Controversies in the management of patients with PMF 0/1

Transcription

1 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

2 Chronic idiopathic myelofibrosis Treatment indications Thrombocytosis Anaemia Bleeding (pancytopenia) Symptomatic splenomegaly Hyperuricaemia

3 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

4 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

5 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

6 Univariate analysis for risk factors Prediction of fatal and nonfatal thrombotic events in PMF (follow-up, n = 707) Barbui et al, 2010

7 Risk factors at presentation of PMF Cox regression model - association with fatal and nonfatal thrombosis in the follow-up Barbui et al, 2010

8 Interaction of JAK2V617F status and leukocyte count (multivariable model) Barbui et al, 2010

9 Main outcome events during follow-up in Primary Myelofibrosis (PVSG-criteria) (n=707) Barbui et al, 2010

10 Cumulative incidence of fatal and nonfatal thrombotic events versus deaths from other causes (competing risk analysis) in PMF (n = 707) Barbui et al, 2010

11 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

12 ET PMF-0

13 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

14 ET ET PMF-0

15 ET PMF-0

16 WHO-diagnosis PMF 0/1: Influence on clinical parameters (The Vienna-Colone Study) ET PMF-0/1 PV/ET No. of patients Age yrs.* Gender Male/Female 40/59 36/29 8/2 Hemoglobin male female g/dl* Hematocrit male female % Leukocytes 10 9 /L* Peripheral blasts % Platelets 10 9 /L* 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

17 Survival in early MPNs with thrombocythemia ET PMF-0 % Survival Relative survival according to WHO (%) 5 yrs. 10 yrs. 15 yrs. ET PMF PMF Years after diagnosis PMF-1 n=476

18 Observed survival according to WHO diagnosis ET - Vienna % survival ET - Cologne 0.2 PMF-0/1 - Cologne PMF-0/1 - Vienna years after diagnosis

19 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

20 Treatment modalities for thrombocytosis in early primary myelofibrosis Hydroxurea Anagrelide Interferon alpha JAK2-Inhibitors?

21 Comparative evaluation of two major diagnostic classification systems (PVSG vs. WHO) PT-1 Study patients ANAHYDRET-Study patients Thiele et al, 2003

22 PT1 Study: Arterial thrombosis-free survival analyzed by bone marrow reticulin grade at diagnosis Campbell et al, 2009

23 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

24 Difference in thrombotic events PT1-Trial vs. ANAHYDRET-Study PT1-Trial vs. ANAHYDRET-Study ET Related Events Free Survival Anagrelide Hydroxy st Year 2nd Year 3rd Year Time [Months]

25 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

26 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

27 Effect of PegIntron in myelofibrosis Disease No. of pts. CR PR SD PD Characteristics evaluable Thrombocytosis n= ( 600 G/L) Anaemia n= (Hb < 10g/dl) Splenomegaly n= Gisslinger et al, 2006

28 Treatment modalities for thrombocytosis in early primary myelofibrosis Which one will make the race? Hydroxurea Anagrelide Interferon alpha JAK2-Inhibitors?

29 Recent developments in myelofibrosis Targeted therapy of Primary myelofibrosis Time V617F Mutation JAK2

30 JAK-2 Inhibitors are active but not targeted