2014 Florida Patient Symposium
Laura C. Michaelis, MD
Medical College of Wisconsin, Milwaukee
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– “clinical conditions with high relevance for the duration and quality of the patient’s life, but with limited evidence to support sound diagnostic and therapeutic recommendations…”
– Tiziano Barbui. 2010
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EMD
• Spleen
Catabolic
State
• Fatigue,
Weight loss
Clone
Cytokines
• Fevers, fatigue,
NS
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Dyspoesis
• Clotting,
Bleeding
Milwaukee

• Day-to-Day
– Fatigue, Itching, Night sweats, Bone Pain,
Fevers, Bleeding, Erythromelagia
• Life-Threatening
– Arterial and Venous Clots, Bleeding
• Medication Associated
– Side Effects, Anxieties, Financial
• Special Circumstances
– Surgery, Contraception and Pregnancy
We Practice What We Teach Milwaukee

0,5
0,4
0,3
0,2
0,1
0
0,9
0,8
0,7
0,6
Polycythemia Vera
N=405
Essential
Thrombocythemia N=304
Primary Myelofibrosis
N=456
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Mesa, Cancer 2007
Milwaukee

Sx of
Disease
SX of
Disease
Tox
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TX
Milwaukee

• 46 yo woman with newly diagnosed PV
– History of a blood clot in the left leg following her last pregnancy, 8 years ago
– She has had 5 phlebotomies since diagnosis and her
CBC demonstrates good control of her blood counts
– She has been allergic to aspirin since childhood
• She tells you: I’m still having a lot of itching after showering
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• Often occurs with PV
– Stinging, itching – often after contact with water
– Majority of patients experience it
• Recent German study demonstrated 68% of
PV patients reported about pruritus
• Can be relentless and may not always respond to treatment for the disease
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• Symptom-Oriented
– Antihistamines
– Paroxetine
– Light therapy
– Aprepitant
• Disease-Oriented
– Cytoreduction: HU or IFN
– Jak-Stat Pathway therapy
– Aspirin
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• 64 yo woman with ET
– Diagnosed after a stroke at the age of 55
– Blood numbers are under good control
– Taking HU to control platelet count
• But
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• Symptom-Oriented
– Exercise (low-intensity as good as high intensity)
– Healthy Lifestyle and Diet
– Correction of Iron Deficiency When Possible
– Stimulants: Ritalin/Provigil/ Nuvigil
• Disease Treatment
– JAK2 Inhibitors
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Prevalence
80%
70%
60%
50%
40%
30%
20%
10%
0%
PV
ET
MF
Severity
3,5
3
2,5
2
1,5
1
0,5
0
PV
ET
PMF
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Scherber Blood 2011
Milwaukee

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• 42 yo mother
• Essential
Thrombocythemia
• Diagnosed on routine blood testing at GYN office
• No risk factors
• WBC 12.3; Hgn 13;
Plts 560
• 1.5 years after diagnosis, reports
“foot pain.”
• Occurs when walking or standing on her feet
• Burning, painful, reddish
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We Practice What We Teach Milwaukee

• Erythromelalgia
– Neurovascular pain disorder
– Can occur secondary to ET
– Characterized by severe burning pain and redness
– Can be debilitating
• Treatment
– Aspirin, Cytoreduction
– Gabapentin
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• Day-to-Day
– Fatigue, Itching, Night sweats, Bone Pain,
Fevers, Bleeding, Erythromelagia
• Life-Threatening
– Arterial and Venous Clots, Bleeding
• Medication Associated
– Side Effects, Anxieties, Financial
• Special Circumstances
– Surgery, Contraception and Pregnancy
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• Gerald S.
– 56 yo man with newly diagnosed
Polycythemia Vera
• Hgn 19.3 gm/dL
• Hct 58%
• WBC 12.4 k/uL
• Plts 338 k/uL
– I recommend phlebotomy and starting a lowdose aspirin. He asks – how many treatments will I need and what’s our goal?
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January 2013
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365
Hct <45%
BLEEDING
High Hct Low Hct
18/183
9.8%
5/182
2.7%
3 8
5 2
Hct 45-50%
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• So – answers?
– Phlebotomy goal should be a hematocrit of less than 45%
– In women, generally aim for even lower than that, 42-43%
• Frequency varies – but as often as needed
• Sometimes medication also needed, but you have to give phlebotomy a chance
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• 57 yo man with Essential
Thrombocythemia
– Incidentally discovered two years ago
– No symptoms, no history of blood clots
– Platelet count of 1,380 k/uL
– Now with found to occult + stools
– Colonscopy normal, but stomach ulcers noted on endoscopy
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• Not as common as clotting problems
• Often manifest with
– Nosebleeds
– Gum bleeding
– Menorrhagia
– Less likely to be deep tissue bleeding
• Rarely can be life threatening
• Risk increases with
Platelets>1,000,000/uL
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Normal Blood Vessel
Increase in platelets
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• What can we do about his nose bleeds?
– Normalization of platelet count
– Medication vigilance  combos in particular
• Anagrilide + Aspirin
• Plavix or Aspirin + heparin products
– Predictable bleeding
• i.e. interventions to prevent menorrhagia
– Special care in individuals with gastric ulcers or esophageal varices
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• 67 years old with PV
• TIA in her late 50s
• Treatment: HU and aspirin
• Recently diagnosed with small left-sided breast cancer, has opted for mastectomy
• What are my surgical risks?
• Surgery and VTE
• Increased risk for patients with MPN
• Likely due to differences in the
– Blood vessels
– Platelets
– Clotting factors?
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Planning
--Assessment by hematologist
--Optimize blood counts
--Especially platelets if splenectomy planned
Preoperative
--Discontinue ASA
Postoperative
--Anticoagulation – LMWH
--Clinical vigilance re hemorrhage
--US of abdominal veins
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• Day-to-Day
– Fatigue, Itching, Night sweats, Bone Pain,
Fevers, Bleeding, Erythromelagia
• Life-Threatening
– Arterial and Venous Clots, Bleeding
• Medication Associated
– Side Effects, Anxieties, Financial
• Special Circumstances
– Surgery, Contraception and Pregnancy
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• Differences between the disease incidence in men and women
• Problems specifically faced by women
• Contraception
• Pregnancy/Fertility
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Breast
Ovarian
Cervical
Testicular
Prostate
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We Practice What We Teach Milwaukee

• Does the disease occur more frequently in one sex vs. the other?
– Diagnostic bias?
– Due to exposure?
– Due to genetic predisposition?
• Does the disease behave differently in one sex vs the other?
– Modulated hormones? Gender-based lifestyle differences?
– Interactions that we don’t understand?
• Are there different consequences to the disease or treatment that depend on gender?
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Disease
AML
ALL
HD
Multiple Myeloma
CLL
CML
ET
PV
MF
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Male:Female Ratio
1:1
1.3:1.0
1.3:1.0
1.4:1
2:1
3:2
Female Predominance
1.2:1.0
1:1
Milwaukee

25-29 30-50 Over 50 years
Sex Ratio: MPN
More women diagnosed than men
All MPNs
Essential
Thrombocythemia
More men diagnosed than women
Cartwright et al.
British Journal of Hematology 2002, 118 1071-1077
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Trial
Total
Patients
HU in High-Risk ET
NEJM 1995
ASA in PV
NEJM 2004
HU vs Anagrilide in high-risk
ET
NEJM 2005
Ruxolitinib in MF (US Study)
NEJM 2012
114
518
809
309
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Male Female
37
(32%)
308
(59%)
342
(42%)
167
(54%)
77
(68%)
210
(41%)
467
(58%)
142
(46%)
Milwaukee

• 37 yo woman with a history of thrombosis in her right calf while on birth control
• Found to have JAK2 mutation and a slightly elevated platelet count
• She asks you:
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• ET – most common MPN in fertile women
• Hormonal contraception +
ET = hypercoaguable state
• Pregnancy + ET = hypercoaguable state
• Thrombosis -- #1 cause of maternal death
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• Contraception
– Combination hormones
>progesterone only OCPs
– General population have a 3–6-fold increased risk of venous thrombosis with OCPs
• One retrospective study of >300 patients. Subset on OCPs
– ET + OCPs = 23% VTE
– ET no OCPs = 7% VTE
We Practice What We Teach Milwaukee

We Practice What We Teach Milwaukee

• Pregnancy outcomes likely impacted
– Live birth rate 50-70%
– First trimester loss 10-20%
– Late pregnancy loss 10%
– Increased rates of placental abruption, intrauterine growth restriction
• Can we change those outcomes?
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• Risk Assessment
– Prior VTE or arterial clot
– Prior hemorrhage
– Prior pregnancy complication
– Diabetes or Hypertension requiring treatment
– Platelet count of >1500 X 10 9 before or during pregnancy
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• Multidisciplinary approach
• Discussion of teratogenic drugs
• Therapeutic options
– Aspirin
– LMWH
– Cytoreductive therapy
• Delivery and post-partum plan
• Breastfeeding information
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Antiplatelet agents  reduce risk of VTE in ET patients
Pregnancy is thrombotic
Aspirin is likely safe in pregnancy (APLA pts)
• Generally
– Continue low-dose aspirin
– Monitor platelet or Hct
• Keep HCT under 45%
• Consider venesection if necessary
– Increased plasma volume of pregnancy means no set targets
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• Remove possible teratogeneic drugs
– Taper off hydrea or anagrilide 3-6 months prior to conception
– Hydrea likely contraindicated, men and women
– Anagrilide crosses the placenta
• Cytoreduction
– Interferon-alpha -- Case reports indicating likely safe
• Prevent Clotting
– LMWH
– Prophylactic or, in some cases, therapeutic doses
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• Some symptoms can be addressed with a palliative approach
• Some require that the disease be treated
• Target Hgn, PV
• Preventing Bleeding
• Undergoing Surgery
• Gender-specific issues: Contraception, Fertility and Pregnancy
• Modifying risk – lifelong effort for all patients
– Cholesterol, Blood pressure, SMOKING
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Outcomes:
Venous, Arterial
Events like stroke, heart attack, VTE, bleeding
Exercise
HTN control
MPN
Smoking lipids DM
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Healthy
Weight
Milwaukee

• Get involved in your care
– Partner with your physician
– Educate other physicians, care-providers
• Ask questions
• Participate in clinical trials
• Control what you can
• Any questions?
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Thank yous to
All the patients
Ann Brazeau
MPN Research Foundation
The Chicago MPN
Roundtable
Jamile Shammo
Toyosi Odenike
Brady Stein
Damiano Rondelli
My mentors
Wendy Stock
Richard Larsen
Patrick Stiff
Sucha Nand
Mary Horowitz
Ruben Mesa
We Practice What We Teach Milwaukee