MPNs 2021

Gaps and Guidelines

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Ruben A. Mesa, MD

Executive Director, Mays Cancer Center

Mays Family Foundation Distinguished University Presidential Chair

mesar@uthscsa.edu

Twitter: @mpdrc

Disclosures

Consulting: Novartis, La Jolla, Samus, Sierra Oncology, Blueprint, Abbvie, BMS, Genentech, Roche

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Research Support: Incyte, Celgene, CTI, Promedior, Genentech, Abbvie, Imago

What is a treatment guideline?

MPNs 2021

• Burden of Having an MPN
• Essential Thrombocythemia
• Polycythemia Vera
• Myelofibrosis
• Complementary Approaches

Assessing MPN Burden

WHO Diagnosis Does Not Tell Whole Story

Evolution of MPN Symptom Assessment Tools

MF, myelofibrosis; MPN, myeloproliferative neoplasm; QOL, quality of life; SAF, symptom assessment tool; TSS, total symptom score.

*Scherber et al. Blood 2011;118:401-408.

†Emanuel et al. J Clin Oncol. 2012;30:4098-4103.

Vascular and Ψ symptoms

9 Items

Constitutional symptoms

5 Items

Spleen symptoms

4 Items

Brief Fatigue Inventory

9 Items

Quality of life�1 Item

MPN-SAF

2011

(27 items)*

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MPN-SAF TSS

2012

(10 items)^†

MPN-SAF Languages

• Albanian
• Czech
• Chinese
• Danish
• Dutch
• English
• French
• German
• Hebrew
• Hungarian
• Italian
• Japanese
• Portuguese
• Romanian
• Swedish
• Spanish
• Urdu

MF-SAF

2009

(19 items)

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MF-SAF 2.0

2011

(7 items)

MPN Symptom Burden�A Diverse, Disabling Constellation of Symptoms

Fatigue

92%

3.2

Incidence

Fevers

20%

0.4

Insomnia

65%

2.8

Sad Mood

62%

2.2

Concentration Difficulties

61%

2.2

Early Satiety

61%

2.3

Inactivity

60%

2.1

Sexual Problems

57%

3.0

Night Sweats

56%

2.3

Dizziness

55%

1.9

Abdominal Discomfort

53%

2.0

Bone Pain

48%

2.0

Headache

48%

1.4

Abdominal Pain

48%

1.4

Cough

46%

1.5

Weight Loss

34%

1.2

MPN Recent Phase 3 Trials�MPN Symptom Assessment

ET, essential thrombocytopenia; MF, myelofibrosis; MPN, myeloproliferative neoplasm; PEG INFa2a, Pegylated interferon alfa-2a; PV, polycythemia vera; SAF, symptom assessment tool.

Symptoms Change During the Natural History of MPNs

Cytoreduction

Symptomatic iron deficiency

Thrombosis

Medication Side Effects

Therapies

Disease Progression

Worsened Baseline Health

Organ Dysfunction

Psychological Comorbidites

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Further Disease Progression

Severe Cytopenias

Transfusions

Therapies

Baseline Health Status

Inflammation

Vascular Events

Inflammation in MPNs �Inflammation Drives Clonal Proliferation

MPN Development

Effect of Inflammation

zz

Suppressed growth WT

Acquisition of the JAK2v617f mutation

Auto-production of inflammatory cytokines

Induce bystander cell production of inflammatory cytokines

TNF-a

TNF-a

TNF-a

TNF-a

Fleischman, et al. Blood 118, 6392-6398 (2011).

Koschmieder et. al. Leukemia 2016

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TGF-B

Production of IL-6, bFGF, LCN2

Inflammatory cells

Production of IL-6, IL-8, IL1B

BM Stromal Cells

Production of TNF-a, VEGF, TGF-b, BMP2, RUNX2, osteoprogerin, collagen type I

CALR mutated cells secrete mutant CALR that acts in a autocrine fashion similar to cytokines

TNF-a

Calretuculin

What do symptoms tell us about MPN Biology?

MPN

Symptoms

Mood Disorders

Anxiety over Uncertainty

Cytokine Driven Symptoms

Spleen/ Inflammation

?

Fatigue

Cancer, vol. 92, no. 6, pp. 1684–1688, 2001.

Cancer, vol. 104, no. 4,pp. 788–793, 2005.

Brain, Behavior, and Immunity, vol. 21,no. 3, pp. 251–258, 2007.

Cancer, vol. 106, no. 4, pp. 751–758, 2006.

[American Journal ofPsychiatry, vol. 158, no. 8, pp. 1252–1257, 2001.

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Abdominal Symptoms

Constitutional Symptoms

Microvascular Symptoms

Treatment Goals

• Avoiding thrombosis and bleeding?
• Improving MPN associated symptoms?
• Increase activity?
• Decreasing splenomegaly?
• Improving anemia?
• Improving low platelets?
• Decreasing progression?
• Preventing progression?
• Live longer?

MPNs 2021

• Burden of Having an MPN
• Essential Thrombocythemia
• Polycythemia Vera
• Myelofibrosis
• Complementary Approaches

Diagnosis

Time

Counts

Symptoms

Progression

Vascular

PV/ET: When Do Problems Occur?

Management of ET 2021

Front Line ET Medical

Management

Treatment Gaps - ET

1. What is the optimal front line therapy for ET?

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• How do we prevent disease progression?

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• What is the role of JAK inhibition?

Hepcidin Agonists

(PTG-300)

HDAC Inhibition

(Givinostat)

MDM2 Inhibitors

Idasanutlin-KRT232

Other?

Pipeline – PV and ET

PV

RoPEG vs ANAG

IMG7289

Other?

ET

MPNs 2021

• Burden of Having an MPN
• Essential Thrombocythemia
• Polycythemia Vera
• Myelofibrosis
• Complementary Approaches

Symptom Burden and Quality of Life in High-Risk ET and PV Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of MPN-RC 111 and 112 Trials

Gina L. Mazza

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on behalf of

Carolyn Mead-Harvey, John Mascarenhas, Abdulraheem Yacoub, Ronald Hoffman, Heidi E. Kosiorek,

Josef T. Prchal, Richard T. Silver, Tiziano Barbui, Amylou C. Dueck, Ruben A. Mesa

Results – Patients

Results – Symptoms

• MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever
• MPN-RC 112 PEG patients had significant worsening of fever
• MPN-RC 112 HU patients had significant worsening of inactivity
• MPN-RC 111 and 112 PEG patients had significant worsening of PEG-related symptoms

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Conclusions

• Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not MPN-RC 112
• Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and quality of life during treatment with PEG or HU
• These results may explain the improvements seen in the more advanced MPN-RC 111 patients compared to MPN-RC 112 patients

MPNs 2021

• Burden of Having an MPN
• Essential Thrombocythemia
• Polycythemia Vera
• Myelofibrosis
• Complementary Approaches

Management of Myelofibrosis 2021

Front Line MF Medical

Management

JAK Inhibitor Landscape 2021

Approved

Seeking Approval

Inactive

Ruxolitinib

1L – MF, 2L PV

Pacritinib

MF (Low PLT)

Fedratinib

MF-1L

NS - 018

MF

Momelotinib

MF

XL-019

BMS-911543

AZD-1480

Approved

Ruxolitinib Combinations

LY-2784544

CTI

PAC203

NCT03165734

NOW Approved

INREBIC

Sierra Oncology

NCT04173494

32 | Strictly Confidential

6/28/2021

+/- Ruxolitinib

Fedratinib | JAK2 (Celgene)

Pacritinib | JAK2/FLT3 (CTI Bio)

Momelotinib | JAK2/1/ACVR1 (Sierra)

Itacitinib | JAK1 (Incyte)

P3

P3

P3

P2

Imetelstat | Telomerase Inhibitor (Geron)

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P2

Cell-cycle Checkpoint

Alisertib | Aurora Kinase Inhibitor (Takeda)

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P1

A selection of novel agents/targets being developed in MPN particularly MF

P1

P1

P1

Navitoclax | BCL2 inhibition (Abbvie)

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P2

Apoptosis/MDM2/BCL

Slide Courtesy of Prof Claire Harrison

Takeaway 1:

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Effective MF Therapies May Prolong Overall Survival

Questions? MF and Survival

1. Is survival benefit across all responders to JAKi?

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• Do all patients who experience clear response for splenomegaly and/or symptoms have improved survival? Mechanism?

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• What might be better surrogates of OS benefit? What thresholds of clinical benefit will predict OS benefit?

Takeaway 2:

What is successful front line therapy for MF?

Comparison for 1L MF Therapy

Verstovsek et. al. NEJM 2012

Pardanani et. al. JAMA Inc 2015

Mesa et. al. JCO 2017

Mesa et. al. Lancet Hematology 2017

Mascarenhas et. al. ASH 2020

COMBO

Questions? Front Line and MF

1. Does OS benefits to medical therapy alter decision for transplant in certain candidates?

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• Would a lower rate of response to spleen or symptoms be a good exchange for expanded additional areas of efficacy?

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• To justify 2 agent front line approach is a broader response needed? Deeper? In certain subsets?

Takeaway 3:

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Second line – Add on to JAKi or Switch Gears All Together?

Comparison for 2L Therapy

Pemmaraju et. al. ASH 2020

Verstovsek et. al. ASH 2020

Harrison et. al. ASH 2019

Verstovsek et. al.

Mascarenhas et. al.

Yacoub et. al. ASH 2020

Mascarenhas et. al. ASH 2020

Talpaz et. al ASH 2020

ADD ON

TO RUX

Treatment Efficacy Observed/ ENDPOINTS

MPNs 2021

• Burden of Having an MPN
• Essential Thrombocythemia
• Polycythemia Vera
• Myelofibrosis
• Complementary Approaches

Non Pharmacological Approaches for �MPN Burden Relief

MPN Burden

Yoga

Phase 2 trials

ASH 2017

Physical Activity

In development

Meditation

Ongoing and Accrued

Nutrition

Scherber ASH 2017

Diet Intervention

In Preparation

ACT Therapy

Ongoing

MPN Patients Completing the Yoga Study

(N=38)

Yoga participation averaged 50.8 min/week.

Patient Satisfaction:

• 68% of participants were either satisfied or very satisfied
• 75% felt that is was helpful for coping

12 Week Online Yoga Course

Significant improvements in total symptom burden (effect size =-0.36, p=0.004)

• Anxiety (ES=-0.67, p=0.002)
• Depression (ES=-0.41, p=0.049)
• Sleep (ES=-0.58, p<0.001)
• Fatigue (ES=-0.33, p=0.04)

Huberty et. al., Blood 2016 128:5478

Huberty et al., BMC CAM 2019 19(1)

Yoga In MPNs

Cytokine analysis: Significant decrease in TNF-a from wk 0 to wk 12 (-1.3±1.5; p=0.005) but no significant differences in CBC or IL-6.

Initial Investigation Efforts

Subsequent Investigation Efforts

PROs analysis: Significant decrease in depression from wk 0 to wk 12 and wk 16 (figure 3 below)

Cognitive/Mindfulness Interventions in MPNs

MyACT Study:

Meditation App Study:

Usual Care Control

Asked to maintain usual routine for 4 weeks

Calm Meditation

10 min/day of meditation using Calm app for 4 weeks

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Outcomes:

• Emotional distress (i.e., anxiety, depression),
• Sleep disturbance
• Fatigue
• Quality of life
• MPN10 Score change

MPN Patients

R

10% Happier Meditation

10 min/day of meditation using 10% Happier app for 4 weeks

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OR

Findings:

• Small/moderate improvements in anxiety, depression, fatigue, sleep disturbance, physical health, and MPN10 TSS in all participants
• Calm users reported greater participation, use, and satisfaction

Huberty et. al., JMIR Form Res 2019

Initial Investigation Efforts

Subsequent Investigation Efforts

Nutrition in MPNs

Calm for Cancer Sleep

Calm for Cancer App Development

STTR grant

Ongoing/Planned Trials in Cancers

Current Enrollment:

• 36 enrolled in Calm app #1 group
• 23 enrolled in Calm app #2 group
• 22 enrolled in podcast control group

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Target Enrollment:

• 100 enrolled in Calm app #1 group
• 100 enrolled in Calm app #2 group
• 100 enrolled in podcast control group

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Recently funded by NIH – 1 year grant to develop and beta-test a cancer-specific version of the Calm meditation app

Phase 1

• Advisory board consisting of 10 cancer patients/survivors and 10 healthcare professionals uses the app for a week and participates in a focus group to give feedback on app

Phase 2

• Calm developers utilize feedback and additional available evidence from the literature to develop cancer-specific prototype of Calm app

Phase 3

• 30 cancer patients/survivors will test the cancer-specific Calm app prototype and provide feedback for further refinement of the app to be tested again in a future RCT

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Calm App #2

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• Use the Calm app for ~10 min/day for 12 weeks
• Listen to a sleep story before bed
• Primary outcome: sleep disturbance

Conclusions�Improving Outcomes

1. Adequately assess the burden on the MPN and develop appropriate therapy and goals

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• If therapy is not beneficial change to alternative therapy or clinical trial

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• JAK inhibitors and interferons do have a benefit for many subsets of MPN patients, yet opportunities exist

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• Multiple additional pathway targeted agents are undergoing parallel testing – primarily in 2^nd line MF and 3^rd line PV or ET

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• Non pharmacological therapies may augment treatment options for MPNs