European Focus on Myeloproliferative Diseases and Myelodysplastic Syndromes A critical reappraisal of anagrelide in the management of ET

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1 European Focus on Myeloproliferative Diseases and Myelodysplastic Syndromes 2012 Clinical i l Aspects of Polycythemia and Essential Thrombocythemia A critical reappraisal of anagrelide in the management of ET Heinz Gisslinger Medical University of Vienna, Austria Anagrelide Mechanism Anagrelide suppresses megakaryocytopoiesis by inhibiting PDE III-dependent and PDE III-independent mechanisms The so far unknown mechanism has no DNA damaging or cytotoxic effect 1

2 Mechanism - Anagrelide vs Hydroxyurea Hong and Erusalimsky, Leukemia 2002 Anagrelide vs. Hydroxyurea Thromboreductive vs. Cytoreductive Activity Anagrelide is a potent and selective inhibitor of megakaryocytopoiesis acts thrombocytoreductive, having no significant activity against cell expansion on granulopoiesis or erythropoiesis In contrast, the anti-megakaryocytopoietic activity of Hydroxyurea cannot tbe dissociated i dfrom its more general cytoreductive and cytotoxic actions Hong et al., Leukemia

3 Basis of decision-making for the use of Anagrelide WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET Leukocytosis as a risk factor in ET and ppmf influences the managment PT1 Trial The ANAHYDRET-Study Clinical differences between WHO-ET and early/prefibrotic PMF in the Vienna Cohort Characteristics WHO ET (n=126) early/prefibr. PMF (n=81) p value Age, y 58.1 ( ) 64.9 ( ).037 Hemoglobin, g/dl 14.2 ( ) 13.2 ( ).009 Hematocrit, % 42.5 ( ) 39.6 ( ) Leukocytes, x10 9 /L 8.8 ( ) 10.0 ( ).005 Erythroblasts, % 0 (0 0) 0 (0 2).001 Myeloblasts, % 0 (0 1) 0 (0 2).002 LDH, U/l 212 ( ) 321 ( ) <.001 Spleen, cm below cost.marg. 0 (0 11) 1.5 (0 15) <.001 values are median (range) Thiele et al, Blood

4 WHO-ET vs. early pre-fibrotic PMF Impact on clinical cours Different overall survival Different myelofibrosis-free survival Different leukemia-free survival No difference in thrombosis-free survival There is a difference in the risk for thrombosis and bleeding Clinical characteristics in WHO-ET vs. early pre-fibrotic PMF Barbui et al,

5 WHO-ET vs. early pre-fibrotic PMF Impact on clinical course Different overall survival Different myelofibrosis-free survival Different leukemia-free survival No difference in thrombosis-free survival There is a difference in the risk for thrombosis and bleeding Basis of decision-making for the use of Anagrelide WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET Leukocytosis as a risk factor in ET and ppmf influences the managment PT1 Trial The ANAHYDRET-Study 5

6 WHO-ET: Multivariate analysis for risk factors predicting fatal and nonfatal thrombotic events in the follow-up of 891 patients Major thrombosis AT DVT HR (95% CI) p HR (95% CI) p HR (95% CI) p Age > 60 years 1.5 ( ) ( ) ( ) 0.51 Prev. thrombosis 1.9 ( ) ( ) ( ) 0.12 Male sex 1.3 ( ) ( ) ( ) 0.04 CV risk factors 1.6 ( ) ( ) ( ) 0.56 WBC > 11 G/l 1.1 ( ) ( ) ( ) 0.52 Hb < 12 g/dl 1.4 ( ) ( ) ( ) 0.48 Plt count > 1000 G/l 0.5 ( ) ( ) ( ) 0.94 JAK2 V617F 2.0 ( ) ( ) ( ) 0.37 Analysis adjusted also for chemotherapy and antiplatelet needs during follow-up. CV indicates cardiovascular; and WBC, white blood cell count. * Smoking, arterial hypertension, and diabetes (at least one). Carobbio et al, 2011 Early prefibrotic PMF: Multivariate analysis (metric variables) for risk factors predicting fatal and nonfatal thrombotic events in the follow-up of 264 patients Major thrombosis AT DVT HR (95% CI) p HR (95% CI) p HR (95% CI) p Female gender 1.0 ( ) ( ) ( ) 0.13 Age 1.0 ( ) ( ) ( ) 0.28 Prev. thrombosis 1.8 ( ) ( ) ( ) 0.51 Hb (higher) 0.9 ( ) ( ) ( ) 0.01 Plt count (higher) 1.0 ( ) ( ) ( ) 0.15 WBC (higher) 1.2 ( ) ( ) ( ) JAK2 V617F 1.5 ( ) ( ) ( ) 0.89 CV risk factors 0.6 ( ) ( ) ( ) 0.91 Analysis adjusted also for chemotherapy and antiplatelet needs during follow-up. CV indicates cardiovascular; and WBC, white blood cell count. * Smoking, arterial hypertension, and diabetes (at least one). Buxhofer et al.,

7 Multivariate analysis of risk factors for bleeding HR (95% CI) p-value early/prefibrotic PMF 1.74 ( ) WBC 11 x10 9 /L 1.74 ( ) Previous bleeding 2.35 ( ) Aspirin use 316(163608) 3.16 ( ) Finazzi et al, 2011 Major bleeding in WHO-ET vs. early prefibrotic PMF WHO-ET early prefibrotic PMF n major bleeding 55 (6%) 21 (12%) p=0.009 rate per pt/year 0.79% 1.39% p=0.039 Finazzi et al,

8 Treatment needs: which parameters should be improved or normalized? Early prefibrotic myelofibrosis (e.g.pvsg-et) - normalization of white blood cell count (WBC) - normalization of the platelet count Essential thrombocythemia (WHO-ET) - improvement/elimination of classical risk faktors for thrombosis - normalization of the platelet count Basis of decision-making for the use of Anagrelide WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET Leukocytosis as a risk factor in ET and ppmf influences the managment PT1 Trial The ANAHYDRET-Study 8

9 PT-1 Randomized comparison of HU with Anagrelide in high risk* ET diagnosed according to PVSG criteria N= 809 Fixed combination with aspirin mg/d Primary end points Time to death from thrombosis/ hemorrhage or Occurrence of arterial or venous thrombotic event/ serious hemorrhage Secondary end points Time to first arterial or venous thrombotic event/ serious hemorrhage Time to death Incidence of transformation to MF/ acute leukemia/ MDS/ PV Control of platelet count * Age 60, current or previous platelets >1 Mio/L, history of ischemia, thrombosis, embolism, hemorrhage; hypertension or diabetes mellitus requiring therapy Harrison et al, NEJM 2005 Estimates of Survival Free of Primary Endpoint Kaplan-Meier Estimates of Survival Free of the Primary End Point of Arterial or Venous Thrombosis, Serious Hemorrhage, or Death from Any of These Causes Harrison, C. et al. N Engl J Med 2005;353:

10 Estimates of Survival Free of the Secondary Endpoints Kaplan-Meier Estimates of Survival Free of the Secondary End Points of Arterial Thrombosis (Panel A), Venous Thrombosis (Panel B), Serious Hemorrhage (Panel C), and Myelofibrotic Transformation (Panel D) Harrison, C. et al. N Engl J Med 2005;353:33-45 Complication rates analyzed by bone marrow reticulin grade at diagnosis 2009 by American Society of Clinical Oncology Campbell P J et al. JCO 2009;27:

11 Association of reticulin grade at diagnosis with presentation laboratory features Campbell P J et al. JCO 2009;27: by American Society of Clinical Oncology PT1-Study: PVSG-ET (prefibrotic PMF and PMF1) is not an indication for Anagrelide as first line therapy A persistent elevated WBC counts in Anagrelide treated patients may explain higher rates of arterial events in PVSG ET PVSG ET (prefibrotic PMF and PMF1) may be associated with a higher bleeding tendency after exposure to Anagrelide+Aspirin In contrast to HU, Anagrelide does not suppress the progression of fibrosis in PVSG ET (prefibrotic PMF and PMF1) 11

12 Treatment guidelines for PVSG-ET (prefibrotic PMF and PMF1) Cytoreduction is needed, therefore HU is superior! Hydroxyurea lowers Plt and WBC counts protects from progression to fibrosis no impact on bleeding tendency Anagrelide selectively lowers platelet and might induce bleeding counts Interferon alpha may be an alternative to for cytoreduction HU Basis of decision-making for the use of Anagrelide WHO classification True-ET (WHO-ET) has to be treated differently from PVSG-ET Leukocytosis as a risk factor in ET and ppmf influences the managment PT1 Trial The ANAHYDRET-Study 12

13 ANAHYDRET study vs UK-PT1 study Diagnosis according to (applied criteria) Pretreatment ANANAHYDRET* (n=258) WHO criteria mandatory BM biopsy with central review only newly diagnosed WHO-ET patients PT1** (n=805) PVSG criteria pretreated PVSG-cohort Concomitant t therapy preferred monotherapy fixed combination with Asprin Angrelide formulation Thromboreductin Agrylin /Xagrid * Gisslinger et al., Blood 2008, ASH Abstract 661 **Harrison et al., N Engl J Med 2005; 353:33-45 No difference in platelet lowering effect ANA vs HU 95% CI for median difference: ( 4.575/15.406) P = PLT ( x10 9 /L) Hydroxyurea Thromboreductin (Anagrelide) Number of patients Anagrelide Hydroxyurea

14 Leukocytes remained constant in ANA treated patients Thromboreductin (Anagrelide) WBC ( x 10 9 /L) Hydroxyurea 95% CI for median difference: (17.414/47.282) P < Anagrelide Hydroxyurea Number of patients No difference in major and minor events ANA (n=122) No. of events HU (n=131) No. of events Major complications (total) Arterial Venous Bleeding Minor complications (total) Arterial Venous Bleeding Gisslinger et al., Blood 2008, ASH Abstract

15 No difference in ET related events Proof of non-inferiority if HR of Lower Bound ANA (n=122) HU (n=131) Total events No. patients (%) 30 (24.6%) 2 34 (26.0%) 1 Test for inferiority: HR = ; CI-LB = and 2 Test for inferiority: HR = ; CI-LB = , indicating a difference no larger than small/medium HR: Hazard Ratio, CI LB: Confidence Interval Lower Bound Gisslinger et al., Blood 2008, ASH Abstract 661 WHO-ET: selective platelet reduction may be sufficient in order to prevent thrombosis Even in Anagrelide treated patients the WBC count remained dbelow the threshold h for the thrombosis risk (<11G/L) WHO ET may be associated with a lower bleeding tendency after exposure to Anagrelide In contrast to prefibrotic PMF and PMF1, WHO ET is associated with a lower tendency for progression to overt bone marrow fibrosis 15

16 The ANAHYDRET Study Outcome: The study clearly proves non inferiority of anagrelide compared to hydroxyurea in WHO-ET based on platelet lowering effect and incidences of ET-related events Fibrotic progression: Was not observed in this homogenous cohort of WHO- ET patients. Gisslinger et al., Blood 2008, ASH Abstract 661 ANAHYDRET-Study vs. PT1-Trial Difference in the patient cohorts may explain the difference in study-results ANAHYDRET-Study PT1-Trial true-et PVSG-ET e.g. prefibrotic PMF and PMF ET Related Eve ents Free Survival Anagrelide Hydroxy st Year 2nd Year 3rd Year Time [Months] 16

17 Difference in the prevention of thrombotic and haemorrhagic events PT1-Trial vs. ANAHYDRET-Study Beer PA and Green AR, 2009 Conclusion WHO-ET and PVSG-ET (prefibrotic PMF) two separate entities significant clinical differences implications on treatment thromboreductive (WHO-ET) vs. cytoreductive therapy (PVSG-ET) 17

18 Conclusion Anagrelide has to be considered as first-line therapy in WHO-ET because of: Non-inferiority compared to hydroxyurea - ANAHYDRET study Superior versus hydroxyurea - non-leukemogenic and non-cancerogenic drug Documented long term efficacy and safety - International patient registry long term data 18