NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) Myelodysplastic Syndromes Version 2.2014

® NCCN NCCN Guidelines Index MDS Table of Contents Discussion

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* Peter L. Greenberg, MD/Chair ‡ Karin Gaensler, MD ‡ Margaret R. O’Donnell, MD ‡ Stanford Cancer Institute UCSF Helen Diller Family City of Hope Comprehensive Cancer Center Comprehensive Cancer Center Eyal Attar, MD † ‡ Paul J. Shami, MD ‡ Dana-Farber/Brigham and Women’s Guillermo Garcia-Manero, MD Huntsman Cancer Institute Cancer Center | Massachusetts General The University of Texas at the University of Utah Hospital Cancer Center MD Anderson Cancer Center Brady L. Stein, MD, MHSÞ ‡ John M. Bennett, MD Þ† Steven D. Gore, MD † ‡ Robert H. Lurie Comprehensive Cancer Consultant The Sidney Kimmel Comprehensive Center of Northwestern University Cancer Center at Johns Hopkins Clara D. Bloomfield, MD † Richard M. Stone, MD ‡ The Ohio State University Comprehensive * David Head, MD ¹ Dana-Farber/Brigham and Women’s Cancer Center - James Cancer Hospital Vanderbilt-Ingram Cancer Center Cancer Center | Massachusetts General and Solove Research Institute Hospital Cancer Center Rami Komrokji, MD Uma Borate, MD Moffitt Cancer Center James E. Thompson, MD † ‡ University of Alabama at Birmingham Roswell Park Cancer Institute Comprehensive Cancer Center Lori J. Maness, MD ‡ UNMC Eppley Cancer Center at Peter Westervelt, MD, PhD † Carlos M. De Castro, MD † The Nebraska Medical Center Siteman Cancer Center at Barnes- Duke Cancer Institute Jewish Hospital and Washington Michael Millenson, MD Þ ‡ University School of Medicine H. Joachim Deeg, MD † ‡ Fox Chase Cancer Center Fred Hutchinson Cancer Research * Benton Wheeler, MD Center/Seattle Cancer Care Alliance St. Jude Children’s Research Hospital/ University of Tennessee Cancer Institute Olga Frankfurt, MD ‡ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Specialties Index NCCN Maoko Naganuma, MSc * Writing Committee Member Dorothy A. Shead, MS Continue † Medical Oncology ‡ Hematology/Hematology Oncology Þ Internal Medicine NCCN Guidelines Panel Disclosures ¹ Pathology

NCCN Myelodysplastic Syndromes Panel Members Clinical Trials: NCCN believes that the best management for any cancer Summary of Guidelines Updates patient is in a clinical trial. Participation in clinical trials is Initial Evaluation (MDS-1) especially encouraged. Additional Testing and Classification (MDS-2) To find clinical trials online at NCCN Member Institutions, click here: 2008 World Health Organization(WHO) Classification of MDS (MDS-3) nccn.org/clinical_trials/physician.html. Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) WHO Classification NCCN Categories of Evidence and (MDS-4) Consensus: All recommendations are category 2A unless otherwise International Prognostic Scoring System and Revised International Prognostic specified. Scoring System (MDS-5) See NCCN Categories of Evidence and Consensus. WHO-Based Prognostic Scoring System for MDS (MDS-6) Prognostic Category Low, Intermediate-1 Treatment (MDS-7) Prognostic Category Intermediate-2, High Treatment (MDS-9)

Evaluation of Related Anemia/Treatment of Symptomatic Anemia (MDS-10) Recommendations for Flow Cytometry (MDS-A) Supportive Care (MDS-B)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN 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®® (NCCN ) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network® . All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2013.

Updates in Version 2.2014 of the NCCN Guidelines from Version 1.2014 include: DISCUSSION · The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 1.2014 of the NCCN Guidelines from Version 2.2013 include: MDS-1 MDS-4 · Modified footnote “b”: Confirm diagnosis of MDS according to FAB · Modified footnote “p”: “Examples include thrombocytosis, or WHO criteria for classification with application of IPSS. See leukocytosis, and splenomegaly. In addition, RARS-T has been Classification Systems (MDS-3 and MDS-5). The percentage of suggested as a provisionalMDS/MPN entity for individuals with marrow myeloblasts based on morphologic assessment (aspirate RARS and platelet counts³ 450,000 x109 /L.” [Chapter 4, in Swerdlow smears preferred) should be reported. Flow cytometric estimation of S, Campo E, Harris NL, et al (Eds.). World Health Organization blast percentage should not be used as a substitute for morphology Classification of Tumours of Haematopoietic and Lymphoid Tissues, in this context. In expert hands, expanded flow cytometry may be a 4th edition. IARC Press, 2008, pp 85-86.] useful adjunct for diagnosis in difficult cases (See Discussion section, MS-5-6). MDS-5 · Included Revised International Prognostic Scoring System (IPSS-R) MDS-3 · Added the following footnotes: · Removed French-American-British (FAB) Classification of MDS > Footnote “x”: Greenberg PL, Tuechler H, Schanz J, et al. Revised tables. International Prognostic Scoring System (IPSS-R) for · Added “Refractory anemia with excess blasts in transformation myelodysplastic syndromes. Blood 2012;120:2454-2465. (RAEB-T) to the table with footnote “l”. > Footnote “y”: Cytogenetic risks: Very good = -Y, del(11q); Good = · Footnote l: “In the 2008 WHO classification, RAEB-T (as previously Normal, del(5q), del(12p), del(20q), double including del(5q); classified by the FAB group, Bennett JM, Catovsky D, Daniel MT, et Intermediate = del(7q), +8, +19, i(17q), any other single or double al. Proposals for the classification of the myelodysplastic independent clones; Poor = -7, inv(3)/t(3q)/del(3q), syndromes. Br J Haematol 1982;51:189-199) is classified as AML double including -7/del(7q), complex: 3 abnormalities; Very poor = with myelodysplasia-related changes and may be more akin to MDS Complex: >3 abnormalities. than AML. Refer to Arber DA, Brunning RD, Orazi A, et al. Acute > Included the following websites for accessing the IPSS-R calculator myeloid leukaemia with myelodysplasia-related changes. In Chapter tool: http://www.ipss-r.com or 6. Acute Myeloid Leukemia and Related Precursor Neoplasms, in http://mdsfoundation.org/calculator/index.php. A mobile App for the Swerdlow S, Campo E, Harris NL, et al (Eds.). World Health calculator tool is also available for smartphones at MDS IPSS-R. Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC, Lyon, 2008, pp 124-126.”

Note: All recommendations are category 2A unless otherwise indicated. Continued on next page Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Updates in Version 1.2014 of the NCCN Guidelines from Version 2.2013 include: MDS-7 MDS-9 · Added “IPSS-R: Very Low, Low, Intermediate” to the heading. · Added “IPSS-R: Intermediate, High, Very High” to the heading. · Following “Clinically significant cytopenia(s)” added “ or increased · Modifed footnote ll: “Based on age, performance status, major marrow blasts.” comorbid conditions, psychosocial status, patient preference, and · Following “Clinically relevant thrombocytopenia or neutropenia” availability of caregiver. Patients may be taken immediately to added “or increased marrow blasts.” transplant or bridging therapy should be used to decrease marrow · Changed “No response” to “Disease progression/no response.” blasts to an acceptable level prior to transplant.” · Added footnote “bb”: “IPSS-R Intermediate patients may be managed as very low/low risk or high/very high risk depending upon MDS-10 additional prognostic factors such as age, performance status, · Added footnote “gg” to lenalidomide. Footnote gg states: “Except for serum ferritin levels, and serum LDH levels. If patients initially are patients with low neutrophil counts or low platelet counts. managed as lower risk but fail to respond, move to higher risk Recommended initial dose is: 10 mg/d for 21 out of 28 days monthly management strategies.” for 2-4 months to assess response (See Discussion). Alternative · Moved “Immunosuppressive therapy (IST)” earlier under option to lenalidomide may include an initial trial of ESAs in patients Azacytidine/decitabine under treatment. The section now reads: with serum EPO£ 500 mU/mL.” Azacytidine/decitabine or ISTee or Clinical trial. · Footnote “ee” has been modified: “Patients generally££ 60 y, and 5% marrow blasts or those with hypocellular marrows, HLA-DR15 positivity, or PNH clone positivity.”

MDS-8 · Added “IPSS-R: Very Low, Low, Intermediate” to the heading. · Under treatment, changed “No response” to “No response or intolerance.” · Modified footnote “gg”: Except for patients with low neutrophil counts or low platelet counts. Recommended initial dose is: 10 mg/d for 21 out of 28 days monthly for 2-4 months to assess response (See Discussion). Alternative option to lenalidomide may include an initial trial of ESAs in patients with serum EPO£ 500 mU/mL.

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.

INITIAL EVALUATION

Required: · H&P · CBC, platelets, differential, reticulocyte count · Examination of peripheral smear Diagnosis of MDS See Additional Cytopenia(s), · Bone marrow aspiration with iron stain + biopsy + established based Testing: Helpful in suspect cytogenetics by standard karyotyping on morphologic Some Clinical myelodysplasiaa · and clinical Serum erythropoietin (prior to RBC transfusion) Situations (MDS-2) · b,c RBC folate, serum B12 criteria · Serum ferritin, iron, total iron-binding capacity (TIBC) · Documentation of transfusion history · TSH (thyroid stimulating hormone) to rule out hypothyroidism

aMDS is also suspected in the presence of acquired MDS-related cytogenetic abnormalities, and in the unexpected increase in blasts or dysplasia. bConfirm diagnosis of MDS according to FAB or WHO criteria for classification with application of IPSS. See Classification Systems (MDS-3and MDS-5). The percentage of marrow myeloblasts based on morphologic assessment (aspirate smears preferred) should be reported. Flow cytometric estimation of blast percentage should not be used as a substitute for morphology in this context. In expert hands, expanded flow cytometry may be a useful adjunct for diagnosis in difficult cases ()See Discussion section, MS-6-7 . cPatients with significant cytopenias and karyotypes t(8;21), t(15;17), and/or inv(16) or variants should be considered to have AML. (See NCCN Guidelines for AML).

ADDITIONAL TESTING CLASSIFICATION

MDS See Classification Systems (MDS-3 and MDS-5) Helpful in Some Clinical Situations: · Consider flow cytometry (FCM) for MDS diagnostic aidd to assess possible large granular lymphocytic (LGL) diseaseef and to evaluate for PNH clone · HLA typing if hematopoietic stem cell transplant (HSCT) candidateg · Consider HLA-DR15 typingh Consider observation to ·HLA typing if indicated for platelet support document indolent course vs. ·HIV testing if clinically indicated marked progression of severe ·Evaluate CMML patients for 5q31-33 translocations and/or PDGFRb gene cytopenia or increase in blasts rearrangementsi ·Consider molecular testing for JAK2 mutation in patients with thrombocytosis ·Consider additional genetic screening for patients with familial cytopenias, particularly for younger patientsj · Consider evaluation of copper deficiency AML (See NCCN Guidelines for AML) dSee Recommendations for Flow Cytometry (MDS-A) and Discussion. eMarrow or peripheral blood cell FCM may be assayed, and T-cell gene rearrangement studies may be conducted if LGLs are detected in the peripheral blood. Chan WC, Foucar K, Morice WG, Catovsky D. T-cell large granular lymphocytic leukemia. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO classification of tumours of haematopoietic and lymphoid tissues (ed 4th). Lyon: IARC; 2008:272-273. fFCM analysis of granulocytes and monocytes with FLAER (fluorescent aerolysin) and at least one GPI-anchored protein to assess the presence of a PNH clone. Borowitz MJ, Craig FE, Digiuseppe JA, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010;78:211-230. gFamily HLA - evaluation to include all full siblings; unrelated evaluation to include high resolution allele level typing for HLA-A, -B, -C, -DR, and -DQ. hTo assist determination of patient’s potential responsiveness to immunosuppressive therapy. iCMML patients with this abnormality may respond well to tyrosine kinase inhibitors (TKIs) such as imatinib mesylate. jTo assess possible Fanconi anemia or dyskeratosis congenita (DKC). Shortened telomere length has been associated with diseases of bone marrow failure, including inherited disorders such as DKC, particularly in the presence of mutations in the telomerase complex genes. Telomere length can be measured by fluorescence in situ hybridization (FISH) assays using leukocyte samples (See Discussion).

2008 WHOm Classification of MDSk,l

Subtype Blood Bone marrow

Refractory cytopenia with unilineage dysplasia Single or bicytopenia Dysplasia in³ 10% of one cell line, < 5% blasts (RCUD)m

Refractory anemia with ringed sideroblasts Anemia, no blasts ³ 15% of erythroid precursors w/ring (RARS) sideroblasts, erythroid dysplasia only, < 5% blasts Refractory cytopenia with multilineage Cytopenia(s), Dysplasia in³³ 10% of cells in 2 hematopoietic dysplasia (RCMD) < 1 x 109 /L monocytes lineages, ± 15% ring sideroblasts, < 5% blasts

Refractory anemia with excess blasts-1 Cytopenia(s), Unilineage or multilineage dysplasia, (RAEB-1) £ 2%-4% blasts, < 1 x 109 /L No Auer rods, 5%-9% blasts monocytes Refractory anemia with excess Cytopenia(s), Unilineage or multilineage dysplasia 9 blasts-2 5%-19% blasts, < 1 x 10 /L Auer rods, ± 10%-19% blasts (RAEB-2) monocytes Unilineage dysplasia or no dysplasia but Myelodysplastic syndrome, Cytopenias unclassified (MDS-U) characteristic MDS cytogenetics, < 5% blasts

MDS associated with isolated del(5q) Anemia, platelets normal or Unilineage erythroid dysplasia, isolated del(5q), increased < 5% blasts

Refractory anemia with excess blasts in Cytopenias, 5-19% blasts Multilineage dysplasia, Auer rods ±, transformation (RAEB-T)l 20-30 % blasts kRefer to Table 5.01 (p. 89) of 2008 WHO Classification: Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue. IARC, Lyon, 2008. lIn the 2008 WHO classification, RAEB-t (as previously classified by the FAB group, Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189-199) is classified as AML with myelodysplasia-related changes and may be more akin to MDS than AML. Refer to Arber DA, Brunning RD, Orazi A, et al. Acute myeloid leukaemia with myelodysplasia-related changes. In Chapter 6. Acute Myeloid Leukemia and Related Precursor Neoplasms, in Swerdlow S, Campo E, Harris NL, et al (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC, Lyon, 2008, pp 124-126. mThis category encompasses refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT). Cases of RN and RT were previously classified as MDS, unclassified.

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) WHO Classificationn AML with myelodysplasia-related changesqr WHO Classification

Subtype Blood Marrow 1. AML post MDS or MDS/MPN 2. AML with an MDS-related cytogenetic abnormality 3. AML with multilineage dysplasia Chronic myelomonocytic > 1x109 /L monocytes, Dysplasia in≥ 1 leukemia-1 (CMML-1) < 5% blasts hematopoietic line, < 10% blasts

CMML-2 > 1x109 /L monocytes, Dysplasia in≥ 1 5%-19% blasts hematopoietic line, or Auer rods 10%-19% blasts or Auer rods Atypical chronic myeloid WBC > 13x109 /L, Hypercellular, leukemia (CML), BCR- neutrophil precursors < 20% blasts ABL1 negative > 10%, < 20% blasts

Juvenile myelomonocytic > 1x109 /L monocytes, > 1x109 /L monocytes, leukemia (JMML) <20% blastso

MDS/MPN, unclassifiable Dysplasia + Dysplasia + ('Overlap syndrome') myeloproliferative myeloproliferative features featuresp , No prior MDS or MPN nRefer to Tables 4.01 (p. 76), 4.02 (p. 80), 4.03 (p. 82), and 4.04 (p. 85) of 2008 WHO Classification: Orazi A, Bennet JM, Germing U, et al, Myelodysplastic/Myeloproliferative Neoplasms, Chapter 4, in Swerdlow S, Campo E, Harris NL, et al (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC Press, 2008, pp 76-86. oPh negative plus≥ 2 features: Hb F, PB immature myeloid cells, WBC > 10x109 /L, clonal chromosomal abnormality, GM-CSF hypersensitivity in vitro. pExamples include thrombocytosis, leukocytosis, and splenomegaly. In addition, RARS-T has been suggested as a provisional MDS/MPN entity for individuals with RARS and platelet counts³ 450,000 x109 /L [Chapter 4, in Swerdlow S, Campo E, Harris NL, et al (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC Press, 2008, pp 85-86.] qGreater than 20% blasts in PB or marrow. Some cases with 20%-29% blasts, especially if arising from MDS, may be slowly progressive and may behave more similarly to MDS (RAEB-T by FAB classification) than to overt AML. rArber DA, Brunning RD, Orazi A, et al. Acute myeloid leukaemia with myelodysplasia-related changes. In Chapter 6, Acute Myeloid Leukemia and Related Precursor Neoplasms, in Swerdlow S, Campo E, Harris NL, et al (Eds.). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. IARC Press, 2008, pp 124-126.

CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 3 of 4) Continued on next page International Prognostic Scoring System (IPSS)s,t Revised International Prognostic Scoring System (IPSS-R)x Survival and AML evolution Score value Score value Prognostic 0 0.5 1 1.5 2 3 4 Prognostic variable 0 0.5 1.0 1.5 2.0 variable Very Very Cytogeneticsy – Good – Intermediate Poor Marrow blasts (%)u <5 5-10 --- 11-20 21-30 good poor Marrow v ≤2 – >2-<5 5-10 >10 – Karyotype Good Intermediate Poor blasts (%) – Hemogloblin ≥10 – 8-<10 <8 ––– Cytopeniaw 0/1 2/3 Platelets ≥100 50-<100 <50 –– – – ANC ≥0.8 <0.8 – –– – – Median 25% AML IPSS survival (y) in progression (y) Median 25% AML Risk category Overall the absence of in the absence IPSS-R survival (y) in progression (y) (% IPSS pop.) score therapy of therapy Risk category Overall the absence of in the absence (% IPSS-R pop.) score therapy of therapy LOW (33) 0 5.7 9.4 VERY LOW (19) ³ 1.5 8.8 Not reached INT-1 (38) 0.5-1.0 3.5 3.3 LOW (38) >1.5-3 5.3 10.8 INT-2 (22) 1.5-2.0 1.1 1.1 INT (20) >3-4.5 3 3.2 HIGH (7) ³ 2.5 0.4 0.2 HIGH (13) >4.5-6 1.6 1.4

VERY HIGH (10) >6 0.8 0.7 sIPSS should be used for initial prognostic and planning purposes. WPSS permits dynamic estimation of prognosis at multiple time points during the course of MDS. xGreenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System tGreenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis (IPSS-R) for myelodysplastic syndromes. Blood 2012;120:2454-2465. in myelodysplastic syndromes. Blood 1997;89:2079-2088; Erratum. Blood 1998;91:1100. Websites for accessing the IPSS-R calculator tool: http://www.ipss-r.com or © The American Society of Hematology. http://mds-foundation.org/calculator/index.php. A mobile App for the calculator tool is also uPatients with 20%-30% blasts may be considered to have MDS (FAB) or AML (WHO). available for smartphones at MDS IPSS-R. vCytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex yCytogenetic risks: Very good = -Y, del(11q); Good = Normal, del(5q), del(12p), del(20q), (³ 3 abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities. double including del(5q); Intermediate = del(7q), +8, +19, i(17q), any other single or double [This excludes karyotypes t(8;21), inv16, and t(15;17), which are considered to be AML independent clones; Poor = -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3 and not MDS.] abnormalities; Very poor = Complex: >3 abnormalities. wCytopenias: neutrophil count < 1,800/mcL, platelets < 100,000/mcL, Hb < 10g/dL.

CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 4 of 4) WHO-based Prognostic Scoring System (WPSS)z Variable Variable scores 021 3 WHO RCUD, RARS, MDS with RCMD RAEB-1 RAEB-2 category isolated deletion (5q) Karyotypev Good Intermediate Poor --- Severe anemia (hb < 9 g/dL in males or < 8 g/dL Absent Present------in females)

WPSS risk Sum of individual variable scores Very low 0 Low 1 Intermediate 2 High 3-4 Very high 5-6

xCytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex (³ 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 and not MDS.] zMalcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). Haematologica 2011;96:1433-1440.

IPSS: Low/Intermediate-1 IPSS-R: Very Low, Low, Intermediatebb WPSS: Very Low, Low, Intermediate del(5q) ± other See (MDS-8) cytogenetic abnormalities

Symptomatic Serum EPO anemia See (MDS-8) £ 500 mU/mL

Clinically No del(5q) ± other significant Supportive carecc cytogenetic abnormalities cytopenia(s) as an adjunct to Serum EPO or increased See (MDS-8) treatment > 500 mU/mL marrow blasts

Clinically relevant Clinical trial Azacitidine/decitabine thrombocytopenia Disease or or neutropenia or or progression/ Consider allo-HSCT increased marrow Immunosuppressive No responsedd ee for selected IPSS blasts therapy (IST) intermediate-1 or patientsff Clinical trial aaPresence of comorbidities should also be considered for evaluation of prognosis (See references 128-133 in the Discussion section). bbIPSS-R Intermediate patients may be managed as very low/low risk or high/very high risk depending upon additional prognostic factors such as age, performance status, serum ferritin levels, and serum LDH levels. If patients initially are managed as lower risk but fail to respond, move to higher risk management strategies. ccSee Supportive Care (MDS-B). ddResponse should be evaluated based on IWG criteria: Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-425. eePatients generally££ 60 y, and 5% marrow blasts or those with hypocellular marrows, HLA-DR15 positivity, or PNH clone positivity. ffIPSS Intermediate-1, IPSS-R and WPSS Intermediate patients with severe cytopenias would also be considered candidates for HSCT (hematopoietic stem cell transplant): Allogeneic-matched sibling transplant including standard and reduced-intensity preparative approaches or matched unrelated donor (MUD).

IPSS: Intermediate-2, Highee IPSS-R: Intermediate,kk High, Very High WPSS: High, Very High Azacitidine/decitabine If Yes Allo- or relapse Transplant HSCTmm,nn Clinical trial High-intensity candidate Responsedd Continue therapy and candidatecc,ll Donor available Azacitidine (preferred) (category 1)/decitabineoo or No High-intensity chemotherapypp or Clinical trial No Clinical trial responsedd or cc Azacitidine (preferred) (category 1)/decitabineoo or relapse Supportive care Not high-intensity or cc,ll therapy candidate Clinical trial aaPresence of comorbidities should also be considered for evaluation of prognosis (See references 128-133 in the Discussion section). ccSee Supportive Care (MDS-B). ddResponse should be evaluated based on IWG criteria: Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419-425. ffIPSS Intermediate-1, IPSS-R and WPSS Intermediate patients with severe cytopenias would also be considered candidates for HSCT (hematopoietic stem cell transplant): Allogeneic-matched sibling transplant including standard and reduced-intensity preparative approaches or matched unrelated donor (MUD). kkIPSS-R Intermediate patients may be managed as very low/low risk or high/very high risk depending upon additional prognostic factors such as age, performance status, serum ferritin levels, and serum LDH levels. llBased on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver. Patients may be taken immediately to transplant or bridging therapy should be used to decrease marrow blasts to an acceptable level prior to transplant. mmAzacitidine, decitabine, or other therapy may also be used as a bridge to transplant while awaiting donor availability. However, these agents should not be used to delay available HSCT. nnHematopoietic stem cell transplant (HSCT): Allogeneic-matched sibling including standard and reduced-intensity preparative approaches or MUD. ooWhile the response rates are similar for both drugs, survival benefit from a Phase lll randomized trial is reported for azacitidine and not for decitabine ppHigh-intensity chemotherapy: · Clinical trials with investigational therapy (preferred), or · Standard induction therapy if investigational protocol is unavailable or if it is used as a bridge to HSCT.

RECOMMENDATIONS FOR FLOW CYTOMETRY Initial Evaluation ()from MDS-1 · Flow cytometry: > Consideration should be given to obtain FCM testing at initial evaluation of MDS to include antibody combinations to characterize blasts and to identify abnormal lymphoid populations (such as increased hematogones, which may mimic blasts, leading to erroneous myeloblast quantitation). For example, a combination using anti-CD45, -CD34, -CD33, and -CD19 (with forward scatter and side scatter) could be useful. > It is understood that the blast percent for both diagnosis and risk stratification should be determined by morphologic assessment, not solely by FCM. If blasts are increased and morphologic questions arise regarding their subtype (ie, myeloid or lymphoid), they should be characterized with a more elaborate panel of antibodies. > In diagnostically difficult cases, in expert hands, an expanded panel of antibodies to demonstrate abnormal differentiation patterns or aberrant antigen expression may help confirm diagnosis of MDS (See Discussion section, MS-6-7).

SUPPORTIVE CARE1 · Clinical monitoring · Psychosocial support · Quality-of-life assessment · Transfusions: > RBC transfusions (leuko-reduced) are recommended for symptomatic anemia, and platelet transfusions are recommended for thrombocytopenic bleeding. However, they should not be used routinely in patients with thrombocytopenia in the absence of bleeding unless platelet count < 10,000/mm3 . Irradiated products are suggested for transplant candidates. > Cytomegalovirus (CMV)-negative blood products are recommended whenever possible for CMV-negative transplant candidates. · Antibiotics are recommended for bacterial infections, but no routine prophylaxis is recommended except in patients with recurrent infections. · Aminocaproic acid or other antifibrinolytic agents may be considered for bleeding refractory to platelet transfusions or profound thrombocytopenia. · Iron chelation: > If > 20-30 RBC transfusions have been received, consider daily chelation with deferoxamine subcutaneously or deferasirox orally to decrease iron overload, particularly for LOW/INT-1 and for potential transplant patients. For patients with serum ferritin levels > 2500 ng/mL, aim to decrease ferritin levels to < 1000 ng/mL.2 > Patients with low creatinine clearance (< 40 mL/min) should not be treated with deferasirox. · Cytokines: > EPO: See Anemia Pathway ( )MDS-9 > G-CSF or GM-CSF: 7 Not recommended for routine infection prophylaxis 7 Consider use if recurrent or resistant infections in neutropenic patient 7 Combine with EPO for anemia when indicated (See Anemia Pathway [MDS-9]) 7 Platelet count should be monitored

1See NCCN Guidelines for Supportive Care. 2Clinical trials in MDS are currently ongoing with oral chelating agents.

Discussion Therapeutic Options ...... MS-14 Supportive Care ...... MS-15 NCCN Categories of Evidence and Consensus Low-Intensity Therapy ...... MS-19 Category 1: Based upon high-level evidence, there is uniform NCCN High-Intensity Therapy ...... MS-24 consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform Recommended Treatment Approaches ...... MS-24 NCCN consensus that the intervention is appropriate. Therapy for Lower Risk Patients (IPSS Low, Intermediate-1, IPSS-R Very Low, Low and Intermediate, or WPSS Very Low, Low, and Category 2B: Based upon lower-level evidence, there is NCCN Intermediate) ...... MS-24 consensus that the intervention is appropriate. Therapy for Higher Risk Patients (IPSS Intermediate-2, High, IPSS- Category 3: Based upon any level of evidence, there is major NCCN R Intermediate, High, Very High, or WPSS High, Very High) ... MS-25 disagreement that the intervention is appropriate. Evaluation and Treatment of Related Anemia ...... MS-27 All recommendations are category 2A unless otherwise noted. Summary ...... MS-29

References ...... MS-30 Table of Contents

Overview ...... MS-2

Diagnostic Classification ...... MS-2

Initial Evaluation ...... MS-5

Pediatric MDS ...... MS-8

Prognostic Stratification ...... MS-9

Prognostic Scoring Systems ...... MS-9

Molecular Abnormalities in MDS ...... MS-13

Comorbidity Indices ...... MS-14

Overview Diagnostic Classification The myelodysplastic syndromes (MDS) represent myeloid clonal Initial evaluation of patients with suspected MDS requires careful hemopathies with relatively heterogeneous spectrums of presentation. assessment of their peripheral blood smear and blood counts, marrow The major clinical problems in these disorders are morbidities caused morphology, duration of their abnormal blood counts, other potential by patients’ cytopenias and the potential for MDS to evolve into acute causes for their cytopenias and concomitant illnesses. The NCCN myeloid leukemia (AML). In the general population, the incidence rate of Guidelines for MDS includes the World Health Organization (WHO) MDS is approximately 5 per 100,000 people per year.1,2 MDS is rare classification system for diagnostic evaluations. The among children/adolescents and young adults, with an incidence rate of French-American-British (FAB) classification is discussed below to 0.2 per 100,000 people per year in those under 40 years of age; provide a historical overview of the diagnostic classification system however, among individuals older than age 70, the incidence rate utilized in MDS. increases to approximately 26 per 100,000 people, and the rate increases further to 48 per 100,000 people among those 80 years and The FAB classification initially categorized patients for the diagnostic 4 older.1 evaluation of MDS. Dysplastic changes in at least two of the three hematopoietic cell lines have been used by most histopathologists to Managing MDS is complicated by the generally advanced age of the diagnose MDS. These changes include megaloblastoid erythropoiesis, patients (median age at diagnosis is 70 to 75 years),2 the attendant nucleocytoplasmic asynchrony in the early myeloid and erythroid non-hematologic comorbidities, and the older patients' relative inability precursors, and dysmorphic megakaryocytes.5 Patients with MDS are to tolerate certain intensive forms of therapy. In addition, when the classified as having one of five subtypes of disease: refractory anemia illness progresses into AML, these patients experience lower response (RA); RA with ringed sideroblasts (RARS); RA with excess of blasts rates to standard therapy than patients with de novo AML.3 (RAEB); RAEB in transformation (RAEB-t); and chronic myelomonocytic leukemia (CMML). MDS are generally indolent, with patients' blood The multidisciplinary panel of MDS experts for the NCCN Clinical counts remaining relatively stable over at least several months. Practice Guidelines in Oncology (NCCN Guidelines®) meets annually to update recommendations on standard approaches to the diagnosis and With a moderate degree of variability, RAEB patients (those with 5% to treatment of MDS in adults. These recommendations are based on a 20% marrow blasts) and those with RAEB-t (20% to 30% marrow review of recent clinical evidence that have led to important advances in blasts) generally have a relatively poor prognosis, with a median treatment or have yielded new information on biological factors that may survival ranging from 5 to 12 months. In contrast, RA patients (fewer have prognostic significance in MDS. than 5% blasts) or RARS patients (fewer than 5% blasts plus more than 15% ringed sideroblasts) have a median survival of approximately 3 to 6 years. The proportion of these individuals whose disease transforms to AML ranges from 5% to 15% in the low-risk RA/RARS group to 40% to

50% in the relatively high-risk RAEB/RAEB-t group. The FAB the rationale behind the changes in the 2008 WHO classification of classification categorizes patients with more than 30% marrow blasts as MDS and AML evolving from MDS.12 having AML. Other categories within the WHO classification include refractory In a study evaluating time-to-disease evolution, 25% of RAEB cases cytopenia with multilineage dysplasia (RCMD) with or without ring and 55% of RAEB-t cases underwent transformation to AML at 1 year, sideroblasts, RARS, RAEB cases separated into those with less than whereas 35% of RAEB cases and 65% of RAEB-t cases underwent 10% marrow blasts (RAEB-1) and those with 10% or more marrow transformation to AML at 2 years.3 In contrast, the incidence of blasts (RAEB-2), 5q deletion [del(5q)] syndrome, and MDS unclassified transformation for RA was 5% at 1 year and 10% at 2 years. None of (with MDS cytogenetics, with or without unilineage dysplasia). The the RARS patients developed leukemia within 2 years. del(5q) syndrome, recognized by WHO as a separate MDS category, includes patients with an isolated 5q31-33 deletion and marrow showing In 2001, the World Health Organization (WHO) proposed a classification less than 5% blasts, often with thrombocytosis.6-8 This disorder 6-8 for MDS. The report suggested modifying the FAB definitions of MDS. generally has a relatively good prognosis13 and is highly responsive to Although most prior data require dysplasia in at least two lineages for lenalidomide therapy.14 the diagnosis of MDS, the WHO guidelines accept unilineage dysplasia for the diagnosis of RA and RARS provided that other causes of the The category myelodysplastic/myeloproliferative neoplasms dysplasia are absent and the dysplasia persists for at least 6 months. (MDS/MPN), includes CMML (CMML-1 and CMML-2); atypical CML, To establish the diagnosis of MDS, careful morphologic review and BCR-ABL1 negative; and juvenile myelomonocytic leukemia (JMML) as correlation with the patient’s clinical features are important, because a disorders having overlapping dysplastic and proliferative features, and number of medications and viral infections (including HIV infection) may the MDS/MPN unclassifiable group.15 The distinction between CMML-1 cause morphologic changes in marrow cells similar to MDS.3,9 and CMML-2 is based on the percentage of blasts plus monocytes in peripheral blood and bone marrow. CMML had been categorized by In 2008, a revision of the WHO classification incorporated new scientific FAB as MDS; by the International MDS Risk Analysis Workshop and clinical information and refined diagnostic criteria for previously (IMRAW) as proliferative type (WBC 12,000/mm3) (a myeloproliferative described neoplasms; it also introduced newly recognized disease disorder (MPD) or non-proliferative type (dysplastic MDS).13 The 10 entities. A new subtype in the MDS classification is refractory MDS/MPN unclassifiable group includes the provisional entity, RARS cytopenia with unilineage dysplasia (RCUD), which includes: RA associated with marked thrombocytosis (RARS-T), which includes (unilineage erythroid dysplasia), refractory neutropenia (RN) (unilineage cases that present with clinical and morphological features consistent dysgranulopoiesis), and refractory thrombocytopenia (RT) (unilineage with MDS, and thrombocytosis (platelet counts ≥ 450 × 109/L).16 The dysmegakaryocytopoiesis). RN and RT were previously classified as morphology of RARS-T is characterized by RARS features (no blasts in 11 MDS unclassifiable. A review article discusses the major changes and peripheral blood, dysplastic erythroid proliferation, ring sideroblasts ≥15% of erythroid precursors, and <5% blasts in marrow) with

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-3 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion proliferation of large atypical megakaryocytes similar to those seen in be considered as either MDS or AML. Such patients have previously essential thrombocythemia or primary myelofibrosis; up to 60% of been included in and benefited from many therapeutic trials for MDS RARS-T cases have the JAK2 V617F mutation or MPL W515K/L should continue to be eligible for MDS-type therapy. Thus, the MDS mutation.16 Panel recommends using the WHO classification but having the RAEB-t patient subgroup considered as either MDS or AML. Studies The WHO classification excludes RAEB-t patients from MDS (proposing have provided evidence supportive of the use of the WHO that AML should now include patients with 20% or more marrow blasts, proposals.20-24 rather than the previously used cut-off of 30% or more). However, MDS are not only related to blast quantitation, but also possess a differing AML evolving from MDS (AML-MDS) is often more resistant to standard pace of disease related to distinctive biologic features that differ from de cytotoxic chemotherapy than is de novo AML, which arises without novo AML.17,18 In addition, therapeutic responses generally differ antecedent hematologic disorder. High-risk MDS, AML-MDS, and some between these two patient groups. elderly patients with AML may have a more indolent course in terms of short-term progression compared with patients with standard The 2008 WHO classifications have helped clarify the clinical presentations of de novo AML. Separate protocols for treating patients 19 differences between the FAB RAEB-t patients and AML. The current with standard presentation of de novo AML and for these other patient WHO classification lists the entity ‘AML with myelodysplasia-related groups (such as MDS-AML, elderly AML, and high-risk MDS groups) changes’, which encompasses patients with AML post-MDS, AML with seem appropriate (see NCCN Guidelines for Acute Myeloid Leukemia). multilineage dysplasia and AML with MDS-associated cytogenetic abnormalities.19 According to the 2008 WHO classification, some To assist in providing consistency in diagnostic guidelines of MDS, an patients with AML with myelodysplasia-related changes having 20% to International Consensus Working Group recommended that minimal 29% marrow blasts, especially those arising from MDS (considered diagnostic criteria for this disease include required diagnostic RAEB-t by the FAB classification) may behave in a manner more similar prerequisites: stable cytopenia (for at least 6 months unless to MDS than to AML. accompanied by a specific karyotype or bilineage dysplasia, in which case only 2 months of stable cytopenias are needed) and the exclusion The decision to treat patients having marrow blasts in the range of of other potential disorders as a primary reason for dysplasia or/and 20% to 30% with intensive AML therapy is thus complex and should cytopenia. In addition to these two diagnostic prerequisites, the be individualized. The clinician should consider such factors as age, diagnosis of MDS requires at least one of three MDS-related (decisive) antecedent factors, cytogenetics, comorbidities, pace of disease, criteria: i) dysplasia (≥10% in one or more of the three major bone performance status and patient’s goal for treatment. The NCCN MDS marrow lineages), ii) a blast cell count of 5% to19%, and iii) a specific panel currently endorses reporting and using the WHO classification MDS-associated karyotype, e.g. del(5q), del(20q), +8, or -7/del(7q). system. However, as indicated on MDS-3, RAEB-t patients (with 20– Further, several co-criteria help confirm the diagnosis of MDS. These 30% blasts AND a stable clinical course for at least 2 months) should co-criteria include studies with flow cytometry, bone marrow histology

Initial Evaluation If patients require platelet transfusions for severe thrombocytopenia, Several types of evaluations are needed to determine the clinical status human leukocyte antigen (HLA) typing (A, B) may be helpful. For of patients with MDS. Understanding clinical status is necessary for hematopoietic stem cell transplant (HSCT) candidates, the patient’s determining diagnostic and prognostic categorization and deciding CMV status and full HLA typing (A, B, C, DR, and DQ) of the patient treatment options. Clinical history should include the timing, severity, and potential donors are needed. Bone marrow flow cytometry for and tempo of abnormal cytopenias; prior infections or bleeding assessing the % of CD34+ cells (blast cells are usually CD34+), and episodes; and number of transfusions. Concomitant medications and HIV screening, if clinically indicated, may also be valuable in some comorbid conditions require careful assessment. Because MDS are clinical situations. It should be emphasized, however, that estimates of relatively indolent disorders, blood count stability is used to distinguish blast percentage by flow cytometry do not provide the same MDS from evolving AML. Other possible causes for patients’ cytopenias prognostic information as the blast percentage derived from also require careful evaluation. morphologic evaluation. Accordingly, data from flow cytometry should not be used in lieu of the determination of morphologic blast In addition to establishing current blood and reticulocyte counts, percentage by an experienced hematopathologist. The screening for clinicians need a peripheral blood smear evaluation to determine the paroxysmal nocturnal hemoglobinuria (PNH) and HLA-DR15 is degree of dysplasia and, thus, potentially dysfunctional cells. Bone potentially useful for determining which patients may be more marrow aspiration with Prussian blue stain for iron and biopsy are responsive to immunosuppressive therapy, particularly in young needed to evaluate the degree of hematopoietic cell maturation patients with normal cytogenetics and hypoplastic MDS27,28 (see abnormalities and relative proportions, percentage of marrow blasts, Prognostic Stratification below). PNH is a rare acquired hematopoietic marrow cellularity, presence or absence of ringed sideroblasts (and stem cell disorder arising from mutations in the PIGA gene resulting in presence of iron per se), and fibrosis. Cytogenetics for bone marrow defective synthesis of the glycophosphatidylinositol (GPI) anchor, samples (by standard karyotyping methods) should be obtained which in turn leads to deficiency of proteins that are normally linked to because they are of major importance for prognosis. the cell membrane of blood cells via a GPI anchor.29-31 Deficiency in GPI-anchored proteins such as those involved in complement Other useful screening laboratory studies include serum erythropoietin inhibition (e.g., CD55, CD59) leads to complement sensitivity of red (sEpo), vitamin B12, red blood cell folate levels, and serum ferritin. blood cells and subsequent hemolysis.29 Flow cytometry is the Serum ferritin levels may be nonspecific, particularly in the face of established method for detecting GPI-anchor-deficient cells for the inflammatory conditions such as rheumatoid arthritis. Therefore, in such

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-5 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion diagnosis of PNH. Recent data showed that fluorescent aerolysin CD45 as markers, to aid in the diagnosis of MDS.38 The scoring system (FLAER), a protein that specifically binds to GPI anchors, was a was developed using multicenter retrospective data from patients with reliable marker for detecting GPI-anchor-deficient clones among low-grade MDS (defined as <5% marrow blasts; n=417) and those with granulocytes or monocytes, with high sensitivity.32 For evaluation of non-clonal cytopenias as controls (n=380). This population of patients PNH clone, it is recommended that multiparameter flow cytometry was chosen for the study because low-grade MDS often lack specific analysis of granulocytes and monocytes using FLAER, and at least diagnostic markers (e.g., ring sideroblasts, clonal cytogenetic one GPI-anchored protein, be conducted.29,32 It should be emphasized abnormalities) and, therefore, may be difficult to diagnose based on that although evidence for a minor PNH clone may be present in about morphology alone. Bone marrow samples from patients with MDS 20% of patients with MDS, there is usually no evidence for PNH- showed different flow cytometric patterns compared with samples from related hemolysis in these patients. patients with non-clonal cytopenias with regards to the following: increased CD34+ myeloblast-related cluster size (defined by wider Bone marrow biopsy staining for reticulin is helpful for evaluating the distribution of CD45 expression and greater side scatter characteristics presence and degree of bone marrow fibrosis. [SSC]), decreased CD34+ B-progenitor cluster size (defined by relatively low CD45 expression and low SSC), aberrant myeloblast Discrete from basic flow cytometric evaluation at presentation for CD45 expression (based on lymphocyte to myeloblast CD45 ratio) and characterization of blasts and evaluation of lymphoid populations, decreased granulocyte SSC value (based on granulocyte to lymphocyte expanded flow cytometry may be a useful adjunct for diagnosis of MDS SSC ratio).38 These four parameters were included in a logistic in difficult cases. In expert hands (both in terms of technical regression model and a weighted score (derived from regression sophistication and interpretation), flow cytometry may demonstrate coefficients) was assigned to each parameter; the sum of the scores abnormal differentiation patterns or aberrant antigen expression in provided the overall flow cytometric score for each sample, with a score myeloid or progenitor cells, which may help confirm diagnosis of MDS, of 2 or higher defined as the threshold for MDS diagnosis.38 Using this exclude differential diagnostic possibilities, and in some patients, flow cytometric score in the learning cohort, a correct diagnosis of MDS provide prognostic information.33-37 To achieve these purposes, the flow was made with 70% sensitivity and 93% specificity. Among MDS analysis should use appropriate antibody combinations with four patients without specific markers of dysplasia, 65% were correctly fluorescence channel instrumentation.33-37 Multiple aberrancies should identified. The positive predictive value and negative predictive value be present for diagnosis of MDS, as single aberrancies are not was 92% and 74%, respectively. These outcomes were confirmed in the infrequent in normal populations. For followup studies, antibody validation cohort, which showed 69% sensitivity and 92% specificity.38 combinations may be tailored to detect specific abnormalities found in This flow cytometric scoring system demonstrated high diagnostic the initial evaluation. While aberrancies have also been described in power in differentiating low-grade MDS from non-clonal cytopenias, and erythroid cells, erythroid analysis is not provided by most flow cytometry may be particularly useful in establishing a diagnosis in situations where laboratories. The European LeukemiaNET recently developed a flow cytometric score based on reproducible parameters using CD34 and

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-6 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion traditional diagnostic methods are indeterminate. Further independent individuals may not display these clinical characteristics.45 Different validation studies are warranted to determine the utility of this method. types of genetic lesions in RUNX1 account for the variable phenotypes associated with familial platelet disorder between different families. Because of the associated expense, requirements for both technical Cryptic genetic lesions in RUNX1 have been reported in some patients and interpretational expertise, and need for greater consensus on with Fanconi’s anemia and MDS/AML.46 The GATA2 gene codes for a specific antibody combinations and procedures that are most transcription factor involved in gene regulation during the development informative and cost effective, flow cytometric assays should be and differentiation of hematopoietic cells, and its expression was shown performed by experienced laboratories, and used in general practice to correlate with severe dysplasia in patients with primary MDS.47 only when diagnosis is uncertain with traditional approaches (e.g., blood Recently, heritable mutations in GATA2 were identified in families with counts, morphology, cytogenetics, increased blasts). Flow cytometry highly penetrant early-onset MDS and/or AML.48 The mutations showed studies may also be used to assess the possibility of large granular an autosomal dominant pattern of inheritance, and affected individuals lymphocytic (LGL) disease, if relevant as indicated by LGLs being with this familial form of MDS/AML had poor outcomes in the absence 39 present in the peripheral blood. of allogeneic stem cell transplant.48 Identification of familial MDS is of clinical importance because it is associated with chromosomal fragility Additional genetic screening should be considered for patients with and such patients may therefore respond differently to hypomethylating familial cytopenias, which will help evaluate for Fanconi's anemia or agents; more importantly, family members may not be eligible as donors dyskeratosis congenita (DC). Shortened telomere length has been for allogeneic hematopoietic stem cell transplant. associated with diseases of bone marrow failure, including inherited disorders such as DC, particularly in the presence of mutations in the Determination of platelet-derived growth factor receptor beta (PDGFR) DKC1, TERT or TERC genes that encode for components of the gene rearrangements is helpful for evaluating CMML/MPD patients with 40,41 telomere complex. Telomere length can be measured by FISH 5q31-33 translocations. The activation of this gene encoding a receptor assays using leukocyte (or leukocyte subset) samples.40,42 Other genetic tyrosine kinase for PDGFR has been shown in some of these lesions such as those occurring in the RUNX1 or GATA2 gene have patients.49,50 Data have indicated that MPD/CMML patients with such been implicated in familial cases of MDS and other myeloid PDGFR fusion genes may respond well to treatment with the tyrosine malignancies. Lesions within the RUNX1 gene (mutations, deletions or kinase inhibitor imatinib mesylate.51-53 translocations) have been identified as a cause of a relatively rare autosomal dominant familial platelet disorder that predisposes to The frequency of activating mutations of the tyrosine kinase known as 43,44 myeloid malignancies. In affected families with the RUNX1 lesions, Janus Kinase 2 (JAK2) in MDS and de novo AML is lower compared to the incidence of MDS/AML is high, ranging from 20-60%; median age of that in myeloproliferative disorders.54 If one encounters thrombocytosis 45 onset is 33 years. This familial platelet disorder is characterized by the in patients with MDS, screening for JAK2 mutations may be helpful. A presence of thrombocytopenia, and a tendency for mild to moderate positive test for JAK2 mutation is consistent with presence of a bleeding generally present from childhood; however, some affected myeloproliferative component of their disorder.55

Recent flow cytometric studies suggest the potential utility of this leukemia [JMML]); and Down syndrome disease (transient abnormal methodology for characterizing MDS marrow blast cells and as an aid myelopoiesis and myeloid leukemia of Down syndrome).10 RCC is the for assessing prognosis of these patients.56,57 However, due to the most common subtype of MDS found in children, accounting for non-standardized nature of these analyses, further investigations are approximately 50% of cases.64 Abnormal karyotypes are found in 30% warranted prior to suggesting their routine use. to 50% of children with MDS,83 more commonly numerical anomalies; fewer than 10% show structural abnormalities. Monosomy 7 is the most There have been reports that copper deficiency can mimic many of the common cytogenetic abnormality, occurring in 30% of cases,84,85 58-60 peripheral blood and marrow findings seen in MDS. Thus, followed by trisomy 8 and 21. The del(5q) abnormality is rarely seen in assessment of copper and ceruloplasmin levels may be indicated as children.86 Clinically, isolated refractory anemias are uncommon in part of the initial diagnostic workup of suspected MDS in certain children. Thrombocytopenia and/or neutropenia, often accompanied by instances. Clinical features associated with copper deficiency include hypocellular marrow, is a common presentation. Fetal hemoglobin 58-60 vacuolation of myeloid and/or erythroid precursors, prior levels are often elevated. gastrointestinal surgery,58,59 and a history of vitamin B12 deficiency.59,61 Differential diagnoses include aplastic anemia (AA) and AML. Pediatric MDS Compared to AA, children with MDS have significantly elevated mean Several differences exist between adult and childhood myelodysplasia. corpuscular volume (MCV); clonal hematopoiesis is confirmatory. MDS and myelodysplasia are quite rare in children, occurring in 1 to 4 Higher expression of p53 and low survivin and MDS-related cytogenetic cases per million per year with a median age of 6.8 years.62-64 MDS in abnormalities can also help differentiate MDS from AA.87 Compared children is strongly associated with congenital disorders.65 Genetic with AML, low WBC, multi-lineage dysplasia, and clonal hematopoiesis syndromes are evident in 50% of cases, including Down syndrome,66-68 with numerical, rather than structural, cytogenetic abnormalities suggest trisomy 8 syndrome,69 Fanconi anemia,70,71 congenital neutropenia MDS. Bone marrow blast count of less than 20% also suggests MDS, (Kostmann syndrome),72,73 Diamond-Blackfan anemia,74 Shwachman- but biological features are more important than a strict blast cut-off Diamond syndrome,75 dyskeratosis congenita, neurofibromatosis type 1, value. Monosomy 7 strongly suggests MDS. When patients present Bloom syndrome, Noonan syndrome,76 and Dubowitz syndrome. Prior with AML, the marrow frequently shows dysplastic features, but this exposure to cytotoxic therapy, such as alkylating agents, does not necessarily indicate that the AML arose after MDS. Indeed, epipodophyllotoxins, and topoisomerase II inhibitors,77-80 and criteria for diagnosis of MDS in a patient who presents with AML are radiation81,82 increases the risk for MDS. stringent.88 Dysplasia in bone marrow cells may also be due to other etiologies including infection (e.g., Parvo virus,89,90 herpes viruses,91 The revised WHO classification (2008) separates myeloproliferative HIV), deficiencies of B12 and copper,92 drug therapy, and chronic disorders into three groups: MDS (refractory cytopenia of childhood disease. Congenital dyserythropoietic anemia and Pearson syndrome [RCC], RAEB, RAEB-t or AML with MDS-related changes); should also be excluded. myelodysplastic/myeloproliferative disease (juvenile myelomonocytic

Children with Down syndrome have an increased risk for developing the best prognosis. Poor prognostic features include high hemoglobin F, leukemia (50-fold greater risk if less than 5 years old), usually acute older age, and thrombocytopenia. megakaryoblastic leukemia (AMKL, M7).66,68,93,94 This commonly has a prodromal phase of cytopenia(s) similar to MDS and may be considered Pediatric AML or MDS with monosomy 7 is associated with poor a spectrum of the same disease. Prognosis of patients with Down prognosis with conventional therapies. A recent review of 16 patients syndrome and AMKL is quite good with 80% cure rate with intensive with AML and MDS with monosomy 7 treated by two transplant chemotherapy. HSCT is not indicated in first complete remission for programs from 1992 to 2003 (MDS, n=5; therapy-related MDS, n=3; these children. Newborns with Down syndrome can develop abnormal AML, n=5; and therapy-related AML, n=3) reported a 2-year event-free 100 myelopoiesis with leukocytosis, circulating blasts, anemia, and survival of 69%. Four of the 5 deaths occurred in patients thrombocytopenia, but this resolves spontaneously within weeks to transplanted with active leukemia. Seven of 8 MDS patients were alive months. Approximately 20% of children with Down syndrome who have without evidence of disease (6 in first complete remission, 1 in second 100 transient abnormal myelopoiesis later develop AMKL.67 complete remission, and 1 death due to complications).

There is a paucity of clinical trials due to the rarity and heterogeneity of As the NCCN Guidelines for MDS focus on recommendations for the MDS in children. The primary goal of treatment is generally a cure, diagnosis, evaluation and treatment of adult patients with MDS, the rather than palliation. HSCT is the only curative option in childhood discussions that follow pertain to adults. MDS with 3-year disease-free survival rates of approximately 50%.95-97 Prognostic Stratification Myeloablative therapy with busulfan, cyclophosphamide, melphalan, followed by either matched family or matched unrelated donor Despite its value for diagnostic categorization of patients with MDS, the allogeneic HSCT is the treatment of choice for children with MDS. Other prognostic limitations of the FAB classification have become apparent treatments such as chemotherapy, growth factors, and with quite variable clinical outcomes within the FAB subgroups. The immunosuppressive therapy have a limited role. Prognosis for untreated morphologic features contributing to this variability include the wide MDS depends upon the rate of progression to AML. The stage of the range of marrow blast percentages for patients with RAEB (5% to 20%) disease at the time of HSCT strongly predicts outcome.85 and CMML (1% to 20%); lack of inclusion of critical biologic determinants such as marrow cytogenetics; and the degree and number Patients with RCC have a median time to progression to advanced of morbidity associated cytopenias. These well perceived problems for MDS of 1.7 years,85 but the time to progression is highly variable, categorizing patients with MDS have led to the development of depending upon the underlying cause of MDS and standard prognostic additional risk-based stratification systems.101 factors.98 Patients with JMML have a variable prognosis, with some younger patients with favorable genetics and clinical features having Prognostic Scoring Systems resolution of JMML without treatment, and others progressing rapidly The International Prognostic Scoring System (IPSS) for primary MDS despite allogeneic HSCT.99 Children diagnosed before age 2 years have emerged from deliberations of the IMRAW.13 Compared with previously

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-9 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion used systems, the risk-based IPSS has markedly improved prognostic intermediate in outcome (14%). Of the patients in the “complex” stratification of MDS cases. In this analysis, cytogenetic, morphologic, category, the vast majority had chromosome 5 or 7 abnormalities in and clinical data were combined and collated from a relatively large addition to other anomalies. group of MDS cases that had been included in previously reported prognostic studies.13,101 FAB morphologic criteria were used to establish To develop the IPSS for MDS, relative risk scores for each significant the diagnoses of MDS. In addition, relative stability of peripheral blood variable (marrow blast percentage, cytogenetic subgroup, and number 13 counts for 4 to 6 weeks was needed to exclude other possible etiologies of cytopenias) were generated. By combining the risk scores for the for the cytopenias, such as drugs, other diseases, or incipient evolution three major variables, patients were stratified into four distinctive risk to AML. CMML was subdivided into proliferative and non-proliferative groups in terms of both survival and AML evolution: low, intermediate-1 subtypes. Patients with proliferative type CMML (those with white blood (INT-1), intermediate-2 (INT-2), and high. When either cytopenias or cell counts greater than 12,000/mcL) were excluded from this analysis.13 cytogenetic subtypes were omitted from the classification, discrimination Patients with non-proliferative CMML (with white blood cell counts of among the four subgroups was much less precise. Both for survival and 12,000/mcL or less as well as other features of MDS) were included in AML evolution, the IPSS showed statistically greater prognostic the analysis.102 discriminating power than earlier classification methods, including the FAB system.13 Significant independent variables for determining outcome for both survival and AML evolution were found to be marrow blast percentage, Recent data have indicated that additional clinical variables are additive number of cytopenias, and cytogenetic subgroup (good, intermediate, to the IPSS regarding prognosis for MDS patients. The WHO- poor). Patients with the chromosome anomalies t(8;21) or inv16 are classification based prognostic scoring system (WPSS) incorporates the considered to have AML and not MDS, regardless of the blast count. WHO morphologic categories, the IPSS cytogenetic categories and the 103 Age was also a critical variable for survival, although not for AML patients’ need or lack of RBC transfusion dependence. This system evolution. The percentage of marrow blasts was divisible into four demonstrated that the requirement for RBC transfusions is a negative categories: 1) less than 5%, 2) 5% to 10%, 3) 11% to 20%, and 4) 21% prognostic factor for patients in the lower risk MDS categories. In to 30%. addition, depth of anemia per se has additive and negative prognostic import for the intermediate IPSS categories.104 As compared with the Cytopenias were defined for the IPSS as having hemoglobin level less four groups defined by the IPSS, the WPSS classifies patients into five than 10 g/dL, an absolute neutrophil count (ANC) below 1,800/mcL, and risk groups differing in both survival and risk of AML. The five risk platelet count below 100,000/mcL. Patients with normal marrow groups are: Very low, Low, Intermediate, High, and Very high. Following karyotypes, del(5q) alone, del(20q) alone, and -Y alone had relatively initial report of the usefulness of WPSS by Malcovati et al,103 there have good prognoses (70%), whereas patients with complex abnormalities been confirmatory studies.105-107 The initial WPSS has recently been (three or more chromosome anomalies) or chromosome 7 anomalies refined to address the notion that the requirement for RBC transfusion had relatively poor prognoses (16%). The remaining patients were may be somewhat subjective. In the refined WPSS, the measure of the

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-10 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion degree of anemia by transfusion dependency is replaced by the differences in outcomes among the IPSS-R risk categories were found presence (or absence) of severe anemia, defined as hemoglobin levels for overall survival, AML evolution, and progression-free survival (latter <9 g/dL for males and <8 g/dL for females.108 This approach allows for defined as leukemic evolution or death from any cause).113 Notably, in an objective assessment of anemia, while maintaining the prognostic this cohort, the predictive power (based on Harrell’s C statistics) of implications of the five risk categories defined in the original WPSS (as IPSS-R was found to be greater than IPSS, WPSS and refined WPSS mentioned above).108 At this time, there is still an ongoing debate for the three outcome measures mentioned above. The investigators whether the WPSS offers an improvement over the IPSS. Based on the acknowledged the short follow up (median 17 months) of the study current available data, the NCCN MDS Panel has included the WPSS in cohort.113 In a retrospective analysis of data from lower risk MDS (IPSS the current version of the treatment algorithm with a category 2B Low or INT-1) patients in a large multicenter registry (N=2410) from designation. Spain, the IPSS-R could identify 3 risk categories (Very Low, Low, Intermediate) within the IPSS Low-risk group with none of the patients Most recently, a revised IPSS (IPSS-R) was developed that also defines categorized as IPSS-R High or Very High.115 Within the IPSS INT-1-risk five risk groups (Very low, Low, Intermediate, High, and Very high) group, the IPSS-R further stratified patients into 4 risk categories (Very 109 versus the four groups defined in the initial IPSS. The IPSS-R, which Low, Low, Intermediate, High) but with only 1 patient categorized as was derived from an analysis of a large dataset from multiple Very High risk. The IPSS-R was significantly predictive of survival international institutions, refined the original IPSS by incorporating the outcomes in both the subgroups of IPSS Low and INT-1 patients. Within following into the prognostic model: more detailed cytogenetic the IPSS Low risk group, median survival based on the IPSS-R risk subgroups, separate subgroups within the “marrow blasts <5%” group, categories was 118.8 months for Very Low, 65.9 months for Low, and and depth of cytopenias defined with cut-offs for hemoglobin, platelet 58.9 months for Intermediate (P<0.001). Within the IPSS INT-1 risk and neutrophil counts. In the IPSS-R, the cytogenetic subgroups group, median survival based on the IPSS-R risk categories was 113.7 comprise five risk groups (versus three in the original IPSS) based on months for Very Low, 60.3 months for Low, 30.5 months for 110 the recently published cytogenetic scoring system for MDS. Other Intermediate, and 21.2 months for High risk (P<0.001).115 In addition, parameters including age, performance status, serum ferritin, lactate within the IPSS INT-1 risk group (but not for IPSS Low risk), IPSS-R dehydrogenase (LDH), and beta-2 microglobulin provided additional was significantly predictive of the 3-year rate of AML evolution.115 Thus, prognostic information for survival outcomes, but not for AML evolution; in this analysis, the IPSS-R appeared to provide prognostic refinement age as an additional factor was more prognostic among lower risk within the IPSS INT-1 group, with a large proportion of patients (511 of 109 groups compared with the higher risk groups. The predictive value of 1096 IPSS INT-1 patients) being identified as having poorer prognosis the IPSS-R was recently validated in a number of independent studies (median survival 21–30 months). This study also applied the refined based on registry data, including in studies that evaluated outcomes for WPSS to further stratify the IPSS Low and INT-1 risk groups, and was 111-116 patients treated with hypomethylating agents. In a multiregional able to identify a group of patients (refined WPSS High risk group) study of MDS patient registry data from Italy (N=646), significant within the IPSS INT-1 group who had poorer prognosis (185 of 1096

IPSS INT-1 patients; median survival 24.1 months). However, the IPSS- identified and a prognostic model was constructed based on results of R identified a larger proportion of poor-risk IPSS INT-1 patients than the multivariate Cox regression analysis. The final model included the refined WPSS (47% vs. 17%).115 Outcomes of risk stratification using following factors that were independent predictors for survival the MD Anderson Lower-Risk Prognostic Scoring System are discussed outcomes: unfavorable cytogenetics, older age (≥ 60 years), decreased in the section below. In a retrospective database analysis of MDS hemoglobin (<10 g/dL), decreased platelet counts (<50 × 109/L or 50– patients from a single institution (N=1029), median overall survival 200 × 109/L), and higher percentage of bone marrow blasts (≥ 4 %).117 according to IPSS-R risk categories was 82 months for Very Low, 57 Important to note, however, is that the cytogenetic categories in this months for Low, 41 months for Intermediate, 24 months for High and 14 system were derived from the previously defined IPSS categories rather months for Very High risk groups (P<0.005).114 The median follow up in than from the more refined IPSS-R. Each of these factors were given a this study was 68 months. IPSS-R was also predictive of survival weighted score, and the sum of the scores (ranging from a total of 0 to 7 outcomes among the patients who received therapy with points) were used to generate 3 risk categories; a score of 0 to 2 points hypomethylating agents (n=618). A significant survival benefit with was assigned to category 1, score of 3 or 4 was category 2 and a score hypomethylating agents was shown only for the group of patients with of 5 to 7 was category 3. Using this scoring system, median survival Very High risk IPSS-R (median 16 vs. 7 months with no was 80.3 months for category 1, 26.6 months for category 2, and 14.2 hypomethylating therapy; P<0.005). In addition, significantly longer months for category 3; the 4-year survival rates were 65%, 33%, and overall survival with allogeneic HSCT was only observed for patients 7%, respectively. The scoring system allowed for further stratification with High (median 42 vs. 21 months without HSCT; P=0.004) and Very into these 3 risk categories for both the subgroup of patients with IPSS High (median 31 vs. 12 months without HSCT; P<0.005) risks.114 The Low-risk and IPSS INT-1-risk disease.117 The LR-PSS could therefore IPSS-R may therefore provide a tool for therapeutic decision-making, be a useful tool to identify patients with lower risk disease who may although prospective studies are needed to confirm these findings. have poorer prognosis and may require earlier treatment. The Further evaluation is warranted and ongoing regarding the utility of the prognostic value of the LR-PSS has been validated in several IPSS-R in both the settings of clinical trials and routine clinical practice. independent studies.115,118-120 In a retrospective analysis of data from lower risk MDS (IPSS Low or INT-1) patients in the multicenter Spanish registry (N=2410), the LR-PSS was able to further stratify these lower The Lower-Risk Prognostic Scoring System (LR-PSS) developed by risk patients into 3 risk categories.115 The LR-PSS was significantly investigators at the MD Anderson Cancer Center is another prognostic predictive of survival outcomes in both the subgroups of IPSS Low and model used in the evaluation of MDS, and was designed to help identify INT-1 patients. Within the IPSS Low risk group, median survival using patients with lower risk disease (IPSS Low or INT-1) who may have the LR-PSS risk categories was 130.3 months for category 1 (low risk), 117 poor prognosis. The prognostic model was developed using clinical 69.7 months for category 2 (intermediate risk), and 58.4 months for and laboratory data from patients with IPSS Low (n=250) and INT-1 category 3 (high risk)(P<0.001); the corresponding median survival (n=606) risk MDS. Factors associated with decreased survival were values within the IPSS INT-1 risk patients were 115.2 months, 51.3

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-12 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion months, and 24.1 months, respectively (P<0.001). The LR-PSS cases without TET2 mutations.122,123 In the present analysis, the identified an important proportion of patients (334 of 1096 patients; presence of TET2 mutations was found to be associated with normal 30.5%) within the IPSS INT-1 risk group who had poorer prognosis karyotype and a median survival similar to that of the overall patient (median survival 24 months, as above). In addition, within the IPSS INT- cohort.122 Mutations in ASXL1 is another relatively common lesion in 1 risk group (but not for IPSS Low risk), LR-PSS was significantly patients with MDS (about 15% of cases) and as also reported in another predictive of the rate of AML evolution at 3 years.115 In another analysis recent study, is associated with significantly shorter overall using data from a cohort of lower risk MDS patients from two centers survival.122,124 Mutations in TP53 were associated with complex (N=664), median survival according to the LR-PSS risk categories was karyotype and chromosome 17 abnormalities. Importantly, TP53 91.4 months for category 1, 35.6 months for category 2, and 22 months mutations were associated with the worse prognosis with respect to for category 3.120 Using data from the same cohort of patients, median survival outcomes, which confirms earlier reports of the significant survival according to the IPSS-R risk groups was 91.4 months for IPSS- negative prognostic impact of TP53 mutations in MDS.122,125 In this R Very Good, 35.9 months for Good, and 27.8 months for the combined analysis, mutations in TP53, RUNX1, or NRAS were significantly Intermediate/High/Very High risk groups. Both of these prognostic associated with severe thrombocytopenia and elevated blast scoring systems were significantly predictive of survival outcomes. The percentages.122 predictive power (based on Harrell’s C statistics) of LR-PSS and IPSS- R was 0.64 and 0.63, respectively.120 Among the frequently occurring genetic lesions mentioned above, mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 were found to be Molecular Abnormalities in MDS significant independent predictors of decreased overall survival in a In recent years, various gene mutations have been identified among multivariable regression model that also included age and IPSS risk 122 patients with MDS, which may in part contribute to the clinical groups as variables. When these five poor-risk gene mutations were heterogeneity of the disease course, and thereby influence the integrated into the survival analysis by IPSS categories, the presence of prognosis of patients.121,122 Such gene mutations may be present in a a mutation was shown to shift the survival curve of the IPSS risk substantial proportion of newly diagnosed patients, including in patients category to resemble that of the next highest IPSS risk level (e.g., with normal cytogenetics. In a recent genetic study in samples from survival plot for low-risk IPSS group with a gene mutation was similar to 122 patients with MDS (N=439), at least one gene mutations was identified that for INT-1 risk). Thus, the combined analysis of the gene in 52% of samples and multiple gene mutations were found in 18% of mutational status and IPSS may improve upon the risk stratification samples.122 The most frequently occurring genetic lesions were provided by assessment of IPSS alone. Common molecular mutations in the TET2, ASXL1, RUNX1, TP53, EZH2, NRAS, JAK2, abnormalities involving the RNA splicing machinery have also been ETV6, CBL, and IDH2 genes. Mutations in TET2 is among the most reported in patients with MDS, including gene mutations in SRSF2 (11– common genetic lesions reported in patients with MDS (about 20% of 12%), U2AF1/U2AF35 (5–7%), ZRSR2 (3–11%), and SF3B1 (14.5– 126,127 cases), and appears to confer a more favorable prognosis compared to 16%), Mutations in SRSF2 and ZRSR2 have been associated with

Comorbidity Indices Therapeutic Options Given that patients with MDS predominantly comprise an elderly adult The patient's IPSS risk category is used in initial planning of therapeutic population, the presence of comorbid conditions pose potential options because it provides a risk-based patient evaluation (category challenges in terms of treatment tolerability and outcomes. About 50% 2A). In addition, factors such as the patient’s age, performance status, of patients with newly diagnosed MDS present with one or more and presence of comorbidities are critical determinants because they comorbidities, with cardiac disease and diabetes being among the most have a major influence on the patient's ability to tolerate certain frequently observed conditions.128-132 Assessment of the presence and intensive treatments. The WPSS provides dynamic estimation of degree of comorbidities using tools such as the Charlson Comorbidity prognosis at any time during the course of MDS. Index (CCI) or the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCT-CI) has demonstrated the significant If the patient was only recently evaluated, determining the relative prognostic influence of comorbidities on the survival outcome of patients stability of the patient’s blood counts over several months is important to with MDS.128,130-132 Recent studies have shown that comorbidity (as assess whether the patient’s disease progresses, including incipient measured by HCT-CI or ACE-27) was a significant prognostic factor for transformation to AML. In addition, this assessment permits survival, independent of IPSS129,132; in these studies, comorbidity indices determination of other possible etiologies for cytopenias. The patient’s provided additional prognostic information for survival outcomes in preference for a specific approach is also important in deciding patients categorized as IPSS INT or High risk, but not for patients treatment options. The therapeutic options for MDS include supportive considered to have Low-risk disease. Interestingly, in another recent care, low-intensity therapy, high-intensity therapy, and/or participation in study, comorbidity (as measured by HCT-CI or CCI) was a significant a clinical trial. In evaluating results of therapeutic trials, the panel found predictor of overall and event-free survival in patients within the Low- it important for studies to use the standardized International Working 134-136 risk or INT-1-risk groups, but not in the INT-2- or High-risk groups.130 Group (IWG) response criteria. Comorbidity has also been shown to provide additional risk stratification For the MDS therapeutic algorithm, all patients should receive relevant among WPSS risk categories (for very low-, low- and intermediate-risk supportive care. Following that, the MDS panel has proposed initially groups but not for high- or very high-risk groups), prompting the stratifying patients with clinically significant cytopenia(s) into two major development of a new MDS-specific comorbidities index that can be risk groups: (1) relatively lower-risk patients (who are in the IPSS Low,

Intermediate-1 category, IPSS-R Very Low, Low and Intermediate (generally leukocyte-reduced) or platelet transfusions for bleeding categories, or WPSS Very Low, Low, and Intermediate categories); and events; however, platelet transfusions should not be used routinely in (2) higher-risk patients (who are in the IPSS Intermediate-2/ High patients with thrombocytopenia in the absence of bleeding. There was categories, IPSS-R Intermediate, High, Very High categories, or WPSS non-uniform consensus among the panel members based on differing High, Very High categories). Patients that fall under the IPSS-R institutional policies regarding the necessity for routine irradiation of Intermediate category may be managed as Very Low/Low risk or blood products used in patients with MDS; however, the panel agreed High/Very High risk depending upon evaluation of additional prognostic that all directed-donor products and transfused products for potential factors such as age, performance status, serum ferritin levels, and stem cell transplant patients should be irradiated. Additionally, CMV serum LDH levels.109 In addition, those Intermediate risk patients whose negative blood products are recommended whenever possible for CMV disease does not respond to therapy for lower risk disease would be negative recipients. Aminocaproic acid or other antifibrinolytic agents eligible to receive therapy for higher risk MDS. may be considered for bleeding episodes refractory to platelet transfusions or for profound thrombocytopenia. Based upon IWG response criteria, the major therapeutic aim for patients in the lower risk group would be hematologic improvement, Hematopoietic Cytokines whereas for those in the higher risk group, alteration of the disease Hematopoietic cytokine support should be considered for refractory natural history is viewed as paramount. Cytogenetic response and symptomatic cytopenias.137 For example, recombinant human quality of life parameters are also important outcomes to assess. The granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte algorithms outline management of primary MDS only. Most patients with CSF (GM-CSF) treatment could be considered for neutropenic MDS therapy-related MDS have poorer prognoses than those with primary patients with recurrent or resistant bacterial infections. MDS, including a substantial proportion with poor risk cytogenetics. These patients are generally managed as having higher risk disease. Erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin (Epo) or darbepoetin, with or without G-CSF, has been Supportive Care evaluated in the treatment of symptomatic anemia in patients with 138-142 Currently, the standard of care in the community for MDS management MDS. In a phase II study in patients with MDS (RA, RARS and includes supportive care (see Supportive Care section in the Guidelines RAEB; N=50), Epo combined with G-CSF (n=47 evaluable) resulted in and NCCN Supportive Care Guidelines). This entails observation, hematologic response in 38% of patients (complete response [CR] in 138 clinical monitoring, psychosocial support, and quality-of-life (QOL) 21%). Epo and G-CSF appeared to have synergistic activity. Lower assessment. Major efforts should be directed toward addressing the serum Epo levels (<500 mU/mL) and lower pretreatment RBC relevant QOL domains (e.g., physical, functional, emotional, spiritual, transfusion requirement (<2 units per month) were associated with social), which adversely affect the patient. Supportive care should higher response rate; response rates were not significantly different 138 include red blood cell transfusions for symptomatic anemia as needed across IPSS risk groups. Median survival (N=71; including patients from a prior study) was 26 months. Among patients with low-risk IPSS,

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-15 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion median survival had not been reached at 5 years; the 5-year survival cohort of untreated patients (n=225), multivariate analysis showed a rate was 68%. Median survival among INT-1 an INT-2 risk groups was significant association between treatment with ESAs and survival 27 months and 14 months, respectively. AML progression occurred in outcomes. The frequency of AML progression was similar between the 28% of patients overall, during the observation period; the frequency of cohorts.142 In a phase II study that evaluated darbepoetin (given every 2 AML progression in the low-, INT-1, INT-2, and high-risk groups were weeks for 12 weeks), with or without G-CSF (added at 12 weeks in non- 12%, 21%, 45%, and 100%, respectively. Among responding patients responders), in MDS patients with lower-risk IPSS with anemia (and who received maintenance treatment with Epo and G-CSF, the median with serum Epo levels <500 mU/mL), hematologic response rate was duration of response was 24 months.138 A subsequent analysis on long- 48% at 12 weeks and 56% at 24 weeks.140 Median duration of response term outcomes with Epo combined with G-CSF (given 12–18 weeks, was not reached with a median follow up of 52 months. The 3-year followed by maintenance in responders) in patients with MDS (n=121; cumulative incidence of AML progression was 14.5% and the 3-year patients from 3 phase II Nordic trials) reported a hematologic response survival rate was 70%. This study also showed improvements in QOL rate of 39% with a median duration of response of 23 months.139 Long- parameters among responding patients.140 Collectively, these studies term outcomes of these patients were compared with outcomes from suggest that ESAs may provide clinical benefit in patients with lower risk untreated patients (n=237) as controls. Based on multivariate Cox MDS with symptomatic anemia. Limited data are available on the regression analysis, treatment with Epo plus G-CSF was associated effectiveness of ESAs in the treatment of anemia in lower risk patients with significantly improved survival outcomes (hazard ratio=0.61, 95% with del(5q). Epo has been shown to promote the growth of CI 0.44–0.83; P=0.002). An exploratory analysis revealed that the cytogenetically normal cells isolated from patients with del(5q), while association between treatment and survival was significant only for the having minimal proliferative effects on MDS progenitor cells from these IPSS low-risk group. In addition, the survival benefit with treatment was patients in vitro.143 Retrospective studies from the French group observed only in patients requiring fewer than 2 units of RBC reported hematologic response rates of 46% to 64%, with a median transfusions per month. No significant association was found between duration of response of 11 months (and mean duration of 13–14 treatment and frequency of AML progression.139 Similar findings were months) among patients with del(5q) treated with ESAs, with or without reported in a study from the French group, which analyzed outcomes G-CSF.141,142 Duration of response in these patients was significantly with ESAs (epoetin or darbepoetin), with or without G-CSF, in MDS decreased compared with that in patients without del(5q) (mean patients with anemia (N=403).142 Based on IWG 2000 criteria, duration 25–27 months).141 Based on multivariate analysis, del(5q) was hematologic response rate was 62% with a median duration of a significant predictor of shorter response duration with treatment.142 response of 20 months. Based on IWG 2006 criteria, the corresponding The use of ESAs to treat symptomatic anemia is discussed further results were 50% and 24 months, respectively. IPSS low/INT-1-risk was under the Guidelines recommendations for “Therapy for Lower Risk associated with significantly higher response rates and longer response Patients” and under “Evaluation and Treatment of Related Anemia”. durations. In a comparison of outcomes (in the subset of low/INT-1-risk group with anemia) between treated patients (n=284) and a historical

Severe thrombocytopenia is associated with increased risks for normal megakaryopoiesis in vitro in bone marrow cells isolated from bleeding events, and is currently managed with platelet transfusions. patients with MDS.152,153 Ongoing phase I and II clinical trials are The mechanism of thrombocytopenia in patients with MDS may be investigating the activity and safety of this agent in the treatment of attributed to decreased platelet production (possibly related to thrombocytopenia in patients with MDS. Concerns for potential regulatory pathways involving the production and/or metabolism of proliferation of leukemic blasts in response to exogenous TPO have endogenous thrombopoietin [TPO]) as well as increased destruction of been raised in early in vitro studies in the past, particularly for high-risk bone marrow megakaryocytes or circulating platelets.144,145 Endogenous MDS cases.154,155 Results from ongoing clinical trials with the TPO thrombopoietin (TPO) levels has been reported to be increased among mimetics mentioned above will help to elucidate the risks for leukemic patients with MDS compared with those of healthy individuals.145 At the transformations in patients with MDS. It should be noted that neither same time, TPO receptor (c-mpl) sites per platelet appear to be romiplostim nor eltrombopag are currently approved for use in patients decreased among patients with MDS compared with healthy subjects. with MDS. Within patients with MDS, those with RA appeared to have the highest TPO levels compared with RAEB or RAEB-t patients, while the number Management of Iron Overload of TPO receptor sites remained similar across subtypes.145 In addition, RBC transfusions are a key component of the supportive care for MDS studies have reported that high endogenous TPO levels correlated with patients. Although the specific therapies patients receive may alleviate decreased platelet counts in RA patients, but not in RAEB or RAEB-t RBC transfusion need, a substantial proportion of MDS patients may patients.145,146 This observation suggest that the regulatory pathway for not respond to these treatments and may develop iron overload as well 156 endogenous TPO may be further disrupted in patients with RAEB or as its consequences. Thus, effective treatment of such transfusional RAEB-t, potentially due to overexpression of TPO receptors in blasts siderosis in MDS patients is necessary. that may lead to inadequate TPO response.145,146 A number of studies Studies in patients requiring relatively large numbers of RBC are investigating the role of the thrombopoietin receptor agonist transfusions (e.g., thalassemia and MDS) have demonstrated the romiplostim in the treatment of thrombocytopenia in patients with lower pathophysiology and adverse effects of chronic iron overload on risk MDS.147-151 Phase I/II studies with romiplostim showed promising hepatic, cardiac and endocrine function. Increased non-transferrin rates of platelet response (46–65%) in patients with lower risk bound iron (NTBI) levels, generated when plasma iron exceeds MDS.148,150 Recent randomized placebo-controlled studies in patients transferrin binding capacity, combines with oxygen to form hydroxyl and treated for lower risk MDS have reported beneficial effects of oxygen radicals. These toxic elements cause lipid peroxidation and cell romiplostim in terms of decreased bleeding events and reduced needs membrane, protein, DNA and organ damage.157,158 for platelet transfusions in patients receiving hypomethylating 147,149 agents, and decreased frequency of dose reductions or delays in Although limited, there is evidence suggesting that organ dysfunction 151 those receiving lenalidomide therapy. Eltrombopag is another can result from iron overload in patients with MDS.159-161 Retrospective thrombopoietin receptor agonist that has been shown to increase data suggest that transfusional iron overload might be a contributor of

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-17 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion increased mortality and morbidity in early stage MDS.162 The WPSS has blood transfusions.168 This agent has been evaluated in multiple phase shown that requirement for RBC transfusion is a negative prognostic II clinical trials in patients with transfusion-dependent MDS.171-174 A large factor for patients with MDS.103 multicenter phase III randomized controlled trial is currently underway to evaluate outcomes with deferasirox compared with placebo in patients For patients with chronic RBC transfusion need, serum ferritin levels with MDS; the primary endpoint of this ongoing study is event-free and associated organ dysfunction (heart, liver, and pancreas) should be survival (registered at clinicaltrials.gov; NCT00940602). The prescribing monitored. The NCCN panel members recommend monitoring serum information for deferasirox contains a black-box warning pertaining to ferritin levels and number of RBC transfusions received to assess iron increased risks for renal or hepatic impairment/failure and overload as practical means to determine iron stores. Monitoring serum gastrointestinal bleeding in certain patient populations, including in ferritin may be useful, aiming to decrease ferritin levels to <1,000 patients with high-risk MDS. Deferasirox is contraindicated in patients mcg/L. It is recognized that such measurements, though useful, are less with high-risk MDS. A third oral chelating agent, deferiprone, was precise than SQUID (Superconducting Quantum Interference Device) or approved (October 2011) in the U.S. for the treatment of patients with the more recent development of specific measurement of hepatic iron transfusional iron overload due to thalassemia when current chelation 163,164 content using MRI. therapy is inadequate.175 Controversy remains with regards to the use of this agent, however, as the FDA approval was based on results from a Reversal of some of the consequences of iron overload in MDS and retrospective analysis of existing data pooled from previous safety and other iron overload states (e.g., thalassemia) by iron chelation therapy efficacy studies of deferiprone in patients with transfusion-related iron has been shown in patients in whom the most effective chelation overload refractory to existing chelation therapy. The prescribing occurred.136,158 This included transfusion independence in a portion of a information for deferiprone contains a black-box warning pertaining to small group of carefully studied MDS patients who had undergone risks for agranulocytosis, which can lead to serious infections and effective deferoxamine chelation for 1 to 4 years.165 In addition, death.175 improvement in cardiac iron content was demonstrated in these patients 166 after chelation. Such findings have major implications for altering the Clinical trials in MDS are ongoing with oral iron chelating agents to morbidity of MDS patients, particularly those with pre-existing cardiac or address the question whether iron chelation alters the natural history of hepatic dysfunction. patients with MDS who are transfusion dependent. A NCCN task force report titled “Transfusion and Iron Overload in Patients with MDS”, The availability of iron chelators such as deferoxamine167 and discusses in detail the available evidence regarding iron chelation in deferasirox168-170 provides potentially useful drugs to more readily treat patients with MDS.176 this iron overload state. Deferoxamine (given as intramuscular or subcutaneous injections) is indicated for the treatment of chronic iron The NCCN Guidelines panel recommends considering chelation with 167 overload due to transfusion-dependent anemias. Deferasirox (given deferoxamine SC or deferasirox/ICL670 orally once daily to decrease orally) is indicated for the treatment of chronic iron overload due to iron overload in IPSS low or intermediate-1 risk patients who have

received or are anticipated to receive greater than 20 RBC transfusions, randomized phase III trials to decrease the risk of leukemic for whom ongoing RBC transfusions are anticipated and for those with transformation, and, in a portion of the patients, to improve survival.177- serum ferritin > 2500 ng/mL, aiming to decrease ferritin levels to 180 In a phase III trial that compared AzaC with supportive care in <1000 ng/ml. patients with MDS (N=191; previously untreated in 83%; all IPSS risk groups), hematologic responses occurred in 60% of patients in the As mentioned above, a black-box warning by the FDA and Novartis was AzaC arm (7% complete response, 16% partial response, 37% 168 added to the prescribing information for deferasirox. Following post- hematologic improvement) compared with a 5% hematologic marketing use of deferasirox, there were case reports of acute renal improvement (and no responses) in patients receiving supportive failure, or hepatic failure, some with a fatal outcome. Most of the care.180 The median time to AML progression or death was significantly fatalities reported were in patients with multiple co-morbidities and who prolonged with AzaC compared with supportive care (21 vs. 13 months; were in advanced stages of their hematological disorders. Additionally, P=0.007). Additionally, the time to progression to AML or death was there were post-marketing reports of cytopenias, including improved in patients who received AzaC earlier in the course of agranulocytosis, neutropenia and thrombocytopenia and GI bleeding in disease, suggesting that the drug prolonged the duration of stable patients treated with deferasirox where some of the patients died. The disease. Subsequently, Silverman and colleagues provided a summary relationship of these episodes to treatment with deferasirox has not yet of three studies of AzaC in a total of 306 patients with high-risk MDS.181 been established. However, it is recommended to closely monitor In this analysis, which included patients receiving either subcutaneous patients on deferasirox therapy including measurement of serum or intravenous delivery of the drug (75 mg/m2/d for 7 days every 28 creatinine and/or creatinine clearance and liver function tests prior to days), complete remissions were seen in 10% to 17% of AzaC-treated initiation of therapy and regularly thereafter. Deferasirox should be patients; partial remissions were rare; 23% to 36% of patients had 168 avoided in patients with creatinine clearance <40 mL/min. hematologic improvement. Ninety percent of the responses were seen by cycle 6 and the median number of cycles to first response was Low-Intensity Therapy three.181 The authors concluded that AzaC provided important clinical Low-intensity therapy includes the use of low-intensity chemotherapy or benefits for patients with high-risk MDS. Results from a phase III biologic response modifiers. Although this type of treatment is mainly randomized trial in patients (N=358) with higher risk MDS (IPSS INT-1, provided in the outpatient setting, supportive care or occasional 5%; INT-2, 41%; High-risk, 47%) demonstrated that AzaC was superior hospitalization (for example, for treatment of infections) may be needed to conventional care (standard chemotherapy or supportive care) after certain types of these treatments. regarding overall survival.177 AzaC was associated with a significantly longer median survival compared with conventional care (24.5 vs. 15 Hypomethylating Agents months; hazard ratio=0.58, 95% CI 0.43–0.77; P=0.0001), thus As a form of relatively low-intensity chemotherapy, the DNA methyl providing support for the use of this agent in patients with higher risk transferase inhibitor (DMTI) hypomethylating agents 5-azacytidine disease. (AzaC) and decitabine (5-aza-2'-deoxycytidine) have been shown in

AzaC therapy should be considered for treating MDS patients with higher risk MDS. As the treatment regimen was generally associated progressing or relatively high-risk disease. This drug has been with low intensity-type toxicities, it is also considered to be ‘low-intensity approved by the FDA for treatment of patients with MDS. The drug is therapy’. In earlier phase II studies, the drug resulted in cytogenetic generally administered at a dose of 75 mg/m2/day subcutaneously for 7 conversion in approximately 30% of patients,185 with an overall response days every 28 days for at least 4 to 6 courses. Treatment courses may rate of 49%, and a 64% response rate in patients with a high-risk IPSS need to be extended further or may be used as a bridging therapy to score.186 Comparison of results of these studies with those of AzaC more definitive therapy (e.g., HSCT, for patients whose marrow blast showed similarity.187,188 counts require lowering prior to that procedure). Although the optimal 2 duration of therapy with AzaC has not been defined, some data suggest The results of a phase III randomized trial of decitabine (15 mg/m IV 2 that continuation of AzaC beyond first response may improve remission infusion over 3 hours every 8 hours [i.e., 45 mg/m /day] on 3 quality. Secondary analysis from the aforementioned phase III consecutive days every 6 weeks for up to 10 cycles) compared with randomized trial of AzaC in patients with higher risk MDS177 showed that supportive care in adult patients (N=170) with primary and secondary among patients responding to AzaC, response quality was improved in MDS with IPSS INT-1 (31%), INT-2 (44%) and High (26%) risk disease 48% with continued therapy; although most responding patients indicated higher response rates, remission duration, time to AML 178,187 achieved a first response by 6 cycles of therapy, up to 12 cycles was progression and survival benefit in the INT-2 and High risk groups. required for the majority of responders to attain a best response.182 In Overall response rate (CR + PR) with decitabine was 17%, with an this study, the median number of cycles from first response to best additional 13% having hematologic improvement; the median duration response was 3 to 3.5 cycles, and responding patients received a of response was 10 months. The probability of progression to AML or median of 8 additional cycles (range, 0–27 cycles) beyond first death was 1.68-fold greater for supportive care patients than for those response.182 An alternative 5-day schedule of AzaC has been receiving decitabine. Based on this study and three supportive phase II 189 evaluated, both as a subcutaneous regimen (including the 5-2-2 trials, the drug has also been approved by the FDA for treating MDS schedule: 75 mg/m2/day SC for 5 days followed by 2 days of no patients. treatment, then 75 mg/m2/day for 2 days, every 28 days; also, 5-day In a recent phase III randomized trial, decitabine was compared with schedule: 75 mg/m2/day SC for 5 days every 28 days)183 and as an best supportive care in older patients age ≥60 years (N=233; median intravenous regimen (75 mg/m2/day IV for 5 days every 28 days).184 age 70 years, range 60–90 years) with higher risk MDS (IPSS INT-1, Although response rates with the 5-day regimens appeared similar to 7%; INT-2, 55%; High-risk, 38%) not eligible for intensive therapy.179 the approved 7-day dosing schedule,183,184 survival benefit with AzaC Median progression-free survival (PFS) was significantly improved with has only been demonstrated using the 7-day schedule. Similarly, the decitabine compared with supportive care (6.6 vs.3 months; hazard other DMTI hypomethylating agent, decitabine, given intravenously and ratio=0.68, 95% CI 0.52–0.88; P=0.004) and the risk of AML administered with a regimen which required hospitalization of patients, progression at 1 year was significantly reduced with decitabine (22% vs. has also shown encouraging results for the therapy of patients with 33%; P=0.036). However, no significant differences were observed

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-20 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion between decitabine and supportive care for the primary endpoint of Several retrospective studies have evaluated the role of cytoreductive overall survival (10 vs. 8.5 months, respectively) or for median AML-free therapy with hypomethylating agents prior to allogeneic HSCT (with survival (8.8 vs. 6.1 months, respectively).179 In the decitabine arm, both myeloablative and reduced-intensity conditioning regimens).192-195 complete and partial responses were observed in 13% and 6% of These studies suggest that hypomethylating agents may provide a patients, respectively, with hematologic improvement in an additional feasible alternative to induction chemotherapy regimens prior to 15%; in the supportive care arm, hematologic improvement was seen in transplant, and may serve as a bridge to allogeneic HSCT. 2% of patients (with no hematologic responses). In addition, decitabine was associated with significant improvements in patient-reported QOL Currently, AzaC and decitabine are considered to be therapeutically measures (as assessed by the EORTC QOL Questionnaire C30) for the relatively similar, although the improved survival of higher risk patients dimensions of fatigue and physical functioning.179 treated with AzaC compared to control patients in a phase III trial, as indicated above, supports the preferred use of AzaC in this setting. Alternate dosing regimens using lower doses of decitabine administered ‘Failure to respond to hypomethylating agents’ is considered if there is in an outpatient setting are currently being evaluated. In 2007, lack of CR, PR, hematologic improvement or for frank progression to Kantarjian and colleagues provided an update of their results in 115 AML, in particular with loss of control (proliferation) of peripheral counts, patients with higher risk MDS using alternative and lower dose or excess toxicity that precludes continuation of therapy. The minimum decitabine treatment regimens.190 Patients received 1 of 3 different number of courses prior to considering the treatment a failure should be schedules of decitabine, including both subcutaneous and IV 4 to 6 courses. As discussed earlier, the optimal duration of therapy with administration and received a mean of 7 courses of therapy. Responses hypomethylating agents has not been well defined and no consensus were improved with this longer duration of therapy. Overall, 80 patients exists. The NCCN Guidelines panel generally feels that treatment (70%) responded with 40 patients (35%) achieving a complete response should be continued if there is ongoing response and if there are no and 40 (35%) achieving a partial response. The median remission toxicities, in which case modifications should be made to the dosing duration was 20 months, and the median survival time was 22 months. frequency for individual patients. Kantarjian and colleagues also compared the three different schedules of decitabine in a randomized study of 95 patients with MDS or CMML, As data have predominantly indicated altered natural history and receiving either 20 mg/m2 intravenously daily for 5 days; 20 mg/m2 decreased evolution to AML in responders, the major candidates for subcutaneously daily for 5 days; or 10 mg/m2 intravenously daily for 10 these drugs are MDS patients with IPSS Intermediate-2 or High risk days.191 The 5-day intravenous schedule was considered the optimal disease or IPSS-R Intermediate, High or Very High-risk disease. Such schedule; the complete response rate in this arm was 39%, compared candidates include the following: with 21% in the 5-day subcutaneous arm and 24% in the 10-day  Patients who are not candidates for high-intensity therapy. intravenous arm (P< 0.05).  Patients who are potential candidates for allogeneic HSCT but for whom delay in receipt of that procedure is anticipated (e.g., due to

need to further reduce the blast count, time to improve the patient’s combined with cyclosporine, in previously untreated patients with performance status, or delays due to the need to identify a donor). In severe aplastic anemia (N=120) who were not eligible for these circumstances, the drugs may be used as bridging therapy for transplant.203,204 This study demonstrated that in this patient population, that procedure. rabbit ATG was inferior to equine ATG as shown by the lower 6-month  Patients who relapse after allogeneic HSCT. hematologic response rate (primary endpoint: 37% vs. 68%; P<0.001) and higher number of deaths (14 vs. 4 patients) resulting in decreased In addition, hypomethylating agents are appropriate options for patients survival rates among patients treated with rabbit ATG. The 3-year with IPSS Low or Intermediate-1-risk or IPSS-R Very Low or Low-risk survival rate was significantly inferior with rabbit ATG compared with disease without symptomatic anemia, or with symptomatic anemia and equine ATG (76% vs. 96%; P=0.04).204 The 3-year cumulative incidence elevated serum Epo levels who are not expected to respond to (or who of relapse was not significantly different between treatment groups relapsed after) immunosuppressive therapy (IST). (11% vs. 28%, respectively).203 Within the setting of MDS, however, only limited data are available regarding the comparative effectiveness of the Biologic Response Modifiers and Immunosuppressive Therapy two ATG formulations. In a relatively small phase II study in patients The non-chemotherapy, low-intensity agents (biologic response with MDS (N=35; primarily RA subtype), both equine and rabbit ATG modifiers), currently available, include: anti-thymocyte globulin (ATG), were shown to be feasible and active.205 cyclosporine, thalidomide, lenalidomide, anti-TNF receptor fusion protein, and vitamin D analogues, all of which have shown some Lenalidomide (a thalidomide analog) is an immunomodulating agent 3,196-201 efficacy in phase I and phase II trials with activity demonstrated in patients with lower risk MDS.14,206 Beneficial results have been particularly evident for patients with del(5q) Use of anti-immune type therapy with ATG with or without chromosomal abnormalities.14,206,207 In a multicenter phase II trial of cyclosporine198,199 has been shown in several studies to be most lenalidomide (10 mg/day for 21 days every 4 weeks or 10 mg daily) in efficacious in MDS patients with HLA-DR15 histocompatability type, anemic RBC transfusion-dependent MDS patients with del(5q), with or marrow hypoplasia, normal cytogenetics, low-risk disease, and without additional cytogenetic abnormalities (N=148), hematologic evidence of a PNH clone.27,28 Researchers from the NIH have updated response to lenalidomide was rapid (median time to response, 4.6 their analysis of 129 patients treated with IST. The patients were treated weeks; range, 1–49) and sustained.14 RBC transfusion independence with equine antithymocyte globulin (ATG) and cyclosporine alone or in (assessed at 24 weeks) occurred in 67% of patients; among patients combination.202 This study demonstrated markedly improved response with IPSS Low/INT-1 risk (n=120), 69% achieved transfusion rates in younger (≤60 years old) and IPSS INT-1 patients as well as in independence.14 Cytogenetic responses were achieved in 62 of 85 those with high response probability characteristics as indicated by their evaluable patients (73%); 45% had a complete cytogenetic response. prior criteria (HLADR15+, age and number of transfusions).202 Both The most common grade 3 or 4 adverse events included equine and rabbit ATG are available in the U.S. for IST. A randomized myelosuppression (neutropenia in 55%; thrombocytopenia in 44% of study from the NIH compared the activity of equine versus rabbit ATG,

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-22 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion patients), which often required treatment interruption or dose reduction. lenalidomide 5 mg, 10 mg, and placebo groups (≥35.5 vs. 44.5 vs. 42 Thus, careful monitoring of the patients’ blood counts during the months, respectively). The most common grade 3 or 4 adverse events treatment period is mandatory when using this agent, particularly in were myelosuppression and deep vein thrombosis (DVT). Grade 3 or 4 patients with renal dysfunction (due to the drug’s renal route of neutropenia was reported in 74%, 75%, and 15% of patients in the excretion). Lenalidomide has been approved by the FDA for the lenalidomide 5 mg, 10 mg, and placebo arms, respectively; treatment of transfusion-dependent anemia in IPSS Low/INT-1 risk thrombocytopenia occurred in 33%, 41%, and 1.5%, respectively. MDS patients with del(5q) with or without additional cytogenetic Grade 3 or 4 DVT occurred in 4 patients (6%) in the lenalidomide 10 mg abnormalities. arm, and one patient each in the lenalidomide 5 mg (1%) and placebo (1.5%) arms.208 A recent phase III randomized controlled trial compared the activity of lenalidomide (5 mg daily for 28 days or 10 mg daily for 21 days of a 28- A recent comparative analysis evaluated outcomes with lenalidomide day cycle) versus placebo in RBC transfusion-dependent patients (based on data from the two aforementioned trials; n=295) compared (N=205) with lower risk MDS (IPSS Low- and INT-1 risks) with with no treatment (based on data from untreated patients in a del(5q).208 The primary endpoint was RBC-transfusion independence multicenter registry; n=125) in patients with RBC transfusion-dependent 209 (TI) for ≥26 weeks, which was achieved in a significantly greater IPSS Low/INT-1 risk MDS with del(5q). Untreated patients from the proportion of patients treated with lenalidomide 5 mg or 10 mg versus registry had received best supportive care, including RBC transfusion, placebo (43% vs. 56% vs. 6%, respectively; P<0.001 for both iron chelation therapy and/or ESAs. The 2-year cumulative incidence of lenalidomide groups vs. placebo). Among patients achieving RBC-TI AML progression was 7% with lenalidomide and 12% in the untreated with lenalidomide, onset of erythroid response was rapid, with 86% of cohort; the corresponding 5-year rate was 23% and 20%, respectively. patients experiencing response onset within the first two cycles (49% in Thus, the median time to AML progression has not been reached in Cycle 1).208 Among lenalidomide-treated patients with baseline sEpo either cohort. Lenalidomide was not a significant factor for AML levels >500 mU/mL, the 10 mg dose resulted in significantly higher progression in either univariate or multivariate analyses. The 2-year rates of RBC-TI compared with the 5 mg dose (76% vs. 33%; P=0.004). overall survival probability was 90% with lenalidomide and 74% in the Cytogenetic response rates were significantly higher for the untreated cohort; the corresponding 5-year probability was 54% and lenalidomide 5 mg or 10 mg arms compared with placebo (25 vs. 50 vs. 40.5%, respectively. The median overall survival was 5.2 years and 3.8 0%, respectively; P<0.001 for both lenalidomide groups vs. placebo; years, respectively (P=0.755; Kaplan-Meier plot with left truncation to 209 P=NS between lenalidomide dose groups); complete response rates adjust for differences in timing of study entry between cohorts). Based were observed in 16% and 29% of patients in the lenalidomide 5 mg on multivariate analysis using Cox proportional hazard models (also and 10 mg arms, respectively. Median time to AML progression has not with left truncation), lenalidomide was associated with significantly yet been reached in the lenalidomide treatment arms. No significant decreased risk of death compared with no treatment (HR=0.597, 95% differences were observed in median overall survival between the CI 0.399–0.894; P=0.012). Other independent factors associated with

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-23 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion decreased risk of death were female sex, higher hemoglobin levels and A high degree of multi-drug resistance occurs in marrow hematopoietic higher platelet counts. Conversely, independent factors associated with precursors from patients with advanced MDS,213 with associated increased risk of death included older age and greater RBC transfusion decreased responses and shorter response durations with many burden.209 standard treatment regimens use for induction chemotherapy. Thus, chemotherapeutic agents used to treat “resistant-type” AML, and agents A phase II study evaluated lenalidomide treatment in that modulate this resistance, are now being evaluated for treating transfusion-dependent patients (N=214) with Low- or INT-1-risk MDS patients with advanced MDS. Although several studies using multi-drug without the 5q deletion.210 Results showed 26% of the non-del(5q) resistance modulators were positive in this setting,214,215 others were patients (56 of 214) achieved TI after a median of 4.8 weeks of not.216 Further clinical trials evaluating other multi-drug resistance treatment. TI continued for a median duration of 41 weeks. The median modulators are ongoing. rise in hemoglobin was 3.2 g/dL (range, 1.0–9.8 g/dL) for those achieving TI. A 50% of greater reduction in transfusion requirement was Allogeneic HSCT from an HLA-matched sibling donor is a preferred noted in an additional 37 patients (17%), yielding an overall rate of approach for treating a selected group of patients with MDS, particularly 217-224 hematologic improvement of 43%. The most common grade 3 or 4 those with high-risk disease. Matched non-myeloablative transplant adverse events were neutropenia (30%) and thrombocytopenia (25%). regimens and matched unrelated donor stem-cell transplants are 225-233 Further evaluation in more extended clinical trials is needed to becoming options at some centers to treat these patients. In determine the efficacy of this drug and other agents for non-del(5q) certain investigative settings, autologous bone marrow or peripheral 234 MDS patients. The NCCN Guidelines panel recommends lenalidomide blood stem cell transplantation is being considered. Whether be considered for treatment of symptomatically anemic non-del(5q) transplants should be performed before or after patients achieve patients whose anemia did not respond to initial therapy. remission following induction chemotherapy has not been prospectively established.235 Comparative clinical trials are needed to determine these High-Intensity Therapy points. High-intensity therapy includes intensive induction chemotherapy, or HSCT.3,211 Although these approaches have the potential to change the Recommended Treatment Approaches natural history of the disease, they also have an attendant greater risk Therapy for Lower Risk Patients (IPSS Low, Intermediate-1, IPSS- of regimen-related morbidity and mortality. The panel recommends that R Very Low, Low and Intermediate, or WPSS Very Low, Low, and such treatments be given in the context of clinical trials. Comparative Intermediate) studies have not shown benefit between the different intensive Regarding the algorithm for therapeutic options for the lower risk chemotherapy regimens (including idarubicin-, cytarabine-, fludarabine-, patients with clinically significant cytopenias or increased bone marrow and topotecan-based regimens) in MDS.212 blasts, the NCCN Guidelines panel recommends stratifying these patients into several groups. Those with del(5q) chromosomal

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-24 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion abnormalities and symptomatic anemia should receive lenalidomide. Non-responders to IST would be considered for treatment with AzaC, The recommended dose of lenalidomide in this setting is 10 mg once decitabine, or a clinical trial. Patients with sEpo levels >500 mU/mL who daily for 21 days, every 28 days; response should be assessed 2 to 4 have a low probability of responding to IST should be considered for months after initiation of treatment. However, lenalidomide should be treatment with AzaC, decitabine, or lenalidomide. Others or avoided in patients with clinically significant decrease in neutrophil non-responders to these treatments could be considered for a clinical counts or platelet counts; in the previously discussed phase III trial with trial or for allogeneic hematopoietic stem cell transplantation. Patients lenalidomide in patients with del(5q), patients with low neutrophils without symptomatic anemia who have other clinically relevant (<500/mcL) or platelet counts (<25,000/mcL) were excluded from the cytopenias (particularly clinically severe thrombocytopenia) or increased study.208 An alternative option to lenalidomide in patients with del(5q) bone marrow blasts should be considered for treatment with AzaC or and symptomatic anemia may include an initial trial of ESAs in cases decitabine, ISTs (if there is a good probability of responding to these where serum Epo levels are 500 mU/mL or less. agents) or a clinical trial. Data from the phase III randomized trial of AzaC compared with conventional care showed significantly higher Other patients with symptomatic anemia are categorized on the basis of rates of major platelet improvement with AzaC compared with their levels of sEpo. Those with levels ≤500 mU/mL should be treated conventional care (33% vs.14%; P=0.0003); it should be noted, with ESAs (recombinant human erythropoietin [rHu Epo] or darbepoetin) however, that the rates for major neutrophil improvements were similar with or without granulocyte colony stimulating factor (G-CSF) (see between AzaC and the control arm (19% vs.18%), and that the study section on Evaluation and Treatment of Related Anemia below). was conducted in patients with higher risk MDS.177 Patients who do not Non-responders should be considered for IST (with anti-thymoglobulin respond to hypomethylating agents should be considered for treatment or cyclosporine) if there is a high likelihood of response to such therapy. with IST, a clinical trial, or for allogeneic HSCT. In patients with lower risk MDS, the most appropriate candidates for IST include those who are age 60 years or younger, are HLA-DR15 positive, Careful monitoring for disease progression and consideration of the have a PNH positive clone, or have 5% or less marrow blasts or patient’s preferences play major roles in the timing and decision to hypocellular marrow. Alternatively, or in the case of non-response to embark on treatment for Lower or Higher Risk disease. IST, treatment with AzaC or decitabine or lenalidomide should be considered. Patients with no response to hypomethylating agents or Therapy for Higher Risk Patients (IPSS Intermediate-2, High, IPSS-R Intermediate, High, Very High, or WPSS High, Very High) lenalidomide in this setting should be considered for participation in a clinical trial with other relevant agents, or for allogeneic HSCT (see Treatment for higher risk patients is dependent on whether they are felt section on Allogeneic Hematopoietic Stem Cell Transplantation [HSCT] to be candidates for intensive therapy (e.g., allogeneic HSCT or below). intensive chemotherapy). Clinical features relevant for this determination include the patient’s age, performance status, absence of Anemic patients with sEpo level >500 mU/mL should be evaluated to major comorbid conditions, psychosocial status, patient’s preference determine whether they have a good probability of responding to IST. and availability of a suitable donor and caregiver. In addition, the

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-25 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion patient’s personal preference for type of therapy needs particular study published in 2008 retrospectively evaluated the impact of the consideration. Supportive care should be provided for all patients. WHO classification and WPSS on the outcome of patients who underwent allogeneic HSCT.105 The data suggest that lower risk Intensive Therapy patients (based on WPSS risk score) do very well with allogeneic Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) HSCT, with a 5-year overall survival of 80%. With increasing WPSS The potential for patients to undergo allogeneic HSCT is dependent scores, the probability of 5-year survival after HSCT declined upon several factors including the patient’s age, performance status, progressively to 65% (Intermediate risk), 40% (High risk), and 15% 105 major comorbid conditions, psychosocial status, availability of a (Very High risk). caregiver, IPSS or WPSS score and the availability of a suitable donor. Based on data regarding RIC for transplantation from two reported For those patients who are transplant candidates, the first choice of a series238,239 and two comprehensive reviews of this field,240,241 patient age donor has remained an HLA-matched sibling, although results with HLA and disease status generally dictate the type of conditioning to be matched unrelated donors have improved to levels comparable to those utilized. Patients older than 55 or 60 years, particularly if they have less obtained with HLA-matched siblings. With the increasing use of cord than 10% marrow myeloblasts, would generally undergo HSCT after blood or HLA haploidentical related donors, HSCT has become a viable RIC; if the blast count is high, pre-HSCT debulking therapy is generally option for many patients. High dose conditioning is typically used for given. Younger patients, regardless of marrow blast burden, will younger patients, whereas the approach using reduced/low intensity generally receive high dose conditioning. Variations on these conditioning (RIC) for HSCT is generally the strategy in older approaches would be considered by the individual transplant physician individuals.236 based on these features and the specific regimen utilized at that center. To aid therapeutic decision-making regarding the timing and selection of Some general recommendations have been presented recently in a 242 MDS patients for HSCT, a study compared outcomes with HLA- review article. matched sibling HSCT in MDS patients 60 years old or younger to the Intensive Chemotherapy data in non-treated MDS patients from the IMRAW/IPSS database. 237 For patients eligible for intensive therapy but lacking a stem cell donor, Using a Markov decision analysis, this investigation indicated that IPSS or for those in whom the marrow blast count requires reduction, INT-2 and High risk patients 60 years old or younger had the highest life consideration should be given to the use of intensive induction expectancy if transplanted (from HLA identical siblings) soon after chemotherapy.243 Although the response rate and durability of this diagnosis, whereas patients with IPSS low risk had the best outlook if treatment is lower than for standard AML, this treatment (particularly in HSCT was delayed until MDS progressed; for patients in the INT-1 risk clinical trials with novel agents) could be beneficial in a portion of the group there was only a slight gain in life expectancy if HSCT was patients. For those patients with a potential stem cell donor who require delayed, and in this group, decisions should probably be made on an reduction of their tumor burden (i.e., to decrease the marrow blast individual basis (e.g., dependent upon platelet or neutrophil counts).237 A count), achievement of even a partial remission may be adequate to

and nutritional deficiency. If needed, iron, folate, or vitamin B12 studies Non-Intensive Therapy should be obtained and the cause of depletion corrected, if possible. For higher risk patients who are not candidates for intensive therapy, After excluding these causes of the anemia and providing proper the use of AzaC, decitabine, or a relevant clinical trial should be treatment for them, further consideration for treating the anemia related considered. Based on the recently published results of the phase III trial to MDS should be undertaken. Currently, the standard of care for showing superior median survival with AzaC compared to best symptomatic anemic patients is red blood cell (RBC) transfusion supportive care, the NCCN Guidelines panel has made this a preferred support (using leuko-poor products). If the patient is a potential HSCT category 1 recommendation compared with decitabine. Results from candidate, the panel recommends consideration of CMV negative (if the another recent phase III trial comparing decitabine to supportive care in patient is CMV negative serologically) and irradiated transfused higher risk patients failed to demonstrate a survival advantage although products. response rates are similar to those previously reported for AzaC.179,244 However, it should be noted that no trials to date have compared AzaC Anemia related to MDS generally presents as a hypoproductive head-to-head with decitabine. macrocytic anemia, often associated with suboptimal elevation of serum Epo levels.3,245 To determine WHO subtype, iron status, and the level of For some patients eligible for HSCT therapy who require a reduction in ring sideroblasts, bone marrow aspiration with iron stain, biopsy, and tumor burden, the use of azacytidine or decitabine may be a bridge to cytogenetics should be examined. Patients should also be considered sufficiently decrease the marrow blast count enough to permit the for HLA-DR15 typing as indicated above. transplant. Individuals having symptomatic anemia and del(5q) with or without Supportive Care Only other cytogenetic abnormalities should receive a trial of lenalidomide. For patients with adverse clinical features or disease progression As mentioned earlier, an alternative option to lenalidomide may include despite therapy and absence of reasonable specific anti-tumor therapy, an initial trial of ESAs in patients with serum Epo levels 500 mU/mL or adequate supportive care should be maintained. less. Those with normal cytogenetics and with <15% marrow ringed sideroblasts and serum Epo levels 500 mU/mL or less may respond to Evaluation and Treatment of Related Anemia Epo if relatively high doses of recombinant human Epo are Major morbidities of MDS include symptomatic anemia and associated administered.137,246,247 The Epo dose required is 40,000-60,000 units 1-3 fatigue. Much progress has been made in improving the management of times a week subcutaneously. Erythroid responses generally occur this anemia. However, along with giving specific treatment for anemia within 6 to 8 weeks of treatment.138,248-250 A more prompt response may related to MDS, the health care provider must identify and treat any be obtained by starting at the higher dose. This Epo dose is much coexisting causes of anemia. higher than that needed to treat renal causes of anemia wherein

Version 2.2014, 05/21/13 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-27 NCCN Guidelines Version 2.2014 NCCN Guidelines Index MDS Table of Contents Myelodysplastic Syndromes Discussion marrow responsiveness would be relatively normal. If a response suggested for patients with endogenous serum Epo levels >500 mU/mL occurs, the recommendation is to continue this dose but attempt to due to the very low erythroid response rate to these drugs in this patient decrease it to tolerance. The literature supports daily or 2-3 times per population. week dosing. Darbepoetin alfa is a longer-acting form of Epo. Studies predominantly Iron repletion needs to be verified before instituting Epo or darbepoetin with patients having lower risk MDS have demonstrated a substantial therapy. If no response occurs with these agents alone, the addition of proportion of erythroid responses with the initial trials, showing G-CSF should be considered. Evidence suggests that G-CSF (and, to a response rates of 40% and 60% (combined major and minor responses lesser extent, GM-CSF) has synergistic erythropoietic activity when using IWG response criteria).252,253 Results of clinical trials in patients used in combination and markedly enhances the erythroid response with MDS have suggested that the overall response rates to rates.138,247-249 This is particularly evident for patients with ≥15% ringed darbepoetin are similar to or possibly higher than to epoetin.252-255 sideroblasts in the marrow (and serum Epo level ≤500 mU/mL) as the very low response rates in this subgroup to Epo or darbepoetin alone These response rates may in part be due to the dosage used (150 to are markedly enhanced when combined with G-CSF.138,249 300 mcg per week, subcutaneously) or to the fact that better risk patients were enrolled in studies of darbopoetin compared to epoetin. For the erythroid synergistic effect, relatively low doses of G-CSF are Features predictive of response have included relatively low basal needed to help normalize the neutrophil count in initially neutropenic serum Epo levels, low percentage of marrow blasts and relatively few patients or to double the neutrophil count in patients who are initially prior RBC transfusions. normal. For this purpose, an average of 1 to 2 mcg/kg subcutaneously is administered daily or 1 to 3 times per week.138,247-249 G-CSF is In March 2007 and 2008, the FDA announced alerts and strengthened available in single use vials or prefilled syringes containing either 300 safety warnings for the use of ESAs. They noted that increased mcg or 480 mcg and requires refrigeration. Patients may be taught to mortality, possible tumor promotion and thromboembolic events were self administer the drug. Again, detection of erythroid responses observed in non-MDS patients receiving ESAs when dosing has generally occurs within 6 to 8 weeks of treatment. If no response occurs targeted hemoglobin levels >12 g/dL (study patients had chronic kidney in this time frame, treatment should be considered a failure and failure; were receiving radiation therapy for various malignancies, or discontinued. In the case of treatment failure, one should rule out and including head and neck, advanced breast cancer, lymphoid or treat deficient iron stores. Clinical trials or supportive care are also non-small cell lung cancer; were cancer patients not receiving treatment options in this category of patients. A validated decision chemotherapy; or were orthopedic surgery patients). model has been developed for predicting erythroid responses to Epo However, as indicated above, ESAs have been used safely in large plus G-CSF, based on the patient’s basal serum Epo level and number numbers of adult MDS patients and have become important for of previous RBC transfusions.249,251 Improved quality of life has been symptomatic improvement of those affected by the anemia caused by demonstrated in responding patients.251 This cytokine treatment is not

Clinical trials with other experimental agents which are reportedly capable of increasing hemoglobin levels should be explored in patients not responding to standard therapy. These drugs should be used in the context of therapeutic approaches for the patient’s underlying prognostic risk group.

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