Upload
others
View
4
Download
0
Embed Size (px)
Citation preview
Vol 3, 733-739, May 1997 Clinical Cancer Research 733
Response to Recombinant Human Erythropoietin in Patients with
Myelodysplastic Syndromes
Roberto Stasi,’ Maurizio Brunetti, Stefano Bussa,
Marina Conforti, Claudio Di Giulio,
Anna Crescenzi, Edmondo Terzoli,Aldo Vecchione, and Adalberto Pagano
Department of Medical Sciences, Regina Apostolorum Hospital,00041 Albano Laziale [R. S., M. B., S. B., M. C., C. D. G., A. C.,A. P.]; Department of Oncology, University of Rome “La Sapienza,”00100 Rome [A. V.]; and Department of Complementary Oncology,Regina Elena Institute, 00100 Rome [B. T.], Italy
ABSTRACT
Recombinant human erythropoietin (rhEPO) at phar-macological doses was used to improve anemia and reduce
the transfUsional requirements of 43 patients with myelo-
dysplastic syndrome (MDS). rhEPO was given by s.c. injec-tion three times per week for 12 weeks. The EPO dose was
started at 150 lU/kg and was increased to 300 lU/kg If after
6 weeks there was no or suboptimal erythroid response.Responses were defined as being a complete response (CR),
partial response (PR), or no response (NR). A CR was
considered a rise in untransfused hemoglobin concentra-lions of at least 2 g/dI or a 100% decrease in RBC transfu-sion requirements over the treatment period. A PR was
defined as an increase in untransfused hemoglobin values of1-2 g/dl or a decrease in RBC transfusion requirements
equal to or greater than 50%. NR was defined as responses
less than a PR. Patients who responded to therapy werecontinued on rhEPO at the same dose for 6 additionalmonths. An objective response (CR and PR) was observed in
7 of 42 (16.7%) assessable cases after 6 weeks of treatmentat the dose of 150 lU/kg. Dose escalation (300 lU/kg) in
nonresponders resulted in another six patients attaining a
rise In hemoglobin concentrations. The final response ratewas 13 of 41 (31.7%); 4 patients became transfusion lode-
pendent. Therapy was tolerated well, with no relevant sideeffects. MDS progression was seen in one case. An elevatedbone marrow erythrold infiltration (erythrold index) anddetectable pretreatment circulating erythrold progenitors
(burst-forming unlts-erythrold) were the best predictors ofhemoglobin response when we controlled for other van-ables. These data suggest that rhEPO has a role in the
treatment of certain patients with MDS, particularly in
those with a high erythnold index and detectable CircUlatingerythrold burst-forming units.
INTRODUCTION
The MDSs2 are a group of clonal stem cell disorders
characterized by abnormal bone marrow proliferation, differen-
tiation, and maturation, leading to ineffective hematopoiesis.
Peripheral cytopenias and functional defects, as well as a high
likelihood ofleukemic transformation, are the clinical hallmarks
of MDSs. In the absence of effective treatment, many patients
receive supportive therapy only, the mainstay of which has been
blood transfusions. Due to limits and risks oftransfusion therapy
(namely immunization, transmission of viral diseases, and iron
overload), there is a strong necessity for alternative approaches
to relieve anemia in these disorders. In vitro studies of bone
marrow progenitors from myelodysplastic patients grown in
semisolid cultures have suggested that high concentrations of
rhEPO can overcome the decreased responsiveness of these
cells to physiological doses of EPO (1). Furthermore, some
patients with MDS have an inadequate endogenous EN) re-
sponse relative to the degree of anemia that may benefit from
the administration of pharmacological doses of rhEPO (2-4).
On these grounds, several trials have been designed to evaluate
the efficacy of rhEPO in the enhancement of erythropoiesis in
MDS (reviewed in Ref. 5). We herein report the results of a
phase II study in which we evaluated the efficacy of high doses
of rhEPO to improve anemia and/or reduce the transfusional
requirements of patients with MDS. Special emphasis was
placed on the identification of those categories of patients who
are most likely to benefit from rhEPO treatment because thus far
no consensus has been reached about a decision model for the
use of this growth factor in MDS.
PATIENTS AND METHODSFrom September 1992 to October 1995, 43 patients with
MDS were entered into the study after informed consent had
been obtained. MDS was classified according to the FAB Group
criteria (6) as either RA, PARS, RAEB, CMML, or RAEB-T.
Patients’ clinical and hematological characteristics on entry into
the study are reported in Table 1. At enrollment, 23 patients
were transfusion dependent, requiring a median of 5 units
Received 11/4/96; accepted 2/11/97.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.I To whom requests for reprints should be addressed, at Regina Apos-tolorum Hospital, Via S. Francesco 50, 00041 Albano Laziale, Italy.Phone: 39-6-9324661; Fax: 39-6-9321 138; E-mail: [email protected].
2 The abbreviations used are: MDS, myelodysplastic syndrome; EPO,
erythropoictin; rhEPO, recombinant human EPO; FAB, French-Amen-can-British; PA, refractory anemia; PARS, refractory anemia with ringsideroblasts; RAEB, refractory anemia with excess of blasts; CMML,chronic myelomonocytic leukemia; RAEB-T, refractory anemia withexcess of blasts in transformation; CR, complete response; PR, partialresponse; NR. no response; BFU-E, burst-forming unit-erythroid; El,erythroid index.
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
66
38-86
194
1424
8.15.7-9.9
20,2604,860-87,400
269
48-1012
23.76.8-65.4
3 per 2 X 10-’ cells0-21 per 2 X 10’ cells
44762-3930 Bone marrow cellularity X % of erythroblasts
166-62
100
734 Response to rhEPO in Patients with MDSs
Table I Summary of patients’ pretreatment characteristics
Characteristic Value
432518
No. of patientsMenWomen
Age (yr)MedianRange
FAB subtype (no. of patients)RA
RARSRAEBCMMLRAEB-T
Hemoglobin levels (g/dl)MedianRange
Reticulocyte count (per p.1)MedianRange
Serum erythropoietin (mJU/ml;n = 38)
MedianRange
ElMedianRange
BFU-E (n = 34)
MedianRange
Serum ferritin (ng/ml; n = 40)
MedianRange
MDS duration before rhEPO treatment(months)
MedianRange
(range, 3-12) of packed RBC transfusions during the 3 months
prior to study.
Eligibility criteria were as follows: histologically and cy-
tologically established diagnosis of MDS of at least 6 months
duration; a performance status �2 according to the Eastern
Cooperative Oncology Group scale (7); hemoglobin levels
steadily below 10 g/dl or a transfusion-dependent anemia; nor-
mal renal and hepatic function; and absence of iron, vitamin
B12, and folate deficiency. All patients had to present stable
disease for at least 2 months before entry, without cytostatic
treatment or administration of other hematopoietic growth fan-
tors. Exclusion criteria were clinically significant heart and
central nervous system disease, uncontrolled hypertension,
florid infections, or other malignancies.
Study Design. rhEPO (Eprex; Cilag, Milan, Italy) was
given s.c. 3 times/week for 12 weeks. The EN) dose was started
at 150 lU/kg and increased to 300 lU/kg if after 6 weeks there
was no or suboptimal erythroid response. Patients who re-
sponded to therapy were continued on rhEPO at the same dose
for 6 additional months. The first EPO injections were given at
the medical centers; subsequent therapy was administered under
outpatient conditions. Patients were questioned weekly concern-
ing possible adverse events. Treatment had to be discontinued if
severe side effects occurred, or at the patient’s request. Support-
ive care was given throughout the study as clinically indicated.
Response Criteria. Responses were defined as being a
CR, PR, or NR. A CR was considered a rise in untransfused
hemoglobin concentrations of at least 2 g/dl or a 100% decrease
in RBC transfusion requirements over the treatment period. A
PR was defined as an increase in untransfused hemoglobin
values of 1-2 g/dl or a decrease in RBC transfusion require-
ments �50%. NR was defined as less than a PR.
Study Parameters and Monitoring of Patients. Pa-tients’ evaluation before entry included a complete history,
physical examinations, bone marrow biopsy and aspirate, anal-
ysis of karyotype, chest roentgenogram, electrocardiogram, and
baseline laboratory tests that included a complete blood cell
count with reticulocytes, serum EPO, vitamin B12 and RBC
folate levels, erythroid progenitor cell assay (BFU-E), routine
serum chemistry, coagulation tests, and urinalysis. Vital signs,
complete blood cell count, and reticulocytes were monitored
weekly. Serum EPO levels were determined using a commer-
cially available enzyme-linked immunoassay (Quantikine IVD
Erythropoietin; R&D Systems, Minneapolis, MN). Bone mar-
row aspirates were performed at study entry and at the end of the
12-week treatment. The degree of bone marrow erythroid hy-
perplasia was calculated on the basis of the bone marrow ccl-
lularity, measured on bioptic histological slides, and differential
bone marrow counts evaluated on bone marrow films, according
to the following formula (El):
Karyotyping was carried out at study entry and on conclusion of
the treatment period with standard techniques, as described
previously (8). For cultures of erythroid progenitor cells, hepa-
riized blood samples were collected at baseline, at 6 weeks,
and at 12 weeks, and BFU-E was assayed in viscous medium
using a modification of the method of Iscove et al. (9). Briefly,
2 X iO� peripheral blood mononuclear cells were plated in
triplicate in 35-mm Petri dishes with 1-mi aliquots of 0.9%
methylcellulose viscous Iscove’s modified Dulbecco’s medium
(Life Technologies, Inc., Grand Island, NY) supplemented with
30% human AB serum, 10% BSA (Fraction V; Sigma Chemical
Co., St. Louis, MO), 1 X l0� s� 2-mercaptoethanol (Sigma),
and 2 units of rhEPO (Cilag). After incubation for 14 days at
37#{176}Cin a humidified atmosphere supplemented with 5% CO2.the cultures were scored for BFU-E (defined as bursts of cob-
nies consisting of hemoglobinized cells) with an inverted mi-
croscope.
Statistical Analysis. Statistical evaluation was per-
formed with the STATISTICA for Windows (StatSoft, Inc.;
Tulsa, OK) software package on an IBM computer. Results are
summarized as mean ± SD or as median and range. Student’s t
test and ANOVA were used to compare continuous variables
between different groups of patients. The x2 test was used to
compare qualitative or noncontinuous variables. A P of 0.05 or
less was designated as statistically significant. All Ps are two-
tailed. Correlations of variables with other variables were cal-
culated by Spearman’s rank correlation coefficient. For the
multivariate analysis, clinical and laboratory parameters were
entered into a forward stepwise logistic regression model to
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Clinical Cancer Research 735
� �uznoz L) ZZZ�.ZZQQ.ZOoZZZZZZZZO.QZZ�.ZZZZQZZZZ�.ZZZZ�.
- � 00 �
r.u �‘-�c’� �.O �r�l-c-9- l,� �--c�4--�m-r�1 -r�lr-1c’�l-- ---�-�-C’�-r�4-m
��� I � ©r-�-�’ ©�2I �
#{149}E� I�1c� I
� I � � r-1 r1 � � in �n �‘ r’� � �4 � � � r-� � � � � C �fl � 0 � � �4 (� (1 (� � � � � C � � � � f’� � �
‘�
F�
.��.
.� � � -‘ � ��‘ � - - r�l r-i�’4 - 0.-� ?‘ 0. � � a’ p.0. �o
� �e4 ;: � � � c�4� If�1 - C-� � (‘4 � � � � �‘ �
.c - � � � � � ‘a � �&C)
.� � � � t:: � �
#{149}lll � .�EN�,--0 I .�+ I r:�’u’o +�‘u � � �+ I � .� I I �oob :=‘,,� N �).�u V
:� � � � � � �.0 � 1< � � �.�
.�
Q
:�.�
2.� � r-�
z -z z- z r�
��V #{149}� 2� �
� � � � - � � � � � � � � � � - � - � � � � � 00 N � m � 00 � � S 00 - � � � � �r�l ‘,C m �,O � �� w � ‘� � � � � ‘n t- t� a’ - ‘� a’ r- in � in � �O � � N � - � �.� -‘ r�i � Z � e�l O� �.O � � ‘t� - � r�i � � ‘,� e’� - � r�i - e�l � � � � � � � - - ‘,� t- Z - � � � � �: �I �
i� � .2V .�
2 I�� I� � � � �<b©� .E
�. __�I� � O� � �
� �� :�in. .�
r-9 � .�.� �I.� - I �#{176}� � � ‘.0 c�1 � 0’ r-� � 00 a� � � � � oo � � - ‘r� � r’� 00 c’� t-. � � � � � � � �. � � � � < � ,(� �.
�2 .E � a�r.:o#{226}a� � � �‘.01 - - - -0I z.�0Ici V
El�Vic
�IV
I � ‘n �� � ooo6r-.:o� r.: � _
� 0
�. E-’ F- E�’ F-’ Z� � � c#)� � � C,, � � � � � � ,� �i
IL� IU �ILULl �LUU �� �u �u � �u �u � �u�u �u� � � �
IL:
‘� � � � ©mso�’�s EbO NC\�O :�< �o�cr� 00 �
� � - r-� � �‘ ‘n ‘� r- � C� 0 el � � ‘n � c- oc a� © r-� � � ‘n �C N 00 O� © r-i � �‘ r� �0 N 00 0� � - r�0
L) � - - r-1 � � � C�4 r-1 r-i c�a e-i � c� � � e’� r’� � m r’� � � � �‘ �
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
- Responders50
40
30
20
10
U,
8
t�jLl�
U
P200
P180
P160
80
20
1� 0
0� I � I I I � I � I � I I I
Fig. 2 Effects of rhEPO on Hb concentrations and reticulocytes in case25. Arrows, transfusions of packed red cells.
-V.-. Reticulocytes
-0- Hb
0 6 12
0 1 2 3 4 5 6 7 8 9 10 11 12
wee�� of rhEPO treatment
736 Response to rhEPO in Patients with MDSs
0
Weeks of rhEPO treatment
14
13
12
11
10
a
.0I 6�
5.
4.
3.
2
Fig. I Number of circulating BFU-Es during rhEPO treatment. Bar,normal range.
determine the most appropriate combination of covariates for
predicting response to rhEPO therapy.
RESULTS
Response to Treatment. Forty-one of forty-three pa-
tients completed the study and were evaluated for response. Of
the two patients who interrupted the study, one (case 17) died of
the consequences of a traumatic femur fracture on week 6 of
treatment (he had not responded to the lower dose of rhEPO);
the other (case 40) discontinued rhEPO therapy on week 3 when
he was hospitalized for bacterial pneumonia, dying a few weeks
later of heart failure. Changes in hemoglobin concentrations,
transfusion requirements, and BFU-E before and after rhEPO
treatment are summarized in Table 2. According to defined
response criteria, on week 12 of rhEPO treatment S patients
showed CR, 8 patients PR, and 28 patients NR. Of the five
patients who attained a CR, four exhibited an optimal response
at the dose of 150 lU/kg and were maintained with that dose,
whereas the fifth patient achieved CR only at the higher dose.
Three of the eight patients with PR had signs of response after
the first 6 weeks of treatment but did not benefit from the higher
dose of rhEPO; the other five patients showed PR only after
being challenged with rhEPO at 300 lU/kg. Seven of the 13
responders who received rhEPO during the extension phase had
a continued response. In all responders, the rise of hemoglobin
concentration was associated with a significant increase in re-
ticulocyte counts. Similarly, as shown in Fig. 1, the number of
circulating BFU-Es consistently increased in all responders. The
increase between baseline and peak BFU-E was significantly
higher in responders than in nonresponders (P < 0.001), al-
though a slight increase in the number of circulating BFU-Es
was also observed in five nonresponders at the end of treatment.
Two of these patients (patients 31 and 39) also showed an
increase in reticulocyte counts. Because it was hoped that these
patients might present a delayed response, they continued
rhEPO treatment for another 12 weeks, but no response was
observed. No significant changes in white blood cell and platelet
counts were noted over the course of treatment (data not shown).
A representative responding patient’s course (case 25) is shown
in Fig. 2.
Examination of bone marrow aspirates on conclusion of the
study (available in 39 of 41 cases), showed an increase in the
percentage of erythroid cells in 4 of the 5 complete responders
and in 5 of 7 partial responders. As assessed by bone marrow
morphology, disease progression during therapy was observed
in 1 patient (case 36), who showed an increase in bone marrow
blasts from 7 to 18%. This patient eventually developed overt
acute myeloid leukemia 5 months later. The other patients
showed an almost unchanged bone marrow morphology.
Analysis of karyotype at the end of treatment (available in
33 cases) did not show remarkable changes except for case 12,
who had an abnormal karyotype at diagnosis but showed only
normal metaphases in the post-EN) bone marrow, and case 36,
who displayed metaphases with multiple complex abnormalities
in addition to metaphases with the original monosomy of chro-
mosome 7.
Side Effects. rhEPO treatment was well tolerated overall,
and no relevant adverse effects were observed. A mild increase
in arterial blood pressure, which was easily controlled by mcd-
ical therapy, was seen in patient 12 after 8 weeks of treatment.
Two other patients (patients 3 and 19) complained of painful
erythema at the site of rhEPO injections; however, rhEPO
administration was not interrupted.
Prognostic Factors. In univariate analysis, three pre-
treatment variables turned out to be significantly different be-
tween responders (CR and PR) and nonresponders: the El (P =
0.0000), BFU-E values (P = 0.0057), and serum EPO levels
(P = 0.0471). Responders had a higher El than patients who did
not respond to rhEPO treatment (37.09 ± 13.40 versus 18.35 ±
5.91). BFU-E values also were more elevated in cases who
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
00
Table 3 Summary of stepwise regression#{176}
Variable �3 coefficient SE t P (2-tail)
InterceptEl -0.730328 0.122939BFU-E -0.412871 0.144793
Transfusion need -0.0288291 0.192697Baseline hemoglobin -0.158004 0.216716Reticulocyte Count 0.108809 0.129422
3.02979-5.94057
-2.85145
- 1 .49608-0.72908
0.84073
0.0066160.0000080.009865
0.1502460.4744040.410436
a Dependent variable: type of response. r
0.76734824; adjusted r� = 0.66265495.
0.87598416; r�
0 5 20 2510 15
BFU-E /2x105 cells
Fig. 3 Correlation between serum EN) levels and circulating BFU-E
before rhEPO treatment. - - - -, 95% confidence limits.
achieved CR or PR than in those who did not benefit from
therapy (8.40 ± 7.12 versus 3.08 ± 3.27); only one responder
(case 33) presented undetectable BFU-E. Serum EPO levels
were 225.5 ± 121.3 mlU/ml in responders versus 393.4 ± 256.4
mIU/ml in nonresponders.
No differences in serum iron, ferritin, vitamin B12, and
folate levels were found between the two categories of patients.
The FAB type did not hold a statistically significant prognostic
value (P = 0.348), but no assessable case of CMML and
RAEB-T auained a response. Age, sex, karyotype, transfusion
requirements on entry of the study, pretreatment hemoglobin
levels, reticulocyte count, and length of MDS duration before
rhEPO therapy also did not predict treatment outcome.
Regression analysis allowed us to demonstrate only an
inverse relationship between serum EPO levels and BFU-E
values (r = -0.444; P = 0.012; Fig. 3).
Multivariate analysis (Tables 3 and 4) indicated El and
BFU-E but not serum EN) as independent prognostic parame-
ters. Attempts to define clear-cut values of these variables to be
used to make treatment decisions led us to identify a subset of
patients with a high likelihood of response. In fact, eight of the
nine patients characterized by BFU-E > 0 and an El > 26.2
were responders (Table 2). Patients who did not fit the above
criteria were all nonresponders, except for case 9, who had the
highest BFU-E concentrations, and case 33, who had an El of
48.2.
DISCUSSION
In this study, rhEPO was administered to 43 MDS patients
in a dose-escalating fashion. An objective response (CR and PR)
was observed in 7 of 42 (16.7%) assessable cases after 6 weeks
of treatment at the lower dosage (150 lU/kg). Increasing the
dosage to 300 lU/kg resulted in 6 other patients attaining a rise
in hemoglobin concentrations. The final response rate was 13 of
41 (31.7%); 4 patients became transfusion independent. Therapy
was tolerated well, with no relevant side affects. MDS progres-
sion was seen in one case. Statistical analysis indicated bone
marrow erythroid infiltration (El) and the number of circulating
erythroid precursors as independent pretreatment variables as-
sociated with response to treatment. In particular, we found that
eight of nine patients with detectable BFU-E and a high El
(>26.2) were responders, and that the only two assessable
responders of our series who did not meet these criteria had
either BFU-E concentrations or an El far above the median
values. Serum EN) levels were significantly more elevated in
nonresponders but had a poor predictive value as compared to
the El and BFU-E values.
The response rate in our series falls within the range of
those reported in the literature. Data compiled from 15 separate
trials of rhEPO, involving 308 patients with MDS, show an
overall response rate of approximately 20%, with a range of
0-40% (5). In the largest trial carried out until now, a response
to rhEPO treatment has been reported in 28 of 100 MDS patients
(10). However, a comparison with single studies is difficult. The
number of patients is often small, and they differ from each
other in terms of patient selection, definition of response, dose
of rhEPO, route of administration, and duration of treatment.
The same arguments apply for prognostic factors. Thus far, no
individual clinical trial has been sufficiently extensive to pro-
vide a basis for a decision model for the use of rhEPO. This
would minimize the cost and improve the design of future
studies. An accurate insight into the data has been provided by
a recent meta-analysis by Hellstrom-Lindberg (1 1). Her evalu-
ation included a total of 205 patients with MDS who had beentreated with rhEPO. This analysis showed that the efficacy of
rhEPO in MDS in general is low, with only 16% of cases
presenting a significant response to treatment, and that the
groups of patients with an acceptable response rate were those
with no transfusion requirement and FAB type other than
RARS, irrespective of their serum level of EPO.
Information regarding the actual duration of rhEPO treat-
ment in patients who do not respond initially is lacking. In most
trials, patients discontinued rhEPO administration if they did not
respond within 8 -16 weeks from the start because later re-
sponses had not been reported. In our experience, two patients
who had not presented clinical signs of response after 12 weeks,
but did show an increase in BFU-E and reticulocyte counts,
were challenged for 12 additional weeks because it was hoped
that they might present a delayed response. However, no im-
provement in hemoglobin or transfusion requirements was ob-
served during this extension phase, and it may be speculated that
changes in laboratory parameters reflected an increase of pre-
Clinical Cancer Research 737
EC
I
1200
1000
800
600
400
200
0
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
738 Response to rhEPO in Patients with MDSs
Table 4 ANOVA
Source Sum of squares df Mean square F P
Regression 4.834294 9 0.537144 7.329488 0.000111Residual 1.465706 20 0.073285Total 6.300000
cursors leading to ineffective erythropoiesis or a reduced RBC
survival.
Our analysis includes data on the El and circulating BFU-E
that have been reported in a few previous studies with a very
limited number ofpatients and/or selection biases (12-17). Both
parameters were found to indicate the potential for erythroid
response.
The El is proportional to the mass of erythroid precursors.
It is now apparent that the main physiological role of EN) is to
prevent apoptosis and sustain differentiation of erythroid pre-
cursors, especially erythroid colony-forming units and their
progeny (18). This explains why, in our series, patients with a
high bone marrow El responded better than those with a low
index. Both normal and malignant erythroid precursors probably
have varying degrees of sensitivity to EPO (19). Therefore,
although serum EPO levels are usually highly increased in
MDS, the endogenous EPO response may be inadequate to
recruit those precursors with higher thresholds. The response
observed in some of our patients when rhEPO dose was esca-
lated supports a mechanism of this type.
Assessment of in vitro erythropoiesis represented another
criterion for predicting the efficacy of rhEPO. All responders
but one in our study showed lower than normal but detectable
pretreatment circulating BFU-E, which consistently increased
during rhEPO administration. Differences in composition of
study populations and in culture techniques might account for
the conflicting results obtained in other studies (15, 16). Actu-
ally, a significant increase in the number of erythroid progeni-
tors in response to high levels of rhEPO has been observed in
vitro in a subset of MDS patients (20). These findings provide
further evidence that at least in some MDS patients, EN)-
sensitive progenitor cells are present and are able to respond to
high doses of rhEPO. However, it remains unknown whether
rhEPO preferentially stimulates residual normal cells or abnor-
mal clones in MDS.
The third prognostic parameter found in univariate analysis
in our series, baseline serum EN), was inversely correlated with
BFU-E. This is in line with the report by Vadhan-Raj et a!. (21)
and suggests that elevated serum EN) might be related to a
deficiency in erythroid target cells. As previously emphasized,
circulating concentrations of EN) have been shown to be highly
variable among MDS patients with similar hemoglobin concen-
tration, and an inadequate endogenous EN) response has been
demonstrated in a substantial proportion of cases (2-4). In most
reports, responders generally have lower serum EN) levels than
nonresponders, and various cutoff points, ranging from 50 to
500 mIU/ml, have been proposed to forecast the response to
rhEN) (5, 10, 22-24). However, because of methodological
differences in EN) measurements and the wide distribution of
values even within the same category of patients, it is difficult
to establish an absolute value as a guideline for the use of rhEN)
in MDS. Besides, our multivariate analysis does not place this
degree of importance on EPO levels, although it stresses the
impact of the El and BFU-E.
In conclusion, the results discussed above indicate that
rhEN) is a safe, well-tolerated, and effective treatment for
anemia in a substantial subset of MDS patients. Our data suggest
that it is appropriate to assign rhEN) treatment to patients
presenting both an elevated bone marrow erythroid infiltration
(>26.2) and detectable circulating BFU-E, and also to those
showing highly increased values of either parameters (relative to
our suggested cutoff values). Challenging nonresponders with
rhEN) for more than 3 months may not be warranted because
clinical responses are usually not seen after that time.
ACKNOWLEDGMENTS
We acknowledge the Cilag company for supplying, in part, the
thEN) used in this study. We thank Franco Nasella and Gabriele
Mazzitelli for bibliographic assistance.
REFERENCES
1. Majani, H., Baines, P., Bowen, D. T., and Jacobs A. In vitro growthof myeloid and erythroid progenitor cells from myelodysplastic syn-dromes in response to recombinant human granulocyte-macrophagecolony-stimulating factor. Leukemia (Baltimore), 3: 29-32, 1989.
2. Jacobs, A., Janowska-Wieczorek, A., Cam, J., Bowen, D. J., andLewis, T. Circulating erythropoietin in patients with myelodysplasticsyndromes. Br. J. Haematol., 73: 36-39, 1989.
3. Rafanelli, D., Grossi, A., Longo, G., Vannucchi, A. M., Bacci, P.,and Rossi-Ferrmni, P. Recombinant human erythropoietin for treatmentof myelodysplastic syndromes. Leukemia (Baltimore), 6: 323-327,1992.
4. Aul, C., Arning, M., Runde, V., and Schneider, W. Serum erythro-poietin concentrations in patients with myelodysplastic syndromes.Leuk. Res., 15: 571-575, 1991.
5. Legare, R. D., and Gilliland, D. G. Myelodysplastic syndrome. Curr.Opin. Hematol., 2: 283-292, 1995.
6. Benneu, J. M., Catovsky, D., Daniel, M. T., Flandrin, 0., Galton,D. A. G., Gralnick. H. R., and Sultan, C. Proposals for the classificationofthe myelodysplastic syndromes. Br. J. Haematol., 51: 189-199, 1982.
7. Miller, A. B., Hoogstraten, B., Staquet, M., and Winkler, A. Report-ing results of cancer treatment. Cancer (Phila.), 47: 207-214, 1981.
8. Stasi, R., Del Poets, G., Masi, M., Tribalto, M., Venditti, A., Papa,G., Nicoletti, B., Vernole, P., Tedeschi, B., Delaroche, I., Mingarelli, R.,and Dallapiccola, B. Incidence of chromosome abnormalities and cm-ical significance of karyotype in de novo acute myeloid leukemia.Cancer Genet. Cytogenet., 67: 28-34, 1993.
9. Iscove, N. N., Sieber, F., and Winterhalter, K. H. Erythroid colonyformation in cultures of mouse and human bone marrow: analysis of therequirement for erythropoietin by gel filtration and affinity chromatog-raphy on agarose concanavalin A. J. Cell Physiol., 83: 309-318, 1974.
10. Rose, E. H., Abels, R. I., Nelson, R. A., McCullough, D. M., andLessin, L. The use of r-HuEpo in the treatment of anemia related to
myelodysplasia (MDS). Br. J. Haematol., 89: 831-837, 1995.
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Clinical Cancer Research 739
11. Hellstrom-Lindberg, E. Efficacy of erythropoietin in the myelodys-plastic syndromes: a mets-analysis of 205 patients from 17 studies.Br. J. Haematol., 89: 67-71, 1995.
12. Isnard, F., Najman, A., Jaar, B., Fenaux, P., Baillou, C., Khoury, E.,Labopin, M., Laporte, J. P., Woler, M., and Gorin N. C. Efficacy ofrecombinant human erythropoietin in the treatment of refractory ane-mias without excess of blasts in myelodysplastic syndromes. LeukLymphoma, 12: 307-314, 1994.
13. Depaoli, L., Levis, A., Isabella, N., Ficara, F., Priotto, C., Lists. P.,Fo#{224},R., and Resegotti L. Serum erythropoietin level and marrow eryth-mid infiltration predict response to recombinant human eiythropoietin inmyelodysplastic syndromes. Haematologica, 78: 118-122, 1993.
14. Bessho, M., Jinnai, I., Matsuda, A., Saito, M., and Hirashima, K.Improvement of anemia by recombinant human erythropoietin in pa-tients with myelodysplastic syndromes and aplastic anemia. mt. J. CellCloning, 8: 445-458, 1990.
15. Van Kamp, H., Prinsze-Postema, T. C., Kluin, P. M., denOttolander, G. J., Beverstock, G. C., Willemze, R., and Fibbe, W. E.Effect of subcutaneously administered human recombinant erythropoi-etin on erythropoiesis in patients with myclodysplasia. Br. J. Haematol.,78: 488-493, 1991.
16. Verhoef, G. E. G., Zachee, P., Ferrant, A., Demuynck, H., Selleslag,D., Van Hove, L., Deckers, F., and Boogaerts, M. A. Recombinanthuman erythropoietin in patients with myelodysplastic syndrome: aclinical and erythrokinetic assessment. Ann. Hematol., 64: 16-21, 1992.
17. Ghio, R., Balleari, E., Ballestrero, A., Gatti, A. M., Mareni, C.,Massa, G., Patrone, F., Sessarego, M., and Timitilli, S. Subcutaneous
recombinant human erythropoietin for the treatment of anemia in my-elodysplastic syndromes. Acts Haematol., 90: 58-64, 1993.
18. Koury, M. J., and Bondurant, M. C. Erythropoietin retards DNAbreakdown and prevents programmed death in erythroid progenitorcells. Science (Washington DC), 248: 378-380, 1990.
19. Kebley, L. L., Koury, M. J., Bondurant, M. C., Koury, S. T., Sawyer,S. T., and Wickrema, A. Survival or death of individual proerythroblastsresults from differing erythropoietin sensitivities: a mechanism for con-trolled rates of erythrocyte production. Blood, 82: 2340-2352, 1993.
20. Aoki, I., Higashi, K., Homori, M., Chikazawa, H., and Ishikawa K.Responsiveness of bone marrow erythropoietic stem cells (CFU-E andBFU-E) to recombinant human erythropoietin in vitro in aplastic anemiaand myelodysplastic syndrome. Am. J. Hematol., 35: 6-12, 1990.
21. Vadhan-Raj, S., Hittebman, W. N., Lepe-Zuniga, J. L., Gutterman,J. U., and Broxmeyer, H. E. Regulation of endogenous erythropoietinlevels in anemia associated with myelodysplastic syndromes. Blood, 75:1749-1750, 1990.
22. Stone, R. M., Bernstein, S. H., Demetri, G., Facklam, D. P., Arthur,K., Andersen, J., Aster, J. C., and Kufe, D. Therapy with recombinanthuman erythropoietin in patients with myelodysplastic syndromes.Leuk. Rca., 18: 769-776, 1994.
23. Mittelman, M. Recombinant erythropoietin in myelodysplastic syn-dromes: whom to treat and how? More questions than answers. ActsHaematol, 90: 53-57, 1993.
24. Erslev, A. J. Erythropoietin. N. Engl. J. Med., 324: 1339-1344,
1991.
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
1997;3:733-739. Clin Cancer Res R Stasi, M Brunetti, S Bussa, et al. myelodysplastic syndromes.Response to recombinant human erythropoietin in patients with
Updated version
http://clincancerres.aacrjournals.org/content/3/5/733
Access the most recent version of this article at:
E-mail alerts related to this article or journal.Sign up to receive free email-alerts
Subscriptions
Reprints and
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Permissions
Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)
.http://clincancerres.aacrjournals.org/content/3/5/733To request permission to re-use all or part of this article, use this link
Research. on March 28, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from