Geriatric Impairments and Low Muscle Mass Are Associated with Treatment Discontinuation and Overall Survival in Newly Diagnosed Non-Transplant Eligible Multiple Myeloma Patients (nte-NDMM) Treated with Dose-Adjusted Melphalan-Prednisone-Bortezomib (MPV) — Results of the Dutch HOVON 123 Study

Abstract Introduction There is a high rate of treatment discontinuation (TD) in elderly patients with nte-NDMM, that negatively impacts overall survival (OS). In order to prevent TD identification of unfit and frail patients is a prerequisite, either to withhold or adapt treatment. Although the IMWG frailty score (IMWG-FS) identifies frail patients with higher TD and inferior OS there is a need for refinement. Therefore, we prospectively evaluated the feasibility of a dose-adjusted Melphalan-Prednisone-Bortezomib (MPV) regimen in nte-NDMM patients ≥75 years of age. In addition, we investigated the prognostic value of a geriatric assessment (GA) and muscle mass and function for TD and OS. This is a preliminary analysis of 220/240 included patients. A final update, including multivariable prediction models, of 240 patients will be available at the ASH meeting. Methods Patients were treated with 9 cycles of MPV: M 6 mg/m2, day 1-4; P 30 mg/m2, day 1-4; and V 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. Functional, cognitive, mental health, nutritional status and comorbidities were assessed at baseline (Table 1). Muscle mass and function were determined by CT scan and hand grip strength (HGS) and gait speed (GS), respectively. Presarcopenia was defined as low skeletal muscle mass (Skeletal Muscle Index (SMI) cm/m2) only, sarcopenia when additionally low muscle function (HGS or GS) was present, and severe sarcopenia when all 3 parameters were abnormal. Cut offs for muscle mass parameters were defined by sex-specific p5 and p10 values reported in the literature and a Bayesian statistical change point model. Associations between TD or OS and aforementioned factors were assessed via univariable regression models. Multivariable prediction models will be developed using variable selection procedures. Results 218/220 patients were eligible for frailty analysis; 61% frail, 28% unfit and 3% fit patients (7% unknown), according to IMWG-FS. Median follow-up was 22 months (inter quartile range (IQR) 15-32). TD within 9 cycles of MPV was 44%, being significantly higher in frail as compared to unfit patients (51% vs 29%, hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.32-4.80, p=0.005, Fig. 1A). Overall response rate and median progression free survival were 74% and 17 months (IQR 12-22 months), both unaffected by frailty. Median OS was 45 months. Frail patients had a significant inferior OS as compared to unfit patients (median 31 versus 45 months, HR 2.13, 95% CI 1.21-3.76, p=0.009) (Fig. 1b). Frail patients were older, had significantly more comorbidities, lower physical function (both self-reported [EORTC QoL questionnaire and (i)ADL] and by physical examination [GS and HGS]), worse cognitive function, and more depression and malnutrition as compared to unfit patients (Table 1). Low muscle mass was detected in 13-22% of frail (depending on cut off) versus 5% of unfit patients. Sarcopenia was detected in 13-18% of frail (depending on cut off) and 5% of unfit patients. These data indicate that there are biological differences between unfit and frail patients. Subsequently, we investigated which GA and sarcopenia characteristics were associated with TD and OS. For TD, all IMWG-FS parameters but ADL, WHO ISS 3, muscle mass, depression and risk for malnutrition were associated (table 2). For OS all IMWG-FS parameters, WHO ISS 3, cytogenetic risk, muscle mass, depression, (risk of) malnutrition and cognitive function were associated (table 2). Interestingly, although there was a strong association between muscle mass as determined by CT-scan and both TD and OS, muscle function tests (HGS and GS) were not. Neither were sarcopenia definitions incorporating muscle function. Remarkably, self-reported physical functioning revealed from the QLQ-C30 was associated with TD and OS. Conclusion We here confirm the predictive value of the IMWG-FS for TD and OS. Importantly, we provided a biological background of frailty by showing more geriatric impairments and loss of muscle mass in frail versus unfit patients. In addition to known predictive factors for OS; IMWG-FS, ISS and cytogenetics, we found that GA and low muscle mass, but not muscle function, were associated with clinical outcome. We are currently developing a novel predictive scoring system for TD and OS incorporating these novel parameters, with the aim to refine currently available prediction models for identification of elderly patients who will benefit from therapy. Disclosures Levin: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Minnema:Servier: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Sarcopenia Is a Clinically Relevant and Independent Predictor of Health Outcomes after Chimeric Antigen Receptor T-Cell Therapy for Lymphoma

Blood ◽

10.1182/blood-2021-149784 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2502-2502

Author(s):

Alex Iukuridze ◽

Jennifer Berano Teh ◽

Justin Ramos ◽

Teresa Cabrera Vera ◽

Kyuwan Lee ◽

...

Keyword(s):

Skeletal Muscle ◽

B Cell ◽

Board Of Directors ◽

Muscle Mass ◽

Research Funding ◽

Independent Predictor ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Car T ◽

One Year

Abstract Introduction: Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) or other B-cell lymphomas. However, the potent anti-lymphoma effect of CAR-T is balanced by the risk of acute toxicities, namely cytokine release syndrome (CRS) and Immune effector cell-Associated Neurotoxicity Syndrome (ICANS), as well as the variable length of progression-free survival (PFS) after CAR-T. Tools to better risk-stratify for adverse outcomes and to guide targeted interventions are lacking. Sarcopenia (loss of lean muscle mass) is an important cause of age-related functional decline in the general population and is an independent predictor of health outcomes in patients with solid and hematologic cancers, irrespective of age or comorbidity. Advances in software technology have facilitated the near real-time integration of body composition measurements into imaging studies obtained as part of standard clinical care. To date, there have been no studies to examine the association between sarcopenia and outcomes after CAR-T therapy. Methods: Using a retrospective cohort design, 280 consecutive patients with DLBCL or B-cell lymphoma, age ≥18y, and treated with CAR-T therapy between 2015 to 2020 at a single center were included in the study. This analysis was restricted to 226 (80.7%) patients with available computed tomography scans ≤60d from CAR-T. Skeletal muscle area was ascertained from abdominal scans using an automatic image analysis software (APACS; Voronoi Health Analytics; Vancouver, Canada); 3rd lumbar vertebra was used as a landmark because of its high correlation with whole-body muscle mass (J Clin Oncol 2016 34:1339); Figure. Trained researchers blinded to patient demographics and outcomes manually validated these measurements (SliceOmatic; Tomovision; Quebec, Canada). Skeletal muscle index (SMI) was calculated as the ratio of skeletal muscle area (cm 2) divided by height (m). Sarcopenia was defined according to sex-based cutoffs (lowest SMI tertile). Kaplan-Meier method was used to examine PFS at one-year. Multivariable regression was used to calculate the hazard ratio (HR) for PFS and odds ratio (OR) for toxicities with 95% confidence intervals (CI), adjusted for covariates (demographics [age, race/ethnicity], disease characteristics [largest lymph node diameter, blood lactate dehydrogenase], CAR-T product, ECOG performance status). Results: Median age at CAR-T was 63y (range: 18-84); 65.9% were male; 50.9% were non-Hispanic white; 8.8% had ECOG ≥2; 80.5% had a diagnosis of DLBCL; CAR-T products: axicabtagene ciloleucel (51.3%), lisocabtagene maraleucel (31.9%), other (16.8%); 46.9% were treated on a clinical trial; median residual lymph node diameter prior to CAR-T was 2.3cm (range: 0-17.2); 8.0% underwent HCT <1 year after CAR-T and follow-up was censored at HCT. Outcomes: 59.1% developed CRS (18.2% grade ≥2) and 30.1% developed ICANS (15.9% grade ≥2). In adjusted analyses, the odds of developing CRS or ICANS was 1.9-fold (CRS: 1.89 [95%CI: 1.02-3.5], ICANS: 1.93 [1.06-3.51]) higher among patients who were sarcopenic (reference: normal body composition). Average length of hospitalization was also longer (25.6d vs. 21.9d; p=0.037) among patients with sarcopenia. Survival: One-year PFS for the overall cohort was 50.1% (±4.2); PFS was significantly worse for patients who were sarcopenic compared to those with normal muscle mass (35.1% [±6.2] vs. 57.7% [±4.3], p=0.005; Figure). In adjusted analyses, sarcopenia was associated with inferior one-year PFS (HR=1.73 [CI: 1.12-2.68]) compared to those with normal muscle mass. Conclusion: Sarcopenia is an important and independent predictor of outcomes after CAR-T with potential downstream health-economic consequences, including increased burden of acute toxicities and prolonged length of hospitalization. Taken together, these data form the basis for real-time decision making prior to CAR-T (e.g. pre-habilitation, consideration of alternative treatments), or during/shortly after CAR-T (e.g. increased supportive care, rehabilitation), setting the stage for innovative strategies to improve outcomes after CAR-T therapy. Figure 1 Figure 1. Disclosures Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Budde: Merck, Inc: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Herrera: Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Kite, a Gilead Company: Research Funding; Seagen: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Tubulis: Consultancy; Genentech: Consultancy, Research Funding. Popplewell: Novartis: Other: Travel; Pfizer: Other: Travel; Hoffman La Roche: Other: Food. Shouse: Kite Pharmaceuticals: Speakers Bureau; Beigene Pharmaceuticals: Honoraria. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company.

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NEUROMUSCULAR CHANGES WITH AGING AND SARCOPENIA

Journal of Frailty & Aging ◽

10.14283/jfa.2018.35 ◽

2018 ◽

pp. 1-3

Author(s):

B.C. Clark

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Function ◽

Skeletal Muscle Mass ◽

The Past ◽

Conceptual Definition ◽

Age Related ◽

Per Se ◽

Definition Of ◽

And Function

Sarcopenia was originally conceptualized as the age-related loss of skeletal muscle mass. Over the ensuing decades, the conceptual definition of sarcopenia has changed to represent a condition in older adults that is characterized by declining muscle mass and function, with “function” most commonly conceived as muscle weakness and/or impaired physical performance (e.g., slow gait speed). Findings over the past 15-years, however, have demonstrated that changes in grip and leg extensor strength are not primarily due to muscle atrophy per se, and that to a large extent, are reflective of declines in the integrity of the nervous system. This article briefly summarizes findings relating to the complex neuromuscular mechanisms that contribute to reductions in muscle function associated with advancing age, and the implications of these findings on the development of effective therapies.

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Preliminary Safety Results from the Phase IIIb GREEN Study of Obinutuzumab (GA101) Alone or in Combination with Chemotherapy for Previously Untreated or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.3345.3345 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3345-3345 ◽

Cited By ~ 7

Author(s):

Francesc Bosch ◽

Thomas Illmer ◽

Mehmet Turgut ◽

Agostino Cortelezzi ◽

Susan F. Lasserre ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Safety Data ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Phase Iiib ◽

Unfit Patients ◽

Grade 3

Abstract Background: The novel, glycoengineered type II anti-CD20 monoclonal antibody, obinutuzumab (GA101) has demonstrated superior efficacy to chlorambucil (Clb) monotherapy and to Clb in combination with rituximab (R-Clb) with an acceptable safety profile in CLL. However, an increased rate of infusion-related reactions (IRRs) has been observed with the obinutuzumab(G)-Clb combination compared with R-Clb during the first cycle of treatment. The GREEN study (NCT01905943) is an ongoing phase IIIb, multicenter, open-label trial investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL. We report safety data from cohort 1, which aimed to reduce IRRs on the first day of obinutuzumab administration in previously untreated patients using a lower dose and slower infusion rate than in previous studies. Methods: Subjects aged ≥18 years withdocumented CLL, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate hematologic function are enrolled. Treatment includes obinutuzumab (1000mg) administered intravenously on days (D) 1 (25mg) and 2 (975mg), D8, and D15 of cycle (C) 1, and on D1 of C2–6, alone (any patient: n=18) or in combination with 28-day cycles of chemotherapy: fludarabine plus cyclophosphamide (FC; n=46) for fit patients (cumulative illness rating scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min), Clb (n=8) for unfit patients (CIRS >6 and/or CrCl <70mL/min) or bendamustine (B; n=86) for fit/unfit patients. The primary outcome is safety, including the frequency, type and severity of adverse events (AEs). The present analysis focuses on IRRs, defined as treatment-related AEs occurring during or within 24 hours of infusion. Results were assessed to determine if a low obinutuzumab dose (25mg) and slow infusion rate (12.5mg/hour) on D1 (the current recommended C1D1 regimen is 100mg at 25mg/hour) could reduce IRRs. Analysis was based on a data cut-off of 28 April 2014, planned for when the first 150 previously untreated patients had completed cohort 1. Results: Of 158 subjects eligible for the IRR analysis (Table), median age was 65.0 (34.0–83.0) years and the majority were males (65.2%) with Binet stage B (52.5%) or C (31.0%) CLL. Median observation time was 2.09 (0.2–6.0) months and median exposure time was 1.0 (0.0–4.8) month. IRRs occurring in ≥10% of patients were chills (14.6%) and pyrexia (15.2%). Serious IRRs in ≥1% of patients were tumor lysis syndrome (TLS; 3.8%) and pyrexia (1.3%). Grade ≥3 IRRs experienced by ≥1% of patients were TLS (5.7%), hypertension (1.3%) and hypotension (1.3%). IRRs were most frequent in C1D1 (Fig). In the overall safety population (n=172; previously untreated patients) the most frequently reported serious AEs of special interest included IRR (8.1%) and neutropenia (11.0%). AEs of particular interest, thrombocytopenia, cardiac, and hemorrhagic events, were experienced by 16.3%, 3.5% and 3.5% of patients, respectively. Table. Table. Conclusions: Preliminary safety data from the GREEN study, assessing the use of obinutuzumab alone or in combination with chemotherapy (B, FC or Clb) in subjects with untreated CLL, are in line with the known safety profile of obinutuzumab in similar populations. Although there is limited exposure time available for subjects in GREEN, IRRs seemed to be more manageable and a lower proportion of subjects with IRRs grade ≥3 was observed compared with previous studies. No new safety signals were reported. However, since the number of discontinuations during C1 was comparable with previous obinutuzumab studies, the decision was taken to further improve IRR rates by assessing additional dexamethasone premedication in cohort 2. Final safety data from the study will be presented at a later timepoint. Figure 1 Figure 1. Disclosures Bosch: Roche: Consultancy, Research Funding, Speakers Bureau. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL.. Lasserre:F. Hoffmann–La Roche: Employment. Truppel-Hartmann:F. Hoffmann–La Roche: Employment. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche-Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

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Evaluation of Health Related Questionnaire Among Mycosis Fungoides and Lymphomatoid Papulosis

Blood ◽

10.1182/blood.v126.23.5603.5603 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5603-5603 ◽

Cited By ~ 1

Author(s):

Rakhshandra Talpur ◽

Iris Wieser ◽

Casey Wang ◽

Lyons Genevieve ◽

Madeleine Duvic

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Research Funding ◽

Brentuximab Vedotin ◽

Function Score ◽

Advisory Committees ◽

Significant Difference ◽

And Function

Abstract INTRODUCTION AND OBJECTIVES: Mycosis Fungoides (MF) andlymphomatoid papulosis (LyP) are relatively rare and itchy skin disorders. The cosmetic disfigurement and severe pruritus dramatically affects the patient's quality of life. The focus is to examine the validity and reliability of the skindex-29, M.D. Anderson symptom inventory (MDASI) and itch-related quality of life (IQOL) questionnaire in 62 patients in a phase II trial of Brentuximab Vedotin. MATERIALS AND METHODS: Patients completed survey questionnaires related to symptoms and quality-of-life several times over the course of Brentuximab Vedotin. We compared patients' baseline scores to their end-of-study (EOS) scores. Patients were grouped by diagnosis into Mycosis Fungoides and Lymphomatoid papulosis group. Questionnaires included skindex-29, focusing on the skin conditions the patient was bothered the most. (MDASI) for patients with cancer and following the symptoms of cancer and the itchy quality of life (I-QoL) questionnaire was developed to measure the symptoms associated with cancer therapeutic agents and their effect on daily activities. Scoring for the Skindex-29, M. D. Anderson Symptom Inventory (MDASI) and the Quality of Life (QOL) survey were done according to the questionnaire specific scoring guide. Responses were compared between 2 groups using the Wilcoxon rank-sum test. RESULTS Questionnaires from 62 patients (23 LyP and 39 MF) were studied at baseline and end of study. Patients were 33 males and 29 females with median age of 60 years (range: 27-86 years). The median overall survival (OS) was significant P = 0.041, when comparing patients with MF to LyP. The median survival time for patients from time of diagnosis with MF was 14.66 years and LyP was not reached. There was no significant difference in progression free survival (PFS) between MF and LyP. The median number of Brentuximab Vedotin cycles was 7 (1-19). Skindex-29 scales, showed change in emotion scale and function scale from baseline to EOS, both groups had a decrease, patients with LyP had a larger decrease in emotion score (P = 0.069) and function score (P =0.096) over the course of the study. There was no difference in the symptom scale from baseline to EOS. The patients with LyP had a larger decrease in function score from baseline to EOS. When comparing patients with MF to those with LyP for MDASI, there is no evidence of a difference, from baseline to EOS, in either symptom severity or symptom interference in daily life. In the IQOL when comparing the LyP patients' QOL responses from baseline to EOS, did not show significant difference. Table 1. Change in Skindex-29 scales, by group Skindex Scale MF LYP p-value Change from baseline to end-of-study: N Median Min Max N Median Min Max Emotion 35 -10 -65 35 20 -22.50 -61.94 12.5 0.0698 Symptoms 35 -7.14 -46.43 42.86 20 -10.71 -53.57 28.57 0.4782 Function 35 -2.08 -50.38 27.08 20 -16.29 -44.70 14.58 0.0962 Table 2. Change in MDASI scales, by Diagnosis MDASI Scale Item MF LYP p-value Change from baseline to end-of-study: N Median Mean Std. Dev Range N Median Mean Std. Dev Range Severity 35 0.23 0.18 1.96 (-5.85, 3.15) 21 0.38 0.46 1.61 (-1.69, 5.0) 0.9595 Interference 35 0.17 0.06 3.07 (-9.17, 5.17) 19 0.0 0.11 1.59 (-3.0, 4.67) 0.6764 CONCLUSIONS A significant improvement in emotions and functional part of skindex-29 was observed when comparing patients with MF to patients with LyP. While both groups had a decrease, the patients with LyP had a larger decrease in emotion and function score over the course of the study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Therakos: Research Funding, Speakers Bureau; Soligenics: Research Funding; Huya Bioscience Int'l: Consultancy; Spatz Foundation: Research Funding; MiRagen Therapeutics: Consultancy; Eisai: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Array Biopharma: Consultancy; Cell Medica Ltd: Consultancy; Tetralogics SHAPE: Research Funding; Innate Pharma: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Growth differentiation factor 15 (GDF-15) inhibition to increase muscle mass and function in cancer cachexia.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15633 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15633-e15633

Author(s):

Matthew Peloquin ◽

Brianna LaCarubba ◽

Stephanie Joaqium ◽

Gregory Weber ◽

John Stansfield ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Muscle Mass ◽

Muscle Function ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Tumor Model ◽

Growth Differentiation Factor 15 ◽

Myostatin Inhibition ◽

And Function

e15633 Background: Almost half of cancer deaths are attributed to cancers most frequently associated with cachexia. Cachexia is a complex metabolic disease characterized by anorexia and unintentional weight loss. Skeletal muscle depletion has been recognized as a key feature of the disease, however muscle anabolic therapies have not been successful, suggesting that treatments that target multiple aspects of the disease will be most effective. Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia and weight loss and is associated with cachexia in cancer patients. In preclinical cancer cachexia models, GDF-15 inhibition is sufficient to normalize food intake and body weight, including skeletal muscle mass. However, it remains to be determined whether the increased skeletal muscle mass also results in restoration of muscle function. Therefore, we examined the effect of GDF-15 inhibition on muscle mass and function in mouse models of cancer cachexia in comparison with myostatin inhibition, an established muscle anabolic pathway. Methods: Cachectic mouse tumor models were established with subcutaneous implantation of tumor cell lines reported to be GDF-15-dependent; mouse renal cell carcinoma (RENCA) and human ovarian cancer (TOV-21G) cell lines. Mice were treated with anti-GDF-15 (mAB2) or anti-myostatin (RK35) monoclonal antibodies and skeletal muscle function was assessed in vivo via maximum force, maximum rate of contraction and half relax time. In the RENCA tumor model, GDF-15 inhibition fully restored body weight and skeletal muscle mass whereas myostatin inhibition showed only a modest effect. Results: Consistent with the muscle mass improvement, GDF-15 inhibition dramatically increased functional muscle endpoints compared to the partial effect of myostatin inhibition. Interestingly, in the TOV-21G tumor model GDF-15 inhibition only partially restored body weight, however skeletal muscle mass and muscle function were completely normalized. Consistent with the functional assessment, GDF-15 inhibition in the RENCA tumor model decreased the expression of several catabolic genes (i.e. Trim63, Fbxo32, Myh7 and Myh2). The GDF-15 effect is likely to be secondary to the reversal of anorexia since wildtype mice pair-fed to Fc-GDF-15-treated mice demonstrated equivalent muscle mass loss. Conclusions: Taken together these data suggest that GDF-15 inhibition holds potential as an effective therapeutic approach to alleviate multiple aspects of cachexia.

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Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

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Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (IDd) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; First Interim Safety Analysis of the Phase II HOVON 143 Study

Blood ◽

10.1182/blood-2018-99-114668 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 596-596 ◽

Cited By ~ 9

Author(s):

Claudia A.M. Stege ◽

Kazem Nasserinejad ◽

Mark-David Levin ◽

Noortje Thielen ◽

Saskia K. Klein ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Frailty Index ◽

Safety Analysis ◽

Hematological Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Frail Patients ◽

Grade 3

Abstract Introduction Data from clinical trials indicate that elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies. However, overall survival is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index, caused by a high discontinuation rate due to toxicity. Therefore, there is a need for less toxic treatment for unfit and frail patients. In view of the favorable safety profile of ixazomib and daratumumab, we investigated the efficacy and feasibility of treatment with ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail patients. This trial was registered at www.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial treatment consisted of 9 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15), daratumumab (D) 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dexamethasone (in combination with daratumumab (d); cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with I (days 1, 8, 15, 29, 36, 43) and D (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary objective is to determine the overall response rate (ORR) on induction therapy. Aiming for an ORR of at least 65% and considering 50% as a too low ORR, with an optimal Simon 2-Stage design, α = 0.10 and β = 0.20, 60 unfit and 60 frail patients should be included, increased to 66 for both populations to account for ineligibility. A pre-specified safety analysis was planned when for the first 10 unfit and 10 frail patients separately the data of the first 4 cycles of induction therapy are available. Inclusion criteria were NDMM, either being unfit or frail according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 <50% of expected and a creatinine clearance of <20 ml/minute. We here report the results of the planned safety interim analysis of the first 10/32 included frail patients who completed the first 4 induction cycles. The safety interim analysis of the first 10 unfit patients is planned in September, of which the results will be available at the ASH meeting. In addition, we here report the severe adverse events (SAE) for 58 eligible patients (26 unfit, 32 frail) who were included in the study until July 16, 2018. Results The demographic data of the first 10 frail patients are described in Table 1. Median FU of the first 10 frail patients is 5.2 months (range 0.6-9) and of the 58 included patients 1.6 months (range 0-9). Toxicity is described in Table 2. Hematological toxicity was limited, being mainly thrombocytopenia; 3/10 grade 3, 1/10 grade 4, the latter being disease-related. Non-hematological toxicity was manageable, with only 2 grade 3 gastro-intestinal events and 1 pulmonary embolism. No infusion related reactions and neuropathy were reported. There were minor dose reductions only. The median and inter-quartile range of relative dose intensity (RDI) were 1.0 (0.9, 1.0) for ixazomib, 0.9 (0.9, 1.0) for daratumumab and 1.0 (0.9, 1.0) for dexamethasone. SAEs occurred in 9/26 unfit and 14/32 frail patients, mainly caused by prolongation of hospitalization (82% and 88% respectively). Two patients died during cycle 1, both not related to therapy. One 81-year old patient unexpectedly died at home at day 35 of cycle 1 (delay due to low platelet count) after having recovered from thrombocytopenia and a decreased renal function, grade 3, probably caused by cotrimoxazole and valaciclovir. The second 81-year old patient had a thrombocytopenia of 18x109/l related to MM and died of gastrointestinal bleeding for which he declined therapy at day 15 of cycle 1. In the first included 58 patients a total of 4 patients died (6.9%, 4/32 frail (12.5%) and 0/26 unfit (0%)), of whom 2 not related to therapy (see above) and 2 possibly therapy-related; 1 due to Influenza B and 1 acute pre-renal failure due to vomiting and diarrhea. Preliminary response during the first 4 cycles of therapy is promising is; ORR 70% of which 20% VGPR, 10% MR, 10% SD and 10% not evaluable. Conclusion This planned safety analysis of frail patients in the HOVON 143 showed that Ixazomib-Daratumumab-low dose dexamethasone is feasible with a low rate of therapy-related toxicity and mortality. Preliminary response rates are promising. Disclosures Levin: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Combination of Frailty and ISS Scores Identifies a Simple Prognostic Index for Overall Survival in Elderly Patients Treated with Novel Agents-Based Induction Therapy

Blood ◽

10.1182/blood.v124.21.4740.4740 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4740-4740

Author(s):

Alessandra Larocca ◽

Sara Bringhen ◽

Roman Hajek ◽

Maria Teresa Petrucci ◽

Massimo Offidani ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Dose Intensity ◽

Staging System ◽

Advisory Committees ◽

Frail Patients ◽

International Staging System ◽

Frailty Score

Abstract Background: Several biological parameters define patients with multiple myeloma (MM) at high-risk of progression or death. The well-known International Staging System (ISS), as well as age per se, are insufficient to explain differences of overall survival (OS) in patients over 65 years, who are 2/3 of newly diagnosed (ND) MM patients. We have recently showed that a frailty score combining age, functional status (Activity of Daily Living and Instrumental Activity of Daily living scores) and comorbidities (Charlson index) defines 3 categories of patients - fit, intermediate-fitness, frail - with significantly differences in OS and progression-free survival (Larocca A, et al. Blood 2013 122:687). Here we assess the causes of the different mortality in intermediate-fitness and frail groups compared to fit ones and present a final prognostic score based on the combination of ISS and frailty scores. Methods: NDMM patients over 65 years enrolled in 3 clinical trials, receiving either lenalidomide, bortezomib or carfilzomib were included in the analysis. Details on treatment regimens and results of these studies have previously been reported (Palumbo A, et al. Blood 2013 122:536; Larocca A, et al. Blood 2013 122:539, Bringhen S et al. Blood 2014 Jul 3;124(1):63-9). The cumulative incidences of discontinuation and toxicities were calculated using the Fine & Gray model. The frailty score was combined with ISS with the CHi-squared Automatic Interaction Detector method used as an iterative decision tree. Results: 869 patients (median age 74 years) were included in the analysis; 260 (30%) were frail, 269 (31%) intermediated-fitness and 340 (39%) fit. The 3-year OS was 57% in frail, 76% in intermediated-fitness and 84% in fit patients. Overall, 143 patients (16%) died, 70 (27%) frail, 39 (14%) intermediate-fitness and 34 (10%) fit. The causes of death were: disease progression [35 (13%) in frail, 22 (8%) in intermediate-fitness and 18 (5%) in fit patients] and toxicity [21 (8%), 10 (4%) and 11 (3%), respectively]. The higher risk of death for progression was related with the lower dose-intensity due to the higher rate of drug discontinuation and/or dose reduction. The average dose intensity was lower in frail (74%, p=0.0006) and intermediate-fitness patients (80%, p=0.07) compared with fit patients (85%). The cumulative incidence of drug discontinuation for any cause, excluding progression and death, was higher in frail (25%; HR 2.21, p<0.001) and intermediate-fitness (22%; HR: 1.41, p=0.052) patients compared with fit ones (17%). The most frequent reasons for toxicity-related death were cardiac events [11 (4%) in frail patients, 2 (1%) in intermediate-fitness, 3 (1%) in fit] and infections [8 (3%), 2 (1%) and 2 (1%), respectively]. When we combined the frailty score with the ISS, 6 groups of patients and 4 risk categories were identified: fit patients with ISS I at low risk (15%; 3-year OS: 94%), fit patients with ISS stage II or III and intermediate-fitness patients with ISS I, II or III at intermediate risk (55%; 3-year OS: 75-77%.), frail patients with ISS stage I or II at high risk (19%; 3-year OS: 61%) and frail patients with ISS stage III at very-high risk (11%, 3-year OS: 55%) (Figure 1). Conclusion: The inferior survival observed among intermediate-fitness and in frail patients as compared to fit ones, is related to a higher rate of toxic deaths and disease progression, due to a lower dose intensity. The combination of the frailty score, evaluating the patient's status, and the standard ISS, taking into account the biological characteristics of the disease, can predict survival and enhances the single predictive values of the scores, thus representing a valuable tool for treatment-decision in the clinical practice. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Disclosures Larocca: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Use off-label of lenalidomide (immunomodulatory drug), carfilzomib (proteasome inhibitor), subcutaneous bortezomib (proteasome inhibitor) in terms of schedule used and combination.. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Maracci:Mundipharma: Honoraria. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marasca:Janssen: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding. Musto:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria.

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Sexuality Challenges, Intimacy, and MPN Symptom Burden: An Analysis By The MPN Quality Of Life International Study Group (MPN-QOL ISG)

Blood ◽

10.1182/blood.v122.21.4088.4088 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4088-4088 ◽

Cited By ~ 5

Author(s):

Holly Lynn Geyer ◽

Amylou C. Dueck ◽

Robyn M. Emanuel ◽

Keith Cannon ◽

Jean-Jacques Kiladjian ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Multivariate Model ◽

Advisory Committees ◽

Final Multivariate Model ◽

Night Sweats ◽

Sad Mood ◽

And Function

Abstract Background We have previously reported on the high prevalence and severity of challenges with intimacy and sexuality amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between issues of intimacy (sexual desire and function), their relationships to MPN disease features, individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF sexuality item asked about “problems with sexual desire or function”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF sexuality item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the sexuality item with the final multivariate model selected using forward regression. Results Demographics A total of 1908 MPN patients (essential thrombocythemia=799, polycythemia vera=671, myelofibrosis=432, missing=6) completed the sexuality item. Participants were of typical age (median=60, range 15-94) and gender (female=53%). Overall, 1218 subjects described sexuality related complaints (score >0) with an overall mean symptom score of 3.5 (median=2.0, SD=3.7, range 0-10); 725/1908 (38%) patients had severe sexuality related complaints (score >4). Univariate Analysis Among the QLQ-C30 functioning scales, all domains had similar statistically significant correlations (r=-.26 to -.32, all p<0.001). Among QLQ-C30 symptom scales, all QLQ-C30 symptoms displayed correlations ranging between .08 and .29 (all p<0.001). Among MPN-SAF items, the MPN-SAF sexuality item correlated most significantly with the TSS (r=.41, p<0.001), along with MPN-SAF symptoms (r=.16 to .39; all p<0.001). MPN-SAF sexuality measure significantly differed by anemia (means: absent 3.3, present 4.5; p<0.001), leukopenia (means: absent 3.4, present 4.4; p=0.01), thrombocytopenia (means: absent 3.3, present 4.5; p<0.001), red cell transfusion (means: no 3.5, yes 5.0; p<0.001), MPN subtype (ET mean 3.1, PV mean=3.6, MF mean=4.4; p<0.001) and language (means ranged from 2.4 [Swedish] to 4.6 [Chinese]; p<0.001). MPN-SAF sexuality did not significantly differ by age, gender, prior thrombosis or prior hemorrhage. Multivariate Analysis In a multivariate model of MPN-SAF sexuality containing all QLQ-C30 functioning scales, physical (p=0.001), emotional (p=0.01), cognitive (p=0.005) and social (p=0.002) functioning were all statistically significant. Numerous symptoms were also significant in a multivariate model of MPN-SAF sexuality containing all other MPN-SAF symptoms (all p<0.05; abdominal pain, inactivity, dizziness/vertigo/lightheadedness, insomnia, depression/sad mood, cough, night sweats and overall QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, language, QLQ-C30 role functioning and MPN-SAF items (insomnia, depression/sad mood, night sweats and QOL) to be significant (p<0.05). Conclusions Sexuality related complaints have been linked to both physiologic and psychologic origins and are highly prevalent within the MPN population. The results of this study congruently identified close associations between sexuality and function within emotional, cognitive and social domains. Additionally, the correlations of sexuality issues with MPN symptoms and disease features further suggest this item is a key correlate of overall functionality and quality of life. Future investigations into the causative factors and biological correlates of this complaint may assist in addressing this ongoing challenge. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding.

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Quality of Life Scores Improve with Increasing Hemoglobin but Optimal Thresholds Vary According to Transfusion Dependence and Clinical Risk Scores: A Canadian Cross Sectional Study of 689 Patients with 2969 Measurements

Blood ◽

10.1182/blood.v128.22.3192.3192 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3192-3192

Author(s):

Rena Buckstein ◽

Richard A. Wells ◽

Nancy Y Zhu ◽

Michelle Geddes ◽

Mitchell Sabloff ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Advisory Board ◽

Risk Scores ◽

Advisory Committees ◽

Cross Sectional ◽

And Function

Abstract Background : We previously presented that selected quality of life (QOL) domains in MDS patients are impaired compared with age-matched controls and most impacted by hemoglobin (Hgb) level, transfusion dependence, frailty and comorbidity in an initial cohort of 236 patients from a Canadian MDS registry (Buckstein R. et al, Abstract 699, ASH 2012 and Abstract 2500, ASH 2009). The optimal Hgb threshold associated with improved QOL may vary according to health states that may fluctuate for any given patient. With longer follow up and greater sample size, we now examine the impact of Hgb levels on QOL in transfusion dependent (TD) versus independent (TI) patients and according to IPSS-R risk scores. Methods:Since 2008, we have prospectively assessed QOL in all patients registered in the Canadian national MDS registry using the instruments EORTC QLQ-C30, FACT-F, global fatigue scale (GFS) and EQ-5D, at enrollment and every 4-6 months. These QOL data are paired with disease specific and laboratory information at the same time intervals. Each patient could provide multiple QOL measurements at different time points. Clinically significant score differences were considered 10 points for the EORTC, 0.08 for the EQ-5D and 4 for the FACT F. General linear regression analysis was applied to search for a significant relationship between physical and social functioning, dyspnea, fatigue and QOL with Hgb, according to transfusion dependence, IPSS and IPSS-R measured categorically. To account for multiple comparisons among 5 Hgb categories, Bonferroni adjusted p-value < .01 was considered statistically significant. Results: 689 patients from 15 Canadian sites completed their first QOL assessment at a median time of 7.8 (IQR 2.7-23) months from MDS diagnosis. The median time from MDS diagnosis to death or last follow-up was 2.5 years (IQR 1.2-4.9). The median Hgb at enrollment was 100 g/L (IQR 86-113) and the distribution of risk scores included: very low (13%); low (35%); intermediate (28%); high (15%); and very high (10%). 27% of patients were TD at enrollment and 54% were TD at any time. The median number of QOL assessments per patient completed was 3 (IQR 2-6) with 547 patients completing at least 2, 424 at least 3 and 335 at least 4 serial QOL measurements at a median time interval of 17 weeks (IQR 13-25). When examined by Hgb thresholds, mean physical functioning, dyspnea, fatigue (QLQ-C30 and GFS) and global QOL improved with increasing Hgb. QOL symptom and function scores were clinically and statistically significantly superior in TI versus TD patients (table 1). The optimal discriminating Hgb threshold for improved symptom and function scores was 100 g/L for patients that were TI or with IPSS-R very low, low and intermediate risk MDS; and 90 g/L for high and very high risk disease (table 2). No discriminating threshold was found in TD patients. Conclusions: In the largest reported serial cross sectional population based assessment of QOL in MDS patients, we confirm that higher Hgb and transfusion independence have significant impact on QOL, symptoms and self-reported function and should be considered important surrogate endpoints for clinical improvement. Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding. Wells:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Alexion: Honoraria, Other: Advisory board. Zhu:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Geddes:Celgene: Other: Advisory Board, Research Funding. Sabloff:Gilead: Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leitch:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. St-Hilaire:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shamy:Celgene: Honoraria, Other: Advisory board; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Delage:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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