S-HAM induction chemotherapy with or without GM-CSF in patients with high-risk myelodysplastic syndromes

 Thirty-one adult patients with high-risk myelodysplastic syndromes (MDS) were enrolled in a prospective randomized double-blind placebo-controlled trial evaluating the efficacy of sequential high-dose Ara C/mitoxantrone chemotherapy with or without GM-CSF. GM-CSF or placebo was given subcutaneously once daily at a dose of 250 μg/m² starting 48 h prior to chemotherapy and continued until neutrophil recovery. This design allowed us to investigate the role of GM-CSF as a priming factor for the leukemic clone, as well as its effect on the recovery of normal hematopoiesis. Twenty-eight patients are currently evaluable for response. Ten patients reached a complete remission (36%), eight patients had persistent MDS (29%), and ten patients died within 6 weeks after the onset of treatment (early death). Infectious complications during cytopenia were the major cause of death (8/10). Median time to complete hematologic recovery (neutrophils >500/μl and platelets 20 000/μl) and time to neutrophil recovery above 1500/μl was 29 and 35 days, respectively. Median remission duration was 190 days (6.4 months). Analysis of prognostic subgroups showed a low CR rate (25%) and a high early-death rate (44%) in patients >55 years of age, suggesting that the intensified treatment approach should be limited to younger patients. No data concerning the influence of GM-CSF on response to chemotherapy or duration of neutropenia are presently available. Received: 19 September 1996 / Accepted: 12 February 1997     

Treatment of patients with low-risk myelodysplastic syndromes using a combination of all-trans retinoic acid, interferon alpha, and granulocyte colony-stimulating factor

 Used as single agents, ATRA, G-CSF, and IFN-α have shown a moderate benefit in patients with low-risk MDS, with a response rate of 10%. The aim of the present study was to evaluate the efficacy of a combination of these agents. The effect on hemoglobin (Hb), platelets, and absolute neutrophil count (ANC), as well as on transfusion frequency, was examined in 25 patients with MDS (11 RA, four RARS, eight RAEB, two CMML). The median age was 61 years (range 44–81), and the male/female ratio was 14/11. Treatment consisted of ATRA at 25 mg/m²/day p.o. for months 1, 3, 5, 7, 9, and 11, IFN-α at 1.5 MIU twice a week s.c. for 52 weeks, and, in patients with initial ANC <500/μl, G-CSF at 100–480 μg daily s.c. according to the degree of ANC. The duration of therapy was scheduled for 12 months. Two patients achieved ongoing CR (+19 months; +16 months), one patient with RA after 3 months and one with CMML after 7 months of treatment. In all patients, the mean ANC increased significantly from 1400±200/μl before the start of therapy to 3500±600/μl at the end of treatment (p=0.025). In two patients an increase of Hb was observed, and one patient ceased to require transfusions. In an additional patient with RA and 5q-syndrome, the platelet count normalized following administration of ATRA/IFN-α, increasing from 89,000/μl to 293,000/μl. The eight RAEB patients were nonresponders. We conclude that therapy with ATRA, IFNα, and G-CSF is effective in approximately 35% of low-risk MDS patients (in this study: six of 17) and may induce complete remission in individual cases. Received: November 18, 1998 / Accepted: December 29, 1998     

A randomized phase-I/II multicenter study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for patients with myelodysplastic syndromes and a relatively low risk of acute leukemia

Summary To assess the effects of GM-CSF in patients with myelodysplasia, a total of 101 patients with refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with an excess of blasts provided that the percentage of blasts in the bone marrow did not exceed 10% (RAEB) were enrolled in the EORTC Leukemia Cooperative Group study 06885. They were randomized to receive two daily subcutaneous injections of rhGM-CSF (mammalian, glycosylated, Sandoz/Schering-Plough) at a daily dose of either 108g glycoprotein (group I) or 216g glycoprotein (group II) for 8 weeks. Response was defined as an increase in Hb (> 2.5 g%), neutrophil count (more than 100%), or platelet count (more than 100%) without progression of the disease. After exclusion of 19 patients who did not meet the entry criteria, 82 were evaluated. Fifty-four patients (66%) responded (27 of 42 patients in group I and 27 of 40 in group II). Progressive disease was seen in two patients of group I and in four of group II. Two of the latter developed leukemia. All responses were reflected in the granulocytic series. In two patients platelet numbers also increased. Cytogenetic analysis, successfully performed in 43 cases, showed that 14 of 16 patients with normal karyotypes responded, compared with 14 of 27 patients with abnormal karyotypes (p=0.008). In some cases GM-CSF was reduced in dose or discontinued prematurely due to side effects so that only 35% of all evaluable patients finished 8 weeks of treatment without a change of dose.     

再生障碍性贫血和骨髓增生异常综合征患者骨髓CD34+细胞及其粒细胞集落刺激因子受体的研究

目的:检测再生障碍性贫血(AA)和骨髓增生异常综合征(MDS)患者CD34 细胞占骨髓单个核细胞(BMMNC)的比率及其表面粒细胞集落刺激因子受体(G-CSFR)的表达率。方法:用流式细胞术(FCM)检测13例AA、22例MDS及12例非血液病患者CD34 细胞占BMMNC的比率及其表面G-CSFR的表达率。结果:AA组与对照组、AA组与MDS组、MDS-难治性贫血(RA)组与难治性贫血伴原始细胞增多(RAEB)组BMMNC中CD34 细胞的比率比较差异有统计学意义(P<0.05),但G-CSFR的表达率差异无统计学意义(P>0.05)。多数重型AA(SAA)患者(3/4)及少数慢性AA(CAA)患者(1/9)BMMNC中的CD34 细胞少于0.1%。多数G-CSFR表达率低(<14%)的患者(7/9)外周血中性粒细胞减少;而表达率正常(14.0%~28.9%)的患者(1/6)很少见;表达率高(>28.9%)的患者(3/7)也可存在中性粒细胞减少。结论:造血干细胞减少是AA的主要发病机制之一,其表面G-CSFR的表达率不是影响AA的主要因素;MDS患者CD34 细胞比率升高是一个预后不良的指标,G-CSFR的检测可部分解释MDS患者外周血中性粒细胞减少的原因。     

Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid,granulocyte colony-stimulating factor,erythropoietin and α-tocopherol

 Differentiation induction therapy is being tested in myelodysplastic syndromes to ameliorate maturation defects and to restore normal hematopoietic function. To this end, 17 patients (eight with refractory anemia, two with refractory anemia and ring sideroblasts, and seven with refractory anemia and excess of blast cells) were treated with a combination of all-trans-retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and α-tocopherol for durations of 8–16 weeks. Absolute neutrophil counts increased in all patients; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients. Stimulation of erythropoiesis was seen in eight patients with an increase in hemoglobin concentration in three, a discontinuation of transfusion requirements in another three, and a significant increase in reticulocyte counts as the only parameter in two patients. Clinically important multilineage responses with increases of hemoglobin levels or discontinuation of transfusion needs were thus seen in six patients (35.3%) with three patients having a trilineage response. Serum erythropoietin concentrations did not differ significantly between responders and nonresponders, but the erythroid response was accompanied by a rise in the serum transferrin receptor levels. In the bone marrow, the myeloid-to-erythroid ratio and the maturation index of myeloid cells increased during therapy, while the percentage of blast cells did not change. Cytogenetic analysis demonstrated the persistence of the abnormal clones. Prior to therapy, nonresponders had a significantly higher serum TNF level than responders. Serum concentrations of TNF-α and soluble TNF-α receptor significantly increased during therapy, but mainly in the patients without an erythroid and platelet response. Soluble IL-2 receptor and soluble ICAM-1 concentrations both increased. This pilot study demonstrates that treatment with ATRA/G-CSF/EPO/tocopherol is well tolerated, leading to normalization of neutrophil counts in most, and to improvement of platelets and red blood cells in a significant subgroup of patients. Received: 27 October 1995 / Accepted: 11 December 1995     

Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes

The combination of fludarabine (FDR), high dose cytarabine and granulocyte colony stimulating factor (FLAG) with or without idarubicin (Ida) was used in the treatment of poor risk acute leukaemia or myelodysplastic syndrome (MDS) in a single centre experience. A total of 105 patients were treated over a 4-year period with 59% achieving a complete remission (CR); no statistical difference observed between FLAG and FLAG-Ida. For patients responding to FLAG +/- Ida, the median event-free survival (EFS) was 11 months and 23% at 5 years. Such patients proceeded either to further chemotherapy or a haematopoietic stem cell transplant (HSCT). The median EFS (13 months vs. 8 months) and projected 5-year survival (37% vs. 13%) of patients undergoing HSCT was significantly better than those who did not (P = 0.021). In all, 14 of 72 patients remain alive in continuing CR (median duration 43 months) with 10 of 31 having had a HSCT vs. four of 41 that did not (P = 0.033). Both regimens were well tolerated, with the majority of patients experiencing grade 1 or less non-haematological toxicity (mainly nausea and vomiting). The median time to neutrophil and platelet recovery was 28 and 31 d, respectively. No significant differences were seen with the addition of ida. There was a 17% incidence of treatment-related deaths, of which 39% was caused by invasive aspergillus infection. The results show that FLAG +/- Ida is an effective and well-tolerated remission induction regimen for poor risk leukaemia and MDS.     

The prophylactic effect of itraconazole capsules and fluconazole capsules for systemic fungal infections in patients with acute myeloid leukemia and myelodysplastic syndromes: a japanese multicenter randomized, controlled study

We performed a randomized, controlled study comparing the prophylactic effects of capsule forms of fluconazole (n = 110) and itraconazole (n = 108) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) during and after chemotherapy. There were 4 cases with possible systemic fungal infection in the itraconazole group, and there were 8 possible and 3 probable cases in the fluconazole group. Adverse events did not significantly differ in the 2 groups. In patients with MDS or in the remission-induction phase of chemotherapy, the numbers of cases with probable or possible infections were lower in the itraconazole group than in the fluconazole group, whereas no difference was seen in patients with AML or in the consolidation phase of therapy. In patients with neutrophil counts of >0.1 x 10(9)/L lasting for more than 4 weeks, the frequency of infection in the fluconazole group (5 of 9 patients) was significantly higher than in the itraconazole group (0 of 7 patients; P = .03). Our results suggest that both drugs were well tolerated in patients with AML or MDS who received chemotherapy and that the efficacy of itraconazole for prophylaxis against systemic fungal disease is not inferior to that of fluconazole.     

Assessment of the value of treatment with granulocyte colony-stimulating factor in children with acute lymphoblastic leukemia: a randomized clinical trial

Abstract: The present trial was designed to test the effects of G-CSF on the duration of the second phase of induction chemotherapy in children with newly diagnosed acute lymphoblastic leukemia (ALL). A total of 32 patients were assigned randomly to a group that received (14 patients; group A) or a group that did not receive (18 patients; group B) G-CSF (10 g/kg/day subcutaneously and daily) throughout of the second phase of induction therapy. One of 14 (7.1%) patients in group A and 2 of 18 (11.1%) patients in group B completed the course of chemotherapy within the planned time. The median length of this phase was 37 days (range, 29 to 65; mean, 40; SD, 8.6) for patients in group A and 36 days (range, from 29 to 55; mean, 38; SD, 7.4) for those in group B, and the difference was not statistically significant. The number of days during which patients had granulocyte counts of less than 2 × 10⁹/l, the number of febrile episodes of unknown origin, the number of bacterial and fungal infections and the number of days of hospitalization did not differ in a statistically significant manner between the two groups. Our data suggest that G-CSF supportive therapy may be unnecessary in children with neutropenia of short duration, for whom the risk of infection is low.     

Granulocyte-macrophage colony-stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial

A total of 110 patients, aged 64 years or over, with de novo acute myeloid leukaemia (AML) and white blood cell counts <50 x 109/l were treated with 3 d of cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 and etoposide 200 mg/m2, randomized with or without the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) 200 microg/m2. The primary aim was to evaluate the effect of GM-CSF on the remission rate. Secondary aims included comparison of duration of remission, survival and infectious complications and the impact of maintenance therapy with thioguanine. Complete remission (CR) was achieved by 64% of patients without GM-CSF, and by 65% of patients who received GM-CSF, the median remission duration was 13 vs. 6 months, the median overall survival (OS) was 14 vs. 9 months, the mean time to neutrophil recovery was 25 vs. 17 d (P = 0.03) and the number of positive blood cultures was 46 vs. 39 (P = 0.05) respectively. The impact of thioguanine remains unanswered since only 30 patients remained in CR after consolidation therapy. We conclude that induction therapy is feasible with acceptable toxicity in elderly patients with AML, albeit with a high relapse rate and short OS. GM-CSF prior to, and in combination with, induction treatment reduced the time to neutrophil recovery and the number of neutropenic septicaemia cases but did not improve the OS of AML in the elderly.     

Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party

The role of granulocyte colony stimulating factor (G-CSF) as supportive therapy following intensive induction chemotherapy for acute myeloid leukaemia (AML) in adults was investigated in a randomized trial. G-CSF (Lenograstim, 263 μg/d) or placebo was administered from day 8 after the end of chemotherapy until neutrophil recovery to 0·5 × 10⁹/l (or for up to 10 d). Eight hundred and three patients were entered. Neutrophil recovery was quicker with G-CSF ( P  < 0·0001), but this did not lead to differences in the number, severity or duration of infections. There were no substantial supportive care savings, although G-CSF patients spent 2 d less in hospital ( P  = 0·01). Complete remission (CR) rates were similar between arms (73% G-CSF, 75% placebo, P  = 0·5), as were reasons for failure (induction death: P  = 0·7; resistant disease: P  = 0·5) and, for remitters, 5-year disease-free survival (34% vs. 38%, P  = 0·3). Overall survival at 5 years was 29% with G-CSF vs. 36% with placebo ( P  = 0·10). Both CR rate ( P  = 0·006) and overall survival ( P  = 0·006) were worse with G-CSF in patients aged <40 years, but this may be a chance effect. There is some evidence from this trial of an adverse effect of G-CSF but these data need to be viewed in the context of the evidence from the other trials.