Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment

Leukemia Research 25 (2001) 13 – 18 www.elsevier.com/locate/leukres

Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment Robert Hast a,*, Jonas Wallvik b, Annika Folin a, Per Bernell a, Leif Stenke a a

Di6ision of Hematology, Department of Medicine, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden b Department of Medicine, Sunds6all Hospital, Sunds6all, Sweden Received 6 January 2000; accepted 10 June 2000

Abstract The outcome of continued EPO therapy was studied in 18 responding MDS patients. The EPO dose was reduced in a stepwise fashion to find the lowest possible maintenance dose. Relapses of anemia were associated with either progressive disease or reduction of the administered EPO dose. In the latter group second responses to renewed EPO therapy were readily achieved. Long-term responses were seen in about a third of the patients. Thus, it seems safe to reduce the EPO dose among responding patients. This approach may have advantages both from a medical and a socio-economic perspective. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Myelodysplastic syndromes; Erythropoietin; Maintenance therapy; Long-term follow-up; Costs

1. Introduction Anemia in patients with myelodysplastic syndromes (MDS) can be successfully reduced when patients are treated with recombinant human erythropoietin (EPO). Response rates of only 10 – 30% in the first clinical studies of EPO therapy in MDS [1 – 4], and indeed the high costs for the treatment prompted a need to clarify which individuals were most likely to respond to EPO. Stenke et al. [5] reported that patients with relatively low serum EPO levels, normal cytogenetics, low bone marrow blast cell counts, and not in need of red blood cell transfusions were the ones that responded the best. The discriminatory power of a relatively low serum EPO concentration

Abbre6iations: AML, acute myeloid leukemia; EPO, erythropoietin; G-CSF, granulocyte colony-stimualting factor; INT, intermediate risk group; IPSS, international prognostic survival score; MDS, myelodysplastic syndromes; RA, refractory anemia; RAEB, RA with excess of blasts; RARS, RA with ringed sideroblasts. * Corresponding author. Tel.: + 46-8-51772602; fax: +46-8317303. E-mail address: [email protected] (R. Hast).

and lack of transfusion need to predict a positive response to EPO was confirmed in a meta-analysis of some 200 MDS patients [6]. Also a low serum concentration of tumor necrosis factor-alpha seems to correlate with a favorable outcome of EPO therapy [7,8]. Even though it now seems possible to select subgroups of MDS patients with \ 50% chance to respond to EPO therapy using different combinations of prognostic variables, little is known about the remission duration and long-term outcome among the responders. There are only a few reports of long-term responses to EPO in MDS, either given alone or in combination with granulocyte colony-stimualting factor (G-CSF) [9–11]. Before EPO can be recommended outside clinical trials in MDS, it is important to know more about the outcome of continued EPO therapy in responding cases. Specific problems include finding the optimal maintenance dose of EPO, study the causes for failing continued EPO and whether these patients will respond to renewed EPO therapy, and defining which patients are most likely to obtain long-term responses. In the present report we have tried to address some of these queries by studying the outcome of continued EPO therapy in 18 MDS patients that responded to the initial treatment.

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R. Hast et al. / Leukemia Research 25 (2001) 13–18

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2. Materials and methods

2.1. Patients Eight-teen MDS patients [11 refractory anemia (RA), five RA with ringed sideroblasts (RARS), and two RA with excess of blasts (RAEB)] were included in the study (Table 1). All patients but two had participated in earlier published clinical trials on the role of EPO therapy in MDS [5,12–14]. For inclusion in the present study it was required that the patients had fulfilled our criteria for a positive response to the EPO therapy, i.e. either a sustained increase in hemoglobin by \ 15 g/l, or an eliminated transfusion requirement [5]. The first patient was started on EPO in August 1989 and the last one in June 1996. The median age was 79.5 years (range 68–87), 14 were females and four males. Abnormal bone marrow cytogenetics were found in five of 17 evaluated patients; three presented with del(5q) as a single aberration, while the other two had more complex changes, including one case with monosomy 7. Subgrouping according to the IPSS criteria [15] is shown in Table 1. The serum EPO levels ranged between 16 and 280 U/l (median 59 U/l). No patients had any signs of deficient stores of iron, vitamin B12 or folic acid. The study was approved by the Ethics Committee of the Karolinska Hospital, and all patients participated after informed consent.

month of therapy. The median duration time of the initial erythroid response was 7 months (range: 1–56+ ) (Table 1). At time of follow-up, three of the 18 patients were still in a responsive phase 30, 41, and 56 months, respectively, after fulfilling the response criteria (Fig. 1). Two of these cases were maintained on a lower EPO dose, while one had been without EPO therapy for 48 months. In seven patients anemia recurred when the initial EPO dose of 30 000 U/week was tapered off. In one case the decrease in hemoglobin level was seen when the maintenance EPO dose was 20 000 U/week, in three at 10 000 U/week, and in three after cessation of the therapy (Fig. 1). The remaining eight patients died during or shortly after the initial EPO treatment period. Two died early from cardiac failure after 3 and 4 months, while still responding to the EPO therapy. One other patient died suddenly from an intractable brain tumor after having been in hematological remission for 11 months, eight of which without EPO therapy. Three patients transformed to acute myeloid leukemia (AML) and died 10, 13 and 15 months, respectively, after the start of EPO therapy (Fig. 1). Two patients became refractory to EPO when they developed other progressive malignancies; one case suffered a relapse of malignant lymphoma after having responded to EPO for 21 months, while the other failed EPO therapy when she developed metastatic carcinoma of the colon (Fig. 1).

2.2. Study design All patients were initially given recombinant human epoietin-alpha (Eprex®) 10 000 U s.c. thrice weekly according to our standard protocol [5]. Once a patient had fulfilled the response criteria, the objective was to continue with an unaltered EPO dose for another 2 months, and then to reduce the dose in steps of 10 000 U/week on an individual basis, with the ultimate goal to try to stop the treatment entirely. If anemia returned at any time during dose tapering, it was recommended to give a second course of full-dose EPO therapy, i.e. 30 000 U/week s.c., followed by a new attempt to reduce the EPO dose in responding cases.

2.3. Statistics Differences between mean values were analyzed using the Student’s unpaired t-test, while correlations between individual survival and treatment response times were studied using simple regression analysis. 3. Results

3.1. Duration of initial EPO response All 18 MDS patients responded to EPO within the first

3.2. Outcome of reiterated EPO therapy A second course of EPO was given to six of the seven patients where the anemia recurred when the EPO dose was decreased, and all but one responded again (Fig. 1). Four of the patients that responded a second time did so within the first treatment month at EPO doses of 20 000–30 000 U/week. The fifth patient was given only 10 000 U/week, and in this case the time to second response was 6 months. Only one patient proved refractory to the renewed EPO therapy. The reason for the lack of effect in this case was not clear. At follow-up 5 years later he still had refractory anemia, without any need for red blood cell transfusions. The clinical effect of the second course was of short duration in one patient that died from progressive heart failure, while the other four cases maintained their erythroid responses to EPO for more than a year (Fig. 1). Case 10 experienced two more relapses of anemia when the EPO dose again was decreased or stopped. She responded on both occasions to renewed EPO treatment, and was at time of follow-up showing continuous erythroid response on a maintenance dose of 10 000 U/week after 66 months. In case 8 the anemia returned after a remission period of 12 months without EPO therapy. This patient was also able to respond again when EPO was restarted 3 years later.

78

87

84

87 76

86

87

82

85

73

83

77 62

77

81

71

73 68

1

2

3

4 5

6

7

8

9

10

11

12 13

14

15

16

17 18

F F

F

F

M

F M

F

F

F

F

F

F

M M

F

F

F

Sex

8/95 4/94

6/96

7/93

4/93

4/93 8/89

7/90

5/93

3/93

8/91

3/93

3/93

3/91 1/94

9/91

6/91

11/92

EPO start (m/yr)a

RA RA

RA

RARS

RA

RARS RAEB

RA

RA

RA

RARS

RAEB

RA

RA RARS

RA

RA

RARS

FAB subtype

b

m/yr, month/year. ND, not done. c IPSS, International prognostic survival score.

a

Age (years)

Patient no.

4 137

12

32

2

20 16

3

10

36

4

13

16

2 2

32

10

19

Pre-treatment duration time (months)

46,XX, del(5)(q13;q33) 46,XX 46,XX

46,XX

46,XX 47,XY, del(20)(q?),+mar ND

46,XX

46,XX, del(5)(q21) 46,XX

45,XX,-7, i(17q) 46,XX

46,XX

46,XY 46,XY

46,XX, del(5)(q22) 46,XX

46,XX

Karyotypeb

Low Low

Low

Low

ND

INT-1 INT-1

INT-1

Low

INT-1

Low

INT-2

INT-1

Low Low

Low

Low

Low

IPSSc

70 36

111

16

56

62 43

49

46

224

27

113

134

280 69

98

54

28

s-EPO (U/L)

41+ 56+

30+

19

13

11 11

9

7

7

6

5

4

3 4

2

2

1

Duration of initial EPO response (months)

– –

Decreased EPO dose Decreased EPO dose death AML development AML development Relapse of NHL –

Decreased EPO dose Death Decreased EPO dose Cessation of EPO AML development Cessation of EPO Ca colon

Cessation of EPO Death

Suggested cause of EPO failure

Table 1 Clinical and hematological description of the 18 MDS patients that were continued on EPO therapy after an initial response

– –

–

–

–

– –

Yes

Yes

–

Yes

–

–

– No

Yes

–

Yes

Second response to EPO

41+ 56+

30+

21

13

11 11

10

53+

7

39+

5

4

3 4

34

2

21

Total EPO response duration time (months)

42+ 57+

31+

25

15

12 13

14

66+

12

89+

10

11

4 60+

83

3

52

Survival time from start of EPO therapy (months)

Alive Alive

Alive

NHL

AML

Tumor cerebri AML

Heart failure

Alive

Ca colon

Alive

Ruptured ao. aneurysm AML

Dead, not known Heart failure Alive

Dead, not known Heart failure

Clinical outcome and cause of death

R. Hast et al. / Leukemia Research 25 (2001) 13–18 15

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R. Hast et al. / Leukemia Research 25 (2001) 13–18

3.3. Prediction of prolonged EPO response At time of follow-up 12 of the 18 patients had died. The median survival time after start of the initial EPO therapy was 20 months (Table 1). Patients with serum EPO levels B 100 U/L at start of treatment had significantly longer survival time after start of EPO therapy compared to those with serum EPO \100 U/L (PB 0.01; Student’s t-test). There was also a significant positive correlation between the survival time after EPO therapy and the total number of months the patients showed an erythroid response to EPO, including iterated courses (r 2 =0.528; P = 0.0006). In contrast the survival time after EPO therapy did not correlate to the pre-treatment duration time of MDS (r 2 =0.039; P= 0.431). The mean (SD) survival time after start of EPO in the IPSS low-risk subgroup was 47.0 (29.4) months compared to 12.4 (1.7) in the INT-1/INT-2 subgroups (Table 1; PB0.01). The mean (SD) duration of the EPO response was significantly longer in the IPSS low-risk subgroup than in the INT-1/INT-2 subgroups [low: 27.6 (19.2) vs. INT: 8.7 (3.4); P B 0.01] (Table 1).

There was no significant difference between the mean (SD) serum EPO levels in the different IPSS subgroups [low: 75.9 (74.0) U/L vs. INT-1/INT-2: 104.2 (69.1); P\ 0.05].

4. Discussion and conclusions We have studied the long-term outcome of continued EPO therapy in 18 responding MDS patients that were started on EPO between 1989 and 1996. The objective of the treatment schedule was to reduce the initial EPO dose step-wise on an individual basis in an effort to find the lowest effective maintenance dose. This meant that both the dose and the length of therapy came to vary between patients due to the wishes of the patients and the opinion of the doctors. One patient was kept on the initial dose for almost 2 years while another refused further therapy after 2 months. Nevertheless, we feel that it is possible to identify certain response patterns, which might form a basis for future prospective studies. The study confirms earlier reports that long-term erythroid responses to continued EPO therapy can be

Fig. 1. Schematical presentation of the clinical course of 18 MDS patients treated with EPO. The given EPO dose is indicated by the relative height of the bars (30 000, 20 000, 10 000 U/week). Patient responding to treatment with EPO ; patient not responding to EPO treatment b. A solid line indicates continued erythroid response after cessation of EPO therapy, while a dotted line means recurrence of anemia after EPO therapy had been stopped. An asterisk (*) shows that the patient was alive at time of follow-up.

R. Hast et al. / Leukemia Research 25 (2001) 13–18

achieved in about a third of the responding cases [9]. In our experience an EPO dose of 30 000 U/week s.c. is sufficient to achieve an primary response in about 30% of MDS patients [14], but others have found additional effect from using higher doses [10,11]. It is possible that our use of prognostic factors to identify MDS patients likely to respond to EPO [5], not only gave a higher response figure but also led to a selection of cases prone to respond to lower EPO doses. At time of follow-up five patients maintained their hemoglobin levels with a median response duration time of 36+ months, which is similar to what has been shown with combined G-CSF and EPO therapy [11,16]. Development of resistance did not seem to be a major clinical problem, since only one patient failed continued EPO therapy without any obvious cause. Instead it appeared that the two main reasons why an individual patient would stop responding to EPO were lowering of the EPO dose or progressive disease and death. In eight patients the lack of response to continued EPO therapy was clearly associated with terminal illness. Three cases transformed to AML and one other patient with secondary RARS died in a relapse of her malignant lymphoma. The other four patients died from unrelated disorders. It should be noted that all eight patients continued to respond until the last few months prior to death, presumably adding improved life quality [17]. In seven cases did we observe that the failure of EPO treatment was associated with our efforts to reduce the EPO dose. Most patients relapsed with clinically significant anemia at an EPO dose of 10 000 U/week or less. Therefore 20 000 U/week seemed to be the lowest EPO dose on which a majority of the MDS patients could be maintained. This dose is lower than what has earlier been suggested to be the required maintenance dose of EPO [11]. Moreover, five of our patients continued to respond for up to 5 years after the EPO therapy had been decreased to 10 000 U/week, or stopped entirely. Perhaps the EPO therapy triggered a shift towards a more effective erythropoiesis, which could be sustained with very little or no EPO supplementation. These differences between patients suggest that the optimal maintenance EPO dose must be titrated individually for each patient. An interesting observation was that five of the six patients, where the anemia returned after the EPO dose had been reduced or stopped, were able to respond for a second time to full-dose EPO therapy. The existence of a dose-response relationship was further supported by the findings in two individual cases. One patient responded three times to renewed EPO therapy after having failed repeat attempts to reduce the EPO dose, and another responded when EPO therapy was resumed after more than 2 years off treatment. Only one patient proved refractory to renewed EPO therapy.

17

Since most relapsing patients will respond to a second attempt with EPO it seems safe to try to reduce the initial EPO therapy in effort to find the lowest possible maintenance dose. Most cases in the present study could be classified into the low or INT-1 risk subgroups, according to the IPSS [15]. The over-all median survival time from diagnosis was 34.5 months, which is in agreement with earlier findings in the respective risk groups. We recently reported that serum EPO levels at start of therapy, but not the pre-treatment duration time of the disease, was a prognostic factor not only for response to EPO therapy, but also for survival in an unselected group of MDS patients [14]. In this study we could show that the same seemed to be true also for the MDS patients that had responded to EPO therapy. The relatively small number of patients studied did not allow a detailed characterization of the patients with long-term responses to EPO. However, it seemed that cases with a relatively low serum EPO or a low IPSS risk score at diagnosis responded the best to continued EPO therapy, and also had the longest survival. The results of the present study show that the EPO dose which is required to maintain an erythroid response could be titrated on an individual basis, and that in patients where this lead to return of the anemia, renewed full-dose EPO therapy seemed to have a high probability of success. The concept of step-wise reduction of the EPO dose in responding cases of MDS to find the lowest possible maintenance dose thus appears reasonably safe. This finding may be important since most patients and doctors do not want to take the risk of abandoning an effective therapy, without some indications that the treatment again could be applied successfully. Acknowledgements This study was supported by the Cancer Society in Stockholm (98:111, 99:151), the Swedish Cancer Society (4148-B98-01XAB), and Emil Andersson’s Fund. References [1] Bessho M, Jinnai I, Matsuda A, Saito M, Hirashima K. Improvement of anemia by recombinant human erythropoietin in patients with myelodysplastic syndromes and aplastic anemia. Int J Cell Cloning 1990;8:445. [2] Bowen D, Culligan D, Jacobs A. The treatment of anemia in myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol 1991;77:419. [3] Hellstro¨m E, Birgega˚rd G, Lockner D, Helmers C, O8 st A, , Wide L. Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol 1991;47:355. [4] Stein RS, Abels RI, Krantz SB. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood 1991;78:1658.

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