ALBERT

Beschreibung: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS®measures, to assess outcomes of patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) who were treated with CD19-targeted CAR-T cells on a clinical trial in our institution (NCT01865617) and survived at least one year after treatment. Between October 2018 to February 2019, 52 patients (at their 1-5 year anniversary after CAR-T cell therapy) were sent a questionnaire. The questionnaire included the PROMIS Scale v1.2-Global Health and the PROMIS-29 Profile v2.1, as well as 30 additional questions, including questions pertaining to cognitive function. As of February 28, 2019, 40 questionnaires were returned (76.9% response rate) and were included in the analysis. Patients' characteristics are summarized in Table 1. Cognitive function was assessed by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems since their CAR-T cell therapy; answer "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). PROMIS measures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 participants (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1), and 7 participants (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. On risk factor analysis, younger age was found to be associated with worse Global Mental Health (p=0.02), anxiety (p=0.01) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). Multivariate analysis confirmed association between age and PROMIS Global Mental Health score (p=0.03). 15 participants (37.5%) reported cognitive difficulties post CAR-T cell therapy. On multivariate analysis, depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported cognitive difficulties after CAR-T therapy (p=0.02) and there was a trend for association between acute neurotoxicity after CAR-T cell infusion and self-reported long-term cognitive difficulties (p=0.08). Having more cognitive difficulties was associated with worse Global Mental Health (p=0.0001) and worse Global Physical Health (p= 0.01). Similarly, worse scores for pain interference, sleep disturbance, fatigue, depression, anxiety, physical function, and social function were associated with more long-term self-reported cognitive difficulties (p=0.007,p=0.0003, p=0.00006, p=0.01, p=0.0007, p=0.003, p=0.0004 respectively). Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, despite good overall mean scores, nearly 50% of patients in the cohort reported at least one negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), and almost 20% scored at least one standard deviation lower than the general US population mean in Global Mental Health, indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, anxiety and depression pre-CAR-T cell therapy, and acute neurotoxicity after CAR-T cell infusion may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings. Disclosures Shaw: Therakos: Other: Speaker Engagement. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

Beschreibung: Background: Treatment of chronic myeloid leukemia (CML) with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet has been associated with reduced health-related quality of life and very high cost. Discontinuing TKIs with regular monitoring is safe, but little is known about the impact of discontinuation on patient-reported outcomes (PROs). In the largest U.S. study to date, we evaluated molecular recurrence of CML and PROs after TKI discontinuation. Methods: The Life After Stopping TKIs (LAST) study was a prospective single-group longitudinal study. Key inclusion criteria were age 〉 18 years, patient on TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib) for 〉 3 years with documented BCR-ABL 〈 0.01% by PCR for 〉 2 years, and no previous TKI resistance. We monitored disease outcome (PCRs by central lab) and PROs (PROMIS computerized adaptive tests via REDCap) monthly for the first 6 months, every 2 months until 24 months, then every 3 months until 36 months. Molecular recurrence was defined as 〉 0.1% BCR-ABL IS by central lab (loss of major molecular response [MMR]). We considered 3 points to be clinically meaningful and hypothesized that by 6 months after TKI discontinuation, fatigue, depression, sleep disturbance, and diarrhea would improve by at least 3 points each, corresponding to a standardized effect size of 0.3. Given reports of a withdrawal syndrome of musculoskeletal pain in some patients after discontinuation, pain was an additional outcome of particular interest. For each PRO domain, we estimated a polynomial piecewise linear mixed effects model that specified one nonlinear trajectory after TKI discontinuation and, for those with molecular recurrence, another trajectory after TKI restart. The models included patient-level random effects for the intercepts and linear slopes. Results: From 12/2014 to 12/2016, 172 patients enrolled from 14 U.S. sites. Median age was 60 years (range 21-86) and 89 (52%) were female. The median time on TKI prior to enrollment was 81 months (IQR 54-123). With a minimum follow-up of 24 months, 107 (62%) patients remained in a treatment free remission (TFR). Reasons for restarting therapy were: loss of MMR by central (n=56) or local (n=2) lab, patient decision (n=4), and withdrawal syndrome (n=3). Missing PRO data was minimal (〈 5%) with 〉 2000 assessments completed. For patients in TFR at 6 months, the average estimated improvement in fatigue was 2.6 points (95% CI 2.5-2.7), depression was 1.9 points (95% CI 1.8-1.9), sleep disturbance was 0.9 points (95% CI 0.8-1.0), and diarrhea was 2.7 points (95% CI 2.6-2.7). The average estimated worsening in pain interference (i.e., the extent to which pain affects daily life) was 0.4 points (95% CI 0.3-0.5). The figure shows the distribution of estimated change for each domain at 6 months. All patients showed improvements in depression, diarrhea, and fatigue. About 1 in 6 patients (17%) experienced a clinically meaningful (i.e., at least 3 points) improvement in fatigue and/or diarrhea at 6 months. Conclusion: The LAST study is the largest US TKI discontinuation study to date, and the first to include comprehensive PRO measurement. For patients in TFR at 6 months, TKI discontinuation conferred modest benefits in fatigue and diarrhea on average, with a negligible increase in pain interference. Some patients experienced more notable improvements in fatigue and diarrhea. Planned secondary analyses will include change over time up to 3 years and evaluation of additional PRO domains, including anxiety, physical function, social function, and sexual function. Our results provide important new evidence to support shared patient-provider clinical decision making regarding TKI discontinuation for patients with CML. Figure. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy. Larson:Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy. Oehler:Blueprint Medicines: Consultancy; NCCN: Consultancy; Pfizer Inc.: Research Funding. Deininger:Humana: Honoraria; Incyte: Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Sangamo: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Ritchie:Tolero: Other: Advisory board; Celgene: Other: Advisory board; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene, Incyte, Novartis, Pfizer: Consultancy; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Genentech: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Atallah:Jazz: Consultancy; Helsinn: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy.

Beschreibung: Background: Light chain (AL) amyloidosis is associated with misfolded, insoluble fibril deposits in vital organs such as the heart, kidneys, liver, and nerves, derived from immunoglobulin light chains made by clonal plasma cells. Plasma cell-directed, standard-of-care chemotherapy has no effect on pre-formed fibrils. Hematologic response is thus insufficient for organ amyloid responses and organ improvement can lag hematologic response by months to years. Fibril-directed therapies are critical to improve early mortality of AL. Doxycycline has been reported to produce fibril disruption, reduce AL deposits and control light chain toxicity. It has been studied in localized AL amyloidosis and other amyloid subtypes. We conducted a phase 2 trial of doxycycline for use in conjunction with chemotherapy in AL. Herein, we report the outcomes of systemic AL patients treated on this study. Patients and Methods: This was an open label, single center, phase 2 pilot trial listed under clinicaltrials.gov (NCT02207556). The study was opened between 12/2014 - 06/2017. The last patient completed end-of-study assessment in 07/2018. Based on predominant symptoms and organ involvement, each patient was labeled to have 1 target amyloid organ involved. Patients were treated with oral doxycycline 100 mg twice daily in conjunction with chemotherapy per physician discretion. Patients were staged using the 2012 staging system. Hematologic and organ responses were categorized based on the consensus guidelines for conduct and reporting of clinical trials in AL amyloidosis published in 2012 for cardiac, renal and hepatic organ involvement and by radiologic measures for soft tissue involvement. The objectives were to study early mortality at 1, 3, 6, and 12 months after enrollment, target amyloid organ response rates at 6 and 12 months, and quality of life (QoL) using the PROMIS Global Health Index at 3-monthly intervals during the study. Results: Of 31 patients enrolled on this study, 25 had systemic AL (6 patients with localized AL syndromes will be described separately). The median age at diagnosis was 61.3 years (range 38.3-77.3), 64% were male, 2012 stage was I in 3 (12%), II in 9 (36%), III in 6 (24%) and IV in 7 (28%). The amyloid clone was lambda in 17 (68%). The median baseline values with range were: hemoglobin 12.3 (9.7-16.5) g/dL, albumin 3.7 (1.1-4.8) g/dL, creatinine 1.07 (0.6-2.42) mg/dL, 24-hour urine protein 0.97 (0.15-16.7) g/day and alkaline phosphatase 77 (42-597) IU/L. The median difference in involved and uninvolved free light chains was 258.6 (26-978.4) mg/L, NT-proBNP was 2564 (65-18333) pg/mL and troponin T was 0.017 (3 organs involved with amyloid, with 60% cardiac, 72% renal, 24% hepatic, 36% soft tissue, 28% gastrointestinal, 20% autonomic nervous system, and 8% peripheral nerve AL involvement. The median follow-up was 21.4 (12.2-40.3) months. All patients received concurrent CyBorD chemotherapy. Early mortality was 0 at 1 month, 2 (8%) at 3 months, 3 (12%) at 6 months and 5 (20%) at 1 year. Target organ involvement and responses at 6 and 12 months are shown in the table. In an intent-to-treat analysis of organ responses, at 6 months 24% had response, 32% had stable disease and 44% had progression (including 3 deaths prior to 6 months). At 12 months, 36% had target organ response, 32% had stable disease and 36% had progression (including 5 deaths). QoL showed improvement in both physical and mental domains at the end of treatment (figure). Overall hematologic response among survivors was 100% at 1-year including 40% complete, 45% very good, and 15% partial responses. The most common adverse event was skin rash and photosensitivity. One patient with end-stage heart failure and multiple hospitalizations, developed Clostridium difficile diarrhea while hospitalized, during the study period. Fifteen patients (60%) underwent melphalan-based autologous stem cell transplantation- 14 within 1 year after diagnosis, and in 1 delayed until relapsed disease 2 years after diagnosis. The 100-day mortality among transplanted patients was 0. Conclusions: In newly diagnosed systemic AL amyloidosis, doxycycline was safe with concurrent chemotherapy. The low 1-year early mortality of 20% and autologous stem cell transplant rate of 60% compares favorably to prior reports. These findings warrant a randomized, multicenter study. Disclosures D'Souza: Prothena: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Dhakal:Celgene: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria. Hari:Janssen: Honoraria; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Beschreibung: Introduction: The development of tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of patients (pts) with chronic myeloid leukemia (CML), with the perception by healthcare professionals that this is now a chronic disease to be managed. However, the need for continuous TKI therapy may result in ongoing toxicities, limits on fertility, and financial hardship. The H. Jean Khoury Cure CML consortium (HJKC3) is a collaborative effort of physicians and researchers at 17 academic centers. The HJKC3-001 2017 Patient Survey sought to define pts' expectations for treatment in CML to serve as a guidepost for future research in this area. Methods: Pts with CML were recruited by HJKC3 physicians, CML advocacy groups, and social media. An online survey platform (Qualtrics®) was used to obtain informed consent and administer the questionnaire. The anonymous survey was designed to gauge priorities for research in CML, understand patient definitions of cure, and elicit patient interest in future directions for CML therapy. Patient demographic and health characteristics were also collected. The data were analyzed using descriptive statistics. Results: Of the 458 pts who completed the survey, the median age of respondents was 54 years (range 18-81); 88% of pts identified as non-Hispanic white, 2% as non-Hispanic black, 2% as non-Hispanic Asian, 4% as Hispanic, and 4% other. Patients rated their overall health as poor (4%), fair (18%), good (40%), very good (28%) and excellent (9%). All but one respondent said that more research was needed for CML, with pts indicating their preferences for where they considered the need was greatest (Table 1). Overwhelmingly, 94% of respondents considered cure in CML as not taking any more pills. All but three respondents had received treatment with a TKI, with 26% (n=119) of pts having previously stopped their TKI medication for at least one month. When presented with the possibility of stopping all future treatment for CML with additional treatment, 97% of pts were willing to add another oral medication to their TKI while 89% of pts would accept intravenous treatment in addition to a TKIs. Half of the pts had discussed treatment discontinuation with their physician, with 45% considering this option in an attempt at treatment-free-remission. Of the pts that stopped taking their TKIs for at least one month, 65% did so because of side effects and another 10% because of cost. Conclusion: This survey demonstrates that pts do not consider disease control with life-long oral medication as cure; rather, cure requires the absence of treatment. Overwhelmingly, pts indicated the importance of continuing CML research with an ultimate goal of treatment-free cure. The advent of oral TKIs has been a tremendous success for pts with this disease. Nevertheless, it remains a source of disruption in pts' lives, particularly through side effects and costs. The HJKC3 was initiated with the goal of curing CML. Disclosures Atallah: Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Abbvie: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding. Goldberg:COTA Inc.: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Druker:ARIAD: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; McGraw Hill: Patents & Royalties; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Oregon Health & Science University: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Celgene: Consultancy. Larson:Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ritchie:Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharma: Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria.