Oral Therapies and Adherence in Lymphoma Roundtable Christopher - - PowerPoint PPT Presentation

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”?

Als

Compliance may change over time on trial

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 g/dL; <LLN - 6.2 mmol/L; <LLN - 100 g/L Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9 mmol/L; <100 - 80g/L Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; transfusion indicated Life-threatening consequences; urgent intervention indicated Death 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% reduction from normal cellularity for age Moderately hypocellular or >25 - <50% reduction from normal cellularity for age Severely hypocellular or >50 - <=75% reduction cellularity from normal for age Aplastic persistent for longer than 2 weeks Death 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 10e9 /L <3000 - 2000/mm3; <3.0 - 2.0 x 10e9 /L <2000 - 1000/mm3; <2.0 - 1.0 x 10e9 /L <1000/mm3; <1.0 x 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

• ver baseline; mild increase in
• stomy output compared to

baseline Increase of 4 - 6 stools per day

• ver baseline; moderate

increase in ostomy output compared to baseline Increase of >=7 stools per day

• ver baseline; incontinence;

hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL Life-threatening consequences; urgent intervention indicated Death Definition: A disorder characterized by frequent and watery bowel movements. Dry mouth Symptomatic (e.g., dry or thick Moderate symptoms; oral intake Inability to adequately aliment

• Definition: A disorder characterized by inflammation of the oral mucosal.

Nausea Loss of appetite without alteration in eating habits Oral intake decreased without significant weight loss, dehydration or malnutrition Inadequate oral caloric or fluid intake; tube feeding, TPN, or 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 instrumental ADL Severe pain; limiting self care 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.
• Subjective/Relies on patient perception
• May be intermittent in frequency
• May be variable in severity

Trouble separating grade 1 and 2: Headache

Patient 1

• “Terrible headache: 5 out of

10”

• Needs to stay in bed all day
• Does not want to take any

medications for the headache because he hates taking pills

• Stays home from work

Patient 2

• “Terrible headache: 5 out of

10”

• Felt like staying in bed but

took OTC medications and feels much better

• Goes to 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

Table 2. Multivariable Models for Cumulative Incidence of 2 Failure Types: Disease Progression and Toxicity, Adjusted for Monotherapy

Variable Event Progression Toxicity HR (95% CI)a P Value HR (95% CI)a P Value Age, 10-y increase NA NA 1.87 (1.33-2.64) <.001

• No. of prior treatments, 1 unit increase

NA NA 1.09 (1.00-1.19) .054 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

Maddocks JAMA Onc 2016

q Patient age q Language barrier q Education barrier q Physician and/or nurse accessibility q Culture of reporting

There’s an app for that

Falchook Advances in Radiation Oncology: April-June 2016; De Vries Drug Saf (2017) 40:443–455

Factors influencing use of an app:

• Type of feedback given
• n reported ADR’s
• How ADR reports are

stored

• Security of the app
• Layout
• Operating systems
• Cost

Capturing delayed toxicities requires vigilance

Ibrutinib

• Early events:

– Petecchiae – Rash – Diarrhea (mild)

• Late events:

– Hypertension – Headaches – Atrial fibrillation

Idelalisib

• Early events:

– Diarrhea (mild) – Transaminase elevation – Rash

• Late events:

– Colitis (severe) – Infection

Challenges in capturing toxicity

• Subjectivity
• Communication and documentation
• Unpredictable timing of events

– Need to capture late effects particularly relevant for chronic therapies