Transcript Document

Case Study:
A Woman with Post-PV MF
of Long Duration
Ruben A. Mesa, MD, FACP
Chair, Division of Hematology & Medical Oncology
Deputy Director, Mayo Clinic Cancer Center
Professor of Medicine
Co-Presenters
Jeffrey C. Bryan, PharmD, RPh
Clinical Pharmacy Specialist, Leukemia
Division of Pharmacy, University of Texas
MD Anderson Cancer Center
Houston, TX
Otitolola Arterbery, MSN, RN, OCN
Clinical Nurse
MD Anderson Cancer Center
Houston, TX
Case Study: Louise H.
• 1999 - Diagnosed with JAK2V617F mutationpositive polycythemia vera (PV) at 51 years of age
– Low risk disease (ie, young age, no history of
thrombosis)
– Well managed with phlebotomy, low-dose aspirin, and
control of CV risk factors
– Non-palpable spleen
– Fatigue, pruritus were her most troublesome
symptoms
Case Study (cont.): Louise H.
• 2010 (11 years post-diagnosis) – Signs of advancing disease
– Worsening pruritus, night sweats; 12% weight loss in 6 months
– Palpable spleen (5 cm below the costal margin), persistent
abdominal discomfort
– Reduced need for phlebotomy
– Hematology
• Hb: 13.5 g/dL [normal range (female): 12-16 g/dL]
• Platelets: 485 x 109/L [normal range: 150-350 x 109/L]
• WBC: 14.5 x 109/L [normal range: 4.3 – 10.8 x 109/L ]
• Peripheral blasts: 0%
– Bone marrow biopsy – megakaryocyte atypia; grade 3 fibrosis,
• Confirmed post-PV MF
What are the Short- and Long-term
Considerations for MF Disease Course?
Mughal TI et al. Int J Gen Med. 2014;7:89-101.
Case Study (cont.): Louise H.
• Post-PV MF confirmed in 2010
• Prognostic models
– Risk factors for dynamic post-PV MF1
• Hb <10 g/dL [patient, 13.5 g/dL]
• Platelets <100 x 109/L [patient, 485 x 109/L ]
0 risk factors = Low risk
• Leukocytes >30 x 109/L [patient, 14.5 x 109/L ]
– Risk factors for DIPSS2
• Age >65 years [patient, 62 years]
• Hb <10 g/dL (2 points) [patient, 13.5 g/dL]
• WBC >25 x 109/L [patient, 14.5 x 109/L ]
• Peripheral blasts, ≥1% [patient, 0%]
• Constitutional symptoms [patient, Yes]
1. Passamonti F, et al. Blood. 2008;111(7):3383-7; 2. Passamonti F, et al. Blood. 2010;115:1703-8.
1 risk factor = Int-1 risk
Case Study (cont.): Louise H.
• Post-PV MF confirmed in 2010
– Lower-risk
– Treated with a cytoreductive therapy (hydroxurea) to manage
splenomegaly and elevated platelets, WBCs
• 2011 - worsening splenomegaly, constitutional symptoms,
and leukocytosis
– Palpable spleen length 12 cm below costal margin
– Platelet count was 180 x 109/L
– WBC count increased to 28 x 109/L, changing her DIPSS to Int-2
• She started on ruxolitinib, which had just become available
Case Study (cont.): Louise H.
Q: What is the recommended starting dose for
ruxolitinib for this patient with platelet count
180 x 109/L?
A. 25 mg twice daily
B. 20 mg twice daily
C. 15 mg twice daily
D. 5 mg twice daily
Case Study (cont.): Louise H.
Q: What is the recommended starting dose for
ruxolitinib for this patient with platelet count
180 x 109/L?
A. 25 mg twice daily
B. 20 mg twice daily
C. 15 mg twice daily
D. 5 mg twice daily
1 Jakafi
prescribing information, 2014.
Recommended Ruxolitinib Starting Dose1
Case Study (cont.): Louise H.
Ruxolitinib Dose Adjustments
Weeks
0
BL
4
8
12
16
20
24
28
32
-5
% Change
-10
-15
-20
-25
-30
-35
Increased dose to 15 mg BID
Platelet count
Reduced dose to 10 mg BID
Hemoglobin
•
•
•
•
Starting platelet count 180 x 109/L
Starting dose 15 mg BID
Monitor CBC every 2-4 weeks
Week 12 - reduced to 10 mg BID
• Thrombocytopenia (platelets
119 x 109/L)
• Anemia (Hb 11.9 g/dL)
• Week 24- increased to 15 mg BID
(stabilized dose)
-40
• Spleen reduction
• Substantial improvement in constitutional and abdominal symptoms
• Non-hematologic adverse events – headaches, dizziness, urinary tract
infection
Ruxolitinib: Individualized Dosing and
Appropriate Monitoring
• Ruxolitinib treatment requires an individualized dosing strategy
with close monitoring for thrombocytopenia and anemia
• Monitor CBC every 2 to 4 weeks during the first 8 to 12 weeks or
until a stable dose is reached
• Dose titration for thrombocytopenia should follow guidelines in
accordance with US prescribing information
• Anemia can often be managed without going off ruxolitinib
– Dose lowering
– RBC transfusion as needed
– Rarely a cause for permanent treatment discontinuation
Filling Prescriptions for Ruxolitinib
• Available as 5 mg, 10 mg, 15 mg, 20 mg and 25 mg tablets1
• Ruxolitinib is only available through a network of specialty pharmacies2
1. Jakafi prescribing information, 2014. 2. https://www.incytecares.com/how-to-fill-my-prescription.aspxx
Accessed Oct 21, 2014 3. Hobson S, et al. Hosp Pharm 2013;48(2):104–107.
Case Study (cont.): Louise H.
• In the first 24 weeks, Louise had a nice spleen
response (60% reduction in spleen length) and
alleviation of various constitutional symptoms,
including pruritus and fatigue, which were
troublesome.
• Over the next year, she has not seen further
improvement and is worried that it’s no longer
working.
Case Study (cont.): Louise H.
Q. Benefits obtained during the first 24 weeks
of ruxolitinib are generally maintained with
long-term treatment.
A. True
B. False
Case Study (cont.): Louise H.
• In the first 24 weeks, Louise had a nice spleen response (60%
reduction in spleen length) and alleviation of various constitutional
symptoms, including pruritus and fatigue, which were troublesome.
• Over the next year, she has not seen further improvement and is
worried that it’s no longer working.
Q. Benefits obtained during the first 24 weeks of ruxolitinib are
generally maintained with long-term treatment.
A. True
B. False
Mean Percentage Change in Spleen
Volume Over Time (COMFORT-II)
Cervantes F, et al. Blood. 2013;122(25):4047-53.
Duration of Spleen Response
(COMFORT-II)
Cervantes F, et al. Blood. 2013;122(25):4047-53.
Durability of Spleen Volume Reduction in
COMFORT-I
Change from Baseline,
Mean (SEM)
Week
Ruxolitinib
Placebo
24
-31.6 (1.6)
8.2 (1.5)
46
-31.6 (2.1)
NA
72
-34.1 (2.5)
NA
96
-34.9 (3.0)
NA
NA = Not available
Verstovsek S, et al. Haematologica. 2013;98(12):1865–71.
• ≥10% reduction linked to improved
QoL by patients’ global impression
of change
Long-Term Effect of Ruxolitinib on Global
Health Status/Quality of Life in COMFORT-I
EORTC QLQ-C30 Global Health Status/Quality of Life*
Change from Baseline, Mean (SEM)
Week
Ruxolitinib
Placebo
24
12.3 (2.2)
-3.7 (2.1)
46
13.6 (2.2)
NA
72
14.1 (2.5)
NA
96
13.0 (2.4)
NA
*Increase by >10 points indicates clinically meaningful improvement.
Abbreviations: EORTC = European Organization for Research and Treatment of Cancer;
NA = Not available; QLQ = Quality of Life Questionnaire; SEM = standard error of the mean.
Verstovsek S, et al. Haematologica. 2013;98(12):1865–71.
Effect on Survival and Natural Disease History
• Overall survival in the COMFORT trials at 1, 2, and 3 years of
follow-up1
COMFORT-I
COMFORT-II
RUX (n=155) vs PBO (n=154)
RUX (n=146) vs BAT (n=73)
Median follow-up
HR (95% CI)
P value*
Median follow-up
HR (95% CI)
1 year (51 weeks)
0.50 (0.25–0.98)
0.04
1 year (52 weeks)
0.70 (0.20–2.49)
2 years (102 weeks)
0.58 (0.36–0.95)
0.03
2 years (112 weeks)
0.51 (0.27–0.99)
0.041
3 years (149 weeks)2
0.69 (0.46–1.03)
0.067
3 years (151 weeks)3
0.48 (0.28–0.85)
0.009
1. Yacoub A et al. Ruxolitinib: Long-term management of patients with myelofibrosis and future directions in the treatment
of myeloproliferative neoplasms. Curr Hematol Malig Rep . [Epub ahead of print Aug 22, 2014]
2. Verstovsek S et al. Long-Term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from
COMFORT-I. Blood 2013 122:396. {ASH 2013 Oral session].
3. Cervantes F et al. 3-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib
with best available therapy for myelofibrosis. Blood 2013;122 (25):4047-53.
P value*
Ruxolitinib
Mughal TI et al. Int J Gen Med. 2014;7:89-101.
Ruxolitinib
Case Study (cont.): Louise H.
• Over the past 4 months, she’s had worsening
anemia (9-10 g/dL), which is now RBC
transfusion-dependent (every 6-8 weeks)
Q. Is anemia an expected side effect of long-term
JAK inhibitor therapy?
A. Yes, often
B. Sometimes, but not often
C. No
Case Study (cont.): Louise H.
• Over the past 4 months, she’s had worsening
anemia (9-10 g/dL), which is now RBC
transfusion-dependent (every 6-8 weeks)
Q. Is anemia an expected side effect of long-term
JAK inhibitor therapy?
A. Yes, often
B. Sometimes, but not often
C. No
Hemoglobin Levels and Platelet Counts
Over Time (COMFORT-II)
Adverse Events of Special Interest by
6-month Intervals (COMFORT-II)
Case Study (cont.): Louise H.
• Louise turned 66 years of age last month
• Age >65 years is an additional risk factor that
we have not had to deal with over her long
MPN disease course
• Now, in addition to her anemia, advancing age
has increased her DIPSS High-Risk
• She declined HSCT option due to worries
about treatment-related mortality rate
Case Study (cont.): Louise H.
Q. Would you continue her current therapy or try
something else?
A. Continue JAK inhibitor at current dosage (15 mg twice
daily)
B. Increase dose of JAK inhibitor by 5 mg increments as
tolerated
C. Discontinue JAK inhibitor and re-treat with
hydroxyurea
D. Discontinue JAK inhibitor and enroll in a clinical trial
Case Study (cont.): Louise H.
Q. Would you continue her current therapy or try something
else?
A. Continue JAK inhibitor at current dosage (15 mg twice
daily)
B. Increase dose of JAK inhibitor by 5 mg increments as
tolerated
C. Discontinue JAK inhibitor and re-treat with hydroxyurea
D. Discontinue JAK inhibitor and enroll in a clinical trial
• No dosage adjustment is needed based on older age alone
Clinical Benefits of Ruxolitinib by Subgroup
(COMFORT-I)
Percentage change in spleen volume
from baseline to Week 24
Verstovsek et al. Br J Haematol. 2013;161:508-516.
Percentage change in Total Symptom
Score from baseline to Week 24
Forest Plot of OS by Patient Subgroups
Verstovsek et al. Br J Haematol. 2013;161:508-516.
Case Study (cont.): Louise H.
• MPN for 15 years
– PV for 11 years
– Post-PV MF for 3.5 years (first Int-1, now High-risk)
• Increasingly difficult to cope with her disease
and management
Coping with Myelofibrosis
• Living with MF may involve coping with:
– Pain, discomfort, feeling sick
– Frequent blood work, medical appointments
– Regular bone marrow exams
– Uncertainty
– Side effects of long-term treatment
Coping with Myelofibrosis
• Common emotions experienced by MF patients:
–
–
–
–
–
–
–
–
Anxiety
Depression
Anger
Irritability
Grief and loss for their old life (‘loss of normal’)
Helplessness
Frustration
Fear
Coping with Myelofibrosis
• Some ways to ease the challenges and help patients
feel more in control:
– Learn about MF
– Get support
• Enlist the help of family, friends
• Join a support group for people with MF
– Explore ways to cope with the disease
• Activities such as yoga or regular exercise
• Social outings
• Adopt a more flexible work schedule
– Talk to a counselor, therapist, or oncology social worker
– Pharmacologic interventions might be considered
Anti-Depressants & Drug Interactions with
Ruxolitinib
• Drugs that inhibit CYP3A4 activity will increase
plasma concentrations of ruxolitinib
• Some SSRI antidepressants are known CYP3A4
inhibitors:
– Fluoxetine
– Fluvoxamine
– Sertraline
– Paroxetine (weak)
• Consider alternatives that are metabolized via other
pathways
Case Conclusion: Louise H. (cont.)
• Louise’s case illustrates a patient with a long history of PV, and then
post-PV MF.
• She a good early response with JAK inhibitor therapy and was able
to stay on ruxolitinib for >3 years, with sustained spleen response
and symptom/QoL benefit.
• Despite her increasing worries about her disease, she’s decided to
stay on ruxolitinib
• What can we do to help her avoid unnecessary treatment
interruption or discontinuation going forward?
– Frequent monitoring for treatment-related and disease-related effects
– Dose adjustments and/or interventions for cytopenias, as needed
– Help with personalized strategies for coping with MF and its treatment