Oral Therapies and Adherence in Lymphoma Roundtable Christopher Flowers, MD Winship Cancer Institute of Emory University John P. Leonard, MD Weill Cornell Medicine and New York Presbyterian Sonali Smith, MD The University of Chicago
Adherence and Oral Therapies in Lymphoma and CLL Christopher Flowers, MD Winship Cancer Institute of Emory University LRF Scientific Advisory Board
2016 Projected Incidence Lymphoid Cancers U.S. cancer statistics for lymphoid malignancies by World Health Organization subtypes Teras LR, DeSantis CE, Morton LM, Cerhan JR, Jemal A, Flowers CR
Oral Therapy: Cost Considerations • Patient-administered anti-cancer medication routinely covered under pharmacy benefit/ plans in the United States • Patients responsible for extremely high co-payments • Abandonment of newly-prescribed oral therapy not uncommon • Likelihood of abandonment increases for patients enrolled in health plans with pharmacy benefit designs that require high cost sharing* * Sonya Blesser Streeter, Lee Schwartzberg, Nadia Husain, and Michael Johnsrud, Journal of Oncology Practice 2011 7:3S, 46s-51s
Oral Therapy: Cost Considerations • H.R. 1409 – The Cancer Drug Coverage Act of 2017 • Seeks to address health plan/ benefit design which has not kept pace with advances in cancer care and increasing number of patient- administered/ oral anti-cancer therapies • Requires group and individual health plans that cover anti-cancer medications prescribed by a health care provider to provide no less favorable cost sharing for patient-administered anti-cancer medications • Bill has been endorsed by the Lymphoma Research Foundation
Adherence and Oral Therapies in Lymphoma and CLL John P. Leonard, M.D. Weill Cornell Medicine and New York Presbyterian LRF Scientific Advisory Board
Adherence Issues and Clinical Trials • Definition of “Adherence” • Patient self report, refill history, pill count • What % “compliance” is adequate? • Dose (full vs lower) and schedule (skipping days) • If “non-adherent” • Trial efficacy measures potentially underestimated • Trial toxicity measures potentially underestimated (or over in double dose) • Real world experience may ultimately differ • Are specific patient populations (elderly, less support) more or less likely to be “non-adherent” • Compliance “penalties” for investigators (regulatory implications) • Should reporting be “intent to treat”?
Compliance may change over time on trial Als Alsumidaie, Applied Clinical Trials 2017
How do we best measure and support adherence in clinical trials? • Diaries • Pill counts • Blood or urine levels • Pill boxes (with electronics?) • Reminders/mobile devices
“Smart Pill Bottle” in clinical trials
Monitoring and reporting of toxicity associated with oral antineoplastics Sonali M. Smith, MD Elwood V. Jensen Professor of Medicine Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago Medicine and Biologic Sciences October 5, 2017
Challenges in capturing toxicity • Subjectivity • Communication and documentation • Unpredictable timing of events – Need to capture late effects particularly relevant for chronic therapies
Traditional toxicity assessment: grading of adverse events Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute
Laboratory assessments are well- defined… 2. Blood and lymphatic system disorders Blood and lymphatic system disorders Grade Adverse Event 1 2 3 4 5 Anemia Hemoglobin (Hgb) <LLN - 10.0 Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9 Hgb <8.0 g/dL; <4.9 mmol/L; Life-threatening consequences; Death g/dL; <LLN - 6.2 mmol/L; <LLN - mmol/L; <100 - 80g/L <80 g/L; transfusion indicated urgent intervention indicated 100 g/L Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability. Bone marrow hypocellular Mildly hypocellular or <=25% Moderately hypocellular or >25 - Severely hypocellular or >50 - Aplastic persistent for longer Death reduction from normal cellularity <50% reduction from normal <=75% reduction cellularity from than 2 weeks for age cellularity for age normal for age Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements. Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve. White blood cell decreased <LLN - 3000/mm3; <LLN - 3.0 x <3000 - 2000/mm3; <3.0 - 2.0 x <2000 - 1000/mm3; <2.0 - 1.0 x <1000/mm3; <1.0 x 10e9 /L - 10e9 /L 10e9 /L 10e9 /L Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
…physical symptoms are more complex Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous. Diarrhea Increase of <4 stools per day Increase of 4 - 6 stools per day Increase of >=7 stools per day Life-threatening consequences; Death over baseline; mild increase in over baseline; moderate over baseline; incontinence; urgent intervention indicated ostomy output compared to increase in ostomy output hospitalization indicated; severe baseline compared to baseline increase in ostomy output compared to baseline; limiting self care ADL Definition: A disorder characterized by frequent and watery bowel movements. Definition: A disorder characterized by inflammation of the oral mucosal. Dry mouth Symptomatic (e.g., dry or thick Moderate symptoms; oral intake Inability to adequately aliment - - Nausea Loss of appetite without Oral intake decreased without Inadequate oral caloric or fluid - - alteration in eating habits significant weight loss, intake; tube feeding, TPN, or dehydration or malnutrition hospitalization indicated Definition: A disorder characterized by a queasy sensation and/or the urge to vomit. Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve). Headache Mild pain Moderate pain; limiting Severe pain; limiting self care - - instrumental ADL ADL Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve. o Subjective/Relies on patient perception o May be intermittent in frequency o May be variable in severity
Trouble separating grade 1 and 2: Headache Patient 2 Patient 1 • “Terrible headache: 5 out of • “Terrible headache: 5 out of 10” 10” • Needs to stay in bed all day • Felt like staying in bed but took OTC medications and • Does not want to take any feels much better medications for the headache because he hates • Goes to work taking pills • Stays home from work GRADE 2 GRADE 1
ESMO 2017: Clinical Trial Toxicity Reporting by Investigators May Not Reflect Patients’ Viewpoint Methods : • Comparison of HRQoL by patient assessment (EORTC QLQ-C30) versus toxicity reporting (CTCAE) by physicians in a phase III adjuvant breast cancer trial • Evaluated 13 toxicities and 36 EORTC QLQ-C30 items Results : • Strong and moderate agreement for diarrhea, vomiting and fatigue • Weak or no agreement for the other 10 items Brandberg Y, Karolinska Institute in Stockholm, ESMO 2017, Madrid, Spain; www.esmo.org (accessed October 2017)
Likelihood of patients speaking up q Patient age Table 2. Multivariable Models for Cumulative Incidence of 2 Failure Types: Disease Progression and Toxicity, Adjusted for Monotherapy q Language barrier Event Progression Toxicity q Education barrier HR (95% CI) a HR (95% CI) a Variable P Value P Value Age, 10-y increase NA NA 1.87 (1.33-2.64) <.001 q Physician and/or No. of prior treatments, 1 unit increase NA NA 1.09 (1.00-1.19) .054 nurse accessibility BCL6 abnormality, yes vs no 2.70 (1.25-5.85) .01 NA NA Complex karyotype, yes vs no 4.47 (1.50-13.34) .007 NA NA q Culture of reporting Maddocks JAMA Onc 2016
There’s an app for that Factors influencing use of an app: • Type of feedback given on reported ADR’s • How ADR reports are stored • Security of the app • Layout • Operating systems • Cost Falchook Advances in Radiation Oncology: April-June 2016; De Vries Drug Saf (2017) 40:443–455
Capturing delayed toxicities requires vigilance Ibrutinib Idelalisib • Early events: • Early events: – Petecchiae – Diarrhea (mild) – Rash – Transaminase elevation – Diarrhea (mild) – Rash • Late events: • Late events: – Hypertension – Colitis (severe) – Headaches – Infection – Atrial fibrillation
Challenges in capturing toxicity • Subjectivity • Communication and documentation • Unpredictable timing of events – Need to capture late effects particularly relevant for chronic therapies
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