case study: a woman with post-pv mf of long duration ruben a. mesa, md, facp chair, division of...

Case Study:A Woman with Post-PV MF

of Long Duration

Ruben A. Mesa, MD, FACPChair, Division of Hematology & Medical Oncology

Deputy Director, Mayo Clinic Cancer CenterProfessor of Medicine

Co-Presenters

Jeffrey C. Bryan, PharmD, RPhClinical Pharmacy Specialist, Leukemia

Division of Pharmacy, University of TexasMD Anderson Cancer Center

Houston, TX

Otitolola Arterbery, MSN, RN, OCNClinical Nurse

MD Anderson Cancer CenterHouston, TX

Case Study: Louise H.

• 1999 - Diagnosed with JAK2V617F mutation-positive 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.


• 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 ]

• 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.

0 risk factors = Low risk

1 risk factor = Int-1 risk


• 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


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


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

Recommended Ruxolitinib Starting Dose1

1 Jakafi prescribing information, 2014.

BL 4 8 12 16 20 24 28 32

-40

-35

-30

-25

-20

-15

-10

-5

0

Platelet countHemoglobin

Case Study (cont.): Louise H. Ruxolitinib Dose Adjustments

• 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)

Weeks

Reduced dose to 10 mg BID

• Spleen reduction• Substantial improvement in constitutional and abdominal symptoms• Non-hematologic adverse events – headaches, dizziness, urinary tract

infection

% C

hang

e Increased dose to 15 mg BID

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

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.

• Available as 5 mg, 10 mg, 15 mg, 20 mg and 25 mg tablets1 • Ruxolitinib is only available through a network of specialty pharmacies2

Filling Prescriptions for Ruxolitinib


• 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

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

Verstovsek S, et al. Haematologica. 2013;98(12):1865–71.

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

• ≥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

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

Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; NA = Not available; QLQ = Quality of Life Questionnaire; SEM = standard error of the mean.

EORTC QLQ-C30 Global Health Status/Quality of Life*

*Increase by >10 points indicates clinically meaningful improvement.

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

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.

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) P value*

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

Mughal TI et al. Int J Gen Med. 2014;7:89-101.

Ruxolitinib Ruxolitinib


• 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)


• 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


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


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)

Verstovsek et al. Br J Haematol. 2013;161:508-516.

Percentage change in spleen volume from baseline to Week 24

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.

• 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


• Common emotions experienced by MF patients: – Anxiety

– Depression

– Anger

– Irritability

– Grief and loss for their old life (‘loss of normal’)

– Helplessness

– Frustration

– Fear


• 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

case study: a woman with post-pv mf of long duration ruben a. mesa, md, facp chair, division of...

Documents