Adding growth factors or interleukin-3 to erythropoietin has limited effects on anemia of transfusion-dependent patients with myelodysplastic syndromes unresponsive to erythropoietin alone

BACKGROUND AND OBJECTIVES: Recombinant erythropoietin (r-EPO) induces erythroid responses in patients affected by myelodysplastic syndromes (MDS). However, the response rate declines to 10-15% in MDS with substantial transfusion needs. Both in vitro and in vivo studies have suggested that the addition of growth factors (G-CSF, GM-CSF) or interleukin-3 (IL-3) may potentiate the effect of r-EPO on dysplastic erythropoiesis. The aim of this study was to evaluate the effects of the combination of r-EPO with G-CSF, GM-CSF or IL-3 on the anemia of heavily transfusion-dependent MDS patients, previously unresponsive to r-EPO alone. PATIENTS AND METHODS: Sixty patients with transfusion-dependent MDS, already treated without significant erythroid response with r-EPO alone, were scheduled to receive, for at least 8 weeks, r-EPO subcutaneously at the dose of 300 U/kg t.i.w. in combination with G-CSF (300 microcg s.c. t.i.w., 27 patients), or GM-CSF (300 microcg s.c. t.i.w., 23 patients), or IL-3 (5 microcg/kg s.c. t.i.w., 10 patients), after a two-week pre-phase during which G-CSF, GM-CSF and IL-3 were administered daily at the same dose, as single drugs. RESULTS: Ten patients were not evaluable for erythroid response because of relevant side effects related to GM-CSF or IL-3 administration. Overall, among 50 patients who completed the study, there were 3 erythroid responses (as determined by complete abolition of red-cell transfusions): 1 (4%) in the G-CSF + r-EPO and 2 (10.5%) in the GM-CSF + r-EPO treated groups. No patient responded to the combination of r-EPO + IL-3. All responders had inappropriate serum levels of endogenous EPO and a relatively short disease duration. Both responders to GM-CSF + r-EPO developed acute myeloid leukemia 2-9 months after the start of the combined therapy. A third elderly patient, treated with the same association, developed marrow hypoplasia. A significant increase in leukocyte count occurred in 96% of patients who received r-EPO + G-CSF, 78.9% of those treated with r-EPO + GM-CSF and 66% of subjects receiving r-EPO + IL-3. A significant increase in platelet count was observed in a single patient receiving r-EPO and GM-CSF, while a slight decrease in platelet count with respect to baseline levels occurred in about 20% of patients. INTERPRETATION AND CONCLUSIONS: Our results suggest that the combination of r-EPO with G-CSF, GM-CSF or IL-3, at least at the doses and schedules employed in the present study, has limited efficacy on the anemia of heavily transfusion-dependent MDS patients previously unresponsive to r-EPO alone. However, in this setting of patients, the combination of G-CSF or GM-CSF + r-EPO may occasionally be effective in subjects with low circulating levels of serum EPO and short disease duration.     

Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis

Abstract: Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c, 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistant number of circulating erythroid precursors BFU–E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.     

High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study

In a dose escalation study we tested the feasibility and tolerance of high-dose recombinant human erythropoietin (r-HuEPO) therapy in four patients with ineffective erythropoiesis due to myelodysplastic syndromes (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Recombinant human EPO was administered i.v. with an initial dose of 50 U/kg body weight (BW) three times per week. The dose was increased by steps of 25 or 50 U/kg bW with intervals of 1-4 weeks up to a maximum dose of 500 U/kg BW three times per week. All patients were treated as outpatients. Pre-study treatment with cyclosporin A and/or Danazol was continued in three patients. In one patient r-HuEPO was discontinued after 20 weeks because of relapse of severe aplastic anemia. No major side effects were observed even at the maximum dose. One patient with PNH showed an increase of hemoglobin from 89 to 139 g/liter that permitted monthly phlebotomies to reduce his iron overload. In one patient with MDS the reticulocyte count increased from 2.5 to 50 x 10(9)/liter, and the transfusion requirement decreased to 2 U every 3-4 weeks instead of every 2 weeks. Two patients did not complete the whole treatment period and showed no rise in reticulocyte count. We conclude that high dose r-HuEPO therapy is feasible in patients with anemia due to MDS or PNH. High-dose r-HuEPO appears to have some effect on anemia due to ineffective erythropoiesis in a subgroup of patients. Further studies are needed to identify potential responders and to define the optimal administration of r-HuEPO.     

Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes

In vitro studies suggest that all-trans retinoic acid (ATRA) synergizes with erythropoietin (EPO) for the stimulation of hematopoiesis in patients with myelodysplastic syndrome (MDS). A clinical trial was performed to evaluate whether a combination of these agents was effective in relieving the cytopenias associated with MDS. Twenty-seven patients with low- or intermediate-risk MDS were enrolled in a 12-week study. ATRA was administered orally at the dose of 80 mg/m(2) per day in 2 divided doses for 7 consecutive days every other week. Recombinant human EPO was given subcutaneously 3 times a week. The EPO dose was initiated at 150 U/kg and was increased to 300 U/kg if after 6 weeks there was no or there was suboptimal erythroid response. Patients who responded to therapy were continued on ATRA and EPO at the same doses for 6 additional months (extension phase). Further treatment was given to patients with a continued response. Clinically significant erythroid responses with increases of hemoglobin levels of at least 1 g/dL or reduction of transfusion needs were seen in 13 (48%) patients, with 4 showing improved responses after dose escalation of EPO. Ten (37%) patients displayed continued responses during 6 months of extended treatment, and 7 (26%) are still responsive after a follow-up period of 13 months. Neutrophil responses were observed in 5 of 12 patients with neutropenia, and platelet responses were observed in 6 of 9 patients with thrombocytopenia. Three patients displayed trilineage responses that were sustained during continuation therapy. Side effects were observed in all patients but were of mild entity and did not require discontinuation of therapy. It is concluded that the combination ATRA + EPO is an effective and well-tolerated treatment for patients with low- and intermediate-risk MDS. The optimal ATRA and EPO schedule and the role of maintenance treatment remain to be determined and warrant further investigation.     

Sequential administration of recombinant human granulocyte-macrophage colony-stimulating factor and human erythropoietin for treatment of myelodysplasia syndromes

Abstract: Treatment of myelodysplastic syndromes (MDS) with recombinant human erythropoietin (Epo) is successful in only 10% to 25% of patients. We performed a pilot study in 10 anaemic patients with MDS to examine whether sequentially applied recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and Epo improves haemoglobin levels and/or reduces red blood cell transfusion requirements. Morphological diagnoses of patients were refractory anaemia (RA) in 3 cases, RA with ring sideroblasts in 3 cases and RA with excess blasts in 4 cases. GM-CSF was given subcutaneously at a dose of 150 μg/m²/d during the initial 10 days. From day 11, Epo was administered by subcutaneous injections for 8 weeks at a dose of 100 U/kg/d and subsequently at an escalated dose of 200 U/kg/d in 3 patients. Changes in reticulocyte counts, haemoglobin levels, RBC support and ferrokinetic parameters were compared with pretreatment values. Two out of 8 évaluable patients showed a rise in haemoglobin levels at week 8 and 10, respectively, and lost their transfusion dependency for a period of 13 and 27 weeks. In 1 patient, haemoglobin level increased only after dose escalation of Epo (200 U/kg/d). Leukocyte counts remained uneffected by treatment with Epo, while 1 patient showed a 4-fold increase in platelet numbers. Toxicity was mild. Two patients died of pneumonia and global heart failure, respectively, unrelated to growth factor therapy. Based on this pilot study, we conclude that sequential treatment with GM-CSF and Epo does not increase erythroid responses in anaemic patients with MDS. Because of the delayed increase in haemoglobin in both responders, we surmise that the beneficial effects were induced by Epo alone.     

Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes

In vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors in patients with myelodysplastic syndrome (MDS). We performed a clinical trial to evaluate whether the combination of these growth factors was effective in relieving the cytopenias associated with MDS. 31 anaemic patients with low and intermediate-risk primary MDS were enrolled in a 12-week study. Therapy was initiated with GM-CSF at 1 microgram/kg/d.s.c., and then adjusted to either normalize or double the absolute neutrophil count. EPO was given subcutaneously on alternate days starting from day 2. The EPO dose was initiated at 150 U/kg and increased to 300 U/kg if after 6 weeks there was no or suboptimal erythroid response. 26 patients completed the study treatment. All evaluable cases had a neutrophil response. Clinically significant erythroid responses with increases of haemoglobin levels of at least 1 g/dl and/or reduction of transfusion needs were seen in 9/26 (34.6%), five patients improving their response after dose escalation of EPO. Treatment had no apparent effect on mean platelet counts, a single case displaying a trilineage response. An elevated bone marrow erythroid infiltration and low concentrations of circulating tumour necrosis factor-alpha were the only predictors of haemoglobin response both in univariate and in multivariate analysis. We conclude that the combination GM-CSF + EPO can abrogate neutropenia and substantially relieve transfusion requirements in a large proportion of patients with low and intermediate risk MDS. However, in vivo synergy between these growth factors for the production of erythroid precursors is not supported by our data.     

Induction of soluble IL-2 receptor in patients with myelodysplastic syndromes undergoing high-dose interleukin-3 treatment

Summary Sera of ten healthy controls and of 15 patients with myelodysplastic syndromes (MDS) were investigated for soluble interleukin-2 receptor (sIL-2R) with a cell-free enzyme-linked immunosorbent assay (ELISA). The patients with MDS underwent treatment with IL-3: eigth patients at dose levels of 250 and 500 g/m² s.c. daily for 15 days, and seven patients at the dose levels of 60 and 125 g/m² s.c. three times per week for 12 weeks. None of the patients had reported infectious episodes or been under treatment with cytotoxic drugs and/or cytokines within the preceding 2 months. sIL-2R levels were elevated in MDS patients compared with healthy controls (p<0.001). sIL-2R increased in the high-dose treatment group from 504±68 U/ml to 731±199 U/ml (p<0.025). The increased sIL2R expression in MDS could be a primary event due to involvement of lymphocytes in the malignant clone or due to a secondary alteration of the cytokine network caused by chronic neutropenia. A down-regulation of the immune response caused by neutralization of free IL-2 by sIL-2R during IL-3 therapy seems possible.     

Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients

Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count < 10% (RAEB-I), and 27 with RAEB and blast count between 11-20% (RAEB-II). rHuEpo was given subcutaneously at a dose of 150 U/kg thrice weekly, for a minimum of 26 weeks. Response to treatment was evaluated after 12 and 26 weeks of therapy. The overall RR was 45.1%; the RR for RA, RARS, RAEB-I and RAEB-II were 48.3%, 58.4%, 33.8% and 13% respectively. A significant increase in RR was observed at week 26 in RA, RARS and RAEB-I patients, as the response probability increased with treatment duration. The RR was higher in the good cytogenetic prognostic group and serum Epo level of > 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21.7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.     

The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS)

One hundred and sixteen (116) anaemic patients with myelodysplastic syndromes (MDS) were treated with recombinant human erythropoietin (r-HuEpo) in an openlabel, multicentre, compassionate treatment trial; 100 patients received therapy for ≧ 4 weeks and were evaluable for efficacy. The distribution of FAB subtypes was: 44 RA, 40 RARS, eight RAEB, two RAEB-t, one CMML, and five not specified. Mean baseline haematocrit was 24.5%, and the mean prestudy transfusion requirement in the 12 weeks immediately prior to study entry was 6.5 units. r-HuEpo treatment was initiated at a dose of 150U/kg three times weekly, with dose escalations of 50U/kg monthly (up to 300U/kg 3 x /week) permitted if the haematocrit failed to rise. Response to therapy was defined as either an increase in haematocrit of ≧ 6 percentage points over baseline, unrelated to transfusion, or a ≧ 50% decrease in transfusion requirement in the last 3 months of study treatment, compared to the baseline period (12 weeks), By these criteria, 28% (28/100) of patients responded to r-HuEpo treatment. Overall, 86% (24/28) of patients responding to therapy had baseline Epo levels ≧ 100 mU/ml. Response rates by FAB subtype were: RA 39% (17/44), RARS 17.5% (7/40) and RAEB 12.5% (1/8). Additionally, a 54% (15/28) response rate was seen in RA patients with baseline EPo levels ≧ 100 mU/ml. Responses to therapy were durable and generally occurred at r-HuEpo doses of 150-200 U/kg t.i.w. There were no reports of thrombosis, seizures or therapy-related hypertension. The data show that patients with MDS, especially those with the RA and RARS subtypes, can benefit from treatment with r-HuEpo. Those patients with baseline Epo levels ≧ 100 mU/ml were most likely to respond to therapy.     

Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia

We examined the in vitro effect of recombinant human granulocyte colony- stimulating factor (rhG-CSF) on neutrophil anomalies in 20 patients with myelodysplastic syndromes (MDS) and eight patients with chronic myelogenous leukemia (CML). Neutrophil alkaline phosphatase (NAP) activity was determined in nine MDS patients and eight CML patients by a scoring method. NAP scores were decreased in six of the nine patients with MDS and in all of the patients with CML. In all patients with these diseases, NAP scores increased by incubating the blood with rhG- CSF. An increase in NAP scores by rhG-CSF was observed even at a concentration of 1 U/mL in patients with MDS but was observed only at higher concentrations (1,000 to 10,000 U/mL) in patients with CML. Significant increases in NAP scores occurred at 12 hours' incubation in patients with MDS, whereas the increase was more gradual in patients with CML. This time course difference was thought to be due mainly to the difference in cell populations of circulating myeloid cells between MDS patients and CML patients. Induction of NAP activity by rhG-CSF in patients with both these diseases was suppressed by the addition of inhibitors of RNA or protein synthesis. Neutrophil superoxide anion (O2- ) production induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was determined in the other 11 patients with MDS. This neutrophil function was decreased in seven of the 11 patients with MDS, normal in two patients, and increased in two patients. Preincubation with rhG-CSF caused a significant increase in fMLP-induced O2- production in nine of the 11 patients with MDS. rhG-CSF enhanced this neutrophil function in a time- and dose-dependent manner, and maximal stimulation was observed at 2,000 to 4,000 U/mL of rhG-CSF and at five to ten minutes' incubation. The present results show that rhG-CSF is able to repair at least in part the neutrophil anomalies in these patients, and our data, especially for patients with MDS, suggest the clinical usefulness of rhG-CSF for this preleukemic disorder.     

Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group

BACKGROUND AND OBJECTIVE: Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes (MDS). Human recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) have been used to treat patients with anemia of MDS, but fewer than 50% respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS. DESIGN AND METHODS: A non-randomized multicenter trial was carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years, refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb <= 100 g/L or receiving transfusions and serum erythropoietin <= 250 U/L. These patients were treated with subcutaneous rHuEpo (300 U/kg) three times a week for 8 weeks. In the case of partial response (PR) or no response (NR) subcutaneosly administered G-CSF (1 microg/kg) three times a week was added to the rHuEpo for 8 more weeks. If the patient achieved complete response (CR) or PR in the second phase, he was included in a follow-up phase of 24 weeks in which the dose of growth factors was tapered down. Several variables, including the score published by the Scandinavian-American group, were used as possible predictive variables. RESULTS: An erythroid response was observed in 16 patients (50%); in 12 it was a CR and in 4 it was a PR. During the period of rHuEpo administration, 7 CR and 4 PR (34.4%) were documented. Of the 14 patients in whom G-CSF was added to rHuEpo, 7 (50%) responded (3 CR and 4 PR). No major side-effects associated with growth factors were observed. The multivariate analysis showed that of the different variables evaluated only the Scandinavian-American response score was significant with a relative probability of response of 11.8 (95% confident intervals: 2.5-53) when this score was > +1 (77% of cases responded). In contrast, when this score was <= 1 only 15 % of the cases responded. INTERPRETATION AND CONCLUSIONS: Use of the Scandinavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term study evaluating the regimen's cost-benefit ratio is warranted.     

Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825-11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).     

A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms

Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28‐day cycles for the first 3 cycles. Azacytidine 25 mg/m² (Day 1‐5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m² (Days 1‐5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty‐five patients were treated (MDS/MPN‐U, n =14; CMML, n =17; aCML, n =4), with a median follow‐up of 15.2 months (range, 1.0–41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2‐mutated (P = .02) and had splenomegaly (P = .03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN‐U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P = .034). The combination of ruxolitinib and azacytidine was well‐tolerated with an ICP MDS/MPN‐response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN‐U.     

A Phase II intra‐patient dose‐escalation trial of weight‐based darbepoetin alfa with or without granulocyte‐colony stimulating factor in myelodysplastic syndromes

This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate‐1 risk myelodysplastic syndrome (MDS). Intra‐patient dose escalation of DA was undertaken in three 6‐week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte‐colony stimulating factor (G‐CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight‐based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G‐CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low‐level non‐neutralizing anti‐DA antibodies. Our data indicate that weekly weight‐based dosing of DA, with the addition of G‐CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower‐risk MDS patients. Am. J. Hematol, 2009. © 2008 Wiley‐Liss, Inc.     

Plasma soluble interleukin-2 receptor level in patients with primary myelodysplastic syndromes: a relationship with disease subtype and clinical outcome

To assess the hypothesis that the plasma soluble interleukin-2 receptor (sIL-2R) level may have predictive value for morbidity/mortality in patients with myelodysplastic syndromes (MDS), we determined the plasma sIL-2R level of 80 MDS patients and examined their subsequent clinical course. Compared with low-risk MDS (refractory anaemia (RA) and RA with ringed sideroblasts) patients and normal subjects, the plasma sIL-2R level was significantly elevated in high-risk MDS (three other MDS subtypes and acute leukaemia following MDS) patients (high-risk MDS versus low-risk MDS, P  < 0.01; high-risk MDS versus normal subjects, P  < 0.01). 14/40 low-risk MDS patients developed at least one of the following during the follow-up period: erythrocyte transfusion dependence, infections requiring hospitalization, disease progression or MDS-related death. The plasma sIL-2R level was higher in these eventful subjects than in event-free low-risk subjects ( P  < 0.0001), and all of 10 low-risk subjects with a plasma sIL-2R level > 540 U/ml experienced at least one event. By logistic regression analysis of various parameters in these 40 low-risk subjects, the plasma sIL-2R level was identified as the strongest independent parameter for predicting eventful subjects ( P  < 0.0047). The plasma sIL-2R level did not show a predictive value in high-risk MDS. This study revealed that the plasma sIL-2R level is significantly elevated in high-risk MDS and suggested that the plasma sIL-2R level is a valuable predictive factor for the clinical outcome in low-risk MDS.     

Results of combination therapy with amifostine, pentoxifylline, ciprofloxacin and dexamethasone in patients with myelodysplastic syndrome and acute myeloid leukemia

Myelodysplastic syndrome (MDS) is a clonal disease of the bone marrow characterized by abnormal hematopoiesis and cytopenias. It has been shown that abnormal cytokine production together with apoptosis are major contributors to the cytopenias associated with the disorder. As the interaction of cytokines plays a role in the pathogenesis, suppression of the cytokine production by the administration of the combination of pentoxifylline, ciprofloxacin, and dexamethasone (PCD combination) has resulted in the correction of at least some aspects of the cytopenias in the majority of patients and in complete hematologic remission in a small percentage. The aminothiol prodrug amifostine, a compound to protect tissues from cytotoxic drugs and radiotherapy has been found to stimulate proliferation of normal hematopoiesis and suppress apoptosis in patients with MDS. In this study we report the results of combination therapy of amifostine and PCD in 12 patients with MDS and acute myeloid leukemia (AML). Amifostine was given in a dose of 200 mg/m(2), as an i.v. infusion administered in 10 min, three times a week; pentoxifylline 2400 mg/day, (3 x 800 mg) p.o.; ciprofloxacin, 1 g/day p.o.; dexamethasone 4.5 mg/day p.o. We achieved 66% response rate in our patients. In some cases responses were achieved in only thrombocytopenia or anemia whereas in others responses were achieved in multiple series. As a result it was found that amifostine + PCD combination may be beneficial in reversing cytopenias in the treatment of MDS and AML and is worth further study.     

Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M(2), 300 mg/M(2), and 400 mg/M(2)) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered. (Blood. 2000;95:1580-1587)     

Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin [see comments]

We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty- four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.     

A pharmacokinetic analysis of a novel enzyme replacement therapy with Gene-Activated human glucocerebrosidase (GA-GCB) in patients with type 1 Gaucher disease

OBJECTIVES: To evaluate pharmacokinetics of Gene-Activated human glucocerebrosidase (GA-GCB), a novel enzyme replacement therapy, in patients with type 1 Gaucher disease. STUDY DESIGN: Open-label study of GA-GCB, administered as a 1-h intravenous (IV) infusion every other week was evaluated. The first three patients sequentially received one infusion each at 15 U/kg, 30 U/kg, and 60 U/kg at 2-week intervals and then continued with 60 U/kg/infusion every other week; subsequently nine more patients received GA-GCB at 60 U/kg/infusion every other week. Each patient received 20 infusions (40 weeks). Pharmacokinetic (PK) parameters reported are from blood samples collected at Weeks 1, 3, and 5 for dose-escalated patients and at Week 1 from the other nine patients. RESULTS: GA-GCB was rapidly cleared from the circulation and followed first-order elimination kinetics in the 12 patients who received IV infusions. Maximum serum concentration (C(max)) coincided with the end of the 1-h infusion. Both C(max) and area under the curve (AUC) were linearly proportional to dose from 15 U/kg to 60 U/kg. Elimination half-life was independent of dose; mean elimination half-life at 60 U/kg was approximately 10 min (range: 4-15 min). Mean serum clearance was 13 ml/min/kg (range: 9-20 ml/min/kg) and V(ss) (apparent volume of distribution) was approximately 18% body weight (range: 11-27% body weight). CONCLUSIONS: GA-GCB demonstrated linear PK parameters over clinically relevant doses (15 U/kg-60 U/kg) indicating that the dose of IV-administered GA-GCB to target tissues should also be linearly proportional to dose.     

Improvement of anemia in hemodialysis patients treated by hemodiafiltration with high-volume on-line-prepared substitution fluid

BACKGROUND: Hemodiafiltration (HDF) is associated with a lower incidence of neuropathy, carpal tunnel syndrome, joint pain, and partial correction of anemia. HDF with on-line-prepared substitution fluid (OL HDF), as compared with conventional hemodialysis, increases the treatment tolerance and, as compared with standard HDF, avoids storage problems and allows a higher substitution volume at low cost. METHODS: Thirty-two hemodialysis patients treated by OL HDF for at least 9 months were studied. Hemoglobin, hematocrit, iron metabolism, serum albumin, dialysis dose and dry body weight were determined under a settled condition with regular hemodialysis 3 months before the transfer to OL HDF. The same parameters were analyzed 3, 6 and 9 months after the beginning of the new treatment modality. RESULTS: During OL HDF, hemoglobin values significantly increased in patients without addition of recombinant human erythropoietin (rHuEPO): baseline vs. 6 months 11 +/- 1.7 vs. 12 +/- 1.8 g/dl (p < 0.01); baseline vs. 9 months 11 +/- 1.7 vs. 12 +/- 1.6 g/dl (p < 0.05). In patients on a maintenance dose of rhuEPO, this could be significantly reduced, while the target hemoglobin levels were maintained (10.6 +/- 0.9 g/dl): baseline 99.8 +/- 50.4 U/kg/week, 3rd month 76.2 +/- 43 U/kg/week, 6th month 64.3 +/- 37 U/kg/week, and 9th month 59.4 +/- 38.6 U/kg/week (p = 0.007, p = 0.0006, and p = 0.0007, respectively, vs. baseline). Iron metabolism, dialysis dose, dry body weight and serum albumin levels did not significantly change during the follow-up period. Further, a stability of the rHuEPO supplementation was observed in 14 patients followed up for 24 months. CONCLUSIONS: OL HDF influences anemia and rHuEPO dose. It allows considerable anemia correction in patients without rHuEPO treatment, while it significantly reduces rHuEPO doses in those on rHuEPO treatment as compared with standard hemodialysis. The rHuEPO costs are consequently reduced.