East Midlands Cancer Network Guidelines for the Investigation and Management of Adult Myelodysplastic Syndromes

East Midlands Cancer Network Guidelines for the Investigation and Management of Adult Myelodysplastic Syndromes Written by: Dr Emma Das-Gupta and Dr Jane Parker 1. Scope of the Guideline Consultation Group: EMCN Haematology NSSG This guidance has been produced to support the following: a. The investigation of patients suspected of having a myelodysplastic syndrome b. the management of patients diagnosed with a myelodysplastic syndrome 2. Guideline Background These guidelines support the BCSH Guidelines for the Diagnosis and Therapy of Adult Myelodysplastic Syndromes 5. They also take into account newer therapies that have become available for the treatment of myelodysplastic syndromes since the publication of the BCSH guidelines. 3. Diagnostic Workup of Suspected Myelodysplastic Syndrome (MDS) 3.1 History should be taken including: a. Symptoms of anaemia, recurrent infections, bleeding/bruising b. Prior exposure to chemotherapy/radiation c. Prior chemical exposure, especially benzene d. Family history of MDS/Acute Myeloid Leukaemia 3.2 Physical Examination should include: a. Pallor/infection/bruising b. Splenomegaly c. Dysmorphic features (suggesting congenital bone marrow failure) d. Cutaneous lesions Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 1/14

3.3 Initial Blood Tests should take place as follows: a. Full blood count and blood film: o cytopenia(s) o Monocytosis, o red cell macrocytosis, o dysplastic features b) Reticulocyte count c) Ferritin d)β 2 Microglobulin e) LDH 3.4 Consider and Exclude other Causes of Dysplasia and Cytopenias B12 / folate deficiency Recent cytotoxic therapy Drug-induced cytopenias Chronic liver disease Excessive alcohol intake Hypothyroidism Exposure to heavy metals, e.g. lead, arsenic HIV infection Anaemia of chronic disorders (infection, inflammation, cancer) Autoimmune cytopenia Other hemopoietic stem cell disorders including acute myeloid leukaemia, myeloproliferative disorders, aplastic anaemia, paroxysmal nocturnal haemoglobinuria, LGL leukaemia and hairy cell leukaemia. 3.5 Additional Blood Tests to consider a. PNH clone in suspected hypoplastic MDS b. JAK2 analysis in RARS-T c. Fanconi screen if constitutional MDS considered possible 3.6 Bone Marrow Aspirate A good quality bone marrow aspirate is necessary to make a confident diagnosis of MDS and to provide important information regarding disease classification and prognosis. MGG / equivalent and iron stains should be undertaken. A bone marrow aspirate may not be necessary in elderly patients in whom a definitive diagnosis of MDS would not alter management or whose poor general health precludes active treatment. Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 2/14

3.7 Bone Marrow Trephine Bone marrow histology complements the morphological information obtained from a marrow aspirate and hence a trephine biopsy should be performed in all cases of suspected MDS where bone marrow examination is indicated. The trephine can provide information regarding marrow cellularity and fibrosis, aiding the identification of hypocellular MDS and overlap myelodysplastic/myeloproliferative syndromes. 3.8 Cytogenetic Analysis of Bone Marrow A chromosomal abnormality confirms the presence of a clonal disorder aiding the distinction between MDS and reactive causes of dysplasia. In addition it provides major prognostic value. Cytogenetic analysis should therefore be performed in all patients for whom bone marrow examination is indicated. FISH analysis may be helpful to clarify complex aberrations or to detect monosomy 5 or 7. 3.9 Immunophenotypic Analysis of Bone Marrow Immunophenotyping of bone marrow is recommended and can be useful in determining the percentage of marrow blasts, particularly when myeloid dysplasia makes morphological enumeration difficult. The marrow blast percentage is necessary for disease classification and prognostication. 3.10 Morphological Diagnostic Criteria for MDS Minimal diagnostic criteria are not clearly defined in MDS and the diagnosis of MDS is susceptible to inter-observer variation. Difficulties also arise because a variety of reactive disorders are associated with dysplastic morphology and mild dysplastic features are frequently seen in the marrow of healthy people with normal blood counts 2. In order to increase the reliability of diagnosing MDS, the following recommendations are made: a. Where possible at least 200 marrow cells and 20 megakaryocytes should be evaluated. b. For significant dysplasia, dysplastic features should be present in at least 10% of the nucleated cells in the lineage in consideration. c. The presence of pseudo-pelger neutrophils, ring sideroblasts, micromegakaryocytes and increased blasts correlate most strongly with the presence of clonal markers in MDS and show least interobserver variation. d. It is recommended that a diagnosis of MDS is not based on the presence of neutrophil hypogranularity alone, due to the fact that neutrophil granularity is critically dependent on optimal staining. For a full description of dysplastic features see WHO 2008, page 90 1 Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 3/14

If morphological diagnosis remains uncertain, it is recommended that the patient be monitored with repeat morphological assessment at appropriate intervals. 3.11 Hypocellular MDS versus Aplastic Anaemia The diagnosis of hypocellular MDS is of importance, as preliminary data suggest that the response to immunosuppressive therapy is higher than in cases of MDS with normo or hypercellular marrows 4. The diagnosis of myelodysplasia requires the presence of dysplastic features in megakaryocytes and/or myeloid cells or/ and excess of blasts. Erythroid dysplasia is found in aplastic anaemia and cannot be used alone to distinguish MDS from AA. The presence of an abnormal karyotype strongly favours the diagnosis of MDS, but cases of aplastic anaemia with an abnormal karyotype, without morphological features of MDS, and with a low risk of transformation to MDS or AML, have been described 4. 3.12 Idiopathic Cytopenia of Undetermined Significance (ICUS) Patients with maintained (>6 months) cytopenias of one or more myeloid lineages (erythroid, neutrophil and megakaryocytic), which do not meet the (minimal) criteria for MDS and cannot be explained by any other hematologic or non-hematologic disease may be considered as ICUS. In some patients, the type of cytopenia (e.g., transfusion-dependent macrocytic anemia) may point to the potential existence of an underlying MDS or an MDS pre-phase. 3.13 MDS Classification Patients with MDS are classified according to the WHO classification system 1 (Tables 1 and 2). Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 4/14

Table 1: WHO 2008 Classification of MDS Disease Blood Findings Bone Marrow Findings Refractory cytopenias with unilineage dysplasia (RCUD) Refractory anaemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT) Unicytopenia or bicytopenia 1 No or rare blasts (<1%) Refractory anaemia with ring sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anaemia with excess blasts-1 (RAEB- 1) Refractory anaemia with excess blasts-2 (RAEB- 2) Myelodysplastic syndrome unclassified (MDS-U) Anemia No blasts Cytopenia(s) No or rare blasts (<1%) 2 No Auer rods <1x109/l monocytes Cytopenia(s) <5% blasts No Auer rods <1x109/l monocytes Cytopenia(s) 5-19% blasts Auer rods 3 <1x109/l Unilineage dysplasia; 10% of the cells of the affected lineage are dysplastic <5% blasts <15% of the erythroid precursors are ring sideroblasts Erythroid dysplasia only 15% of erythroid precursors are ring sideroblasts Dysplasia in 10% of cells in two or more myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes) <5% blasts No Auer rods 15% ring sideroblasts Unilineage or multilineage dysplasia 5-9% blasts 2 No Auer rods Unilineage or multilineage dysplasia 10-19% blasts Auer rods monocytes Cytopenias a. Dysplasia in less than 10% but 1% blasts 2 typical cytogenetic abnormality b. RCUD/RCMD with 1% blasts in peripheral blood c. RCUD with pancytopenia MDS associated with isolated del(5q) Anaemia Usually normal or increased platelet count No or rare blasts (<1%) Normal to increased megakaryocytes with hypolobated nuclei <5% blasts Isolated del(5q) cytogenetic abnormality No auer rods 1 Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U 2 If the marrow myeloblast percentage is <5% but there are 2-4% myeloblasts in the blood, the diagnostic classification is RAEB-1. If the marrow myeloblast percentage is <5% and there are 1% myeloblasts in the blood, the case should be classified as MDS-U. 3 Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2 Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 5/14

Table 2 WHO 2008 classification of myelodysplastic/myeloproliferative neoplasms Disease Blood findings Bone marrow findings Chronic myelomonocytic leukaemia (CMML) (CMML-1; <5% blasts in PB, <10% in BM, CMML-2; 5% blasts in PB, 10% in BM) Atypical chronic myeloid leukaemia, BCR- ABL1 negative (acml) Juvenile myelomonocytic leukaemia (JMML) Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN) 1Refractory anaemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) (provisional entity)2 Peripheral blood monocytosis > 1x109/l No BCR/ABL-1 fusion gene <20% blasts Leukocytosis, neutrophilia Neutrophilic dysplasia Neutrophil precursors 10% of leukocytes Blasts <20% No BCR-ABL1 fusion gene No rearrangement of PDGFR or PDGFR Minimal basophilia Monocytes < 10% of leukocytes Peripheral blood monocytosis >1x109/l <20% blasts Usually WBC > 10x109/l Mixed MDS and MPN features No prior diagnosis of MDS or MPN No history of recent growth factor or cytotoxic therapy to explain MDS or MPN features No BCR-ABL1 fusion gene of rearrangements of PDGFR or PDGFR Persistent thrombocytosis >450x10 9 /L Anaemia BCR-ABL1 negative Cases with t(3;3)(q21;q26), inv(#)(q21q26) and isolated del(5q) are Dysplasia in one or more myeloid lineage 1 <20% blasts. Blasts include myeloblasts, monoblasts and promonocytes. No rearrangement of PDGFR or PDGFR Neutrophil dysplasia with or without dysplastic lineages <20% blasts <20% blasts Evidence of clonality Mixed MDS and MPN features <20% blasts Morphologic features of RARS; 15% of erythroid precursors are ring sideroblast Abnormal megakaryocytes similar to those observed in BCR-ABL1 negative MPN 50% JAK2 mutations in RARS-T with plt>600. excluded 1 I f myelodysplasia minimal or absent, CMML can still be diagnosed if the other requirements are met and there is an acquired clonal cytogenetic or molecular genetic abnormality. Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U 2 If the marrow myeloblast percentage is <5% but there are 2-4% myeloblasts in the blood, the diagnostic classification is RAEB-1. If the marrow myeloblast percentage is <5% and there are 1% myeloblasts in the blood, the case should be classified as MDS-U. 3 Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2 Note: Therapy-associated MDS and MDS/MPN should classified in the category therapy-associated myeloid malignancies Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 6/14

3.14 MDS Prognosis Since its publication in 1997, the International Prognostic Scoring System (IPSS) has been an important tool for assessing the outcome of patients with untreated, primary adult MDS 8 (Tables 3 and 4). The Revised IPSS (IPSS-R) has recently described the relative importance of defined clinical factors with regards to prognosis by multivariate analysis of 7012 primary, untreated adult MDS patients 12 (Tables 5 a-c). The IPSS-R has 5 prognostic categories and has improved the prognostic ability to determine survival and AML evolution in untreated adult patients with primary MDS. This model should be the preferred scoring system for determining prognosis and appropriate treatment. The score can be calculated on the following webpage http://www.mds-foundation.org/ipss-r-calculator Table 3 IPSS for MDS Prognostic Variable Score Value 0 0.5 1.0 1.5 2.0 BM Blasts (%) <5 5-10 11-20 21-30 Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 Karyotype: Good: normal, -Y, del(5q), del(20q). Poor: complex ( 3 abnormalities) or chromosome 7 anomalies. Intermediate: other abnormalities. Cytopenias: Hemoglobin <10 g/dl, ANC <1.8 x 10 9 /l, platelets <100 x 10 9 /l. Table 4: IPSS Interpretation Risk group Score Median survival (years) Time to AML transformation (for 25% in years) Low risk 0 5.7 9.4 INT-1 0.5-1.0 3.5 3.3 INT-2 1.5-2.0 1.2 1.1 High risk 2.5 0.4 0.2 Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 7/14

Table 5a. IPSS-R Cytogenetic Prognostic Subgroups (Greenberg, et al 2012) 12 Very good -Y, del(11q) Good Normal, del(5q), del(12p), del(20q), double including del(5q) Intermediate del(7q), +8, +19, i(17q), any other single or double independent clones Poor -7, inv(3)/t(3q), double including - 7/del(7q), complex: 3 abnormalities Very Poor Complex: >3 abnormalities Table 5b. IPSS-R Prognostic Score Values (Greenberg, et al 2012) Prognostic 0 0.5 1 1.5 2 3 4 variable Cytogenetics Very Good Good Intermediate Poor Very Poor BM blast % 2 >2-<5 5-10 >10 Haemoglobin 10 8-<10 <8 Platelets 100 50- <50 <100 ANC 0.8 <0.8 Table 5c. IPSS-R Prognostic Risk Categories/Scores and Clinical Outcomes (Greenberg, et al 2012) RISK CATEGORY RISK SCORE SURVIVAL (median years) AML/25% (median years) Very Low 1.5 8.8 NR Low >1.5-3 5.3 10.8 Intermediate >3-4.5 3.0 3.2 High >4.5-6 1.6 1.4 Very High >6 0.8 0.73 Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 8/14

Additional differentiating features were noted in the IPSS-R that are additive to the 5 major parameters for predicting survival but not for AML evolution. These features are performance status, serum ferritin, LDH, and possibly β 2 - microglobulin. Additional adverse features that may influence management decisions are heavy transfusion dependence and marrow fibrosis. 6. Management of Patients Diagnosed with a Myelodyspastic Syndrome 6.1. Pre-treatment Management All patients with a diagnosis of MDS must be discussed at an MDT Referral to a Haematology Specialist Nurse if available Written material to be provided according to local protocol, for example: o MDS UK Patient Support Group leaflet and news letter o LLR MDS booklet o Leukaemia CARE booklet o Leukaemia CARE contact card o Macmillan booklet o Macmillan contact card o Macmillan Cancerline contact number o NHS Choices Information Presrciption o Haematology Ward contact details? then divide sections into A. Supportive care B. low risk MDS, C. high risk MDS as in the BCSH guidelines 6.2 Supportive Care 6.2.1 Anaemia 6.2.1 Red Cell Transfusion The use of red cell transfusions should be considered in any patient with symptoms of anaemia. Blood transfusions should be administered according to local Trust transfusion policies. 6.2.2 Neutropenia Neutropenic sepsis should be managed as for patients undergoing chemotherapy according to the hospital antibiotic policy. There is no indication for routine antibiotic or antifungal prophylaxis. The use of GCSF may be considered in patients with recurrent infections who have low risk disease. Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 9/14

6.2.3 Thrombocytopenia Both the degree of thrombocytopenia and platelet dysfunction can contribute to bleeding problems. Routine prophylactic platelet transfusion may be of symptomatic value in individual patients but there is no evidence to support their routine use in stable thrombocytopenia (in patients not undergoing intensive chemotherapy), even with platelet counts less than 10x10 9 /l 5. In the absence of bleeding or fever, the threshold for platelet transfusion in symptomatic patients is 10 x 10 9 /L. Antifibrinolytics may be useful in some patients but caution should be taken in patients with ischaemic heart disease. 6.3 Low Risk MDS Low risk MDS is defined as patients who have an IPSS of Low or Intermediate-1, or an IPSS-R of Very Low or Low 6.3.1 Iron Chelation Iron chelation should be considered principally in stable transfusiondependent patients with low/int-1 IPSS. The clinical relevance of iron overload in MDS is still not clear and the role of iron chelation therapy, in terms of patient suitability and specific benefit, has yet to be clearly defined in prospective clinical studies. Consensus guidelines and statements for the treatment of iron overload in patients with MDS have been published 73. The BCSH guidelines recommend treatment of iron overload in low IPSS risk patients when they have received approximately 25 units of blood (5g of iron) aiming to maintain serum ferritin levels below 1000μg/l 5. The EMCN has elected to use T2* MRI to guide the initiation of iron chelation in MDS according to the algorithm given in figure 1 Drugs for Iron Chelation First line: s/c Desferrioxamine, -consider home care provider. Refer to link: Application for new patient on Desferrioxamine inc MDS (word version) Second Line: Deferasirox may be considered in patients who are intolerant of desferrioxamine Annual eye and ear assessments should be carried out in patients taking these drugs. There is no evidence for benefit from IV desferrioxamine given at the same time as blood transfusion and this is not recommended. Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 10/14

Figure 1: Algorithm for the Initiation of Iron Chelation in MDS Consultant Haematologist Decision to Consider Chelation Life Expectancy >2 years IPSS low or int -1 >25 units RBC Transfused Ferritin 1500 MRI possible No Ferritin 3000 New Onset Endocrinopath y at any Stage T2* MRI of Heart and Liver No Liver Iron or Mild Liver Iron Overload (T2*>2.7ms) Moderate Liver Iron Overload (T2*2.7ms - 1.4ms) High Liver Iron Overload (T2* 1.4ms) and/or any Cardiac Iron Loading (T2* 20ms) Repeat MRI Annually Repeat MRI Six Monthly Start Chelation Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 11/14

6.3.2 Erythropoietin (EPO) and GCSF EPO ±GCSF can reduce transfusion requirements and potentially improve long term survival in selected patients 9,10. Patients with low or Int-1 MDS, who have a serum EPO level <500 and whose transfusion requirement is 2 units of blood per month should be considered for an eight week trial of EPO. For those who show no response, consider a further 8 week trial of EPO with GCSF. Consider combining EPO with GCSF from the outset in sideroblastic cases. The haemoglobin should not be allowed to rise above 12 g/dl. 6.3.3 Immunosuppressive Therapy Immunosuppression with ATG or cyclosporin can be beneficial in subgroups of MDS (mainly younger int-1 patients) 11. Immunosuppressive therapy with ATG (horse) can be considered for patients with low or Int-1 IPSS MDS below the age of 60 years, particularly those who have a hypoplastic bone marrow and a normal karyotype or trisomy 8. ATG should only be used in centres with experience of its use in aplastic anaemia. 6.3.4 5q- Syndrome Lenalidomide is not currently licensed for use in this group of patients and applications for use would need to be made locally on an individual patient basis. 6.3.5 Stem Cell Transplantation Allogeneic HSCT is the only treatment modality with proven curative potential for MDS. Therefore all patients with newly diagnosed MDS should be discussed at an MDT and the role of allogeneic HSCT considered. 6.4 High Risk MDS 6.4.1 Non-Intensive Treatment Patients >60 years with >10% blasts, who are not considered candidates for intensive chemotherapy, should be offered therapy within the LI1 nonintensive trial or consider AML18 if available. 5-Azacitidine (Vidaza) Azacitidine is a hypomethylating agent with efficacy in high grade MDS that has been shown to significantly increase overall survival compared to conventional care regimens (specifically, best supportive care, low dose cytarabine and intensive AML-type therapy) 6. Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 12/14

Azacitidine is approved by NICE as a treatment option for adults who are not eligible for haematopoietic stem cell transplantation and who have: Intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) or Chronic myelomonocytic leukaemia with 10 29% marrow blasts without myeloproliferative disorder or Acute myeloid leukaemia with 20 30% blasts and multilineage dysplasia, according to the World Health Organization classification and if the manufacturer provides azacitidine with the discount agreed as part of the patient access scheme. The recommendation in the East Midlands is that patients should be considered for entry into clinical trials such as LI1 or AML18 as initial treatment of their high grade MDS. Azacitidine is an alternative therapy that may be considered. Patients who are initially treated with azacitidine for high grade MDS and who then progress to AML may still be offered entry into LI1. Low dose ara C may also be offered to patients with >10% blasts including patients with CMML2. Hydroxycarbamide should be considered as cytoreductive therapy for patients with CMML associated with a high white cell count. 6.4.2 Intensive chemotherapy and transplantation Patients with >10% blasts in the marrow who are considered fit to tolerate intensive chemotherapy should be offered therapy within the AML18 or AML17 trials. Non-trial patients fit for intensive chemotherapy should receive chemotherapy as per the AML guidelines. Outside of a trial setting, chemotherapy is usually limited to 2-3 courses due to the risk of prolonged cytopenias and poor haemopoietic regeneration with more courses. Indications for allogeneic transplantation in MDS are published by the BSBMT: http://www.bsbmt.org/indications_table/indications_table.pdf. For patients in AML 17, which uses a different risk score, patients defined as high risk are eligible for sibling or unrelated donor transplantation. Written By: Dr Emma Das-Gupta Dr J Parker Authorised by: Haem NSSG Page Number: 13/14

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