Klepin, Heidi D.

6015 Background: Comorbidity increases with age. We evaluated how comorbidity was associated with toxicity and clinical outcomes among older women with BC who received adjuvant chemotherapy. Methods: Cancer and Leukemia Group B (CALGB 49907) enrolled 633 women ≥65 years with early stage BC and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women on the Quality of Life companion study completed a pre-treatment health survey (Older American Resources and Services Questionnaire, physical health subscale). The survey evaluates 14 conditions and the degree to which each interferes with daily activities (rated from 1 “not at all” to 3 “a great deal”). Comorbidity was analyzed as follows: 1) total number 2) comorbidity burden score (summed conditions multiplied by interference rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall survival (OS). Contingency table methods were used to evaluate the association between comorbidity and toxicity. Cox proportional hazards models were used to evaluate TTR and survival outcomes. Results: Among 329 women [median age 71 years (range 65-89), 86% white, 98% ECOG performance score 0-1, 75% stage 1-2] the median number of comorbidities was 2 (0-10), median comorbidity burden score was 3 (0-25), and most common conditions were arthritis (58%) and hypertension (54%). Few patients had diabetes (17%), heart disease (16%), and pulmonary disease (9%). No comorbidity measure was associated with toxicity or TTR. With a median follow-up of 5.4 years, increasing comorbidity was associated with shorter OS. For each additional comorbid condition the hazard of death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for age, tumor size, treatment, node status and receptor status. Comorbidity burden score was similarly associated with OS (HR 1.08 [95% CI; 1.03-1.14]), while no specific condition was independently associated. Conclusions: Among older women with good functional status, comorbidity was not associated with toxicity or BC relapse. However, comorbidity burden was associated with shorter OS.

Uproleselan (GMI-1271) is a novel antagonist of E-selectin, an adhesion molecule expressed on endothelial cells. E-selectin is expressed transiently in the normal vasculature during an inflammatory response and constitutively in the bone marrow (BM). Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand (E-sel-L), on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. In preclinical models, blockade of E-selectin with uproleselan disrupts the activation of cell survival pathways and enhanced the efficacy of chemotherapy across multiple AML tumor models. Furthermore, uproleselan protected against chemotherapy-induced mucositis by regulating macrophage trafficking to the site of injury in the gut lining. A previous phase I/II study of uproleselan added to chemotherapy in patients with untreated AML (older adults ≥60 yrs) and relapsed/refractory AML (≥ 18yrs) showed promising remission rates (CR/CRi) and survival outcomes, and reduced rates of mucositis. In the newly diagnosed older patients, high remission rates were achieved overall (CR/CRi 72%) and for the high risk subgroup with sAML (CR/CRi 69%). In this phase 2/3 study, we will test the addition of uproleselan to a standard daunorubicin/cytarabine regimen in older adults with previously untreated AML. The study will enroll patients age ≥ 60 yrs with untreated acute myeloid leukemia. Patients with acute promyelocytic leukemia, activating mutations in FLT3, or evidence of central nervous system involvement are excluded. Subjects are randomized to 7+3 induction (cytarabine + daunorubicin) +/- uproleselan. Subjects achieving a CR/CRi may receive up to 3 cycles of consolidation with intermediate dose cytarabine 2 gm/m2 IV d1-5 +/- uproleselan. The primary phase II objective is to compare the event-free survival (EFS). A sample size of 262 patients was selected for the phase II to detect an improvement in median EFS from 7 months to 11 months (HR= 0.64) with > 95% power, using a log rank test. The phase III primary objective will compare overall survival (OS). For the phase III, a sample size of 335 evaluable patients per arm (670 total inclusive of patients enrolled in phase II) will provide >90% power to detect an improvement in median OS from 12 months to 16 months (HR= 0.75), using a log-rank test. Correlative studies will measure E-selectin ligand on AML blasts and soluble E-selectin and will also measure minimal residual disease after remission induction by multiparameter flow cytometry. A comprehensive geriatric assessment will identify baseline measures associated with EFS and develop a risk model to predict OS among older adults receiving intensive AML therapy. The study is endorsed by SWOG and ECOG-ACRIN and opened to enrollment on 1/16/2019. Figure Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Strickland:Jazz: Consultancy; Sunesis Pharmaceuticals: Research Funding; Pfizer: Consultancy; Kite: Consultancy; Astellas Pharma: Consultancy; AbbVie: Consultancy. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Novartis, Agios, Arog: Research Funding. OffLabel Disclosure: Uproleselan in AML

Abstract Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML. The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts. A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo. This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001). Disclosures Uy: Novartis: Research Funding. Off Label Use: Sorafenib for AML. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta Pharma BV: Research Funding. Stone:Celator: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; AROG: Consultancy; Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Juno: Consultancy; Agios: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

BACKGROUND/OBJECTIVES The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. DESIGN Prospective cohort study. SETTING Two academic medical centers. PARTICIPANTS A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. MEASUREMENT Participants completed a primarily self‐administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. RESULTS Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. CONCLUSION Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987–991, 2019.

Objectives To analyze self‐reported changes in physical function in older women with breast cancer receiving adjuvant chemotherapy. Design Secondary analysis of the Cancer and Leukemia Group B (CALGB) 49907 prospective randomized clinical trial. Setting CALGB institutions in the United States. Participants Women aged 65 and older with Stage I to III breast cancer enrolled in CALGB 49907 who had physical function data from before and after receipt of adjuvant chemotherapy (N=256; mean age 71.5, range 65–85). Measurements Participants were administered the physical function subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire before chemotherapy, at the end of chemotherapy, and 12 months after chemotherapy initiation. Functional decline was defined as a more than 10‐point decrease from baseline at each time point. Resilience was defined as return to within 10 points of baseline. Multivariable regression was used to examine pretreatment characteristics associated with physical function changes. Results Of 42% of participants who had physical function decline from before to the end of chemotherapy, 47% recovered by 12 months (were resilient). Almost one‐third experienced functional decline from before chemotherapy to 12 months later. Pretreatment fatigue was a risk factor for functional decline from before to the end of chemotherapy ( P =.02). Risk factors for functional decline at 12 months included pretreatment dyspnea ( P =.007) and being unmarried ( P= .01). Conclusion Functional decline was common in older women receiving adjuvant chemotherapy for breast cancer in a clinical trial. Although half recovered their physical function, one‐third had a clinically meaningful decline at 12 months. Strategies are needed to prevent functional decline in older adults receiving chemotherapy. J Am Geriatr Soc 67:920–927, 2019.

Key Points The addition of sorafenib to chemotherapy for older adults with FLT3-ITD mutated AML is safe and may improve overall survival.

Abstract Background: Older adults represent 50% or more of all newly diagnosed cancer patients annually; these patients have multiple morbidities, complicating treatment decision-making.. Discussions about the risks and benefits of cancer treatments might be improved by having data on estimated all-cause survival. ePrognosis (http://eprognosis.ucsf.edu/carey2.php) is an online tool validated in older adults without cancer. We compared survival estimates using ePrognosis to observed survival in a population of women with early stage breast cancer who volunteered for cooperative group studies. Methods: Participants in CALGB 49907 (n=194) and 369901 (n=809) who were age 70+ were included (total n=1003). Both studies had comparable eligibility: primary, newly diagnosed, invasive, non-metastatic breast cancer. In 49907, eligibly also included PS 0-2; in 369901 there were no PS restrictions, but women who failed a screening cognitive exam were excluded. The Carey 2-year Index from ePrognosis was used to estimate all-cause 2-year survival, based on age, sex, and daily function. Function (needing help from another person to bath and shop for groceries, difficulty walking several blocks and pushing or pulling a heavy object) was derived from the EORTC QLC-30. The Carey index from ePrognosis generates scores from 1-10, with higher scores indicating higher probability of death. Kaplan-Meier methods were used to obtain point estimates and confidence intervals for the observed 2-yr survival. A two sided z-test was used to test the hypothesis that the observed survival rate is equivalent to the predicted survival rate. Results: At two years from study entry, 921 women were alive; 56 had died, and 26 were lost to follow-up/withdrawn. The population was, on average, 76 years old (SD 4.8), primarily white (89.3%), and the majority had hormone receptor positive tumors (79.4%). In our population, the Carey 2-years index predicated survival was not significantly different than observed rates in the 0-2 points and underestimated the survival rates for patients who had 3-6 points and 7-10 points. ePrognosis Prediction49907 & 369901 PatientsPointsPredicted Probability of SurvivalNNumber of DeathsObserved Probability of Overall Survival at 2 years (%, 95% CI)p-value0-295%5332595% (93-97%)0.7433-688%4272394% (92-96%)&lt;0.0017-1064%43881% (65-90%)0.017 Conclusions: In this population of older women with breast cancer, using a few readily available data items, ePrognosis provided accurate survival estimates for women with a low probability of death (0-2 points) and underestimated all-cause survival in women with an increased probability of death (3-10 points). Further studies are needed to assess the validity of this tool in samples of cancer patients with higher risks of 2-year mortality. Extended follow-up to validate the tools in predicting 5- and 10-year all-cause and non-cancer mortality risk will further contribute to decision making in older patients. Citation Format: Kimmick G, Pitcher B, Mandelblatt J, Clapp J, Ballman K, Barginear M, Freedman R, Artz A, Klepin H, Lafky J, Hopkins J, Winer E, Hudis C, Muss H, Cohen H, Jatoi A, Hurria A. All-cause survival estimates compared to observed survival in older women with breast cancer in CALGB 49907 and 369901 (Alliance A151503). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-10.

Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.