-30 months), the 2-year PFS estimate is 96% (95% CI 92-100%) with only 2 pts experiencing progression to date. The ORR is 98% (85 CR, 1 PR), 92% achieved a CR at the first response assessment (cycle 4, day 1). Correlative studies are underway including serial circulating tumor DNA measurements. No deaths have been observed to date. Eleven pts (12%) discontinued therapy as a result of an adverse event (AE), upper respiratory infection was the most common reason (N=5). Other reasons included bradycardia with sick sinus syndrome, urinary tract infection, constipation, abdominal pain, fatigue, foot neuroma (N=1 for each instance). The most common grade 3 or higher AEs include neutropenia (16%, grade 3 N=5, grade 4 N= 9), rash (10%), lung infection (4%), neutropenic fever (1%). Conclusions: O-Len was associated with very high CR rates and 2-year PFS estimates in untreated, high tumor burden FL. The toxicity profile was manageable. Further study of this effective, immune therapy approach in untreated FL is warranted. Figure Disclosures Nastoupil: Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Poseida: Research Funding; Karus: Research Funding; Novartis: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding. Fowler:ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy. OffLabel Disclosure: Lenalidomide in untreated follicular lymphoma

scholarly journals Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3011-3011 ◽  
Author(s):  
Lucia Masarova ◽  
Jorge E. Cortes ◽  
Keyur P. Patel ◽  
Susan M. O'Brien ◽  
Graciela M. Nogueras González ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research ◽  
Phase 2 Study ◽  
Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; 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. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

scholarly journals A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor in Patients with Myelofibrosis Refractory or Intolerant to JAK Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 143-143
Author(s):  
Srinivas K. Tantravahi ◽  
Soo Jin Kim ◽  
Divya Sundar ◽  
Ami B. Patel ◽  
Anthony D. Pomicter ◽  
...  
Keyword(s):  
Weight Loss ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Median Duration ◽  
Research Funding ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Management Committee ◽  
Study Management ◽  
Grade 3

Abstract Background: Selinexor is an oral, small molecule, selective inhibitor of nuclear export (SINE) compound that specifically blocks the karyopherin protein exportin 1 (XPO1, CRM1). In an shRNA library screen, we discovered that the survival of JAK2V167F mutant HEL cells is dependent on XPO1-mediated nuclear-cytoplasmic transport. Selinexor selectively suppressed primary myelofibrosis (MF) cells as compared with normal progenitor cells and induced hematologic responses in an MPN mouse model. Methods: An open label, prospective, investigator-initiated single center study is ongoing in adults with primary or secondary MF with resistance or intolerance to JAK inhibitor (JAKi) therapy with platelets &gt; 30 K/μL and neutrophils &gt; 500/μL. Selinexor was given orally once a week. Spleen volume was assessed by MRI at week 12 and week 24. The study was amended to include additional MRIs every 12 weeks in the year 1 and 24 weeks in the year 2. Primary end point is spleen response, defined as ≥ 35% spleen volume reduction (SVR) by MRI or CT, where applicable) at week 24. Bone marrow was evaluated at baseline and at week 24. The projected sample size of 24 will provide 83% power to reject a response rate of 15% and allow for up to a 25% dropout rate. We provide an interim report after completing 50% enrollment. Results: Between May 2019 and February 2021, 12 patients (pts) were enrolled. JAK2, CALR and MPL mutations were present in 7 (58.3%), 4 (33.3%) and 1 (8.3%) pts respectively. Eight pts (66.6%) had at least one high molecular risk mutation at baseline (Table 1). Median duration of prior JAKi therapy was 22 months (0.5 to 96 months) and 11 out of 12 were refractory to ruxolitinib at study enrollment. Median baseline spleen volume was 1454 cm 3(range 835 to 5792). Selinexor starting dose was 80 mg weekly in the first 6 pts and 60 mg for subsequent pts. At data cutoff, median duration of selinexor therapy was 36 weeks (range 11-114 weeks). One pt was not response evaluable and died due to liver abscess at week 12 (unrelated). One pt discontinued selinexor at week 18 due to grade 3 fatigue and was not evaluable for the primary end point. Of the 11 pts who had week 12 MRI or CT, 6 showed ≥ 10% SVR, 3 showed ≥ 25% SVR and 1 pt had early progression (Figure 1). At week 24, 5/9 (56%) pts had ≥ 25% SVR and 2/9 (22%) had ≥ 35% SVR (Figure 1). In 9 pts who had ≥24 weeks of selinexor, SVR ≥ 25% and ≥ 35% occurred at any point during study treatment in 4 (44%) and 3 (33%) pts, respectively. Two pts were red cell transfusion dependent at baseline; 1 became transfusion independent after 36 weeks of treatment, has not required transfusion for 49 weeks and remains on study treatment to date (114 weeks). Six pts (50%) discontinued selinexor. Reasons for treatment discontinuation are death in 1 pt, progressive disease in 1 pt, alternative treatment in 2 pts, and toxicity in 2 pts. Ten pts required dose reduction due to fatigue (1pt), anemia (1 pt), thrombocytopenia (2 pts), abdominal pain (1pt) and weight loss (5 pts). The most common treatment related adverse event was weight loss (grade 2 in 4 pts and grade 3 in 1 pt). This was manageable with treatment interruption and dose reduction, except in one pt who discontinued selinexor. As yet no changes in reticulin fibrosis MF grade were observed among 9 patients who received at least 24 weeks of treatment. Conclusions: Once weekly, oral selinexor showed single agent activity with sustained spleen responses in pts with JAKi refractory MF. Long-term administration of selinexor was well tolerated over time in MF pts. Correlatives studies including circulating inflammatory cytokine levels and mutant allele burden, as well as clonality studies by X-chromosome inactivation studies in woman, are underway and will be presented. Figure 1 Figure 1. Disclosures Tantravahi: BMS: Research Funding; Novartis: Research Funding; CTI BioPharma: Research Funding; Abbvie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding. Patel: Stemline: Research Funding; Genentech: Research Funding; Roche: Research Funding. Chamoun: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm: Current Employment. George: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy; Blueprint Medicines: Consultancy. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding.

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

scholarly journals Mismatch-Repair Deficiency in Follicular Lymphoma Tumors Is Common and Associated with a Favorable Overall Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3523-3523
Author(s):  
Jithma P. Abeykoon ◽  
Dominick E Nowakowski ◽  
Jonas Paludo ◽  
Michelle K. Manske ◽  
Rebecca L. King ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Mismatch Repair ◽  
Solid Tumors ◽  
Research Funding ◽  
Somatic Hypermutation ◽  
Age At Diagnosis ◽  
Advisory Committees ◽  
High Degree

Abstract Introduction: DNA mismatch repair (MMR) is a major mechanism cells use to repair erroneous insertion or deletion of bases during DNA replication. MMR deficiency (MMR-d), including rare germline mutations (Lynch syndrome) and somatic inactivation, has been extensively studied in solid tumors, such as colon, endometrial, pancreatic, and ovarian cancers. The prevalence of MMR-d in solid tumors ranges from 1% - 20% of somatic defects, and patients with MMR-d tumors have a longer overall survival. It is also well-known that MMR is an integral part of activation-induced cytidine deaminase (AID)-mediated somatic hypermutation and immunoglobulin class switch processes in normal mature B lymphocytes, while mice deficient in the MMR genes are prone to develop T and B cell lymphomas. It is also known that follicular lymphoma (FL) carries a high degree of somatic hypermutation with some heterogeneity induced by AID. Our understanding of MMR status in human blood cancers, especially in FL remains very limited. One could hypothesize that MMR-d status could permit cells to acquire and sustain high-degree of mutation rates, better sensitivity to DNA damaging chemotherapy while hindering rapid cell proliferation, which could manifest to a better prognosis in patients. Herein, we conducted an exploratory analysis to understand the frequency of MMR-d status and its prognostic significance in FL. Methods: Following approval of the Institution Review Board, we assessed the expression of MMR proteins; MLH1, PMS2 and MSH6 on formalin fixed paraffin embedded (FFPE) lymph node tissue obtained from patients with FL by immunohistochemistry (IHC) using standard methods on Ventana Benchmark XT automated stainers (Ventana Medical Systems, Tucson, AZ). Dako (clone ES05), Cell Marque (clone EPR3947) and Biocare (clone BC/44) antibodies were used to stain MLH1, PMS2 and MSH6, respectively. Fifty cases of FL with existing FFPE blocks were selected randomly. The expression of MLH1, PMS2 and MSH6 proteins in the tumor cells was scored as 0, +1 or +2, (Figure 1A). Cases with absence of the IHC signal (score of 0) in any one of the three proteins were classified as MMR-d. Progression free survival at 12 months (PFS12) or 24 months (PFS24) was defined as being free from disease progression or death at 12 or 24 months, respectively. All time-to-event analyses were done from the time of diagnosis. Results: Fifty patients with FL were included in the study. The median age at diagnosis was 65 years (range 34-85) and 58% were females. At initial diagnosis, 36 (72%) patients had advanced stage (stage 3, n=8, stage 4, n=28) disease. Of the 50 patients, 26 (52%) required treatment; chemotherapy (n=14), radiation treatment alone (n=9), surgery alone (n=3). Out of the 50 patients, 23 (46%) were classified as MMR-d due to lack of expression of one of the three assessed proteins: MLH1 (n=1, 2%), PMS2 (n=11, 22%) and MSH6 (n=19, 38%). The patient who had MLH1 loss had concomitant PMS2 loss. Stage IV disease was observed in 52% of the MMR-d patients and 59% in the MMR proficient (MMR-p) patients, p=0.77. Median age at diagnosis was 62 (range: 34-84) years and 67 (range: 34-85) years in MMR-d and MMR-p patients, respectively, p=0.1. FLIPI score was similar between the MMR-d [low n=10 (43%), intermediate n=9 (39%), high n=4 (18%)] and MMR-p [low n=5 (18%), intermediate n=14 (52%), high n=8 (30%)] patients, p=0.16. Fourteen (61%) of MMR-d patients required initiation of therapy upon diagnosis compared to 12 (44%) of MMR-p patients, p=0.27. The median follow-up for the entire cohort was 17 years [95% confidence interval (CI): 11.7-29.4]. The median overall survival (OS) of MMR-d patients was 10 years (95%CI: 7.8-20.7) compared to 6 years (95%CI: 4.5-NR) in MMR-p patients, p=0.036, Figure 1B. In patients with MMR-d and MMR-p, 83% and 55% achieved PFS12, p=0.04 and 65% and 41% achieved PFS24, p=0.08, respectively. After adjusting for FLIPI score, MMR status remained associated with OS (MMR-d HR: 0.51, 95%CI: 0.2-1.02, p=0.05). Discussion and Conclusion: In this pilot study, MMR-d in the FL tumors was common (46%) and, as predicted, was associated with a favorable OS. Association of MMR-d status with PFS in general and patients with early progression (short PFS12 and PFS24) and relationship of MMR-d with types of therapy need further study in large FL datasets. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. King: Celgene/BMS: Research Funding. Maurer: Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding.

Safety and Efficacy of Subcutaneous-Administered Omacetaxine Mepesuccinate in Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patients Who Harbor the Bcr- Abl T315I Mutation–Results of An Ongoing Multicenter Phase 2/3 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 644-644 ◽  
Author(s):  
Jorge Cortes-Franco ◽  
H. Jean Khoury ◽  
Franck Emmanuel Nicolini ◽  
Selim Corm ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Hematologic Response ◽  
T315i Mutation ◽  
Grade 3

Abstract Abstract 644 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML patients (Pts) who harbor the Bcr-Abl T315I mutation. Study Goals: To evaluate the safety and efficacy of subcutaneously (SC) administered omacetaxine in Pts with imatinib (IM)-resistant T315I+ Ph+ CML. Methods: Eligible Pts include adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with a confirmed Bcr-Abl T315I mutation and resistance to IM therapy. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 90 Pts have been enrolled, with data available for analysis on 66 Pts (40 CP, 16 AP and 10 BP). The median age was 58 yrs (19-83) with 70% male Pts and a median disease duration of 54 mo (5-285). All Pts failed prior IM therapy, and 79% failed two or more prior TKIs. The presence of baseline T315I mutation was confirmed in all Pts. Baseline clonal evolution was evident in 10 (25%) CP, 6 (38%) AP, and 7 (70%) BP Pts. Eight CP Pts entered the study in CHR. The median follow-up for all Pts was 6.4 mo (0.2 to 29.6). Efficacy: In CP Pts, CHR was achieved in 26 Pts and maintained in 8 Pts for an overall CHR rate of 85%; the median duration of CHR was 7.7+ mo (1.7 to 23.6). Overall cytogenetic response was 27.5% with 6 (15%) Pts achieving a major cytogenetic response (MCyR, 4 complete, 2 partial). The median duration of MCyR was 6+ mo (0.8 to 16.1). Major molecular response was achieved in 15% of Pts and a reduction of baseline T315I mutated clone occurred in 56.7% of CP Pts. In AP Pts, overall hematologic response was achieved in 6 (37.5%) Pts with 5 CHR and 1 return to chronic phase (RCP). Median duration of response was 3.9+ mo (1.7 to 14.8). One AP Pt achieved a complete cytogenetic response; duration 1.9+ mo. In BP Pts, overall hematologic response was achieved in 3 (30%) Pts with 2 CHR and 1 RCP. The median overall survival for CP Pts has not been reached and 35 (88%) Pts were alive at the time of data cut- off. The median overall survival was 18.8 mo for AP and 1.8 mo for BP Pts. Median time to progression was 11.2, 3.1, and 1.2 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 45 of 66 (68%) Pts. The most commonly reported events were thrombocytopenia (58%), anemia (36%) and neutropenia (33%). Non-hematologic toxicities were primarily grade 1/2 with the most frequently reported events of diarrhea (44%), fatigue (35%), pyrexia (32%), nausea (26%), and asthenia (21%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in >5% of Pts and infection (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 12 days for all disease phases and cycles (CP=12, AP=10, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Sixteen deaths occurred during the study (5 CP, 4 AP, and 7 BP).Three deaths (1 CP, 1 AP, and 1 BP) were considered to have a possible relationship to omacetaxine: sepsis, pancytopenia, and sudden death with unknown cause, respectively. Conclusions: Omacetaxine administered by subcutaneous injection produces durable hematologic and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Omacetaxine may provide a treatment option for this patient population who currently has no available approved drug therapies. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoury:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:ChemGenex: Research Funding. Corm:ChemGenex: Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 933-933 ◽  
Author(s):  
Nathan Fowler ◽  
Brad S Kahl ◽  
Peter Rosen ◽  
Jeffrey Matous ◽  
Amanda Cashen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Clin Oncol ◽  
Board Of Directors ◽  
Research Funding ◽  
High Risk Population ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

Phase II Study with R-FND Followed by 90-Y Ibritumomab Tiuxetan Radioimmunotherapy and Rituximab Maintenance for Untreated High-Risk Follicular Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 99-99
Author(s):  
Nathan H. Fowler ◽  
Sattva S. Neelapu ◽  
Michelle A. Fanale ◽  
Maria A. Rodriguez ◽  
Barbara Pro ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Stage Iii ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Rituximab Maintenance

Abstract Abstract 99 Background: Follicular lymphoma (FL) patients (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of approximately 50% with conventional chemotherapy. The incorporation of anti-CD20 monoclonal antibody therapy has improved results in this poor risk subgroup. (Buske, Blood 2006;108:1504) We have previously demonstrated that R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) is an effective regimen for indolent lymphoma, capable of inducing molecular remissions. (McLaughlin, ASCO 2003;102:564). Both extended dosing of rituximab following induction, and consolidation of first remission with 90-Y ibritumomab tiuxetan radioimmnotherapy (RIT) can improve complete response rates and progression free survival (PFS) rates for patients with advanced FL. (Morschhauser, JCO 2008;32:5156; Salles, Lancet 2011;377:42) This is the first report of a chemoimmunotherapy approach followed by both RIT consolidation and rituximab maintenance. Methods: Untreated patients with FL (grade 1–3), with high risk disease (FLIPI score ≥ 3) who had adequate hematologic function and extensive stage (III/IV) disease were eligible for study entry. Patients received rituximab (375mg/m2 days 1 and 8 of cycle 1, and day 1 of subsequent cycles) fludarabine (25mg/m2 days 1–3), mitoxantrone (10mg/m2 day 1), and dexamethasone (20mg days 1–5) for four 28 day cycles. RIT was given 12–16 weeks following R-FND pending hematologic recovery. Six weeks following RIT, patients received rituximab 375mg/m2 every two months for one year. The primary objective of the study was to determine the PFS rates based on 1999 International Working Group criteria. The secondary objectives included assessing the safety and tolerance of RIT and maintenance rituximab after R-FND, assessing the CR and overall response rates, and determining the overall survival following treatment. Results: Forty nine patients were enrolled and 47 received treatment between October 2004 and April 2009. Forty-six patients were eligible for efficacy analysis. The median age was 61 (37–78), 80% had bone marrow involvement, and all had stage III/IV disease. Twenty four (51%) patients had bulky disease (>5cm) and 42 (91%) had elevated β2M. Thirty six patients completed all planned courses of treatment. Eight patients did not receive RIT, two due to neutropenia after R-FND. One patient had progressive disease while on treatment. Following R-FND, the complete (CR + CRu) and partial response rates were 87% and 13%. With RIT consolidation, the CR rate increased to 91%. At a median follow up of 50 months, the projected five year overall survival and PFS rates were 93% and 74%. Toxicity was mainly hematologic. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 57% and 35% of patients respectively. Thirty seven patients required growth factors and 17 patients required transfusions. The median time to hematologic recovery following RIT was 10 weeks. The most common non-hematologic adverse events (≥Gr 3) were fatigue (17%), dypsnea (13%), and myalgia (11%). There were 3 cases of myelodysplasia (MDS), one in a patient who did not receive RIT. Conclusions: The combination of R-FND followed by RIT intensification and rituximab maintenance results in OS and PFS outcomes that are better than traditional combinations in this high risk population. Given the potential for serious toxicity (eg. MDS) seen in this trial and other intensive treatment strategies, this approach may be most appropriate in high-risk FLIPI patients whose outlook with standard therapy is poor. Acknowledgments: This study was sponsored by Genentech and Spectrum. Disclosures: Fowler: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Younes:Genentech, SBIO, Seattle Genetics, Syndax, Sanofi-Aventis: Honoraria, Research Funding.

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