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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3671-3674
PERSPECTIVE
Report of an international working group to standardize response
criteria for myelodysplastic syndromes
Bruce D. Cheson,
John M. Bennett,
Hagop Kantarjian,
Antonio Pinto,
Charles A. Schiffer,
Stephen D. Nimer,
Bob Löwenberg,
Miroslav Beran,
Theo M. de Witte,
Richard M. Stone,
Moshe Mittelman,
Guillermo F. Sanz,
Pierre W. Wijermans,
Steven Gore, and
Peter L. Greenberg
From the National Cancer Institute, Bethesda, MD;
University of Rochester Cancer Center, Rochester, NY; MD Anderson
Cancer Center, University of Texas, Houston, TX; Centro di Riferimento
Oncologico, Aviano, Italy; Karmanos Cancer Center, Wayne State
University, Detroit, MI; Memorial Sloan-Kettering Cancer Center, New
York, NY; University Hospital, Rotterdam, The Netherlands; University
Hospital Nijmegen, Rijmegen, The Netherlands; Dana Farber Cancer
Institute, Boston, MA; Rabin Medical Center-Hasharon Hospital,
Petah-Tikva Tel-Aviv University, Tel-Aviv, Israel; Hospital
Universitario La Fe, Valencia, Spain; Ziekenhuis, Leyenburg,
The Hague, The Netherlands; Johns Hopkins Oncology Center, Baltimore,
MD; Stanford University Medical Center and Veterans Administration
Hospital, Palo Alto, CA.
 |
Abstract |
Standardized criteria for assessing response are essential to
ensure comparability among clinical trials for patients with myelodysplastic syndromes (MDS). An international working group of
experienced clinicians involved in the management of patients with MDS
reviewed currently used response definitions and developed a uniform
set of guidelines for future clinical trials in MDS. The MDS differ
from many other hematologic malignancies in their chronicity and the
morbidity and mortality caused by chronic cytopenias, often without
disease progression to acute myeloid leukemia. Whereas response rates
may be an important endpoint for phase 2 studies of new agents and may
assist regulatory agencies in their evaluation and approval processes,
an important goal of clinical trials in MDS should be to prolong
patient survival. Therefore, these response criteria reflected 2 sets
of goals in MDS: altering the natural history of the disease and
alleviating disease-related complications with improved quality of
life. It is anticipated that the recommendations presented will require
modification as more is learned about the molecular biology and
genetics of these disorders. Until then, it is hoped these guidelines
will serve to improve communication among investigators and to ensure
comparability among clinical trials.
(Blood. 2000;96:3671-3674)
© 2000 by The American Society of Hematology.
| |
Classification |
The myelodysplastic syndromes (MDS) are a
heterogeneous group of hematopoietic disorders characterized in most
patients by peripheral blood cytopenia with hypercellular bone marrow
and dysplasia of the cellular elements.1-3 MDS may develop
after exposure to toxins such as benzene, chemotherapy drugs, or high doses of radiation, though its etiology is unknown in more than 80%
of patients.
MDS have historically been referred to as oligoblastic leukemia,
refractory anemia, smoldering acute leukemia, or preleukemia. In 1982, the French-American-British (FAB) group presented a classification, modified in 1985, that is the most widely used.1,2
Recently, a World Health Organization (WHO) steering committee proposed modifications to the MDS subtypes. The major changes were a decrease, from 30% blasts to 20% blasts, in the threshold for diagnosing acute
myeloid leukemia (AML) and the creation of a category of MDS/myeloproliferative disorders to include patients with chronic myelomonocytic leukemia.4 However, these recommendations
have not yet been uniformly adopted, and the distinction between AML and MDS reflects the pace of the disease, the biologic differences in
neoplastic cells, and the number of bone marrow blasts. Thus, because
of its known clinical usefulness, we have elected to retain the FAB
classification of MDS.
| |
Prognostic factors |
MDS are heterogeneous with regard to clinical
characteristics, cytologic and pathologic features, and cytogenetics.
Even within morphologic subtypes, there are differences in outcome.
Therefore, effective and prospective stratification of patients for
clinical studies is critical for designing trials and for evaluating
and clarifying outcomes of treatments.
Recently an international working group of experienced clinicians
developed a prognostic scheme that has been widely
adopted.5 Critical prognostic factors regarding survival
and the potential for evolution to AML, which were identified and
included in the International Prognostic Scoring System (IPSS),
included bone marrow cytogenetics, percentage of bone marrow blasts,
and number of cytopenias; age and gender were also important for
predicting survival in a multivariate analysis. Within the IPSS,
patients were categorized according to these features into relatively
low risk (IPSS Low or Intermediate-1) and relatively high risk (IPSS Intermediate-2 or High) subgroups for risk-based treatment options.
| |
Therapeutic goals |
The MDS differ from many other hematologic malignancies in their
chronicity and in the morbidity and mortality caused by chronic cytopenias, often without disease progression to AML.6 As
such, alleviation of disease-related complications and improved quality of life (QOL) are important goals of therapy. Thus, improvements in
cytopenias (ie, clinically meaningful hematologic improvement) and
their associated complications should be objectively measured and
evaluated. In addition, some of the newer classes of drugs are more
likely to be cytostatic than cytotoxic, or they may induce cellular
differentiation; therefore, time to disease progression may be the
primary endpoint rather than the response rate. Responses, then, should
reflect the goals of the treatments.
Various strategies have been used to treat patients with MDS, often
with varying objectives. Low-intensity therapies, defined as treatments
capable of permitting predominantly outpatient management (eg,
cytokines, certain biologic response modifiers, immunosuppressive therapy), are often directed at patients with low risk MDS (IPSS Low
and Intermediate-1). The goals of many of these low-intensity therapies
are improvement in blood counts, disease palliation, and enhanced
quality of life.7 Such treatments are not necessarily associated with improved survival or progression-free survival. Thus,
hematologic improvement is appropriate for measuring responses to this
type of treatment.
The aim of other low-intensity therapies (low-dose chemotherapy,
5-azacytidine; low-dose cytarabine) and high-intensity therapies (aggressive anti-leukemic chemotherapy, stem cell transplantation) is
to induce hematologic responses (complete remission [CR] or partial
remission [PR]) and to alter the natural history of the disease
(prolonging survival, progression-free survival). Cytogenetic responses
may be helpful to determine the degree to which the natural history of
the disease may be altered.
There are no curative therapies for patients with MDS other than bone
marrow transplantation, which is successful in only a subset of treated
patients.8-11 As a result, numerous therapies have been
and are being evaluated to improve the outlook for these patients.
However, the published results of clinical trials are difficult to
interpret for a number of reasons, including patient selection bias,
sample size, and inconsistent response criteria. For example,
hematologic improvement has been used to indicate variable levels of
increase in one hematologic lineage in some studies or multilineage
improvement in others.12-14
Several new agents are used in clinical trials for MDS, including
5-azacitidine, decitabine, amifostine, topotecan, and
others.12,13,15-18 In addition to defining comparable
patient groups among studies and collecting complete prognostic factor
information, the availability of uniform response criteria would
improve analysis of clinical trials in MDS.
| |
An approach to standardizing response criteria |
To resolve the problems resulting from variability in definitions
of the quality and quantity of response in MDS, a group of
international investigators with expertise in MDS convened to establish
standardized response criteria for clinical trials involving patients
with MDS. Some of the response categories (hematologic improvements)
are more relevant to therapies designed with palliative intent, whereas
others (complete remission, partial remission) are relevant to the
goals of treatments directed at altering the natural history of the
disease. The proposal for evaluating response is shown in Table
1 and indicates 4 levels of response
criteria based on the intent of specific therapies:
hematologic response, altering the natural
history of the disease, cytogenetic response, and quality of life.
Although data are lacking regarding the correlation between cytogenetic
response and clinical outcome in MDS, based on the valuable role of
this parameter in the management and prognosis of patients with chronic
myelogenous leukemia,19,20 we have included this category
to facilitate prospective evaluation.
Similarly, whereas only limited data exist regarding the value of
quality of life instruments in assessing treatment outcomes in MDS,
such methods of evaluation have been valuable for patient assessment in
other neoplasms.21,22 QOL studies are most valuable in
randomized trials, not only with placebo controls but also when
comparing 2 approaches. QOL studies may also be useful in single-arm
trials to assess interactions among disease-related symptoms,
treatment-related toxicity, and disease response. These aims should be
defined prospectively. We anticipate that the use of this criterion in
appropriate clinical trials, using instruments such as the WHO
Performance Score or the FACT Questionnaire,22 will
provide valuable insights into patients' physical, functional, emotional, and social status.
Also critical for evaluating and clarifying outcomes of treatments and
for designing clinical trials is to stratify patients effectively and
prospectively using risk-based criteria for patient entry and
evaluation (FAB subtype or, perhaps more important, IPSS risk
group5). For example, comparison of survival or
progression-free survival for patients at IPSS low risk would differ
from those at IPSS high risk and should be indicated as such. Such
stratification could include age, performance status, and prognostic
risk category, as suggested by the National Comprehensive Cancer
Network Panel on MDS.5,7
| |
Conclusion |
The goals of clinical research in MDS are to prolong the survival
of patients and to improve their quality of life. In phase 2 trials, in
which the activity of a new agent may be the most important objective,
response rates are valuable and may provide support for approval by
regulatory agencies. However, in some clinical settings, incremental
increases in response rates have not translated into prolongation of
time to treatment failure or survival. In MDS, added objectives for
patients with this often indolent, chronic illness are to reduce
morbidity associated with cytopenias (diminish transfusion
requirements, infections, or bleeding) and to improve quality of life.
In this regard, we believe that the use of risk-based prognostic
stratification and clinically relevant response criteria would be
valuable for evaluating clinical outcomes and for trial design
in MDS.
It will be important to apply these guidelines prospectively in large
trials and to critically assess their validity and usefulness. Uniform
criteria will help to determine the impact of a specific clinical
outcome on patient survival or improved quality of life. The IPSS
should be used as the primary stratification factor. In addition,
studies should prospectively assess whether there is a difference in
outcome for patients from 0 to 6 months, 6 to 12 months, and longer
than 12 months from diagnosis of MDS. We have also set an arbitrary
threshold for minor cytogenetic response at 50% normal metaphases;
future studies must better correlate cytogenetic response with
survival. We anticipate that these recommendations may require
modification as more is learned about the molecular biology and
genetics of these disorders. We hope that these guidelines will serve
to improve communication among investigators and to ensure
comparability among clinical trials.
| |
Footnotes |
Submitted January 24, 2000; accepted August 8, 2000.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Bruce D. Cheson, National Cancer Institute,
Executive Plaza North, Room 741, Bethesda, MD 20892; e-mail:
chesonb{at}ctep.nci.nih.gov.
| |
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[Abstract]
[Full Text]
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S. D. Nimer
Clinical Management of Myelodysplastic Syndromes With Interstitial Deletion of Chromosome 5q
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G. J. Schiller, J. Slack, J. D. Hainsworth, J. Mason, M. Saleh, D. Rizzieri, D. Douer, and A. F. List
Phase II Multicenter Study of Arsenic Trioxide in Patients With Myelodysplastic Syndromes
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R. M. Stone
Is Intravenous Arsenic Trioxide a Useful Therapy in Myelodysplastic Syndromes?
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A. Boula, M. Voulgarelis, S. Giannouli, G. Katrinakis, M. Psyllaki, C. Pontikoglou, F. Markidou, G. D. Eliopoulos, and H. A. Papadaki
Effect of cA2 Anti-Tumor Necrosis Factor-{alpha} Antibody Therapy on Hematopoiesis of Patients with Myelodysplastic Syndromes.
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A. A.N. Giagounidis, U. Germing, and C. Aul
Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies
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P. Fenaux and C. Kelaidi
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Hematology,
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D. P. Steensma and J. M. Bennett
The Myelodysplastic Syndromes: Diagnosis and Treatment
Mayo Clin. Proc.,
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R. Stasi, E. Abruzzese, G. Lanzetta, E. Terzoli, and S. Amadori
Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes
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L. R. Silverman, D. R. McKenzie, B. L. Peterson, R. M. Stone, B. L. Powell, C. Mayo, J. T. Backstrom, R. A. Larson, and The Cancer Leukemia Group B (CALGB)
Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS).
Blood (ASH Annual Meeting Abstracts),
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[Abstract]
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R. Lyons, T. Cosgriff, S. Modi, L. Lintz, C.L. Beach, and J. T. Backstrom
Azacitidine (Vidaza(R)) Treatment Response Assessed Using Three Alternative Dosing Schedules in Patients with Myelodysplastic Syndromes (MDS).
Blood (ASH Annual Meeting Abstracts),
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[Abstract]
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L. R. Silverman, D. R. McKenzie, B. L. Peterson, C. M. De Castro, J. Ellerton, K. N. Knapp, C.L. Beach, R. A. Larson, and The Cancer Leukemia Group B (CALGB).
Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine.
Blood (ASH Annual Meeting Abstracts),
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[Abstract]
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G. Barosi, D. Bordessoule, J. Briere, F. Cervantes, J.-L. Demory, B. Dupriez, H. Gisslinger, M. Griesshammer, H. Hasselbalch, R. Kusec, et al.
Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET)
Blood,
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M. Jadersten, S. M. Montgomery, I. Dybedal, A. Porwit-MacDonald, and E. Hellstrom-Lindberg
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Blood,
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E. Kaminskas, A. Farrell, S. Abraham, A. Baird, L.-S. Hsieh, S.-L. Lee, J. K. Leighton, H. Patel, A. Rahman, R. Sridhara, et al.
Approval Summary: Azacitidine for Treatment of Myelodysplastic Syndrome Subtypes
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D. P. Steensma and A. F. List
Genetic Testing in the Myelodysplastic Syndromes: Molecular Insights Into Hematologic Diversity
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J. Cortes, S. Faderl, E. Estey, R. Kurzrock, D. Thomas, M. Beran, G. Garcia-Manero, A. Ferrajoli, F. Giles, C. Koller, et al.
Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes
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A. List, S. Kurtin, D. J. Roe, A. Buresh, D. Mahadevan, D. Fuchs, L. Rimsza, R. Heaton, R. Knight, and J. B. Zeldis
Efficacy of Lenalidomide in Myelodysplastic Syndromes
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A.-M. Tsimberidou, F. J. Giles, I. Khouri, C. Bueso-Ramos, S. Pilat, D. A. Thomas, J. Cortes, and R. Kurzrock
Low-dose interleukin-11 in patients with bone marrow failure: update of the M. D. Anderson Cancer Center experience
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Darbepoetin alfa Maintains Hemoglobin Levels in Patients with Myelodysplastic Syndromes (MDS) after Therapeutic Interchange from Epoetin alfa: Results of a Retrospective Chart Review.
Blood (ASH Annual Meeting Abstracts),
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R. Stasi, M. Brunetti, E. Terzoli, E. Abruzzese, and S. Amadori
Once-weekly dosing of recombinant human erythropoietin alpha in patients with myelodysplastic syndromes unresponsive to conventional dosing
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Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid
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Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial
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S. Giannouli, M. Voulgarelis, E. Zintzaras, A. G. Tzioufas, and H. M. Moutsopoulos
Autoimmune phenomena in myelodysplastic syndromes: a 4-yr prospective study
Rheumatology,
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[Abstract]
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R. B. Howe, A. Porwit-MacDonald, R. Wanat, R. Tehranchi, and E. Hellstrom-Lindberg
The WHO classification of MDS does make a difference
Blood,
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[Abstract]
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R. Kurzrock, H. M. Kantarjian, J. E. Cortes, N. Singhania, D. A. Thomas, E. F. Wilson, J. J. Wright, E. J. Freireich, M. Talpaz, and S. M. Sebti
Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting
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[Abstract]
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Side effects of retroviral gene transfer into hematopoietic stem cells
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[Abstract]
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A. F. List
New Approaches to the Treatment of Myelodysplasia
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[Abstract]
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R. Stasi, M. Brunetti, E. Terzoli, and S. Amadori
Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes
Blood,
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[Abstract]
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M. B. Steins, T. Padro, R. Bieker, S. Ruiz, M. Kropff, J. Kienast, T. Kessler, T. Buechner, W. E. Berdel, and R. M. Mesters
Efficacy and safety of thalidomide in patients with acute myeloid leukemia
Blood,
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[Abstract]
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P. L. Greenberg, N. S. Young, and N. Gattermann
Myelodysplastic Syndromes
Hematology,
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[Abstract]
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B. D. Cheson, J. M. Bennett, H. Kantarjian, C. A. Schiffer, S. D. Nimer, B. Lowenberg, R. M. Stone, M. Mittelman, G. F. Sanz, P. W. Wijermans, et al.
Myelodysplastic syndromes standardized response criteria: further definition
Blood,
September 15, 2001;
98(6):
1985 - 1986.
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A. Raza, P. Meyer, D. Dutt, F. Zorat, L. Lisak, F. Nascimben, M. du Randt, C. Kaspar, C. Goldberg, J. Loew, et al.
Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes
Blood,
August 15, 2001;
98(4):
958 - 965.
[Abstract]
[Full Text]
[PDF]
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A. Raza
Improve or abandon the standardized response criteria for myelodysplastic syndromes recommended by the International Working Group
Blood,
July 1, 2001;
98(1):
251 - 251.
[Full Text]
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D. P. Steensma, L. Letendre, A. Tefferi, B. D. Cheson, J. M. Bennett, and P. L. Greenberg
Clarifications to the standard neutrophil response criteria for clinical trials in myelodysplastic syndromes are needed
Blood,
May 15, 2001;
97(10):
3321 - 3322.
[Full Text]
[PDF]
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Top
Abstract
Classification