Venetoclax Improves Quality of Life for Patients with Elapsed/Refractory Chronic Lymphocytic Leukemia

Abstract INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.

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IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sezary Syndrome: Results from a Multicenter Phase 1 Trial

Blood ◽

10.1182/blood-2018-99-118021 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 684-684 ◽

Cited By ~ 1

Author(s):

Martine Bagot ◽

Pierluigi Porcu ◽

Basem M. William ◽

Maxime Battistella ◽

Maarten Vermeer ◽

...

Keyword(s):

Quality Of Life ◽

Monoclonal Antibody ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Multicenter Phase ◽

Equity Ownership

Abstract Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽

10.1182/blood.v130.suppl_1.683.683 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 683-683

Author(s):

Jeffrey P. Sharman ◽

Habte Yimer ◽

Michael Boxer ◽

Nicholas Di Bella ◽

Sunil Babu ◽

...

Keyword(s):

Quality Of Life ◽

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Induction Treatment ◽

Future Health ◽

Employment Equity ◽

Equity Ownership ◽

Eortc Qlq

Abstract Introduction: Maintenance and/or improvements in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an ongoing, open-label, single-arm Phase II study of the combination of obinutuzumab (GA101; G) and bendamustine (B) (BG) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with BG (Sharman et al. ASCO 2017). Here, we present the HRQoL data from GIBB. Methods: In the GIBB trial, patients received BG by intravenous infusion over six 28-day cycles: obinutuzumab 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle 1, then 1000mg on D1 of Cycles 2-6; B 90mg/m2 on D2-3 of Cycle 1, and on D1-2 of Cycles 2-6. The European Organisation for Research and Treatment of Cancer Quality of Life - Core (EORTC QLQ-C30) questionnaire includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries; EORTC website, accessed July 25, 2017). Both questionnaires were completed by patients on D1 of Cycles 1 (baseline), 3, and 6, at the end of induction treatment (defined as +28 days from D1 of Cycle 6 or early treatment termination visit), at the response visit (defined as 2-3 months after the end of induction treatment, for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits. HRQoL scores were linear transformed to a 0-100 point scale. Mean baseline scores and mean score changes at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. Results: Of 102 patients enrolled in the trial, 98 completed a questionnaire at baseline and at least one other questionnaire during a follow-up visit. Questionnaire completion rates were 86.7%, 77.6%, 80.6%, and 86.7% at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Median age was 61 years and 68.4% of patients were male. According to the EORTC QLQ-C30 (Figure 1), clinically meaningful improvements were observed for global health status at the response visit, and for role functioning at the end of induction treatment and at the response visit. A trend was observed for improvement in emotional functioning. The greatest improvement in HRQoL score was observed for fatigue (mean baseline score: 37.64), with mean changes from baseline of −4.01, −5.48, −11.67, and −16.34 at Cycles 3, 6, at the end of induction treatment, and at the response visit, respectively. Improvements were also observed for insomnia (mean baseline score: 33.33), with mean changes from baseline of −6.59, −9.09, −9.7, and −10.98, respectively. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the end of induction treatment and/or at the response visit. The greatest change at the response visit was observed for fatigue (−21.23) and future health worries (−20.24). A positive trend was also observed for improvements in the social activities scale. Conclusions: We previously reported that BG is an effective regimen for first-line treatment of CLL with no unexpected safety signals. In addition, the HRQoL data from the GIBB trial suggest that BG treatment improves patient HRQoL. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries at the time of the response visit. Disclosures Sharman: Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Other: GIBB is sponsored by Genentech Inc. Third-party editorial support, under the direction of Anthony Masaquel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Yimer: Juno pharma: Equity Ownership; Bellucum Pharma: Equity Ownership. Babu: Alexion: Speakers Bureau; Abbvie: Consultancy. Li: Genentech: Employment, Equity Ownership. Mun: Genentech: Employment, Equity Ownership. Trask: Genentech: Employment, Other: stock. Masaquel: Genentech Inc.: Employment, Other: I Receive Roche stock options. Reyes: Genentech Inc.: Employment, Equity Ownership.

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Health-Related Quality of Life Among Patients with Relapsed or Refractory Multiple Myeloma Who Received Pomalidomide, Bortezomib, and Low-Dose Dexamethasone Versus Bortezomib and Low-Dose Dexamethasone - Results from the Phase 3 Optimismm Study

Blood ◽

10.1182/blood-2018-99-112155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1960-1960 ◽

Cited By ~ 1

Author(s):

Katja Weisel ◽

Meletios A Dimopoulos ◽

Philippe Moreau ◽

Munci Yagci ◽

Alessandra Larocca ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Groups ◽

Equity Ownership

Abstract Introduction : A diagnosis of multiple myeloma (MM) has a substantial impact on health-related quality of life (HRQoL) due to associated symptoms, such as bone pain, infection, and fatigue. Furthermore, HRQoL deteriorates with each subsequent line of therapy. The phase 3 OPTIMISMM study (NCT01734928) demonstrated that pomalidomide, bortezomib, and low-dose dexamethasone (PVd) resulted in a significantly longer progression-free survival (PFS) and greater overall response rate (ORR) compared with bortezomib and low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), all of whom had received prior treatment with lenalidomide. Given that HRQoL in RRMM is an important consideration, we conducted this analysis to evaluate the effect of PVd versus Vd on HRQoL in patients enrolled in the OPTIMISMM study. Methods : The OPTIMISMM study was a phase 3, multicenter, randomized, open-label study that enrolled adult RRMM patients who had received 1 to 3 prior anti-myeloma regimens including lenalidomide. Patients (N=559) were randomly assigned to receive PVd (n=281) or Vd (n=278) per 21-day treatment cycle until progression or treatment discontinuation. HRQoL was assessed as an exploratory endpoint using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) questionnaire at Day 1 of each 21-day cycle prior to treatment administration and at the end of treatment. The primary domain of interest was the Global Health Status/QoL domain of the QLQ-C30. Analyses were performed in the HRQoL-evaluable population, which included randomized patients who completed the QLQ-C30 assessment at baseline and at least one post-baseline visit. Key primary analyses of PVd versus Vd on the global QoL domain of the QLQ-C30 included a longitudinal assessment of change from baseline using a mixed-model repeated measure (MMRM) approach; an assessment of the proportion of patients experiencing clinically meaningful deterioration (i.e., ≥10 points worsening from baseline) at pre-selected post-baseline visits; and an analysis of time to first clinically meaningful deterioration. Results : The HRQoL-evaluable population consisted of 240 patients in the PVd group and 209 in the Vd group; baseline characteristics were well-balanced between the treatment groups. HRQoL compliance rates based on the number of patients expected to complete the QLQ-C30 at each given visit exceeded 80% for most visits among both groups. Mean (SD) baseline scores for the global QoL domain of the QLQ-C30 were similar between groups (61.0 [23.2] in the PVd group and 63.5 [21.3] in the Vd group); these scores were maintained over time for both treatment groups, with no clinically meaningful differences observed between the treatment groups at any cycle (Figure 1). The MMRM analyses showed no clinically meaningful difference in global QoL of patients between the PVd group and the Vd group. There was also no significant difference observed in the proportion of patients who experienced clinically meaningful worsening in the global QoL domain between the treatment groups throughout the pre-selected post-baseline visits. The median time to the first clinically meaningful worsening was also similar between treatment groups: 3.0 months for the PVd group and 3.4 months for the Vd group, respectively (hazard ratio: 1.20; 95% confidence interval: 0.9456, 1.5151; p=0.1351; Figure 2 for when death was considered as an event); similar results were observed when death was censored. Conclusions: The results from this analysis of the OPTIMISMM study showed that the triplet regimen of PVd, which consisted of pomalidomide added to the doublet regimen of Vd, did not compromise HRQoL in lenalidomide-treated patients with RRMM. Overall, there were no clinically meaningful differences in the Global Health Status/QoL domain of the QLQ-C30 between treatment groups. These results are meaningful and provide further evidence of the clinical benefits of the addition of pomalidomide to Vd, which include significant improvements in PFS and ORR. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Rodriguez Otero:Clínica Universidad de Navarra: Employment; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hayden:Celgene: Honoraria; Jassen: Honoraria; Amgen: Honoraria. Krauth:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Guo:Celgene Corporation: Consultancy. Purnomo:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Grote:Celgene: Employment. Biyukov:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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.

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Survival Outcomes Following Idelalisib Interruption in the Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-110655 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3149-3149 ◽

Cited By ~ 1

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Wei Ye ◽

Guan Xing ◽

Carrie Ellen Brubaker ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Anti Cd20 ◽

The Impact

Abstract Introduction: Idelalisib (Zydelig®, IDELA) is a PI3Kδ inhibitor approved for treatment of relapsed or refractory (R/R) follicular lymphoma and in combination with anti-CD20 for R/R chronic lymphocytic leukemia (CLL). While IDELA is efficacious, emergence of adverse events (AEs) such as diarrhea, colitis, and transaminitis may limit its long-term administration. We hypothesize that IDELA dose interruption followed by re-initiation as a strategy to manage AEs will permit patients to remain on drug longer and improve clinical outcomes. Objective: To evaluate the impact of IDELA treatment interruption on duration of IDELA therapy (DoT), progression-free survival (PFS), and overall survival (OS) in patients with R/R indolent non-Hodgkin's lymphoma (iNHL) and R/R CLL. Methods: Using clinical outcomes data from Gilead-sponsored trials of patients with R/R iNHL treated with IDELA (101-09, N=125, Gopal et al., N. Engl. J. Med. 2014; 370:1008) or with R/R CLL treated with IDELA + anti-CD20 (312-0116/0117, N=110, Furman et al., N. Engl. J. Med. 2014; 370:997 and 312-0119, N=173, Jones et al., Lancet Haematol. 2017; 4:e114), the effect of IDELA interruption on DoT, PFS, and OS was evaluated retrospectively. Interruption was defined as missing at least one treatment day due to an AE. Patients were stratified according to number of treatment interruptions (0, 1, or ≥2) and by percentage of time off therapy (0, ≤8%, and >8%). The 8% threshold was based on the median (m) percentage of time off therapy in patients with ≥1 drug interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a stratified log-rank test. Results: Among patients with R/R iNHL, 49.6% interrupted therapy, with 31.2% experiencing 1 interruption and 18.4% ≥2 interruptions. Among patients with R/R CLL, 55.5% interrupted therapy, with 27.2% experiencing 1 interruption and 28.3% ≥2 interruptions. Baseline patient and disease characteristics were similar among the various treatment interruption groups (Table 1). The most common AEs (any grade) leading to any treatment interruption were diarrhea (iNHL, 14.5%; CLL, 28%), cytopenias or febrile neutropenia (iNHL, 4.8%; CLL, 22.3%), hepatic toxicity (elevated transaminases, alkaline phosphatase, or bilirubin; iNHL, 4.8%; CLL, 16.6%), and pneumonia (iNHL, 9.7%; CLL, 9.6%). iNHL and CLL patients without treatment interruption tended to have a shorter total DoT (iNHL, 3.8 months; CLL, 10.7 months) than patients with either 1 (iNHL, 12.7 months; CLL, 19 months) or ≥2 (iNHL, 12.2 months; CLL, 18.6 months) interruptions. iNHL and CLL patients with any treatment interruption achieved a longer PFS and OS than patients with no interruption (iNHL, mPFS=5.6 months, 14.2 months, and 16.5 months for 0, 1, and ≥2 interruptions, respectively [Fig. 1] and mOS=not reached (NR) for all groups; CLL, mPFS=13.9 months, 20.9 months, and 28.9 months [Fig. 2] and mOS=33.6 months, NR, and 47.4 months for 0, 1, and ≥2 interruptions, respectively). To account for differences in DoT across the treatment interruption groups, we compared PFS and OS based on percentage of time off therapy (no time off therapy, ≤8% time off therapy, and >8% time off therapy). Patients who interrupted with time off therapy ≤8%, but not >8%, had improved PFS and OS compared to patients who did not interrupt (iNHL, mPFS=5.6 months, 20.3 months, and 11.1 months for no, ≤8%, and >8% time off therapy, respectively [Fig. 3] and mOS=NR for all groups; CLL, mPFS=13.9 months, 28.9 months, and 16.2 months [Fig. 4] and mOS=33.6 months, 47.4 months, and NR for no, ≤8%, and >8% time off therapy, respectively). Conclusion/Discussion: In these clinical trials, approximately half the patients interrupted IDELA therapy due to AEs. Patients who interrupted therapy had a longer DoT and achieved longer PFS and OS than patients who did not interrupt. While limited time off therapy appeared to confer a clinical benefit, additional time off therapy (defined by an 8% threshold) did not provide a benefit beyond that achieved with no interruption. These findings suggest that management of IDELA AEs via treatment interruption and clinically appropriate re-initiation may benefit some patients by improving tolerability and prolonging PFS and OS. Additional analyses evaluating the influence of dose reductions are ongoing. The impact of IDELA treatment interruption on clinical outcomes should be confirmed with prospective clinical studies. Disclosures Ma: Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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. Ye:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead Sciences, Inc.: Employment. Brubaker:Gilead Sciences: Employment, Equity Ownership. Roudet:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

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Treatment Decision Making in AML: Factors of Importance to Clinicians, AML Patients and Their Family

Blood ◽

10.1182/blood-2019-124660 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3498-3498

Author(s):

Thomas W. LeBlanc ◽

Roland B. Walter ◽

Loriana Hernandez-Aldama ◽

Kate Sully ◽

Timothy J Bell ◽

...

Keyword(s):

Quality Of Life ◽

Decision Making ◽

Board Of Directors ◽

Research Funding ◽

Treatment Decision ◽

Employment Equity ◽

Advisory Committees ◽

Trade Offs ◽

Equity Ownership

INTRODUCTION: Acute myeloid leukemia (AML) is a rare hematologic cancer primarily affecting older people, with a median age at diagnosis of 67 years old (Almeida & Ramos, 2016). Heterogeneity in the presentation, functional status and presence of comorbidities among AML patients presents unique challenges for treatment. Intensive chemotherapy (IC), although the best option for prolonging survival, carries a risk of early death and other trade-offs, including significant time spent in the hospital. The toxicity of IC treatment and the requirement for prolonged hospitalizations may negatively affect patients' physical functioning and health-related quality of life (HRQoL). Novel, low-intensity treatments can be administered in the clinic and may pose less risk of immediate toxicities but may be associated with reduced efficacy. Each patient and family will approach these trade-offs differently, yet few studies examine the process of shared decision-making in AML. We aimed to better understand this process by eliciting patient/family and physician narratives about expectations and attitudes towards AML treatments. METHODS: Ten physicians in the US (n=4), UK (n=3) and Canada (n=3) and 12 AML patients (all US) and a member of their family took part in an individual, 60-minute qualitative telephone interview. Further interviews are scheduled and any additional data at the time of presentation will also be reported. The interviews followed a semi-structured guide comprising open-ended questions. The overarching aim of the interviews was to understand the value of living longer for AML patients who are not candidates for standard IC and to explore the treatment decision process from the patient, family and physician perspective. During the interviews, each participant (patient, family member or physician) completed a rating exercise in which they were asked to rate a list of pre-defined factors (9-10 factors) on a scale of 0 (not at all important) to 3 (very important) to determine their importance in AML treatment decisions. As well as providing a numerical rating for each factor, each participant was asked why they selected their rating and which three factors they would consider the most important. RESULTS: Across all three groups, relief in AML symptoms (namely fatigue and pain), longer survival and better QoL were equally considered the three most important factors when making a treatment decision. All three groups described the interaction between QoL and longer survival, explaining that any increase in survival would be important, but only if QoL (time spent with family, maintaining hobbies/interests) was maintained or improved. Physician's advice was also important to AML patients when making decisions regarding treatment. Other treatment-related factors within the rating task were rated as very important for at least a subset of patients, with no factors widely considered to be of limited importance. All participants noted that while relief of AML symptoms, longer survival and quality of life were all important, these had to be considered in light of treatment side effects and risk of infection. Likelihood of being hospitalized was important to family members, as they wanted to spend quality time at home with their loved ones, while patients and physicians considered hospitalization as an inevitable consequence of the disease and treatment. All participants reported that AML patients would consider taking any form of treatment if suitable and effective, regardless of the mode of administration. However, it was acknowledged that oral treatments would be more convenient and less invasive. The relative importance of location of care/treatment delivery was influenced by proximity to resources and whether the participant was based in an urban or rural setting. The ability to receive treatment at home was considered beneficial. CONCLUSIONS: The results from this rating exercise and qualitative interviews showed convergence across all stakeholders, indicating that AML patients, family and physicians have similar priorities regarding treatment decisions, prioritizing symptom relief, survival, and quality of life. The predominant treatment pathways in AML each require trade-offs in these factors, demonstrating the importance of shared decision making in ensuring the most appropriate treatment is selected for a given individual, in accordance with their values, goals, and preferences. Figure Disclosures LeBlanc: Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Heron: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Flatiron: Consultancy; NINR/NIH: Research Funding; Duke University: Research Funding; Astra Zeneca: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Celgene: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareVive: Consultancy. Walter:Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy. Hernandez-Aldama:Pfizer Inc: Consultancy. Sully:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Johnson:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Peloquin:Pfizer Inc: Employment, Equity Ownership. Gater:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Welch:Pfizer Inc: Employment, Equity Ownership. O'Hara:Adelphi Values Ltd: Employment; Pfizer Inc: Consultancy. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Horikoshi:Pfizer Inc: Consultancy. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Variation in Health-Related Quality of Life by Age Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.2085.2085 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2085-2085

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Lymphocytic Leukemia ◽

Age Group ◽

Employment Equity ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Equity Ownership

Abstract Abstract 2085 Introduction. Although advanced patient age is commonly used as a factor in selecting therapy for patients with chronic lymphocytic leukemia (CLL), based on presumed associations with functional status, limited data exist regarding the relationships between age and physical, emotional, social, and functional well being. We examined the relationships between age and these domains of health-related quality of life (HRQOL) for CLL patients treated in US community practices. Methods. Baseline data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by patients in the clinic at enrollment. Patients completed 3 psychometrically validated instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BFI, EQ-5D and FACT-Leu scores were analyzed by age group (<65, 65–74, >74). Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Baseline HRQOL data were reported by 604 patients, enrolled from 161 centers. Patients were predominantly male (62%) and white (90%) with mean age at 69.9 (standard deviation [SD] 11.2) yrs. HRQOL scores by age group are presented: There were no significant differences between the age groups in fatigue as measured by the BFI, or differences in overall HRQOL as measured by the EQ-5D Visual Analogue Scale (VAS) or the FACT-G. Anxiety/depression and self care are EQ-5D domains that also did not vary by age. Although mobility was most impaired in the oldest age group compared to the two younger groups, usual activities and pain/discomfort were worse in both the younger and older cohorts compared to those 65–74 years of age. FACT-Leu results indicated that the social/family domain scores did not vary by age, but that physical, emotional, and functional domains did vary statistically with the oldest typically doing better than the 65–74 year olds, but not necessarily better than those <65. Conclusions. Initial results from the Connect CLL® Registry indicate that HRQOL does not worsen monotonically with older age. In this cohort, both the youngest and oldest age groups had worse HRQOL in certain domains, presenting an inverted v-shaped relationship. Future analyses should be conducted on: (1) how HRQOL may be affected over time with changes in disease; and, (2) how HRQOL may be influenced by alternative therapies. Results reported here should serve as a useful baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

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

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Patient-Reported Outcomes (PRO) Data from Patients (Pts) with Essential Thrombocythemia (ET) Enrolled in the MOST Study

Blood ◽

10.1182/blood-2019-124527 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1665-1665

Author(s):

Ellen K. Ritchie ◽

Anas Al-Janadi ◽

Philomena Colucci ◽

Patricia Kalafut ◽

Dilan Paranagama ◽

...

Keyword(s):

Quality Of Life ◽

Global Health ◽

Research Funding ◽

Symptom Burden ◽

Advisory Board ◽

Employment Equity ◽

Scale Scores ◽

Equity Ownership ◽

Eortc Qlq

Introduction: ET is a chronic myeloproliferative neoplasm (MPN) characterized by thrombocytosis and an increased risk for thrombotic and hemorrhagic events. ET can be associated with substantial symptom burden, impaired quality of life (QoL), and reduced survival. PRO data pertaining to the impact of ET on QoL and symptom burden in these pts are limited. The ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) was designed to collect data about the demographics, disease burden, PROs, and management of pts with ET or myelofibrosis (MF) in clinical practices throughout the United States. This analysis describes PROs from pts with ET enrolled in MOST. Methods: MOST is a longitudinal, multicenter, noninterventional, prospective, observational study (NCT02953704). Eligible adults with ET were ≥60 years of age, had a history of thrombotic events, or were receiving ET-directed therapy. PROs were collected in conjunction with usual-care visits approximately every 6 months over a planned observation period of 36 months. Patient-reported symptom burden was assessed with the disease-specific MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), composed of 10 items (fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, night sweats, itching, bone pain, fever [>100oF], weight loss). The MPN-SAF numbness/tingling item was also included in the questionnaire but was not included in the TSS calculation. Symptom severity was graded from 0 (absent) to 10 (worst imaginable), with a possible TSS ranging from 0 to 100. Health-related QoL was evaluated with the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30 v3.0), composed of 5 functional scales, 3 symptom scales, 6 additional single-symptom items, and a global health/QoL scale. For functional and global health/QoL scales, higher scores indicate higher functioning and better global health/QoL, respectively. For symptom scales/items, higher scores indicate greater symptom burden. High-risk pts and low-risk pts receiving ET-directed therapy (excluding aspirin only) with baseline PRO data were included in this analysis. Data were summarized with descriptive statistics. Results: The MOST study enrolled 1234 pts with ET between Nov 29, 2016 and March 29, 2019 at 124 sites. Of these pts, 794 qualified for this analysis (data cut-off date, June 17, 2019); median age was 70 (range, 19-93) years, 80% were ≥60 years of age, 68% were women, 90% were white, 42% were working full or part-time, and 4% had a documented family history of MF, ET, or polycythemia vera. The majority of pts (87%) had high-risk ET. At enrollment, 768 pts completed the MPN-SAF. Mean (SD) TSS was 17.1 (15.6); 33% of pts had TSS ≥20. Women had higher mean (SD) TSS than men (18.5 [15.8] vs 14.2 [14.9]) and had higher mean individual symptom scores, except for weight loss and fever. The highest mean (SD) individual symptom scores were fatigue (3.4 [2.7]), numbness/tingling (2.3 [3.0]), inactivity (2.3 [2.8]), and early satiety (2.3 [2.7]) (Fig A). The most frequently reported severe symptoms (ie, score ≥7) were fatigue (17% [127/746]), numbness/tingling (14% [107/767]), and inactivity (11% [86/762]). At enrollment, 794 pts completed the EORTC QLQ-C30. The highest mean (SD) symptom scale scores (score ≥15) were fatigue (29.6 [25.8]), insomnia (28.6 [30.6]), pain (22.1 [27.9]), dyspnea (17.2 [25.5]), and constipation (15.7 [25.2]) (Fig B). The mean (SD) global health status/QoL score was 72.7 (21.9); functional scores ranged from 79.9 (21.9) for emotional functioning to 85.2 (24.1) for social functioning (Fig C). The average functional scale scores and symptom scale scores indicate higher functioning and less symptom burden, respectively, in men vs women. Conclusion: Pts with ET experienced a high symptom burden; fatigue was the most common and highest in severity. Symptom burden and quality of life scores in the current study were similar to prior reports (Emanuel J Clin Oncol 2012; Scherber Blood 2011). Women reported higher symptom burden than men in both the MPN-SAF and EORTC QLQ-30. Of note, numbness/tingling, which is not included in the MPN-SAF TSS calculation, was one of the most frequently reported severe symptoms for pts with ET in MOST. Future analyses from this trial will continue to increase understanding of the symptom burden and its impact on QoL in pts with ET. Disclosures Ritchie: Celgene, Incyte, Novartis, Pfizer: Consultancy; Genentech: Other: Advisory board; Tolero: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau. Al-Janadi:Incyte: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech/Abbvie: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Genentech/Roche: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sandoz-Novartis: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; MEI Pharma: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Colucci:Incyte: Employment, Equity Ownership. Kalafut:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Mesa:Genotech: Research Funding; Promedior: Research Funding; Sierra Onc: Consultancy; Celgene: Research Funding; AbbVie: Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; CTI Biopharma: Research Funding; Samus: Research Funding; Incyte: Research Funding.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Sensitivity of Ibrutinib Exposed Chronic Lymphocytic Leukemia B-Cells to Inhibition of Axl Receptor Tyrosine Kinase

Blood ◽

10.1182/blood.v128.22.2020.2020 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2020-2020

Author(s):

Sutapa Sinha ◽

Justin C Boysen ◽

Kari G. Chaffee ◽

Brian F Kabat ◽

Susan L. Slager ◽

...

Keyword(s):

B Cells ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Axl Receptor Tyrosine Kinase ◽

Equity Ownership

Abstract Introduction: The use of B-cell receptor (BCR) signal inhibitors-based therapies (e.g., Ibrutinib) for B-chronic lymphocytic leukemia (CLL) was initiated just a few years ago but has rapidly escalated due to their clinical efficacy and relative ease of use. However newer therapeutic approaches are needed due to multiple issues including the continued need to improve complete responses and reduce toxicity profiles. To that end our group has discovered a novel membrane target in the ubiquitous presence of Axl receptor tyrosine kinase (Axl RTK) on CLL B-cells and has reported that the Axl RTK inhibitor TP-0903 is able to induce apoptosis of CLL B-cells at nanomolar doses (Sinha, Clin Cancer Res, 2015). Given this we assessed if TP-0903 would be effective in the induction of apoptosis of leukemic B-cells from CLL patients who are currently on Ibrutinib therapy or whom have relapsed while on Ibrutinib treatment. Methods: Relapsed/refractory CLL patients (n=22) who were placed on Ibrutinib for progressive disease provided blood samples at a median of 3.2 months after Ibrutinib therapy initiation for these studies. We also obtained sequential samples on 8 patients from initial start of ibrutinib therapy and then over a 6 month follow-up period. CLL B-cells from these blood samples were subject to Ficoll separation, purified by using a Rosette Sep B-cell enrichment kit and then studied by flow cytometry to determine Axl RTK expression levels by flow cytometric analysis. Purified CLL B-cells (CD19+/CD5+) were cultured with TP-0903 in vitroat increasing doses (0.01µM - 0.50µM) for 24 hours and the LD50 dose was determined. In addition, 3 CLL patients who had been on Ibrutinib therapy and had a documented relapse were studied in similar fashion using TP-0903. LD50-sensitivity was measured. "LD50-sensitivity" was defined as an LD50 ≤0.50µM and "insensitive" was defined as an LD50 dose >0.50µM. CLL prognostic factors (e.g., FISH, IGHV mutation status, Rai stage, CD38, and CD49d) were evaluated at the time of ibrutinib treatment. Differences in factors between sensitive and insensitive cases were computed using the Kruskal-Wallis test for continuous variables and Chi-square test for categorical variables. Results: Twenty-two CLL patients (5 female, 17 male) were included in the analysis. Fourteen (64%) patients were found to be TP-0903 LD50-sensitive. Axl expression on CLL B-cells for this cohort was heterogeneous with a median of CD19+/CD5+ cells positive for Axl at 69.9% (range of 2.7-91.3%). The sensitive subjects tended to be younger with a median age at Ibrutinib treatment initiation of 62 vs 75.5 years (p=0.004). There were no significant differences in gender, FISH, IGHV mutation status, CD38, CD49d, or Rai stage between the sensitive and insensitive LD50 groups. There were no significant differences in relation to median Axl expression on CLL B-cells (sensitive: 72.6%, range: 2.7-91.3%; insensitive: 41.5%, range: 16.5-83.1%; p=0.35). The median number of treatments prior to initiation of ibrutinib did not differ between sensitivity groups (sensitive: 2.53, range: 8-10; insensitive: 43.5, range 12-20; p=0.2833). Association for ZAP70+ CLL B-cells tended to have more apoptosis induction by TP-0903 (sensitive: 84.6% ZAP70+; insensitive: 42.9% ZAP70+; p=0.052). In 8 CLL patients that were studied sequentially while on Ibrutinib continued to express Axl or increased their Axl expression (n=2) over a 3-6 month follow-up period. Three CLL patients who had relapsed on Ibrutinib were sensitive to TP-0903 with LD50 values of ≤0.50µM. Summary: Here we find that CLL B-cells from over 60% of relapsed CLL patients on Ibrutinib therapy were highly sensitive to the high-affinity Axl inhibitor TP-0903 with induction of apoptosis at nanomolar doses (≤0.50µM). The sensitivity of CLL B-cells to TP-0903 appears to be independent of Axl expression levels and of the known CLL prognostic factors but more evident for younger patients and for ZAP70+ expression status. Given this level of activity for apoptosis induction of CLL B-cells by TP-0903 encourages the further testing of this drug in clinical trials for CLL patients. Disclosures Parikh: Pharmacyclics: Honoraria, Research Funding. Shanafelt:Pharmacyclics: Research Funding; Janssen: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Hospira: Research Funding. Warner:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Bearss:Tolero Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Kay:Pharmacyclics: Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-Sys: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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