Will drugs targeted to genetic and epigenetic defects become the - PowerPoint PPT Presentation

Will drugs targeted to genetic and epigenetic defects become the best future option in therapy of MPNs? Tiziano Barbui, MD Ospedali Riuniti di Bergamo-Italy 1st COHEM Congress Rome, Sunday, September 5, 2010 1

Two points for this debate: - which are current medical needs in patients with MPNs - Which are the criteria to assess the efficacy of novel JAK2 inhibitors 2

Two points for this debate: - which are current medical needs in patients with MPNs - Which are the criteria to assess the efficacy of novel JAK2 inhibitors 3

Similar issues in Ph-neg and Ph-positive Myeloproliferative Neoplasms • In both categories,deregulated protein tyrosine kinases BCR-ABL and JAK2-V617F seem to be seminal, though they are still incompletely defined. • In both categories, genomic instability seems to increase the risk of disease progression. • BCR-ABL-positive CML responds remarkably well, in most but not all cases, to tyrosine kinase inhibitors. • Question: Are comparable results achievable in MPNs by inhibiting JAK2 ? 4

OVERALL SURVIVAL IN MYELOPROLIFERATIVE DISORDERS Wolanskyj A et al., Mayo Clin Proc. 2006 Barbui T et al., BJH 1997 5

Major Vascular Events During Follow-up in PV and ET ECLAP study (PV) BVF study (ET) Low-risk Events/100 HR Low-risk (n=517) persons/yr 2.5 1 Rate: 1.5 (%/patients/year) Intermediate-risk High risk (n=546) Events/100 HR persons/yr 5.0 2.00 Rate: 2.0 (%/patients/year) 4.9 1.96 High-risk Events/100 HR persons/yr 10.9 4.35 6 Marchioli R et al., JCO 2005; Carobbio et al,Blood 2008;Barbui et al,Blood 2009, 2010 )

Current Treatment Choices in PMF Asymptomatic PMF patients No therapy Anemia/thrombocytopenia Age less than 60 Intermediate or high risk Corticosteroids Danazol Allo-SCT Erythropoietin transplantation Thalidomide Lenalidomide Pomalidomide Splenectomy Accelerated/blast Myeloproliferation/Progressive phase splenomegaly Chemotherapy Hydroxyurea, Interferon, Alkeran Busulphan Splenectomy 7

IWG-MRT Scoring System (IPSS) Adverse prognostic factors 1. Age > 65 years 2. Constitutional symptoms 3. Hb < 10 g /dL 4. WBC >25 x10 9 /L 5. Blood blasts ≥1% The scoring system Factor No Risk group Cases (%) Median survival (mo) 0 Low 22 135 1 Intermediate-1 29 95 2 Intermediate-2 28 48 =>3 High 21 27 8 Cervantes et al. Blood 2009;113:2895 Cervantes et al. Blood 2009;113:2895

Symptoms in 1179 MPD Patients 100% ET (n=304) PV (n=405) 80% MMM (n=456) 60% 40% 20% 0% Weight Bone Night Pruritus Fatigue Loss Pain Sweats 9 Mesa et. al. Cancer 2007;109:68-76

Two points for this debate: - which are current medical needs in patients with MPNs - Which are the criteria to assess the efficacy of novel JAK2 inhibitors 10

RESPONSE CRITERIA IN MPNs •standardization of response criteria •to accurately assess the value of new treatment modalities, •to allow accurate comparison between studies, •To ensure that the definition of response reflects meaningful health outcome 11

ELN RESPONSE CATEGORIES FOR ET/PV 1. Clinico-Hematological respose 2. Molecular response 3. Histologic bone marrow response These categories should be applied to patients with ET receiving disease modifying therapies. The categories of response should be used in a cumulative sequential manner starting from the clinico- hematological response (the minimal set of criteria). The decision to use a composite definition of response (eg, clinico-hematological and molecular..) will depend on the goal of the therapy 12 Blood, 14 May 2009, Vol. 113, No. 20, pp. 4829-4833

Definition of clinico-hematologic response in ET Response grade Definition Complete response 1. Platelet count =< 400 x109/L AND 2. No disease related symptoms AND 3. Normal spleen size on imaging AND 4. WBC count < 10 x 109/L Partial response In patients who do not fulfill the criteria for complete response: Platelet count below 600 x 109/L or decrease > 50% of baseline No response Any response that does not satisfy partial response Blood, 14 May 2009, Vol. 113, No. 20, pp. 4829-4833 13

Definition of clinico-hematologic response in PV Response grade Definition Complete response • Ht lower than 45% without phlebotomy AND • Platelet count <= 400 x109/L AND • WBC count <=10 x 109/L AND • Spleen normal on imaging AND • No disease related symptoms Partial response In patients who do not fulfill the criteria for complete response: 1. Ht lower than 45% without phlebotomy; OR 2. Response in 3 or more of the other criteria No response Any response that does not satisfy minor response 14 Blood, 14 May 2009, Vol. 113, No. 20, pp. 4829-4833

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in PV Evolution of %V617F during treatment with peg-IFN-2a 15 Kiladjian, J.-J. et al. Blood 2008;112:3065-3072

Unanswered questions Do we need to target JAK2 V617F ? Could the JAK2 inhibitors decrease stromal reactions to clonal megakaryocytes in PV and ET and slow the progression to advanced myelofibrosis? Could the JAK2 inhibitors, which decrease the JAK2V617F allele burden, affect the frequency of vascular events? Could they become an option when we want to avoid hydroxyurea or when patients become intolerant to pegylated-interferon? Long term toxicity 16