State of the art treatments of patients with MPNs Turracher Höhe 2010 Controversies in the management of patients with PMF 0/1 Heinz Gisslinger Medical University of Vienna Divison for Hematology, Vienna Austria PMF
Chronic idiopathic myelofibrosis Treatment indications Thrombocytosis Anaemia Bleeding (pancytopenia) Symptomatic splenomegaly Hyperuricaemia
Thrombocytosis: the treatment indications in Early primary myelofibrosis Alleviate microvascular symptoms that occur in a high percentage of patients Prevent arterial and venous thrombosis, the most important complications in early PMF Prevent major bleeding when platelet counts are excessively elevated
Recent developments Basis of decision-making for treatment Leukocytosis and JAK2 as possible risk factors may influence the managment WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET or early PMF PT1 Trial vs. The ANAHYDRET-Study
Recent developments Basis of decision-making for treatment Leukocytosis and JAK2 as possible risk factors may influence the managment WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET or early PMF PT1 Trial vs. The ANAHYDRET-Study
Univariate analysis for risk factors Prediction of fatal and nonfatal thrombotic events in PMF (follow-up, n = 707) Barbui et al, 2010
Risk factors at presentation of PMF Cox regression model - association with fatal and nonfatal thrombosis in the follow-up Barbui et al, 2010
Interaction of JAK2V617F status and leukocyte count (multivariable model) Barbui et al, 2010
Main outcome events during follow-up in Primary Myelofibrosis (PVSG-criteria) (n=707) Barbui et al, 2010
Cumulative incidence of fatal and nonfatal thrombotic events versus deaths from other causes (competing risk analysis) in PMF (n = 707) Barbui et al, 2010
Recent developments Basis of decision-making for treatment Leukocytosis and JAK2 as possible risk factors may influence the managment WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET or early PMF PT1 Trial vs. The ANAHYDRET-Study
ET PMF-0
Megakaryocyte features of PMF-0/1 versus ET frequency histotopography size nuclear features aberrant nuclear/cytoplasmic ratio PMF-0/1 increased loose to dense clusters median to giant irregular foldings, bulbous lobulation, cloud-like features +++ ET markedly increased loose clusters or randomly distributed large to giant staghorn-like, deep lobulation no
ET ET PMF-0
ET PMF-0
WHO-diagnosis PMF 0/1: Influence on clinical parameters (The Vienna-Colone Study) ET PMF-0/1 PV/ET No. of patients 99 65 10 Age yrs.* 61 65 55.5 Gender Male/Female 40/59 36/29 8/2 Hemoglobin male female g/dl* 14.2 14.1 13.8 12.5 15.8 15.3 Hematocrit male female % 42.6 42.4 41.4 38.7 48.3 45.2 Leukocytes 10 9 /L* 8.3 10.2 10.6 Peripheral blasts % 0 0 0 Platelets 10 9 /L* 769 872 685 Palpable spleen n (%) 19 (21 %)** 36 (61 %)** 3 (33 %) LDH U/L* 216** 312** 248 * median **ET vs. PMF-0/1, p < 0,05 Thiele, et al; 2009
Survival in early MPNs with thrombocythemia 100 80 ET PMF-0 % Survival 60 40 Relative survival according to WHO (%) 5 yrs. 10 yrs. 15 yrs. ET 100.0 4.4 99.1 7.8 83.9 17.6 20 PMF-0 92.1 7.1 80.8 11.7 67.9 23.7 PMF-1 83.0 9.5 67.3 17.8 55.4 29.8 0 0 2 4 6 8 10 12 14 Years after diagnosis PMF-1 n=476
Observed survival according to WHO diagnosis 1 0.8 ET - Vienna % survival 0.6 0.4 ET - Cologne 0.2 PMF-0/1 - Cologne PMF-0/1 - Vienna 0 0 5 10 15 20 years after diagnosis
Recent developments Basis of decision-making for treatment Leukocytosis and JAK2 as possible risk factors may influence the managment WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET or early PMF PT1 Trial vs. The ANAHYDRET-Study
Treatment modalities for thrombocytosis in early primary myelofibrosis Hydroxurea Anagrelide Interferon alpha JAK2-Inhibitors?
Comparative evaluation of two major diagnostic classification systems (PVSG vs. WHO) PT-1 Study patients ANAHYDRET-Study patients Thiele et al, 2003
PT1 Study: Arterial thrombosis-free survival analyzed by bone marrow reticulin grade at diagnosis Campbell et al, 2009
Difference in the patient cohorts included PT1-Trial vs. ANAHYDRET-Study Different diagnostic criteria with different patient cohorts Newly diagnosed patients in the ANAHYDRET cohort Restrictive use of Aspirin Differences in the white blood cell counts and reticulin fibrosis might be considered as additional risk factor for thrombosis
Difference in thrombotic events PT1-Trial vs. ANAHYDRET-Study PT1-Trial vs. ANAHYDRET-Study 1.0 1.0 0.9 0.9 0.8 0.8 ET Related Events Free Survival 0.7 0.6 0.5 0.4 0.3 Anagrelide Hydroxy 0.7 0.6 0.5 0.4 0.3 0.2 1st Year 2nd Year 3rd Year 0.2 0.1 0.1 0.0 0.0 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536 Time [Months]
PegIntron in myelofibrosis Inclusion criteria Patients with low/intermediate risk myelofibrosis who are untreated or pretreated low risk: Hb > 10g/dl Plt 100G/L WBC 4 and < 20G/L WBC precursors < 10% intermediate risk: Hb < 10g/dl Plt 100G/L WBC precursors < 10 % Secondary myelofibrosis after Polycythaemia vera or essential Thrombocythaemia
PegIntron in myelofibrosis Patient characteristics No. of patients 25 Age (years) 64 (35-88) Sex (m/f) 14/11 Risk score: low 19 intermediate 3 high 3
Effect of PegIntron in myelofibrosis Disease No. of pts. CR PR SD PD Characteristics evaluable Thrombocytosis n=21 10 10 1 - ( 600 G/L) Anaemia n=9 1 2 4 2 (Hb < 10g/dl) Splenomegaly n=20-11 8 1 Gisslinger et al, 2006
Treatment modalities for thrombocytosis in early primary myelofibrosis Which one will make the race? Hydroxurea Anagrelide Interferon alpha JAK2-Inhibitors?
Recent developments in myelofibrosis Targeted therapy of Primary myelofibrosis Time V617F Mutation JAK2
JAK-2 Inhibitors are active but not targeted