Clinical Outcomes and Health-Related Quality of Life (HRQoL) Among Randomized Clinical Trial (RCT)-Eligible and RCT-Ineligible Patients: Results from the Connect® MM Registry

Background: MM clinical trials often have stringent eligibility criteria that limit the enrollment of patients (pts) reflective of the general patient population (Shah, Clin Lymphoma Myeloma Leuk 2017). The Connect® MM Registry, a prospective observational study of pts with newly diagnosed MM (NDMM) in the US, provided the opportunity to examine differences between pts with MM who were identified as RCT-eligible vs -ineligible, to observe the generalizability of clinical trial results to real-world clinical settings. Differences in baseline characteristics, treatment, clinical outcomes, and HRQoL were examined in RCT-eligible and -ineligible pts from this registry, which represents an unselected, broad real-world population. Methods: Pts with NDMM were enrolled at 250 community, academic, and government sites. Eligible pts were ≥18 y of age with symptomatic MM diagnosed ≤2 months preenrollment per the International Myeloma Working Group (IMWG) criteria. For this analysis, pts were considered ineligible for RCT per the following key exclusion criteria previously described: absolute neutrophil count ≤1.5 × 109/L, platelet count ≤75 × 109/L, creatinine >2.5 mg/dL, AST/ALT >3 times the ULN, peripheral neuropathy grade >2; ECOG PS 3/4; history of myelodysplastic syndromes/other hematologic malignancies, or solid tumors (Shah 2017). Sites administered pt HRQoL questionnaires and provided clinical data at baseline and quarterly during follow-up until death or study discontinuation. Differences in HRQoL at baseline, changes from baseline to 1 and 2 years, and survival outcomes, adjusted for covariates via propensity score, were compared between RCT-eligible/-ineligible pts. Results: Of the 3011 pts enrolled, 2873 pts met the CRAB (hyperCalcemia, Renal failure, Anemia, and Bone disease) criteria per IMWG at enrollment. Of these, 1622 (56.5%) were identified as RCT-eligible and 1251 (43.5%) as RCT-ineligible (data cut-off February 7, 2019). Both groups were similar in median age, sex, race, and ethnicity distribution, although the RCT-ineligible group had more pts aged ≥75 y (26.3% vs 23.2%) and more pts with ECOG PS 3/4 (6.2% vs none). Overall, 34.5% of RCT-ineligible pts received a transplant vs 42.8% of RCT-eligible pts. More RCT-ineligible pts had ISS stage III disease (39.4% vs 19.8%), elevated calcium (≥11.5 mg/dL; 12.7% vs 6.8%), elevated creatinine (>2.0 mg/dL; 40.3% vs 6.5%), and low hemoglobin (<10 g/dL or >2 g/dL <LLN; 60.8% vs 40.3%). Use of triplet treatment (54.2% vs 56.2%) and alkylator (24.9% vs 20.1%) was similar between the RCT-ineligible/-eligible groups. Lenalidomide + bortezomib + dexamethasone (RVd) was the most common initial therapy, and R was the most common maintenance therapy in both groups, but fewer RCT-ineligible pts received RVd as initial therapy (23.9% vs 31.0%) and R as first maintenance regimen (18.1% vs 22.7%). Absolute baseline HRQoL scores were significantly higher, indicating better HRQoL, in RCT-eligible (115.9) vs -ineligible (111.5) pts on the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) Total score (P=0.007), FACT-MM Trial Outcome Index (74.3 vs 70.3, P=0.002), and FACT-MM Subscale (37.3 vs 35.5, P=0.003). Scores were similar for EuroQol-5D Overall Index (0.73 vs 0.72, P=0.5) and Brief Pain Inventory (3.42 vs 3.43, P=0.9). Both RCT-eligible and -ineligible pts showed significant improvement in HRQoL from baseline at years 1 and 2, although the magnitude of improvement was similar between both groups (Fig. 1a and b). RCT-ineligible pts showed significantly shorter median PFS and OS vs RCT-eligible pts (Fig. 2 & 3, respectively). Conclusions: The CONNECT MM registry provided the opportunity to examine key differences between RCT-eligible and -ineligible pts. By applying common RCT eligibility criteria, a substantial proportion of MM pts (43.5%) in this real-world population may have been ineligible to participate in a RCT. RCT-ineligible pts had advanced disease, poor performance status, and poor laboratory parameters at baseline vs RCT-eligible pts, which could affect PFS and OS. These findings enhance our understanding of HRQoL among MM pts, which at present, is largely based on RCT participants. A similar magnitude of HRQoL improvement in both groups at 1 and 2 years suggests the need to evaluate RCT eligibility criteria in MM to help broaden enrollment and maximize external validity. Disclosures Wagner: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Toomey:Celgene: Consultancy. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Jagannath:Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Rifkin:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline plc: Research Funding; Amgen: Consultancy, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Catamero:Celgene: Employment, Equity Ownership. Abonour:BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Patterns of Care of Aged Chronic Lymphocytic Leukemia Patients in the United States: Systematic Analysis of 457 Patients in the Connect CLL Registry

Blood ◽

10.1182/blood.v124.21.4672.4672 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4672-4672

Author(s):

Chadi Nabhan ◽

Natalie Galanina ◽

Neil E. Kay ◽

Anthony R. Mato ◽

David L. Grinblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

The United States ◽

Initial Therapy ◽

Patterns Of Care ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Baseline Characteristics

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.

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Real-World Outcomes for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone, or Bortezomib and Dexamethasone: An Enhanced Electronic Health Records Database Analysis

Blood ◽

10.1182/blood-2018-99-111121 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2243-2243

Author(s):

Ajai Chari ◽

Brian Ung ◽

Marc Tian ◽

Amit Agarwal ◽

Kejal Parikh

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Second Line ◽

Second Line Therapy ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

Equity Ownership

Abstract Background: For transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), the only category 1 regimens recommended by the National Comprehensive Cancer Network (NCCN) are lenalidomide and dexamethasone (Rd)-based, including triplet therapy with lenalidomide, bortezomib, and dexamethasone (RVd) (NCCN Myeloma v4.2018). Other doublet regimens, such as bortezomib and dexamethasone (Vd), are still a first-line option for patients with NDMM, especially for those who are elderly and/or frail. However, the latter population is either excluded or markedly underrepresented in clinical trials. Using an electronic health records (EHRs) database, we compared outcomes when either RVd or Vd were used in the treatment of transplant-ineligible patients with NDMM in a real-world practice setting, after adjusting for baseline demographic and clinical differences between the two cohorts. Methods: A retrospective observational study of patients with NDMM was conducted using EHRs from a nationally representative database (Flatiron Health). The Flatiron Network database is an enhanced oncology EHR database of patients treated at 265 clinics throughout the USA. Patients diagnosed with multiple myeloma, ICD-9 (203.0x) or ICD-10 (C90.xx), between January 2011 and May 2018 who were treated with RVd or Vd and did not undergo stem cell transplantation were included in the analysis. The primary comparison was time to next therapy (TTNT) in the overall population and in a subset of frail patients, as determined by a composite score based on age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, and Charlson Comorbidity Index (CCI). Data regarding overall and progression-free survival (PFS) were limited as patient data prior to adoption of the Flatiron Network database were incomplete. Treatment-free interval (TFI) for patients who initiated a second-line therapy was defined as time from start of first-line to start of second-line therapy minus the duration of therapy (DOT). The Kaplan-Meier and Cox proportional hazard methods were used to calculate TTNT after adjusting for differences in patient baseline demographic and clinical characteristics. Results: Of the 8,470 transplant-ineligible patients with NDMM in the database, 2,369 were treated with either RVd (n = 1,309) or Vd (n = 1,060) and met the criteria for inclusion in this analysis. Patients treated with Vd were more likely to be older (median age 75 vs 70 years; P < 0.0001), frail (76.3% vs 65.4%; P = 0.0002), have creatinine clearance < 30 mL/min (23.9% vs 10.7%, P < 0.0001), have a higher ECOG PS score (P = 0.0031), and have International Staging System stage III disease (45.1% vs 28.8%; P < 0.0001). There were no significant differences in baseline neutropenia, anemia, or thrombocytopenia, or in median CCI. The proportion of patients with high-risk cytogenetics was lower in the Vd group (19.7% vs 26.0%; P < 0.0001). The mean DOT was longer for RVd (11.4 ± standard deviation [SD] 13.3 months) than for Vd (7.7 ± SD 9.7 months). However, the median adjusted TTNT was significantly longer with RVd than Vd (40.9 vs 14.8 months; hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.33-0.55; P < 0.0001). The proportion of patients initiating a new treatment was lower in the RVd group (24.8% vs 40.6%; P < 0.0001). Among those who initiated a second-line therapy, the mean TFI for RVd compared with Vd was 42.6 versus 39.3 days, respectively (P = 0.2214). Among the 735 frail patients (416 RVd and 319 Vd), the median TTNT was significantly longer with RVd (32.6 vs 17.1 months; HR 0.40; 95% CI 0.29-0.54; P < 0.0001; Figure). Similar to the overall population, there were no significant differences in TFI (54.9 vs 29.6 days, P = 0.2598) and a significantly higher proportion of Vd patients initiated a new treatment (22.1% vs 36.4%; P < 0.001). Conclusions: In this real-world practice setting where PFS cannot be measured directly, triplet therapy with RVd significantly prolonged TTNT compared with Vd by 26.1 months in the overall patient population, and by 15.5 months in frail transplant-ineligible patients with NDMM. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Array Biopharma: Research Funding; Bristol Myers Squibb: Consultancy. Ung:Celgene Corporation: Employment, Equity Ownership. Tian:Celgene Corporation: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Parikh:Celgene Corporation: Employment, Equity Ownership.

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Demographics By Age Group (AG) and Line of Therapy (LOT) in Chronic Lymphocytic Leukemia (CLL) Patients (Pts) Treated in US Practices from the Connect® CLL Registry

Blood ◽

10.1182/blood.v124.21.3338.3338 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3338-3338 ◽

Cited By ~ 1

Author(s):

Jeff P. Sharman ◽

Anthony Mato ◽

Neil E. Kay ◽

Thomas J. Kipps ◽

Nicole Lamanna ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Center ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

The Us ◽

Equity Ownership ◽

Line Of Therapy ◽

Ecog Ps

Abstract Introduction: CLL pts who qualify for participation in clinical trials are often thought of as a highly selected population. Therefore whether safety and efficacy data from these trials can be generalized to all CLL pts treated in the community setting is unknown. Prospective, observational studies can provide significant insight into pt and disease characteristics as well as practice patterns in different clinical settings. Here we report on baseline demographics and clinical characteristics for 1495 pts who participated in the Connect CLL observational study and were followed prospectively. Methods: Connect®CLL is a non study-specific intervention treatment registry which collects data on the management and outcomes of CLL pts in clinical, academic and community practices in the US. Clinical information was prospectively collected for pts treated in community (n=1312), academic (n=155), or government (n=28) centers in the US between March 2010 – Jan 2014. Pts eligible for treatment or on treatment not more than 2 months were eligible for enrollment. Here we report on the baseline demographics and clinical characteristics of a large CLL cohort stratified by AG, LOT and type of treatment center. Results: In total,1,495 pts were accrued with a median age at enrollment of 69 (range 22–99). Pts were Caucasian (92.2%), African American (6.9%), and male (63.7%). Median duration from diagnosis until initial therapy was 3.7 years (range 0-32). Age of enrolled pts was as follows; 527 pts age <65 years (AG1; 35%); 511 age 65–75 (AG2; 34%); and 457 age ≥75 (AG3; 31%) at the time of enrollment. Eight hundred and ninety-four pts (60%) were treated with front-line therapy (LOT1); 259 pts (17%) treated with second-line therapy (LOT2); and 342 pts (23%) treated beyond second-line therapy (LOT≥3). Patient age: Pt age was associated with significant variation in several clinical variables: Charlson comorbidity index (CCI) score ≥3 (AG 1-3 35/46/52%; p<0.0001), ECOG PS = 0 (AG1-3 60, 48, 33%, p<0.0001) and mean creatinine clearance (CrCl) decreased (AG 1-3 101/74/53 mL/min; p<0.0001). Line of therapy: Differences in baseline characteristics were observed between pts enrolled at LOT1 (previously untreated) and LOT2/≥3 (relapsed). Median age of pts accrued at LOT1 was 68 vs. 70 years for pts enrolled at LOT2/≥3 (p=0.007). ECOG PS = 0 was more frequent at LOT1 (50%) vs. LOT2/≥3 (42%) (p=0.0057). CCI ≥3 at LOT1 was 41% vs 48% at LOT2/≥3 (p=0.0072). When adjusted for differences in age, logistic regression also demonstrated significant differences in performance status (PS=0; p=0.02) and CCI (p=0.03) stratified by LOT. Treating institution: Baseline characteristics also differed by type of treating institution. Median age was 63 vs 70 at academic vs non-academic (p<0.0001). Pts treated at academic sites also had lower CCI (CCI≤2; 72.9% vs 54.2%, academic vs non-academic) and higher median CrCl (86.4 vs 71.4) (p=0.0017). In this registry, only 16% of patients under age 75 had CCI <= 2, CrCl >= 70 mL/min, ECOG 0-1; 18% of patients on LOT1 and 12% of pts on LOT=2 would satisfy these criteria. They represent 36% of eligible pts from academic treating institutions and 13% from community/government centers. Only 20% of patients on LOT1 would satisfy enrollment criteria for CLL8 (FCR vs. FC; Hallek; Lancet 2010) CLL 10 (BR vs FCR; NCT00769522). which did not have enrollment restrictions for age. Conclusions:Baseline characteristics of pts with CLL vary by age, LOT, and type of treatment center. In this large prospective observational study, our data confirms that older pts typically have a worse ECOG PS, more medical comorbidities, more advanced disease when initiating therapy and a lower probability of being treated at an academic medical center. Based on inclusion criteria used for entry in either CLL10 or CLL8, fewer than 20% of pts satisfy age, renal clearance, and fitness profile to be considered suitable for aggressive chemoimmunotherapy in the front line setting. This observation supports the notion that current clinical trial data might not always be applicable to the general CLL population seen in the community and argues for designing clinical trials that are more generalizable to the broader pt population. Disclosures Sharman: Gilead: Research Funding; Calistoga: Honoraria; Phamacyclics: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; TG therapeutics: Research Funding; Roche: Research Funding. Mato:Millennium: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau. Kay:Celgene: Research Funding. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy; Phamacyclics: Consultancy; Gilead: Consultancy. Nabhan:Celgene: Honoraria, Research Funding. Flinn:Celgene: Research Funding. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kozloff:Celgene: Consultancy. Farber:Alexion: Equity Ownership, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Flowers:TG Therapeutics: Research Funding; Phamacyclics: Research Funding; Acerta: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Spectrum: Research Funding; Gilead: Research Funding; Genentech: Unpaid consultancy Other; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Seattle Genetics: Consultancy; Prescription Solutions: Consultancy; Celgene: Unpaid consultancy Other.

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Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial

Blood ◽

10.1182/blood-2019-124557 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3122-3122

Author(s):

Salmon Manier ◽

Meletios A. Dimopoulos ◽

Cyrille Hulin ◽

Xavier Leleu ◽

Michel Delforge ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Late Relapse ◽

Line Treatment ◽

Second Line ◽

Employment Equity ◽

Advisory Committees ◽

Early Relapse ◽

Equity Ownership ◽

Ecog Ps

BACKGROUND: Rd continuous is now a standard treatment option in patients (pts) with transplant-ineligible NDMM based on the results of the large phase 3 registrational FIRST trial showing significant PFS and OS benefits of lenalidomide (LEN) + low-dose dexamethasone until disease progression (Rd continuous) vs melphalan + prednisone + thalidomide (MPT). However, pts who relapse on frontline LEN represent a growing population for whom there is limited clinical evidence on subsequent treatment. Factors associated with relapse within 12 mos in Rd- and MPT-treated pts (LDH ≥ 200 U/L, ISS stage III, high-risk cytogenetics, ECOG PS ≥ 2, and baseline platelet count ≤ 150 × 109/L) indicate that the individual risk of progression may involve a combination of disease biology, genetics, and pt-specific factors (Facon, EHA 2019). Physicians may consider these early relapse factors when making treatment decisions. To characterize pts relapsing while receiving frontline LEN, this analysis evaluated Rd-treated pts from the FIRST trial who progressed while receiving LEN based on their time of relapse, type of relapse (CRAB [symptomatic] vs non-CRAB [nonsymptomatic]), and second-line treatment. METHODS: Pts randomized to Rd continuous (n = 535) or Rd for 18 cycles (n = 541) arms and who progressed while receiving LEN or within 60 days of treatment end (per IMWG criteria) were pooled and grouped according to their time of relapse after randomization (< 12 mos = early< 12; 12-18 mos = early12-18, and > 18 mos = late relapse). The data cutoff was January 2016. RESULTS: Of the 389 pts who relapsed, 203 had early< 12 relapse, 69 had early12-18 relapse, and 117 had late relapse. Pts who relapsed within the first 12 mos or between 12 and 18 mos had higher rates of elevated LDH, ISS Stage III disease, and ECOG PS 2 compared with those who relapsed beyond 18 mos (Table). Early< 12 and early12-18 relapses were also associated with poor PFS and OS outcomes. Median PFS in pts with early< 12, early12-18, and late relapse was 6.5, 15.9, and 26.4 mos, and median OS was 26.8, 41.6, and 78.0 mos, respectively (Figure). Pts with late relapse had more dose reductions prior to PD vs those with early relapse and were more likely to experience nonsymptomatic progression. Across the 3 groups, in pts experiencing a nonsymptomatic progression who started second-line treatment, 88% started second-line treatment prior to experiencing CRAB symptoms. The median time from PD to second-line treatment was shorter in those with CRAB relapse (1.4-2.5 mos) vs non-CRAB relapse (2.5-5.9 mos). Second-line treatment was reported in 170 (83.7%), 62 (89.9%), and 99 (84.6%) pts with early< 12, early12-18, and late relapse, respectively. The majority of these pts received bortezomib-based regimens (65.6% overall), most commonly bortezomib + dexamethasone, bortezomib + melphalan + prednisone, or bortezomib + alkylator (cyclophosphamide or bendamustine). Second PFS was similar regardless of time of relapse. CONCLUSIONS: This analysis focused on an emerging and clinically relevant population of transplant-ineligible pts relapsing on frontline LEN. Pts with late relapse on LEN more commonly had nonsymptomatic progression vs pts relapsing early. This raises the question on the possible impact of the immune stimulatory effects of LEN in pts able to remain on therapy and achieve a longer OS and warrants further investigation of the biological impact of IMiD agent-based therapies on long-term disease control. The increase in dose reductions in the late- vs early-relapse groups is also an important consideration for continuous treatment. Consistent with the prior analysis of the FIRST study exploring Rd and MPT-treated pts with early< 12 relapse (Facon, EHA), pts relapsing on LEN within 12 mos and between 12-18 mos both appeared to have functionally high-risk disease and represent a population with an unmet need that should be considered for inclusion in clinical trials investigating new therapeutic strategies. Due to the timing of the FIRST trial, limited novel-novel agent combination treatments were available at relapse, and the majority of pts received bortezomib-based second-line regimens. These results highlight the need for effective therapies for pts with early relapse. Further characterization of first- and second-line outcomes according to type of relapse are ongoing and will be reported at the meeting. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Merck: Honoraria. Delforge:Amgen, Celgene, Janssen , Takeda: Honoraria. Weisel:Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Costa:Celgene: Employment, Equity Ownership. Robinson:Celgene: Employment, Equity Ownership. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

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Combination of Umbralisib, Ublituximab, and Bendamustine Is Safe and Highly Active in Patients with Advanced Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-118917 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4197-4197 ◽

Cited By ~ 1

Author(s):

Matthew A. Lunning ◽

Philip Bierman ◽

R. Gregory Bociek ◽

Marshall T. Schreeder ◽

Tanya Siddiqi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Ecog Ps

Abstract Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: 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; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: 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; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.

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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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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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Characterization of Real World Survival Outcomes Among Older Adults with Chronic Lymphocytic Leukemia Receiving Second Line Treatment in the Pre Novel-Agents Era: An Analysis of the 2007-2013 SEER-Medicare Database

Blood ◽

10.1182/blood.v128.22.4790.4790 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4790-4790 ◽

Cited By ~ 1

Author(s):

Anthony R. Mato ◽

Jordan Jahnke ◽

Pengxiang Li ◽

Maneesha Mehra ◽

Vrushabh P Ladage ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Initial Therapy ◽

Fee For Service ◽

Line Treatment ◽

Second Line ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries with a median age of 72 years at diagnosis. Prior to the introduction of kinase inhibitor therapies, chemoimmunotherapy (CIT) combinations, monoclonal antibody monotherapies, and chemotherapy combinations were the predominant therapy regardless of line of CLL treatment. Given the increased frequency of high-risk features (del17p, del11q,) and prior exposure to CIT combinations, shortened disease-free periods and increased short-/long-term toxicities are frequently seen in relapsed CLL setting. However, data from recent randomized clinical trials of novel agents, such as ibrutinib in the relapsed setting, have shown significant improvements in overall survival (OS). While we await real-world data on how novel agents impact real-world CLL outcomes, little is known about the management and survival among CLL patients prior to their availability, particularly in the relapse setting. Our study uses comprehensive prescription and medical insurance claims linked with registry data to describe survival outcomes in older adults with CLL receiving second line treatment between 2007-2013--an era that predates the approvals of ibrutinib, idelalisib, venetoclax and obinutuzumab. Methods: This retrospective cohort study used the 2007 to 2013 SEER-Medicare linked database. The sample included patients with first primary tumor site as CLL or SLL (ICD-O histology codes '9670' and '9823') diagnosed between 2007 and 2011. This date of first diagnosis of CLL or SLL defines the index date. Patients aged > 65 years with Medicare fee-for-service coverage in the 12 months pre-index and Medicare fee-for-service and prescription drug coverage in the 6-months post-index period or until death were included. Second line treatment date was defined as the date a treatment was received that was not part of the initial therapy or the date where initial therapy was restarted after a 180+ day gap in treatment. Our primary study outcome was overall survival (OS) from the date of initiation of second line treatment. The association of patient-level characteristics with OS was measured using cox regression analysis. Results: Of the 1047 patients who received any CLL treatment, 387 (37%) patients met the definition for receiving a second line of therapy. The mean age of this second line cohort was 76 years (SD = 6) and 48.3% were male. Only 9 patients who left fee-for-service Medicare during the second line follow up period were excluded from analysis. Of our 387 patient cohort, 25.3% (n=98) received fludarabine as part of their initial treatment, with remaining 74.7% (n=289) receiving a non-fludarabine containing initial therapy. The median time from CLL diagnosis date to second treatment was 664 days (Q1-Q3 390-1159 days). Rituximab containing regimens were the most common second line treatment (n=276, 71.3% of patients), with 118 patients (30.5%) in our second line cohort receiving rituximab monotherapy. Another 35 (9%) patients received chlorambucil monotherapy and the remaining 76 (19.6%) patients received a non-rituximab mono- or combination chemotherapy as their second line treatment. The median follow-up time in the sample from second line treatment was 14.9 months. Median OS for the cohort from initiation of their second line of treatment was 34.3 months, with 72% OS at 1-year and 58% at 2-years (See Figure). Multivariate Cox regression modeling showed OS from second line of treatment was associated with year of CLL diagnosis (2011 vs. 2007, HR 2.2; p=0.02), higher age at time of treatment (70-74 vs 80+, HR 0.67; P=0.04), male gender (HR 1.5; P=0.01), Northeast census region (vs West, HR 1.7; P=0.01),and initial treatment that included fludarabine (HR 1.5; P=0.04). Conclusions: In our real world analysis, over one-third of the newly diagnosed CLL patients who received treatment progressed to second line therapy. We found poor survival in these older adults following initiation of second line CLL therapy treated in the pre-kinase / BCL-2 inhibitor era with about half who died within two years of initiating second line therapy. While available clinical trials suggest novel CLL agents offer significant improvements in OS in relapsed CLL, future studies should examine real world CLL outcomes to correlate how results obtained in recent landmark clinical trials translate into clinical practice. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Mehra:Janssen: Employment, Equity Ownership. Mahler:Janssen Research & Development: Employment. Doshi:Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Other: Spouse owns stock in company, Research Funding; Alkermes: Membership on an entity's Board of Directors or advisory committees; Forest Labs: Membership on an entity's Board of Directors or advisory committees; National Pharmaceutical Council: Research Funding; PhRMA: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Merck & Co., Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Spouse owns stock; Sanofi: Research Funding; Humana: Research Funding. Huntington:Pharmacyclics: Honoraria; Celgene: Consultancy, Honoraria; Johnson & Johnson: Consultancy; Oncosec Medical: Equity Ownership; Exelixis: Equity Ownership; Geron: Equity Ownership.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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