Myeloproliferative Neoplasms

Transcription

1 Myeloproliferative Neoplasms Judit Demeter CML chronic myeloid leukemia Semmelweis University, I st Department of Internal Medicine PV polycythaemia vera ET essential thrombocythaemia MF myelofibrosis

2 Leukemic white cell mass removed by cytapheresis from a 34-years-old patient diagnosed with blastic phase CML

3 Chronic myeloid leukemia (CML) Clonal disorder of the hematopoietic stem cells Aberrant granulopoesis Leukocytosis, basophilia, thrombocytosis Splenomegaly Normal CML

4 Defining Phases of CML Baccarani M, et al. Blood. 2013;122: ELN (European Leukemia Net) definitions of CML-CP, -AP, and BP Phase Definition Chronic None of the criteria for AP or BP are met Accelerated Blast 15%-29% blasts in blood or bone marrow > 30% blasts plus promyelocytes in blood or bone marrow, with < 30% blasts only 20% basophils in blood Persistent thrombocytopenia (platelet count < /L) unrelated to therapy Major route CCA/Ph+ on treatment 30% blasts in blood or bone marrow Extramedullary blast proliferation, apart from spleen AP, accelerated phase; BP, blast phase; CCA/Ph+, clonal chromosomal abnormalities in Philadelphia chromosome positive cells. 1. Baccarani M, et al. Blood. 2006;108: ; 2. Baccarani M, et al. J Clin Oncol. 2009;27:

5 Features of the chronic phase of CML 25-35% of all cases is asymptomatic, but accelerated and blastic phase Blood count: Physical exam: granulocytosis (frequently G/l) left shift in differenteial blood count Eosinophila,basophilia Thrombocytosis splenomegaly

6 140 years in the treatment CML (up to 2000) No treatment Palliative care Curative treatment Arsenic salts Splenic irradiation Busulphan Hydroxyurea (Litalir) Stem cell transplant Interferon-alpha

7 Once upon a time CML BCR-ABL1. Imatinib Philadelphia chromosome t(9;22) translocation BCR-ABL fusion proterin B. Druker STI 571 Imatinib (Glivec)

8 The breakthrough yrs survival>80%! Minimal side effects FDA appr Glivec (Imatinib), Novartis 9 22 Substrate 22q11.2 bcr abl bcr-abl IMATINIB Y Survival IM Proliferation ATP P P P Migration 9q34 Continuous treatment

9 Baccarani M, et al. Blood. 2013;122: European LeukemiaNet definitions of hematological and cytogenetic responses Response Hematologic CHR Definition WBC count < /L Basophils < 5% No myelocytes, promyelocytes, myeloblasts in the differential Platelet count < /L Spleen nonpalpable Cytogenetic CCyR No Ph+ metaphases PCyR 1%-35% Ph+ metaphases mcyr 36%-65% Ph+ metaphases mincyr 66%-95% Ph+ metaphases None > 95% Ph+ metaphases CCyR, complete cytogenetic response; CHR, complete hematologic response; mcyr, minor cytogenetic response; mincyr, minimal cytogenetic response; PCyR, partial cytogenetic response; WBC, white blood cell.

10 Grades of molecular response to TKI treatment CML monitoring categories Depth of molecular response At dg of CML number of leukemic cells 10 12, BCR-ABL1 level usually 100% ( International Scale =IS). Complete hematological response already after one nagyságrendnyi decrease in the numer of leukemic cells Complet cytogenetic response after another/further nagyságrendnyi decrease. Major molekular response after 3 log decrease, if BCR-ABL1 level is below 0,1%. Even deeper : deep molecular response (MR4.0, MR4.5, MR5.0). Kiss R et al (Bödör Cs), Magyar Onkológia (Hungarian Oncolgoy), 2017, 67 (1), 57-66

11 Chronic myeloid leukemia (CML) molecular monitoring ( Ist Dept of Pathology, Mol Hemat Lab)

12 Treatment and monitoring of CML: International recommendations Imatinib yearly cost (before generics): ~9 billionhuf

13 Before 2000 Disease duration and survival in CML Chronic phase Accelerated phase Blastic phase 3-5 years months 3-9 months After 2000 (most patients TKI treatment) Chronic phase Survival > 20 years? Permanent cure (w/o ASCT)? Ca patients in Hungary today (prevalence)

14 CML calculation of relative risk online risk calculator bloodref.com Sokal, Hasford and Eutos Score Calculator elérve

15 Chronic myelogenous leukemia CP CML First line treatment Available first line treatment: Imatinib (Glivec) 1x400 mg Nilotinib (Tasigna) 2x300 mg Dasatinib (Sprycel)1x100 mg Search for allogenic transplant donor and HLA typing warranted: Related donor: Warning signs at diagnosis (high risk, CCA/Ph+) TKI intolerance Failure of first line TKI treatment MUD search, if no available related donor: Failure of 2nd generation TKI in first line treatment Presence of T315I mutation Accelerated, or blast phase. Allogenic HSCT is mostly recommended for 3rd line of treatment. For indicating allo HSCT additional risk factors are also to be considered (HCT-CI, EMBT) Baccarani M et al.: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Blood. 2013;122(6):

16 CML - calculation of relative risk Clinical study calculation Definition of risk groups Sokal et al Exp 0,0116 x (age-43,4) + 0,0345 x (spleen size 7,51) + 0,188 x [(platelet count + 700) 2 0,563] + 0,0887 x (blasts 2,1) Low risk: <0,8 Intermediate risk: 0,8-1,2 High risk:>1,2 Euro Hasford et al ,666, if age >50 ys + (0,042 x spleem) + 1,0956, if platelet count > 1500 G/L + (0,0584 x blast cells) + 0,20399, if basophils >3% + (0,0413 x eosiophils) x 100 Low risk: 780 Közepes kockázat: High risk>:1481 Significance of risk stratification in choice of first line TKI high risk score supports using II. generation TKI in first line treatment. EUTOS Hasford et al Spleen x4 + basophils x 7 Low risk: 87 High risk: >87 Age is measured in years. Spleen size is measured in largest distance from costal arc in centimetres. Blast cells, eosinophils and basophils are calculated in percentage based on peripheral smear. ELN 2013 Baccarani M et al.: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: Blood. 2013;122(6):

17 Proposed schema for individualizing therapy based on comorbidities, goals of therapy, and disease risk profile. Hughes T, and White D Hematology 2013;2013: by American Society of Hematology

18

19 Myeloproliferative Neoplasms (MPN) - Genetics?

20 The evolving landscape of Ph- MPNs (2016) Ph. kr. JAK2 V617F JAK2 e 12 MPL CALR

21 Polycythaemia vera (PV), Essential Thrombocythaemia (ET) and myelofibrosis (MF) PV pancytosis, dominant polyglobulia splenomegalia aquagenic pruritus thrombotic risk increased ET platelet counts above 450 G/L Arterial thrombotic risk and bleeding tendencies Myelofibrosis (MF)

22 Polycythaemia vera WHO diagnosztic criteria (2016) Two major, or first major and two minor criteria Major criteria: 1. Hb>165 g/l; Hct>49% (male), or Hb>160 g/l; Hct >48% (nő), or increased red blood cell mass 2. Trilinear proliferation in the bone marrow 3. JAK v617f or JAK exon 12 mutation Minor criterium: 1. Subnormal szerum erythropoetin (EPO) level Arber DA et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;

23 Polycythaemia vera First line treatment: phlebotomy Repeated removal of 300 ml blood volume Replacement with physiologic saline infusion Keep hematocrit values below 0,45 Second line treatment : cytoreduction hydroxyurea Platelet aggregation inhibitors: aspirin

24 Essentialis thrombocythaemia: ET Chr. myeloproliferative disorder characterized by thrombocytosis. Bone marrow: the number of megakaryocytes is increased arterial thrombophilia + Significant tendency for bleeding

25 ET: increased number of megakaryocytes in bone marrow

26 Treatment of essential thrombocythaemia Is treatment necessary? Determinants 1. age 2. Presence of disease related symptoms (or former presence) 3. The platelet count Treatment is necessary 1. At any age, if the number of platelets is above 1500 G/l 2. In case of complications, already with platelet counts above 450 G/l 3. In asymptomatic elderly patients already when platelet count is 600 G/l cytoreductive treatment + platelet aggregation inhibitors

27 MYELOFIBROSIS hepatosplenomegaly

28 Myelofibrosis Chronic, clonal, malignant disorder splenomegaly, leukoerythroblastic blood count -teardrop shaped redblood cells (dacryocytes) in the peripheral smear Varying degree bone marrow fibrosis and extramedullary hemopoesis Incurable with conventional chemotherapy Survival: 4-5 years worst prognosis among chronic MPNs Occurrence: male/female ratio:1,2:1 Median age: 65 years

29 Myelofibrosis: peripheral smear Bone marrow fibrosis

30 Three Interrelated Concerns Comprise the Disease Burden of MF Debilitating symptoms combine to drastically impair quality of life (QoL) for patients with MF Spleen-related symptoms Profound discomfort Early satiety Painful infarcts Change in bowel habits Variceal bleeding Compromised mobility Portal hypertension Ascites Edema Splenomegaly Anemia/ Cytopenia MF Symptom Burden Prognostic constitutional symptoms Low-grade fever Weight loss/cachexia Night sweats Other MF-associated symptoms Recurrent gout Bone pain Ecchymosis Increased infection risk Pruritus Cytopenias Leukemic transformation RBC transfusion complications 1. Mesa RA, et al. Cancer. 2007;109:68-76; 2. Mesa RA. Blood. 2009;113: ; 3. Barosi G. J Clin Oncol. 1999;17:

31 MYELOFIBROSIS :treatment Supportive Treatment RBC transfusion in case of anaemia (hb under 100 g/l, symptomatic) No established treatment algorhytm hydroxyurea (Litalir) and/or -interferon cytoreduction steroids in cases with immunhemolysis+hypersplenism treatment of iron overload!! Stem cell transplantation?

32 Ruxolitinib Oral JAK1/JAK2 inhibitor FDA approval 2011 Size of spleen decreases in 28-41% of patients. Decrease of symptoms ( in 50%). Side effects : Anaemia Thrombocytopenia dose reduction Survival advantage: Probabiltiy at 5 years 56% with ruxo vs bets avalaible therapy (BAT) (44%) Harrisson C et al.: JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. N Eng J Med : Verovstek S et al.: A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. N Eng J Med : Harrisson C et al.: Long Term findings from COMFORT-II. Leu

33 Myeloproliferative Neoplasms Judit Demeter CML Semmelweis University, I st Department of Internal Medicine PV ET MF

34 Myeloproliferative Neoplasms (MPN) - Genetics?

35 Thank you for your attention!