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

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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

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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

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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

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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 ?

5 Barbui T et al., BJH 1997 Wolanskyj A et al., Mayo Clin Proc. 2006

OVERALL SURVIVAL IN MYELOPROLIFERATIVE DISORDERS

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Major Vascular Events During Follow-up in PV and ET

Marchioli R et al., JCO 2005; Carobbio et al,Blood 2008;Barbui et al,Blood 2009, 2010 ) Events/100 persons/yr

HR

2.5 1

Events/100 persons/yr

HR

5.0 4.9 2.00 1.96

Events/100 persons/yr

HR

10.9 4.35

High-risk Low-risk Intermediate-risk

ECLAP study (PV) BVF study (ET) Low-risk (n=517) Rate: 1.5 (%/patients/year) High risk (n=546) Rate: 2.0 (%/patients/year)

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Current Treatment Choices in PMF

PMF

Allo-SCT transplantation

Asymptomatic patients

No therapy

Anemia/thrombocytopenia Corticosteroids Danazol Erythropoietin Thalidomide Lenalidomide Pomalidomide Splenectomy Myeloproliferation/Progressive splenomegaly

Hydroxyurea, Interferon, Alkeran Busulphan Splenectomy

Accelerated/blast phase

Chemotherapy

Age less than 60 Intermediate or high risk

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IWG-MRT Scoring System (IPSS)

Adverse prognostic factors

• 1. Age > 65 years
• 2. Constitutional symptoms
• 3. Hb < 10 g /dL
• 4. WBC >25 x109/L
• 5. Blood blasts ≥1%

The scoring system Factor No Risk group Cases (%) Median survival (mo) Low 22 135 1 Intermediate-1 29 95 2 Intermediate-2 28 48 =>3 High 21 27

Cervantes et al. Blood 2009;113:2895 Cervantes et al. Blood 2009;113:2895

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0% 20% 40% 60% 80% 100%

Weight Loss Bone Pain Night Sweats Pruritus Fatigue

ET (n=304) PV (n=405) MMM (n=456)

Symptoms in 1179 MPD Patients

Mesa et. al. Cancer 2007;109:68-76

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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

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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

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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

Blood, 14 May 2009, Vol. 113, No. 20, pp. 4829-4833

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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

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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

Blood, 14 May 2009, Vol. 113, No. 20, pp. 4829-4833

15 Kiladjian, J.-J. et al. Blood 2008;112:3065-3072

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in PV

Evolution of %V617F during treatment with peg-IFN-2a

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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

• f vascular events?

Could they become an option when we want to avoid hydroxyurea

• r when patients become intolerant to pegylated-interferon?

Long term toxicity