Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation.

BACKGROUND: Explore safety and efficacy of three palonosetron-containing regimens for emesis prevention over 7 days in multiple myeloma (MM) patients receiving melphalan (100 mg/m(2)) and hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: Randomized, double-blind pilot study in MM patients (n=73) receiving 1, 2, or 3 days of 0.25 mg palonosetron (30-s i.v. bolus) 30 min before melphalan (days -2 and -1) and HSCT (day 0). Patients received dexamethasone (20 mg i.v., days -2 and -1) immediately before or after study drug/placebo. Daily diaries recorded emesis, rescue medication, nausea duration, and adverse events (AEs). RESULTS: Seven-day complete protection (no emesis) occurred in 41.7% [95% confidence interval (CI) 22.1% to 63.4%], 41.7% (95% CI 22.1% to 63.4%), and 44.0% (95% CI 24.2% to 65.1%) of patients receiving 1, 2, or 3 days of palonosetron, respectively (P=0.43). Complete response (emesis free without rescue medication) occurred in 8.3%, 20.8%, and 20.0% (P=0.14). Common AEs (≥10%) were mild-to-moderate diarrhea, constipation, headache, insomnia, and flatulence. No serious AEs occurred. CONCLUSIONS: Palonosetron with dexamethasone was safe and effective in preventing emesis in MM patients receiving melphalan and HSCT. This pilot study with a limited number of patients suggests that multiple doses of palonosetron could be more effective than a single dose in making patients emesis free without need for rescue medication. However, even multiple doses of palonosetron resulted in only 20% of patients being emesis free without rescue medication, suggesting that further improvement will require development of more effective combination antiemetic therapy.

Usage of megestrol acetate in the treatment of anorexia-cachexia syndrome in the elderly.

UNLABELLED: The aim of this review is to assess the efficacy and safety of megestrol acetate (MA) in geriatric cachexia. The paper presented here reviews a previously published study of MA use in 69 patients in a randomized double blind placebo-controlled trial. This paper will also address the underlying pathogenesis of cachexia (specifically, the role of cytokines) along with the use of MA, its mechanism of action and its side effects. OBJECTIVE: To compare the effects of MA oral suspension (O.S.), 800 mg/day, versus placebo on weight in geriatric nursing home patients with weight loss or low body weight. DESIGN: Twelve weeks, randomized, double-blind, placebo-controlled trial with a 13-week follow-up period. PATIENTS: Northport VAMC Nursing home patients with weight loss of * 5% of usual body weight over the past 3 months, or body weight 20% below their ideal body weight. INTERVENTIONS: Patients were randomly assigned to receive placebo or MA 800 mg/d for 12 weeks and were then followed for 13 weeks off treatment and mortality 4 years post treatment. MEASUREMENTS: Primary outcome- weight and appetite change. Secondary outcome-sense of well being, enjoyment of life, change in depression scale, laboratory nutrition parameters, energy intake counts, body composition, and adverse events. RESULTS: At 12 weeks there were no significant differences in weight gain between treatment groups, while MA-treated patients reported significantly greater improvement in appetite, enjoyment of life, and well being. At week 25 (3 months after treatment), 61.9% of MA-treated patients had gained * 1.82 kg (4 lbs) compared to 21.7% of placebo patients. There was no difference in survival between MA and placebo groups. Considering possible confounders, higher initial IL-6, initial TNFR-p75 levels, and final neutrophil percentage were associated with elevated mortality, whereas higher initial pre-albumin, initial albumin, final pre-albumin, final albumin and final weight gain were associated with decreased death.

Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies.

BACKGROUND: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl < or =50 vs >50 ml min(-1) (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl < or =50 vs >50 ml min(-1). These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials.

In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.

Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome.

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.

Novel therapeutics for chemotherapy-resistant acute myeloid leukaemia.

Patients with chemotherapy-resistant acute myeloid leukaemia are rarely cured by non-allogeneic transplant therapies. Multiple new investigational agents have become available for treatment of these patients and there are few tools to permit rational drug and clinical trial selection. In this review, we describe the chemical and biological properties of some of these agents and some of their initial clinical activity to date. The selected agents react with either cell surface molecules or signal pathway intermediates and include antibody and antibody conjugates to CD33 and CD45, a fusion protein directed to the granulocyte-macrophage colony-stimulating factor receptor, an anti-sense oligonucleotide to Bcl2, a farnesyl transferase inhibitor, and a protein kinase C agonist/inhibitor. The challenge for the next decade will be how to select patients for particular molecularly targeted therapeutics and how to combine these agents.

The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients.

BACKGROUND: Cachexia is associated with elevated levels of cytokines in cancer and human immunodeficiency virus patients. Studies in cancer and acquired immunodeficiency syndrome patients showed that treatment with megestrol acetate (MA) is associated with improvement in appetite and weight gain. Reduction in the levels of cytokines is associated with weight gain in laboratory animals with cancer. This study evaluates the correlation between changes in cytokine (or their receptor) levels and weight following MA treatment in geriatric weight-loss patients. METHODS: Veterans Administration Medical Center nursing home patients (N = 69) with a weight loss of > or =5% of usual body weight over the past 3 months or body weight 20% below their ideal body weight participated in a 12-week, randomized, double-blind, placebo-controlled trial, with an additional 13-week follow-up period. Patients were randomly assigned to receive a placebo or MA oral suspension of 800 mg/d for 12 weeks. Levels of the following cytokines (or their receptors) were measured at baseline and after 12 weeks of treatment: tumor necrosis factor soluble receptor (TNFR) subunits. TNFR-p55 and TNFR-p75: interleukin 6 (IL-6); and the soluble interleukin-2 receptor (sIL-2R). The subjects' weight and body composition were measured at the start of the study. Weight and mortality were followed up for another 13 weeks after discontinuing the MA study drug. RESULTS: Elevated levels of IL-6 in almost all geriatric cachexic patients, compared with normal volunteers (mean, <4.6 pg/ml). were noted at baseline. At 12 weeks after the study drug treatment, there was a decrease in cytokine levels (or their receptors) in the MA group (mean change in IL-6, 3.63+/-6.62 pg/ml; TNFR-p55, -0.06+/-0.11 ng/ml; TNFR-p75. -0.01+/-0.29 ng/ml; and sIL-2R, 0.08+/-0.07 ng/ml) and the placebo group (mean change in IL-6, -2.08+/-3.92 pg/ml; TNFR-p55, -0.02+/-0.08 ng/ml; TNFR-p75, -0.20+/-0.18 ng/ml; and sIL-2R, 0.02+/-0.03 ng/ml). Although the change in cytokine levels was not statistically significant between the two groups, significant negative correlation (p < .05) was found. For example, increased weight correlated with decreased sIL-2R levels (r = .36) and TNFR-p75 (r = -.31; fat-free mass (FFM) gain and reduction of sIL-2R (r = -.39), TNFR-p75 (r = -.30). There was a significant correlation between weight gain and reduction of TNFR-p75 (r = .54), TNFR-p55 (r- = .47), and sIL-2R (r = -.53); FFM gain and reduction of sIL-2R (r = -.59), TNFR-p75 (r = -.41), TNFR-p55 (r = -.42); and fat gain and reduction of TNFR-p75 (r = -.41) in the MA group (p < .05), but not in the placebo group. CONCLUSIONS: Although there was no significant change in cytokine levels between the two groups, the reduction in cytokine levels after MA treatment correlated with improvement in weight, fat mass, and FFM at 12 weeks.

Quality of life and stimulation of weight gain after treatment with megestrol acetate: correlation between cytokine levels and nutritional status, appetite in geriatric patients with wasting syndrome.

BACKGROUND: The geriatric wasting syndrome (GWS) has been associated with proinflammatory cytokines, depression and progressive decline in quality of life (QOL). The objective of this study was to evaluate the correlation between the changes in cytokine levels and appetite, nutritional markers, and QOL in geriatric patients with GWS following a randomized clinical trial of megestrol acetate (MA) versus placebo. METHODS: This was a prospective, double-blind, placebo-controlled trial. We evaluated 69 predominantly male (3 females) nursing home residents with weight loss of > or =5% of their usual body weight over the past three months or body weight 20% below their ideal body weight. Patients were randomly assigned to receive either placebo or megestrol acetate (MA) oral suspension (O.S.) 800 mg/day for 12 weeks and were then followed for 13 weeks off treatment. Data on appetite, weight, nutritional status, QOL and cytokine levels were collected at baseline and week 12. The correlation between appetite, weight, nutritional status, sense of well being and cytokine level changes in response to MA treatment was examined at week 12. RESULTS: Appetite, sense of well being, and QOL assessed by an "enjoyment list" significantly improved in the MA arm. Rising prealbumin showed a negative correlation with decreasing IL-6 (r = -0.51), TNFR-p 55 (r = -0.49) and sIL-2R (r = -0.38). There was also an improvement in prealbumin and a decrease in IL-6 and TNFR-p55 in the MA-arm (p < 0.01). A correlation between a decrease in the IL-6 levels and improvement in depression (r = 0.50) was seen in the MA arm as well. Improvement in appetite positively correlated with increased enjoyment of life (r = -0.41), less depression (r = -0.34), improved sense of well being (r = 0.36), prealbumin gain (r = 0.30), and weight gain (r = 0.38) by 12 weeks. Also, improvement in appetite positively correlated with improvement in nutritional parameters such as prealbumin, albumin, fat free mass and weight in the MA arm. CONCLUSIONS: In a geriatric nursing home population with weight loss, reduction in cytokine levels after MA treatment correlates with improvement in appetite, prealbumin, albumin, and improvement in quality of life.

Mobilization of peripheral-blood stem cells by concurrent administration of daniplestim and granulocyte colony-stimulating factor in patients with breast cancer or lymphoma.

PURPOSE: To evaluate the safety and hematopoietic activity of daniplestim administered concurrently with granulocyte colony-stimulating factor (G-CSF) for peripheral-blood stem-cell (PBSC) mobilization. PATIENTS AND METHODS: In the initial dose-escalation phase, 25 patients with adenocarcinoma of the breast (AB; 13 patients) or lymphoma (12 patients) were given daniplestim at doses ranging from 0.1 to 3.75 microgram/kg/d plus G-CSF 10 microgram/kg/d. In the randomized phase, 52 patients with AB (27 patients) or lymphoma (25 patients) were randomized within disease categories to the daniplestim dose chosen in the dose-escalation phase plus G-CSF 10 microgram/kg/d (D+G) or placebo plus G-CSF 10 microgram/kg/d (P+G) for up to 7 days. RESULTS: A daniplestim dose of 2. 5 microg/kg/d was chosen for further study because it was hematopoietically active and had an acceptable side-effect profile. In the randomized phase, in patients with AB, D+G was associated with a higher probability (P =.0696) of collecting >/= 2.5 x 10(6) CD34(+) cells/kg and significantly higher circulating CD34(+) cell counts (P =.0498) on days 6 through 9 after the initiation of dosing. The target level was more likely to be reached with additional leukaphereses in the patients given D+G. Patients given P+G did not benefit from additional leukaphereses beyond the first procedure. The type of mobilization did show a trend toward a shorter duration of neutropenia in the D+G group. The adverse events with D+G consisted largely of mild to moderate flu-like symptoms, including headache and fever, and occurred more frequently than with P+G. CONCLUSION: Daniplestim administered at 2.5 microgram/kg/d is tolerable and active when combined with G-CSF, and the combination may prove more effective than G-CSF alone in promoting the collection of adequate numbers of CD34(+) cells for PBSC infusion in patients with AB.

Improvement in quality-of-life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: results of a double-blind, placebo-controlled study.

BACKGROUND: Weight loss among older patients is a severe problem, associated with an increased incidence of infections, decubiti, and death. Megestrol acetate (MA) causes weight gain in cachectic cancer and AIDS patients, but its effects in older cachectic patients are unknown. OBJECTIVE: To compare the effects of MA oral suspension (O.S.), 800 mg/day, versus placebo on weight in geriatric nursing home patients with weight loss or low body weight. DESIGN: Twelve-week, randomized, double-blind, placebo-controlled trial with a 13-week follow-up period. SETTING: Veterans Administration Medical Center (VMAC) nursing home. PATIENTS: Nursing home patients with weight loss of > or =5% of usual body weight over the past 3 months, or body weight 20% below their ideal body weight. INTERVENTIONS: Patients were randomly assigned to receive placebo or MA 800 mg/day for 12 weeks and were then followed for 13 weeks off treatment. MEASUREMENTS: Primary outcome was measured by weight and appetite change. Secondary outcome measures included sense of well-being, enjoyment of life, change in depression scale, laboratory nutrition parameters, energy intake counts, body composition, and adverse events. RESULTS: At 12 weeks there were no significant differences in weight gain between treatment groups, whereas MA-treated patients reported significantly greater improvement in appetite, enjoyment of life, and well-being. Body composition was not statistically different between the two groups. At Week 25 (3 months after treatment), 61.9% of MA-treated patients had gained > or =1.82 kg (4 lbs) compared to 21.7% of placebo patients. CONCLUSIONS: In geriatric patients with weight loss or low body weight MA improves appetite and well-being after 12 weeks of treatment. During the 3 months of MA treatment, there was no statistically significant weight gain (> or =4 lbs). Three months after treatment, weight gain (> or =4 lbs) was significantly increased in MA-treated patients.

Secondary hemochromatosis as a long-term complication of the treatment of hematologic malignancies.

The increased cure rate of hematologic malignancies including the use of bone marrow transplantation has focused attention on the chronic toxicity and quality of life of the survivors. We have observed five patients who have been diagnosed with clinically significant iron overload, presumably due to packed red blood cell transfusions, >/=12 months after transplant for a hematologic malignancy. In these patients, there is no history of veno-occlusive disease or family history of hemochromatosis. The allotransplant patient has been free of chronic graft versus host disease. Family screening has been negative. No patient developed clinically significant endocrinopathy, arthropathy, or cardiac disease. The patients have been treated with phlebotomy to bring the transferrin saturation and ferritin levels to normal. The long-term follow-up of patients treated for a hematologic malignancy should include analysis of hepatitis C virus and iron status. This may prevent the development of clinically significant chronic liver disease and possibly malignancy.

Geriatric cachexia: the role of cytokines.

Weight loss in elderly patients is a common clinical problem. Wasting and cachexia are associated with severe physiologic, psychologic, and immunologic consequences, regardless of the underlying causes. Cachexia has been associated with infections, decubitus ulcers, and even death. Multivariate analyses of risk and prognostic factors in community-acquired pneumonia in the elderly have found that age by itself is not a significant factor related to prognosis. Among the significant risk factors, only nutritional status is amenable to medical intervention. Cachexia in the elderly may have profound consequences: medical, cognitive, and psychiatric disorders may diminish self-reliance in activities of daily living, thus reducing quality of life and increasing the frequency of secondary procedures, hospitalizations, and the need for skilled care. Cachexia is associated with higher-than-normal concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1, IL-6, serotonin, and interferon gamma. The role of these proinflammatory cytokines has been established in the cachexia seen in cancer and AIDS patients. Reduction in the concentrations of these cytokines is associated with weight gain. Drugs that promote appetite stimulation and weight gain, such as progestational agents, cyproheptadines, pentoxifylline, and thalidomide may work by down-regulating these proinflammatory cytokines. An understanding of the relation between cachexia and negative regulatory cytokines may point to effective treatment of geriatric cachexia as well.

Comparison of insulin regimens and administration modalities in pregnancy complicated by diabetes.

PURPOSE: To compare insulin administration using premixed insulin (70% NPH/30% Regular) by an injectable pen with traditional self-mixed insulin administered by syringe. METHODS: In this study, 93 women were enrolled into four groups: 1) self-mixed/syringe, 2) premixed/syringe, 3) self-mixed/pen, and 4) premixed/pen. RESULTS: Women in the premixed pen group had significantly less cesarean deliveries for failure to progress in labor and a decrease (not significant) in postpartum infection and infant macrosomia. Patients felt premixed insulin administered by the pen was easier to use. No significant differences were noted in glucose control, compliance among the four groups, or cost. CONCLUSION: Premixed insulin administration via the pen is safe, effective and no more costly than traditional treatment for pregnant diabetic women.

Comparison of insulin regimens and administration modalities in pregnancy complicated by diabetes.

PURPOSE: To compare insulin administration using premixed insulin (70% NPH/30% Regular) by an injectable pen with traditional self-mixed insulin administered by syringe. METHODS: In this study, 93 women were enrolled into four groups.: 1) self-mixed/syringe, 2) premixed/syringe, 3) self-mixed/pen, and 4) premixed/pen. RESULTS: Women in the premixed pen group had significantly less cesarean deliveries for failure to progress in labor and a decrease (not significant) in postpartum infection and infant macrosomia. Patients felt premixed insulin administered by the pen was easier to use. No significant differences were noted in glucose control, compliance among the four groups, or cost. CONCLUSION: Premixed insulin administration via the pen is safe, effective and no more costly than traditional treatment for pregnant diabetic women.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein versus granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for non-Hodgkin's lymphoma: results of a randomized double-blind trial.

PURPOSE: A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery. PATIENTS AND METHODS: One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days. RESULTS: The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment. CONCLUSION: There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.

Comparison of four cytokine regimens for mobilization of peripheral blood stem cells: IL-3 alone and combined with GM-CSF or G-CSF.

Improved methods for mobilization may reduce the number of aphereses required to collect adequate numbers of peripheral blood stem cells (PBSC) and hasten engraftment following high-dose therapy. Mobilization with cytokines alone enables engraftment after myeloablative therapy. The optimal cytokine regimen for mobilization has not been established. The study evaluated the effects of four interleukin-3-containing cytokine regimens administered during steady state hematopoiesis on PBSC mobilization in 30 patients with breast cancer or lymphoid malignancies. These regimens included IL-3 alone (Arm 1), sequential IL-3 --> G-GSF (Arm 2), sequential IL-3 --> GM-CSF (Arm 3) and combined IL-3 + G-CSF (Arm 4). Consecutive days of apheresis were performed until a target of 4-6 x 10(8) mononuclear cells/kg were collected. All patients received intravenous GM-CSF after PBSC infusion. Median days to an ANC > or = 500/ microliters in Arm 3(22 days) was significantly slower than for patients in Arm 2 (13 days) but not significantly different from patients in Arm 1 or Arm 4. There was no significant difference in platelet engraftment or days of hospitalization between the study arms. Addition of GM-CSF to IL-3-containing mobilization regimens results in collection of PBSC that lead to delayed engraftment. Further development of Arms 1, 2, and 4 appear warranted.

Will cytokines alter the treatment of myelodysplastic syndrome?

Myelodysplastic syndrome is a frustrating disorder, which until recently lacked effective treatment. Patients usually succumb to infection, bleeding complications, or progression to acute leukemia. Recombinant cytokines such as granulocyte macrophage-colony stimulating factor, granulocyte-colony stimulating factor, interleukin-3, and erythropoietin have been used to ameliorate the cytopenias associated with this disease. Small clinical trials in myelodysplastic syndrome patients, using cytokines with myeloid activity (G-CSF, GMCSF, IL-3), have shown consistent elevations in the white blood cell counts with little success in elevating hemoglobin or platelets. Erythropoietin is able to increase the hemoglobin in a small group of myelodysplastic syndrome patients. Future trials using combinations of these cytokines may lead to multilineage effects.