Blood, 15 May 2001, Vol. 97, No. 10, pp. 3321-3322
CORRESPONDENCE
To the editor:
Clarifications to the standard neutrophil response
criteria for clinical trials in myelodysplastic syndromes are needed
The recent article by Cheson et al1 represents
an important step toward standardizing the response criteria used in
clinical trials of new therapeutic agents for patients with
myelodysplastic syndromes (MDSs). We believe that 3 clarifications are
necessary to the proposed neutrophil response criteria to avoid
classifying patients with spurious increases in neutrophil count as
having responded to therapy and to appropriately classify patients who enjoy a genuine, physiologically relevant increase in
neutrophil count.
The international working group's proposed criteria for the increment
in peripheral blood counts necessary to qualify as a minor erythroid
response and minor platelet response incorporate minimum absolute
increments of 1 g/dL and 10 000/mm3 (for
transfusion-independent patients), respectively. The proposed minor
neutrophil response criterion, in contrast, does not incorporate a
minimum absolute increment but simply requires an increase in the
absolute neutrophil count (ANC) "of at least 100%, but absolute increase less than 500/mm3".1(p3672)
For patients with very low neutrophil counts, the lack of an absolute
minimum increment required in order to meet the minor criterion may be
problematic. Many factors contribute to day-to-day variability in the
neutrophil count in normal persons, and we have also observed such
day-to-day variability in patients with MDS in the absence of any
specific intervention directed at the neutrophil cell line. The time of
day at which blood is drawn for analysis,2 the degree of
recent physical exertion,3 and (for premenopausal women)
the phase of the patient in the menstrual cycle4 are just
some of the many factors that can contribute to daily variability in
ANC. The precision and accuracy of laboratory determinations of the ANC
in patients with very low neutrophil counts may also be
questionable.5 A hypothetical patient with MDS who began a
clinical trial with an ANC of 100/mm3 and subsequently was
found to have an ANC of 200/mm3 could be listed as a minor
neutrophil response according to the current criterion, but such an
improvement may not be meaningful or reproducible.
The proposed major neutrophil response criterion, "For absolute
neutrophil count (ANC) less than 1500/mm3 before therapy,
at least a 100% increase, or an absolute increase of more than
500/mm3, whichever is greater",1(p3672) is
cumbersome. We understand a need for a clearly defined absolute minimum
increase in ANC but do not appreciate a need for the additional inclusion of a minimum percentage increase. A hypothetical patient with
MDS who began a trial with an ANC of 1000/mm3 and whose ANC
improved to 1900/mm3 would not qualify as a major response
according to the proposed criteria, but the latter value for ANC is
normal in many laboratories and such increments are associated with a
decrease in the risk of infection.6,7 In addition, a
hypothetical MDS patient starting a trial with an ANC of
800/mm3 whose ANC improved to 1500/mm3 would
count as only a minor response according to the proposed criteria but
would qualify as a major response if the count were 1600/mm3; the difference between these 2 responses is of
questionable physiologic relevance. Although we recognize that all
proposed response criteria must incorporate arbitrary numbers to a
certain extent, deleting the percent response clause could minimize the degree of arbitrariness in the proposed major neutrophil response criterion.
Finally, we feel that the consensus neutrophil response criteria (both
minor and major) should include a caveat that any responses observed
should not be attributable to the use of corticosteroids. Some recent
clinical trials in patients with MDS have included dexamethasone as a
therapeutic agent and have classified patients as responding to the
study regimen on the basis of an increment in the ANC alone. But
neutrophil increments in patients taking corticosteroids are thought to
represent leukocyte demargination and egress from the bone marrow of
part of the storage pool of neutrophils, not a genuine increase in the
synthesis of early leukocyte precursors.8 These increases
do not correlate with improved clinical outcomes.
A simpler and more physiologically relevant neutrophil response
criterion might include the requirement for an absolute increase in the
ANC of 500/mm3 for any type of response and the requirement
for normalization of the ANC (ANC of at least 1500/mm3) for
a major response.
David P. Steensma, Louis Letendre, and Ayalew Tefferi
Correspondence: David P. Steensma, Division of Hematology, Mayo
Clinic, 200 First St, SW, Rochester, MN 55905
References
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].
2.
Bain BJ, England JM.
Normal haematological values: sex difference in neutrophil count.
Br Med J.
1975;1:306-309.
3.
Suzuki K, Naganuma S, Totsuka M, et al.
Effects of exhaustive endurance exercise and its one-week daily repetition on neutrophil count and functional status in untrained men.
Int J Sports Med.
1996;17:205-212[Medline]
[Order article via Infotrieve].
4.
Bain BJ, England JM.
Variations in leucocyte count during menstrual cycle.
Br Med J.
1975;2:473-475.
5.
Ross DW, McMaster K.
Neutropenia: the accuracy and precision of the neutrophil count in leukopenic patients.
Cytometry.
1983;3:287-291[Medline]
[Order article via Infotrieve].
6.
Bodey GP, Buckley M, Sathe YS, Freireich EJ.
Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia.
Ann Intern Med.
1966;64:328-340.
7.
Nauseef WM, Clark RA.
Granulocytic phagocytes. In:
Mandell GL,Bennett JE,Dolin R, eds.
Principles and Practice of Infectious Disease. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:89-108.
8.
Nakagawa M, Terashima T, D'Yachkova Y, Bondy GP, Hogg JC, van Eeden SF.
Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes.
Circulation.
1998;98:2307-2313[Abstract/Free Full Text].
Response:
Clarifications of response criteria in myelodysplastic
syndrome
Steensma et al have raised several issues regarding the response
criteria after therapeutic interventions proposed for myelodysplastic syndromes, which we are pleased to help clarify. Their first issue concerns the possible daily fluctuations that may occur in the neutrophil counts of patients with myelodysplastic syndrome (MDS). Although such fluctuations in the absolute neutrophil count (ANC) have
been shown in patients without MDS but not in patients with MDS, our proposals indicate the need to document several observations of neutrophil counts before and after therapy to determine a response (minor or major). Because responses also require a duration of at least
2 months to qualify for that response category, the vagaries of such
potential variations would thus be greatly diminished. An ANC rise from
100/mm3 to 200/mm3 (100%) is potentially
clinically useful, given the association between degree of neutropenia
with infection risk.1
Their second point concerns the major neutrophil response criteria.
Although necessarily arbitrary, a substantive biologic and clinical
effect is believed to be warranted to be considered a major response.
Our criteria were aimed to assure a clinically relevant rise for
both very low ANCs (thus the net ANC increment criterion),
but being more stringent for higher ANCs (eg, with baseline ANCs above
1000/mm3), thus the percentage requirement. This criterion
has also been used previously to determine neutrophil responses to
granulocyte colony-stimulating factor.
Regarding their third point, we agree that the increments in ANCs
should not be considered responses if attributable to steroids. If a
corticosteroid is being used, this point should be clearly delineated
in the study design. As we learn more about the clinical impact of
specific therapies on MDS, we hope to be able to further refine these
response criteria.
Bruce D. Cheson, John M. Bennett, and Peter L. Greenberg
Correspondence: Bruce D. Cheson, National Cancer Institute,
Executive Plaza North, Rm 741, Rockville, MD 20852
Reference
1.
Bodey GP, Buckley M, Sathe YS, Freireich EJ.
Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia.
Ann Intern Med.
1966;64:328-340.
