GREATER MIDLANDS CANCER NETWORK HAEMATOLOGY SITE SPECIFIC GROUP GUIDELINES: MDS. Myelodysplastic Syndrome

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1 Myelodysplastic Syndrome 1. INTRODUCTION Myelodysplastic syndromes represent myeloid clonal haemopathies with relatively heterogeneous presentations. Their overall incidence is estimated to be around 4-5 per 100,000 overall. The incidence increases to greater than 30 per 100,000 in the over 70 year age group with the incidence increasing further to over 40 per 100,000 in the over 80 age group. Although predominantly a disorder of older adults myelodysplasia occurs in all age groups. (1) 2. REFERRAL GUIDANCE Patients with suspected myelodysplastic syndrome should be referred to a haematologist for evaluation and assessment. Some patients will have presenting symptoms or laboratory results that will meet the criteria for referral via the rapid access pathway for possible haematological malignancy. Patients who are diagnosed to have a myelodysplastic syndrome should normally be managed by a haematologist after discussion at the appropriate MDT however in this predominantly elderly group of patients co-morbidities may require a joint approach or close involvement with both palliative care and Care of the Elderly services. 3. DIAGNOSIS Diagnosis and classification of MDS remain dependent on morphological examination of blood and bone marrow cells. Diagnostic criteria should ideally distinguish MDS from other reactive conditions causing dysplastic haemopoiesis and from other clonal myeloid disorders. If a morphological diagnosis remains uncertain after initial investigation it is recommended that the patient is reviewed regularly with repeat laboratory and clinical assessment at appropriate intervals. Normally bone marrow aspiration and biopsy is required to evaluate a patient. Cytogenetic assessment is also required to evaluate fully for all diagnostic groups in addition to the derivation of a prognostic score. (2) 4. CLASSIFICATION The World Health Organisation (WHO) has recently published an updated diagnostic classification of MDS. This supersedes the French American British (FAB) classification published in 1982 and its own earlier scheme. The latest revision was published in 2008 and continues to be based on a combination of morphology, karyotype and clinical features but introduces some new entities and clarifies the position with respect to CMML in particular. When classifying cases wherever possible the current WHO classification should be used. Some clinical trials and the IPSS score require diagnosis by FAB criteria to be used in assessment. In this situation both systems should be recorded. The distinction of high risk from low risk groups by enumeration of blast cells is particularly important in both classifications. The latest revision of the WHO classification requires blast cell identification to be undertaken using morphological criteria. Flow cytometric analysis on its own is not recommended to replace morphological assessment currently. (2, 3) See appendix for details of WHO Classification. 5. ASSESSMENT OF PROGNOSIS Patients diagnosed with myelodysplasia have a reduced life expectancy compared with age and sex matched normal controls with this difference particularly marked in patients less than 60 years old and those with high risk disease at any age. The FAB and WHO classification systems although defining groups with differing biology and outcome have limited prognostic power due to variable clinical outcome within the diagnostic groups. In addition to a specific diagnosis a prognostic score using the current International Prognostic Scoring System should be used to classify patients into prognostic groups at presentation.(4) A prognostic score using the WHO categories may also be used in patients who are transfusion dependant. (5) The details of the IPSS scoring system are included in the appendix. 1

2 6. PATIENT INFORMATION Patients should normally be informed of the diagnosis by a consultant haematologist according to the individual Trust s Breaking Bad News guidelines. Written information should be given to the patient/relative as appropriate. Patients should be offered additional counselling/support from trained nurse counsellors and clinical psychologists. In elderly patients specific support services for this age group should also be offered. 7. FERTILITY Appropriate patients should be offered sperm banking/oocyte cryo-preservation prior to commencing chemotherapy or bone marrow transplantation if desired. 8. MANAGEMENT Once a specific MDS diagnosis has been made it is recommended that management decisions be based on the patient s IPSS score calculated based on clinical and laboratory findings obtained during a stable clinical phase. Management decisions should be taken with the informed involvement of the patient and their family. Management may be complicated by the generally advanced age of many patients, attendant co-morbidities and reduced ability to tolerate intensive therapy interventions. Due to the heterogeneity of presentation possible in MDS it may not be possible to make a clear diagnosis in some patients and reassessment after a further period of time is required in these circumstances. Patients with idiopathic cytopenia of uncertain significance (ICUS) should be followed up in the same way as low risk MDS patients until the diagnosis is clear. Responses to treatment should where appropriate be recorded using the standardised response criteria developed for use in MDS. (6) 9. TREATMENT GOALS AND PRINCIPLES The goals of treatment of MDS whether curative or non-curative are to prolong survival, improve peripheral blood counts and improve quality of life. Therapeutic options include supportive care, low intensity therapy or high intensity therapy. All patients should receive supportive care. This includes clinical monitoring, psychosocial support and appropriate quality of life assessment and intervention. Prognostic scoring in patients with clinically significant cytopenias identifies lower risk patients where the major therapeutic aim is haematological improvement and a higher risk group where alteration of the natural history of the disease and its progression to acute leukemia is the main aim of treatment. Goals for therapy need to be individualised for each patient. Wherever possible new treatments should be conducted within a clinical trial. 10. MANAGEMENT OF ANAEMIA The management of anaemia includes identification of nutritional deficiencies, haemolysis or infection and their specific treatment and the identification of specific syndromes such as hypocellular MDS and 5q- syndrome that might require specific treatment. Repeat assessment by bone marrow examination, PNH screening and general medical review may be required. Options for general management include supportive care with blood transfusion, with the transfusion trigger decided on clinical grounds or treatment with Erythropoietin or in patients with poor response Eryropoietin and GCSF combinations.(7, 8) Predictive testing using serum erythropoietin assay is useful in predicting response to erythropoiesis stimulating agents and should be undertaken prior to institution of erythropoietin therapy. (9) It is good transfusion practice to maintain accurate records of transfusion history in patients receiving long term transfusion support so that audit of practice can be undertaken. The appendix includes details of management of anaemia. 11. MANAGEMENT OF IRON LOADING The management of iron loading is an important consideration in patients who require transfusion support or who have iron loading anaemia. Patients satisfying the following criteria should be considered for iron chelation: 1) patients in whom allogeneic transplantation is being considered. 2) transfusion dependant patients with low risk or intermediate-1 risk disease with a predicted survival of 2

3 greater than 4 years 3) patients in whom more than 25 units of blood have been transfused 4) patients in whom iron loading has resulted in significant end organ damage. (10) 12. MANAGEMENT OF THROMBOCYTOPAENIA Administration of platelet concentrates is indicated for active bleeding and for support during acute episodes of infection or during chemotherapy. Platelet transfusion is not routinely recommended for chronically depressed platelet counts per se. Antifibrinolytic agents may be useful in selected cases. Patients with severe thrombocytopenia may be eligible for clinical trials of newer agents or respond to demethylating agents and other therapeutic interventions. 13. MANAGEMENT OF INFECTION Individual patients may require antibacterial or antifungal prophylaxis if severely neutropenic but there are no published data to support the routine use of these drugs in this situation. Consideration should be given to the use of prophylactic low dose GCSF therapies in severely neutropenic patients where appropriate. Neutropenic sepsis in MDS patients should be treated vigorously with intravenous antibiotics and growth factors according to local protocols as appropriate and BCSH guidelines. 14. MANAGEMENT WITH CHEMOTHERAPY AND BIOLOGIC RESPONSE MODIFIERS Patients with low risk or intermediate risk 1 MDS suitable for more than supportive care should be considered for treatment with biological response modifiers if falling within the groups where these treatments appear effective. Specifically treatment with immunosuppressive treatments with Cyclosporin or antithymocyte or lymphocyte globulin should be considered in hypoplastic MDS or in refractory anaemia patients with HLA DR15 histocompatibility type and in patients with large PNH clones. Patients with 5q syndrome should be considered for treatment with Lenolidomide preferably within the context of a clinical trial. (11) (12) (13) Patients with intermediate risk-2 or high risk MDS suitable for more than supportive care should be considered for treatment with low intensity chemotherapy with Azacytidine or clinical trials appropriate to this prognostic group. Patients with Refractory anaemia with excess blasts may be considered for entry into current national AML trials or intensive chemotherapy. Bridging treatment with Azacytidine is an option in patients within the high risk group prior to transplantation. 15. INTENSIVE CHEMOTHERAPY AND STEM CELL TRANSPLANTATION OPTIONS Allogeneic transplantation is a potentially curative intervention for low and high risk MDS patients but the timing of transplant, pre-transplant management and selection of transplant procedure complex. All patients potentially eligible for a transplant procedure should have this option considered at presentation and discussed in a transplant MDT. Network referral pathways to Level 4 centres are well established and should be followed. Suggested treatment pathways developed by the level 4 centres in the West Midlands are included in the appendix. Intensive chemotherapy options should be considered for patients in the intermediate-2 and high risk IPSS groups or their WPSS equivalents who are not eligible for transplantation. Where possible these treatments should be delivered within a clinical trial. Patients with more than 20% blasts in bone marrow are eligible for AML or intensive MDS regimes and clinical trials. An assessment of pace of disease and appropriateness for active treatment should be made in this group given the poor prognosis of AML arising from MDS. 16. FOLLOW UP OF PATIENTS WITH MYELODYSPLASIA Patients with myelodysplasia should be coded according to ICD10 classification wherever possible and followed up until death. 3

4 17. REFERRAL TO PALLIATIVE CARE Palliative care services should be involved early in the management of patients with myelodysplasia particularly those with a poor prognosis according to local protocols and procedures. 18. SUGGESTED MINIMUM DATA SET a. CIU data (FAB or WHO classification plus ICD10 code) b. IPSS or WPSS score c. Patient entered into clinical trial Yes/no d. Name of trial e. Management f. Palliative Yes/N g. Date of progression h. Treatment on progression i. Date of death j. Cause of death 19. GUIDELINE SOURCES AND REFERENCES 1. Greenberg P. The myelodysplastic syndromes. Hoffman R, Benz E, Shattil S et al. Haematology: Basic Principals and Practice. 3 rd ed. Ed: New York: Churchill Livingstone; 2000; Brunning R OA, Germing U et al. Myelodysplastic syndromes/neoplasms in Chapter 5, In Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 th ed: Lyon, France: IARC Press; 2008: Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the WHO classification of myeloid neoplasms and acute leukaemia: rationale and important changes. Blood. Apr Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluation prognosis in myelodysplastic syndromes. Blood. Mar ; 89(6): Erratum. Blood 1998:2091: Malcovati L, Porta MG, Passcutto C, et al. Prognostic factors and life expentancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. Oct ; 23(30): Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. Dec ; 96(12): Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndromes patients with erythropoietin with or without granulocyte colony-stimulating factor:results of a prospective randomized phase III trial by the Eastern Co-operative Oncology Group (E1996). Blood First Edition Paper, prepublished nonline June 29, 2009; DOI /blood Jadersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. Jul ;26(21): Hellstrom- Lindberg E, Gulbrandsen N, Lindbert G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor significant effects on quality of life. Br J Haematol. Mar 2003:120(6)

5 10. Greenberg PL. Myelodysplastic Syndromes: iron overload consequences and current chelating therapies. J Natl Compr Canc Netw. Jan 2006;4(1): Sloand EM, Wu CO, Greenberg P, Young N Barrett J Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. May ;26(15): List A, Kurtin S, Roe DJ et al. Efficacy of Lenalidomide in myelodysplastic syndromes. N Engl J Med. Feb ; 352(6): Nimer SD. Clinical management of myelodysplastic syndromes with interstitial delation of chromosome 5q J Clin Oncol. Jun ;24(16): Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of Azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. Mar 2009;10(3): GUIDELINE SOURCES 1. Guideline for the diagnosis and therapy of adult myelodysplastic syndromes B J Haem 2003 (120) NCCN Clinical Practice Guidelines in Oncology: Myelodysplasia Version Pan Birmingham Cancer Network Guidelines for the Management of Adult Myelodysplastic Syndrome 2009 Date Completed: May 2010 Date of Review: June 2013: Agreed by: Dr Richard Chasty Haematology NSSG Chairman Greater Midlands Cancer Network 5

6 APPENDIX 1 International Prognostic Scoring System Definitions of Cytopaenias and Cytogenetic Classifications Cytopaenias Neutrophils: <1.5 x10 9 /l Haemoglobin: <10 g/dl Platelets: <100 x10 9 /l Cytogenetics Good: Normal or -5q, -Y, -20q as sole abnormalities Poor: Intermediate: Complex (ie, 3 abnormalities) or chromosome 7 abnormalities All other abnormalities From Greenburg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89: Copyright American Society of Haematology, used with permission. International Prognostic Scoring System for Percentage of Marrow Blasts, Karyotype and Cytopaenias Score Value Prognostic Variable % Marrow Blasts < Karyotype Good Intermediate Poor Cytopaenias 0 or 1 2 or 3 Scoring for risk groups: 0 = Low = Intermediate = Intermediate 2.5 = High From Greenburg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89: Copyright American Society of Haematology, used with permission. 6

7 APPENDIX 2 Algorithm for the Management of IPSS Int-2/High risk MDS patients using stem cell transplant Sibling Ablative <50 years allogeneic SCT Good PS >50 years/ Consider non-ablative co-morbidity allogeneic SCT* INT-2 / High (+ appropriate for intensive chemotherapy) CR/good PR following induction + consolidation chemotherapy No unrelated Consider Adequate harvest* Autologous Good PS SCT* No sibling SC harvest 40 years Good PS Ablative allogeneic SCT Unrelated >40 years/ Consider non-ablative co-morbidity allogeneic SCT* 7

8 APPENDIX 3 Algorithm for the Management of IPSS Int-1 risk MDS patients using stem cell transplant Sibling <50 years Ablative allogeneic SCT >50 years Consider non-ablative allogeneic* SCT Eligible for allogeneic SCT INT-1 No sibling 40 years Ablative Unrelated Good PS allogeneic SCT >40 years/ Consider non-ablative* co-morbidity allogeneic SCT No unrelated Observe Not eligible for allogeneic SCT Observe * Within CRP where available 8

9 APPENDIX 4 Erythropoietin, GCSF and Immunosuppressive Therapy: Management of Symptomatic Anaemia in MDS RARS plus serum EPO <500 U/l Low/absent transfusion Consider therapeutic trial of EPO plus G-CSF for 6 12 weeks Marrow not hypocellular RA/RAEB plus serum EPO Consider therapeutic trial of or marrow hypocellular <200 U/l, low/absent transfusion EPO for 6 weeks, then add but patient unsuitable G-CSF for further 6 weeks for immunosuppression +/- EPO dose escalation ANAEMIA (symptomatic) Other: high serum EPO +/- high transfusion Consider immunosuppression with Antilymphocyte globulin (if suitable) Supportive care Investigational therapy Hypocellular marrow Consider immunosuppression with Antilymphocyte globulin Or Cyclosporin 9

10 APPENDIX 5 WHO CLASSIFICATION 2008 GREATER MIDLANDS CANCER NETWORK 10