EORTC-GIMEMA AML8 protocol. A phase III study on autologous bone-marrow transplantation in acute myelogenous leukemia (AML).
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Bone Marrow Transplantation↗
Biomedical subjects
G Visani
Publications and source records attributed to G Visani.
FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of 'poor risk' acute myeloid leukemias.
Twenty-eight patients with poor prognosis acute myeloid leukemia (AML) received therapy with two courses of fludarabine 30 mg/m2/day + ara-C 2 g/m2/day (days 1-5) and G-CSF 5 mg/kg/day (FLAG) (from day 0 to polymorphonuclear recovery). Eighteen patients were considered 'refractory' (eight primarily resistant, five relapsing within 6 months of initial remission, or at a second relapse; five relapsing after an autologous bone marrow transplantation procedure. Ten cases were defined 'secondary' AML (diagnosis of AML made after a preexisting diagnosis of: myelodysplastic syndrome: five cases; myelodysplastic syndrome after therapy for breast cancer: one case; previously untreated, and concomitant, non-Hodgkin's lymphoma: two cases; Hodgkin's disease treated with chemoradiotherapy: one case). Overall, 15 patients (58%) achieved a complete remission (CR). Two patients died of infection during induction, and 11 had resistant disease. Analyzing the data in relation to selected host and disease characteristics, the response varied widely. The highest CR rates (89%) were obtained in secondary AML; in particular, two cases of 'second-primary' (concomitant with low-grade non-Hodgkin's lymphoma) AML obtained CR for both diseases. Refractory AML differed widely for response: high CR rate (75%), although with short mean CR duration for primary resistance AML, and very poor response (11% CR) for relapsed (early, second, after ABMT) cases. Interestingly, a slow kinetic of leukemic growth in vivo before FLAG administration was significantly related to the response and outcome (p = 0.0002). Hematological and nonhematological toxicities were acceptable. In conclusion, the FLAG regimen has significant antileukemic activity and acceptable toxicity especially in secondary AML, both with and without coexisting lymphoid malignancy.
Acute Disease↗
Fludarabine + Ara-C + G-CSF: cytotoxic effect and induction of apoptosis on fresh acute myeloid leukemia cells.
It has been reported that the adenine nucleoside analogue fludarabine is able to increase the phosphorylation and the cytotoxicity of cytosine arabinoside (Ara-C) in different leukemic models, both in vitro and in vivo. In poor prognosis acute myeloid leukemia (AML), the combination of fludarabine with Ara-C and granulocyte colony-stimulating factor (G-CSF) has proven to be a highly effective regimen. In this study we aimed to further investigate the effects of this drug combination. In vitro, on fresh AML cells from ten patients, our results confirm an additive cytotoxic effect displayed by fludarabine + Ara-C, as demonstrated by isobologram analysis of the data. The addition of G-CSF significantly increased the efficacy of the drug combination. These effects appeared to be related to an increased incorporation of [3H]Ara-C into cellular DNA in the presence of fludarabine + G-CSF. Furthermore, the quantitative evaluation of programmed cell death (apoptosis) showed that fludarabine + Ara-C + G-CSF induce apoptosis to a higher degree than either compound alone. This finding suggests that cooperative induction of apoptosis could be the potential mechanism of action of this drug combination.
Antineoplastic Agents↗
All-trans retinoic acid potentiates megakaryocyte colony formation: in vitro and in vivo effects after administration to acute promyelocytic leukemia patients.
In this study, we evaluated the in vitro growth of normal hematopoietic progenitors (CFU-GM, BFU-E, CFU-GEMM, CFU-meg) stimulated by optimal sources of colony stimulating activity in the absence or presence of 10(-6) M all-trans retinoic acid (ATRA). ATRA alone did not show any colony-stimulating ability when added in culture to partially purified bone marrow populations. On the other hand, it significantly increased the number of CFU-GM (p = 0.003) and both the number (p = 0.009) and size (p = 0.002) of CFU-meg in the presence of appropriate colony-stimulating activity. Since ATRA had only modest stimulatory effects on purified CD34+ cells, the megakaryocyte colony-stimulating activity of ATRA was mainly due to an increased production of endogenous cytokines by bone marrow accessory cells. In parallel experiments, the in vitro growth of the different hematopoietic progenitors was evaluated in 28 patients affected by acute non-lymphoid leukemia (ANLL), mainly acute promyelocytic leukemia (APL). Bone marrow cells were harvested after remission induction obtained: (i) in ten APL patients treated with ATRA followed by one chemotherapy cycle (CHT) (3/7: Daunorubicin+Ara-C): group A ('ATRA/CHT'); (ii) eight APL patients treated with one CHT cycle alone (3/7 as above): group B ('APL-CHT'); (iii) in ten ANLL-non-APL patients after one CHT cycle (3/7 as above): group C ('ANLL-CHT'). The number of the different hematopoietic progenitors, and in particular CFU-GM and CFU-meg, was significantly higher in APL patients treated with ATRA plus CHT (group A) compared to APL (group B) or ANLL-non-APL (group C) patients treated with CHT alone (CFU-GM: p = 0.01; CFU-meg: p = 0.03). Our data demonstrate that ATRA is able to potentiate both normal and APL megakaryocytopoiesis and suggest that the in vivo administration of ATRA could be beneficial in other pathological conditions, where the megakaryocyte progenitor cell compartment is impaired.
Antigens, CD↗
Acute myeloid leukemia from diagnosis to bone marrow transplantation: experience from a single centre.
We analysed the use of allogeneic bone marrow transplantation (BMT) in the treatment of acute myelogenous leukemia (AML). We evaluated 271 adult patients with newly diagnosed AML treated here between 1983 and 1992; 113 patients (42%) were eligible for BMT because of their age (< 45 years until 1986 and < 50 years later). Of these, HLA typing was performed on 81 patients (72%); 32 patients were not typed (19 had no sibling, 8 had a primary refractory leukemia, 3 died during induction, 1 had important previous toxicity and for one patient there was no recorded reason). Of the 81 typed, 36 patients (44.4%) were found to have an HLA-matched sibling donor and 21 (25%) underwent BMT (8% of the total population); 15 patients did not undergo BMT (6 relapsed before transplantation and did not obtain a second remission, 3 declined the procedure, 1 died during induction, 1 had positive MLR, 1 had positive MLR and HCV hepatitis, 1 was a drug addict with HCV hepatitis, 1 had previous organ toxicity, 1 was psychotic). These data show that only a small fraction of unselected patients with AML can undergo BMT. Such findings make the comparison of BMT with other types of post-remission therapy more complex.
Adolescent↗
Limiting dilution analysis of a novel tripeptide anticancer agent Ambamustine (PTT-119): effect on K-562, CCRF-SB and multidrug resistant LoVo-Dk cell lines.
Cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SB or K-562 lines. After incubating the cell mixtures in vitro with different dose levels of Ambamustine (PTT-119), a quantity of 10(4) treated cells were dispensed into microculture plates, and graded cell numbers of the lines used to contaminate the normal marrow were added. Limiting dilution analysis (LDA) was used to estimate the frequency of leukemic cells persisting after treatment. Incubation with 50 micrograms/mL of PTT-119 produced a total elimination of K-562 acute myelogenous blasts, whereas nearly 0.17 and 0.27 leukemic cells were still present in the cell mixtures after treatment with 5 and 25 micrograms/mL, respectively. When normal bone marrow was contaminated with CCRF-SB lymphoblastic cells, incubation with either 50 or 25 micrograms/mL of PTT-119 produced a complete clearing of leukemic cells, whereas with 5 micrograms/mL the leukemic cells in each well were 0.18. When PTT-119 was incubated with LoVo-DX, a colon cancer cell line which expresses the pleiotropic drug resistance MDR phenotype, virtually complete inhibition of clonogenic colonies was observed with as little as 5 micrograms/mL. This suggests that PTT-119 could be used in clinical trials as a non-cross-resistant agent in multidrug protocol.
Antineoplastic Agents↗
A randomized phase II study of low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in myelodysplastic syndromes (MDS) with a high risk of developing leukemia. EORTC Leukemia Cooperative Group.
In a randomized phase II study, patients with myelodysplastic syndromes (MDS) with 10-30% blasts in the bone marrow and hematopoietic failure were treated with low-dose Ara C (2 x 10 mg/m2 subcutaneously (s.c.) days 1-14) and rhGM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day s.c.) given either following Ara C (days 15-21) or simultaneously (days 8-14) for 1-5 cycles. 108 patients with a median age of 65 years, range 17-80 years and refractory anemia with an excess of blasts (RAEB, n = 54), RAEB with transformation (RAEBt, n = 50) or with chronic myelomonocytic leukemia (CMML, n = 4) were evaluable. Complete remission was achieved in 15 cases (14%), 11 had a partial response (10%), and 16 a minor response (15%). Stable disease was reached in 35 cases (32%). There were 16 cases of toxic death (15%), progression occurred in 15 patients (14%). No differences existed between the two treatment arms with respect to response and duration of response. Prognostic factors for poor response included the presence of cytogenetic abnormalities and a history of previous blood transfusions. Major adverse events during treatment were hemorrhage (55%), infections (54%), and fever associated with GM-CSF administration (40%). The overall response rate ws 39%, median duration was 12.5 months from start of treatment which allowed responding patients to lead good quality life without further therapy. The question whether the combination is indeed superior to LD-Ara C alone is not settled but will be evaluated in an ongoing clinical trial.
Acute Disease↗
Relief of intractable pruritus in polycythemia vera with recombinant interferon alfa.
Following reports that recombinant interferon alfa (rIFN alpha), besides inducing clinical and hematologic remission in polycythemia vera (PV), can also resolve intractable pruritus, we used rIFN alpha to treat 13 PV patients complaining of severe pruritus refractory to conventional treatment (venesection and/or cytostatics). rIFN alpha was administered intramuscularly three times a week at a dosage of 3.0 x 10(6) U. Eight patients (61.5%) reported a > or = 50% reduction of pruritus, which occurred within 2-8 weeks from the start of rIFN alpha treatment, leading to a substantial improvement in their quality of life. Three patients had to stop rIFN alpha within the first month of therapy because of unacceptable side effects. Thus rIFN alpha seems to be capable of providing considerable relief of otherwise intractable pruritus in a good proportion of PV patients.
Aged↗
Comparative effects of racemic verapamil vs R-verapamil on normal and leukemic progenitors.
R-Verapamil (R-VPM), an enantiomer of racemic verapamil (VPM), has been recently reported to possess an activity equivalent to VPM in reverting drug resistance in vitro, without showing remarkable cardiovascular toxicity in animal models, even in doses three times higher than VPM. In this study, we assessed the effects of R-VPM in vitro, on clonogenic leukemia cells (CFU-L) from 15 patients with acute nonlymphoid leukemia (ANLL) at diagnosis, and on bone marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors from 15 healthy volunteers. On CFU-L, continuous exposure to VPM or R-VPM alone showed a slight inhibitory activity; in combination with daunorubicin (DNR), R-VPM proved more effective (mean IC50 of DNR: alone = 24.53 ng/ml +/- 6.2 SE, + VPM = 18.8 ng/ml +/- 4.6 SE, +R-VPM = 17.9 ng/ml +/- 4.8 SE). On CFU-GM, both VPM and R-VPM were minimally toxic at the lowest concentration used, but 30 microM VPM were significantly more toxic than R-VPM at the same dose (residual growth = 39.2% +/- 6.5% vs. 71.8% +/- 9.3% with R-VPM, p = 0.005). On BFU-E, both VPM and R-VPM caused more consistent growth inhibition; at high doses, VPM was again more toxic than R-VPM (33.4% +/- 12.8% vs 53.4% +/- 10.4% residual growth at 30 microM, p = 0.03). DNR toxicity on bone marrow was more greatly enhanced by VPM than R-VPM, and this difference was statistically significant on erythroid progenitor colony growth (p = 0.04). In conclusion, in comparison to VPM, R-VPM appeared to be at least equally effective on leukemic clonogenic cells and less toxic on normal bone marrow precursors, thus suggesting a possible safe use in vivo, even in concentrations that cannot be achieved with VPM, owing to its toxic effects.
Bone Marrow Cells↗
Impairment of GM-CSF production in myelodysplastic syndromes.
In this study we evaluated the production of granulocyte/macrophage-colony stimulating factor (GM-CSF), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) by enriched bone marrow (BM) macrophages in 15 patients affected by myelodysplasia and 20 normal BM donors. The presence of GM-CSF, IL-6 and TNF-alpha in the culture supernatants of BM macrophages was detectable only after stimulation with lipopolysaccharide (LPS), whereas no differences were present in the amount of IL-6 and TNF-alpha between myelodysplastic patients and normal controls, GM-CSF production appeared eight-fold reduced in BM macrophage culture supernatants from myelodysplastic patients with respect to normal controls. After further experiments, we concluded that the impaired release of GM-CSF by BM macrophages could not be due to a different production kinetic in myelodysplastic patients. Moreover, the number of multipotent (CFU-GEMM), granulocyte/macrophage (CFU-GM) and erythroid (BFU-E) progenitors was significantly impaired in myelodysplastic patients. In conclusion, we demonstrated that the production of GM-CSF by purified adherent cells from MDS patients is markedly impaired in spite of the peripheral blood cytopenia. This selective defect in GM-CSF production, along with an intrinsic defect of haematopoietic progenitor cells, might contribute to the impairment of haematopoiesis always observed in myelodysplastic patients.
Adult↗
Reduced responsiveness of bone marrow megakaryocyte progenitors to platelet-derived transforming growth factor beta 1, produced in normal amount, in patients with essential thrombocythaemia.
In this study we evaluated the amount of transforming growth factor-beta 1 (TGF-beta 1) in platelet lysates obtained from 12 patients affected by essential thrombocythaemia (ET) in comparison with five patients affected by myelofibrosis with myeloid metaplasia (MMM) and 15 healthy donors. The levels of both bioactive and latent TGF-beta 1, evaluated in a bioassay on CCL64 cells, before and after transient acidification, were similar in platelet lysates from ET patients and normal donors and significantly (P < 0.01) elevated in platelet lysates from MMM patients. Moreover, platelet lysates from ET patients and normal controls, showed a similar degree of colony suppression when tested on haematopoietic progenitor (CD34+) cells, purified from normal bone marrows, whereas platelet lysates from MMM patients showed a higher (P < 0.01) inhibitory activity on normal CFU-meg and BFU-E growth. In parallel, platelet lysates form ET patients and normal controls were tested on CD34+ cells, purified from ET bone marrows. ET bone marrow BFU-E, similarly to normal bone marrow BFU-E, were markedly inhibited by platelet lysates, whereas ET bone marrow CFU-meg were significantly (P < 0.05) less responsive to the inhibitory activity of platelet lysates than normal bone marrow CFU-meg. The main factor responsible for the inhibitory activity contained in platelet lysates was transforming growth factor-beta 1 (TGF-beta 1), as demonstrated by the ability of a polyclonal neutralizing anti-TGF-beta 1 antibody to almost completely reverse the suppressive effect of platelet lysates on CFU-meg and BFU-E growth. Our data demonstrate that the amount of intraplatelet TGF-beta 1 is similar in ET patients and normal controls, whereas it is increased in platelets from MMM patients. Moreover, megakaryocyte progenitors in ET show a reduced sensitivity to platelet-derived inhibitors and, in particular, to TGF-beta 1.
Blood Platelets↗
Synergistic cytotoxicity of AZT plus alpha and gamma interferon in chronic myeloid leukemia cell line K562.
We have previously reported that the antineoplastic activity of 3'-azido 3' deoxythymidine (AZT) can be increased by drugs that inhibit "de novo" thymidylate synthesis, such as 5-fluorouracil, methotrexate and hydroxyurea. In the present study we tested the combinations AZT+alpha interferon (IFN) and AZT+gamma IFN on in vitro growth of the human acute-phase chronic myeloid leukemia (CML) cell line K562. After 72 hours incubation, not only AZT+alpha-IFN but also AZT+gamma-IFN were synergistic in inhibiting K562 growth, as demonstrated by isobologram analysis of the data. This enhanced cytotoxicity was confirmed by the evaluation of [3H]AZT incorporation into cellular DNA, that was increased by 50% and 222% in the presence of alpha- and gamma-IFN, respectively. The addition of 50 mumol/l thymidine to the culture medium was able to reduce the cytotoxicity of the drug combinations to the degree observed with each compound alone; furthermore, the increased incorporation of AZT into DNA was completely reversed. These data indicate the existence of a biochemical interaction between AZT and IFNs that results in an increased cytotoxic effect. While the combination AZT+alpha-IFN is currently being tested in HIV-related malignancies, AZT+gamma-IFN is new and deserves further study in human CML acute and chronic phase models, in view of possible clinical applications.
Cell Division↗
Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction.
Since according to the early studies, the outcome after splenectomy in the individual patient with myelofibrosis with myeloid metaplasia (MMM) is unpredictable, we assessed retrospectively the pre-intervention characteristics that best predicted adverse events, hematological consequences, and survival in 71 splenectomized MMM patients. The findings indicate that the operative risk of splenectomy for both mortality (8.4%) and morbidity (39.3%) was unpredictable. New hemorrhagic or thrombotic complications occurred in 16.9% of surviving patients and were predicted by age < 50 years, a normal to high platelet count (> 200 x 10(9)/l) and huge splenomegaly (> 16 cm from the costal margin). Massive liver enlargement occurred in 24% of patients and has to be expected in patients splenectomized for transfusion-dependent anemia. Anemia improved substantially in 45% and 52% of patients at 3 months and at 1 year, respectively, and was predicted by severe anemia, low platelet count (< 100 x 10(9)/l) or normal to high white blood cell (WBC) count (> 4 x 10(9)/l). Survival from splenectomy was superior in patients < 45 years with WBC < 10 x 10(9)/l count. An unexpectedly high rate of blastic transformation was observed. It accounted for 42.8% of the deaths. The results suggest trials for prophylactic cytoreductive treatment in young patients and when platelet count is normal to increased. Further study is needed for elucidating the possible role played by splenectomy in inducing blastic transformation.
Adult↗
[The need for invasive diagnostic investigations (coronaro-ventriculography), interventions using extracorporeal circulation and coronary angioplasty in a defined population of Emilia-Romagna].
Working on a limited and controlled population of 100,000 living in the territory of Imola, in northern Italy, we tried to determine the need for coronary arteriography examinations, CABG interventions and PTCA procedures (similarly to the 1980 Minnesota survey). Indications for diagnosis or treatment were made according to agreement criteria of published data in 1990. In the 3 year time (1989-91) of this survey, indication to coronary arteriography was done in 433 pts. (367 atherosclerotic, 58 valvular and 8 with other etiologies). 57.7% (250/433) of the pts. were treated with CABG or PTCA, and 42.3% (202/433) were treated medically. Of the 367 pts. documented as having coronary ischemia, 54.5% had further invasive therapy: 35.4% CABG and 19% PTCA. For a population of 100,000 annual need has been estimated as follows: 145 catheterization procedures (99% coronary arteriography), 60 extracorporeal circulation procedures, and 24 PTCA interventions. Comparing programming estimates done by the national Health System for the needs of a population group in Northern Italy, it is clear that they are underestimating the real needs by 50%, and such an important underestimation implies important and pressing considerations for the future planning of the health care of this important pathology.
Adolescent↗
tat protein stimulates production of transforming growth factor-beta 1 by marrow macrophages: a potential mechanism for human immunodeficiency virus-1-induced hematopoietic suppression.
In this study, we examined the potential role of the human immunodeficiency virus (HIV) tat protein in causing the hematopoietic abnormalities frequently observed in HIV-infected individuals. Recombinant tat (r-tat) protein, at concentrations up to 10 micrograms/mL, did not display any stimulatory or inhibitory effect on the survival/proliferative capacity of CD34+ hematopoietic progenitor cells, purified from normal bone marrow (BM). However, exposure of r-tat protein (at concentrations between 10 ng/mL and 10 micrograms/mL) to enriched normal BM macrophages induced the production of a factor(s) in conditioned media that inhibited the in vitro growth of CD34+ cells in liquid cultures and of immature hematopoietic progenitors (day 14 colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid, and colony-forming unit-megakaryocyte) in semisolid assays. Pre-exposure of r-tat protein with a monoclonal neutralizing anti-tat antibody completely abrogated the inhibitory activity present in BM macrophage culture supernatants. The main factor responsible for this suppressive activity was transforming growth factor-beta 1 (TGF-beta 1), as shown by the ability of a polyclonal anti-TGF-beta 1 neutralizing antibody to almost completely reverse the suppressive effect of BM macrophage supernatants on CD34+ cells. TGF-beta 1 bioassays showed that exposure of r-tat protein to BM macrophages significantly increased the levels of both active and latent forms of TGF-beta 1. These results indicate that the production of TGF-beta 1, one of the most potent negative regulator of hematopoiesis, is increased by HIV tat protein and that such increase could contribute to the derangement of the hematopoietic system in HIV-infected individuals.
Antibodies↗
Impaired in vitro growth of purified (CD34+) hematopoietic progenitors in human immunodeficiency virus-1 seropositive thrombocytopenic individuals.
In this report the role played by human immunodeficiency virus type-1 (HIV-1) in the pathogenesis of HIV-1-related thrombocytopenia was investigated. CD34+ hematopoietic stem/progenitor cells were purified from the bone marrow (BM) of HIV-1(+) thrombocytopenic patients, HIV-1(+) nonthrombocytopenic individuals, HIV-1(-) patients with immune thrombocytopenic purpura, and HIV-1(-) normal donors. CD34+ cells from HIV-1(+) thrombocytopenic individuals alone showed a reduced capacity to give rise to megakaryocytic colonies (CFU-Meg) and also a progressive and significant decline in cell number when placed in liquid culture containing recombinant human interleukin-3 (rIL-3). This decline involved not only megakaryocyte but also erythroid and granulocyte/macrophage progenitors. The defects in megakaryocyte colony formation and CD34+ cell growth did not result from a productive HIV-1 infection of CD34+ cells. Moreover, HIV-1 DNA was absent from CD34+ cells in 10 of 12 thrombocytopenic patients examined. On the other hand, the decreased survival/proliferation of CD34+ cells in liquid culture, within the HIV-1(+) thrombocytopenic patients, was correlated with the presence of HIV-1 p24 antigen in BM plasma. These results demonstrate an impairment of CD34+ cells in HIV-1(+) individuals presenting thrombocytopenia as the only hematologic manifestation. Furthermore, these findings suggest that increased viral replication in the BM microenvironment may cause this impairment and possibly contributes to HIV-induced thrombocytopenia.
Acquired Immunodeficiency Syndrome↗
Inhibitory effect of HIV-1 envelope glycoproteins gp120 and gp160 on the in vitro growth of enriched (CD34+) hematopoietic progenitor cells.
The effect of increasing concentrations (from 0.01 to 10 micrograms/ml) of HIV-1 envelope glycoproteins gp160, gp120, gp41 and core protein p24 was evaluated on the in vitro growth of enriched hematopoietic progenitors (CD34+ cells). Both gp120 and gp160, at concentrations from 0.01 to 10 micrograms/ml, caused a progressive and significant (p less than 0.05) decrease in viable CD34+ cell count in liquid cultures supplemented with 2 ng/ml of human recombinant (r) interleukin-3 (IL-3), evaluated by means of Trypan-blue exclusion and [3H]thymidine ([3H]TdR) incorporation. In the absence of rIL-3, no inhibitory effects were observed even at the highest gp160 and gp120 concentrations explored (10 micrograms/ml). On the contrary, gp41 and p24 did not affect the number of viable CD34+ cells, either in the presence or in the absence of rIL-3. Moreover, gp160 and gp120, but not gp41 and p24, significantly (p less than 0.05) inhibited the in vitro growth of granulomacrophage progenitors (CFU-GM) in a dose-dependent fashion. These data clearly demonstrate that HIV-1 envelope glycoproteins inhibit the growth of purified hematopoietic progenitors. We propose that HIV-1 can impair hematopoiesis through the interaction of gp120/gp160 with CD34+ cell surface, independently of an infectious process.
Antigens, CD↗
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. EORTC Leukemia Cooperative Group.
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 108 micrograms glycoprotein (group I) or 216 micrograms glycoprotein (group II) for 8 weeks. Response was defined as an increase in Hb (greater than 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.
Acute Disease↗