New Perspectives on Polycythemia Vera: Overcoming Challenges in Diagnosis, Risk Assessment, and Disease Management
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1 New Perspectives on Polycythemia Vera: Overcoming Challenges in Diagnosis, Risk Assessment, and Disease Management Jorge E. Cortes, MD The University of Texas MD Anderson Cancer Center Houston, Texas Francesco Passamonti, MD University Hospital of Varese Varese, Italy Rebecca B. Klisovic, MD The Ohio State University Columbus, Ohio Srdan Verstovsek, MD, PhD The University of Texas MD Anderson Cancer Center Houston, Texas
2 Faculty Disclosures Jorge E. Cortes, MD, has a financial interest/relationship or affiliation in the form of: Consultant for: Incyte Corporation; Novartis Corporation; and sanofi-aventis. Grant/Research Support from: Incyte Corporation; Novartis Corporation; and sanofi-aventis. Rebecca B. Klisovic, MD, has no financial interests/relationships or affiliations in relation to this activity. This CME/CNE activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education; the activity is also co-provided by the Institute for Advancement of Human Behavior. This activity is supported by an educational grant from Incyte Corporation. This activity is a Friday Satellite Symposium on New Perspectives on Polycythemia Vera: Overcoming Challenges in Diagnosis, Risk Assessment, and Disease Management, preceding the 56th ASH Annual Meeting.
3 Faculty Disclosures Francesco Passamonti, MD, has no financial interests/relationships or affiliations in relation to this activity. Srdan Verstovsek, MD, PhD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from: AstraZeneca; Bristol-Myers Squibb Company; Celgene Corporation; Cell Therapeutics, Inc.; Geron; Gilead; Hoffmann-La Roche Inc.; Incyte Corporation; Infinity Pharmaceuticals, Inc.; Lilly Oncology; NS Pharma Inc.; Novartis Pharmaceuticals Corporation; Promedior, Inc.; Seattle Genetics, Inc.; and YM BioSciences Inc. This CME/CNE activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education; the activity is also co-provided by the Institute for Advancement of Human Behavior. This activity is supported by an educational grant from Incyte Corporation. This activity is a Friday Satellite Symposium on New Perspectives on Polycythemia Vera: Overcoming Challenges in Diagnosis, Risk Assessment, and Disease Management, preceding the 56th ASH Annual Meeting.
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5 Before We Begin A Brief Poll on Polycythemia Vera Test your expertise in recognizing the signs and symptoms of this disease and in managing the patient with PV
6 PV at a Glance 1-4 Polycythemia vera Characterized by Abnormal myeloproliferation in PV Chronic myeloproliferative neoplasm (MPN) Overproduction of morphologically normal RBCs, WBCs, and platelets in the absence of a definable stimulus Is sustained by constitutively active JAK-STAT signal transduction pathway, caused by the JAK2 V617F mutation within exon 14 (in ~95% of PV cases) 1. Kralovics R et al. N Engl J Med. 2005;352: James C et al. Nature. 2005;434: Levine RL et al. Cancer Cell. 2005;7: Baxter EJ et al. Lancet. 2005;365:
7 PV in the MPN Continuum 1 1. Harrison C. Hematology. 2010;2010:
8 Unmet Needs and Ongoing Questions in PV New evidence on diagnostic principles and prognostic assessment what does it mean for practice? Although outcomes are generally good, we need to more adequately address uncontrolled PV symptoms and progression Can we overcome the limitations of current therapy in newly diagnosed patients? And what about treatment-refractory PV?
9 Tonight s Discussion Case Discussions PV diagnosis and prognostic assessment Managing patients with low- vs high-risk disease Clinical challenges in treatment-refractory PV Questions From the Chair Quizzing our expert panel on PV Audience Q&A and Conclusion
10 Case Discussions in PV: Recognizing and Diagnosing PV Rebecca B. Klisovic, MD The Ohio State University Columbus, Ohio
11 Case: An Older Man With Hypertension and Diabetes Patient and Presentation A 72-year-old man presents with history of hypertension, diabetes mellitus New diagnosis of gout by primary care doctor Other Features Complains of excessive sweating, dizziness, pruritus Mild splenomegaly noted on examination
12 Case: An Older Man With Hypertension and Diabetes (Cont d) CBC Ordered WBC Hg 14,000/mcL 18.9 g/dl PLT 510,000/mcL
13 Case: Additional Tests Confirm a Diagnosis of PV Mutational analysis shows the presence of JAK2 exon 12 mutation Serum EPO: 1.1 IU/L Diagnosis of PV confirmed
14 Review of the Classic MPNs 1,2 BCR-ABL1+ Chronic myeloid leukemia (CML) MPN Primary myelofibrosis (PMF) BCR-ABL1 Polycythemia vera (PV) Essential thrombocythemia (ET) Myelofibrosis (MF) comprises PMF, post-pv MF, and post-et MF Chronic, unregulated proliferation may occur in one or more myeloid cell lines, involving erythrocytes, platelets, and granulocytes 1. Tefferi A et al. Leukemia. 2008;22: Thiele J, Kvasnicka HM. Curr Hematol Malig Rep. 2009;4:33-40.
15 Types of Polycythemia: Differential Diagnosis 1 Primary PV Secondary Hypoxia Pulmonary disease, high altitude Inappropriate production of erythropoietin Hemangioblastomas, uterine leiomyomas, renal cell carcinoma, pheochromocytoma Relative or apparent polycythemia Dehydration 1. Bueso-Ramos CE, Vardiman JW. In: Verstovsek S, Tefferi A, eds. Myeloproliferative Neoplasms: Biology and Therapy. New York, NY: Humana Press, Springer Science+Business Media, LLC; 2011:1-37.
16 Epidemiology of PV 1,2 Incidence approximately 2/100,000 population-year Highest in men aged y (24/100,000 per y) Male:female incidence ratio, 2.8:1.3 Median OS Untreated: approximately 18 mo 3 Treated: approximately y 4 In SEER data: approximately 5.4 y 5 SEER: Surveillance, Epidemiology, and End Results. 1. Anía BJ et al. Am J Hematol. 1994;47: Berk PD et al. In: Wasserman LR et al, eds. Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, PA: WB Saunders; 1995: Chievitz E, Thiede T. Acta Med Scand. 1962;172: Tefferi A et al. Leukemia. 2013;27: Price GL et al. PLoS ONE. 2014;9:e90299.
17 Classic Signs and Symptoms of PV Erythrocytosis Thrombocytosis Leukocytosis Thrombosis (arterial, venous) Hemorrhage Hyperuricemia Splenomegaly Plethora Conjunctival injection Pruritus Migraines Erythromelalgia Paresthesias Diaphoresis Gout Gastric distress Dizziness Visual disturbance
18 Relative Local Distribution of AP in PV 1 AP: aquagenic pruritus. 1. Siegel FP et al. Am J Hematol. 2013;88:
19 Splenomegaly in PV CT scan of the abdomen showing massive splenomegaly (white arrows) with (A) the spleen extending to the pelvis and crossing the midline and (B) a mass effect of the stomach and the left kidney (red arrow) Cunningham SC, Napolitano LM. Am J Surg. 2004;188:94-95.
20 PV in the MPN Context: Clinical Presentation and Evolution 1 1. Kildajian JJ et al. Hematology Am Soc Hematol Educ Program. 2012;2012:
21 Laboratory Findings in PV Erythrocytosis Leukocytosis Thrombocytosis Microcytosis Depressed erythropoietin Iron deficiency Elevated B12 Elevated leukocyte alkaline phosphatase (LAP)
22 Red Scalp Sign: Erythrocytosis 1 Possible sign of underlying erythrocytosis related to PV 1. Marinella MA. Mayo Clin Proc. 2003;78:
23 Molecular Findings in PV Molecular Feature Comments JAK2 V617F mutation, exon 14 >95% of patients 1 JAK2 exon 12 mutations 4% of patients 2 PRV-1 mrna Overexpressed 3 Chromosomal abnormalities 2 +8, +9, del(13q), del(20q), del(5q) <20% of PV patients Del(5q) associated with poor prognosis 4 Calreticulin mutations may be associated with JAK2-negative PV 5 1. Rege-Cambrin G et al. Cancer Genet Cytogenet. 1987;25: Passamonti F et al. Blood. 2012;120: Spivak JL. Blood. 2002;100: Tefferi A. Am J Hematol. 2008;83: Broseus J et al. Blood Oct 10. [Epub ahead of print]
24 Overview of the JAK2 Gene 1 JAK2 V617F Exon 14 mutation 95%-97% PV patients 1. Vainchenker et al. Semin Cell Dev Biol. 2008;19:
25 Common Mutations in the MPN Setting 1-4 All mutations have a common outcome: JAK-STAT dysregulation 1. Levine R et al. Nat Rev Cancer. 2007;7: Oh ST et al. Therap Adv Hem. 2011;2: Delhommeau F et al. Int J Hematol. 2010;91: Vannucchi AM et al. Haematologica. 2008;93:
26 Dysregulated JAK2 Signaling: A Prevalent Mechanism in PV 1 JAK-STAT pathway dysregulation present in all MPN patients Regardless of presence or absence of JAK2 V617F or any other known mutations Involves over-activation of both normal (wild-type) and mutated JAK2 1. Levine RL et al. Curr Top Microbiol Immunol. 2012;355:
27 JAK2 Allele Burden, Clinical Phenotype, and Disease Symptoms 1 1. Passamonti F et al. Haematologica. 2009;94:7-10.
28 Clinical Profile of Homozygous JAK2-V617F in PV 1 25%-30% of PV patients are homozygous JAK2-V617F (>50% allele burden) Factors Associated With Homozygous JAK2 V617F Older age Leukocytosis Higher HCT Splenomegaly Aquagenic pruritus Increased risk of progression to MF Increased need for cytoreductive therapy Not associated with increased risk of cardiovascular events 1. Vannucchi AM et al. Blood. 2007;110:840.
29 Overlap in Molecular Features With PV and Other MPNs 1 1. Kildajian JJ et al. Hematology Am Soc Hematol Educ Program. 2012;
30 PV Study Group Diagnostic Criteria 1 Major Criteria Minor Criteria 1. Increased red cell mass: males 36 ml/kg, females 32 ml/kg 2. No secondary cause of polycythemia Thrombocytosis (>400,000/mcL) Leukocytosis (>12,000/mcL) 3. Splenomegaly Marrow panmyelosis 4. Clonal defect (other than BCR-ABL) 5. Endogenous erythroid colony formation in vitro Low serum erythropoietin level For PV Diagnosis Major Criteria 1 + 2; 1 Other Major or Major Criteria 1 + 2; Two Minor Criteria 1. Campbell PJ, Green AR. Hematology Am Soc Hematol Educ Program. 2005;
31 Diagnosing PV: WHO Criteria (2008) 1 Major Criteria Minor Criteria 1. Hg >18.5 g/dl in men and >16.5 g/dl in women, or other evidence of increased red cell volume Bone marrow biopsy showing hypercellularity (for age) with trilineage myeloproliferation 2. Presence of JAK2 V617F mutation or other functionally similar mutation, such as JAK2 exon 12 mutation For PV Diagnosis Both Major and One Minor Criteria or Major Criteria 1 + Any Two Minor Criteria Serum erythropoietin level below reference range of normal Endogenous erythroid colony formation in vivo 1. Vardiman JW et al. Blood. 2009;114:
32 Diagnosing PV: A Potential Algorithm 1 1. Tefferi A. Am J Hematol. 2013;88:
33 Bone Marrow Features in PV 1 Absence of stainable iron Hypercellularity Increased atypical megakaryocytes Variable levels of reticulin fibrosis Hypercellular bone marrow with increased numbers of erythroblasts and pleomorphic megakaryocytes Megakaryocytes show hyperlobated nuclei and are arranged in loose clusters 1. Bittencourt RI et al. Rev Bras Hematol Hemoter. 2012;3:
34 Criteria for Post-PV (or Post-ET) MF 1-4 Major/Required Criteria WHO-based diagnosis of PV Bone marrow fibrosis grade 2 Minor/Additional Criteria (Must Have 2) Anemia or no need of phlebotomy or therapy Leukoerythroblastosis Increasing splenomegaly Development of constitutional symptoms 1. Barosi G et al. Leukemia. 2008;22: Swerdlow SH et al, eds. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. Lyon, France: IARC Press; Thiele J et al. Haematologica. 2005;90: Manoharan A et al. Br J Haematol. 1979;43:
35 RCM Criterion vs Hemoglobin Criterion in Male MPN Patients 1 a Patient met by ml/kg. 1. Silver RT et al. Blood. 2013;122:
36 Masked PV 1 1. Barbui T et al. Am J Hematol. 2014;89:52-54.
37 Cytokines in PV 1 Cytokine Correlation With Phenotype Cytokine IL-12 IL-1b, IL-2, IL-7, FGF-b, and HGF IFN-α and IFN-γ Phenotype HCT Leukocytosis Thrombocytosis Cytokine MIP-1β IL-1β, IL-5, IL-6, IL-10, IL-12, IL- 15, IL-17, and IP-10 Cytokine Prognostication in PV Outcome Reduced OS Fibrotic transformation 1. Vaidya R et al. Am J Hematol. 2012;87:1003.
38 The Clinical Burden of PV: Survival 1 Survival of 1,625 patients with PV compared with controls (SEER) 1. Price GL et al. PloS ONE. 2014:9:e90299.
39 1.. Berk PD et al. In: Wasserman LR et al, eds. Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia, PA: WB Saunders; 1995: Tefferi A et al. Leukemia. 2013;27: Causes of Early Death in PV 1 Cause Berk PD et al 1 Tefferi A et al 2 Thrombosis, % 29 9 Leukemia/MDS, % Solid malignancy, % Hemorrhage, % 7 1 Myelofibrosis, % 3 3
40 Thrombosis: A Major Cause of Mortality in PV 1 Data from large prospective multicenter project in PV (ECLAP trial) 164 of 1,638 patients deceased at time of analysis 1. Marchioli R et al. J Clin Oncol. 2005;23:
41 Risk Factors for Complications 1 Overall risk assessment is based on age and history of thrombosis Complication CV event Myelofibrosis (10-y risk: 10% 2 ) Leukemia (10-y risk is 6% 2 ) Age >60 y Risk Factors History of thrombosis (arterial or venous) Long disease duration Age >60 Cytoreductive therapy other than hydroxyurea 1. Marchioli R et al. J Clin Oncol. 2005;23: Tefferi A et al. Am J Hematology. 2008;83:
42 Proposed Risk Model for Survival in PV 1 Risk Factor Points Age 67 y 5 Age y 2 Leukocytes 15 x 10 9 /L 1 VTE 1 1. Tefferi A et al. Leukemia. 2013;27:
43 Prognostic Relevance of Leukocytosis in PV 1 Mayo Clinic study of 459 patients with PV Survival curves risk-stratified by 2 factors: 1) Age 60 y and 2) Leukocytes 15X10 9 /L Inferior survival associated with Advanced age (P <.0001) Leukocytosis (P =.0006) Arterial thrombosis at diagnosis (P =.01) Leukocytosis independent predictor of LT and VTE in follow-up Low risk: absence of both factors Intermediate risk: 1 adverse factor High risk: both factors 1. Gangat N et al. Br J Haematol. 2007;138:
44 Conclusions PV is the most common MPN Associated with near universal presence of the JAK2 V617F mutation Major clinical features include erythrocytosis, thrombocytosis, pruritus, splenomegaly, and increased risk of thrombosis WHO diagnostic criteria are valid for diagnosis, although revisions are under discussion CV events remain the major cause of reduced survival
45 Case Discussions in PV: Making Treatment Decisions in Low- and High-Risk PV Francesco Passamonti, MD University Hospital of Varese Varese, Italy
46 Case 1: A Woman With Recently Diagnosed PV and Low-Risk Features Patient and Presentation 52-year-old woman Recent diagnosis of PV according to the WHO criteria Other Features No history of thrombosis Low JAK2 V617F allele burden Normal WBC and PLT counts No bone marrow fibrosis Patient is low risk based on age, lack of prior thrombosis, and other findings
47 Case 1: Is It Necessary to Ask About Symptom Burden? 1,a a P <.001. b N = 1, Scherber R et al. Blood. 2011;118:
48 Survival of PV Compared With Healthy Populations 1 Survival of 396 patients with PV compared with life expectancy of the general population 1. Passamonti F et al. Am J Med. 2004;117:
49 Mortality in PV 1 Data from large prospective multicenter project in PV (ECLAP trial) 164 of 1,638 patients deceased at time of analysis 1. Marchioli R et al. J Clin Oncol. 2005;23:
50 Risks Associated With PV Short term Thrombosis Bleeding Long term Post ET/PV MF MPN blast phase Goals of treatment: reduce thrombosis rate and delay disease transformation
51 Management of Low-Risk Patients 1 Phlebotomy To maintain HCT <45% Aspirin, if not contraindicated For primary anti-plt prophylaxis Aggressive control of CV risk factors Obesity, smoking, hypertension, diabetes 1. Barbui T et al. J Clin Oncol. 2011;29:
52 Why Phlebotomy? Low Risk of Thrombosis 1 1. Marchioli R et al. J Clin Oncol. 2005;23:
53 Why Phlebotomy? To Be Conservative 1 1. Kiladjian J-J et al. J Clin Oncol. 2011;29: FPSG trial on hydroxyurea vs pipobroman 283 PV patients treated with hydroxyurea alone (94 for 12 y) and pipobroman alone (130 for 9.5 y) Estimate in a competing risk setting Results AML: less in hydroxyurea group OS: longer in hydroxyurea group Switching chemotherapy did not lead to increase in AML
54 Why Maintain Hematocrit <45%? To Prevent CV Events With Cytoreductive Therapy 1 CYTO-PV Trial Eligible Patients WHO 2008 diagnosis All comers: newly diagnosed and previously treated 1:1 R Standard arm (A) HCT <45% a Experimental arm (B) HCT 45%-50% a a Median follow-up: 31 mo (range: ). CYTO-PV: Cytoreductive Therapy in PV. 1. Marchioli R et al. N Engl J Med. 2013;368: Primary endpoint: time until death from CV causes or thrombotic events
55 Risk of Total Cardiovascular Events per HCT 1 1. Marchioli R et al. N Engl J Med. 2013;368:22-33.
56 Risk of the Primary Endpoint in Prespecified Subgroups 1 1. Marchioli R et al. N Engl J Med. 2013;368:22-33.
57 Why Aspirin in PV? To Reduce Risk of CV Events 1 The ECLAP trial studied 518 PV patients randomized to low-dose aspirin (100 mg/d) or placebo Demonstrated a significant advantage for aspirin in terms of non-fatal MI, non-fatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40) Higher risk of any bleeding also noted (relative risk, 1.82), although this did not reach statistical significance 1. Landolfi R et al. N Engl J Med. 2004;350:
58 Case 1: Revisited 52-year-old woman with low-risk PV Started phlebotomy and baby aspirin on a regular basis Two years later she developed leukocytosis: WBC: 16 x10 9 /L
59 Is it Time to Change Therapy? 1,2 Leukocyte count >15 x10 9 /L at diagnosis is associated with a higher risk of myocardial infarction (vs leukocyte counts <10 x10 9 /L) Leukocyte count >15 x10 9 /L at diagnosis is associated with a higher risk of death Risk Factors Score (points) Age >67 y 5 Age WBC >15 x10 9 /L 1 Venous thrombosis 1 0: Low risk 1-2: Int risk 3: High risk 1. Landolfi R et al. N Engl J Med. 2004;350: Tefferi A et al. Leukemia. 2013;27:
60 Case 1: 15 Years Later At the age of 67, she was diagnosed with post-pv myelofibrosis based on progressive increase in spleen size (to 10 cm below LCM) and symptomatology Patient initiated treatment with ruxolitinib
61 Criteria for Diagnosis of Post-PV MF 1 Major/Required Criteria WHO-based diagnosis of PV Bone marrow fibrosis grade 2 Minor/Additional Criteria (Must Have 2) Anemia or no need of phlebotomy or therapy Leukoerythroblastosis Increasing splenomegaly Development of constitutional symptoms 1. Barosi G et al. Leukemia. 2008;22:
62 Case 1: For Discussion Patient: This is a typical case of PV transformed to post PV MF Should we have considered treatment with hydroxyurea at the initial diagnosis, despite her low risk? Should we perform a bone marrow biopsy regularly during follow-up? Should we check blood film regularly?
63 Case 2: A 61-Year Old Man Presenting With High-Risk PV Patient and Presentation 61-year-old man Recent diagnosis of PV according to the WHO criteria Other Features Myocardial infarction 6 months before JAK2 V617F allele burden: 42% Normal WBC and PLT counts No bone marrow fibrosis Patient is high risk based on prior CV event
64 European LeukemiaNet: Indications for Cytoreduction 1 Factors High-risk PV Frequent phlebotomy requirement Severe disease-related symptoms PLT >1,500 x10 9 /L Progressive leukocytosis 1. Barbui T et al. J Clin Oncol. 2011;29:
65 Management of High-Risk Patients 1 Phlebotomy To maintain hematocrit below 45% Cytoreductive therapy Hydroxyurea, IFN (first- or second-line) Busulfan, pipobroman, 32 P (second-line) Aggressive control of CV risk factors Obesity, smoking, hypertension, diabetes IFN: interferon. 1. Barbui T et al. J Clin Oncol. 2011;29:
66 Is Hydroxyurea Leukemogenic? Chemo AML Cases No chemo 3/123 (2.4%) Hydroxyurea alone Other than hydroxyurea 7/153 (4%) 15/129 (11.6%) 2 chemos 9/54 (16.7%) 459 PV patients 1 No differences among treatments in terms of AML High WBC count predicts AML Chemo HR for AML No chemo 1 Hydroxyurea alone Other than hydroxyurea 0.86 ( ) 5.46 ( ) 1,638 PV patients (ECLAP) 2 Median follow-up: 3.5 y before and 2.8 y after enrollment Incidence of 0.29 x 100 p/y for hydroxyurea and 1.8 x 100 p/y for others Advanced age predicts AML 1. Gangat N et al. Br J Haematol. 2007;138: Finazzi G et al. Blood. 2005;105:
67 Exposure to 32 P and Alkylators: Population-Based Data From Sweden 1 11,039 MPN patients: 162 post-mpn AML, 242 matched controls 25% of post-mpn AML patients were never exposed to cytotoxic drugs Hydroxyurea at any dose is not associated with an increased risk of AML Increasing cumulative dose of alkylators is associated with AML 2 drugs = more AML 1. Björkholm M et al. J Clin Oncol. 2011;29:
68 Intolerance to Hydroxyurea in the PV Setting Pneumonitis, n = 1 N = 3,411, MPN 1 Side effects, n = 184 (5%, 11%, 2 12% 3 ) No side effects, n = 2,831 Fever, n = 16 (8.5%) Mucosal/cutaneous, n = 167 (91%) 1. Antonioli E et al. Am J Hematol. 2012;87: Harrison C et al. N Engl J Med. 2005;353: Hernández-Boluda JC et al. Br J Haematol. 2011;152:81-88.
69 Case 2: Continued Patient starts therapy with hydroxyurea (licensed in Italy) Obtains normalization of CBCs Treatment generally well-tolerated, except for pruritus (still present)
70 Revised ELN Definition of Response in PV, 2013: Complete Remission (2013) 1 Complete Remission A B C D Criteria Durable a resolution of disease-related signs, including palpable hepatosplenomegaly, large symptoms improvement b and Durable a peripheral blood count remission, defined as HCT <45% without phlebotomy; PLT count 400 x 10 9 /L, WBC < 10 x 10 9 /L, and Without progressive disease, and absence of any hemorrhagic or thrombotic event, and Bone marrow histological remission, defined as the presence of ageadjusted normocellularity and disappearance of trilinear hyperplasia, and absence of grade >1 reticulin fibrosis Includes addition of histologic response and standardized assessment of improvement in constitutional symptoms a Lasting 12 wk. b Large symptom improvement ( 10-point decrease in MPN-SAF TSS). MPN-SAF TSS: Myeloproliferative Neoplasm Symptom Assessment Form total symptom score. 1. Barosi G et al. Blood. 2013;121:
71 Case 2: For Discussion A 61-year old patient with high-risk PV who received hydroxyurea as a first-line treatment Are there any alternative first-line treatments for this patient?
72 PEG-IFN in PV ( mcg/wk) 1,2 37 PV patients untreated or treated for <2 y Hematological complete response at 12 mo: 94.6% Still on PEG-IFN α2a alone at 31 mo: 78.4% AEs in 89% (grade 1, 2); decreasing over time Treatment discontinuation: 35% (24% for toxicity) JAK2 V617F allele burden response Complete: 7/29 (24%) Partial: 14/29 (48%) Reduction also in homozygous and 9pLOH Targets JAK2 V617F clones without affecting TET2 mutant cells 1. Kiladjian J-J et al. Blood. 2008;112: Kiladjian J-J et al. Leukemia. 2010;24:
73 PEG-IFN in PV and ET: Myeloproliferative Disorders Research Consortium (MPD-RC) 1 High-risk PV and ET MPD-RC 112 Phase 3 randomized trial of PEG-IFN vs hydroxyurea Continuous therapy for up to 24 months to assess maximal confirmed response to PEG-IFN or hydroxyurea Primary endpoint: complete response by LeukemiaNet Criteria (stratified by ET and PV) Secondary endpoints: partial response rate, mutation allele burden, rate of vascular events, toxicity/tolerability, impact on symptoms and QOL, rates of progression and/or death 1. Accessed October 17, 2014.
74 AOP2014: A New Formulation of PEG-IFN 1 Next-generation long-lasting PEG-IFN Subcutaneous every 14 d 34 patients (dose-finding and extension phases) Median time from PV diagnosis: 24 mo Results 71% ORR in 21 pts at wk 28 (33% CR, 38% PR) 91% ORR in 11 pts at wk 52 (46% CR, 46% PR) 27 pts (79%) developed drug-related AEs Phase 3 study (PROUD): ongoing 1. Gisslinger H et al. 54th Annual Meeting of the American Society of Hematology (ASH 2012). Abstract 175.
75 Conclusions Several effective strategies in place for the management of low- and high-risk PV Some are suboptimal What are the limitations of current treatment of PV? Insufficient efficacy for symptom control Vascular events even with therapy Therapy-related toxicity No effect on the clone Progressive disease to post-pv MF
76 Case Discussions in PV: Rising to the Challenge of Treatment-Refractory PV Srdan Verstovsek, MD, PhD The University of Texas MD Anderson Cancer Center Houston, Texas
77 Case: An Older Man Presenting With High-Risk PV Patient and Presentation 68-year-old white man Presented in 2005 to his local doctor with fatigue, occasional visual blurring Testing Results Hematocrit: 60% WBC: 12,300 PLT: 516,000 Spleen palpable at 2 cm Bone marrow 90%; cellularity myeloid and erythroid hyperplasia JAK2 V617F positive, diploid cytogenetics Diagnosis: PV
78 Case Continued: Treatment History Phlebotomy and aspirin, plus hydroxyurea Continued on hydroxyurea 1 g/d along with allopurinol and aspirin, without need for phlebotomy for 9 years
79 Case Continued: Worsening Symptoms Noted Patient presents for a second opinion after 9 years on hydroxyurea Symptoms Increasing abdominal fullness worsening over the year (splenomegaly at 8 cm) Fatigue, low-grade fevers, worsening itching Treatment recommendation Increased dose of hydroxyurea to 1.5 g/d Assessment after 6 mo Patient developed mouth ulcers (lost 10 lb over 6 mo) HCT: 44%; WBC: 17,200; and PLT: 345,000 No leukoerythroblastosis; bone marrow biopsy compatible with PV
80 Case Continued: Options for Hydroxyurea-Refractory Disease What are the possible options for this older patient, now at age 77, and likely failing therapy with hydroxyurea? Potential treatment options IFN A possible option, though given patient age, potential for toxicity Pipobroman or busulfan Likely overly toxic for this patient Ruxolitinib JAK inhibition validated in PV in the recent RESPONSE study
81 Definition of Hydroxyurea Intolerance or Resistance (After 3 Months of 2 g/d) in PV 1,2 Need for phlebotomy to keep HCT <45% Uncontrolled myeloproliferation PLT >400 x10 9 /L and WBC >10 x10 9 /L Less than 50% reduction of massive splenomegaly No complete relief of splenomegaly-related symptoms Hematological toxicity at the lowest active dose of hydroxyurea Presence of leg ulcers or other unacceptable hydroxyurea-related nonhematologic toxicities 1. Barosi G et al. Br J Haematol. 2009;148: Barosi G et al. Leukemia. 2007;21:
82 The Effect of Hydroxyurea Resistance on Survival and Disease Progression in PV 1 Survival Progression Resistance and intolerance to hydroxyurea occurred in 11% and 13%, respectively, of 261 PV patients Resistance to hydroxyurea implied a 5.6 fold increase in the risk of death and 6.8 fold increase in the risk of transformation 1. Alvarez-Larran A et al. Blood. 2012;119:
83 Second-Line Therapy for PV: Pharmacologic Options 1 IFN-α, if hydroxyurea-resistant/intolerant Hydroxyurea, if IFN α resistant/intolerant Pipobroman, busulfan, 32 P 1. Barbui T et al. J Clin Oncol. 2011;29:
84 PEG-IFN in Advanced PV 1 43 patients (median age: 53 y; PV duration 50 mo) Follow-up: 42 mo Treatment Response/ Toxicity Results ORR 79% CHR 76% Median time to complete response 40 d (range: ) CMR 18% PMR (>50% reduction) 35% Drug-related treatment discontinuation 20% 1. Quintás-Cardama A et al, Blood. 2013;122:
85 AOP2014: A New Formulation of PEG-IFN for PV 1 Next-generation, long-lasting PEG-IFN Subcutaneous every 14 d Early data in 34 patients (dose finding and extension phases) 1 Median time from PV diagnosis: 24 mo Results 1 71% ORR in 21 patients at wk 28 (CR: 33%; PR: 38%) 91% ORR in 11 patients at wk 52 (CR: 46%; PR: 46%) 27 patients (79%) developed drug-related AEs 1. Gisslinger H et al. ASH Abstract 175.
86 Activation of the JAK/STAT Pathway: A Central Role in MPN Pathogenesis 1 1. Vannucchi AM et al. CA Cancer J Clin. 2009;59:
87 Mutations Affecting Epigenetic Regulation in MPNs 1 1. Vannucchi AM, Biamonte F. Haematologica. 2011;96:
88 HDAC Inhibitors Reduce Proliferation of JAK2V617F+ Cells by Down-Regulating JAK/STAT Signaling 1,2 This effect is largely caused by the inhibition of JAK2 binding with hsp90, leading to proteasomal degradation of JAK2 in MPD cells 1. Guerini V et al. Leukemia. 2008;22: Wang Y et al. Blood. 2009;114:
89 HDAC Inhibitors: Clinical Experience in PV HDAC inhibitor/regimen Givinostat (ITF2357) 1 Givinostat + hydroxyurea 2 Summary Findings Among 13 PV/ET patients, 7 responders at study end (24 wk) Pruritus disappeared in most patients Reduction of splenomegaly observed in 75% of PV/ET patients Median treatment duration: 20 wk 44 patients with PV unresponsive to MTD of hydroxyurea Response noted in half of patients; control of pruritus in two-thirds of patients 1. Rambaldi A et al. Br J Haematol. 2010;150: Finazzi G et al. Br J Haematol. 2013;161:
90 HDAC: Clinical Experience in PV (Cont d) HDAC inhibitor/regimen Vorinostat (Nordic Group) 1 Summary Findings 44 PV patients; response rate 35% Pruritus resolved; prevalence of splenomegaly lowered 52% of patients discontinued study drug before end of intervention (24 wk) due to AEs (28 patients) or lack of response (5 patients) 1. Anderson CL et al. Br J Haematol. 2013;162:
91 Phase 2 Study of Ruxolitinib in Advanced PV 1 PV diagnosis according to WHO criteria 2 ECOG PS 2 Refractory or intolerant to hydroxyurea; contraindication for hydroxyurea PV: HCT >45% or 2 phlebotomies in prior 6 months (1 in last 3 months) N = mg BID (n = 7) 25 mg BID (n = 8) 50 mg QD (n = 7) 10 mg BID (n = 12) Part 1 Individualized dose modification depending on safety and efficacy Part 2 1. Verstovsek S et al. Cancer. 2014;120: Tefferi A, Vardiman JW. Leukemia. 2008;22:14-22.
92 Phase 2 Study of Ruxolitinib in Advanced PV 1 (Cont d) 34 patients with PV enrolled Median age: 58 y Median time from PV diagnosis: 115 mo WBC >15 x 10 9 /L in 47% PLT >600 x 10 9 /L in 38% Splenomegaly in 74% Median follow-up duration: ~3 y 26 remain on study 8 discontinued Progression to MF (n = 3) Withdrawal of consent (n = 2) Patient decision to conceive Patient complained of shortness of breath AEs (n = 2) Renal neoplasm Atrial flutter Lack of response (n = 1) 1. Verstovsek S et al. Cancer. 2014;120:
93 Ruxolitinib in PV: Time to First Response 1 Response was achieved in 97% (33/34) by wk 24 CR: 59% (PLT count <400 x10 9 /L, WBC <10 x10 9 /L, normal spleen, no disease-related symptoms) PR: 38%, as their best response 1. Verstovsek S et al. Cancer. 2014;120:
94 Phase 3 RESPONSE Study 1 Resistance to or intolerance of hydroxyurea (modified ELN criteria) Phlebotomy requirement Splenomegaly Pre-randomization (day 28 to day 1) HCT 40%-45% R Ruxolitinib 10 mg BID n = 110 BAT n = 112 Week 32 (primary endpoint) Crossover to ruxolitinib a Week 48 Extended treatment phase Week 208 Week 80 Week 208 Primary endpoint: phlebotomy independence and spleen volume reduction at week 32 Investigator-selected BAT: hydroxyurea, IFN/PEG-IFN, anagrelide, pipobroman, IMIDs, or observation a At wk 32 if patients on BAT failed to meet the primary endpoint or later in case of progression (phlebotomy requirement and/or splenomegaly progression). 1. Verstovsek S et al. American Society of Clinical Oncology 2014 Annual Meeting (ASCO 2014). Abstract
95 RESPONSE: Baseline Characteristics 1 Parameter a BAT: hydroxyurea (n = 66; 59%), IFN/PEG-IFN (n = 13; 12%), anagrelide (n = 8; 7%), pipobroman (n = 2; 2%), IMIDs (n = 5; 4%), and observation (n = 17; 15%). b After HCT control period prior to randomization. 1. Verstovsek S et al. ASCO Abstract Ruxolitinib (n = 110) BAT a (n = 112) Age, median (range), y 62 (34-90) 60 (33-84) Male, % Hydroxyurea resistance/intolerance, % Resistance Intolerance JAK2 V617F mutation positive, % History of prior thromboembolic event, % HCT, mean (SD), % b 43.6 (2.2) 43.9 (2.2) WBC 10 9 /L, mean (SD) 17.6 (9.6) 19.0 (12.2) PLT count 10 9 /L, mean (SD) 485 (323) 499 (319) 3 Phlebotomies in prior 24 wk, % Palpable spleen length, median (range), cm 7 (0-24) 7 (0-25) Spleen volume, median (range), cm ( ) 1322 ( )
96 RESPONSE: Patient Disposition 1 The pre-defined data cutoff for the primary analysis occurred when all patients reached wk 48 or discontinued Parameter Ruxolitinib (n = 110) BAT (n = 112 a ) On randomized treatment at wk 32, n (%) 98 (89.1) 100 (89.3) Discontinued before wk 32, n (%) Adverse event 3 (2.7) 1 (0.9) Lack of efficacy 0 5 (4.5) Disease progression 4 (3.6) 1 (0.9) Patient decision 4 (3.6) 3 (2.7) Physician decision 1 (0.9) 2 (1.8) Crossed over between wk 32-48, n (%) 94 (83.9) Median exposure on randomized treatment, wk Continued on randomized treatment at time of data cutoff, n (%) 93 (84.5) 3 (2.7) a One patient withdrew consent prior to treatment on study; patient is not included in the safety population. 1. Verstovsek S et al. ASCO Abstract 7026.
97 RESPONSE: Ruxolitinib Dose at Week 32 1 At wk 32, two-thirds of patients in the ruxolitinib arm were receiving doses of 10 mg BID or 15 mg BID a Most dose adjustments occurred within the first 8 wk of treatment Patients, % a Maximum dose within a 2-week window of the wk 32 study visit. 1. Verstovsek S et al. ASCO Abstract 7026.
98 RESPONSE: Primary Response at Week % of patients randomized to ruxolitinib met at least one component of the primary endpoint 91% of patients who met the primary endpoint had a confirmed response at wk 48 SV: spleen volume. 1. Verstovsek S et al. ASCO Abstract 7026.
99 RESPONSE: Duration of Primary Response 1 At data cutoff, only 1 patient lost primary response 37.1 wk after start of that response The probability of maintaining primary response for 1 y was 94% 1. Verstovsek S et al. ASCO Abstract 7026.
100 RESPONSE: Rate of Phlebotomy Procedure Weeks 8 to 32 1 The phlebotomy rate wk 8-32 was more than three times higher in the BAT arm compared with the ruxolitinib arm Only 2.8% of patients in the ruxolitinib group vs 20.2% in the BAT group required three or more phlebotomies during this time 1. Verstovsek S et al. ASCO Abstract 7026.
101 RESPONSE: Percentage Change in Spleen Volume at Week Verstovsek S et al. ASCO Abstract 7026.
102 RESPONSE: Complete Hematologic Remission at Week 32 1 n = 26 P =.0034 a OR, 3.19 (95% CI, ) n = % of patients (23/26) who achieved CHR maintained it at wk 48 a P value, odds ratio, and 95% CI were calculated using stratified exact Cochran-Mantel-Haenszel test. CHR is defined as HCT control, PLT count /L, and WBC count /L. CHR: complete hematologic remission. 1. Verstovsek S et al. ASCO Abstract 7026.
103 RESPONSE: Improvement in Individual Symptoms 1,a Median Percentage Changes From Baseline at wk 32 in Individual Symptom Scores (MPN-SAF) a Patients with assessments at baseline and wk 32, with baseline value >0. 1. Verstovsek S et al. ASCO Abstract 7026.
104 RESPONSE: Thromboembolic Events Up to Week 32 1 Ruxolitinib (n = 110) BAT (n = 111) Patients, n (%) All Grade Grade 3/4 All Grade Grade 3/4 All thromboembolic events 1 (0.9) 1 (0.9) 6 (5.4) a 2 (1.8) a Portal vein thrombosis 1 (0.9) 1 (0.9) 0 0 Myocardial infarction (0.9) 1 (0.9) Deep vein thrombosis (1.8) 1 (0.9) Pulmonary embolism (0.9) 1 (0.9) Splenic infarction (0.9) 0 Thrombophlebitis (0.9) 0 Thrombosis (0.9) 0 A higher proportion of patients in the ruxolitinib arm had a history of prior thromboembolic events at baseline than in the BAT arm (35.5% vs 29.5%) There was one additional event in the ruxolitinib group over the course of randomized treatment (median exposure 81 wk) a 1 patient in the BAT group had both myocardial infarction and pulmonary embolism. 1. Verstovsek S et al. ASCO Abstract 7026.
105 RESPONSE: New or Worsening Hematology Laboratory Values Up to Week 32 1 Patients, % Ruxolitinib (n = 110) BAT (n = 111) All Grades Grade 3/4 All Grades Grade 3/4 Hg (low) PLTs (low) Neutrophils (low) No patients discontinued treatment because of anemia or thrombocytopenia 1. Verstovsek S et al. ASCO Abstract 7026.
106 RESPONSE: Nonhematologic Adverse Events Up to Week 32 1,a,b Patients, % Ruxolitinib (n = 110) BAT (n = 111) All Grades Grade 3/4 All Grades Grade 3/4 Headache Diarrhea Fatigue Pruritus Dizziness Muscle spasms Dyspnea Abdominal pain Asthenia Exposure-adjusted rates of AEs and grade 3/4 AEs per 100 patient-years over the entire course of treatment were lower in patients randomized to ruxolitinib than in those randomized to BAT (64.7 vs and 28.8 vs 44.0) Exposure-adjusted rates of serious AEs per 100 patient-years were comparable in both arms (15.3 and 13.7) a Events occurring in 10% of patients in either treatment group. b Regardless of causality. 1. Verstovsek S et al. ASCO Abstract 7026.
107 Conclusions Patients with resistant PV are at higher risk of mortality and need new therapeutic options PEG-IFN obtained a high rate of CHR at diagnosis and at advanced phase, with a 20% rate of discontinuation due to toxicity but a relevant effect on the clone Novel PEG-IFN formulations also being tested in advanced PV HDAC inhibitors (givinostat, vorinostat) are being investigated in PV
108 Conclusions (Cont d) In patients with PV who had an inadequate response to or were intolerant of hydroxyurea, ruxolitinib was superior to BAT in Controlling HCT without phlebotomy Normalizing blood cell count Reducing SV Improving symptoms Responses to ruxolitinib were durable; rate of thromboembolic events appears to be lower in the ruxolitinib group Ruxolitinib was generally well tolerated Ruxolitinib may be a valuable new treatment option in this population of patients with PV
109 Panel Discussion and Q&A What s Next in PV Management Jorge E. Cortes, MD The University of Texas MD Anderson Cancer Center Houston, Texas
110 Audience Q&A Jorge E. Cortes, MD The University of Texas MD Anderson Cancer Center Houston, Texas Francesco Passamonti, MD University Hospital of Varese Varese, Italy Rebecca B. Klisovic, MD The Ohio State University Columbus, Ohio Srdan Verstovsek, MD, PhD The University of Texas MD Anderson Cancer Center Houston, Texas
111 Presentation Title Conclusion Jorge E. Cortes, MD The University of Texas MD Anderson Cancer Center Houston, Texas
112 Thank You and Good Evening! Please remember to complete and submit your Post-Test and Evaluation for CME/CNE credit. Missed anything? Visit us at Download slides and Practice Aids Watch for the ondemand version of this symposium PVI, PeerView Institute for Medical Education Penn State College of Medicine, and the Institute for Advancement of Human Behavior are responsible for the selection of this report s topics, the preparation of editorial content, and the distribution of this report. The preparation of PeerView reports is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI, Penn State College of Medicine, and the Institute for Advancement of Human Behavior. Our reports may contain references to unapproved products or uses of these products in certain jurisdictions. For approved prescribing information, please consult the manufacturer's product labeling. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. Copyright , PeerView Press
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