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 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

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

Risks and Benefits TX Sx of Disease SX of Disease Tox

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 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

Spleen-Related Symptoms: N=1433 Prevalence Severity 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 Treatment Neurovascular pain disorder Can occur secondary to ET Characterized by severe burning pain and redness Can be debilitating Treatment Aspirin, Cytoreduction Gabapentin

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

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 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%

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 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

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

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

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

Cancer: Sex-based differences Breast 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 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

More women diagnosed than men More men diagnosed than women Cartwright et al. British Journal of Hematology 2002, 118 1071-1077

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%)

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 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

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

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 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)

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

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

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?

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