Goals of therapy and criteria for response for PV/ET in clinical practice vs. clinical trials Giovanni Barosi Center for the Study of Myelofibrosis. IRCCS Policlinico S. Matteo Foundation, Pavia, Italy European Focus on Myeloproliferative Neoplasms and Myelodysplastic Syndromes 2014. Prague, 2-3 May 2014

Goals of therapy in PV/ET (by a general perspective) To avoid first occurrence and/or recurrence of thrombotic and bleeding complications; To minimize the risk of acute leukemia and post-PV/ET myelofibrosis; To control systemic symptoms; To treat complications (thrombosis and hemorrhage); To manage risk situations (e.g. pregnancy, surgery). ELN recommendations, Barbui et al, JCO 2012

Goals of therapy in PV/ET (by relevance) To prevent vascular events in patients with high-risk of thrombosis by contrasting myeloproliferation (off-target therapy)

The key therapeutic question in PV/ET How to contrast myeloproliferation to nullify the vascular risk? Clinical trials Clinical practice Comparing different cytoreductive strategies (PT-1, CYTO-PV) Testing new drugs (JAK2 inhibitors) Testing old drugs with the intention of clonal remission (interferon) Optimizing disease control

Operational needs for clinical research in PV/ET Standard definition of response (for comparing different trials with different agents) Standard definition of resistance/ intolerance (for enrollment of patients in second-line trials)

Response in PV/ET: an evolving concept The starting point: the 2009 ELN criteria for response Aim: having a common standard for evaluating response in clinical practice and clinical trials Method: Consensus project Result: Criteria specifically reflected the proliferative status of the disease. Molecular and histological response were ancillary criteria Barosi et al, Blood 2009

ELN Definition of Response in ET (2009) 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: 1. Platelet count below 600 x 109/L or decrease > 50% of baseline No response Any response that does not satisfy partial response 7

ELN Definition of Response in PV (2009) 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: Ht lower than 45% without phlebotomy; OR Response in 3 or more of the other criteria No response Any response that does not satisfy minor response 8

ELN molecular response criteria (2009) Response grade Definition Complete response Reduction of any specific molecular abnormality to undetectable levels Partial response* (1) A reduction of ≥ 50% from baseline value in patients with < 50% mutant allele burden at baseline OR (2) reduction of ≥ 25% from baseline value in patients with > 50% mutant allele burden at baseline. No response Any response that does not satisfy partial response * Applies only to patients with a baseline value of mutant allele burden greater than 10%. Barosi et al, Blood 2009

ELN histological response criteria (2009) Essential thombocythemia Polycythemia vera Bone marrow histological remisssion Bone marrow histological remission Absence of megakaryocyte hyperplasia Presence of age-adjusted normocellularity and no reticulin fibrosis Barosi et al, Blood 2009

Response in PV/ET: an evolving concept Validation of ELN-2009 clinico-hematological response criteria In 154 ET patients receiving anagrelide, the ELN response criteria did not correlate with clinically relevant outcomes (Hernandez –Boluda et al, Ann Hematol, 2013) In 261 PV patients treated with hydroxyurea, achieving ELN response (complete or partial) did not result in better survival or less thrombosis and bleeding (Alvarez-Larran, Blood 2012).   In 416 ET patients treated with hydroxyurea, ELN responses were not associated with lower risk of thrombosis (Carobbio et al, Blood 2010).

Response in PV/ET: an evolving concept The revised ELN/IWG-RT response criteria (2013) Aim: having a response assessment that provides clinically relevant measure of benefit for patients, to be used in clinical trials Method: Consensus project Result: New definitions of response incorporated clinical, hematological, and histological response assessments, included a standardized symptom assessment form (SAF) and considered absence of disease progression and vascular events.  Barosi et al, Blood 2013

Revised Definition of Response in ET (2013) Response grade Definition COMPLETE REMISSION 1. Durable* resolution of disease-related symptoms§ and signs including palpable hepato-splenomegaly, AND 2. Durable* peripheral blood count remission, defined as platelet count =< 400 x109/L , WBC count < 10 x 109/L, absence of leuko-erythroblastosis 3. Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND 4. Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis PARTIAL REMISSION 1-3 as complete remission 4. Without bone marrow histological remission, defined as the persistence of megakaryocyte hyperplasia * Lasting at least 16 weeks; §>10pts decrease in MPN-SAF Barosi et al, Blood 2013 13

Revised Response Definition in PV (2013) Response grade Definition COMPLETE REMISSION 1. Durable* resolution of disease-related symptoms§ and signs including palpable hepato-splenomegaly, AND 2. Durable* peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count =< 400 x109/L , WBC count < 10 x 109/L, AND 3. Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND 4. Bone marrow histological remission defined as the presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of >grade 1 reticulin fibrosis PARTIAL REMISSION 1-3 as complete remission 4. Without bone marrow histological remission PROGRESSIVE DISEASE Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute leukemia * Lasting at least 8 weeks; §>10pts decrease in MPN-SAF Barosi et al, Blood 2013 14

Recommendations for primary endpoints in clinical trials in Ph-neg MPNs. An ELN/IWG-MRT Project (unpublished) Population Primary endpoint Therapy key question: Developing new drug therapies in MPNs Phase I trials Patients with high-risk prognostic categories Dose limiting toxicity Maximum tolerated dose Pharmacokinetic and pharmacodynamic profile Phase II trials Patients in need of therapy for ET and PV. Overall response rate and duration of response Phase III trials Patients in need of any therapy for the disease Overall survival/progression free survival Therapy key question: Preventing disease progression in MF patients with early disease Previously untreated patients with IPSS score O (low-risk disease) Progression free survival/event free survival Therapy key question: Testing new drugs for the relief of MF associated symptoms Patients in need of therapy for splenomegaly Response on splenomegaly (IWG-MRT/ELN criteria) Phase III trial Patients in need of therapy for anemia Response on anemia (IWG-MRT/ELN criteria) Therapy key question: Preventing vascular events in PV and ET PV patients or ET patients with high risk of thrombosis or low risk of thrombosis with JAK2 V617F mutation or vascular risk Time to vascular event

Definition of resistance/intolerance to Hydroxyurea after 3 months of at least 2 g/day Need for phlebotomy to keep hematocrit <45% Uncontrolled myeloproliferation PLT >400 x109/l, WBC >10 x109/l Less than 50% reduction of massive splenomegaly No complete relief of splenomegaly-related symptoms Hematological toxicity at the lowest active dose of HU Presence of leg ulcers or other unacceptable HU-related non-hematological toxicities PV Platelet higher than 600 x109/l, Platelets less than 400 x109/l with WBC less than 2.5 x109/l, or with Hb less than 10 g/dl at any dose of HU Unacceptable HU-related non-hematological toxicities ET Barosi et al. BJH, 2009 Barosi et al. Leukemia, 2007

The key therapeutic question in PV/ET How to contrast myeloproliferation to nullify the vascular risk? Clinical trials Clinical practice Comparing different cytoreductive strategies (PT-1, CYTO-PV) Testing new drugs (JAK2 inhibitors) Testing old drugs with the intention of clonal remission (interferon) Optimizing disease control

Operational needs for clinical practice in PV/ET Reliable and feasible monitoring tools for response evaluation A decision criterion for when changing therapeutic strategy because of resistance or intolerance

Monitoring therapy in ET/PV Monitoring of response to cytoreductive therapy of individual patients with PV/ET should adopt the ELN criteria (2009) proposed for defining the clinico-hematologic response. There is no strict indication to monitor molecular response routinely, except if the therapeutic intervention may induce molecular responses (to date IFN-α in PV). There is no indication to monitor BM response ELN recommendations, Barbui et al, JCO 2012

Changing therapeutic strategy (switching or intensifying therapy) Complete response Partial response Resistance or intolerance Uncontrolled disease No change Individualized decision Change

Individualized decision making in pts with partial response to therapy WBC Previous vascular event Ptl Need of phlebotomy spleen symptoms Change therapy Maintain therapy

Decision options in pts non responding to first-line conventional therapy (hydroxyurea) Second-line conventional therapy (interferon, busulphan, anagrelide) Experimental therapy (JAK2 inhibitors)