1. Symptoms and Special Circumstance in MPNs
2014 Florida Patient Symposium
Laura C. Michaelis, MD
Medical College of Wisconsin, Milwaukee

2. Spectrum of Symptoms
“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

3. Clone
EMD
Spleen
Dyspoesis
Clotting, Bleeding
Cytokines
Fevers, fatigue, NS
Catabolic State
Fatigue, Weight loss

4. Spectrum of Symptoms Day-to-Day Life-Threatening Medication Associated
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

5. Heterogeneous Presentations: Symptoms
20% will be asymptomatic at diagnosis
Otherwise
Present with Sx/Symptoms of anemia
Symptoms related to splenomegaly
Internet based survey of
Fatigue
Mesa, Cancer 2007

6. Risks and Benefits TX
Sx of Disease
SX of
Disease
Tox

7. Case #1: Denise 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

8. Aquagenic pruritus 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

9. Treatment options for Pruritis
Symptom-Oriented
Antihistamines
Paroxetine
Light therapy
Aprepitant
Disease-Oriented
Cytoreduction: HU or IFN
Jak-Stat Pathway therapy
Aspirin

10. Case #2: Carla 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 “I’m so tired at night – especially after eating.”

11. Managing MPN Fatigue Symptom-Oriented Disease Treatment
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

12. Spleen-Related Symptoms: N=1433
Prevalence
Severity
Scherber Blood 2011

13. COMFORT-1: Symptoms
Verstovsek S et al. NEJM 2012; 366;

14. Case #3: Jessica 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

16. Case #3 Jessica Erythromelalgia Treatment Neurovascular pain disorder
Can occur secondary to ET
Characterized by severe burning pain and redness
Can be debilitating
Treatment
Aspirin, Cytoreduction
Gabapentin

17. Spectrum of Symptoms Day-to-Day Life-Threatening Medication Associated
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

18. Case #4: Gerald
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 low-dose aspirin. He asks – how many treatments will I need and what’s our goal?

19. PV: What is the optimal hematocrit?
January 2013

20. Target Hematocrit 365 High Hct Low Hct All Events 18/183 9.8% 5/182
2.7%
MF/MDS/AML 3 8
BLEEDING 5 2
Which group developed more arterial and venous clots?
Which group experiences more bleeding episode?
Which group develops fibrosis or leukemia more readily?
365
Hct 45-50%

21. Case #4: Gerald 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

22. Case #5: Kyle 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

23. Bleeding vs. Clotting 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

24. Acquired VWD
Normal Blood Vessel
Increase in platelets

25. Case #5: Kyle 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

26. Case #6: Bonnie Surgery and VTE Increased risk for patients with MPN
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?
Italians looked at 255 patients with ET PV who underwent surgeries. They found high rates of post op complications including clotting in the arterial circulation – like MI, stroke and also in the venous circulation – like PE and DVT. There was also a relatively high rate of major bleeding.
One has to remember that the blood system is deranged and that there are differences in the way that the blood will clot and the way vessels will respond to the stress of surgical intervention

27. Modifying Surgical Risk
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

28. Spectrum of Symptoms Day-to-Day Life-Threatening Medication Associated
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

29. Gender-based differences
Differences between the disease incidence in men and women
Problems specifically faced by women
Contraception
Pregnancy/Fertility

30. Cancer: Sex-based differences
Breast
Ovarian
Cervical
Testicular
Prostate

31. Cancer: Gender-based differences

32. Gender and Cancer
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?

33. Sex Ratio Hematologic diseases
Male:Female Ratio
AML
1:1
ALL
1.3:1.0 HD
Multiple Myeloma
1.4:1
CLL
2:1
CML
3:2 ET
Female Predominance PV
1.2:1.0 MF

34. More women diagnosed than men
More men diagnosed than women
Cartwright et al.
British Journal of Hematology 2002,

35. Clinical Trial Inclusion
Total Patients
Male
Female
HU in High-Risk ET
NEJM 1995
114
37 (32%)
77 (68%)
ASA in PV
NEJM 2004
518
308 (59%)
210 (41%)
HU vs Anagrilide in high-risk ET
NEJM 2005
809
342 (42%)
467 (58%)
Ruxolitinib in MF (US Study)
NEJM 2012
309
167 (54%)
142 (46%)

36. Case #7: Jennifer
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: did the birth control or ET cause the blood clot? Can she take birth control again? Can she try and get pregnant?

37. Challenges: Clotting ET – most common MPN in fertile women
Hormonal contraception + ET = hypercoaguable state
Pregnancy + ET = hypercoaguable state
Thrombosis -- #1 cause of maternal death
Most studies report the overall risk of VTE as
similar in women compared with men, but there
are specific trends related to sex. In a multi-center,
cross-sectional, observational study performed on
more than 1,500 general surgical patients in Italy,
more women than men had risk factors for VTE,
most commonly varicose veins, obesity and estrogen
therapy. 1
Eighty percent of women and 67% of men
had at least one risk factor, and 51% of women and
35% of men had at least two risk factors. Simon and
colleagues in a recent retrospective case–control
study reported that lifetime estrogen exposure may
be related to the overall risk of VTE. 2
After statistical adjustment for other common risk factors for
VTE, it was found that the risk of VTE increased
by 6% for each year’s delay in menopause. Moreover, women with higher parity, especially those
with more than two children, were at higher risk.
The combination of late menopause and oral estrogen use had the highest risk of VTE. Other studies
have confirmed an association of late menopause
and increased parity with risk of VTE.
3,4

38. Challenges: Fertility
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
General Recommendation is not to use OCPs in these individuals.
Solution – non-hormonal birth control

40. Challenges: Pregnancy
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?

41. Preconception Counseling
Risk Assessment
Prior VTE or arterial clot
Prior hemorrhage
Prior pregnancy complication
Diabetes or Hypertension requiring treatment
Platelet count of >1500 X 109 before or during pregnancy

42. Preconception Counseling
Multidisciplinary approach
Discussion of teratogenic drugs
Therapeutic options
Aspirin
LMWH
Cytoreductive therapy
Delivery and post-partum plan
Breastfeeding information

43. Pregnancy: Low-Risk Patients
Antiplatelet agents  reduce risk of VTE in ET patients
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
Pregnancy is thrombotic
Aspirin is likely safe in pregnancy (APLA pts)

44. Pregnancy: High-risk patients
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

45. Summary and Conclusions
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

46. Venous, Arterial Events like stroke, heart attack, VTE, bleeding
Outcomes:
Venous, Arterial Events like stroke, heart attack, VTE, bleeding
Exercise
HTN control
MPN
Smoking
lipids DM
Healthy
Weight

47. Conclusions Get involved in your care Ask questions
Partner with your physician
Educate other physicians, care-providers
Ask questions
Participate in clinical trials
Control what you can
Any questions?

48. MPN Research Foundation The Chicago MPN Roundtable Jamile Shammo
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