Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes

Annals of Oncology 16: 1921–1927, 2005 doi:10.1093/annonc/mdi400 Published online 15 September 2005

Original article

Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes R. Stasi1*, E. Abruzzese2, G. Lanzetta3, E. Terzoli4 & S. Amadori2 1

Department of Medical Sciences, Regina Apostolorum Hospital, Albano Laziale; 2Department of Hematology, University of Rome ‘Tor Vergata’, S. Eugenio Hospital, Rome; 3Department of Oncology, INI, Grottaferrata; 4Department of Complementary Oncology, IFO – Regina Elena Institute, Rome, Italy

Received 19 April 2005; revised 26 June 2005; accepted 21 July 2005

Introduction The current management of myelodysplastic syndromes (MDS) involves an individualized care plan for each patient. In this regard, the International Prognostic Scoring System (IPSS) has become an indispensable tool in the identification of treatment goals [1]. However, the generally advanced age of patients and the attendant non-hematological comorbidities often limit therapeutic options, with many patients receiving supportive care only irrespective of their IPSS risk group [2]. In low- and intermediate-1-risk MDS anemia is often the major or only clinical problem, and red cell transfusions the mainstay of therapy. Recombinant human erythropoietin (rhEPO) has been consistently used to relieve anemia and reduce transfusion requirements in these patients. The overall response rate to rhEPO is 20% [3], but it can be as high as 60% in a subset of low-risk MDS, particularly those with a diagnosis of refractory anemia, no transfusions prior to rhEPO therapy and low serum levels of endogenous EPO [4].

*Correspondence to: Dr R. Stasi, Department of Medical Sciences, ‘Regina Apostolorum’ Hospital, Via S. Francesco 50, 00041 Albano Laziale, Italy. Tel: +39-06-932989; Fax: +39-06-233231809; E-mail: [email protected] Ó 2005 European Society for Medical Oncology

Darbepoetin alfa (DA) is a novel erythropoietic agent with greater sialic acid content, an approximately three-fold longer terminal half-life and greater biological activity than rhEPO, allowing less-frequent administration with a similar efficacy and safety profile and increased biological activity [5]. Recent clinical trials have demonstrated the efficacy of this erythropoietic agent in the treatment of cancer-related anemia [6, 7]. In this phase II study we evaluated the impact of DA therapy on hemoglobin levels, transfusion requirements and changes in quality of life (QoL) in anemic patients with previously untreated low- and intermediate-1-risk MDS.

Patients and methods Patients Fifty-three patients with low- and intermediate-1-risk MDS according to the IPSS were included in this study after they had signed an institutional review board-approved informed consent. Patients’ clinical and laboratory characteristics on study entry are reported in Table 1. MDS cases are reported according the World Health Organization classification as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) or refractory anemia with excess blasts-1 (RAEB-1) [8]. Median time from diagnosis to initiation of DA therapy was 16 months (range 9–21). At enrollment, 46 patients were

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Background: The hematological and quality of life (QoL) changes associated with darbepoetin alfa (DA) therapy were assessed in anemic patients with previously untreated low- and intermediate-1-risk myelodysplastic syndrome (MDS). Patients and methods: Fifty-three patients received DA administered subcutaneously once a week for 24 weeks. Treatment was initiated at 150 lg fixed dose and was doubled if after the first 12 weeks there was no or suboptimal erythroid response. Results: The final response rate was 24/53 (45%), with 21 major and three minor responses. Most of the responses (21/24; 87.5%) were obtained at the dose of 150 lg. With a median follow-up of 9.4 months, 17 patients maintain their response. Treatment was well tolerated with no relevant side-effects. MDS progression was observed in one case. Increases in hemoglobin levels were positively correlated with improved QoL scores using both the linear analog scale assessment (energy level, r = 0.429, P = 0.036; daily activities, r = 0.653, P < 0.001; overall well-being, r = 0.457, P = 0.024) and the Functional Assessment of Cancer Therapy-Anemia questionnaire (r = 0.247, P = 0.025). In multivariate analysis, only low levels (<200 IU/l) of endogenous erythropoietin predicted response to DA therapy. Conclusions: DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients’ QoL. Key words: anemia, darbepoetin alfa, erythropoietin, myelodysplastic syndrome, predictive factors

1922 Table 1. Summary of patients’ pretreatment characteristics No. of patients

53

Men

30

Women

23

Age (years) Median

70

Range

59–82

WHO subtype RA

31

RCMD

10

RAEB-1

8

RARS

3

RCMD-RS

1

Good

47

Intermediate

6

IPSS risk groupb Low risk

29

Intermediate-1 risk

24 c

Transfusion requirements (U/month) Median

2

Range

0–5

Hemoglobin levels (g/dl) Median Range

7.9 6.8–9.3

Absolute neutrophil count (·109/l) Median Range

1.8

Treatment plan Therapy consisted of a 24-week schedule of DA (AranespÒ; Amgen, Milan, Italy) administered subcutaneously once a week. DA treatment was initiated at 150 lg fixed dose and was increased to 300 mg fixed dose if after 12 weeks there was no or suboptimal erythroid response. If responders achieved hemoglobin levels >13 g/dl, the DA doses had to be adjusted to maintain their hemoglobin levels between 11 and 13 g/dl. Treatment extended beyond 24 weeks, individually tailored, was given to patients with a continued response. Treatment was discontinued at the patient’s request, if patients developed severe diseases other than MDS, and if severe side-effects or transformation to AREB-2 or acute myelogenous leukemia occurred.

0.5–3.6

Response criteria

Platelet count (·109/l) Median

167

Range

38–344

Serum erythropoietin levels (IU/l) Median

171

Range

26–515

Serum ferritin levels (ng/ml) Median

486

Range

75–1040

Responses were categorized according to the criteria developed by the International Working Group [10]. In particular, a major response (MaR) for the erythroid lineage was considered a rise in untransfused hemoglobin concentrations of at least 2 g/dl or a 100% decrease in RBC transfusion requirements during the treatment period. A minor response (MiR) was defined as an increase in untransfused hemoglobin values of 1–2 g/dl or a ‡50% decrease in RBC transfusion requirements. No response was defined as a response less than a MiR. All responses were evaluated at the end of the 24 weeks of DA therapy. Patients who did not complete the study were classified as non-responders by default.

a

Good: normal, ÿY, del(5q), del(20q); poor: complex (‡3 abnormalities) or chromosome 7 anomalies; intermediate: other abnormalities. b International Prognostic Scoring System [1]. c Median packed red blood cell transfusions per month for 3 months before the study. RA, refractory anemia; RCMD, refractory cytopenia with multilineage dysplasia; RAEB-1, refractory anemia with excess blasts-1; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts.

Study parameters and monitoring of patients Patient evaluation before entry included complete history and physical examination. All patients underwent chest roentgenography and electrocardiography. Baseline laboratory evaluation included a complete blood cell count with reticulocytes, serum EPO, serum ferritin, vitamin B12 and folate levels, routine serum chemistry, coagulation tests, and urinalysis. The possible development of iron deficiency in responders to DA therapy was monitored by measuring serum ferritin levels and the saturation of circulating transferrin every 4 weeks. Vital signs and complete blood cell counts were monitored once a week. Serum EPO levels were determined using a commercially available enzyme-linked immunoassay (Quantikine IVD Erythropoietin; R&D Systems, Minneapolis, MN, USA). Bone marrow aspirates and biopsy specimens were taken at enrollment and at the end of the study

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Karyotypea

transfusion dependent, with a median of 2 U (range 1–5) of packed red blood cell (RBC) transfusions per month for 3 months before the study. Transfusions were usually given when the hemoglobin concentration was <8 g/dl, although occasionally we adopted different thresholds in individual patients in accordance with their compliance with low hemoglobin levels. In addition, sometimes transfusions were delayed because of a shortage of blood products, which occurred frequently during the holidays. Eligibility criteria were as follows: primary MDS of at least 6 months’ duration; <10% blasts on bone marrow examination; low or intermediate-1 IPSS risk group; Eastern Cooperative Oncology Group performance status of £2 [9]; untransfused hemoglobin levels <10 g/dl; normal renal and hepatic function; normal iron, vitamin B12 and folate levels. Exclusion criteria included: prior treatment with rhEPO; prior treatment with other hematopoietic growth factors or other biological response modifiers; patients with active malignancies (except localized squamous or basal cell skin carcinoma); prior chemotherapy or radiotherapy; pregnant or lactating women; uncontrolled hypertension (systolic blood pressure >180 mmHg, and/or diastolic blood pressure >100 mmHg); patients with active severe diseases other than MDS that were expected to prevent compliance with the protocol (e.g. infection, symptomatic congestive heart failure, unstable angina/coronary artery disease, cardiac arrhythmia or psychiatric illness/social situations).

1923 (aspirates) or when clinically required (e.g. in case of progressive cytopenias or appearance of circulating blasts). Karyotyping was carried out with standard techniques at study entry. Erythroid progenitor cell assay was performed at baseline, and at 24 weeks. Erythroid blast-forming units (BFU-E) were assayed in viscous medium as described previously [11].

correlation coefficient. Multivariate analysis was performed by least-squares multiple linear regression. P < 0.05 was designated as statistically significant; all P values were two-tailed.

Results Measurement of apoptosis

Quality of life assessments The impact of DA therapy on patients’ QoL was assessed at the beginning of the study and again at the end of the study using two different instruments: the Linear Analog Scale Assessment (LASA) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An) self-administered questionnaires. Both methods of assessment have previously been tested and validated in cancer patients. The LASA questionnaire is a widely used brief measurement tool, consisting of three questions that evaluate energy level, daily activity and overall QoL [14]. It uses a 100-mm linear analog scale for responses; the opposite ends represent the negative and positive extremes for each measured variable, with 0 being the lowest score and 100 being the highest (best QoL). This tool is easy to use and takes 1–2 min to complete. Patients draw a line on the 100-point scale to reflect their perceived QoL, with the score being measured as the number of millimeters from the zero reference point. FACT-An (version 4) is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (FACT-General, or FACT-G Total) measuring the four general domains of QoL (physical, social/family, emotional and functional wellbeing), and an additional 20-item anemia questionnaire (FACT-An Anemia subscale) that measures 13 fatigue-associated items (FACT-An Fatigue subscale) and seven non-fatigue-related items [15]. Each of these measures is scaled with low scores indicating poor QoL and high scores indicating good QoL. As originally constructed, the FACT-G total scores range from zero to 108, the FACT-An Anemia subscale scores range from zero to 80 and the FACT-An Fatigue subscale scores range from zero to 52. Internal consistency of FACT-An scores was expressed with the Cronbach’s alpha coefficient. An alpha coefficient of 0.70 or higher was considered as sufficient for the purpose of group comparisons.

Statistical analysis Mann–Whitney U-test was used to compare continuous variables between responders and non-responders. Wilcoxon matched-pairs test was used to compare repeated measurements in the same patients. Fisher exact test was used to evaluate the relationship between two dichotomous variables. Correlations of variables with other variables were calculated by Spearman rank

Erythropoietic responses Forty-eight patients (90%) completed the 24 weeks of treatment and were evaluated for toxicity and response. Failure to complete the study in five patients was related to various causes. In one patient (man, age 81 years, RAEB-1) progressive pancytopenia was observed, with bone marrow aspirates demonstrating an increase of the blast counts from a baseline value of 8% to 15% after 12 weeks of treatment. Two patients had to be hospitalized for pulmonary infections: one (man, age 82 years, RCMD) had not shown a response after 6 weeks of DA treatment, while the other one (woman, age 77 years, RARS) had shown a hemoglobin increase of 1.2 g/dl after 9 weeks of treatment. One patient (woman, age 67 years, RA) was hospitalized after a car accident; she had shown no erythroid response at that time. Finally, one patient (man, age 60 years, RCMD) had to undergo urgent surgery because of perforated diverticulitis. The postoperative course was complicated, requiring a long hospital stay. Before surgery this patient had almost completely eliminated his transfusion needs. According to defined response criteria, on week 24 of treatment the erythroid response rate was 45% (95% confidence interval 31% to 59%). Changes in blood cell counts, transfusion requirements, and laboratory parameters before and after treatment in responders are detailed in Table 2. The response was MaR in 21 patients, MiR in three and absent in 29. All but one of the patients who attained a major hematological improvement exhibited an optimal response at the dose of 150 lg, with responses occurring by the eighth week of treatment. The DA dose had to be reduced in two cases, in which the hemoglobin concentrations exceeded 13 g/dl. All three cases with an MiR showed a hematological improvement only after being challenged with DA at 300 mg, and in two of them (cases 9 and 17) the response was based solely on a decrease in transfusion requirements. One patient with a major response (case 5) showed a drop in hemoglobin levels after 9 weeks of DA therapy because of the development of iron deficiency and required iron supplementation to achieve a new response. During the extension phase, 16 patients received DA without modifications of the initial dose, whereas eight received DA at the dose of 150 lg every 2 weeks. Thus far, with a median follow-up of 9.4 months, all three patients with a MiR and three patients with a MaR have relapsed. Figure 1 illustrates a Kaplan–Meier plot of probability of response versus time for the 24 patients with erythroid responses.

Safety Treatment was, in general, well tolerated. Two patients (cases 5 and 22), who had a rapid increase of hemoglobin levels after the

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Apoptosis was measured by flow cytometry as described previously [12, 13]. In brief, mononuclear cell fractions of bone marrow samples were separated after Ficoll–Hypaque gradient centrifugation and washed twice with phosphate-buffered saline. Cells (1 · 106) were then incubated with phycoerythrin-conjugated anti-CD34 mAb (anti-HPCA-2, IgG1; Becton Dickinson; Franklin Lakes, NJ, USA) for 10 min at room temperature in the dark and were washed twice with phosphate-buffered saline. Pelleted cells were resuspended in 100 ml binding buffer (10 mM HEPES/NaOH, pH 7.4, 140 mM NaCl, 2.5 mM CaCl2; Bender Medsystems, Boehringer Ingelheim, Ridgefield, CT, USA) and were incubated with 2 ml fluorescein isothiocyanateconjugated annexin V (Bender Medsystems; Boehringer Ingelheim) for 10 min at room temperature in the dark. Afterward, cells were resuspended in 400 ml binding buffer before flow cytometric analysis. Analysis was based on gating of subpopulations of CD34+ cells by forward scatter versus side scatter and by side scatter versus fluorescence-2. Negative controls included peripheral blood mononuclear cells incubated with neither CD34-PE mAb nor annexin V–FITC and cells incubated with CD34-PE mAb only.

1924 Table 2. Baseline characteristics and changes in hematologic parameters following darbepoetin alfa therapy in responders Case No.

Age

Sex

WHO subtype

MDS duration (months)

IPSS risk group

Baseline serum EPO (IU/l)

Hemoglobin (g/dl)a

RBC transfusions Baseline

At 12 weeks

At 24 weeks

Baseline

At 12 weeks

At 24 weeks

Erythroid response

Time to response (weeks)

Response duration (weeks)

1

62

M

RCMD

18

Int-1

53

3

0

0

8.1

9.3

10.3

MaR

4

2

63

M

RA

15

Low

67

2

2

0

7.7

7.6

9.1

MaR

15

73+ 29

5

76

M

RA

9

Low

26

0

0

0

9.1

13.6

11.2

MaR

2

63+

7

59

F

RA

17

Low

77

1

0

0

8.4

8.9

10.6

MaR

4

58+

8

64

F

RCMD

13

Int-1

113

2

0

0

7.8

8.7

10.1

MaR

5

56+

76

F

RA

14

Int-1

87

2

2

1

8.2

8.3

8.6

MiR

14

21

80

M

RA

13

Low

51

3

0

0

7.4

8.5

10.1

MaR

6

51

12

60

F

RA

17

Int-1

90

0

0

0

8.6

10.1

11.7

MaR

5

49+

15

61

F

RA

13

Low

161

2

0

0

8.1

8.4

10.7

MaR

4

48+

17

73

M

RA

16

Low

370

3

3

1

6.8

7.1

7.6

MiR

16

26

20

68

F

RA

16

Int-1

89

0

0

0

8.8

11.6

10.9

MaR

4

46+

22

73

F

RCMD

17

Int-1

71

0

0

0

9.3

13.2

11.8

MaR

2

47+

23

82

M

RA

20

Int-1

98

2

0

0

7.5

8.1

9.8

MaR

5

43+

25

70

M

RA

16

Low

187

2

0

0

7.6

7.9

9.4

MaR

5

41+

28

80

F

RA

16

Low

61

2

0

0

8.2

9.6

10.5

MaR

4

40+

30

70

M

RA

14

Low

251

0

0

0

8.6

9.3

10.4

MiR

14

32

35

75

M

RA

21

Low

57

3

1

0

8.0

8.5

9.3

MaR

8

15

38

65

F

RA

19

Low

136

2

1

0

7.5

7.9

9.6

MaR

6

35+

40

80

F

RA

14

Low

95

3

0

0

8.0

8.6

10.8

MaR

6

34+

42

69

M

RAEB1

13

Int-1

156

3

0

0

7.6

8.4

8.9

MaR

4

17

44

70

M

RCMD

11

Int-1

151

2

1

0

7.4

7.9

8.9

MaR

8

30+

48

78

F

RA

13

Low

123

3

0

0

8.3

8.8

10.5

MaR

5

31+

50

59

F

RA

11

Int-1

270

3

0

0

7.5

8.0

9.4

MaR

6

29+

52

64

F

RCMD

20

Int-1

121

2

0

0

7.9

8.5

9.3

MaR

6

28+

a

The blood counts before and after treatment were calculated averaging the results of three counts taken over a 2 week period. MDS, myelodysplastic syndrome; IPSS, International Prognostic Scoring System; EPO, erythropoietin; RBC, red blood cell; M, male; F, female; RCMD, refractory cytopenia with multilineage dysplasia; RA, refractory anemia; RAEB-1, refractory anemia with excess blasts-1; Int-1, intermediate-1; MaR, major response; MiR, minor response.

start of DA therapy experienced a mild and transient increase in arterial blood pressure that did not require medical therapy. Three patients complained of pain with or without erythema at the site of DA injections.

Cumulative Proportion Responding

100 90 80 70 60 50

Quality of life

40

By the end of the study, the scores for the three LASA domains showed a statistically significant improvement (P < 0.001). There was a notable difference in mean LASA change scores between hemoglobin responders and non-responders (Figure 2). The measure of energy level, daily activities and the overall assessment actually worsened for non-responders. The association between hemoglobin levels and QoL was reflected in the significant positive correlation between change in LASA and change in hemoglobin: energy level (r = 0.429; P = 0.036), daily

30 20 10 0 0

10

20

30

40

50

60

70

Weeks Figure 1. Kaplan–Meier plot of time to treatment failure in responders to darbepoetin alfa treatment.

80

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9 10

1925

All patients Responders Non responders

22.0 20.0

Changes in LASA Score (mm)

18.0 16.0 14.0 12.0 10.0 8.0 6.0

The clinical relevance of the changes in QoL scores was evaluated following the criteria of a recent publication, indicating that a change in score of 2.54 in FACT-G and 4.24 in FACT-An fatigue subscale corresponds to a minimally important clinical difference [16]. This was defined as the difference in QoL between patients with stable hemoglobin (change of between ÿ1 and 1 g/dl) and those with an hemoglobin change ‡1 g/dl. As shown in Figure 3, in our study the mean increase in FACT-G and FACT-An scores after DA therapy largely exceeded the change required to reflect a clinically significant improvement in QoL.

Laboratory studies At the end of the study, the increase in hemoglobin concentration in responders was associated with a significant increase in BFU-E counts, and a reduction of bone marrow apoptotic cells (P < 0.001 for both variables). In particular, the BFU-E count was 4.5 ± 2.8/2 · 105 cells (baseline) versus 14 ± 4.8/2 · 105 cells (week 24), and the bone marrow CD34+ cell apoptotic fraction was 53.6 ± 10.6% (baseline) versus 40.9 ± 9% (week 24).

Predictive factors Table 3 shows the clinical and laboratory pretreatment characteristics of patients who had erythroid responses (MaR + MiR) compared with those who did not respond. In univariate analysis the variables that significantly differed between the two groups were serum levels of endogenous EPO and transfusion requirements. Twenty-one of 28 patients with serum levels of EPO <200 mIU/ml achieved a response, as compared with three

4.0 2.0

Table 3. Comparison of baseline clinical and laboratory characteristics of MDS patients responding and not responding to darbepoetin alfa treatment

0.0 -2.0 -4.0 -6.0

Energy level

Daily Activities

Overall well-Being

Figure 2. Mean change from baseline in Linear Analog Scale Assessment (LASA) scores. Data presented for all patients and grouped according to response to darbepoetin alfa.

Non-responders

70 (59–82)

69 (60–80)

P value 0.680

Male/female

11/13

19/10

0.174

MDS duration (months)

15.5 (9–21)

16 (9–21)

0.971

Serum EPO (IU/l)

96.5 (26–370)

275 (56–515)

Prior RBC transfusion requirements (U/month)

2 (0–3)

3 (0–5)

0.054

14

Hb levels (g/dl)

8.0 (6.8–9.3)

7.7 (6.9–9.6)

0.156

12

Reticulocytes (·109/l)

15.5 (7.0–23.5)

14.2 (6.6–26.7)

0.588

10

9

20

All patients

18

Responders Non responders

16

Change in Score

Age (years)

Responders

<0.001

ANC (·10 /l)

1.8 (0.5–3.5)

2.0 (0.8–3.6)

0.472

6

Platelets (·109/l)

137 (38–288)

159 (66–344)

0.880

4

BFU-E (n/2 · 105 cells)

4 (0–11)

8

4.5 (0–9)

0.612

IPSS risk group, Low/Int-1 13/11

16/13

0.418

-2

RAEB-1/non-RAEB

1/23

7/22

-4

CD34+ cell apoptosis (%)

54.4 (33.7–72.1) 56.9 (32.9–76.4)

2 0

FACT-An Total

0.059 0.696

FACT-General FACT-An Anemia FACT-An Fatigue

Figure 3. Mean change from baseline in FACT-An scores. Data presented for all patients and grouped according to response to darbepoetin alfa. FACT-An, Functional Assessment of Cancer Therapy-Anemia; FACT-An Anemia, FACT-An Anemia subscale; FACT-An Fatigue, FACT-An Fatigue subscale.

Results are reported as median, with range in parentheses, or as ratios. MDS, myelodysplastic syndrome; EPO, erythropoietin; RBC, red blood cell; Hb, hemoglobin; ANC, absolute neutrophil count; BFU-E, erythroid blast-forming units; IPSS, International Prognostic Scoring System; Int-1, intermediate-1; RAEB-1, refractory anemia with excess blasts-1.

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activities (r = 0.653; P < 0.001) and overall wellbeing (r = 0.457; P = 0.024). The FACT-An scale demonstrated a good internal consistency, as shown by a Cronbach’s alpha of 0.864 at baseline, and 0.812 at week 24. The results obtained with the FACT-An questionnaire substantially replicated those obtained with LASA. As with the LASA data, the FACT scales revealed a marked difference between the results for responders and non-responders. Statistically significant (P < 0.001) differences in mean score were observed for all FACT scales in the responder group, although none of the scores changed significantly for the non-responders (Figure 3). The association between an increase in hemoglobin levels and an increase in QoL was confirmed by a significant correlation between the change in the FACT-An score and the change in hemoglobin for the responder group (r = 0.247; P = 0.025). This correlation was also demonstrated separately for the components of the FACT-An, including the FACT-G (r = 0.315; P = 0.013) and the anemia (r = 0.333; P = 0.011) and fatigue (r = 0.191; P = 0.037) subscales.

1926 of 25 patients with higher levels (P < 0.001). Six patients who had a transfusion requirement ‡4 U per month did not respond to DA therapy, as compared with 18 of 47 patients with lower transfusion requirements (P = 0.005). It should also be noted that only one of the eight patients with RAEB-1 had a response to treatment. In multivariate analysis, only serum EPO levels retained its predictive value (P < 0.001).

Discussion

References 1. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

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In the present study, administration of DA to anemic patients with low- and intermediate-1-risk MDS resulted in an overall erythroid response rate of 45%. With a median follow-up of 9.4 months, 17 of 24 responders maintained their response. All but one of the patients who attained an MaR exhibited an optimal response at the starting dose of 150 lg/week, corresponding approximately to the weekly global dose of rhEPO (30 000 U, usually fractionated in 10 000 U three times a week). However, while it is obvious to cite some of the relevant data about rhEPO, we have to underline that our findings cannot be used to draw comparisons between DA and rhEPO in terms of efficacy. Contrary to previous trials by ourselves and by other groups, in which dose escalation for non-responders was usually attempted after 4–8 weeks of treatment, in this study the initial phase with the lower dose of the erythropoietic agent was extended to 12 weeks. In fact, it has been reported that responses to rhEPO can occur after prolonged administration of the drug [17]. Nevertheless, in this series all responses obtained with the starting dose of DA occurred by the eighth week of treatment. Dose escalation (300 lg/week) resulted in only a small proportion of patients obtaining a MiR, and one patient improving the response from MiR to MaR. Our results confirm previous reports about the safety profile of DA. In particular, we did not observe thromboembolic events or cases of pure red cell aplasia. A mild and transient increase in arterial blood pressure that did not require medical therapy was observed only in two responders, who had a rapid increase of their hemoglobin levels. As with most trials with rhEPO, in our study low levels of endogenous EPO (<200 IU/l) predicted response to the erythropoietic agent, while an elevated transfusion requirement (‡4 U/ month) predicted a non-response [3, 4]. In multivariate analysis only the former stood out as a statistically significant variable. This is also in line with the results of a recently published report, which evaluated a single weekly dose of DA (150 lg/week) in 37 patients with low- or intermediate-risk MDS [18]. In that study, other significant predictors of response in multivariate analysis were a low bone marrow blast count, low or absent transfusion requirements, and a hypoplastic bone marrow. However, when we combined the data from both trials, only low endogenous EPO levels retained a predictive value in a multivariate analysis (data not shown). The exact mechanisms of action of erythropoietic agents in MDS have not been completely elucidated, although there is indication that they involve inhibition of apoptosis of the dysplastic clone [19]. The results of our laboratory investigations essentially replicate those obtained in studies with rhEPO, showing

that response to DA treatment is associated with higher concentrations of BFU-E in the peripheral blood and a remarkable decrease of the bone marrow fraction of apoptic CD34+ cells [12, 20]. However, whether these findings represent a stimulation of residual polyclonal hematopoiesis or an actual reduction in the degree of ineffective hematopoiesis remains undetermined. We would like to emphasize the fact that the primary objective of palliative treatment is to improve the patient’s QoL. Therefore, we profiled fully the effects of DA on QoL parameters with two validated instruments, LASA and FACT-An. Not unexpectedly, responders to DA therapy experienced significant improvements in their QoL. All three LASA scores (energy levels, daily activities and overall wellbeing) showed significant improvements from baseline to study end. Similarly, significant increases were reported for FACT-An and its subscales. Furthermore, improvements in both FACT-An scores and in LASA scores were directly and positively correlated with increases in hemoglobin levels. Interestingly, the anemia subscale and particularly the fatigue subscale showed a greater increment than FACT-G, reflecting the fact that fatigue is one of the hallmark symptoms of anemia. There is mounting agreement that P values indicating statistically significant changes in QoL measures do not necessarily indicate that these changes have clinical significance or relevance [21]. However, there is no universally accepted approach for determining the clinical impact of these findings, and a clinically significant change in QoL is broadly defined as a difference score that is large enough to have an implication for the patient’s treatment or care [22]. A key issue is that clinical significance refers to the fact that any of a number of clinical implications may occur as a result of assessing the patient’s QoL. In our study, an hemoglobin increase of 1 g/dl, which represents the clinical response that can be expected from transfusion of 1 U of packed RBC, was considered a reasonable and clinically meaningful outcome on which to evaluate QoL results. Our data indicate that DA therapy produced not only a statistically significant improvement of QoL scores, but also significant clinical benefits. While the literature abounds with QoL studies in cancer patients [23], a few studies specifically pertaining MDS are available to compare our results. Two reports have confirmed the correlation between increased hemoglobin and improved QoL in MDS patients treated with rhEPO alone [24] or in combination with granulocyte colony-stimulating factor [25], although a recent randomized study has not supported these findings [26]. In conclusion, our results indicate that DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients’ QoL. Additional trials and a longer follow-up are warranted to establish the optimal dose and schedule of the drug, as well as its long-term effects and relative efficacy compared with rhEPO.

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