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Blood, 1 July 2001, Vol. 98, No. 1, pp. 251-251
CORRESPONDENCE
To the editor:
Improve or abandon the standardized response criteria
for myelodysplastic syndromes recommended by the International Working
Group
Standardizing any aspect of a disease as clinically and
biologically heterogeneous as the myelodysplastic syndromes (MDSs), whose natural history is not infrequently confounded by wide
fluctuations in the peripheral blood (PB) indexes and where therapeutic
options range from a simple watch-and-wait policy to stem cell
transplantation, is a formidable task. Previous attempts of
international experts to define some aspects of this cryptic disease
include the French-American-British classification (FAB), the World
Health Organization classification (WHO), and the International
Prognostic Scoring System (IPSS). The latest in this series is a
publication from the International Working Group (IWG) detailing
standardized criteria to be used for response evaluation in
MDS.1 First of all, the attempt must be lauded. It is a
welcome and timely step, especially for those of us whose papers
reporting the results of clinical trials have been returned over and
over because the reviewer's idea of a response did not match the
investigator's. Unfortunately, in keeping with many previous exercises
to harness the complexity of MDS, the IWG's current proposal is also
deficient despite attempts to appear comprehensive by including the
more subtle issues such as emotional, social, and/or spiritual
improvements in quality of life. Below are some of the most
immediate practical problems encountered in applying these
recommendations to a real-life situation. Nowhere in this detailed document does it specify how to calculate
either the baseline or intratherapy values for hemoglobin, absolute
neutrophil count (ANC), or platelets. Should a single pretherapy
absolute complete blood count (CBC) be used as the gold standard
against which to measure response, or should this value be a derivative
of many weekly counts? And if the latter, then how many weeks
should one consider appropriate as being representative? Similarly, how
should one calculate transfusion dependency? I may call a patient
transfusion dependent if they received even a single transfusion in the
preceding 2 months. Should that make them transfusion independent if
they did not receive another for 9 weeks after starting therapy? The
confusion is even worse when one tries to handle weekly CBCs during the
course of therapy. It is recommended that studies should prospectively
assess whether there is a difference in outcome from 0 to 6 months, 6 to 12 months, and longer than 12 months from the diagnosis of MDS. It
sounds eminently sensible, except when one tries to actually use these recommendations practically. Should an average value of CBCs obtained over 6-month periods be used for these calculations, or should an
absolute value closest to the specified times be the standard? Or
perhaps a combination of both may be better? What should these values
be compared with? A single pretherapy CBC or an average of many? And
what about transfusions? Recently, the responses of patients treated on one of our
protocols were evaluated by ourselves and by 2 independent groups. While all 3 evaluators agreed that a significant proportion of the
patients responded to the therapy, the specific percent responders according to the 2 independent groups who used IWG response criteria was different. The major stumbling block was a lack of specific criteria for establishing baseline parameter levels and for identifying the intratherapy values that should be used for response assessment. Another problem is related to the interpretation of subtle differences
between the responses of individual patients. Consider for example, the
variations between just 2 patients whose responses according to the new
criteria might read something like "PR, cytogenetics minor, HI-E
major transfusion, HI-E minor Hb, HI-P minor, HI-N major," versus
"PR, cytogenetics minor (by FISH only), HI-E minor transfusion, HI-E
major Hb, HI-P major, HI-N minor." Are these 2 responders
really different, and if so, among 20 responders, what is the
likelihood of having 20 different types of responses with minor
variations? Further, are not these greatly expanded numbers of
variables likely to affect P values and the interpretation of what constitutes significance? How is this supposed to introduce uniformity in the interpretation of results? I would like to suggest that, before making such detailed
recommendations with the serious intent for universal application, the
writers of these types of classifications should make an attempt to
apply their recommendations to a practical situation, since at least
their obvious deficiencies would be immediately apparent. The IWG
paper1 would have been far more significant if the authors
had included an analysis of an actual clinical trial to back the
significance and universal utility of their recommendations. Failure to
do so has resulted in adding to the confusion in an already complex
situation. By neglecting to standardize baseline, as well as
intratherapy, values of blood counts that must be used for response
assessment, the IWG projects an image of a body far removed from
patient care and evaluation of clinical trials. Rather, their
recommendations appear to be a patchwork representing the unique
interests of a few individual IWG participants. This situation is
analogous to the ancient parable in the Upanishads where descriptions of an unseen elephant varied widely depending upon which part the
narrator felt through a curtain. Perhaps it is time to address the
ultimate Schrödinger-type interrogative: what constitutes MDS? I
suggest that it is more prudent to consider refractory anemia,
refractory anemia with ring sideroblasts, refractory anemia with excess
of blasts, and chronic myelomonocytic leukemia as 4 distinct disorders,
thereby simplifying interpretation of both biologic and clinical studies.
Azra Raza
Correspondence: Section of Myeloid Diseases, Rush University,
2242 W Harrison St, Suite 108, Chicago, IL 60612
Reference
1.
Cheson BD, Bennett JM, Kantarjian H, et al.
Report of an international working group to standardize response criteria for myelodysplastic syndromes.
Blood.
2000;96:3671-3674[Abstract/Free Full Text].
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