Real-World Treatment Patterns and Overall Survival Among Medicare Fee-for-Service Beneficiaries Newly Diagnosed with Peripheral T-Cell Lymphoma

Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of lymphoid malignancies characterized by a clinically aggressive course with poor prognosis. A majority of PTCL patients are ≥60 years of age and typically present with advanced stage disease and multiple comorbidities. There remains no consensus standard of care for patients with most PTCL subtypes. Multi-agent chemotherapy, consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP with etoposide (CHOEP), are guideline recommended options for nodal subtypes. Limited contemporary real-world data exist on the treatment patterns and overall survival (OS) of PTCL patients treated with CHOP or non-CHOP regimens in the United States before the FDA approval of brentuximab vedotin in combination with chemotherapy in November 2018 based on the ECHELON-2 trial. Objective: To evaluate treatment patterns and OS prior to the approval of brentuximab vedotin among Medicare Fee-for-Service (FFS) beneficiaries newly diagnosed with PTCL. Methods: The 100% sample of Medicare FFS claims (Parts A/B/D) was used to identify patients aged ≥65 years with ≥1 inpatient or ≥2 distinct outpatient diagnosis claims for PTCL (index event) from January 2011 to December 2017. Patients were required to have a least 6 months prior and 12 months post-index continuous Medicare enrollment, and were followed until disenrollment, death, or the end of the study period, whichever occurred first. OS, defined as the time from initial episode or treatment start date to the validated date of death, was measured using the Kaplan-Meier method; patients without a death date were assumed to be alive at the time of analysis and were censored. Results: A total of 2551 Medicare FFS beneficiaries with a PTCL diagnosis met study criteria and were included for analysis. The majority of patients were white (86.9%), over half were male (52.9%), and mean age was 75 years. Patients had multiple comorbidities at diagnosis (Charlson Comorbidity Index (CCI) score 4.47), including hypertension (77.3%), diabetes (32.9%), and chronic obstructive pulmonary disease (28.1%). Among the 2551 patients in the study cohort, 62.4% (n=1593 of 2551) received at least one identifiable drug regimen; 25.5% of treated patients received CHOP (n=407), 3.1% CHOEP (n=50) and 71.2% (n=1134) other regimens. Of patients treated with other regimens, 37.7% (n=427) received steroids only, 22.4% (n=254) steroids with unidentifiable chemotherapy, 6.9% (n=78) cyclophosphamide, 6.2% (n=70) methotrexate, 4.6% (n=52) brentuximab vedotin, 3.6% (n=41) bendamustine, 3.5% (n=40) romidepsin, and 15.2% (n=172) other therapy combinations. Among patients who were treated with CHOP, 16.6% (n=66) received an identifiable second line of therapy (LoT), 48.7% (n=194) an unidentifiable second LoT, and the remainder (34.7%, n=138) had no evidence of further anti-cancer treatment. The median time from CHOP initiation to a subsequent LoT was 5.6 months. The mean baseline CCI score for patients treated with CHOP was 4.33 (±2.93) compared with 4.76 (±2.97) for patients treated with other therapies (p=0.0118). In patients receiving an identifiable first LoT, median OS among CHOP and non-CHOP recipients was 4.8 years (95% CI 3.0-6.1) and 4.4 years (95% CI 3.0-4.9), respectively (Table). The 5-year OS estimate was 49% in patients receiving CHOP compared with 46% for non-CHOP recipients. Conclusions: Fewer than 30% of Medicare beneficiaries newly diagnosed with PTCL were treated with intensive chemotherapy as first LoT. Acknowledging a possible selection bias for more fit PTCL patients receiving CHOP, this group had increased OS compared with patients receiving non-CHOP therapy. However, the 5-year OS across all cohorts was less than 50%. New therapies such as brentuximab vedotin may fill the need for PTCL Medicare beneficiaries who may not be able to tolerate CHOP or CHOP-based regimens. Disclosures Shah: Avalere Health, An Inovalon Company: Employment. Petrilla:Avalere Health, An Inovalon Company: Employment. Rebeira:Seattle Genetics: Employment. Feliciano:Seattle Genetics: Employment, Equity Ownership. LeBlanc:Astra Zeneca: Consultancy, Research Funding; Duke University: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; CareVive: Consultancy; Celgene: Honoraria; Flatiron: Consultancy; American Cancer Society: Research Funding; Heron: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy. Lisano:Seattle Genetics, Inc.: Employment, Equity Ownership.

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: 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; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Blood ◽

10.1182/blood.v118.21.443.443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 443-443 ◽

Cited By ~ 9

Author(s):

Ranjana H. Advani ◽

Andrei R. Shustov ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership

Abstract Abstract 443 Background: Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods: Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results: 58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions: Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures: Advani: Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽

10.1182/blood.v118.21.452.452 ◽

2011 ◽

Vol 118 (21) ◽

pp. 452-452 ◽

Cited By ~ 9

Author(s):

Giuseppe Saglio ◽

Philipp D. LeCoutre ◽

Ricardo Pasquini ◽

Saengsuree Jootar ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Safety Data ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-124370 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3165-3165 ◽

Cited By ~ 2

Author(s):

Darrell J White ◽

Suzanne Lentzsch ◽

Cristina Gasparetto ◽

Nizar Bahlis ◽

Christine I Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Phase 2 ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Safety and Efficacy of Dasatinib (DAS) Vs. Imatinib (IM) by Baseline Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial.

Blood ◽

10.1182/blood.v116.21.3421.3421 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3421-3421 ◽

Cited By ~ 7

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Hagop Kantarjian ◽

Michele Baccarani ◽

Neil P. Shah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Initial Therapy ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Abstract 3421 Background: BCR-ABL kinase inhibitors DAS, nilotinib and IM have become the primary treatment modality for patients (pts) with CML-CP. Pre-treatment comorbid conditions have been proposed to help select a second-line BCR-ABL inhibitor for IM-resistant CML-CP. The DASISION trial is a large Phase 3 trial comparing DAS with IM as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of DAS 100 mg once daily after a minimum follow-up of 12 months (Kantarjian, H, et al. N Engl J Med 2010;362:2260). This analysis assessed the impact of baseline comorbidities on safety and efficacy of these agents when used as initial therapy for CML-CP. Methods: 519 pts with newly diagnosed CML-CP were randomized to either DAS 100 mg once daily (n = 259) or IM 400 mg once daily (n = 260). Key exclusion criteria included serious uncontrolled medical disorders or active infections; uncontrolled or serious cardiovascular disease; prior or concurrent malignancy; inadequate hepatic or renal function; and ECOG performance status of ≥ 3. Pts were analyzed according to the number (0, ≥ 1 and ≥ 2) and type of baseline comorbidity (allergic, dermatologic, diabetes, endocrine-metabolic, gastrointestinal, hematologic-lymphatic, hepatobiliary, hyperlipidemia, musculoskeletal, renal and respiratory), and age (< 46, 46–65 and > 65 y). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed across these groups. Cardiovascular comorbidities were analyzed separately and are not included here. Results: Across the 2 treatment arms, 74% of the pts had 31 baseline comorbidity and 47% had 32. The distribution of comorbidities including allergic (n = 61), dermatologic (n = 62), diabetes (n = 31), endocrine/metabolic (n = 98), gastrointestinal (n = 176), hematologic/lymphatic (n = 57), hepatobiliary (n = 56), hyperlipidemia (n = 41), musculoskeletal (n = 150), neoplasia (n = 17), renal (n = 33) and respiratory (n = 72) was balanced across the 2 arms. Proportions of pts across 3 Hasford risk groups were similar between pts with baseline comorbidity and those without. Safety profiles of DAS and IM in pts with and without baseline comorbidities were comparable (Table). Proportions of pts with at least 1 dose interruption or dose reduction were also similar with or without any comorbidity (Table). Pts with 32 comorbidities and pt grouped by comorbidity type including diabetes mellitus, hepatobiliary conditions and hyperlipidemia also had generally similar safety profiles. In both arms, the 12-mo rates of CCyR and MMR were similar (Table). In DAS-treated pts with diabetes (n = 18), hepatobiliary conditions (n = 32) and hyperlipidemia (n = 22), CCyR rates were 67, 78 and 96%, respectively; the respective MMR rates were 44, 56 and 59%. IM pts with diabetes (n = 13), hepatobiliary conditions (n = 24) and hyperlipidemia (n = 19) had CCyR rates of 69, 75 and 79%, respectively; and MMR rates of 15, 29 and 32%, respectively. In DAS-treated pts, CCyR rates were 88% for pts aged < 46 y (n = 128), 78% for those aged 46–65 y (n = 111) and 85% for those aged > 65 y (n = 20); the corresponding MMR rates were 45, 47 and 50%, respectively. The corresponding IM age groups (n = 111, 125 and 24, respectively) had CCyR rates of 70, 70 and 83%, respectively; and MMR rates of 26, 30, 29%, respectively. Safety profiles were generally similar across age groups in both treatment arms, except that fluid retention rates in pts aged < 46, 46–65 and > 65 y were 13, 25 and 35%, respectively, for DAS; and 34, 45 and 67%, respectively, for IM. Conclusions: The presence of baseline comorbidities appeared to have no effect on the safety and efficacy of either DAS or IM as initial therapy for CML-CP. Disclosures: Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani:Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin:Bristol-Myers Squibb: Employment, Equity Ownership. Hochhaus:Brostol-Myers Squibb, Novartis: Consultancy, Research Funding.

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Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽

10.1182/blood.v118.21.3768.3768 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3768-3768 ◽

Cited By ~ 5

Author(s):

Richard A. Larson ◽

Udomsak Bunworasate ◽

Anna G. Turkina ◽

Stuart L. Goldberg ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Current Practice Patterns and Patient Persistence on Anticoagulant Treatments for Cancer-Associated Thrombosis

Blood ◽

10.1182/blood.v126.23.626.626 ◽

2015 ◽

Vol 126 (23) ◽

pp. 626-626 ◽

Cited By ~ 6

Author(s):

Alok A. Khorana ◽

Keith McCrae ◽

Dejan Milentijevic ◽

Jonathan Fortier ◽

Winnie Nelson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Initial Therapy ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Patients With Cancer ◽

Kaplan Meier ◽

Equity Ownership ◽

Cancer Associated Thrombosis

Abstract Introduction: Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain limited. Guidelines recommend anticoagulation with low molecular weight heparin (LMWH) monotherapy for ≥3-6 months, and possibly indefinitely, for patients with active cancer. However, drug cost and patient preference issues may lead to non-compliance with these recommendations. The objective of this study is to describe current treatment patterns and to evaluate patient persistence on various anticoagulants. Methods: Medical and pharmacy claims from the Humana Database were analyzed. To reflect recent treatment patterns, the study population was restricted to patients who had their first VTE between 1/1/2013 and 12/31/2014. Newly diagnosed cancer patients with a first VTE diagnosis (deep vein thrombosis [DVT] or pulmonary embolism [PE]) occurring after their first cancer diagnosis (a 30-day window before the cancer diagnosis was allowed), and with ≥1 dispensing of an anticoagulant agent within 30 days after their VTE diagnosis, were selected. Based on the first anticoagulant agent received, patients were classified into one of the following cohorts: LMWH, LMWH/warfarin, warfarin and rivaroxaban. Use of other anticoagulants including fondaparinux, heparin, apixaban, or dabigatran was low and could not be analyzed due to small sample size. The observation period spanned from the date of the first anticoagulant dispensing to the end of insurance eligibility or the end of data availability, whichever occurred earlier. Discontinuation of the index therapy was defined by a time gap without refill of the index anticoagulant for more than 60 days after the presumed exhaustion of the last known dispensing. For patients in the LMWH/warfarin group, the 2 medications were filled simultaneously as an index therapy, with the expectation that the patients were bridged to warfarin; therefore, their persistence was evaluated based on warfarin therapy. Persistence on therapy was assessed for 12 months using Kaplan-Meier rates, and unadjusted Cox proportional hazards models were used to compare the time to discontinuation between cohorts. Results: A total of 2,941 newly diagnosed patients with cancer who developed VTE and received anticoagulation in outpatient settings were identified. Of these, 97% received anticoagulation with either LMWH (n=735; 25%), LMWH/warfarin (n=550; 18.7%), warfarin (n=853; 29%), rivaroxaban (n=709; 24.1%). Mean age and gender were similar across treatment cohorts. Approximately 90% of the patients had diagnoses of solid tumors. Diagnoses for DVT, PE, and DVT/PE were 55%, 27%, and 18%, respectively, and were similar across cohorts. Treatments for cancers associated with very high VTE risk (stomach, pancreas, and brain) ranged from 15% in LMWH to 6% in rivaroxaban cohorts, while high VTE risk (lung, lymphoma, gynecologic, bladder, testicular, and renal) ranged from 39% in LMWH to 30% in warfarin and LMWH/warfarin cohorts. Around 75% (warfarin) to 58% (rivaroxaban) of the VTE cases were diagnosed in inpatient settings. The median treatment durations for LMWH, LMWH/warfarin, warfarin, and rivaroxaban users were 3.29, 7.76, 8.12, and 7.92 months, respectively. Kaplan-Meier rates of persistence to the initial therapy were 37%, 60%, 62%, and 61% at 6 months, and 21%, 37%, 34%, and 36% and at 12 months for the LMWH, LMWH/warfarin, warfarin and rivaroxaban cohorts, respectively (Figure 1). LMWH/warfarin, warfarin, and rivaroxaban users were significantly more likely to remain on their initial therapy compared to LMWH, with hazard ratios (HRs; 95% CI) of 0.38 (0.32-0.45), 0.40 (0.34-0.46), and 0.42 (0.36-0.50), respectively (all p-values <0.0001). The proportion of patients that switched from their initial treatment to another anticoagulation treatment was 22.9%, 8.9%, 7.3% and 4.7% in the LMWH, LMWH/warfarin, warfarin, and rivaroxaban cohorts, respectively. Conclusion: This real-world analysis showed that despite guidelines recommendations, warfarin and rivaroxaban are nearly equally utilized as LMWH for the treatment of cancer-associated thrombosis. LMWH was associated with significantly lower persistence and shorter duration of treatment than warfarin and rivaroxaban. More patients switched from LMWH to other anticoagulants compared to patients starting on warfarin or rivaroxaban treatments. Disclosures Khorana: sanofi: Consultancy, Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria. McCrae:Janssen Scientific Affairs: Membership on an entity's Board of Directors or advisory committees. Milentijevic:Janssen Scientific Affairs: Employment, Equity Ownership. Fortier:Janssen Scientific Affairs: Research Funding. Nelson:Johnson & Johnson: Equity Ownership; Janssen Scientific Affairs: Employment. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Yannicelli:Janssen Scientific Affairs: Employment, Equity Ownership. Schein:Janssen Scientific Affairs, LLC: Employment.

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Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽

10.1182/blood.v130.suppl_1.896.896 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 896-896

Author(s):

Carlo Gambacorti-Passerini ◽

Michael W. Deininger ◽

Michael J. Mauro ◽

Charles Chuah ◽

Dong-Wook Kim ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Cumulative Incidence ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P <0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P <0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

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Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd), and in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant

Blood ◽

10.1182/blood-2018-99-111244 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 595-595 ◽

Cited By ~ 13

Author(s):

Enrique M. Ocio ◽

Paula Rodriguez Otero ◽

Sara Bringhen ◽

Stefania Oliva ◽

Axel Nogai ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Induction Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells via direct tumor targeting and immune cell engagement. ISA, combined with bortezomib, has demonstrated strong potentiation in a multiple myeloma (MM) xenograft model (Clin Cancer Res 2014:20:4754). This supported evaluation of ISA with bortezomib combinations in pts with newly diagnosed multiple myeloma (NDMM) ineligible for transplant. In the initial cohort, ISA combined with bortezomib, cyclophosphamide, and dexamethasone (dex) was well tolerated with 73% of pts achieving very good partial response (VGPR) or better and 40% with complete response (CR) (Blood 2017; 130: 3160). The combination of bortezomib, lenalidomide, and dex (VRd) is also effective in NDMM (Lancet 2017:389:519-27). Here, we report initial data from a Phase Ib study of ISA plus VRd in pts with NDMM (NCT02513186). Methods: Pts with NDMM ineligible for transplantation were treated in 2 phases: induction and maintenance. Induction phase (four 6-week cycles [C]): ISA (10 mg/kg) on Day (D) 1, 8, 15, 22, 29 (C1), followed by D1, 15, 29 (C2-4); bortezomib (1.3 mg/m2) on D1, 4, 8, 11, 22, 25, 29, 32 (C1-4); lenalidomide (25 mg/day): D1-14 and D22-35 (C1-4); dex (20 mg/day): D1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33. Maintenance phase (4-week cycles): ISA (10 mg/kg) on D1, 15 (all cycles); lenalidomide (25 mg/day): D1-21 (all cycles); dex (40 mg): D1, 8, 15, 22 (all cycles), unless the pt was >75 years of age, then the dose was 20 mg. The primary objective was to evaluate safety and preliminary efficacy (overall response rate [ORR] and CR rate, [IMWG criteria]) of ISA plus VRd. Minimal residual disease (MRD) was evaluated using next generation sequencing (NGS) and flow cytometry (NGF) at a sensitivity of 10-6 in pts achieving VGPR or above. Here, we report results from a protocol-planned interim analysis. Results: All 22 pts were included in the safety analysis (pts who received ≥1 dose of ISA) and 14 were eligible for preliminary efficacy analyses (first 14 pts who completed the 4 induction cycles). Median age was 71 (range 63-77) years. At study entry, 6, 12, and 1 pt were International Staging System Stage I, II, and III, respectively. One pt had extramedullary plasmacytoma at baseline. At data cut-off (Mar 22, 2018), the median number of cycles was 5.5 (1-9). Three pts discontinued treatment (2 VGPR, 1 not efficacy-evaluable): 2 pts due to adverse event (AE); Grade (Gr) 3 infusion reaction (IR) (ISA-related; Gr 3 dyspnea, Gr 2 glottic edema, Gr 2 nasal edema, and Gr 2 generalized rash), and Gr 5 bacteremia (lenalidomide- and dex-related); and 1 pt withdrew consent; 19 (86%) pts are continuing treatment. Dose reduction of bortezomib, lenalidomide, and dex was required in 6 (29%), 4 (16%), and 5 (28%) pts, respectively. TEAEs occurred in 19 (86%) pts. Most frequent TEAEs (any Gr; excluding laboratory abnormalities) were constipation (10 pts [46%]), IRs and peripheral edema (9 pts [41%] each), asthenia, diarrhea, and peripheral sensory neuropathy (8 pts [36%] each), hypotension (7 pts [32%]), fatigue and respiratory tract infection (6 pts [27%] each), cough and dyspnea (5 pts [23%] each). Gr ≥3 AEs were reported in 10 (46%) and serious AEs (SAEs) in 4 (18%) pts. Treatment-related SAEs occurred in 2 (9%) pts (IR and pancreatitis). IRs were Gr 1/2 in all but 1 (5%) pt (Gr 3). Gr 3/4 laboratory hematologic abnormalities: lymphopenia (8/22), neutropenia (4/22), thrombocytopenia (4/22)VGPR, 1 partial response (PR) and 1 pt with stable diseaseMedian time to first response was 1.4 months (end of C1) and, with a median follow-up of 7.49 months (at cut-off date), no pt has progressed, with all except 3 pts continuing on therapy. Five (38.5%) of 13 pts achieved MRD-negative status (by NGF and NGS, or NGS only). Conclusion: These data suggest that ISA plus VRd followed by ISA plus Rd is well tolerated with a high ORR of 93%. All responders had VGPR or CR except 1 pt with PR. Quality of CR may have been underestimated due to ISA interference which could be resolved with an interference assay. Funding: Sanofi Disclosures Ocio: Janssen: Consultancy, Honoraria; AbbVie: Consultancy; BMS: Consultancy; Pharmamar: Consultancy; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Rodriguez Otero:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Clínica Universidad de Navarra: Employment; Bristol Myers Squibb: Research Funding. Bringhen:Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Oliva:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Attal:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Moreau:Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kanagavel:Sanofi: Employment, Equity Ownership. Fitzmaurice:Sanofi: Employment, Equity Ownership. Wu:Sanofi: Employment, Equity Ownership. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau.

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