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Leukemia (2003) 17, 1827–1833& 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 No benefit from adding GM-CSF to induction chemotherapy in transformingmyelodysplastic syndromes: better outcome in patients with less proliferative disease R Hast1,3, E Hellstro¨m-Lindberg2,4, L Ohm1, M Bjo¨rkholm3, F Celsing3, I-M Dahl4, I Dybedal4, G Gahrton3, G Lindberg4, R Lerner4, O Linder4, E Lo¨fvenberg4, H Nilsson-Ehle4, C Paul3, J Samuelsson3, J-M Tangen4, U Tidefelt3, I Turesson4, A Wahlin4,J Wallvik4, I Winquist4, G O 1Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden; 2Department of Hematology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden; 3The Leukemia Group of Middle Sweden(LGMS), Sweden; and 4The Nordic MDS Group, Sweden and Norway In this prospective randomized multicenter trial 93 patients, materials have often been heterogeneous, including elderly median age 72 years, with RAEB-t (n ¼ 25) and myelodysplastic AML, secondary AML, and MDS patients of various age groups.
syndrome (MDS)-AML (n ¼ 68) were allocated to a standard A systematic analysis of prognostic factors in a homogeneous induction chemotherapy regimen (TAD 2+7) with or without cohort of elderly patients with advanced MDS and MDS-AML addition of granulocyte–macrophage-CSF (GM-CSF). The over-all complete remission (CR) rate was 43% with no difference who are not candidates for SCT has not been published.
between the arms. Median survival times for all patients, CR In an effort to decrease the hematological toxicity of treatment patients, and non-CR patients were 280, 550, and 100 days, and increase the remission rates, hematopoietic growth factors like respectively, with no difference between the arms. Response granulocyte colony-stimulating factor (G-CSF) and granulocyte– rates were significantly better in patients with serum lactate macrophage colony-stimulating factor (GM-CSF) have been added dehydrogenase (S-LDH) levels p9.5 lkat/l, bone marrow cellu- to standard chemotherapy regimen. Earlier studies had shown that larity p70%, and WBC counts o4.0 Â 109/l, but S-LDH was theonly variable independently associated with response by priming with GM-CSF could recruit leukemic cells into cell cycle, logistic regression analysis. Cox’s regression analysis identi- both in vitro7,8 and in vivo,9,10 and that GM-CSF could improve fied four significant prognostic factors for survival: bone myeloid recovery after high-dose chemotherapy.11,12 A number of marrow cellularity, S-LDH, cytogenetic risk group (International prospective randomized studies have shown that combined Prognostic Scoring System), and age. Only bone marrow treatment with G-CSF or GM-CSF and chemotherapy in de novo cellularity (P ¼ 0.01) and S-LDH (P ¼ 0.0003) retained statistical AML indeed has a favorable effect on the duration of neutropenia, significance in the log-rank test. Severe adverse events weresignificantly more common in the GM-TAD arm (P ¼ 0.01). Thus, number of fever days, and incidence of infectious complications addition of GM-CSF to chemotherapy showed no clinical benefit after chemotherapy but little or no effect on remission rates, in terms of response but carried an increased risk for side remission duration and survival.13–21 However, the results have effects. We present a clinically useful tool to predict response been less conclusive in patients with HR-MDS and MDS-AML, to chemotherapy and survival in elderly patients with trans- some studies suggesting that combined treatment with hemato- forming MDS, favoring patients with features of less prolifera- poietic growth factors and chemotherapy might improve the tive disease.
Leukemia (2003) 17, 1827–1833. doi:10.1038/sj.leu.2403035 Keywords: myelodysplastic syndromes; acute myeloid leukemia; In this prospective randomized study, patients with MDS-AML chemotherapy; GM-CSF; prognostic factors; S-LDH and RAEB-t were given a single-line standard chemotherapy andwere allocated combined treatment with GM-CSF or noadditional treatment. The hypothesis was that GM-CSF couldimprove remission rate, overall survival (OS) and remission duration, and decrease the hematological toxicity. Moreover,we wanted to utilize a prospectively collected homogeneous Myelodysplastic syndromes (MDS) represent a heterogeneous cohort of elderly patients with advanced MDS or MDS-AML to group of malignant hematological disorders with varying define clinical variables with an impact on outcome of therapy clinical course. The prognosis in an individual case of MDS and survival. Even though no clinical benefit of additive can be estimated using the International Prognostic Scoring treatment with GM-CSF could be demonstrated in our study, System (IPSS).1 Patients with pronounced cytopenia, poor-risk we were able to define a group of clinico-pathological features karyotype, and more than 10% bone marrow blasts show clearly associated with outcome to therapy. Patients with lower generally poor survival and a high risk for leukemic transforma- than normal white blood cell (WBC) counts, bone marrow tion, and are often subjected to chemotherapy. However, cellularity 70% or less and normal serum lactate dehydrogenase because of the relatively poor response rates, high therapy- (S-LDH) levels appeared to have significantly better response related toxicity and no proven survival benefit, indications for rates and survival after induction chemotherapy. The prognostic chemotherapy in high-risk MDS (HR-MDS) and acute myeloid impact of these variables was higher than that of karyotype. The leukemia (AML) that develops after MDS (MDS-AML) have variables could easily be used in clinical practice to aid come to vary between different centers and investigators, with therapeutic decision-making in elderly patients with advanced the possible exception of younger MDS patients where stem cell transplantation can be an option.2 Several studies haveidentified factors indicating a poor response to chemotherapyin HR-MDS and MDS-AML: adverse karyotype includingchromosome 7 anomalies, higher age, and increased WBC counts and blast cell percentage.3–6 However, these patient Correspondence: Dr R Hast, Division of Hematology, KarolinskaHospital, Stockholm SE-171 76, Sweden. Fax: +46 875 521 05 Patients with a diagnosis of MDS-AML, that is, AML preceded Received 28 January 2003; accepted 24 April 2003 by a myelodysplastic phase of at least 2 months’ duration, and patients with a diagnosis of RAEB-t for at least 2 months were hemoglobin level over 4 weeks without transfusion need, eligible for this randomized nonplacebo-controlled, multicenter WBC 41.5 Â 109/l (with a normal differential count), and study. The diagnosis of MDS and AML was made on blood and platelets 4100 Â 109/l. If CR was not achieved after the first bone marrow specimens according to the FAB criteria classifi- induction course, a second identical course was given. Patients cation.26,27 Bone marrow cellularity was estimated as described who failed to achieve CR after the second course of TAD were ¨ st et al.28 Patients with cardiac failure of NYHA grade III taken off the study and only followed for survival. Patients who and IV, renal failure (serum creatinine 4400 mmol/l), liver were given a bone marrow transplant in CR1 were censored at failure (serum bilirubin more than three times the normal value), the time for transplant in the statistical evaluation of relapse-free a diagnosis of rheumatoid arthritis or SLE or previous anaphy- lactic reaction to human protein were excluded from the study.
RFS in CR1 was calculated from the date of CR till the date of There was no upper age limit for inclusion, instead the attending confirmed relapse in AML/RAEB-t, or death in CR1, whatever physician made a general judgment of performance status and the reason. OS was calculated from date of randomization until comorbid conditions. Chromosome analyses were performed date of death. Pretreatment duration of MDS was calculated using standard techniques and the findings were classified from date of MDS diagnosis to date of inclusion.
according to IPSS into good, intermediate- and poor-risk-basedcytogenetic subgroups.1 Individual IPSS score values were notassigned since the majority of patients had MDS-AML, for which the IPSS system is not validated. In all, 97 patients from 15participating centers were included in the study between The study was designed to detect a 30% difference in CR rate at February 1994 and June 1998. The final evaluation was carried the 5% level with 1-b X80%. 95% confidence intervals were out on 1st April, 2001. The study followed the guidelines of the calculated for ratios. Student’s t-test and the Mann–Whitney national Ethical committee and all patients gave their informed U-test were used for comparison of continuous variables, whenever appropriate and w2 analysis (with continuity correc-tion) was used to compare categories. Kaplan–Meier plots were used to describe curves for survival and duration of responseand the log-rank test was used to compare curves. We utilized The induction chemotherapy consisted of a standard TAD (2+7) Cox’s regression analysis for the multivariate analysis of regimen: daunorubicin 60 mg/msq i.v. days 1 and 2, cytarabine predictive factors for survival and duration of response, and 100 mg/msq  2 i.v. day 1–7, thioguanine 200 mg/msq p.o. day logistic regression to analyze variables with an impact on the 1–7. Patients were randomized to no additional treatment achievement of CR, and on the events of early death and severe (control arm, TAD) or to additional treatment with GM-CSF (molgramostim; Schering-plough AB, Stockholm) (experimentalarm, GM-TAD). GM-CSF, in a dose of 200 mg per day, was givensubcutaneously. Treatment started 2 days before chemotherapy in patients with WBC o50  109/l, and concomitantly withchemotherapy in those with WBC X50  109/l. GM-CSF therapy was continued for a maximum of 3 weeks, or untilANC reached 41.0  109/l in the recovery phase after In all, 97 patients were included in the study. Four patients were chemotherapy. GM-CSF therapy was withdrawn in case of excluded after randomization; one patient refused to participate, serious adverse events like pleuritis, pericarditis, thromboem- one had heart failure NYHA grade III, and two were considered bolic disorders, and capillary-leak syndrome. The dose of GM- unsuitable for chemotherapy for other reasons. Of the remaining CSF was reduced by 50% in case of moderate adverse events 93 patients, 47 were randomized to chemotherapy alone (TAD) that could be controlled by the use of corticosteroids, while it and 46 to chemotherapy in combination with GM-CSF (GM- was not changed in case of nonsevere adverse events that could TAD). Of these, 32 patients had MDS-AML and 15 RAEB-t in the be controlled by antipyretic drugs and antihistamine. If the WBC TAD group, while the GM-TAD group comprised 36 MDS-AML counts reached 450  109/l during the first 2 days of GM-CSF and 10 RAEB-t. The median age was 72 years (35–88 years) in administration, chemotherapy was started immediately while the TAD group and 73 years (56–90 years) in the GM-TAD GM-CSF was continued. Common criteria for evaluating fever group. There were no significant differences in clinical and and the use of i.v. antibiotics during the neutropenic phase were hematological characteristics between the two arms (Table 1).
used throughout the study. Prophylactic treatment with standarddose acyclovir and fluconazole was given during neutropenia.
Patients entering complete remission (CR) were eligible to receive a maximum of three consolidation courses with TAD(1+5), with or without GM-CSF subject to the initial randomiza- CR was achieved in 40 (43%, CI 33–52%) of the 93 patients. In tion. Treating physicians could, however, withdraw patients all, 32 (34%) patients reached CR after one induction course. Of from one or more consolidation courses if the patient developed the remaining 61 patients, 28 were given a second induction serious or life-threatening complications to the previous treat- course and eight (29%) of them responded with CR. The median ment. Refractory and relapsing cases received further treatment time to achieve CR was 38 days (range: 19–141). A total of 11 patients (12%) died early, that is, within 4 weeks after start ofchemotherapy, in 10 cases following the first induction course,and in one case after the second. The immediate causes of early In the TAD group, 20 of 47 patients (43%, CI 30–57%) Patients were evaluated on an intention-to-treat basis. CR was entered CR (16 after one course), 23 showed resistant disease, defined as a bone marrow with o5% blast cells, stable and four were early death. The corresponding figures for the 46 Description of 93 evaluable patients treated with TAD Serious adverse events recorded in association with induction therapy in 93 patients treated with TAD or GM-TAD bCytogenetic risk-based subgroups according to IPSS.1 patients in the GM-TAD group were 20 CR (43%, CI 30–58%) (16 after one course), 19 resistant disease, and seven early deaths. There was no significant difference in time to achieve CR or in the number of early deaths (P ¼ 0.33) between the two Ulcerative esophagitis, renal failure, abdominal pain, hyperglycemia.
The number of patients who died early, that is, within 4 weeks after arms. Continuous and category variables associated with start of induction therapy, are shown within brackets.
response to treatment are shown in Tables 3 and 4. Peripheralblood blast counts, S-LDH, bone marrow cellularity, WBCcounts, and percentage of bone marrow blasts were signifi- Continuous variables in CR and non-CR patients cantly associated with a response to treatment in the univariate analysis. S-LDH levels (p or 49.5 mkat/l), bone marrowcellularity (p or 109/l) were significantly associated with response to treatment when used as category variables (Table 4). Logistic regression analysis including both continuous variables and category variables showed that the only variable independently asso- ciated with response to treatment was S-LDH, p or 49.5 mkat/l At the time of follow-up 34 months after the inclusion of the lastpatient, 33 patients had relapsed (16 of 19 (84%) patients in theTAD group and 17 of 20 (85%) in the GM-TAD group), while two Instead, the multivariate analysis identified platelet count before patients in each arm had died in CR1. There was no significant start of treatment as the only clinical or hematological difference in RFS between TAD (median 330 days; range: pretreatment variable significantly associated with the duration 23–2171+) and GM-TAD (median 364 days; range: 76–2478+), P ¼ 0.45. RFS of 41 year was seen in 19 patients, nine in the TAD,and 10 in the GM-TAD group, respectively. One more patient inthe TAD group was alive at follow-up after 2148 days. She had received a bone marrow transplant after 4 months in CR1 and wascensored for the analyses of OS and RFS.
The median survival from date of randomization was 284 days: The number of consolidation courses during CR1 varied 623 days (range: 56–2507+) for CR patients and 103 days between patients, but not between arms. In all, 17 patients (range: 1–553) for non-CR patients. No significant differences in received 0–1 consolidation courses (eight in the TAD group and survival were observed between TAD and GM-TAD (P ¼ 0.95, nine in the GM-TAD group), and 23 cases received two to three Figure 1). Five patients were alive at the time of follow-up, two courses (11 and 12 in the respective arms). Median RFS did not in the TAD group at 1081 and 2229 days, and three in the differ between patients receiving 2–3 and 0–1 consolidation GM-TAD group at 1248, 1442, and 2507 days, respectively.
courses, respectively (352 vs 302 days, P ¼ 0.99). Interestingly, Cox’s regression analysis identified four significant independent variables predicting for CR did not predict for duration of CR.
prognostic factors for survival: bone marrow cellularity Category variables in CR and non-CR patients aP-value calculated on three groups.
**Po0.01.
***Po0.001.
Two patients died of cerebral hemorrhages, and three others suffered major bleeding complications associated with throm-bocytopenia (Table 2), with no differences between treatment groups.
In all, 50 episodes of clinically significant nonhematologicaladverse events were recorded in association with the inductiontherapy; 15 in the TAD group and 35 in the GM-TAD group(Table 2). Fluid retention, that is, capillary-leak syndrome,pulmonary edema, or weight increase was observed in 14patients receiving GM-TAD, while only one patient showedsuch symptoms after TAD. Six of eight patients with exanthemahad received GM-CSF. In total, 21 events involved cardiaccomplications, seven (33%) after TAD, and 14 (67%) after GM- OS in days from date of randomization according to TAD (P ¼ 0.01). All six patients who suffered acute myocardial assigned treatment group. No significant difference was seen between infarction belonged to the GM-TAD group. Other thromboem- the two treatment arms TAD and GM-TAD, respectively.
bolic events included one case with deep venous thrombosisand another with pulmonary emboli, both in the TAD group.
(P ¼ 0.006), log S-LDH (P ¼ 0.001), cytogenetic risk group(P ¼ 0.003), and age (P ¼ 0.03). Using the above-described cutoff values to subcategorize these variables, cellularity andS-LDH retained statistical significance in the log-rank test.
The present study was designed with the purpose to improve Moreover, leukocyte count that did not retain significance as a outcome of treatment in MDS-AML and RAEB-t. An earlier small continuous variable in the Cox model was highly significant as pilot study in MDS-AML had suggested that the addition of GM- a categorized variable (o or X4.0Â 109/l, P ¼ 0.005) (Figure 2a–d).
CSF to standard chemotherapy might improve the outcome of It was not possible to find a cutoff for age that showed treatment substantially,29 and we wanted to test this hypothesis in a prospective study. We also aimed at defining pretreatmentvariables with a predictive value for the outcome of therapy. Theresults showed that the overall CR rate was 43%, the median Hematological toxicity, infections and fever during RFS 11.3 months, and the median OS 9.5 months, with no differences between the two arms. Thus, we were unable toconfirm our initial report that addition of GM-CSF to a standard The mean number of days with ANC o0.5 Â 109/l was 20712 TAD (2+7) regimen could improve the outcome of chemo- in the whole material, 21714 in the TAD group, and 1879 in therapy in MDS-AML and RAEB-t. Since the start of our study, the GM-TAD group (P ¼ 0.21). The mean number of days with only a few comparable randomized studies in transforming MDS fever 4381C was 7.878.0 in the whole group, 8.778.3 in the have been published. Bernasconi et al23 randomized 105 TAD group, and 6.877.7 in the GM-TAD group (P ¼ 0.26). In patients to receive G-CSF or not as an adjuvant after addition, the mean number of days in hospital during the first 90 chemotherapy and found significantly better response rates days from start of chemotherapy was comparable between the (CR+PR) after G-CSF therapy, but no effect on survival, unless two treatment groups; 33715 days for TAD vs 30716 days for stem cell transplantation was performed. A HOVON study reported a nonsignificant trend towards a higher CR rate and Infections were documented in 48 (52%) of the 93 patients.
longer OS in patients who were treated with G-CSF during and There were 30 episodes of bacterial septicemia, six invasive after chemotherapy.24 Estey et al25 found an increased CR rate, fungal infections or fungal septicemia, three pneumonia, and but no effect of the addition of G-CSF to chemotherapy on RFS nine cases with infections of unknown origin (Table 2). Four or OS. In addition, two smaller randomized studies combining patients died early (o4 weeks) as a result of infection.
GM-CSF with chemotherapy failed to show improved response OS in days from date of randomization according to: (a) S-LDH levels at diagnosis – patients with 49.5 mkat/l had significantly poorer survival (P ¼ 0.0003); (b) bone marrow cellularity at diagnosis – patients with 470% cellularity had significantly poorer survival (P ¼ 0.01);(c) cytogenetic risk-based categorization (IPSS) – no significant differences between the three risk groups (P ¼ 0.06); and (d) leukocyte counts atdiagnosis – patients with a WBC count o4.0 Â 109/l showed significantly better survival (P ¼ 0.005). (log-rank test.) rates in MDS-AML and HR-MDS.6,22 Considering all controlled common in the GM-TAD group, and this was largely explained studies in MDS-AML and HR-MDS, including the present one, it by the unexpected finding of six patients suffering acute seems unlikely that G-CSF or GM-CSF given concomitantly with myocardial infarction in this group. Interestingly, Sugiyama or after chemotherapy can significantly improve end points like et al32 recently suggested that endogenous GM-CSF may play an CR rate, RFS, and OS. This is in agreement with the results in de important role in the development of acute coronary syndromes.
It is conceivable that administration of exogenous GM-CSF Most studies of de novo AML and MDS where G-CSF or GM- might likewise contribute to atheroma complications. We are CSF has been used as adjunct to chemotherapy have shown not aware of any earlier reports linking GM-CSF therapy to acute positive effects on neutropenia, febrile episodes, or hospitaliza- myocardial infarction. Perhaps the unusually high median age of tion.13–25 In one study of AML, this effect was translated into a our patients, 72 years, may have contributed. In view of these ‘cost gain’ that could further motivate the routine use of growth findings, it is probably prudent to use GM-CSF with caution in factors in combination with chemotherapy in AML and MDS.30 elderly patients with advanced coronary sclerosis.
In the present study, however, we did not observe any Response rate, response duration, and survival are important significant differences between the two arms, either with respect issues for elderly patients with advanced MDS, for whom cure is to days with neutropenia or fever, number of infectious events, exceedingly rare. The present study is one of the hitherto largest or days spent in hospital. GM-CSF, in contrast to G-CSF, may studies in which patients with MDS-AML and HR-MDS have cause fever that may blur the interpretation of this variable; been treated prospectively in a uniform way and followed-up however, it is still unclear as to why we, in contrast to most other for a relatively long period. Only one variable, S-LDH, was investigators, did not observe an effect on ANC recovery. One independently associated with response rate in the multivariate explanation might be that we used a somewhat lower GM-CSF analysis. Patients with subnormal or normal S-LDH levels dose from the start in an effort to reduce the reported heavy (o9.5 mkat/l) showed a response rate of 71% compared to nonhematological toxicity of GM-CSF.31 In the 25% of our 13% in those with S-LDH X9.5 mkat/l (Po0.0001). An associa- patients who experienced moderate to severe adverse events tion between elevated S-LDH and poorer survival has previously this dose was reduced further, which together with the measures been reported in AML, and in untreated cohorts of MDS outlined in our protocol, allowed all but four patients to patients.33–35 As S-LDH predicted also for survival in our study, continue the treatment with GM-CSF. Cardiac events were more it turns into a clinically highly relevant pretreatment variable.
Karyotype, which usually has a significant impact on outcome myelodysplastic syndrome as defined by French–American–British in studies of de novo AML and younger MDS, was a less criteria: a Cancer and Leukemia Group B Study. J Clin Oncol 1996; important variable in the present study. The CR rate was 40% for patients with an abnormal karyotype compared to 50% for those 5 Estey E, Thall P, Beran M, Kantarjian H, Pierce S, Keating M. Effect of diagnosis (refractory anemia with excess blasts, refractory with a normal karyotype, and 37% for patients belonging to the anemia with excess blasts in transformation, or acute myeloid poor cytogenetic risk group (IPSS), compared to 48% for the leukemia [AML]) on outcome of AML-type chemotherapy. Blood good/intermediate groups. Furthermore, we failed to demon- strate a difference in survival between patients with poor-risk 6 Verbeek W, Wormann B, Koch P, Aul C, Hinrichs H, Balleisen L and intermediate karyotype, while good-risk karyotype (IPSS) et al. S-HAM induction chemotherapy with or without GM-CSF in was associated with better OS. Our hypothesis is that the higher patients with high-risk myelodysplastic syndromes. Ann Hematol1997; 74: 205–208.
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7 Asano Y, Shibuya T, Okamura S, Yamaga S, Otsuka T, Niho Y.
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