NCCN2009-MDS

NCCN Clinical Practice Guidelines in Oncology™ Myelodysplastic Syndromes V.1.2009 Continue www.nccn.org Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. NCCN Myelodysplastic Panel Members Peter L. Greenberg, MD/Chair Stanford Comprehensive Cancer Center Eyal Attar, MD Dana-Farber/Brigham and Women’s Cancer Center | Massachusetts General Hospital Cancer Center Minoo Battiwalla, MD Roswell Park Cancer Institute ‡ ‡ Þ † † † ‡ † † John M. Bennett, MD Consultant Clara D. Bloomfield, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Carlos M. DeCastro, MD Duke Comprehensive Cancer Center H. Joachim Deeg, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Margaret R. O’Donnell, MD City of Hope Hussain I. Saba, MD, PhD H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida Paul J. Shami, MD Huntsman Cancer Institute at the University of Utah Kathy Spiers, MD St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute Richard M. Stone, MD Dana-Farber/Partners CancerCare Martin S. Tallman, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Peter Westervelt, MD PhD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine ‡ ‡ ‡ ‡ ‡ † * * * * * * * * * * * * * * Writing Committee Member † Medical Oncology ‡ Hematology/Hematology Oncology Þ Internal Medicine � Pathology * * ‡ ‡ ‡ Harry P. Erba, MD, PhD University of Michigan Comprehensive Cancer Center ames M. Foran, MD University of Alabama at Birmingham Comprehensive Cancer Center Guillermo Garcia-Manero, MD The University of Texas M. D. Anderson Cancer Center Steven D. Gore, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins David Head, MD Vanderbilt-Ingram Cancer Center Lori J. Maness, MD ‡ UNMC Eppley Cancer Center at The Nebraska Medical Center Michael Millenson, MD Fox Chase Cancer Center † † J † Þ � Stephen D. Nimer, MD † ‡ Memorial Sloan-Kettering Cancer Center Continue * * * * * * * * Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Table of Contents NCCN Myelodysplastic Syndromes Panel Members Initial Evaluation (MDS-1) The French-American-British (FAB), International Prognostic Scoring System (IPSS) and World Health Organization (WHO) Classification for de Novo MDS (MDS-2, 3 Treatment of LOW INT-1 (MDS-4 Treatment of INT-2, HIGH (MDS-5 Evaluation and Treatment of Related Anemia (MDS-6 Supportive Care for MDS (MDS-A Guidelines Index Print the Myelodysplastic Syndromes Guideline Summary of Guidelines Updates ) ) ) ) ) These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2008. For help using these documents, please click here Discussion References Clinical Trials: Categories of Evidence and Consensus: NCCN All recommendations are Category 2A unless otherwise specified. See The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. NCCN To find clinical trials online at NCCN member institutions, click here: nccn.org/clinical_trials/physician.html NCCN Categories of Evidence and Consensus Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Summary of the Guidelines updates UPDATES MDS-1 MDS-4 MDS-5 � � � Consider molecular testing for JAK2 mutation in patients with thrombocytosis was added to the initial evaluation as helpful in some clinical circumstances. Lenalidomide was added as a treatment recommendation to be considered for symptomatically anemic non-del(5q) patients whose anem a did not respond to initial therapy. Footnote “v” was revised to state “ i Based on age, performance status, major comorbid conditions, psychosocial status and availability of caregiver.” Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. MDS-1 INITIAL EVALUATION Cytopenia(s), suspect myelodysplasia Required: � � � � � � � � H&P CBC, platelets, differential, reticulocyte count Examination of peripheral smear Bone marrow aspiration with iron stain + biopsy + cytogenetics Serum erythropoietin (prior to RBC transfusion) RBC folate, and serum B Serum ferritin ± iron, TIBC Documentation of transfusion history 12 Consider observation to document indolent course vs marked progression of severe cytopenia AML (See NCCN AML Treatment Guidelines) a b Confirm diagnosis of MDS according to FAB and WHO criteria for classification with application of IPSS. Percentage of marrow myeloblasts should be reported. Patients with significant cytopenias and karyotypes t(8;21), t(15;17), and/or inv(16) or variants should be considered AML. . cFamily HLA - evaluation to include all full siblings; unrelated evaluation to include high resolution allele level typing for HLAA, B, C, DR, DQ. To aid the evaluation for improved response to immunosuppressive therapy. To assess possible Fanconi anemia or dyskeratosis congenita. d e See Classification Systems (MDS-2 MDS-3) See NCCN AML Guidelines) . ( and CATEGORY Diagnosis of MDS established based on morphological and clinical criteriaa,b Helpful in Some Clinical Situations: � � � � � � � HLA typing if hemopoietic stem cell transplant (HSCT) candidate HLA typing if indicated for platelet support HIV testing if clinically indicated Evaluate CMML patients for 5q31-33 translocations and/or PDGFR gene rearrangements Consider flow cytometry to evaluate for PNH clone or to assess possible large granular lymphocytic (LGL) disease Consider additional genetic screening for patients with familial cytopenias c e �Consider HLA-DR15 typingd � Consider molecular testing for JAK2 mutation in patients with thrombocytosis See Treatment of Low, INT-1 (MDS-4) INT-2, High (MDS-5) and Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Erythroid dysplasia only; < 5% blasts; < 15% ringed sideroblasts Dysplasia in 10% of cells in 2 myeloid cell lines; < 5% blasts; no Auer rods; < 15% ringed sideroblasts � � Erythroid dysplasia only; < 5 % blasts; 15 % ringed sideroblasts� Dysplasia in 10% of cells in 2 myeloid cell lines; < 5% blasts; no Auer rods; 15 % ringed sideroblasts � � � Unilineage or multilineage dysplasia; 5% to 9% blasts; no Auer rods Unilineage or multilineage dysplasia 10% to 19% blasts; Auer rods ± Unilineage dysplasia in granulocytes or megakaryocytes; < 5% blasts; no Auer rods Normal to increased megakaryocytes with hypolobated nuclei; < 5% blasts; no Auer rods; isolated del (5q) Bone marrow Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. MDS-2 CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 1 of 2) Continued on next page f g h i FAB = French-American-British classification system of MDS. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189-199. WHO = World Health Organization classification system of MDS. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-2302. the American Society of Hematology. This research was originally published in Blood. © FAB Classification of MDSf,g WHO Classification of MDSh,i Refractory anemia (RA) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory anemia with ringed sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) Refractory anemia with excess blasts-1 (RAEB-1) Refractory anemia with excess blasts-2 (RAEB-2) Myelodysplastic syndrome, unclassified (MDS-U) MDS associated with isolated del(5q) Anemia; no or rare blasts Cytopenias (bicytopenia or pancytopenia); no or rare blasts; no Auer rods; < 1x 10 /L monocytes 9 Anemia; no blasts Cytopenias (bicytopenia or pancytopenia); no or rare blasts; no Auer rods; < 1 x 10 /L monocytes 9 Cytopenias; < 5% blasts; no Auer rods; < 1 x 10 /L monocytes9 Cytopenias; 5-19% blasts; Auer rods ±; < 1 x 10 /L monocytes9 Cytopenias; no or rare blasts; no Auer rods Anemia; < 5% blasts; platelets normal or increased FAB subtype % of Peripheral blasts % of Bone marrow blasts Refractory anemia (RA) Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-t) Chronic myelomonocytic leukemia (CMML) (> 1,000 monocytes/mcL blood) < 1 < 1 < 5 < 5 < 5 5-20 � 5 21-30 < 5 5-20 Subtype Blood Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MDS-3 Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. j IPSS = International Prognostic Scoring System k l m n o This research was originally published in Blood. G © This research was originally published in Blood. © reenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079-2088. the American Society of Hematology. Greenberg P, Cox C, LeBeau M, et al: Erratum. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1998;91:1100. the American Society of Hematology. Patients with 20-30 % blasts may be considered as MDS or AML. Cytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex ( 3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. [This excludes karyotypes t(8;21), inv16, and t(15;17), which are considered to be AML not MDS.] Cytopenias: neutrophil count <1,800/mcL, platelets < 100,000/mcL, Hb < 10g/dL. � IPSSj,k,l Prognostic variable Marrow blasts (%) Karyotype Cytopenia m n o Survival and AML evolution Risk category (% IPSS pop.) LOW (33) INT-1 (38) INT-2 (22) HIGH (7) Overall score 0 0.5-1.0 1.5-2.0 � 2.5 Median survival (y) in the absence of therapy 5.7 3.5 1.1 0.4 25% AML progression (y) in the absence of therapy 9.4 3.3 1.1 0.2 Score value 0 1.0 1.5 2.0 < 5 5-10 --- 11-20 Good 21-30 Intermediate Poor 2/30/1 CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 2 of 2) 0.5 Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. MDS-4 LOW, INT-1 Clinically significant cytopenia(s) Symptomatic anemia del(5q) ± other cytogenetic abnormalities Serum Epo 500 mU/ml� Serum Epo > 500 mU/ml Lenalidomide Good probability to respond to ISTs Antithymocyte globulin (ATG), cyclosporin A p q r u sParticularly Low/INT-1 patients 60 y, or those with hypocellular marrows, HLA-DR15 or PNH clone positivity. Patients lack features listed in footnote s. � t For information regarding allogeneic hemopoietic stem cell transplant (HSCT) options (See MDS-5). INT-1 patients with severe cytopenias would also be considered candidates. See IPSS Classification System (MDS-3). See Supportive Care (MDS-A) See dosing of hemopoietic cytokines ( ) . .MDS-6 Supportive care as an adjunct to treatment q Thrombocytopenia, neutropenia No response Follow appropriate pathway below Epoetin alfa (rHu EPO) ± G-CSF r or Darbepoetin alfa ± G-CSF No response Azacytidine/ decitabine or Clinical trial Consider lenalidomide or No response Clinical trial or Consider allotransplant for selected INT-1 patientsu No response No response Azacytidine/ decitabine or Clinical trial No response IST or Clinical trial s or Consider allotransplant for selected INT-1 patientsu Progressive Disease - See INT-2, HIGH (MDS-5) IPSS CATEGORYp TREATMENT Poor probability to respond to ISTt Clinical trial or Consider allotransplant for selected INT-1 patientsu Azacytidine/ decitabine or Clinical trial Consider lenalidomide or Follow appropriate pathway below Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. INT-2, HIGHx Intensive therapyq,v Transplant candidate and Donor available Yes No Not intensive therapy candidate High intensity therapy or y Azacytidine/decitabine or Clinical trial Azacytidine/decitabine or Clinical trial or Supportive careq Allogeneic hemopoietic stem cell transplant (HSCT)w IPSS CATEGORYp TREATMENT p v w q Based on age, performance status, major comorbid conditions, Azacytidine or decitabine treatment may be used as a bridge to transplant while awaiting improved patient status or donor availability. xINT-1 patients with severe cytopenias would also be considered candidates for allogeneic HSCT. See IPSS Classification System (MDS-3). See Supportive Care (MDS-A). psychosocial status and availability of caregiver. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. MDS-5 yHigh-Intensity Therapy: �Clinical Trials (preferred) Investigational therapy preferred. Standard induction therapy if investigational protocol unavailable or as a bridge to HSCT. (See text for more detail) Hemopoietic stem cell transplant (HSCT): � � � �allogeneic-matched sibling including standard and (experimental) reduced intensity preparative approaches or matched unrelated donor (MUD) INT-2, HIGHx Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Version 1.2009, 07/10/08 © 2008 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. No response (despite adequate iron stores) bb Continue EPO, decrease dose to tolerance Consider adding G-CSF 1-2 mcg/kg 1-3 x/wk subcutaneous Decrease dose to tolerance Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. TREATMENT OF SYMPTOMATIC ANEMIAEVALUATION OF RELATED ANEMIA � � � � � � � H&P CBC, platelets, differential, reticulocyte count Examination of peripheral smear Bone marrow aspiration with iron stain + biopsy + cytogenetics Serum EPO level Consider HLA-DR 15 typing Rule out coexisting causes � � � � Treat coexisting causes Replace iron, folate, B12 if needed RBC transfusions (leuko-reduced) Supportive careq Less than 15% ringed sideroblasts: Serum EPO 500 mU/ml � Ringed sideroblasts ( 15%): Serum EPO 500 mU/ml � � Serum EPO > 500 mU/ml rHu EPO 40,000 - 60,000 U 1-3 x/wk subcutaneous or Darbepoetin alfa 150-300 mcg/wk subcutaneous rHu EPO 40,000 - 60,000 U 1-3 x/wk subcutaneous + G-CSF 1-2 mcg/kg 1-3 x/wk subcutaneous or Darbepoetin alfa 150-300 mcg/wk subcutaneous + G-CSF MDS-6 No responsebb Response, decrease dose to tolerance No response See Low, INT-1 (MDS-4) FOLLOW-UP q z aa bb Lack of 1.5 gm/dl rise in Hb or decreased RBC transfusion requirement by 3-4 months of treatment. Lack of 1.5 gm/dl rise in Hb or decreased RBC transfusion requirement by 6-8 weeks of treatment. Target hemoglobin up to 12gm/dl. See Supportive Care (MDS-A). See Serum EPO > 500 mU/ml (MDS-4) Lenalidomide No responseaa See Low, INT-1 (MDS-4) See Low, INT-1 (MDS-4) del(5q) ± other cytogenetic abnormalities Responsez Responsez Continue decrease dose to tolerance lenalidomide Responsez Guidelines Index MDS Table of Contents Discussion, References Practice Guidelines in Oncology – v.1.2009 Myelodysplastic SyndromesNCCN ® Ver