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Treatment of high risk myelodysplastic syndromes with idarubicin and cytosine arabinoside supported by granulocyte-macrophage colony-stimulating factor (GM-CSF)
Leukmur
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TREATMENT OF HIGH RISK MYELODYSPLASTIC SYNDROMES WITH IDARUBICIN AND CYTOSINE ARABINOSIDE SUPPORTED BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) Theofanis Economopoulos*, Efstathios Papageorgiou*, Nicholas Stathakist, Maria Constantinidou*, Agapi Parharidou*, Akrivi Kostourou*, John Dervenoulas* Sotos Raptis*
and
*Second Department of Internal Medicine, Propaedeutic, Athens University, Evangelismos Hospital, Athens: and TDepartment of Internal Medicine, School of Medicine, Larissa University, Larissa, Greece (Received 20 October 199.5. Accepted 11 November 1995) Abstract-In this prospective study, patients with ‘high risk’ primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m’ days l-3 and cytosine-arabinoside 200 mg/m* in 12 h infusion, days l-5. The GM-CSF 3 pg/kg S.C. was given on day 6 until the neutrophil count was 1 xlO’/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50-79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 xlO’/l was day 15 (range 3-22) after the first course of treatment and day 14 (range 4-21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months. In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in ‘poor risk’ MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection. Copyright c 1996 Elsevier Science Ltd.
Key words:
Chemotherapy,
GM-CSF,
high risk myelodysplastic
Introduction
syndromes,
treatment.
high incidence of acute myeloid leukemia (AML) and worse prognosis [l-4]. Multidrug chemotherapy, mostly combinations of anthracyclines and cytosine arabinoside (AraC), has been applied by many groups in the treatment of MDS, but has proved to be of limited efficacy [5]. However, relatively favorable results were obtained in patients with RAEBt and normal karyotype [6]. One reasonfor the poor outcome of MDS treated with intensive chemotherapy may be the prolonged duration of treatment-induced BM suppression,resulting in a high toxic death rate [7,8]. The recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the treatment of high risk MDS and older patients with AML, together with low dose AraC or multidrug
Analysis of large series of myelodysplastic syndromes (MDS) based on the FAB classification or on the proposed scoring systems, suggest that patients with excess of blasts in bone marrow (BM), such as refractory anemia with excess of blasts (RAEB), and those with RAEB in transformation (RAEBt), have a Abbreviations: GM-CSF, granulocyte-macrophage colonystimulating factor; MD& myelodysplastic syndrome; RAEB, refractory anemia with excess of blasts; RAEBt, refractory anemia with excess of blasts in transformation. Correspondence to: T. Economopoulos, Second Department of Internal Medicine, Evangelismos Hospital, Athens 106 76, Greece (Fax: 30-l-729-1808). 385
386
T. Economopoulos
chemotherapy [9, lo]. This combination shortens the duration of chemotherapy-induced granulocytopenia and probably decreases the number of toxic deaths, although this has not been shown in a randomized phase III trial. Idarubicin is a new anthracycline derivative which, when given in combination with AraC to patients with AML, was found to be as effective as daunorubicin, but probably less cardiotoxic [ 1 l-151. The object of this prospective study was to determine whether moderately intensive chemotherapy comprising idarubicin and AraC supported by GM-CSF, can improve the complete remission (CR) rate, remission duration and hence survival in selected high risk (RAEB and RAEBt) patients with MDS.
et al.
counts (< 5%) together with peripheral blood values of Hb >lO g/d1 without transfusions, neutrophil counts >1.5 x lo”/1 and platelets >lOO x lO”/l. Minimal myelodysplastic changes were considered compatible with CR. Partial response was defined as a 50% or more decrease of BM blasts, with reduction of blood transfusion requirements, neutrophil counts >l.O x lo”/ 1 and platelet count >50 x lO’/l. A time limit of 1 month was set for both types of responses. Toxic death included any death occurring during the study, mainly in aplasia, to which treatment might have contributed. Actuarial survival curves were constructed according to the Kaplan-Meier model. Differences in survival curves were tested for statistical significance using the two-tailed log-rank test.
Materials and Methods Results
Patients Between April 1991 and October 1994, 22 newly diagnosed patients with RAEB and RAEBt, classified according to the FAB criteria for MDS [16], were enrolled in the study. Only patients with primary MDS aged up to 75 years were accepted. However, one 79year-old man with excellent performance status was included in the study. Patients were excluded if they had a serum creatinine greater than 180 pmol/l, Karnofsky score <50%, hepatocellular enzyme levels >2.5 x normal [17] or any contraindication to anthracycline administration. The patients had not been treated with chemotherapy before the entry into the study. Written, informed consent was required for all patients before the start of therapy.
Study design Treatment was started within approximately 1 month of the time of diagnosis. The treatment regimen consisted of idarubicin 6 mg/m2 days l-3 and AraC 200 mg/m2, 12 h infusion, days l-5. The GM-CSF (Schering-Plough/Sandoz) 3 l&kg/day S.C. was started on day 6 until the neutrophil count increased to 1 x 109/1. A BM aspirate was performed on day 15 of cycle 1 and subsequently when appropriate to document response or resistance of the disease. Subsequently, identical cycles were administered with as short an intercycle interval as possible, the exact timing depending on the patient’s general state of health, the peripheral blood counts and the morphological appearance of the BM. If, after two cycles of treatment, the BM was unchanged, no further treatment was given. If, however, partial response (PR) was achieved, a third cycle was given. Postremission therapy consisted of two courses of the same regimen. Then patients were followed regularly with blood counts and BM aspirations when necessary. The response criteria were as follows: CR was defined as a normocellular BM with normalization of BM blast cell
There were 17 males and five females with a median age of 64 years (range 50-79 years). The diagnosis of RAEB and RAEBt was made in 11 and 11 patients, respectively. The median percentage of BM blasts in the RAEB group was 11% (range 7-19%) while in the RAEBt group it was 25% (range 21-28%). The pretreatment median values for PCV, WBC, neutrophils and platelets were as follows: PCV 27% (range 18-36%) WBC 2.6x 109/1 (range 1.2-12.4 x 109/1), neutrophils 1.0 x lO’/l (range 0.3-6.7 x 109/1), platelets 53 x lO’/l (range 11-213 x 109/1). The pretreatment characteristics of the patients are presented in Table 1.
Response to treatment Twelve (five with RAEB and seven with RAEBt) of the 22 patients (54.5%) entered into CR, four (three with RAEB and one with RAEBt) patients (18.2%) achieved a PR while six patients (27.3%) were resistant to treatment. There were two (9.1%) toxic deaths, one of hemorrhage in the first course of treatment and one of pulmonary aspergillosis in the second. Complete remission was achieved with one course of treatment in seven patients, while five more patients entered CR with the second course. All CR patients but one, who was given only one postremission course of treatment, received the designed postremission chemotherapy. From the four patients with PR, postremission treatment was given in two, without further improvement in their response status. The response of each patient, as well as the survival and the CR duration, are presented in Table 1. Median time to neutrophil recovery (1 x 109/1) was 15 days (range 3-22 days) after the first course and 14 days (range 4-21 days) after the second course of treatment. Thirteen out of 22 (59.1%) patients developed febrile episodes after the first course of treatment, and nine out
387
Treatmentof high risk myelodysplasticsyndromes Table 1. Pretreatment patient characteristics, treatment response, CR duration and survival
Patient no. 1 2 3 4
5 6 7
8 9
10 11 12 13 14
1.5 16 17
18 19 20 21 22
Sex/age sfbype M/67 M/63 M/62 M/63 F/65 F/60 F/57 M/70 Ml53 Ml.50 F/68 M/64 M/69 M/69 M/67 M/59 M/79 F/64 M/68 M/69 Ml64 M/71
‘(z
RAEB RAEB RAEB RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEB RAEB RAEB RAEBt RAEBt RAEB RAEB RAEB RAEB RAEB RAEBt
Neutrophils (x 109/l)
(z$l)
30 26 27 27 24 31 24 36 34 28 34 25
3.6 5.4 12.4 7.4 11.2 1.8 1.4 3.6 8.7 2.7 2.6 1.3
18
1.7
2.5 18 19 24 33 25 33 28 29
2.3 2.2 1.7 1.2 3.2 2.2 4.1 2.1 4.6
CR Peripheral Platelets BM blasts Treatment duration blood outcome* (months) blasts (%) (x 109/1) (“ro)
1.6 2.3 7.9 1.4 4.2
1.1 0.3 1.7 6.7 0.7 1.2 0.4 0.6 0.9
0.8 0.7 0.6
1.1 0.8 2.1 0.3 1.3
3 5 4 2 13 4 0 0 3 1 0 0 0
76 21 55 40 70
11 89 213 21 163 169 67
18
1 2 0 2 0 0 0 0 12
66 21 44 125
108 90 41 19 28
17 8
11 26 28 29 25
21 28 28 23
11 7
19 21 22
10 17 14 15 10 25
CR NR PR PR NR CR CR CR NR CR CR PR CR PR CR CR CR NR CR CR NR NR
6
-
8 39+
18+
Survival (months) 8 9 15 13 17 25 12 9 20 40+ 20+ 20+
17t 6
11
14+ 13+
4
ll+
13 2
-
4 19 9+ 4 6
*CR, completeremission;PR, partial remission;NR, no response. of 21 (42.8%) after the second.After the completion of the first cycle of treatment, there were 11 cases of pneumonia, one case of urinary tract infection and one case of bacteremia with disseminatedskin abscesses. Bacteriological confirmation was obtained in nine cases. In five cases, the blood cultures were positive (three Pseudomonasaeruginosa, two Staphylococcus epidermis), in one case the urine culture showed Escherichia coli, while in three casesPs. aeraginosa was obtained in sputum cultures. After the second course, there were three casesof ----
All patients illa 22 I CR patients IWolZ) Non CR patients IWolO)
pulmonary aspergillosis (Aspergillus spp.), one case with esophagitis and candidemia due to Candida albicans, while in four casesthere was no documentation of the causative agent. Three patients, all resistant to treatment, showed an increase of peripheral blood blasts during GM-CSF administration, which was restored to pretreatment levels on discontinuation of GM-CSF. The median duration of CR was 12 months. As shown in Fig. 1, the median survival duration of the patientswith CR was 24 months, while in the non-respondingpatients (PR and resistant),it was 12 months. This difference was statistically significant (P < 0.05). The mediansurvival of the whole group was 18 months(Fig. 1).
-+-I
si t-.
‘1
-! I
.-.-.-
L--
00
6
12
16
21
30
36
Time(months) Fig. 1. Actuarialsurvival curvesof thepatientswith RAEB and RAEBt.
Adverse effects of GM-CSF In general, treatment with GM-CSF at a doseof 3 pg/ kg/day S.C.was well tolerated by these elderly patients with MDS. The most common adverse effects were skin reaction to injection site (six patients), mild bone pain (nine patients), mild fever (seven patients) and skin eruption (three patients). In two cases,generalized skin eruption developed on the ninth and twelfth days of the first cycle and the treatment was discontinued for that reason.
388
T. Economopoulos et al.
Discussion Most patients with MDS are elderly with other medical problems which complicate their management. In the vast majority, supportive treatment with red blood cells and platelet transfusions,aswell asthe treatment of infections, have been the mainstay of therapy. Many other therapeutic modalities have been studied, such as pyridoxine, androgens,vitamin Ds, retinoid acid and low dose AraC, without substantial effect on survival [lS211. Various studieshave reported experience with multidrug chemotherapy in conventional dosesin MDS. The resultsof these studies,when compared to a concurrent cohort of patients treated with supportive care alone, proved to be of limited value [6-8,221. The most favorable results are generally achieved in younger patients and those with aggressivesubtypes of MDS (RAEB and RAEBt) with normal karyotype [6,23]. Even more favorable results are obtained in selectedpatients, treated with allogeneic BM transplantation [24]. Patients with MDS most commonly fail to respondto therapy because of death from marrow hypoplasia, although a substantial number of them show significant drug resistance[25]. Recently, the colony stimulating factors (CSFs) such as GM-CSF or G-CSF have been used in the treatment of MDS or AML evolving from MDS, alone or in combination with low dose AraC or multidrug chemotherapy [9,26-291. The results of these studies showed that CSFs probably do not affect the incidence of CR, but they are tolerated reasonably well and they are effective in improving neutropenia,as a consequence of shortening the hypoplastic period following chemotherapy. In the present prospective study, high risk MDS patients (RAEB and RAEBt) were treated with a moderately intensive combination chemotherapy regimen, comprising idarubicin and AraC, followed by GMCSF administration. The results of this study showed that 12 out of 22 patients (54.5%) with high risk (RAEB and RAEBt) MDS achieved CR and four (18.2%) achieved PR, while the therapy-related mortality was relatively low (9.1%). The results of the present series are comparable
with
the results of other reports dealing with RAEB and RAEBt treated with various AML regimensconsistedof dannorubicin, fludarabine and, more recently, idarubicin in combination with AraC [6,29-351. The median remission duration of our patients was only 12 months, which is also comparable with the above-mentioned series. The addition of hemopoietic growth factors to the treatment of MDS with combination chemotherapy may
permit the administration of more intensive treatment resulting in prolongation of CR duration. In conclusion, the results of the present prospective study with high-risk MDS, treated with combination chemotherapy comprising idarubicin and AraC supported by GM-CSF, showed that the CR rate was relatively high for these patients and the incidence of toxic deaths relatively low. However, the remission duration was generally short. It appearsthat multidrug chemotherapy is indicated in patients with RAEB and RAEBt, while the administration of GM-CSF is probably of therapeutic benefit, improving the neutrophi1 recovery during aplastic phase.However, which is the most effective chemotherapeutic regimen and the proper postremission treatment, including peripheral blood progenitor cell transplantation [36], remains to be determined. References 1. Economopoulos T., Stathakis N., Foudoulakis A., Papadoulis N., Dervenoulas J., Papageorgiou E., Anastassiou C., Hadjioannou J. & Raptis S. (1987) Myelodysplastic syndromes: analysis of 131 cases according to the FAB classification. Eur. J. Haematol. 38, 338. 2. Mufti G. J., Stevens J. R., Oscier D. C., Hamblin T. J. & Machin D. (1985) Myelodysplastic syndromes: a scoring system with prognostic significance. Br. J. Haematol. 59, 425. 3. Au1 C., Gattermann N., Hey11 A., Germing U., Derigs G. & Schneider W. (1992) Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6, 52. 4. Morel P., Hebbar M., Lai J. L., Duhamel A., Preudhomme C., Wattel E., Bauters F. & Fenaux P. (1993) Cytogenetic analysis has strong independent prognostic value in de nova myelodysplastic syndromes and can be incorporated in a new scoring system: a report of 408 cases. Leukemia 7, 1315. 5. De Witte T. (1994) New treatment approaches for myelodysplastic syndrome and secondary leukemias. Ann. Oncol. 5, 401. 6. Fenaux P., Morel P., Rose C., Lai J. L., Jouet J. P. & Bauters F. (1991) Prognostic factors in adult de nova intensive myelodysplastic syndromes treated by chemotherapy. Br. J. Haematol. 77, 497. 7. Preisler H. D., Raza A., Barcos M., Azarnia N., Larson R., Browman G., Walker I., Grunwald H., D’Arrigo P., Stein A., Bloom M., Coldberg J., Gottlieb A., Bennett J., Kirshner J. & Priore R. (1986) High dose cytosine arabinoside in the treatment of preleukemia disorders. A leukemia intergroup study. Am. J. Haematol. 23, 131. 8. De Witte T., Muus P., De Pauw P. & Haanen C. (1990) Intensive antileukemic treatment of patients younger than 65 years with myelodysplastic syndromes and secondary acute myelogenous leukemia. Cancer 66, 831. 9. Economopoulos T., Papageorgiou E., Stathakis N., Asprou N., Karmas P., Dervenoulas J., Bouronikou H., Chalevelakis G. & Raptis S. (1992) Treatment of myelodysplastic syndromes with human granulocytic-macrophage colony stimulating factor (GM-CSF) or GM-CSF combined
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Pergamon
Copyright
0
Research IYYh
Vul. 20. No 5, pp. 3853Yl1,
El\cvier
Science
lY9h.
Ltd All rights rc\erved Printed in Great Britain
014s-?l?h/Yh
$15.(11)
+ 0.00
0145-2126(95)00169-7
TREATMENT OF HIGH RISK MYELODYSPLASTIC SYNDROMES WITH IDARUBICIN AND CYTOSINE ARABINOSIDE SUPPORTED BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) Theofanis Economopoulos*, Efstathios Papageorgiou*, Nicholas Stathakist, Maria Constantinidou*, Agapi Parharidou*, Akrivi Kostourou*, John Dervenoulas* Sotos Raptis*
and
*Second Department of Internal Medicine, Propaedeutic, Athens University, Evangelismos Hospital, Athens: and TDepartment of Internal Medicine, School of Medicine, Larissa University, Larissa, Greece (Received 20 October 199.5. Accepted 11 November 1995) Abstract-In this prospective study, patients with ‘high risk’ primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m’ days l-3 and cytosine-arabinoside 200 mg/m* in 12 h infusion, days l-5. The GM-CSF 3 pg/kg S.C. was given on day 6 until the neutrophil count was 1 xlO’/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50-79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 xlO’/l was day 15 (range 3-22) after the first course of treatment and day 14 (range 4-21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months. In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in ‘poor risk’ MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection. Copyright c 1996 Elsevier Science Ltd.
Key words:
Chemotherapy,
GM-CSF,
high risk myelodysplastic
Introduction
syndromes,
treatment.
high incidence of acute myeloid leukemia (AML) and worse prognosis [l-4]. Multidrug chemotherapy, mostly combinations of anthracyclines and cytosine arabinoside (AraC), has been applied by many groups in the treatment of MDS, but has proved to be of limited efficacy [5]. However, relatively favorable results were obtained in patients with RAEBt and normal karyotype [6]. One reasonfor the poor outcome of MDS treated with intensive chemotherapy may be the prolonged duration of treatment-induced BM suppression,resulting in a high toxic death rate [7,8]. The recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the treatment of high risk MDS and older patients with AML, together with low dose AraC or multidrug
Analysis of large series of myelodysplastic syndromes (MDS) based on the FAB classification or on the proposed scoring systems, suggest that patients with excess of blasts in bone marrow (BM), such as refractory anemia with excess of blasts (RAEB), and those with RAEB in transformation (RAEBt), have a Abbreviations: GM-CSF, granulocyte-macrophage colonystimulating factor; MD& myelodysplastic syndrome; RAEB, refractory anemia with excess of blasts; RAEBt, refractory anemia with excess of blasts in transformation. Correspondence to: T. Economopoulos, Second Department of Internal Medicine, Evangelismos Hospital, Athens 106 76, Greece (Fax: 30-l-729-1808). 385
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T. Economopoulos
chemotherapy [9, lo]. This combination shortens the duration of chemotherapy-induced granulocytopenia and probably decreases the number of toxic deaths, although this has not been shown in a randomized phase III trial. Idarubicin is a new anthracycline derivative which, when given in combination with AraC to patients with AML, was found to be as effective as daunorubicin, but probably less cardiotoxic [ 1 l-151. The object of this prospective study was to determine whether moderately intensive chemotherapy comprising idarubicin and AraC supported by GM-CSF, can improve the complete remission (CR) rate, remission duration and hence survival in selected high risk (RAEB and RAEBt) patients with MDS.
et al.
counts (< 5%) together with peripheral blood values of Hb >lO g/d1 without transfusions, neutrophil counts >1.5 x lo”/1 and platelets >lOO x lO”/l. Minimal myelodysplastic changes were considered compatible with CR. Partial response was defined as a 50% or more decrease of BM blasts, with reduction of blood transfusion requirements, neutrophil counts >l.O x lo”/ 1 and platelet count >50 x lO’/l. A time limit of 1 month was set for both types of responses. Toxic death included any death occurring during the study, mainly in aplasia, to which treatment might have contributed. Actuarial survival curves were constructed according to the Kaplan-Meier model. Differences in survival curves were tested for statistical significance using the two-tailed log-rank test.
Materials and Methods Results
Patients Between April 1991 and October 1994, 22 newly diagnosed patients with RAEB and RAEBt, classified according to the FAB criteria for MDS [16], were enrolled in the study. Only patients with primary MDS aged up to 75 years were accepted. However, one 79year-old man with excellent performance status was included in the study. Patients were excluded if they had a serum creatinine greater than 180 pmol/l, Karnofsky score <50%, hepatocellular enzyme levels >2.5 x normal [17] or any contraindication to anthracycline administration. The patients had not been treated with chemotherapy before the entry into the study. Written, informed consent was required for all patients before the start of therapy.
Study design Treatment was started within approximately 1 month of the time of diagnosis. The treatment regimen consisted of idarubicin 6 mg/m2 days l-3 and AraC 200 mg/m2, 12 h infusion, days l-5. The GM-CSF (Schering-Plough/Sandoz) 3 l&kg/day S.C. was started on day 6 until the neutrophil count increased to 1 x 109/1. A BM aspirate was performed on day 15 of cycle 1 and subsequently when appropriate to document response or resistance of the disease. Subsequently, identical cycles were administered with as short an intercycle interval as possible, the exact timing depending on the patient’s general state of health, the peripheral blood counts and the morphological appearance of the BM. If, after two cycles of treatment, the BM was unchanged, no further treatment was given. If, however, partial response (PR) was achieved, a third cycle was given. Postremission therapy consisted of two courses of the same regimen. Then patients were followed regularly with blood counts and BM aspirations when necessary. The response criteria were as follows: CR was defined as a normocellular BM with normalization of BM blast cell
There were 17 males and five females with a median age of 64 years (range 50-79 years). The diagnosis of RAEB and RAEBt was made in 11 and 11 patients, respectively. The median percentage of BM blasts in the RAEB group was 11% (range 7-19%) while in the RAEBt group it was 25% (range 21-28%). The pretreatment median values for PCV, WBC, neutrophils and platelets were as follows: PCV 27% (range 18-36%) WBC 2.6x 109/1 (range 1.2-12.4 x 109/1), neutrophils 1.0 x lO’/l (range 0.3-6.7 x 109/1), platelets 53 x lO’/l (range 11-213 x 109/1). The pretreatment characteristics of the patients are presented in Table 1.
Response to treatment Twelve (five with RAEB and seven with RAEBt) of the 22 patients (54.5%) entered into CR, four (three with RAEB and one with RAEBt) patients (18.2%) achieved a PR while six patients (27.3%) were resistant to treatment. There were two (9.1%) toxic deaths, one of hemorrhage in the first course of treatment and one of pulmonary aspergillosis in the second. Complete remission was achieved with one course of treatment in seven patients, while five more patients entered CR with the second course. All CR patients but one, who was given only one postremission course of treatment, received the designed postremission chemotherapy. From the four patients with PR, postremission treatment was given in two, without further improvement in their response status. The response of each patient, as well as the survival and the CR duration, are presented in Table 1. Median time to neutrophil recovery (1 x 109/1) was 15 days (range 3-22 days) after the first course and 14 days (range 4-21 days) after the second course of treatment. Thirteen out of 22 (59.1%) patients developed febrile episodes after the first course of treatment, and nine out
387
Treatmentof high risk myelodysplasticsyndromes Table 1. Pretreatment patient characteristics, treatment response, CR duration and survival
Patient no. 1 2 3 4
5 6 7
8 9
10 11 12 13 14
1.5 16 17
18 19 20 21 22
Sex/age sfbype M/67 M/63 M/62 M/63 F/65 F/60 F/57 M/70 Ml53 Ml.50 F/68 M/64 M/69 M/69 M/67 M/59 M/79 F/64 M/68 M/69 Ml64 M/71
‘(z
RAEB RAEB RAEB RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEBt RAEB RAEB RAEB RAEBt RAEBt RAEB RAEB RAEB RAEB RAEB RAEBt
Neutrophils (x 109/l)
(z$l)
30 26 27 27 24 31 24 36 34 28 34 25
3.6 5.4 12.4 7.4 11.2 1.8 1.4 3.6 8.7 2.7 2.6 1.3
18
1.7
2.5 18 19 24 33 25 33 28 29
2.3 2.2 1.7 1.2 3.2 2.2 4.1 2.1 4.6
CR Peripheral Platelets BM blasts Treatment duration blood outcome* (months) blasts (%) (x 109/1) (“ro)
1.6 2.3 7.9 1.4 4.2
1.1 0.3 1.7 6.7 0.7 1.2 0.4 0.6 0.9
0.8 0.7 0.6
1.1 0.8 2.1 0.3 1.3
3 5 4 2 13 4 0 0 3 1 0 0 0
76 21 55 40 70
11 89 213 21 163 169 67
18
1 2 0 2 0 0 0 0 12
66 21 44 125
108 90 41 19 28
17 8
11 26 28 29 25
21 28 28 23
11 7
19 21 22
10 17 14 15 10 25
CR NR PR PR NR CR CR CR NR CR CR PR CR PR CR CR CR NR CR CR NR NR
6
-
8 39+
18+
Survival (months) 8 9 15 13 17 25 12 9 20 40+ 20+ 20+
17t 6
11
14+ 13+
4
ll+
13 2
-
4 19 9+ 4 6
*CR, completeremission;PR, partial remission;NR, no response. of 21 (42.8%) after the second.After the completion of the first cycle of treatment, there were 11 cases of pneumonia, one case of urinary tract infection and one case of bacteremia with disseminatedskin abscesses. Bacteriological confirmation was obtained in nine cases. In five cases, the blood cultures were positive (three Pseudomonasaeruginosa, two Staphylococcus epidermis), in one case the urine culture showed Escherichia coli, while in three casesPs. aeraginosa was obtained in sputum cultures. After the second course, there were three casesof ----
All patients illa 22 I CR patients IWolZ) Non CR patients IWolO)
pulmonary aspergillosis (Aspergillus spp.), one case with esophagitis and candidemia due to Candida albicans, while in four casesthere was no documentation of the causative agent. Three patients, all resistant to treatment, showed an increase of peripheral blood blasts during GM-CSF administration, which was restored to pretreatment levels on discontinuation of GM-CSF. The median duration of CR was 12 months. As shown in Fig. 1, the median survival duration of the patientswith CR was 24 months, while in the non-respondingpatients (PR and resistant),it was 12 months. This difference was statistically significant (P < 0.05). The mediansurvival of the whole group was 18 months(Fig. 1).
-+-I
si t-.
‘1
-! I
.-.-.-
L--
00
6
12
16
21
30
36
Time(months) Fig. 1. Actuarialsurvival curvesof thepatientswith RAEB and RAEBt.
Adverse effects of GM-CSF In general, treatment with GM-CSF at a doseof 3 pg/ kg/day S.C.was well tolerated by these elderly patients with MDS. The most common adverse effects were skin reaction to injection site (six patients), mild bone pain (nine patients), mild fever (seven patients) and skin eruption (three patients). In two cases,generalized skin eruption developed on the ninth and twelfth days of the first cycle and the treatment was discontinued for that reason.
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Discussion Most patients with MDS are elderly with other medical problems which complicate their management. In the vast majority, supportive treatment with red blood cells and platelet transfusions,aswell asthe treatment of infections, have been the mainstay of therapy. Many other therapeutic modalities have been studied, such as pyridoxine, androgens,vitamin Ds, retinoid acid and low dose AraC, without substantial effect on survival [lS211. Various studieshave reported experience with multidrug chemotherapy in conventional dosesin MDS. The resultsof these studies,when compared to a concurrent cohort of patients treated with supportive care alone, proved to be of limited value [6-8,221. The most favorable results are generally achieved in younger patients and those with aggressivesubtypes of MDS (RAEB and RAEBt) with normal karyotype [6,23]. Even more favorable results are obtained in selectedpatients, treated with allogeneic BM transplantation [24]. Patients with MDS most commonly fail to respondto therapy because of death from marrow hypoplasia, although a substantial number of them show significant drug resistance[25]. Recently, the colony stimulating factors (CSFs) such as GM-CSF or G-CSF have been used in the treatment of MDS or AML evolving from MDS, alone or in combination with low dose AraC or multidrug chemotherapy [9,26-291. The results of these studies showed that CSFs probably do not affect the incidence of CR, but they are tolerated reasonably well and they are effective in improving neutropenia,as a consequence of shortening the hypoplastic period following chemotherapy. In the present prospective study, high risk MDS patients (RAEB and RAEBt) were treated with a moderately intensive combination chemotherapy regimen, comprising idarubicin and AraC, followed by GMCSF administration. The results of this study showed that 12 out of 22 patients (54.5%) with high risk (RAEB and RAEBt) MDS achieved CR and four (18.2%) achieved PR, while the therapy-related mortality was relatively low (9.1%). The results of the present series are comparable
with
the results of other reports dealing with RAEB and RAEBt treated with various AML regimensconsistedof dannorubicin, fludarabine and, more recently, idarubicin in combination with AraC [6,29-351. The median remission duration of our patients was only 12 months, which is also comparable with the above-mentioned series. The addition of hemopoietic growth factors to the treatment of MDS with combination chemotherapy may
permit the administration of more intensive treatment resulting in prolongation of CR duration. In conclusion, the results of the present prospective study with high-risk MDS, treated with combination chemotherapy comprising idarubicin and AraC supported by GM-CSF, showed that the CR rate was relatively high for these patients and the incidence of toxic deaths relatively low. However, the remission duration was generally short. It appearsthat multidrug chemotherapy is indicated in patients with RAEB and RAEBt, while the administration of GM-CSF is probably of therapeutic benefit, improving the neutrophi1 recovery during aplastic phase.However, which is the most effective chemotherapeutic regimen and the proper postremission treatment, including peripheral blood progenitor cell transplantation [36], remains to be determined. References 1. Economopoulos T., Stathakis N., Foudoulakis A., Papadoulis N., Dervenoulas J., Papageorgiou E., Anastassiou C., Hadjioannou J. & Raptis S. (1987) Myelodysplastic syndromes: analysis of 131 cases according to the FAB classification. Eur. J. Haematol. 38, 338. 2. Mufti G. J., Stevens J. R., Oscier D. C., Hamblin T. J. & Machin D. (1985) Myelodysplastic syndromes: a scoring system with prognostic significance. Br. J. Haematol. 59, 425. 3. Au1 C., Gattermann N., Hey11 A., Germing U., Derigs G. & Schneider W. (1992) Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6, 52. 4. Morel P., Hebbar M., Lai J. L., Duhamel A., Preudhomme C., Wattel E., Bauters F. & Fenaux P. (1993) Cytogenetic analysis has strong independent prognostic value in de nova myelodysplastic syndromes and can be incorporated in a new scoring system: a report of 408 cases. Leukemia 7, 1315. 5. De Witte T. (1994) New treatment approaches for myelodysplastic syndrome and secondary leukemias. Ann. Oncol. 5, 401. 6. Fenaux P., Morel P., Rose C., Lai J. L., Jouet J. P. & Bauters F. (1991) Prognostic factors in adult de nova intensive myelodysplastic syndromes treated by chemotherapy. Br. J. Haematol. 77, 497. 7. Preisler H. D., Raza A., Barcos M., Azarnia N., Larson R., Browman G., Walker I., Grunwald H., D’Arrigo P., Stein A., Bloom M., Coldberg J., Gottlieb A., Bennett J., Kirshner J. & Priore R. (1986) High dose cytosine arabinoside in the treatment of preleukemia disorders. A leukemia intergroup study. Am. J. Haematol. 23, 131. 8. De Witte T., Muus P., De Pauw P. & Haanen C. (1990) Intensive antileukemic treatment of patients younger than 65 years with myelodysplastic syndromes and secondary acute myelogenous leukemia. Cancer 66, 831. 9. Economopoulos T., Papageorgiou E., Stathakis N., Asprou N., Karmas P., Dervenoulas J., Bouronikou H., Chalevelakis G. & Raptis S. (1992) Treatment of myelodysplastic syndromes with human granulocytic-macrophage colony stimulating factor (GM-CSF) or GM-CSF combined
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