Symptoms and Special Circumstance in MPNs

We Practice What We Teach Milwaukee

Symptoms and Special Circumstance in MPNs

2014 Florida Patient Symposium Laura C. Michaelis, MD

Medical College of Wisconsin, Milwaukee


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


Clone

EMD•Spleen

Dyspoesis• Clotting,

Bleeding

Cytokines• Fevers, fatigue, NS

Catabolic State

• Fatigue, Weight loss


Spectrum of Symptoms• 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


Heterogeneous Presentations: Symptoms

Fatigu

e

Pruritis

Night S

weats

Bone P

ain

Fevers

Weig

ht Lo

ss

Splenic

Disc

omfor

t0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Polycythemia Vera N=405

Essential Throm-bocythemia N=304

Primary Myelofibrosis N=456

Mesa, Cancer 2007


SX of Disease

TX

Tox

Sx of Disease

Risks and Benefits


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


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


Treatment options for Pruritis

• Symptom-Oriented– Antihistamines– Paroxetine– Light therapy– Aprepitant

• Disease-Oriented– Cytoreduction: HU or IFN– Jak-Stat Pathway therapy– Aspirin


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.”


Managing MPN Fatigue• 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


Spleen-Related Symptoms: N=1433

Prevalence Severity

Abd P

ain

Abd D

iscom

fort

Weig

ht Lo

ss0%

10%20%30%40%50%60%70%80%

PVETMF

Abd P

ain

Abd D

iscom

fort

Weig

ht Lo

ss0

0.51

1.52

2.53

3.5

PVETPMF

Scherber Blood 2011


COMFORT-1: Symptoms

Verstovsek S et al. NEJM 2012; 366; 799-807


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



Case #3 Jessica

• Erythromelalgia– Neurovascular pain disorder– Can occur secondary to ET– Characterized by severe burning pain and

redness– Can be debilitating

• Treatment– Aspirin, Cytoreduction– Gabapentin








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?


PV: What is the optimal hematocrit?

January 2013


Target Hematocrit

Hct <45%

Hct 45-50%

High Hct Low Hct

All Events 18/1839.8%

5/1822.7%

MF/MDS/AML 3 8

BLEEDING 5 2

365Which group developed more arterial and

venous clots?

Which group experiences more bleeding episode?

Which group develops fibrosis or leukemia more readily?


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


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


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


Acquired VWD

Normal Blood Vessel

Increase in platelets


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


Case #6: Bonnie• Surgery and VTE• Increased risk for

patients with MPN• Likely due to

differences in the – Blood vessels– Platelets– Clotting factors?

• 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?


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








Gender-based differences• Differences between the disease incidence

in men and women• Problems specifically faced by women

• Contraception• Pregnancy/Fertility


Cancer: Sex-based differencesBreast

Ovarian

Cervical

Testicular

Prostate


Cancer: Gender-based differences


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?


Sex RatioHematologic diseases

Disease Male:Female RatioAML 1:1

ALL 1.3:1.0

HD 1.3:1.0

Multiple Myeloma 1.4:1

CLL 2:1

CML 3:2

ET Female Predominance

PV 1.2:1.0

MF 1:1


Sex Ratio: MPN

All MPNs

Essential Throm-bocythemia

25-29 30-50 Over 50 years

Cartwright et al. British Journal of Hematology 2002, 118 1071-1077

More women diagnosed than men

More men diagnosed

than women


Clinical Trial InclusionTrial Total

Patients Male Female

HU in High-Risk ET NEJM 1995 114 37

(32%)77

(68%)

ASA in PVNEJM 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%)


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?


Challenges: Clotting• ET – most common MPN in

fertile women

• Hormonal contraception + ET = hypercoaguable state

• Pregnancy + ET = hypercoaguable state

• Thrombosis -- #1 cause of maternal death


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



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?


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


Preconception Counseling• Multidisciplinary approach• Discussion of teratogenic drugs• Therapeutic options

– Aspirin– LMWH– Cytoreductive therapy

• Delivery and post-partum plan• Breastfeeding information


Pregnancy: Low-Risk 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

Antiplatelet agents reduce risk of VTE in ET patients

Pregnancy is thrombotic

Aspirin is likely safe in pregnancy (APLA pts)


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


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


Outcomes:Venous, Arterial

Events like stroke, heart attack, VTE,

bleeding

MPN

Smoking lipids

Exercise

HealthyWeight

DM

HTN control


Conclusions

• 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?


Thank yous to All the patientsAnn Brazeau

MPN Research Foundation

The Chicago MPN RoundtableJamile ShammoToyosi Odenike

Brady SteinDamiano Rondelli

My mentorsWendy Stock

Richard LarsenPatrick StiffSucha Nand

Mary HorowitzRuben Mesa

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