amplifi cation and support an etiologic role for MLL gain of function in myeloid malignanci es. Blood, 103, 229 \200\22335. 230 CHAPTER 6 Myelodysplasia Classi \201 cation of MDS The historical FAB classifi cation has largely been superseded b y the revised 2008 WHO classifi cation of MDS.1 The NCCN guidelines2 include the FAB classi fi cation for historical context, the same is done here. World Health Organization (WHO) system1 (See Table 6.1.) \200 Classifi cation of MDS base d on morphology, karyotype, and clinical features that defi nes subgroups and provides valu able prognostic information useful for clinical decision-making. Initially proposed in 2001 . Revised in 2008.1,3 \200\2236 Diagnosis of AML if \211 20% blasts in PB or BM (as opposed to the FAB classifi cation whi ch has a \200\230RAEB-t \200\231 category, which is acknowledged as a footnote to the WHO classifi cation). Defi nes 2 subtypes of RAEB: RAEB-1 (5 \200\2239% BM blasts) and RAEB-2 (10 \200\22319% BM blasts) refl ecting worse clinical outcomes with \211 10% blasts. A footnote to the classi fi cation acknowledges the RAEB-t category from the old FAB classifi cation. WHO defi nes t his as AML. \200 Recognizes the \200\2305q \210\222 syndrome \200\231 as a distinct narr owly defi ned entity. \200 Removed CMML to a newly created disease group: MDS/MPD. The 2008 revision included a new subtype, refractory cytopenia with unilineage dysplasia (R CUD). Unilineage dysplasia is accepted for diag- nosis provided it persists \211 6 months and other causes of dysplasia are excluded. Further subtyped in refractory anemia (RA), ref ractory neu- tropenia (RN), and refractory thrombocytopenia (RT). French \200\223American \200\223British (FAB) system \200 Its use has been superseded by WHO system. \200 Morphology-based classifi cation used since 1982.7 \200 Requires dyspl astic changes in \211 2 lineages. \200 Useful for predicting prognosis and risk of evolu tion to acute leukemia. FAB classi \201 cation \200 Refractory anemia (RA): cytopenia of 1 peripheral blood (PB) lineage; normo- or hypercellular marrow with dysplasia \211 2 lineages; <1% PB blasts; <5% BM blasts. 25% of patients. Refractory anemia with ringed sideroblasts (RARS): defi ned as for RA plus ringed siderobla sts constituting >15% nucleated erythroid cells; 15% of patients. Refractory anemia with excess blasts (RAEB): cytopenia of \211 2 PB lineages; dysplasia of all 3 BM lineages; <5% PB blasts; 5 \200\22320% BM blasts; 35% of patients. Refractory anemia with excess blasts in transformation (RAEB-t): cytopenia of \211 2 PB li neages; dysplasia of all 3 BM lineages; \211 5% PB blasts; 21 \200\22330% BM blasts or Aue r rods in blasts; 15% of patients. Chronic myelomonocytic leukemia (CMML): PB monocytosis (>1 \227 109/L); <5% PB blasts; \211 20% BM blasts; 10% of patients. 231 CLASSIFICATION OF MDS Table 6.1 WHO classifi cation system1 Condition PB \201 nding BM \201 ndings No or rare blasts 3 subtypes: \200 Refractory anemia Dyserythropoiesis, or Dysgranulopoiesis, or Dysmegakaryocytopoiesis only Refractory cytopenia with unilineage dysplasia (RCUD) (RA) Refractory neutropenia (RN) <5% blasts <15% ringed sideroblasts Refractory thrombocytopena (RT) Anemia No blasts \211 15% ringed sideroblasts erythroid dysplasia only <5% blasts Refractory anemia with ringed sideroblasts (RARS) Cytopenias (bi- or pan-) No or rare blasts No Auer rods <1 \227 109/L monocytes Dysplasia in \211 10% cells in \211 2 myeloid cell lines <5%blasts No Auer rods <15% ring ed sideroblasts Refractory cytopenia with multilineage dysplasia (RCMD) As RCMD As RCMB but with \211 15% ringed sideroblasts RCMD-RS Cytopenias <5% blasts No Auer rods <1 \227 109/L monocytes Unilineage or multilineage dysplasia 5 \200\2239% blasts No Auer rods Refractory anemia with excess blasts (RAEB-1) Cytopenias 5 \200\22319% blasts Auer rods <1 \227 109/L monocytes Unilineage or multilineage dysplasia 10 \200\22319% blasts Auer rods Refractory anemia with excess blasts (RAEB-2) Anemia <5% blasts Platelets n or i MDS with isolated del(5q) n to i megakaryocytes with hypolobated nuclei <5% blasts No Auer rods Isolated del(5q) Cytopenias Unilineage dysplasia or no dysplasia Characteristic MDS cytogenetics Blasts <5% MDS \200\224unclassifi ed (MDS-U) Reproduced from reference 1 with permission. Copyright American Society of Hematology. 232 CHAPTER 6 Myelodysplasia References 1. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoieti c and Lymphoid Tissues, 4th ed. Lyon: IARC. 2. NCCN (2014). NCCN Practice Guidelines in Oncology: Myelodysplastic Syndromes, V2.2014. Fort Washington, PA: NCCN. 3. Swerdlow, et al. (2008). WHO classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC 3. Vardiman, J.W. et al. (2009). The 2008 revision of the World Health Organization (WHO) c lassifi cation of myeloid neoplasms and acute leukemia: rationale and important changes. Bl ood, 114, 937 \200\22351. 4. Germing, U. et al. (2000). Validation of the WHO proposals for a new classifi cation of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leukemia Res, 24, 983 \200\22392. 5. Malcovati, L. et al. (2005). Prognostic factors and life expectancy in myelodysplastic syndromes classifi ed according to WHO criteria: a basis for clinical decision making. J Cl in Oncol, 23, 7594 \200\223603. 6. Bowen, D. et al. (2006). Prospective validation of the WHO proposals for the classifi ca tion of myelodysplastic syndromes. Haematologica, 91, 1596 \200\223604. 7. Bennett, J.M. et al. (1982). Proposals for the classifi cation of the myelodysplastic sy ndromes. Br J Haematol, 51, 189 \200\22399. 233 CLASSIFICATION OF MDS 234 CHAPTER 6 Myelodysplasia Clinical features of MDS \200 Patient may be asymptomatic. Incidence i with age. \200 D iffi cult diagnosis in patient with multiple comorbidities where anemia of chronic disease is also in the diff erential diagnosis. \200 Presentation blood results range from mild a nemia to profound pancytopenia. \200 Macrocytic or normocytic anemia usual (60 \200\22380%). \200 neut ropenia (50 \200\22360%). \200 thrombocytopenia (40 \200\22360%). Isolated thrombocytopenia is an unusual presentation for MDS. \200 Symptoms of underlying cytopenias and cellular dysfunction may develop: \200 Anemia \200\224fatigue, shortness of breath, exacerbation of cardiac symptoms. Neutropenia and dysfunctional granulocytes \200\224recurrent infection. \200 Thrombocytop enia and dysfunctional platelets \200\224spontaneous bruising, purpura, bleeding gums. Constitutional symptoms including anorexia, weight loss, fevers, and sweats usually features of more \200\230advanced \200\231 subgroups. Splenomegaly/organomegaly is not seen in MDS. Investigation and diagnosis History: prior exposure to chemotherapy/radiation; FH of MDS/AM L; symptoms of anemia, recurrent infection, bleeding or bruising; timing, severity, and spe ed of onset of cytopenias; previous transfusion; medi- cation history and co-morbidities. Examination: pallor; infection; bruising. FBC: macrocytic/normocytic anemia neutropenia thrombocyto- penia thrombocytosis: \200 Hb <110g/L and/or \200 Neutrophilis <1.5 \227 109/L and/or \200 Platelets <100 \227 109/L. Blood \201 lm: essential. Morpholog ical dysplastic features: macrocytosis; dimorphic red cells; basophilic stippling in RBCs; dysplastic granulocytes: pseudo-Pelger forms (Fig. 6.1), hypersegmented neutrophils, hypogr an- ular neutrophils, dysmorphic monocytes blasts; platelets can be large or hypogranula r. Reticulocyte count: not i. U&E, LFTs, ECG, and CXR: no typical abnormalities; to assess co-mor- bidity. Serum ferritin, vitamin B12, and RBC folate: usually n levels; ferritin may be elevated in RARS/RCMD-RS. Serum EPO level: (prior to transfusion); indicates potential for response to EPO. BM aspirate: assess cellularity, M:E ratio and blast %; demonstrates >10% dysplastic cells in \211 1 lineage; megaloblastoid erythropoiesis, nuclear- 235 CLINICAL FEATURES OF MDS cytoplasmic asynchrony in myeloid/erythroid precursors, dysmorphic megakaryocytes or micro- megakaryocytes; Perl \200\231s stain: normal/ i storage Fe; \211 15% ringed sideroblasts ( RARS/RCMD-RS). BM trephine biopsy: assess cellularity, usually i/n but note hypocellular va riant (hypoplastic MDS); may show multifocal accumulation of imma- ture (CD34+) progenitors (formerly termed \200\230abnormal localization of immature myeloid precursors \200\231 (A LIPs) centrally in interstitium),1 mega- karyocyte dysplasia, i mast cells; i reticulin or fi brosis; i storage Fe; excludes occult neoplasia or alternative hematological diagnosis. Immunohistochemistry: minimum of CD34, CD31, CD42, or CD61 (megakaryocytes) recommended in most cases; CD3/15/20/25/117 in selected cases.1 BM cytogenetic analysis: may demonstrate c lonal chromosome abnormality(s) confi rming diagnosis and provide prognostic information; k aryotype evolution is associated with progression; diagnosis of MDS associated with isolate d del(5q). \200 FISH useful if low metaphase yield or diffi cult case. \200 To exclude Fanconi and dyskeratosis congenita in familial cytopenia. HLA-typing and CMV serology: for patients eligible for allogeneic SCT. HIV serology: in sel ected cases. Flow cytometry: in selected cases; to exclude PNH (hypoplastic marrow). HLA-DR 15 screening: in younger patients with hypoplastic marrow and normal cytogenetics (possible response to immunosuppression). Clonality studies: used in some centers to establish diagnosis in diffi cult cases; fl ow c ytometry for clonal BM blasts expressing phenotypic devia- tions. Consider HIV testing in all patients: diagnostic criteria are summarized in E Table 6.1, p. 231 according to the WHO classifi cation (2008). Cytopenias are fl uctuant and their trend needs to be observed. A diag- nosis of \200\230idiopathic cytopenia of uncertain (undeterm ined) signifi cance \200\231 (ICUS) was introduced to describe cases with cytopenia in \211 1 lineage for \211 6 months but that do not meet the minimal criteria for MDS and can not be explained by another diagnosis. This entity is diff erent to the MDS-U category. A r epeat BM if MDS is continued to be suspected might be indicated at a later time point. The defi nitive diagnosis of early MDS (e.g. isolated cytopenia) may be diffi cult; regular review with repeat blood count and fi lm assessment is recommended; in all cases a measure of the speed of onset and evolu- tion of the disease over several months is of prognostic value. Labeling a patient as having MDS should only be done once the diag- nosis is clear and conf i rmed. If features are mild or diagnostic criteria are not met the patient should be monit ored. Repeat investigations might be indicated at a later stage. 236 CHAPTER 6 Myelodysplasia Fig. 6.1 Blood fi lm in MDS showing bilobed pseudo-Pelger neutrophil (E see color plate sec tion). Cytogenetic analysis \200 Cytogenetic abnormalities are found in 40 \200\22370% de novo M DS and 80 \200\22390% 2 MDS. Cytogenetic analysis yields 3 patterns: Normal karyotype. \200 Single abnormalities. \200 Complex karyotypes ( \211 3 abnormali ties): 30% de novo MDS and 50% 2 MDS. More complex abnormalities are associated with more aggressive subtypes and higher % blasts and with 2 MDS. They are part of the prognostic scoring systems. Single or complex abnor malities at diagnosis may evolve during course of disease. Most frequent abnormalities involve chromosomes 5, 7, 8, 11, 12, 13, 17, and 20; most typical are 8+, 7 \210\222 or 7q \210\222, 5 \210\222 or 5q \210\222. Prognostic value \200 Specifi c abnormalities hold prognostic value. See E Tables 6.2 to 6.7 later in this chapter. Excluded: t(8;21), t(15;17), inv(16). These fi ndings constitute AML (irrespective of blast count). 237 CLINICAL FEATURES OF MDS Diff erential diagnosis Exclude: \200 Other causes of anemia \200\224haematinic defi cien cy, haemolysis, blood loss, renal failure. Other causes of neutropenia \200\224drugs, viral infection. \200 Other causes of thromboc ytopenia \200\224drugs, ITP. \200 Other causes of bi-/pancytopenia \200\224drugs, infecti on, aplastic anemia. \200 Reactive causes of BM dysplasia \200\224megaloblastic anemia, H IV infection, alcoholism, recent cytotoxic therapy, severe intercurrent illness. Other causes of marrow hypoplasia in hypoplastic MDS \200\224aplastic anemia, PNH. Anemia of chronic disease. Reference 1. Valent, P. et al. (2007). Defi nitions and standards in the diagnosis and trea tment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuke mia Res, 31, 727 \200\22336. 238 CHAPTER 6 Myelodysplasia Prognostic factors in MDS International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R) \200 (The initia l IPSS from 1997/19981 has since been revised in 2012 in the Revised IPSS (IPSS-R).2 Both s coring systems are included here (Tables 6.2 to 6.5).) Uses % BM blasts, BM cytogenetics, and number of cytopenias to calculate a risk score and s tratify patients into 4 distinct groups. Improved prognostic power for both survival and evolution into AML compared with earlier systems. IPSS score should be calculated during a stable clinical state and not, for example, during fl orid infection at initial presentation. IPSS score is the \200\230gold standard \200\231 for risk assessment in patients with de novo DS and may be used to assist management decisions. Table 6.2 Calculation of IPSS Score Prognostic variable Score value 0 0.5 1.0 1.5 2.0 BM blast % <5 5 \200\22310 \200\223 11 \200\22320 21 \200\22330 Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 Karyotype: Good: normal, \210\222Y alone, del(5q) alone, del(20q) alone. Poor: complex ( \211 3 abnormalities) or chromosome 7 anomalies. Intermediate: other abnormalities. Cytopen ias: Hb <100g/L; neutrophils <1.8 \227 109/L; platelets <100 \227 109/L. Table 6.3 Prognosis by IPSS Score1 IPSS risk group (% patients) Combined score Median survival 25% AML evolution Low (33) 0 5.7 years 9.4 years Intermediate \200\2231 (38) 0.5 \200\2231.0 3.5 years 3.3 years Intermediate \200\2232 (22) 1.5 \200\2232.0 1.2 years 1.1 years High (7) >2.5 0.4 years 0.2 years 239 PROGNOSTIC FACTORS IN MDS Table 6.4 Calculation of IPSS-R Score Prognostic variable Score value 0 0.5 1.0 1.5 2.0 3 4 BM blast % \211 2 2 \200\223<5 5 \200\22310 >10 \200\223 Cytogenetics Very good Good Int Poor Very poor Hemoglobin \211 100 80 \200\223<100 <80 Platelets >100 50 \200\223<100 <50 ANC \211 0.8 <0.8 Karyotype: Very good: \210\222Y, del(11q); Good: normal, del(5q), del(12p), del(20q), doub le including del(5q). Intermediate: del(7q), +8, +19, i(17q), any other single or double in dependent clones. Poor: \210\2227, inv(3)/t(3q)/del(3q), double including \210\2227/del(7 q), complex (3 abnormalities). Very poor: complex (>3 abnormalities). Table 6.5 Prognosis by IPSS-R Score IPSS-R risk group (% patients) Overall score Median survival 25% AML evolution Very low (19) \211 1.5 8.8 years Not reached Low (38) 1.5 \200\2233.0 5.3 years 10.8 years Intermediate (20) >3 \200\2234.5 3 years 3.2 years High (13) >4.5 \200\2236 1.6 years 1.4 years Very high (10) >6 0.8 years 0.7 years 240 CHAPTER 6 Myelodysplasia WHO-based Prognostic Scoring System (WPSS) The WHO classifi cation-based system takes into account the transfusion requirement of patients. It is shown that this has a negative progn ostic impact. Initially transfusion requirement was part of the scoring system, but due to its relative subjectivity, the scoring system was refi ned to include \200\230severe anemi a \200\231.3 (Tables 6.6 and 6.7.) Table 6.6 Calculation of WPSS Score Prognostic variable Score value 0 1 2 3 WHO category RCUD RARS 5q \210\222 RCMD RAEB-1 RAEB-2 Karyotype Good Intermediate Poor \200\223 Severe anemia (<90g/L \231\202; <80g/L \231\200) Absent Present \200\223 \200\223 Karyotype: Good: normal, \210\222Y alone, del(5q) alone, del(20q) alone. Poor: complex ( \211 3 abnormalities) or chromosome 7 anomalies. Intermediate: other abnormalities. Table 6.7 Prognosis by WPSS Score IPSS risk group (% patients) Combined score Very low 0 Low 1 Intermediate 2 High 3 \200\2234 Very High 5 \200\2236 References 1. Greenberg, P. et al. (1997). International scoring system for evaluating prog nosis in myelodysplastic syndromes. Blood, 89, 2079 \200\22388. 2. Greenberg, P. et al. (2012). Revised International prognostic Scoring Sytem (IPSS-R) for myelodysplastic syndromes. Blood, 120, 2454 \200\22365. 3. Malcovati, L. et al. (2011). Impact of the degree of anemia on the outcome of patients w ith myelodysplastic syndrome and its integration into the WHO classifi cation-based Prognos tic Scoring System (WPSS). Haematologica, 96, 1433 \200\22340. 241 PROGNOSTIC FACTORS IN MDS 242 CHAPTER 6 Myelodysplasia Clinical variants of MDS These variants though partly discussed on E p.231 have specifi c d iagnostic relevance and distinct clinical characteristics. It remains important to identify several of these because of new therapeutic options. 5q-syndrome = MDS with isolated del(5q) \200 Separately defi ned in WHO classifi cation. \200 \231\200 preponderance. \200 More indolent clinical course. \200 Lower rate of evolution to AML (10%). \200 Severe anemia; pronounced macrocytosis; n or moderate d WBC; n or moderate i platelets; dysplastic megakaryocytes; no blast excess. High response rates to lenalidomide. RARS (See Fig. 6.2.) \200 Good survival: 77% OS at 3 years. \200 Very low risk of AML t ransformation. \200 High risk of transfusion siderosis. \200 Good response to EPO G- CSF. 2 MDS \200 Incidence i due to successful chemotherapy and i pollution. \200 Multiple chromosomal abnormalities in almost all patients. \200 Poorer prognosis than de novo MDS. \200 Prior cancer therapy: notably with radiotherapy, alkylating agents (chlorambucil, cyclophosphamide, melphalan; peak 4 \200\22310 years after therapy) or epipo dophyllotoxins (etoposide, teniposide; peak within 5 years). Hypoplastic MDS \200 <15% of cases of MDS have hypocellular BM on biopsy (<30% cellularit y age <60 years; <20% aged \211 60 years); dysplastic megakaryocytes myeloid cells or e xcess blasts may be diffi cult to see. May be diffi cult to distinguish from aplastic anemia in which pancytopenia usually more severe. Cytogenetic fi ndings typical of MDS may be necessary for diagnosis; n or i %CD34+ cells suggests MDS. Not age associated. \200 May respond to immunosuppressive therapy. MDS with myelo \201 brosis (MDS-MF) \200 <15% of patients with MDS on BM have marked fi brosis. \200 More common in 2 MDS. \200 BM hypercellular with MF, diff use coarse ret iculin fi brosis and dysplasia in at least 2 cell lineages. PB shows pancytopenia and dysplastic features and sometimes leucoerythroblastic picture; organomegaly unusual. Rapid deterioration usual; must distinguish from acute megakaryocytic leukemia, acute panmyelosis with fi brosis and chronic myeloproliferative disorders, metast atic cancer, lymphoma and HCL. 243 CLINICAL VARIANTS OF MDS Fig. 6.2 BM in RARS stained for Fe: note Fe granules round the nucleus of the erythroblast (E see color plate section). 244 CHAPTER 6 Myelodysplasia Management of MDS WHO classifi cation and IPSS(-R) risk category are used in deciding thera py. The speed of onset of symptoms/fi ndings over several weeks/ months is an important par ameter. Most patients are elderly and per- formance status and individual patient preferenc es should be taken into consideration. Guidelines recommend stratifying patients into 2 major risk groups: \200 Lower risk: hema tological improvement is the therapeutic aim. \200 Higher risk: alteration of the natural history is the priority.1 For patients with lower risk MDS, a \200\230watch and wait \200 \231 approach can be adopted prior to the introduction of therapy. Supportive care may be t he only treatment indicated. However, development of transfusion- dependence signifi cantly worsens OS2,3 and more intensive treatment can be appropriate here. Intensive therapy is indicated for patients with higher risk MDS if appro- priate. Palliati ve or investigational therapy is indicated for patients with higher risk MDS ineligible for intensive therapy. Apart from potential cure with allo-HSCT, treatments for MDS have a pal liative intent. Supportive care Supportive care has the aim of reducing morbidity and maintaining QoL. For many patients this will be the mainstay of management. It involves monitoring, psychosocial support, and QoL assessment. Red cell transfusion Should be administered only for symptomatic anemia; symptomatology rat her than a \200\230trigger \200\231 Hb level should initiate red cell support. Platelet transfusion Should be administered for patients with haemorrhagic problems with th e aim of maintaining a platelet count >10 \227 109/L. If no bleeding symptoms lower platel et counts can be accepted. Anti-infective therapy Empirical broad-spectrum antibiotics and/or antifungals should be ad ministered promptly for neutropenic sepsis; no evidence to support routine use of prophylac tic anti-infectives; may be useful in neutropenic patients with recurrent infection. G-CSF May be useful for patients with neutropenia and recurrent or antibiotic resistant inf ections; not recommended simply for chronic prophylaxis. Iron chelation therapy Should be considered once a patient has received 20 \200\22325 units of RBCs if long-term transfusion is required (RA, RARS, 5q \210\222 syndrome), in those wi th serum ferritin >2500mg/L, and those with concurrent cardiac or hepatic dysfunction. Iron overload is a signifi cant cause of morbidity and mortality in low-risk patients with isol ated erythroid dysplasia.2 245 MANAGEMENT OF MDS Desferrioxamine: inconvenient administration (SC infusion) and toxicity; dose 20 \200\22340 mg/kg by 12h SC infusion 5 \200\2237 nights/week; aim for serum ferritin <1000mg/L; monitor renal function; audiometric and ophthal- mological assessments prior to therapy and then a nnually. Deferasirox: 20 \200\22330mg/kg PO od; comparable effi cacy to desferriox- amine.4 Monitor renal and hepatic function monthly and eyes and ears pre-therapy and annually. Deferiprone is another approved orally active chelator; dose 25mg/kg tds; agranulocytosis h as been reported. Treatments Treatment strategies on E p.244. Consider clinical trials where appropriate. Immunosuppression Notable responses in hypoplastic MDS; some responses seen in other lower risk patients. Younger age, shorter duration of transfusion dependence, HLA-DR15, hypoplastic BM, and pres ence of a PNH clone associated with response to immunosuppression: \200 ATG 40mg/kg/d \227 4d can achieve transfusion independence in 733% patients (median response >2 years); e rythroid improvement in up to 66%, and sustained neutrophil and platelet responses in up to 50%; response associated with signifi cant survival benefi t.5,6 Ciclosporin has achieved transfusion independence in a high proportion of patients with RA in small clinical trials.7 ATG+ciclosporin may be used in combination as in aplastic anemia.8 Lenalidomide Achieves ma jor clinical responses and cytogenetic responses in most patients with 5q \210\222 syndrome .9 \200\22311 Mode of action appears to be direct cytotoxic eff ect suppressing 5q \210\222 clone. Long-term follow-up suggests it may alter natural history of MDS with durable respo nses (median 2.2 years), improved OS (10-year estimate of 78% for cytogenetic responders vs 4% in non-responders) and reduced AML transformation (15% at 10 years in responders vs 67% ) at 10 years.12 median duration of major responses >2 years. Similar but less durable resp onses in MDS with 5q \210\222 plus additional abnormalities where it also normalized % BM b lasts in 75%. Epigenetic therapy: hypo-methylating agents azacitidine and decitabine Inhibit DNA methyl t ransferase, reduce DNA methylation, and reac- tivate abnormally suppressed gene expression. In a subset of MDS patients they ameliorate anemia, d the risk of leukaemic transforma- ti on, and improve OS. Azacitidine \200 Achieves hematological responses, delays AML transformation, and improve s QoL (47% OR, 10% CR; 36% hematological improvement (HI) with a trend to i OS.13 246 CHAPTER 6 Myelodysplasia Usual dose 75mg/m2/d SC 7d or 100mg/m2/d SC 5d monthly. Most responses observed between courses 4 and 6. Response often only after several months; minimum 3 cycles required before evaluating response. Decitabine \200 IV administration; requires hospitalization. \200 Up to 39% CR describe d but no phase III survival benefi t data. Non-intensive chemotherapy Classical low-dose chemotherapy (hydroxycarbamide, cytarabine, e toposide) may be used and tolerated by elderly patients with trans- formed or \200\230tran sforming \200\231 MDS. However may lead to i cytopenia and transfusion dependence. Its role has markedly reduced with the intro- duction of epigenetic therapy. Intensive chemotherapy AML induction chemotherapy should be considered in patients <60 year s with higher-risk MDS and good performance status. See treatment strategies on E p.132. \200 Lower responses (40 \200\22350%) and higher treatment-related morbidity and mortality than in de novo AML. Prolonged DFS rare. Without SCT option, benefi t marginal and survival not prolonged in most patients.14 \200 Consolidate with HSCT where possible. HSCT (Mini-) Allogeneic SCT off ers the best prospect of prolonged survival and curative th erapy (35 \200\22340% 3-year DFS); few patients are eligible but treatment of choice for yo unger patients with a higher MDS risk score. \200 IPSS int-2/high-risk patients 60 years should proceed to HLA- matched sibling SCT at diagnosis for best OS but SCT should be delayed in low/int-1 MDS pat ients until progression.15 Need for remission induction chemotherapy pre-transplant unclear. \200 High treatment-rel ated mortality (740%). \200 Relapse rate up to 40%; relapse risk relates to IPSS score \200\224low risk <5%, high risk >25%. 5-year DFS relates to IPSS: low/int-1 60%, int-2 36% and high risk 28%; favorable outcome a ssociated with younger age, shorter disease duration, compatible graft, 1 MDS, <10% blast s, and good risk cytogenetics. RIC regimens have reduced toxicity, TRM, and increase eligible age range for SCT.16 Lower risk group treatment strategy (IPSS low/int-1; IPSS-R and WPSS very low/low/int) Cons ider clinical trials where appropriate. Symptomatic anemia and serum EPO \211 500 mU/mL (and no 5q \210\222) \200 Erythropoietin G-CSF; 20 \200\22330% respond to EPO alone, 40 \200\22360% to EPO+G-CSF; synergistic eff ect. Responses generally occur within 6 \200\2238 weeks; median response 1 \200\2232 years, longer responses associated with lower % BM blasts, low/int-1 I PSS. 247 MANAGEMENT OF MDS rHu EPO 40 \200\22360,000U SC 1 \200\2233 \227/week or darbepoetin alfa 150 \200\223300 mc g/week SC for 6 weeks; in non-responders consider adding daily G-CSF (1 \200\2232mcg/kg/d o r 1 \200\2233 \227/week) SC or double dose EPO or both for further 6 weeks. In responders, reduce G-CSF to 3-weekly and EPO in steps to lowest dose retaining response. No response after 2 \200\2233 months = treatment failure. If good probability to respond to immune suppressive therapy (IST): consider IST with antithymocyte globulin (ATG) or ciclosporin A (CsA). Symptomatic anemia and serum EPO >500 mU/mL (and no del5q \210\222) \200 Good probability to respond to IST: consider ATG or CsA. \200 Poor probability to respond to IST: conside r azacitidine/decitabine; consider lenalidomide; consider allo-HSCT in rare/selected cases if above fails. Clinically relevant thrombocytopenia or neutropenia or increased blasts \200 Consider aza citidine/decitabine. \200 Consider IST. Pre-transplant cytoreductive chemotherapy not necessarily recommended. Best supportive care. MDS with isolated del(5q) \200 Lenalidomide. \200 Dose: 10mg/d for 21d every 4 weeks. \200 Monitor patients with renal dysfunction carefully. Higher risk group treatment strategy (IPSS int-2/high; IPSS-R int, high, very high; WPSS hi gh, very high) Consider clinical trials where appropriate. High-intensity therapy candidate \200 Donor available: allo-HSCT. \200 No donor availab le: Azacitidine (1st choice, phase III trial data showed survival benefi t). \200 Decitabine. \200 High-intensity chemotherapy (AML like chemotherapy). Not high-intensity candidate \200 Azacitidine (1st choice) or decitabine. \200 Best sup portive care. References 1. NCCN (2014). NCCN Practice Guidelines in Oncology: Myelodysplastic Syndromes, V2.2014. Fort Washington, PA: NCCN. 2. Malcovati, L. et al. (2005). Prognostic factors and life expectancy in myelodysplastic syndromes classifi ed according to WHO criteria: a basis for clinical decision making. J Cl in Oncol, 23, 7594-7603. 3. Estey, E.H. (2013). Epigenetics in clinical practice: the examples of azacitidine and de citabine in myelodysplasia (MDS) and acute myeloid (AML). Leukemia, 27(9), 1803 \200\22312. 4. Cazzola, M. et al. (2005). ICL670, a once daily iron chelator, is eff ective and well to lerated in patients with myelodysplastic syndrome (MDS) and iron overload. Haematologica, 9 0(Suppl. 2), 306 (Abst 0769). 5. Killick, S.B. et al. (2003). A pilot study of antithymocyte globulin (ATG) in the treatm ent of patients with \200\230low-risk \200\231 myelodysplasia. Br J Haematol, 120, 6769 \200\2236 84. 248 CHAPTER 6 Myelodysplasia 6. Lim, Z. et al. (2005). European multi-center study on the use of anti-thymocyte globulin in the treatment of myelodysplastic syndromes. Blood, 1056, 707a. 7 Shimamoto, T. et al. (2003). Cyclosporin A therapy for patients with myelodysplastic syndrome: multicentre pilot studies in Japan. Leuk Res, 27, 783 \200\2238. 8. Broliden, P. et al. (2006). Antithymocyte globulin and cyclosporin A as combination ther apy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica, 91, 667 \200 \22370. 9. List, A. et al. (2005). Effi cacy of lenalidomide in myelodysplastic syndromes. N Engl J Med, 352, 549 \200\22357. 10. List, A. et al. (2006). Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med, 355, 1456 \200\22365. 11. Nimer, S.D. et al. (2006). Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. J Clin Oncol, 24, 2576 \200\22382. 12. Melchert, M. and List, A. (2007). Management of RBC-transfusion dependence. Hematology 2007, 398 \200\223404. 13. Silverman, L.R. et al. (2006). Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921 and 9221 by the Cancer and Leukemia Group B. J Clin Oncol, 24, 3895 \200\223903. 14. Oosterveld, M. et al. (2003). The impact of intensive antileukaemic treatment strategie s on prognosis of myelodysplastic syndrome patients aged less than 61 years according to In ternational Prognostic Scoring System risk groups. Br J Haematol, 123, 81 \200\2239. 15. Cutler, C.S. et al. (2004). A decision analysis of allogeneic bone marrow transplantati on 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