Response to Recombinant Human Erythropoietin in Patients ...€¦ · macological doses was used to improve anemia and reduce the transfUsional requirements of 43 patients with myelo-dysplastic

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

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66

38-86

194

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8.15.7-9.9

20,2604,860-87,400

269

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3 per 2 X 10-’ cells0-21 per 2 X 10’ cells

44762-3930 Bone marrow cellularity X % of erythroblasts

166-62

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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



Clinical Cancer Research 735

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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



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-


EC

I

1200

1000

800

600

400

200

0




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.

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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

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Response to Recombinant Human Erythropoietin in Patients ...€¦ · macological doses was used to improve anemia and reduce the transfUsional requirements of 43 patients with myelo-dysplastic