NCCN Clinical Practice Guidelines in Oncology™
Myelodysplastic
Syndromes
V.2.2010
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Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
NCCN Myelodysplastic Panel Members
Peter L. Greenberg, MD/Chair
Stanford Comprehensive Cancer Center
Eyal Attar, MD
Dana-Farber/Brigham and Women’s
Cancer Center | Massachusetts General
Hospital Cancer Center
Minoo Battiwalla, MD
Roswell Park Cancer Institute
Harry P. Erba, MD, PhD
University of Michigan Comprehensive
Cancer Center
‡
‡
Þ †
†
†
‡
‡
†
†
†
John M. Bennett, MD
Consultant
Clara D. Bloomfield, MD
The Ohio State University
Comprehensive Cancer Center - James
Cancer Hospital and Solove Research
Institute
Carlos M. DeCastro, MD
Duke Comprehensive Cancer Center
H. Joachim Deeg, MD
Fred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
Hussain I. Saba, MD, PhD
H. Lee Moffitt Cancer Center & Research
Institute
Paul J. Shami, MD
Huntsman Cancer Institute at the University
of Utah
Kathy Spiers, MD
St. Jude Children’s Research
Hospital/University of Tennessee Cancer
Institute
Richard M. Stone, MD
Dana-Farber/Brigham and Women’s Cancer
Center | Massachusetts General Hospital
Cancer Center
Martin S. Tallman, MD
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Peter Westervelt, MD PhD
Siteman Cancer Center at Barnes-Jewish
Hospital and Washington University School
of Medicine
‡
‡
‡
‡
†
* Writing Committee Member
† Medical Oncology
‡ Hematology/Hematology Oncology
Þ Internal Medicine
� Pathology
‡
‡
‡
J †
Þ
ames M. Foran, MD
University of Alabama at Birmingham
Comprehensive Cancer Center
Guillermo Garcia-Manero, MD
The University of Texas M. D. Anderson
Cancer Center
Steven D. Gore, MD
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
David Head, MD
Vanderbilt-Ingram Cancer Center
Lori J. Maness, MD ‡
UNMC Eppley Cancer Center at The
Nebraska Medical Center
Michael Millenson, MD
Fox Chase Cancer Center
Tariq Mughal, MD
St. Jude Children’s Research
Hospital/University of Tennessee Cancer
Institute
Margaret R. O’Donnell, MD
City of Hope Comprehensive Cancer Center
†
�
Stephen D. Nimer, MD † ‡
Memorial Sloan-Kettering Cancer Center
ContinueNCCN Guidelines Panel Disclosures
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Table of Contents
NCCN Myelodysplastic Syndromes Panel Members
Initial Evaluation (MDS-1)
The French-American-British (FAB) (MDS-2)
World Health Organization (WHO) Classification for de Novo MDS (MDS-2- 3)
4
Treatment of LOW INT-1 (MDS-5
Treatment of INT-2, HIGH (MDS-6
Evaluation and Treatment of Related Anemia (MDS-7
Supportive Care for MDS (MDS-A
Guidelines Index
Print the Myelodysplastic Syndromes Guideline
Summary of Guidelines Updates
International Prognostic Scoring System (IPSS) (MDS- )
)
)
)
)
These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician
seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to
determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kind
whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are
copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in
any form without the express written permission of NCCN. ©2009.
Clinical Trials:
Categories of Evidence and
Consensus:
NCCN
All recommendations
are Category 2A unless otherwise
specified.
See
The
believes that the best management
for any cancer patient is in a clinical
trial. Participation in clinical trials is
especially encouraged.
NCCN
To find clinical trials online at NCCN
member institutions, click here:
nccn.org/clinical_trials/physician.html
NCCN Categories of Evidence
and Consensus
For help using these
documents, please click here
Discussion
References
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Summary of the Guidelines updates
UPDATES
Summary of major changes in the 2.2010 version of the Myelodysplastic Syndromes Guidelines from the 1.2010 version include :
The addition of the updated discussion section.
Replaced the 2001 World Health Organization (WHO) Classification of MDS with the 2008 version and updated the reference in footnote “i”.
Added footnotes “k, l, m, n, and o” with WHO Classification tables.
Added high-intensity therapy candidate with footnote “bb” to better define who should receive intensive chemotherapy. Footnote “bb” has
been modified to include patient preference.
Based on survival data the category of evidence and consensus for azacytidine for the treatment of IPSS category INT-2, High has been
changed to a category 1 recommendation, it was previously a category 2A.
Added recommendation for azacytidine/decitabine or clinical trial for patients who relapse following allogeneic hemopoietic stem cell
transplant.
Footnote “ee” is new to the page “While the response rates are similar for both drugs, survival benefit in Phase lll randomized trials is
reported for azacytidine and not for decitabine.”
Added an extra column recommending clinical trials or supportive care for those that do not respond or relapse after treatment.
Summary of major changes in the 1.2010 version of the Myelodysplastic Syndromes Guidelines from the 2.2009 version include :
�
�
�
�
�
�
�
MDS-2 -3
MDS-6
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
MDS-1
INITIAL EVALUATION
Cytopenia(s),
suspect
myelodysplasia
Required:
�
�
�
�
�
�
�
�
H&P
CBC, platelets,
differential,
reticulocyte count
Examination of
peripheral smear
Bone marrow
aspiration with iron
stain + biopsy +
cytogenetics
Serum
erythropoietin
(prior to RBC
transfusion)
RBC folate, and
serum B
Serum ferritin ±
iron, TIBC
Documentation of
transfusion history
12
Consider
observation to
document
indolent course
vs marked
progression of
severe cytopenia
AML
(See NCCN AML
Treatment
Guidelines)
a
b
Confirm diagnosis of MDS according to FAB and WHO criteria for classification with application of IPSS.
Percentage of marrow myeloblasts should be reported.
Patients with significant cytopenias and karyotypes t(8;21), t(15;17), and/or inv(16) or variants should be considered AML. .
cFamily HLA - evaluation to include all full siblings; unrelated evaluation to include high resolution allele level typing for HLAA, B, C, DR, DQ.
To aid the evaluation for improved response to immunosuppressive therapy.
To assess possible Fanconi anemia or dyskeratosis congenita.
d
e
See Classification Systems (MDS-2 MDS-4)
See NCCN AML Guidelines)
.
(
and
CATEGORY
Diagnosis of
MDS
established
based on
morphological
and clinical
criteriaa,b
Helpful in Some Clinical
Situations:
�
�
�
�
�
�
�
HLA typing if hemopoietic
stem cell transplant (HSCT)
candidate
HLA typing if indicated for
platelet support
HIV testing if clinically
indicated
Evaluate CMML patients for
5q31-33 translocations
and/or PDGFR gene
rearrangements
Consider flow cytometry to
evaluate for PNH clone or
to assess possible large
granular lymphocytic (LGL)
disease
Consider additional genetic
screening for patients with
familial cytopenias
c
e
�Consider HLA-DR15
typingd
�
Consider molecular testing
for JAK2 mutation in
patients with
thrombocytosis
See Treatment of
Low, INT-1 (MDS-5)
INT-2, High (MDS-6)
and
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 1 of 3)
2008 WHO Classification of MDSih
Subtype Blood
Dysplasia in 10 % of one cell line,
< 5% blasts
�
Bone marrow
Refractory cytopenia with
unilineage dysplasia (RCUD)j
Single or bicytopenia
Refractory anemia with
ring sideroblasts (RARS)
Anemia, no blasts � 15 % of erythroid precursors w/ring
sideroblasts, erythroid dysplasia only,
< 5 % blasts
Dysplasia in 10 % of cells in 2
hematopoietic lineages, ± 15 % ring
sideroblasts, < 5 % blasts;
� �Refractory cytopenia
with multilineage
dysplasia (RCMD)
Cytopenia(s),
< 1 x 10 /L monocytes9
Unilineage or multilineage dysplasia,
No Auer rods, 5 % to 9 % blasts
Refractory anemia with
excess blasts-1 (RAEB-1)
Cytopenia(s),
2-4 % blasts,< 1 x 10 /L
monocytes
� 9
Unilineage or multilineage dysplasia
Auer rods ±, 10 % to 19 % blasts
Refractory anemia
with excess blasts-2
(RAEB-2)
Cytopenia(s),
5-19 % blasts, < 1 x 10 /L
monocytes
9
Unilineage dysplasia or no
dysplasia but characteristic MDS
cytogenetics, < 5% blasts
Myelodysplastic
syndrome, unclassified
(MDS-U)
Cytopenias
Unilineage erythroid dysplasia,
isolated del 5(q), < 5 % blasts
MDS associated with
isolated del(5q)
Anemia, platelets
normal or increased
FAB Classification of MDSgf
FAB subtype
% of
Peripheral
blasts
% of Bone
marrow
blasts
Refractory
anemia (RA)
Refractory
anemia with
ringed
sideroblasts
(RARS)
Refractory
anemia with
excess blasts
(RAEB)
Refractory
anemia with
excess blasts in
transformation
(RAEB-t)
Chronic
myelomonocytic
leukemia (CMML)
(> 1,000
monocytes/mcL
blood)
< 1
< 1
< 5
< 5
< 5 5-20
� 5 21-30
< 5 5-20
f
g
h
FAB = French-American-British.
Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification
of the myelodysplastic syndromes. Br J Haematol. 1982;51:189-199.
WHO = World Health Organization.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
MDS-2
i
j
Brunning R, Orazi A, Germing U, et al. Myelodysplastic Syndromes, Chapter 5, in Swerdlow
S, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of
Haematopoietic and Lymphoid Tissue, 4th edition. IARC Press, 2008, p 88-103.
This category encompasses refractory anemia (RA), Refractory Neutropenia (RN) and
Refractory thrombocytopenia (RT). Cases of RN and RT were previously classified as
MDS Unclassified.
Continued on next page
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Myelodysplastic/Myeloprolifierative Neoplasms (MDS/MPN) WHO Classificationk
Subtype Blood Marrow
Chronic myelomonocytic
leukemia-1 (CMML-1)
>1x10 /L monocytes,
<5% blasts
9
Dysplasia in 1
hematopoietic line, <10%
blasts
≥
CMML-2 >1x10 /L monocytes,
5-19% blasts or Auer rods
9
Dysplasia in 1
hematopoietic line, 10-
19% blasts or Auer rods
≥
Atypical chronic myeloid
leukemia (CML), Bcr-Abl 1
negative
WBC 13x10 /L, neutrophil
precursors >10%, <20%
blasts
9 Hypercellular, <20% blasts
Juvenile myelomonocytic
leukemia (JMML)
>1x10 /L monocytes,
<20% blasts
9
l
>1x10 /L monocytes,
<20% blasts
9
l
MDS/MPN, unclassifiable
('Overlap syndrome')
Dysplasia +
myeloproliferative
features , No prior MDS
or MPN
m
Dysplasia +
myeloproliferative
features
k
l
m
n
o
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.
Ph negative plus 2 features: Hb F, PB immature myeloid cells, WBC >10x109/L, clonal chromosomal abnormality, GM-CSF hypersensitivity in vitro.
For example, thrombocytosis, leukocytosis, splenomegaly.
Greater 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 similar
to MDS (RAEB-t by FAB classification) than to overt AML.
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 Press, 2008, pp 124-126.
≥
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.
Acute myeloid leukemia with myelodysplasia-related
changes
WHO Classification
1. AML post MDS or MDS/MPN
2. AML with an MDS-related cytogenetic abnormality
3. AML with multilineage dysplasia
n
o
MDS-3
Continued on next page
CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 2 of 3)
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MDS-4
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.
pIPSS = International Prognostic Scoring System.
q
r
s
t
This research was originally published in Blood. Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic
syndromes. Blood 1997;89:2079-2088; Erratum. Blood 1998;91:1100. © the American Society of Hematology.
Patients with 20-30 % blasts may be considered as MDS or AML.
Cytogenetics: Good = normal, -Y alone, del(5q) alone, del(20q) alone; Poor = complex ( 3 abnormalities) or chromosome 7 anomalies; Intermediate = other
abnormalities. [This excludes karyotypes t(8;21), inv16, and t(15;17), which are considered to be AML not MDS.]
Cytopenias: neutrophil count <1,800/mcL, platelets < 100,000/mcL, Hb < 10g/dL.
�
IPSSp,q
Prognostic variable
Marrow blasts (%)
Karyotype
Cytopenia
r
s
t
Survival and AML evolution
Risk category
(% IPSS pop.)
LOW (33)
INT-1 (38)
INT-2 (22)
HIGH (7)
Overall
score
0
0.5-1.0
1.5-2.0
� 2.5
Median
survival (y) in
the absence
of therapy
5.7
3.5
1.1
0.4
25% AML
progression (y)
in the absence
of therapy
9.4
3.3
1.1
0.2
Score value
0 1.0 1.5 2.0
< 5 5-10 --- 11-20
Good
21-30
Intermediate Poor
2/30/1
CLASSIFICATION SYSTEMS FOR DE NOVO MDS (page 3 of 3)
0.5
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
MDS-5
LOW, INT-1
Clinically
significant
cytopenia(s)
Symptomatic
anemia
del(5q) ± other
cytogenetic abnormalities
Serum Epo
500 mU/ml�
Serum Epo
> 500 mU/ml
Lenalidomide
Good
probability
to respond
to ISTx
Antithymocyte
globulin (ATG),
cyclosporin A
u
v
w
z
xParticularly Low/INT-1 patients 60 y, or those with hypocellular marrows, HLA-DR15 or PNH clone positivity.
Patients lack features listed in footnote x.
�
y
INT-1 patients with severe cytopenias would also be considered candidates. Hemopoietic stem cell transplant: Allogeneic-matched sibling including standard and
reduced intensity preparative approaches or matched unrelated donor (MUD).
See IPSS Classification System (MDS-4).
See Supportive Care (MDS-A)
See dosing of hemopoietic cytokines ( )
.
.MDS-7
Supportive
care as an
adjunct to
treatment
v
Thrombocytopenia,
neutropenia
No
response
Follow appropriate
pathway below
Epoetin alfa
(rHu EPO)
± G-CSF
w
or
Darbepoetin
alfa ± G-CSF
No
response
Azacytidine/
decitabine
or
Clinical trial
Consider
lenalidomide
or
No
response
Clinical trial
or
Consider
allotransplant
for selected
INT-1 patientsz
No
response
No
response
Azacytidine/
decitabine
or
Clinical trial
No
response
IST
or
Clinical trial
x
or
Consider
allotransplant
for selected
INT-1 patientsz
Progressive Disease -
See INT-2, HIGH (MDS-6)
IPSS CATEGORYu TREATMENT
Poor probability to
respond to ISTy
Clinical trial
or
Consider
allotransplant
for selected
INT-1 patientsz
Azacytidine/
decitabine
or
Clinical trial
Consider
lenalidomide
or
Follow appropriate
pathway below
Myelodysplastic Syndromes
Guidelines Index
MDS Table of Contents
Discussion, References
Practice Guidelines
in Oncology – v.2.2010NCCN
®
Version 2.2010 08/26/2009 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
INT-2, HIGHaa
High-intensity
therapy
candidatev,bb
Transplant
candidate
and
Donor
available
Yes
No
Not high-intensity
therapy candidatev,bb
Azacytidine (preferred) (category 1)/decitabine
or
Clinical trial
ee
High-intensity chemotherapy
or
ff
Azacytidine/decitabine
or
Clinical trial
Allogeneic
hemopoietic
stem cell
transplant
(HSCT)cc,dd
IPSS CATEGORYu TREATMENT
u
bb
cc
ee
ff
v
dd
aaINT-1 patients with severe cytopenias unresp