for the myelodysplastic syndromes. Delayed transplantation for low risk myelodysplasia is a ssociated with improved outcome. Blood, 104, 579 \200\22385. 16. Ingram, W. et al. (2007). Allogeneic transplantation for myelodysplastic syndrome (MDS) . Blood Reviews, 21, 61 \200\22371. Further reading Khan, C. et al. (2012). Azacitidine in the management of patients with myel odysplastic syndromes. Ther Adv Hematol, 3(6), 355 \200\22373. Malcovati, L. et al. (2011). Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome an d its integration into the WHO classifi cation-based Prognostic Scoring System (WPSS). Haem atologica, 96, 1433 \200\22340. Mishra, A. et al. (2013). Validation of the revised Interna tional Prognostic Scoring System in treated patients with myelodysplastic syndromes. Am J H ematol, 88(7), 566 \200\22370. Pierdomenico, F. et al. (2013). Effi cacy and tolerability o f 5-day azacytidine dose-intensifi ed regimen in higher-risk MDS. Ann Hematol, 92(9), 1201 \200\2236. 249 MANAGEMENT OF MDS 250 CHAPTER 6 Myelodysplasia Response criteria An International Working Group proposed1 and subsequently modifi ed2 resp onse criteria to standardize assessment of clinical trials of therapy, to identify risk-bas ed treatment goals and to identify clinically meaningful responses. 4 aspects of response w ere defi ned: \200 Altering the natural history of MDS \200\224 see defi nitions in Table 6.9. \200 Cytogenetic response \200\224requires examination of 20 metaphases. \200 Hem atological improvement (Table 6.8 and 6.9) \200\224pre-therapy baseline is average of \211 2 measurements over at least 1 week, not aff ected by transfus ion. QoL \200\224correlation with Hb level.3 QoL assessment should be an integral part of MDS management. Table 6.8 Modifi ed IWG response criteria for hematological improvement2 Hematological improvement (HI) Response criteria (must last \211 8 weeks) Erythroid response (pre-treatment <110g/L) HI-E Hb i by \211 15g/L or d of RBC transfusions (for Hb \211 90g/L) by \211 4U/ 8 weeks comp ared to previous 8 weeks i of \211 30 \227 109/L for patients starting >20 \227 109/L; i from <20 to >20 \227 109/L and by at least 100% At least 100% i and absolute i >0.5 \227 109/L Platelet response (pre-treatment <100 \227 109/L) HI-P Neutrophil response (pre-treatment <1.0 \227 109/L) HI-N Progression or relapse after HI At least 1 of: \211 50% d from max. response in neutrophils or platelets d Hb by \211 15g/L \200 Transfusion dependence 251 RESPONSE CRITERIA Table 6.9 Modifi ed IWG response criteria: altering MDS natural history2 Category Response criteria (must last \211 4 weeks) BM \211 5% myeloblasts \200 persistent dysplasia \200 FBC: Hb \211 110g/L; platele ts \211 100 \227 109/L; Complete remission (CR) neutrophils \211 1.0 \227 109/L; blasts 0% Partial remission (PR) All CR criteria if abnormal pre-treatment except BM blasts d \211 50% but still >5% \200 BM \211 5% blasts and d \211 50% \200 FBC: if HI responses, to be noted in addition Fa ilure to achieve \211 PR but no evidence of progression for >8 weeks Marrow CR Stable disease Failure Death during treatment or worsening cytopenia, i % BM blasts or progression to more advance d subtype Relapse after CR/PR At least 1 of: \200 Return to pre-therapy % BM blasts \200 d \211 50% from max. neutro phil/platelet counts \200 Hb d \211 15g/L or transfusion dependence \200 Complete: dis appearance of abnormality Cytogenetic response without new one Partial: \211 50% reduction of abnormality If: \200 <5% blasts: \211 50% i to >5% \200 5 \200\22310% blasts: \211 50% i to >10% \200 10 \200\22320%blasts: \211 50% i to >20 % \200 20 \200\22330%blasts: \211 50% i to >30% Or any of: \200 \211 50% d max. neutr ophils/platelets \200 d Hb \211 20g/L \200 Transfusion dependence. \200 Endpoints: O S death from any cause \200 EFS: failure/death from any cause \200 PFS: disease progres sion/death from MDS \200 DFS: time to relapse \200 Cause-specifi c death: death related to MDS Disease progression Survival References 1. Cheson, B. et al. (2000). Report of an international working group to standar dize response criteria for myelodysplastic syndromes. Blood, 96, 3671 \200\2234. 2. Cheson, B. et al. (2006). Clinical application and proposal for modifi cation of the International Working Group (IWG) response criteria in myelodysplasia. Blood, 108, 419 \200 \22325. Jansen, A.J.G. et al. (2003). Quality of life measurement in patients with transfus ion- dependent myelodysplastic syndromes. Br J Haematol, 121, 270 \200\2234. 3. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 252 CHAPTER 6 Myelodysplasia Myelodysplastic/myeloproliferative diseases (MDS/MPD) This category was created in the WHO classifi cation of myeloid neo- plasms for a group of disorders that have both dysplastic a nd proliferative features at diagnosis and are diffi cult to assign to either myelodysplast ic or myeloproliferative groups.1 WHO classi \201 cation of MDS/MPD diseases \200 Chronic myelomonocytic leukemia (CMML). \200 Atypical chronic myeloid leukemia (aCML). \200 Juvenile myelomonocytic leukemia (J MML). \200 MDS/MPD unclassifi able (MDS/MPD-U). CMML Many patients who present with low WBC count and minimal spleno- megaly, however ultim ately progress to meet \200\230proliferative \200\231 criteria. Clinical features \200 Predominantly presents in >60 years age group, median 65 \200\2237 5 years; \231\202: \231\200 ratio 72:1. Often asymptomatic and found on routine FBC. \200 Weight loss, fatigue, night sweats may occur. \200 Skin and gum infi ltration may occur. \200 Splenomegaly (50%) and hepatomeg aly (up to 20%) usually only in cases with leucocytosis and constitutional symptoms. Serous eff usions (pericardial, pleural, ascitic, and synovial) associated with high PB monocytosis. Investigations and diagnosis \200 Investigations as for MDS. \200 Variable leucocytosis ; marked in 50%; neutrophilia in some patients. \200 Monocyte count >1.0 \227 109/L is d iagnostic minimum. \200 Variable anemia; platelets usually n or d. \200 Marrow typicall y hypercellular; blasts and promyelocytes <20%. \200 Immunophenotype of PB and BM: CD13+, CD33+, CD14 , CD64 , CD68 ; i % CD34 may be associated with early AML transformation. Karyotypic abnormalities associated with MDS found in 20 \200\22340% (8+, 7 \210\222, 7q \210\222, abnormal 12p); none specifi c for CMML apart from rarity of 5 q \210\222; Exclude 5q31 \200\22333 translocation and/or PDGFR gene re-arrangement; occur s in <1 \200\2232% of CMMLs, usually with marked eosinophilia; may be a unique entity; thes e patients may respond to imatinib.2 Hypokalaemia may be present. \200 Reactive causes of monocytosis must be excluded. WHO diagnostic criteria for CMML \200 Persistent peripheral blood monocytosis >1.0 \227 109/L. \200 No Ph chromosome or BCR-ABL fusion gene. \200 No rearrangement of PDGFRA or PDGFRB. \200 <20% myeloblasts, monoblasts, and promyelocytes in PB or BM. 253 MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES (MDS/MPD) Dysplasia in \211 1 myeloid lineages. If myelodysplasia absent or minimal, CMML may still be diagnosed if above criteria met, and: \200 An acquired clonal cytogenet ic abnormality is present in BM cells, or Monocytosis has been persistent for \211 3 months, and \200 All other causes of monocyto sis have been excluded. 3 subcategories have been de \201 ned: \200 CMML-1: <5% PB blasts and <10% BM blasts. \200 CMML-2: 5 \200\22319% PB blasts or 10 \200\22319% BM blasts or when Auer rods present with <20% BM or PB blasts. CMML-1 or CMML-2 with eosinophilia: above criteria met plus PB eosinophil count >1.5 \227 109/L; associated with complications related to eosinophil degr anulation: fever, fatigue, cough, angioedema, muscle pains, pruritus, diarrhea, endomyocard ial fi brosis, pulmonary infi ltrates. Prognostic factors BM blasts: median survival for CMML with <5% BM blasts 53 months vs 16 m onths for those with 5 \200\22320%. Management \200 Asymptomatic cases with near n hematology apart from a monocytosis of >1.0 \227 109/L require no intervention and should simply be monitored. The rapy otherwise supportive. Patients with symptoms, organomegaly, and/or ii WBC may respond to oral chemotherapy; hydroxycarbamide performed better than oral etoposide in a ra ndomized study.3 Azacitidine: ORR 39%; CR rate 11%; PR rate 3%; hematological improvement (HI) 25%. The medi an overall survival 12 months. Overall survival advantage in responders compared with non- responders: 15.5 months versus 9 months, respectively. Rarely: younger patients may be treated with high-dose therapy and allogeneic SCT which off ers only curative option. EBMT reported 5-year estimated OS 21% and DFS 18% and 52% TRM.4 Natural history Prognosis for asymptomatic patients is favorable (several years). For those requiring therapy, median survival is 6 \200\22312 months. Median survival overall is 20 \200\22340 months. AML (usually FAB M4/M5) develops in 720% after median of 1.5 \200\2232 y ears; poorly responsive to intensive chemotherapy. aCML5 Ph chromosome and BCR-ABL fusion gene \210\222ve CML. Rare; 1 \200\2232 cases per 10 0 cases of CML. \200 Occurs in elderly; median age in 7th or 8th decade. \200 Short med ian survival (11 \200\22318 months). \200 Most have symptoms related to anemia. \200 Sp lenomegaly frequent. \200 FBC: WCC >13; i WBC due to dysplastic immature (>10 \200\22320% ) and mature neutrophils; generally 35 \200\22396 \227 109/L though sometimes >300 \227 109 /L; PB monocytes rarely >10%; PB blasts usually <5%, 254 CHAPTER 6 Myelodysplasia always <20%; anemia and thrombocytopenia common; no or minimal basophilia (<2%) (cf. CML). BM: hypercellular due to i and dysplastic myeloid series; M:E ratio usually >10; often multilineage dysplasia; blasts <20%. Cytogenetic abnormalities frequent: 8+, 13+, 20q \210\222, i(17q), 12p \210\222. \200 No rearrangement of PDGFRA/B. Management: Hydroxycarbamide or etoposide may control the leucocytosis and d splenomegaly. Evolution to AML in 20 \200\22340%; patients die of BM failure. JMML6 Clonal disorder arising in pluripotent stem cell causing selective hyper- sensitivity to GM-CSF due to dysregulated signal transduction through RAS/MAPK pathway. Aff ects infan ts and young children (75% <3 years); \231\202: \231\200 ratio 72:1; 10% of cases occur in children with neurofi bromatosis type 1. \200 Most present with malaise, pallor, fever i nfection, or bleeding. \200 Maculopapular rash in 40 \200\22350%. \200 Hepatosplenomega ly almost universal; due to leukaemic infi ltration. \200 FBC: i WBC (usually 25 \200\223 35 \227 109/L; >100 \227 109/L in 5 \200\22310%) due to neutrophilia (with promyelocytes and myelocytes) and monocytosis (>1.0); eosinophilia and basophilia in a minority; anemia a nd thrombocytopenia usual; nucleated RBCs frequent. Polyclonal hypergammaglobulinaemia and i LDH in majority. \200 BM: hypercellular with mye loid proliferation; monocytes usually 5 \200\22310%. \200 Abnormal karyotype in 30 \200 \22340%; none specifi c. 33% carry PTPN11 mutations, 15 \200\22320% without evidence of neu rofi bromatosis NF1 mutations and 15 \200\22320% RAS mutations. Diagnostic criteria \200 PB monocytosis >1 \227 109/L. \200 Blasts (including promonoc ytes) <20% in PB and BM. \200 No Ph chromosome or BCR-ABL fusion gene. \200 Plus \211 2 of the following: Hemoglobin F i for age. \200 Immature granulocytes in PB. \200 WBC >10 \227 109/L \200 Clonal chromosomal abnormality (e.g. 7 \210\222). \200 GM-CSF hypersensitivity of m yeloid progenitors in vitro. Management No consistently eff ective therapy. Allogeneic SCT is the target-treat- ment of choice (up to 55% relapse). 5-year OS 750%.7 Untreated, 30% progress rapidly and die within 1 year of diagnosis. MDS/MPD-U8 Applied to patients with both myelodysplastic and myeloproliferative fea- tures but who do not meet the criteria for the 3 conditions on E p.252. 255 MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES (MDS/MPD) Diagnostic criteria \200 Clinical, laboratory, and morphological features of one of the categories of MDS with <20% blasts in PB & BM; and Prominent myeloproliferative features e.g. platelets \211 600 \227 109/L or WBC \211 13 \227 109/L prominent splenomegaly; and Has no prior history of MPD or MPS, cytotoxic, or growth factor therapy and no BCR-ABL fusion gene, 5q-, t(3;3)(q21;q26) or inv3(q21;q26); or Patient has mixed features of MPD and MDS and cannot be assigned to any other category of MDS, MPD, or MDS/MPD. JAK2V617F mutation found in 25%.9 Management Manage as in patients with MDS or atypical MPD . References 1. Vardiman, J.W. et al. (2001). Myelodysplastic / myeloproliferative diseases. In Jaff e, E.S. et al. (eds.) World Health Organization classifi cation of tumors. Patholog y and genetics. Tumors of haematopoietic and lymphoid tissues, vol 1. Lyon: IARC Press, pp. 46 \200\22359. 2. Apperley, J.F. et al. (2002). Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor recep tor beta. N Engl J Med, 347, 481 \200\2237. 3. Wattel, E. et al. (1996). A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Blood, 88, 2480 \200\2237. 4. Kroger, N. et al. (2002). Allogeneic stem cell transplantation of adult chronic myelomonocytic leukemia: a report on behalf of the Chronic Leukemia Working Party of the Eu ropean Group for Blood and Marrow Transplantation (EBMT). Br J Haematol, 118, 67 \200\22373 . 5. Costello, R. et al. (1997). Clinical and biological aspects of Philadelphia-negative/BCR - negative chronic myeloid leukemia. Leuk Lymphoma, 25, 225 \200\22332. 6. Vardiman, J.W. et al. (2001). Juvenile myelomonocytic leukemia. In Jaff e, E.S. et al. ( eds.) World Health Organization classifi cation of tumors. Pathology and genetics. Tumors o f haematopoietic and lymphoid tissues, vol 1. Lyon: IARC Press, pp.55 \200\2237. 7. Locatelli, F. et al. (2005). Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood, 10 5, 410 \200\22319. 8. Bain, B. et al. (2001). Myelodysplastic / myeloproliferative disease, unclassifi able. I n Jaff e, E.S. et al. (eds.) World Health Organization classifi cation of tumors. Pathology and genetics. Tumors of haematopoietic and lymphoid tissues, vol 1. Lyon: IARC Press, pp.4 6 \200\22359. Jones, A.V. et al. (2005). Widespread occurrence of the JAK2 V617F mutation i n chronic myeloproliferative disorders. Blood, 106, 2162 \200\2238. 9. Further reading Costa, R. et al. (2011). Activity of azacitidine in chronic myelomonocytic leukemia. Cancer, 117(12), 2690 \200\2236. Thorpe, M. et al. (2012). Treatment of chronic m yelomonocytic leukemia with 5-azacitidine: a case series and literature review. Leuk Res, 3 6(8), 1071 \200\2233. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haema topoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. This page intentionally left blank 257 Chapter 7 Myeloproliferative neoplasms Myeloproliferative neoplasms (MPNs) 258 Pathogenesis of the MPNs 260 Polycythaemia vera (PV ) 264 Natural history of PV 270 Management of PV 272 Secondary erythrocytosis 278 Relative erythrocytosis 279 Idiopathic erythrocytosis 280 Essential thrombocythaemia 281 Reactive th rombocytosis 290 Primary myelofi brosis 292 Chronic neutrophilic leukemia 304 Eosinophilic syndromes and neoplasms 306 Mastocytosis (mast cell disease) 312 Systemic mastocytosis 316 MPN \200\224unclassifi able 323 258 CHAPTER 7 Myeloproliferative neoplasms Myeloproliferative neoplasms (MPNs) The term \200\230myeloproliferative neoplasm \200\231 (MPN) replaces the term \200\230chronic myeloproliferative disorder \200\231 (MPD) in the 2008 revision of the WHO classifi cation.1 This revision refl ects information on molecular pathogenesis not previously available in 2001.2 The MPNs are a het- erogeneous group of cl onal haemopoietic stem cell neoplasms with excessive proliferation of 1 or more of the eryt hroid, megakaryocytic, or myeloid lineages and relatively normal maturation resulting in i numbers of red cells, platelets, and/or granulocytes in the peripheral blood. Constitutive tyrosine kinase activation appears to be a common pathogenetic mechanism. Phenotypic divers ity is a result of diff erent mutations aff ecting protein kinases or related molecules cau sing dif- ferent signal transduction abnormalities.3 MPNs are characterized by eff ective h aematopoiesis devoid of dyserythropoiesis, granulocytic dys- plasia, or monocytosis. Spleno megaly and hepatomegaly are common. The MPNs share a potential to progress to myelofi brosi s, ineff ective haematopoiesis or blastic transformation. The MDS/MPN over-lap syn- dromes are discussed in E Chapter 6 (MDS). The myeloid/lymphoid neoplasms with eosinophilia and ab normalities of PDGFRA/B or FGFR1 are discussed here. 2008 WHO classi \201 cation1,4 MPNs \200 Chronic myelogenous leukemia, CML (discussed on E p.148). \200 Polycythaemia vera (PV). \200 Essential thrombocythaemia (ET). \200 1 myelofi brosis (MF). \200 Chronic neutrophilic leukemia. \200 Chronic eosinophilic l eukemia (CEL), not otherwise categorized. \200 Hypereosinophilic syndrome (HES). \200 M astocytosis: cutaneous, extracutaneous, and systemic mastocytosis, mast cell leukemia, and mast cell sarcoma. MPNs, unclassifi able. Myelodysplastic/myeloproliferative neoplasms: E See Chapter 6. This category was created in the WHO classifi cation of myeloid neo- plasms for a group of disorders that have both dysplastic and pro- liferative features at diagnosis and are diffi cult to assign to either myelodysplastic or myeloproliferative groups: \200 Chronic eosi nophilic leukemia (CEL), not otherwise categorized. \200 CMML. \200 Atypical CML, BCR-A BL1 negative. \200 Juvenile monomonocytic leukemia. \200 Myelodysplastic/myeloprolifera tive neoplasm, unclassifi able. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PGFRA, PDGFRB, or FGF R1 Discussed later in this chapter (E pp.307 \200\223308). 259 MYELOPROLIFERATIVE NEOPLASMS (MPNS) References 1 Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myelo proliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diag nostic algorithms. Leukemia, 22, 14 \200\22322. 2 Vardiman, J.W. et al. (2002). The World Health Organization (WHO) classifi cation of the myeloid neoplasms. Blood, 100, 2292 \200\2232302. 3 Teff erin, A. and Gilliland, D.G. (2007). Oncogenes in myeloproferative disorders. Cell C ycle 6, 550 \200\22366. 4. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 260 CHAPTER 7 Myeloproliferative neoplasms Pathogenesis of the MPNs Although included in the WHO classifi cation of MPNs, CML is widely regarded as a separate entity characterized by the presence of BCR-ABL which is a consequence of t(9;22) and has a clear role in pathogenesis (see E Chronic myeloid leukemia (CML), p.148). Mutations of a number of protein kinases have now been described in the BCR-ABL negative MP Ns. The JAK2-V617F mutation was detected using diff erent methods.1,2 This G >T transversio n in exon 14 is found in up to 95% of patients with PV.3 Several diff erent activating muta tions have been found in JAK2 exon 12 in JAK2-V617F negative patients with PV with isolated erythropoiesis without leucocytosis or thrombocytosis.4 Thus 98% of patients with PV have a JAK2 mutation. This point mutation in the \210\222ve regulatory pseudokinase domain of JAK2 leads to cons titutive activation of the JAK-STAT (signal transducers and activators of transcription) si gnaling pathway involved in regulation of cell growth and diff erentiation. Cytokines and g rowth factors (e.g. EPO) activate this pathway by binding to cell surface receptors. JAKs b ound to the cytoplasmic domain of the receptor are activated by binding of ligand. These ac tivate STAT proteins which dimerize, translocate to the nucleus and activate transcription of target genes. JAK2 is the sole JAK kinase involved in EPO-receptor signaling.1,2 The mut ation has been found in diff erent lineages including B and T lymphocytes. The name \200 \230Janus \200\231 is taken from the 2-faced Roman god of beginnings and endings, because t hese kinases have 2 near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other nega- tively regulates the kinase activity of the fi rst. Expression of JAK2-V617F (or an exon 12 mutant) confers cytokine hypersensitivity and cytok ine-independent growth to haemopoietic cells1,2 and in a mouse model results in erythrocyto sis and marrow fi brosis but not thrombocytosis.5 Constitutive activation of the JAK- STAT pathway causes excessive erythropoiesis in PV though its rela- tionship to thrombotic compl ications and progression to myelofi brosis remains unclear.1 However leucocytosis (mainly n eutrophilia) appears to be a risk factor for thrombosis in PV and ET and JAK2-V617F-mediate d granulocyte activation may contribute to thrombosis.6,7 The fi nding of JAK2-V617F \210 \222ve but clonal AML transformation in PV suggests that a prior abnormality may be present as appears to occur in familial clonal MPN.1,8 Rare families have an i incidence of MPN wi th clonal haematopoiesis and most aff ected members carry a somatic mutation of JAK2. It is suggested that this low penetrance, late onset familial clonal MPN is due to an inherited predisposition to somatic mutations.1,8 The JAK2-V617F mutation has also been found in 58% of patients with PMF, 50% with ET3 and 50% with refractory anemia with ringed sidero- blast s associated with thrombocytosis (RARS-T),9 a provisional \200\230MDS/