Myeloproliferative Neoplasms and Treatment Overview

Transcription

1 Myeloproliferative Neoplasms and Treatment Overview George Nesr Clinical Research Fellow in Haematology Haematology Department Imperial College Healthcare NHS Trust

2 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

3 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

4 Clonal disorders characterised by overproduction of differentiated haematopoietic cells, with overlapping clinical and molecular features. Rare in terms of incidence. Most common years of age. Rare < 20 years and in children. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391.

5 CHRONIC PHASE Polycythaemia vera (PV) Essential thrombocythemia (ET) Primary myelofibrosis (PMF) Or Post PV/ET myelofibrosis MPN Blast Phase/ Leukaemic transformation Prefibrotic/Early PMF

6 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

7 1879: Gustav Heuck, a German surgeon, described PMF. 1892: Louis Henri Vaquez, a French physician, was the first to describe PV. 1934: ET was described in by Emil Epstein and Alfred Goedel, both Austrian pathologists. 1951: William Dameshek postulated that "erythroblasts, granulocytes and megakaryocytes proliferate en masse rather than separately" : Philip Fialkow, an American physician scientist established all four classic MPN as clonal stem cell diseases. 2005: JAK2 V617F mutation identified. 2006: MPL mutation identified. 2007: other JAK2 mutations identified. 2015: CALR mutation identified.

8 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

9 Additional mutations Iron stores Gender JAK 2 CALR EPO level Mutation order MPL? Others Abnormal signaling down the JAK-STAT pathway Disease phenotype Radek et al, Experimental Haematology, 2015

10 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

11 Asymptomatic: accidental discovery on follow up FBC Pruritis, classically after a hot shower (aquagenic pruritis) Non specific symptoms: fatigue, drenching night sweats, weight loss, night fever Increased viscosity: headache, blurring of vision Splenomegaly: lt upper quadrant abdominal discomfort/pain, early satiety Thrombotic manifestations Bleeding tendency (platelets > 1000 x 10 9 /L)

12 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

13 2008 WHO PV criteria Major criteria 1. Hemoglobin > 18.5 g/dl in men or 2016 WHO PV criteria Major criteria 1. Hemoglobin >16.5 g/dl in men Hemoglobin >16.0 g/dl in women or, Hematocrit >49% in men Hematocrit >48% in women or, increased red cell mass (RCM) > 25% above mean normal predicted value. 2. BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size) 3. Presence of JAK2V617F or JAK2 exon 12 mutation Minor criterion Subnormal serum erythropoietin level Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion. Hemoglobin >16.5 g/dl in women or, Hematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence or, hemoglobin > 17 g/dl in men, 15 g/dl in women if associated with a documented and sustained increase of at least 2 g/dl from a person's baseline value that cannot be attributed to correction of iron deficiency or, increased red cell mass (RCM) > 25% above mean normal predicted value. 2. Presence of JAK2V617F or JAK2 exon 12 mutation Minor criterion 1. Subnormal serum erythropoietin level 2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 3. Endogenous erythroid colony formation in vitro Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria

14 2016 WHO ET criteria Major criteria 1. Platelet count /L 2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers 3. Not meeting WHO criteria for BCR-ABL1 + CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms 4. Presence of JAK2, CALR, or MPL mutation Minor criterion Presence of a clonal marker or absence of evidence for reactive thrombocytosis Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion 2008 WHO ET criteria 1.Sustained platelet count /L 2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis. 3. Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABL1 positive CML, or myelodysplastic syndrome, or other myeloid neoplasm. 4. Demonstration of JAK2 V617F or other clonal marker, or in the absence of JAK2 V617F, no evidence of reactive thrombocytosis. Diagnosis requires meeting all 4 criteria

15 2008 WHO overt PMF criteria 2016 WHO overt PMF criteria Major criteria 1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 2. Not meeting WHO criteria for ET, PV, BCR-ABL1 + CML, myelodysplastic syndromes, or other myeloid neoplasms 3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis Minor criteria Presence of at least 1 of the following, confirmed in 2 consecutive determinations: a. Anemia not attributed to a comorbid condition b. Leukocytosis /L c. Palpable splenomegaly d. LDH increased to above upper normal limit of institutional reference range e. Leukoerythroblastosis Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion Major criteria 1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin or collagen fibrosis,or,in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (ie, prefibrotic cellular-phase disease) 2. Not meeting WHO criteria for polycythemia vera, BCR-ABL1 positive chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid disorders 3. Demonstration of JAK2 V617F or other clonal marker (eg, MPLW515K/L), or, in the absence of the above clonal markers, no evidence that bone marrow fibrosis is secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies Minor criteria a. Anemia not attributed to a comorbid condition b. Palpable splenomegaly c. LDH increased to above upper normal limit of institutional reference range d. Leukoerythroblastosis Diagnosis requires meeting all 3 major criteria and 2 minor criteria

16 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

17 PV Low Risk (age < 60 years, no previous history of thrombosis) High Risk (age > 60 years, and/or previous history of thrombosis) Venesection to maintain hematocrit < 45%, low dose aspirin Cytoreduction, ± venesection to maintain hematocrit < 45%, low dose aspirin

18 ET Low Risk (age < 60 years, no previous history of thrombosis, platelets < 1500) High Risk (age > 60 years, and/or previous history of thrombosis, and/or platelets > 1500) Low dose aspirin Cytoreduction ± low dose aspirin

19 Follow up Cytoreduction EPO/ Transfusion Splenectomy/ splenic irradiation According to the prognostic/risk score, and the presence of symptoms Allogeneic SCT Ruxolitinib

20 Unfavourable karyotype +8, -7/7qi(17q), inv(3), -5/5q- 12p- 11q23 rearrangement IPSS: International Prognostic Scoring System; D- IPSS: Dynamic International Prognostic Scoring System

21 Scherber et al, Blood, 2011

22 Hydroxyurea: non specific cytoreductive chemotherapy, skin changes, theoretical risk of acute leukaemia. Anagrelide: platelets mainly, cardiac toxicity, headache,? fertility, dose modification according to egfr. Interferon: injections, flu like symptoms, thyroid dysfunction, depression. Pegylated interferon Ruxolitinib: splenomegaly and disease related symptoms, anaemia, thrombocytopenia, infections (latent TB, HBV, herpes zoster), skin cancer, PML, no live attenuated vaccination, NOT TO BE STOPPED SUDDENLY! Danazol: anaemia, androgenic side effects, PSA monitoring in males, elevated liver enzymes, regular US surveillance, drug interactions, only for 6 months. Thalidomide + steroids: neuropathy, steroids side effects. EPO injections. Transfusion: iron overload.

23 Splenectomy: hepatomegaly,? progression. Splenic irradiation: cytopenias.

24 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

25 ET > PV > PMF JAK II mutation associated with complications and fetal loss. Hydroxycarbamide and anagrelide contraindicated. Aspirin usually all through gestation. Interferon for cytoreduction. Hct level for venesection according to the stage in gestation. LMWH for 6 weeks post partum.

26 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

27 10-19% blasts in bone marrow or peripheral blood (accelerated phase) > 20% blasts in bone marrow or peripheral blood (blast phase) PMF > PV > ET Risk factors: Old age > 60 years? Hydroxycarbmide? Splenectomy Median overall survival duration of 2.6 month. Treatment options: Supportive treatment +/- low dose chemotherapy. Hypomethylators (5 AZA, decitabine). Ruxolitinib + 5 AZA AML induction type chemotherapy. Allogeneic SCT. Clinical trials.

28 Overview Historical Background Pathogenesis Clinical Picture and Complications Criteria for diagnosis (Implications of the 2016 WHO update) Management Pregnancy Progression to leukaemic phase Future directions

29 Orlova et al, Expert Opinion on Therapeutic Targets, 2017 Drug Ruxolitinib Momelotinib Itacitinib NS-018 Pacritinib LY Umbralisib (TGR-1202) Idelalisib INCB Rigosertib Glasdegib (PF ) Sonidegib (LDE225) LCL161 Idasanutlin (RG7388) PRIMA-1MET (APR-246) IMG-7289 Givinostat (ITF2357) Panobinostat Azacitidine Decitabine PU-H71 AUY922 Target JAK1/2 JAK1 JAK2 PI3Kδ PI3K and PLK pathways Sonic hedgehog pathway ciap1 and ciap2 TP53 - MDM2 TP53 LSD1 Class I and class II HDACs Pan-HDAC Hypomethylation HSP90

30 SIMPLIFY 2: In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to best available therapy for the reduction of spleen size by at least 35% compared with baseline. Pacritinib: can be used in thrombocytopenic patients, was on hold in Feb 2016, resolved and currently in a dose finding study.

31 NCT A Phase 2 Study Evaluating Tolerability and Efficacy of Navitoclax in Combination With Ruxolitinib in Subjects With Myelofibrosis Guy's and St Thomas' NHS Foundation, London Recruiting Christie NHS Foundation Trust, Manchester Not yet recruiting NCT Long-term Phase 2 Study Evaluating the Effect of Givinostat in Patients With Chronic Myeloproliferative Neoplasms Belfast City Hospital, Belfast Royal Cornwall Hospital, Truro Recruiting Recruiting

32 NCT A Safety and Efficacy Phase 2 Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasmassociated Myelofibrosis Who Have Anaemia With and Without Red Blood Cell-transfusion Dependence Imperial College London, London Guys Hospital, London University of Oxford, Oxford Recruiting Recruiting Recruiting Belfast Health and Social Care Trust, Belfast University Hospital of Wales, Cardiff Not yet recruiting Not yet recruiting TAMARIN Study EudraCT number Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms MEASURES Study

33 Take home message Heterogeneous group of diseases, sometimes no sharp boundaries. Limited therapeutic options. Address cardiovascular risk factors. Quality of life.