Post on 28-Mar-2015
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Symptoms and Special Circumstance in MPNs
2014 Florida Patient Symposium Laura C. Michaelis, MD
Medical College of Wisconsin, Milwaukee
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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
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Clone
EMD•Spleen
Dyspoesis• Clotting,
Bleeding
Cytokines• Fevers, fatigue, NS
Catabolic State
• Fatigue, Weight loss
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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
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Heterogeneous Presentations: Symptoms
Fatigu
e
Prurit
is
Night S
weats
Bone
Pain
Fever
s
Weig
ht L
oss
Splenic
Disc
omfo
rt0
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
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SX of Disease
TX
Tox
Sx of Disease
Risks and Benefits
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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
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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
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Treatment options for Pruritis
• Symptom-Oriented– Antihistamines– Paroxetine– Light therapy– Aprepitant
• Disease-Oriented– Cytoreduction: HU or IFN– Jak-Stat Pathway therapy– Aspirin
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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.”
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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
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Spleen-Related Symptoms: N=1433
Prevalence Severity
Abd P
ain
Abd D
iscom
fort
Weig
ht L
oss
0%10%20%30%40%50%60%70%80%
PVETMF
Abd P
ain
Abd D
iscom
fort
Weig
ht L
oss
0
0.5
1
1.5
2
2.5
3
3.5
PVETPMF
Scherber Blood 2011
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COMFORT-1: Symptoms
Verstovsek S et al. NEJM 2012; 366; 799-807
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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
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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
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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
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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?
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PV: What is the optimal hematocrit?
January 2013
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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
365
Which group developed more arterial and venous clots?
Which group experiences more bleeding episode?
Which group develops fibrosis or leukemia more readily?
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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
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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
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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
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Acquired VWD
Normal Blood Vessel
Increase in platelets
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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
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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?
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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
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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
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Gender-based differences
• Differences between the disease incidence in men and women
• Problems specifically faced by women• Contraception• Pregnancy/Fertility
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Cancer: Sex-based differences
Breast
Ovarian
Cervical
Testicular
Prostate
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Cancer: Gender-based differences
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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?
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Sex RatioHematologic diseases
Disease Male:Female Ratio
AML 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
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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
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Clinical Trial Inclusion
Trial 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 2005809 342
(42%)467
(58%)
Ruxolitinib in MF (US Study)NEJM 2012 309 167
(54%)142
(46%)
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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?
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Challenges: Clotting
• 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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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
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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?
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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
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Preconception Counseling
• Multidisciplinary approach• Discussion of teratogenic drugs• Therapeutic options
– Aspirin– LMWH– Cytoreductive therapy
• Delivery and post-partum plan• Breastfeeding information
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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)
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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
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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
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Outcomes:Venous, Arterial
Events like stroke, heart attack, VTE,
bleeding
MPN
Smoking lipids
Exercise
HealthyWeight
DM
HTN control
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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?
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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