Module 10: Myelodysplastic Syndromes, - PowerPoint Presentation

1. Module 10: Myelodysplastic Syndromes, Myeloproliferative Neoplasms and Hematologic Disorder-Related Anemia Sarah K Swanson, ANP-BCRami Komrokji, MD

2. Disclosure for Ms SwansonNo relevant conflicts of interest to disclose. 

3. Disclosures for Dr KomrokjiAdvisory CommitteeAgios Pharmaceuticals Inc, Celgene Corporation, Daiichi Sankyo Inc, Geron, Incyte Corporation, Jazz Pharmaceuticals Inc, Novartis, Pfizer IncSpeakers BureauAlexion Pharmaceuticals, Jazz Pharmaceuticals Inc, Novartis

4. Approximately how many patients with the following types of cancer have you interacted with over the past year?Type of cancerMedianBreast cancer40Lung cancer35Colorectal cancer30Myelodysplastic syndromes20Multiple myeloma20Chronic lymphocytic leukemia15Pancreatic cancer10Diffuse large B-cell lymphoma10Prostate cancer10Follicular lymphoma7Melanoma6Type of cancerMedianOvarian cancer6Renal cell carcinoma6Hepatocellular carcinoma5Gastric cancer5Acute myeloid leukemia4Hodgkin lymphoma4Urothelial bladder cancer4Endometrial cancer3Cervical cancer2Mantle cell lymphoma2

5. Day in the Life: Myeloproliferative Neoplasms/MDS91 M, Observation, ETOH use97 M, azacitidine, has a pet duck80 F, azacitidine, continues to cook Sunday dinner for her large family74 F, MDS/CMML, azacitidine, eccentric91 M, azacitidine, anemia76 M, MDS, decitabine, unable to tolerate full dose, has done well for months on 25% dose reduction87 M, MDS, azacitidine, he is in charge! Walks back to treatment room with his own chart, finds his own chair, making this place feel like home and grandpa is visiting! Always sharing recipes and talking about what’s for dinner.

6. Ms Swanson Case66 y/o gentleman who presented with fatigue, dyspnea and exercise intolerance to his primary care providerLooking back, he believes it had all started about a year prior when he had been hiking in the Rocky Mountains at the time, and was having a difficult time with what would have normally been very manageable for himHe was found to have anemia on a blood draw by his PCP

7. He went on to have a bone marrow biopsy which showed low grade MDS with ringed sideroblastsHis Hgb continued to decline dropping into the 6-7 g/dl range and he required weekly blood transfusionsHe also required chelating agents because of his rising ferritin due to his increasing transfusion needsIt was at that time that he was started on darbepoetin alfa with increasing doses but with little response

8. His exercise intolerance began to impact his QoL as did the need to go to the hospital for frequent blood transfusionsThis would have been an ideal patient for luspatercept, an injection that he would receive every 21 days Because of his progressive symptomatic anemia, he eventually started therapy with a hypomethylating agent

9. Myelodysplastic Syndromes and Myeloproliferative NeoplasmsRami Komrokji, MDSenior Member & Professor of Oncologic Sciences Section Head – Leukemia & MDSVice Chair - Malignant Hematology DepartmentH Lee Moffitt Cancer Center & Research InstituteTampa, Florida

10. Case Study 1A 75 year-old man with no prior major medical history sought evaluation for fatigue and dyspnea on exertion over past 2 months.

11. AnemiaAnemia is a sign of disease, not a disease itselfDozens of causes, many commonOrganized approach essentialA specific cause can be found in almost all casesThe most useful inexpensive tests for determining etiology of anemia:peripheral blood smear, reticulocyte countWolanskyj AP, et al. Hematology. In: Ficalora RD, ed. Mayo Clinic Internal Medicine Board Review. 10th ed. 2013;497-511.Inadequate RBC ProductionLoss of RBCsPremature RBC DestructionMarrow FailureNutritionalDeficiencyCauses of AnemiaBleeding(overt or occult)Hemolysis(intrinsic or extrinsic)

12. Case Study 1 No history of recent illness, no history of smoking or ETOH, no new medications.Unremarkable physical examination.B12, folic acid, TSH, liver function, renal function and copper levels normal. Endogenous serum erythropoietin level 67 IU/mBone marrow aspirate and biopsy demonstrated hypercellular bone marrow 70%, erythroid dysplasia and 20% ring sideroblasts, normal karyotype. NGS panel showed SF3B1 mutation.Based on the patient’s test results, what would be the most likely diagnosis?Primary myelofibrosis (PMF)Del 5 q MDSMDS- SLD-RSChronic myelogenous leukemia (CML)The patient developed progressive anemia with Hgb less than 8 g/dL. He was started on an erythroid stimulating agent with an initial response, but later became RBC-TD. After 4 months of lenalidomide therapy there was no reduction in transfusion requirements

13. Key Features of Myelodysplastic Syndromes (MDS)“Preleukemia”Death from infection, bleeding, complications of anemia (50%)Death from other causes (25%) AML (25%)ClinicalcourseDisease featuresPatients>95% of patients have cytopenias, most commonly anemia; less than half have neutropenia or thrombocytopenia at diagnosisMDS Paradox: Bone marrow usually hypercellularCells look abnormal (“dysplastic”), Blasts may be increased~1/2 of patients have abnormal chromosomes on G-banded karyotyping, usually numeric anomalies Median age at diagnosis ~70Prior chemotherapy (alkylators, topoisomerase II inhibitors) in 5%-10%Prior radiation Exposure in <5%2o MDSFenaux P. Semin Hematol. 2004;41(2 suppl 4):6-12.

14. Commonly Employed Treatments for MDS: Risk tailored therapyDecitabine (injectable; FDA approved 2006) †Azacitidine (injectable; FDA approved 2004)†Hematopoietic stem cell transplant.ESAsOral iron chelation (deferasirox is FDA approved for iron overload associated with transfusions and non-transfusion-dependent thalassemia (NTDT); see black box warning about hepatic/renal failure)G-CSF*/GM-CSF*, pegfilgrastim*, TPO receptor agonists*Immunosuppressive therapy (IST)*Lenalidomide (oral; FDA approved 2005)Hypomethylating agents (azacitidine and decitabine)Luspatercept hopefully coming soon 2020 Higher Risk MDSLower risk MDSRIC, reduced intensity conditioning; URD, unrelated donor; TPO, thrombopoietin; ESA, erythropoiesis-stimulating agent, G-CSF, granulocyte-colony stimulating factor, GM-CSF, granulocyte-macrophage-colony stimulating factor *Not FDA approved for MDS; †Oral formulation in development.Steensma DP. Hematol Oncol Clin North Am. 2010;24:423-441. †Garcia-Manero G, et al. J Clin Oncol. 2011;29:2521-2527.

15. Excess Smad2/3 Signaling Suppresses Late-Stage RBC Maturation in MDS TGF-β ligands (e.g. GDF15, GDF11, BMP6, activin A) negatively regulate late erythropoiesisBone marrow microenvironmentLuspatercept releases maturation blockBaso EPoly EOrtho EReticulocyteRBCSCFIL-3EPOBFU-ECFU-EPro-EEPO- responsiveEPO-dependentEPO8–64 cells500 cellsSustained Hb increaseRapid Hb increaseMobilizes cells from precursor pools into bloodEffect relies on continuous formation of late-stage precursors from earlier progenitorsZhou L, et al. Blood. 2008;112:3434-3443.

16. The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) TransfusionsPierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List

17. MEDALIST TrialStudy Design – A Randomized, Double-Blind, Placebo-Controlled, Phase 3 StudyData cutoff: May 8, 2018 Includes last subject randomized + 48 weeks.EPO, erythropoietin; HMA, hypomethylating agent; iMID, immunomodulatory drug; IWG, International Working Group; s.c., subcutaneously; SF3B1, splicing factor 3b subunit 1; WHO, World Health Organization.Patient PopulationMDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 mutation< 5% blasts in bone marrowNo del(5q) MDSIPSS-R Very Low-, Low-, or Intermediate-riskPrior ESA responseRefractory, intolerantESA naive: EPO > 200 U/LAverage RBC transfusion burden ≥ 2 units/8 weeksNo prior treatment with disease-modifying agents (e.g. iMIDs, HMAs)Randomize 2:1Luspatercept 1.0 mg/kg (s.c.) every 21 daysn = 153Placebo (s.c.) every 21 daysn = 76Dose titrated up to a maximum of 1.75 mg/kgDisease & Response Assessment week 24 & every 6 months Treatment discontinued for lack of clinical benefit or disease progression per IWG criteria; no crossover allowedSubjects followed ≥ 3 years post final dose for AML progression, subsequent MDS treatment and overall survival Fenaux P et al. Proc ASH 2018;Abstract 1.

18. MEDALIST TrialPrimary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 WeeksRBC-TI ≥ 8 weeks Luspatercept(n = 153)Placebo(n = 76)Weeks 1–24, n (%)58 (37.9)10 (13.2)95% CI30.2–46.16.5–22.9P valuea< 0.0001a Cochran–Mantel–Haenszel test stratified for average baseline RBC transfusion requirement (≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate).CI, confidence interval.Fenaux P et al. Proc ASH 2018;Abstract 1.

19. MEDALIST TrialSecondary Endpoint: Erythroid Response (HI-E)Luspatercept(n = 153)Placebo(n = 76)Achieved HI-Ea (weeks 1–24), n (%)81 (52.9)9 (11.8)Reduction of ≥ 4 RBC units/8 weeks (baseline transfusion burden ≥ 4 units/8 weeks)52/107 (48.6)8/56 (14.3)Hb increase of ≥ 1.5 g/dL(baseline transfusion burden < 4 units/8 weeks)29/46 (63.0)1/20 (5.0)95% CI44.72–61.055.56–21.29P valueb< 0.0001Achieved HI-Ea (weeks 1–48), n (%)90 (58.8)13 (17.1)Reduction of ≥ 4 RBC units/8 weeks (baseline RBC transfusion burden ≥ 4 units/8 weeks)58/107 (54.2)12/56 (21.4)Hb increase of ≥ 1.5 g/dL(baseline RBC transfusion burden < 4 units/8 weeks)32/46 (69.6)1/20 (5.0)95% CI50.59–66.719.43–27.47P valueb< 0.0001a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria (Cheson et al. 2006) sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran–Mantel–Haenszel test.Fenaux P et al. Proc ASH 2018;Abstract 1.

20. Ms Swanson Case 60 y/o gentleman with a history of HLD and HTNPatient had a long history of essential thrombocytosis initially diagnosed in 1989He was treated with anagrelide on clinical trial, which had been continued after the trial closed

21. He presented to our institution in 2010 to establish careA bone marrow biopsy was recommended at that time which showed he had progressed to myelofibrosisHe never tested positive for the JAK2 mutationContinued on anagrelide with progressively decreasing dose until 2017 when it was discontinued due to worsening anemia

22. In 2017 he retired from a long career as an engineerHe and his wife had plans to travel within the US and abroadHe remained off any therapy from June 2017 until May 2019 aside from supportive care During this time he was noted to have progressive anemia as well as worsening splenomegaly. Spleen was palpable at 14 cm below the LCMAbdominal US FINDINGS:The spleen is enlarged, measuring 21.6 x 8.6 x 21.7 cm (previously 14.4 x 6.6 x 14.6 cm on 11/27/2013). The spleen parenchyma has normal homogeneous echotexture, with no discrete lesion detected. The rest of the imaged left upper quadrant soft tissues are unremarkable.Hemoglobin: 6/20/2017 11.7 (L)7/24/2017 11.4 (L)2/1/2018 10.9 (L)8/2/2018 10.7 (L)2/7/2019 10.8 (L)5/8/2019 10.1 (L)

23. In May of 2019 we recommended he have NexGen sequencing to assess for any pathogenic mutationIt was at this time that he tested positive for the CALR mutationHe also became increasingly symptomatic with bloating, early satiety, night sweats and feeling of “catching” of his spleen with activityAlso noted to have an MPN-SAF score of 9

24. Pre-Therapy Counseling PointsDiscuss the dangers of abruptly stopping the medication, including the abrupt return of symptoms Recommend eligible patients get the shingles vaccine prior to starting because of risk of zoster infectionRecommend patients see a dermatologist for an annual skin exam because of increase risk of skin cancersPlan to see your PCP 8-12 weeks after starting therapy to assess your cholesterol level, ruxolitinib has been associated with increase in cholesterol levelsDiscuss other common side effects including cytopenias, diarrhea, fatigue, headache

25. In May of 2019 he started therapy with ruxolitinib at a dose of 15mg twice dailyAs expected, he had a subsequent decrease in his blood counts: Hemoglobin: 5/8/2019 10.1 (L)6/12/2019 9.6 (L)6/27/2019 9.9 (L)7/11/2019 9.6 (L)8/16/2019 9.3 (L)10/17/2019 10.5 (L)White Blood Cells:5/8/2019 22.75 (H)6/12/2019 16.28 (H)6/27/2019 16.4 (H)7/11/2019 14.8 (H)8/16/2019 11.44 (H)10/17/2019 12.04 (H)Platelet count never decreased below normal level

26. Spleen size decreased on palpation from 14 cm to 8 cm below the LCM.Has not required a dose modification even though he did develop some anemia, his platelet count remained normal. Patient notes an overall improvement in symptoms including bloating, early satiety and spleen size. Also with complete resolution of night sweats.MPN-SAF score decreased to 3.He and his wife travelled to Hawaii last month and he states he was able tofully enjoy his trip.

27. Myelodysplastic Syndromes and Myeloproliferative NeoplasmsRami Komrokji, MDSenior Member & Professor of Oncologic Sciences Section Head – Leukemia & MDSVice Chair - Malignant Hematology DepartmentH Lee Moffitt Cancer Center & Research InstituteTampa, Florida

28. Case Study 2 Patient characteristicsAge, 58 yearsGenerally fit, no major health problemsHealthy lifestyle - low-fat diet, moderate activity level PresentationFatigue, night sweats, generalized bone/joint painAbdominal discomfort that seems to be worseningPhysical examSplenomegaly by palpation (extends 10 cm below the left costal margin)

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31. Overview of Myelofibrosis (MF)1Tefferi A, Vardiman JW. Leukemia. 2008;22:14-22; 2Data on file, Incyte Corporation; 3Verstovsek S. Clin Can Res. 2010;16:1988-1996;4Mesa RA. Blood. 2009;113(22):5394-5400; 5Cervantes F, et al. Blood. 2009;113:2895-2901; 6Tam CS, et al. J Clin Oncol. 2009;27:5587-5593.Myeloproliferative Neoplasms1CMLPrimary MFPost-PV MFPost-ET MFMF, myelofibrosisPV, polycythemia veraET, essential thrombocythemiaCML, chronic myeloid leukemiaMF prevalenceApproximately 16,000 to 18,500 patients in the United States2MF is characterized byBone marrow fibrosis, cytopenias, and constitutional symptoms3Splenomegaly4MF natural historyTime course of disease progression is highly variable but frequently characterized by a period of stable disease followed by a late stage with rapid clinical progression5,6PVETPh positiveBCR-ABLMyelofibrosisPh negative

32. Myelofibrosis: Clinical Manifestations1Constitutional symptomsFatigue, weight loss, cachexia, pruritus, night sweats, bone/joint pain, low-grade fever, coughMarked hepatosplenomegalyEarly satiety, abdominal discomfort, painful splenic infarcts, portal hypertension, cachexiaNonhepatosplenic extramedullary hematopoiesis (rare)Cord compression, ascites, pulmonary hypertension, pulmonary embolism, lymphadenopathy, skin tumorsThrombohemorrhagic complicationsMarked leukocytosis or thrombocytosis; severe anemia, thrombocytopenia, neutropenia; hyperuricemiaIncreased risk of leukemic transformationSplenomegaly21. Barbui T et al. J Clin Oncol. 2011;29:761-770. 2. Image provided courtesy of S. Verstovsek.

33. JAK-STAT Pathway Constitutively Activated in MyelofibrosisJAK-STAT pathway implicated in normal hematopoiesis1An activating mutation in the pseudokinase domain of Janus kinase 2 (JAK2) was identified in approximately 50% of MF patientsDysregulation of JAK-STAT, regardless of JAK mutation status, is a key pathologic feature of MF and other MPNs1,2 1. Vannucchi AM et al. CA Cancer J Clin. 2009;59:171-191. 2. Anand S et al. Blood. 2011;118:1610-1621.

34. PVETMFJAK2 V617FJAK2 Exon12Others (SH2B3) MPL (W515x)CALR mutUnknown (Triple Negative)Klampfl T, et al. NEJM 2013;369(25):2379-90; Nangalia J, et al. NEJM 2013;369(25):2391-405.96%60%60%3%1%3-5%5-8%20-25%20-25%10-15%10-15%Type1/Type1-likeType2/Type2-likePhenotypic Driver Mutations (they activate JAK-STAT pathway) in MPNs

35. Assessment of Prognosis in MF1Dupriez B, et al. Blood. 1996;88:1013-1018. 2Cervantes F, et al. Blood. 2009;113:2895-2901. 3Passamonti F, et al. Blood. 2010;115:1703-1708. 4Gangat N, et al. J Clin Oncol. 2011;29:392-397. 5Vannucchi AM, et al. Blood. 2014;124:405. 6Tefferi A, et al. Blood. 2014;124:406. 7Passamonti F, et al. Leukemia. 2017 May 31; doi:10.1038/leu.2017.169 [Epub ahead of print.]IPSS=International Prognostic Scoring System; DIPSS=Dynamic International Prognostic Scoring System; MIPSS=Molecular International Prognostic Scoring System; GPSS=Genetics-Based Prognostic Scoring System; MYSEC-PM=Myelofibrosis Secondary to PV and ET Prognostic SystemFedratinib

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37. Patient Pre-Ruxolitinib TherapyAfter 2 Months of TherapyIt is good for spleen and symptomsWhat Does Ruxolitinib Do?

38. Ruxolitinib for MF treatmentTrialStudy designpopulationResponse SafetyCOMFORT-IN=309Phase III, randomized, placebo-controlledPatients ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥100×109/L, and splenomegaly.Spleen42%TSS reduction >50%46%Gr 3/4 with ruxolitinib:Anemia 45%Thrombocytopenia 13%COMFORT-IIN=219Phase III, randomized, Ruxolitinib vs BATPatients ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥100×109/L, and splenomegaly.Spleen 32%Gr 3/4 with ruxolitinib:Anemia 42%Thrombocytopenia 8%1. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 2. Harrison C, et al. N Engl J Med. 2012;366:787-98

39. Tips on Using RuxolitinibIndicated for splenomegaly or MF-related symptoms (regardless of a risk of dying)Anemia is NOT contraindication Avoid ‘prophylactic underdosing’ - maintain maximum tolerated dose to achieve larger reductions in splenomegaly early during treatmentDevelopment of anemia DOES NOT affect benefits of JAK2 inhibitorManage anemia as alternative to early dose reductionsAvoid abrupt interruption of ruxolitinib in patients responding wellBe aware of rare possibility of opportunistic infectionsMonitor for skin cancer

40. Fedratinib for MFPardanani A, et al JAMAOncol.2015;1(5):643-651TrialStudy DesignPopulationResponseSafetyJAKARTA-1 N = 289Phase 3, randomized, placebo-controlled, 3-arm study (placebo, fedratinib 400 mg QD, fedratinib 500 mg QD)Patients ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥50×109/L, and splenomegaly.Spleen Fedratinib 400 mg 36% Fedratinib 500 mg 40%TSS reduction >50%Fedratinib 400 mg 36% Fedratinib 500 mg 34%Gr 3/4 with placebo, fedratinib 400 mg, and fedratinib 500 mg:Anemia 25%/43%/60%Thrombocytopenia 9%/17%/27% Diarrhea 0/5%/5%TrialStudy DesignPopulationPrimary OutcomeSafetyJAKARTA-2 (NCT01523171)N = 97Single-arm, open-label, nonrandomized, phase 2, multicenter studyRuxolitinib-resistant/intolerant intermediate/high-risk primary MF, post-ET/PV MFSpleen response55% (95% CI, 44-66) Gr 3/4 AEs: anemia (38%) thrombocytopenia (22%)Discontinued due to AEs 19%Harrison CN et al. Lancet Hematol. 2017;4:e317-24.

41. Case Study 357 year old gentleman noted to have polycythemia on routine blood testing. He has no smoking history, no COPD or sleep apnea, no testosterone use. He had drenching night sweats, 30 LB weight loss over 2 months, and mild splenomegaly on imaging. He had one prior episode of documented TIA. Bone marrow biopsy showed mildly hypercellular bone marrow 50-60% with atypical megakaryocytes, normal karyotype and JAK-2 V617F mutation detected (VAF 46%) and IDH-1 mutation (VAF26%). Based on the patient’s test results, what would be the most likely diagnosis?Primary myelofibrosis (PMF)Polycythemia vera (PV)Essential thrombocythemia (ET)Chronic myelogenous leukemia (CML)

42. Polycythemia Vera (PV)PV is BCR/ABL negative MPNPV is characterized clinically by ErythrocytosisOften with increased white blood cells and plateletsThrombosis (main cause of death)Thrombotic events can be arterial, venous, and microcirculatoryPrevalent, especially at initial presentation (12% to 39% of pts); risk persists after official diagnosis (rate: 2.7% to 4.4% pts/yr)Symptoms May include pruritus, fatigue, shortness of breath, dizziness, and symptoms due to splenomegalyPotential to progress to post-PV MF or AML1. Vardiman JW, et al. Blood. 2009;114:937-951; 2. Vannucchi AM, et al. CA Cancer J Clin. 2009;59:171-191; 3. Stein BL, et al. Ann Hematol. 2014;93:1965-76; 4. Spivak JL. N Engl J Med. 2017;376:2168-81

43. 2016 WHO Criteria for Diagnosis of PVWHO diagnosis of PV requires:Presence of all 3 major criteria, orPresence of the first 2 major criterion together with the minor criterionArber DA, et al. Blood. 2016;127(20):2391-405.Major CriteriaHemoglobin level > 16.5 g/dL in men, > 16.0 g/dL in women OR Hematocrit > 49% in men, > 48% in womenOREvidence of increased red cell mass Bone marrow biopsy showing hypercellularity, trilineage growth (panmyelosis)Presence of JAK2 V617F or JAK2 exon 12 mutationMinor CriterionSubnormal serum erythropoietin (EPO) level

44. Risk factorsAge > 67 years5 pointsAge 57-662 pointsWBC > 15 x109/L1 pointVenous thrombosis1Risk Categories/scoreLR0Int1-2HR≥3Tefferi A, et al. Leukemia (2013) 27, 1874-1881Prediction of Survival in 1545 WHO-based PV27.8 years18.9 years10.9 years1.00.90.80.70.60.50.40.30.20.10.0010203040N=474 N=568 N=503YearsSurvivalN=568Median survival 10.9 yearsHR 10.7; 96% CI 7.7-15.0N=503Median survival 27.8 yearsN=474Median survival 18.9 yearsHR 3.7; 96% CI 2.6-5.2

45. Thrombosis Risk-Adapted Management of PVIndications for cytoreduction in low-risk pts may include:Poor tolerance of phlebotomy – Platelets > 1500 x 109/L (risk of bleeding)Progressive leukocytosis – Severe disease-related symptomsBarbui T, et al. J Clin Oncol. 2011;29:761-770. Tefferi A, et al. Am J Hematol. 2015;90:162-173.CategoryCharacteristicsTreatmentLow riskAge ≤ 60 yrs ANDno history of thrombosisTherapeutic phlebotomy (goal Hct < 45%)Aspirin 81 mg dailyAddress CV modifiable risk factorsHigh riskAge > 60 yrs ORhistory of thrombosisAll the above, ANDCytoreductive therapy First lineHydroxyurea PegIFNSecond line RuxolitinibPegIFN

46. Studies with PegIFNGisslinger et al, ASH 2018, Abstract # 579Mascarenhas JO, et al, ASH 2018. Abstract 577. StudyPopulationFindingsMDACC[3,4]PegIFN α-2aN = 43~ 50% previous cytoreductivesMedian FU: 83 mosMedian response duration: hematologic: 65 mos; molecular: 58 mosFailure to achieve CMR: more likely to have/acquire nondriver mutationsThrombosis and progression can occurToxicity continued over time (new grade 3/4 events in 10% to 17% of PY); d/c for AEs: 22%PROUD-PVPhase III Trial of Ropeginterferon Alfa-2b Vs. HydroxyureaPV patients treatment naïve or HU pretreated but not resistant83 (Ropeg) and 70 (HU/BAT) patients completed the 36-month efficacy analysis time pointAfter 36 months of treatment, maintenance of higher responder rates was shown in the Ropeg arm compared to HU/BAT for CHR (70.5% vs. 51.4%; p=0.0122; RR [95% CI]: 1.38 [1.07-1.79]) and for CHR plus symptom improvement (52.6% vs. 37.8%; p=0.0437; RR [95% CI]: 1.42 [1.01-2.00]). JAK2V617F: after 36 months 66.0% of patients in the Ropeg arm and only 27.0% in the HU/BAT arm had achieved MR (p<0.0001; RR [95% CI]: 2.31 [1.56-3.42]). MR strongly correlated with CHR.Ropeg was able to reduce also non-JAK allele burden including TET2.

47. RESPONSE: Ruxolitinib vs Standard Therapy in Pts With PV and HU Resistance/IntoleranceInternational, multicenter, randomized, open-label phase III studyPts with PV requiring phlebotomy; HU resistance/intolerance; spleen volume ≥ 450 cm3, no JAK inhibitor experience, Hct 40% to 45% before randomization*(N = 222) Primary analysis data cutoff at Wk 48 or treatment discontinuationCrossover at PD or Wk 32 if primary endpoint not metRuxolitinibInitial 10 mg BID; dose titrated to maintain Hct(n = 110)Standard Therapyselected by investigator†(n = 112)Vannucchi AM, et al. N Engl J Med. 2015;372:426-435.All pts received low-dose ASA. *Pts with Hct < 40% or > 50% entered Hct control period prior to randomization. †Excluding 32P, busulfan, and chlorambucil. Stratified by HU status (resistance vs intolerance)Wk 32

48. Symptom Control49.05.0RESPONSE: Key Efficacy Findings at Wk 32Complete hematologic response also significantly improved with ruxolitinib vs standard therapy (23.6% vs 8.9%; P = .003)Vannucchi AM, et al. N Engl J Med. 2015;372:426-435.Pts (%)03040506070Composite Primary Endpoint*1020≥ 35% Reduction in Spleen VolumeHct ControlP < .001Odds ratio: 28.6(95% CI: 4.5-1206)20.90.938.20.960.019.6RuxolitinibStandard therapy*Proportion with Hct control + spleen volume reduction ≥ 35%.

49. SummaryAnemia is major challenge in patients with MDS and remains an unmet need. JAK-2 inhibitors are main choice for treatment of splenomegaly and constitutional symptoms in myelofibrosis. Treatment of polycythemia vera is based on disease risk assessment.

50. Special Issues in Oncology CareSupportive care for patients with myelodysplastic syndromes and other hematologic disorders: Iron overload, prevention of thrombosis, growth factors