Annals of Hematology

, Volume 92, Issue 5, pp 621–631

High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM

Authors

  • C. Kelaidi
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • O. Beyne-Rauzy
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • T. Braun
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • R. Sapena
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • P. Cougoul
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • L. Adès
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • F. Pillard
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • C. Lambert
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • J. C. Charniot
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • A. Guerci
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • B. Choufi
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • A. Stamatoullas
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • B. Slama
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • B. De Renzis
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • S. Ame
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • G. Damaj
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • F. Boyer
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • M. P. Chaury
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • L. Legros
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • S. Cheze
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • A. Testu
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • E. Gyan
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • M. C. Béné
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • C. Rose
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
  • F. Dreyfus
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
    • GFM Service d’Hématogie Clinique, Hôpital Avicenne, Assistance Publique des Hôpitaux de ParisUniversité Paris 13
Original Article

DOI: 10.1007/s00277-013-1686-4

Cite this article as:
Kelaidi, C., Beyne-Rauzy, O., Braun, T. et al. Ann Hematol (2013) 92: 621. doi:10.1007/s00277-013-1686-4

Abstract

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 μg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Keywords

DarbepoetinMyelodysplastic syndromesAnemiaQuality of lifeExercise capacity

Introduction

Myelodysplastic syndromes (MDS) are clonal bone marrow stem cell disorders characterized by ineffective hematopoiesis resulting in blood cytopenias and by frequent acute myeloid leukemia (AML) transformation [1, 2]. According to the International Prognostic Score System (IPSS), MDS are grouped in lower-risk (IPSS low and intermediate-1) and higher-risk disease (IPSS intermediate-2 and high) [3]. While AML transformation is the main concern in higher-risk MDS, cytopenias, mostly anemia, represent the main problem in lower-risk MDS patients. The role of anemia in MDS symptoms (e.g., fatigue, dyspnea, angina pectoris) and its impact on quality of life are well established [4]. The effect of anemia on exercise capacity of MDS patients and changes of this capacity with treatment of anemia, remains, however, less well studied [5].

Erythropoiesis-stimulating agents (ESA), with or without granulocyte colony-stimulating factor (G-CSF), reproducibly induce erythroid response rates of 40 to 50 % in lower-risk MDS patients with anemia, with a median response duration of 24 months [612]. Established predictive factors of response include lower serum erythropoietin (EPO) level and limited or no transfusion burden [6]. Previous phase II trials demonstrated the efficacy of darbepoetin (DAR) alfa dosed at 150–300 μg/week [5, 1319]. We tested in this trial the efficacy of a modified dosage of darbepoetin alfa of 500 μg every 2 weeks with or without G-CSF. This alternative schedule, with less frequent injections, was chosen to improve patient compliance and comfort and reduce healthcare resource utilization while maintaining almost similar weekly dose, compared to our previous experience [15]. Efficacy was evaluated in terms of erythroid response, quality of life, and exercise function (measured by VO2max and the 6-min walking test) at baseline and under treatment.

Patients and methods

Study design

This phase II clinical trial (Clinicaltrials NCT00443339) was conducted in 17 centers of the Groupe Francophone des Myélodysplasies (GFM) in France from November 2006 to January 2009. Darbepoetin and filgrastim were provided by Amgen (Thousand Oaks, CA, USA) which, however, did not participate in the study design and in data reporting and analysis. The study protocol was approved by an ethical committee (Comité de Protection des Personnes, n°10, Aulnay sous Bois, France).

Eligibility criteria included (a) MDS according to WHO 2001 classification; (b) anemia, with hemoglobin level <10 g/dL with or without red blood cell (RBC) transfusion need; (c) IPSS low or intermediate-1; (d) serum EPO level lower than 500 IU/L; and (e) ability to carry physical function tests. Patients with chronic myelomonocytic leukemia (CMML) were eligible if they had <10 % bone marrow blasts and WBC count ≤13 G/L. Patients with any of the following conditions were excluded: treatment-related MDS; uncontrolled arterial hypertension; congestive heart failure, arrhythmia; serum creatinine level ≥120 % upper normal value; nutritional deficiency-related anemia or additional causes of anemia (hemolysis, hemorrhage, hemoglobinopathy); pregnancy; history of seizures or of a thrombotic event; and treatment with an ESA in the previous 8 weeks. All patients gave written informed consent.

Patients received darbepoetin alfa 500 μg every 2 weeks subcutaneously for 12 weeks. Non-responders at 12 weeks were to continue darbepoetin at the same dosing for an additional 12 weeks, but with the addition of filgrastim, initially dosed at 300 μg twice weekly and subsequently adjusted to maintain WBC counts between 5 and 10 G/L. Darbepoetin was definitively discontinued after 24 weeks of treatment in non-responders to this combination.

In responders, darbepoetin dosing was adjusted to maintain hemoglobin levels between 11 and 12 g/dL. According to the adjustment algorithm, darbepoetin was discontinued if Hb raised above 12 g/dL, until Hb level fell below 11 g/dL, and then resumed by increasing intervals by 1 week between injections. The study duration was 52 weeks, after which patients still responding could continue treatment. RBC transfusions were to be made according to ANSM (French Health authority) recommendations at hemoglobin level ≤8 g/dL or at higher levels if dictated by limited cardiopulmonary reserve or severe symptoms [20].

Follow-up and assessment of outcomes

The primary endpoint was the proportion of patients with erythroid response according to IWG 2006 criteria after 12 weeks of treatment [21]. Secondary endpoints were erythroid response rate at 24 weeks (after addition of G-CSF in non-responders), safety, quality of life, physical functioning, and patient long-term outcome, including response duration, cumulative incidence of AML, and overall survival (OS). Progression was defined according to IWG 2006 criteria. The recently proposed Revised International Prognostic Score System (IPSS-R) was also assessed for erythroid response prediction and association with patient outcomes [22].

For physical functioning assessment, maximal and/or submaximal exercise tests were performed, respectively VO2max, for physically fit patients, and a 6-min walking test (measuring the distance walked in 6 min) in patients incapable of performing maximal exercise testing [23, 24]. The Short Physical Performance Battery test, which consists in three simple tasks (walking speed through a 4-m distance, time to perform five chair stands and equilibrium), was used in frail patients, unable to undergo either exercise test, e.g., VO2max or the 6-min walking test [25]. VO2max measurement was made on a cycle ergometer, according to the French Society of Sport Medicine protocol [26]. Symptom-limited VO2max was measured instead of VO2max when only a peak VO2 value, rather than the maximal theoretical value, could be reached by the patient. The Borg scale was used to assess dyspnea. Contra-indications to VO2max measurement were a history of coronary artery disease or cardiac failure, tachycardia or hypertension on the day of testing, a physical handicap precluding cycling (rheumatologic disease, peripheral artery disease, respiratory insufficiency), and hemoglobin level <8 g/dL. In patients with Hb < 8 g/dL, baseline VO2 max measurement was made approximately at the midpoint between consecutive RBC transfusions. A cardiology visit with echocardiography including left ventricular mass measurement was systematically performed before each VO2max measurement.

Quality of life was assessed by the SF-36 and the Anemia version of the Functional Assessment of Cancer Therapy (FACT-An) questionnaires [27, 28]. Physical functioning and quality of life assessments were scheduled at baseline and after 12 and 24 weeks of treatment.

Statistical analysis

A sample size of 99 patients was chosen to provide a power of 95 % to detect a 10 % increment in response rate, as compared with response rates of about 50 % in previous studies with darbepoetin alfa. Statistical analysis was based on the intention-to-treat principle. Safety was considered in patients who received at least one dose of treatment. Quality of life and physical functioning were analyzed in those patients who filled in at least one questionnaire or performed at least one of the physical tests at baseline and during follow-up.

Patient characteristics and response rates were compared using Fisher’s exact test. Logistic regression was used for multivariate analysis of putative predictors of response. Time from diagnosis to onset of treatment was not pre-defined as a model covariate because it was considered as correlated with other variables like age, disease severity, and time to referral and therefore potentially misleading. Response duration was calculated from time of response achievement, assessed either at 12 or 24 weeks. Response duration and OS were measured by the Kaplan–Meier method [29]. OS differences between patient groups were compared using the log-rank test [30]. Cumulative incidences (CI) of AML transformation were estimated taking into account the competing risk of death and compared using the Gray test [31]. Repeated-measures analysis of variance was used to test the within-subject and between-subject differences of quality of life and physical functioning scores, with time as the within-subject factor (from baseline to weeks 12 and 24) and response to darbepoetin as the between-subject factor (responders vs. non-responders). All calculations were performed using R version 2.8.1.

Results

Patient characteristics

Ninety-nine patients were included by 17 centers of the GFM. Four patients were excluded, one for disease progression before starting treatment and three for higher-risk MDS after IPSS revision. Baseline characteristics of the remaining 95 patients are shown in Table 1. Median age was 72 years. Karyotype was normal in 75 % of the patients, and IPSS was low and intermediate-1 in 54 and 46 % of the cases, respectively. IPSS-R was very low, low, intermediate, and high in 11, 60, 18, and 5 %, respectively, and could not be determined in 6 % of patients. Median Hb level was 9.2 g/dL (range 6.2–10), and 46 % of the patients had received at least one RBC transfusion during the previous 8 weeks (median 4 RBC units transfused in the previous 8 weeks). Median levels of serum EPO and ferritin were 60 IU/L (range 3–461) and 549 ng/mL, respectively.
Table 1

Baseline patient characteristics

N = 95

% or median, IQR

Median age

72 (66–77)

Male gender

56 %

WHO classification

 RA

25 %

 RARS

33 %

 RCMD

16 %

 RCMD-RS

7 %

 5q-syndrome

2 %

 RAEB-1

15 %

 CMML

2 %

Hb (g/dL)

9.2 (8.4–9.7)

ANC (G/L)

2.8 (1.9–4.4)

Platelets (G/L)

257 (156–358)

Reticulocytes (G/L)

36 (2–143)

% bone marrow blasts

2 (1–4)

Karyotype

 Normal

75 %

 −Y

3 %

 Isolated del 20q

5 %

 Isolated del 5q

3 %

 + 8

5 %

 Others

6 %

 Failure

3 %

Cytogenetic risk (IPSS)

 Favorable

85 %

 Intermediate

15 %

Cytogenetic risk (IPSS-R)

 Very good

4 %

 Good

84 %

 Intermediate

12 %

IPSS

 Low

54 %

 Int-1

46 %

IPSS-R

 Very low

11 %

 Low

60 %

 Intermediate

18 %

 High

5 %

Serum EPO level

60 (3–460)

 ≤100 IU/L

57 %

% RBC transfusion dependent

46 %

Nb of RBC units transfused during the previous 6 months (in transfused patients)

3 (1–14)

Iron chelation

5 %

Median ferritin level (ng/mL)

549 (223–795)

 ≥1,000 ng/mL

19 %

 <300 ng/mL

30 %

 <100 ng/mL

12 %

Erythroid response

Forty-six of the 95 patients (48 %) (95 % confidence intervals 38–58 %) reached the primary endpoint of erythroid response at 12 weeks of treatment, according to IWG 2006 criteria. Forty (82 %) of the 49 non-responders at 12 weeks had addition of filgrastim to darbepoetin alfa, and nine of them (22 %) were responders after 12 weeks of combined treatment, increasing the overall response rate to 56 % at 24 weeks. According to the previously used IWG 2000 criteria [32], the response rate was 60 and 59 % at 12 and 24 weeks of treatment, and major responses were seen in 41 and 49 % of all cases at 12 and 24 weeks of treatment, respectively.

Median time to response was 5 weeks (range 1–20), including eight patients without baseline transfusion requirement who reached response criteria (i.e., increase in Hb level by at least 1.5 g/dL) within the first 2 weeks of treatment. Hemoglobin level exceeded at some point 12 g/dL in 59 % of the responders. Three patients had an increase in Hb greater than 2 g/dL after the first darbepoetin injection, reaching a Hb level of 11.6, 12.3, and 12.8 g/dL, respectively, 2 weeks after the first injection. Serum EPO level was <100 IU/L in all of them. None of these patients had reduced renal function. No clinical adverse events were associated with those rapid early responses. During maintenance treatment, the interval between darbepoetin injections of 500 μg was greater than 2 weeks in 48 % of the responders, range 2.4–20 weeks, with nine patients requiring injections every 12 weeks or more.

In univariate analysis, response rate at 12 weeks was significantly influenced by serum EPO level (P < 0.0001 by Student’s t test). Receiver operating curve analysis showed that serum EPO level of 100 IU/L was the most discriminant cutoff value for response prediction (response rate 66 vs. 21 % for EPO < 100 vs. ≥100 IU/L, P < 0.0001), as compared to cutoffs of 50, 60 (median value), or 200 IU/L. Other factors associated with response rate were RBC transfusion dependence and its importance, baseline reticulocyte count, and baseline serum ferritin level (Table 2). Patients with RARS had lower response rate than RA patients (P = 0.03), whereas RAEB-1 showed a trend toward lower response rate than all other WHO subgroups (31 vs. 56 %, P = 0.07). IPSS karyotype, IPSS-R karyotype, and IPSS-R were not associated with response rate. However, only one of the five patients with trisomy 8 was a responder at 12 weeks. Response rate at 24 weeks was associated, in addition to previous parameters, with WHO classification (72, 86, 57, 60, and 13 % responses in RCMD, pure RA, RARS, RCMD-RS, and RAEB-1, respectively, P = 0.005), IPSS (64 and 38 % for low and intermediate-1, P = 0.03), and IPSS-R (82, 62, 29, and 0 % responses in very low, low, intermediate, and high, respectively, P = 0.002). Of note, response rate in RAEB-1 patients and patients with high IPSS-R sharply declined between 12 and 24 weeks due to early relapses. In multivariate analysis, only serum EPO level was significantly associated with erythroid response rate at 12 weeks (serum EPO level >100 IU/L: odds ratio (OR) 0.6, 95 % confidence interval 0.5–0.7, P < 0.0001). At 24 weeks, in addition to serum EPO level (>100 IU/L: OR 0.7, 95 % confidence interval 0.6–0.9, P = 0.01), RAEB-1 was independently and adversely associated with response rate (OR 0.6, 95 % confidence interval 0.4–0.8, P = 0.007).
Table 2

Prognostic factors of response (according to IWG 2006 criteria) at 12 and 24 weeks of treatment by univariate analysis

 

12 weeks

24 weeks

Response rate (%)

P

Response rate (%)

P

WHO classification

 

0.17

 

0.002

 RA

79

 

86

 

 RARS

43

 

57

 

 RCMD

45

 

72

 

 RCMD-RS

60

 

60

 

 5q-syndrome

50

 

50

 

 RAEB-1

33

 

13

 

 CMML

67

 

83

 

Hb

 

0.0003

 

0.001

 <8.5 g/dL

19

 

32

 

 ≥8.5 g/dL

60

 

65

 

% BM blasts

 

0.46

 

0.001

 <5 %

49

 

61

 

 ≥5 %

33

 

8

 

Cytogenetic risk (IPSS)

 

0.60

 

0.70

 Favorable

49

 

60

 

 Intermediate

40

 

54

 

Cytogenetic risk (IPSS-R)

 

0.19

 

0.25

 Very good

100

 

100

 

 Good

47

 

52

 

 Intermediate

45

 

63

 

IPSS

 

0.18

 

0.03

 Low

52

 

64

 

 Int-1

38

 

38

 

IPSS-R

 

0.13

 

0.002

 Very low

82

 

82

 

 Low

46

 

62

 

 Intermediate

41

 

29

 

 High

20

 

0

 

Serum EPO level

 

<0.0001

 

0.001

 <100 IU/L

66

 

70

 

 ≥100 IU/L

21

 

32

 

Transfusion dependence

 

0.006

 

0.006

 Yes

61

 

67

 

 No

33

 

39

 

Nb RBC transfused during the previous 6 months

 

0.001

 

<0.0001

 <2

65

 

79

 

 ≥2

27

 

23

 

Serum ferritin

 

0.02

 

0.03

 <190 ng/mL

76

 

82

 

 ≥190 ng/mL

40

 

50

 

The proportion of non-responders rescued by G-CSF did not differ with WHO classification, IPSS, IPSS-R, and baseline serum EPO level. However, none of the ten non-responders with marrow blasts >2 % responded to G-CSF addition vs. eight of the 13 (39 %) non-responders with marrow blasts ≤2 % (P = 0.01).

Quality of life

Quality of life was evaluated by using SF36 and FACT-An at baseline and after 12 and 24 weeks of treatment. Results are shown in Table 3S and Fig. 1. Higher scores indicate a better quality of life.
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-013-1686-4/MediaObjects/277_2013_1686_Fig1_HTML.gif
Fig. 1

Repeated measures of SF-36 sub-classes (a) and FACT-An (b) according to response. Solid line responders; dashed line non-responders

Physical Functioning and Bodily Pain, which evaluate physical health, and Vitality, reflecting both physical and mental health, were the SF-36 scales whose evolution over time was best correlated with erythroid response (mean difference over time in responders vs. non-responders for Physical Functioning 9.6 vs. −11.2, P = 0.0002 for the interaction between group and time; Bodily Pain 7.9 vs. −7.8, P = 0.04; Vitality 11.1 vs. −7.1, P < 0.0001) (Fig. 1a). By contrast, scales evaluating mental health were not significantly correlated with erythroid response. Likewise, the Physical Component Summary was improved over time in responders, as compared with non-responders (mean difference 3 vs. 0.4, P = 0.04), but not the Mental Component Summary (mean difference 3.5 vs. 0.7, P = 0.23).

For FACT-An score, there was a steady improvement of all scales over time in responders as compared with non-responders, i.e., in FACT-General (mean difference over 6 months in responders vs. non-responders 4.1 vs. −5.6, P = 0.007), FACT-An Trial Outcome Index, a composite score of Physical Well-Being, Functional Well-Being and Anemia subscales (mean difference over 6 months in responders vs. non-responders 14.4 vs. −5.5, P = 0.001), and FACT-Anemia total score (mean difference over 6 months in responders vs. non-responders 13 vs. −8.1, P = 0.002) (Fig. 1b).

Physical functioning

Results of physical functioning tests are shown in Table 3S and Fig. 2. The 6-min walking test was performed in 76 patients. There was a trend for increase over time of the distance walked in 6 min in both responders and non-responders (data not shown), but the increase was not higher in responders than in non-responders (mean difference between baseline and 6 months of 22.7 and 32.7 m in responders and non-responders, P = 0.81 for the interaction between group and time) (Fig. 2a). The Short Battery Physical Test, performed in 54 patients, did not show any difference between responders and non-responders.
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-013-1686-4/MediaObjects/277_2013_1686_Fig2_HTML.gif
Fig. 2

Repeated measures of VO2max (a) and the 6-min walking test (b) according to response. Solid line responders; dashed line non-responders

VO2max was serially measured in 15 patients, nine responders and six non-responders. The difference over time between responders and non-responders was significant (mean difference between baseline and 6 months of 212.1 and −89.5 mL/min in responders and non-responders, respectively, P = 0.01 for the interaction between group and time), with VO2max increasing in responders and decreasing in non-responders (Fig. 2b). Echographically measured left ventricular mass index and ejection fraction did not show any significant modification over time in either group of patients (data not shown).

Response duration, progression to AML, and survival

Patient outcomes are summarized in the flow chart of Fig. 3. Median follow-up was 52 months. Only one responder prematurely stopped treatment, after 13 weeks, because of a hip fracture. Median response duration, assessed from response evaluation at 12 weeks, was not reached (95 % confidence intervals 30 months–not reached), with 25 patients having persistent response at 3 years of follow-up (Fig. 4a). Median response duration was not reached in RA, 27.3 months in RARS, 56 months in RCMD, 19.8 months in RCMD-RS, and 20.6 months in RAEB-1 (P = 0.14). Patients with 15 % ring sideroblasts or greater (RS-MDS) (RARS and RCMD-RS) had a shorter response duration (median 30.4 months) than non-RS-MDS without excess of blasts (RA and RCMD) (median not reached, P = 0.02).
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-013-1686-4/MediaObjects/277_2013_1686_Fig3_HTML.gif
Fig. 3

Flow chart of outcomes

https://static-content.springer.com/image/art%3A10.1007%2Fs00277-013-1686-4/MediaObjects/277_2013_1686_Fig4_HTML.gif
Fig. 4

Response duration (a) and OS (b) and cumulative incidence of AML (c) according to response. Solid line responders; dashed line non-responders

The 3-year CI of AML was 14.5 %. Three-year OS was 70 %, and median OS was not reached (Fig. 4b, c). The 3-year mortality considered related to MDS (i.e., by hemorrhage, infection, AML transformation) was 9.9 % in responders and 27.9 % in non-responders whereas no differences between responders and non-responders were found for other causes of death (cardiovascular, neoplasia, others) (not shown).

Adverse events

Serious adverse events included non-fatal pulmonary embolism, non-fatal stroke, and coma from unknown cause leading to death, reported in one patient each (all responders) after 10, 6, and 9 months of treatment, respectively, with corresponding Hb levels of 11.5, 12.6, and 11.5 g/dL. One fatal stroke was seen in a patient with severe cardiovascular comorbidity, 36 days after the first injection of darbepoetin. In that patient, treatment had been discontinued for injection-site reaction and the last Hb value before death was <10 g/dL. Other adverse events included rash, injection-site reactions, and filgrastim-related arthralgia/myalgia and hyperleucocytosis in 3, 2, 3, and 1 patient, respectively. One patient withdrew his consent.

Discussion

In this phase II trial with darbepoetin dosed 500 μg every 2 weeks, we report a response rate of 48 and 56 % after addition of G-CSF and a median response duration that was not reached after a median follow-up of 4.3 years. Half of the responders could increase intervals between injections to longer than 2 weeks. Despite the fact that the total dose of ESA was reduced by approximately 15 %, compared in particular with our previous trial using darbepoetin 300 μg/week, the response rate, using the more stringent IWG 2006 criteria, was equivalent to that reported in previous studies [9, 15]. Comparisons between response rates observed in published studies of darbepoetin in low risk MDS are shown in Table 3. Although inclusion criteria and patient characteristics somewhat differed between those studies, a dose-effect is suggested, with generally higher response rates using weekly doses of 250 to 300 μg, compared to 150 μg. The response rate to ESA in MDS, however, also depends on the proportion of transfusion dependent patients at baseline and inclusion thresholds for hemoglobin level. Thus, the response rate in the present study (56 %) where 10 g/dL was used as inclusion Hb level threshold, and only one half of the patients had baseline transfusion dependency, was similar to that observed by Gabrilove et al. (63 %) using darbepoetin at only 500 μg every 3 weeks, but in a study where only a small minority of patients were transfusion dependent and the Hb threshold for inclusion was 11 g/dL.
Table 3

Studies with darbepoetin in MDS

 

Type of study

Nb of patients

% transfused patients

Darbepoetin dosing

Response rate: IWG 2000 (%)

Response rate: IWG 2006 (%)

Musto, 2005 [13]

Pilot

37

62

150 μg/week

40.5

NA

Stasi, 2005 [12]

Phase II

53

86

150–300 μg/week

45

NA

Giraldo, 2006 [14]

Retrospective

69

43

150–300 μg/week

55

NA

Mannone, 2006 [15]

Phase II

62

66

300 μg/week

74

NA

Gabrilove, 2006 [16]

Phase II

206

4

500 μg/3 weeks

63

NA

Gotlib, 2009 [17]

Phase II

24

67

250–1,100 μg/week (median 390 μg/week)

67

58

Oliva, 2010 [18]

Phase II

41

41

300 μg/week

70

NA

Villegas, 2011 [19]

Phase II

44

73

300 μg/week

73

NA

Nilsson-Ehle, 2011 [5]

Phase II

36

47

300 μg/week

NA

56

Kelaidi, 2013

Phase II

99

46

500 μg/2 weeks

59

56

NA not available

Serum EPO level was the only independent predictive factor of response at 12 weeks of treatment, as in previous studies. The “best” threshold serum EPO level for predicting response to ESAs is often disputed, varying from 100 to 500 IU/L in various series. In the present series, 100 IU/L was the most discriminant one, and the response rate was as low as 30 % in patients with a level ≥100 IU/L. On the other hand, in our recent experience, 60 % of patients with lower risk MDS and hemoglobin ≤10 g/dL had a serum EPO level <100 IU/L [33], whereas that percentage exceeded 80 % in newly diagnosed patients included in the EU low risk registry (T. De Witte, unpublished data), suggesting that a majority of lower risk MDS with anemia may be candidates to ESAs as first-line treatment.

We found that early relapses occurred in patients with RAEB-1 and with IPSS-R high. Conversely, all but two of the 11 patients with very low IPSS-R were responders at 24 weeks.

The percentage of non-responders rescued by the addition of G-CSF (22 %) was relatively small and similar to that of our previous study on darbepoetin dosed at 300 μg weekly (20 %) [15]. Another work suggested that G-CSF addition is less effective when the ESA dose is high [34]. On the other hand, the addition of G-CSF in the Stanford study yielded response in 47 % of cases, essentially in RARS [17]. By contrast, in our study, RARS and RCMD-RS did not have lower response rates to DAR alone, and did not particularly benefit from the addition of G-CSF (although regarding the latter point, patient numbers precluded any answer).

Median response duration, not reached after a median follow-up of more than 4 years, was unexpectedly long. Response duration had not been documented beyond 1 year of follow-up in other registered studies using high-dose darbepoetin, with the exception of the Stanford study where median response duration was 19 months, but in a relatively small series. It is currently unknown whether darbepoetin, with its inherent pharmacokinetic characteristics, could induce longer responses than EPO α or β.

The cumulative incidence of AML was approximately 15 % and median overall survival not reached after a median of 4.5 years of follow-up, consistent with the low-risk profile of the population. In particular, patients still responding after 2 years of treatment had a particularly favorable subsequent outcome (only one death out of 33 patients). Non-responders had an excess of mortality mainly attributed to MDS-related causes. Two retrospective studies and one prospective study showed that responders to ESAs have better long-term outcomes than non-responders [911]. Those results could also suggest that response to ESAs selects patients with intrinsically better prognosis, whereas non-responders are deemed to have more MDS-related complications, especially AML transformation.

Anemia is commonly associated with fatigue and impaired quality of life and exercise capacity. However, improvement of quality of life by ESAs in anemia due to MDS has been disputed [7]. Here, using two different tests (i.e., SF-36, the most widely used psychometric tool for quality of life across disciplines, and a general oncological test, FACT, in its general and anemia-related versions), we found increasing scores over time of approximately 10 points for physical components of SF-36 in responders vs. decreasing scores in non-responders, whereas the increase was more modest for mental components. Likewise, increase in anemia-specific components of FACT exceeded 10 points in responders as compared with inverse time-score relationships in non-responders. A quality of life improvement using FACT-An was also found by Spiriti et al. in responders compared to non-responders and in a randomized trial between treated and non-treated patients (though without significant difference) [8, 11]. On the other hand, the absence of significant improvement in quality of life in the treated groups of a randomized GFM and a phase II Nordic MDS group trial of EPO alpha was possibly due to small patient numbers and “dilution” of the effect in responders by that of non-responders [5, 7]. Very intensive RBC transfusion support in the control arm, not allowing Hb level to fall below 12 g/dL, but rarely achieved in routine practice, could also have explained the lack of significant difference in the Nordic study [5]. In other situations, the durable rise in hemoglobin level obtained in responders to ESAs may improve quality of life compared to variable hemoglobin levels associated to repeated RBC transfusion.

The increase of blood oxygen-carrying capacity enhances maximal oxygen uptake. We could demonstrate using VO2max, despite the small number of patients able to undergo serial measures of effort spirometry, that, in parallel with quality of life, physical effort capacity was improved in responders as compared with non-responders despite regular RBC transfusions in the latter group. In the Nordic group study, using an intensive transfusion program, there was no specific pattern in maximal oxygen uptake with hemoglobin maintained ≥12 g/dL [5]. However, the significant difference over time between responders and non-responders in our study suggests that improving hemoglobin values by transfusion alone in routine practice may be insufficient to induce sustained increase in cardiorespiratory fitness. In contrast, the 6-min walking test and the short battery physical performance test proved less sensitive in this non-institutionalized elderly population, selected on the basis of being able to undergo at least some exercise tests. Whether those widely used geriatric tests can be effectively used by large MDS patient numbers merits further investigation.

As in previous studies, darbepoetin was well tolerated. Venous and arterial thromboembolic events attributable to darbepoetin have been reported, though using either higher doses or with a hemoglobin target higher than 12 g/dL. Close monitoring of hemoglobin values according to current recommendations should guarantee safe delivery of high dose schedules.

In the present study, responses occurred within the first 2 weeks of treatment in 20 % of the responders, with Hb increasing above 12 g/dL after the first darbepoetin injection in three patients. None of these patients had reduced renal function. Although there is no formal contraindication to use high dose ESA in elderly MDS patients with reduced renal function, extra caution is necessary with respect to abrupt Hb increases (>2 g/dL in 2 weeks) and dose adjustment rules in such patients.

In conclusion, darbepoetin 500 μg every 2 weeks ±G-CSF was an effective and safe induction regimen for anemia in lower-risk myelodysplastic syndromes, associated with favorable long-term clinical outcomes in responders, including patient-reported quality of life and objectively measured exercise capacity. Alternative treatments should be rapidly considered in non-responders due to excessive MDS-related mortality.

Conflict of interest

The authors declare no conflict of interest.

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