Acute Myeloid Leukemia or Myelodysplastic Syndrome in Randomized Controlled Clinical Trials of Cancer Chemotherapy With Granulocyte Colony-Stimulating Factor: A Systematic Review

2010 ◽  
Vol 28 (17) ◽  
pp. 2914-2924 ◽  
Author(s):  
Gary H. Lyman ◽  
David C. Dale ◽  
Debra A. Wolff ◽  
Eva Culakova ◽  
Marek S. Poniewierski ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Dose Intensity ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Randomized Controlled ◽  
Chemotherapy Dose ◽  
Stimulating Factor ◽  
Acute Myeloid ◽  
Chemotherapy Dose Intensity

Purpose To evaluate the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and overall mortality in patients receiving chemotherapy with or without granulocyte colony-stimulating factor (G-CSF), a systematic review of randomized controlled trials (RCTs) was conducted. Methods Electronic databases searched through October 2008 identified 3,794 articles for initial screening. Eligibility included solid tumor or lymphoma patients randomly assigned to chemotherapy with or without G-CSF support, ≥ 2 years of follow-up, and reporting AML/MDS or all second malignancies. Dual blinded data extraction was performed. Relative risk (RR) and absolute risk (AR) estimates ± 95% CIs were calculated by the Mantel-Haenszel method. Results In the 25 eligible RCTs, 6,058 and 6,746 patients were randomly assigned to receive chemotherapy with and without initial G-CSF support, respectively. At mean and median follow-up across studies of 60 and 53 months, respectively, AML/MDS was reported in 22 control patients and 43 G-CSF–treated patients, with an estimated RR of 1.92 (95% CI, 1.19 to 3.07; P = .007) and AR increase of 0.41% (95% CI, 0.10% to 0.72%; P = .009). Deaths were reported in 1,845 patients randomly assigned to G-CSF and in 2,099 controls, for estimates of RR and AR decrease of 0.897 (95% CI, 0.857 to 0.938; P < .001) and 3.40% (95% CI, 2.01% to 4.80%; P < .001), respectively. Greater RR reduction for mortality was seen for both larger studies (P = .05) and greater chemotherapy dose-intensity (P = .012). Conclusion Delivered chemotherapy dose-intensity and risk of AML/MDS are increased but all-cause mortality is decreased in patients receiving chemotherapy with G-CSF support. Greater reductions in mortality were observed with greater chemotherapy dose-intensity.

Acute Myeloid Leukemia or Myelodysplastic Syndromes and All-Cause Mortality in Randomized Controlled Trials of Cancer Patients Receiving Chemotherapy with or without Granulocyte Colony-Stimulating Factor: A Systematic Review and Meta-Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3100-3100
Author(s):  
Gary H. Lyman ◽  
Jeffrey Crawford ◽  
Eva Culakova ◽  
Marek S. Poniewierski ◽  
Debra Wolff ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Dose Intensity ◽  
Granulocyte Colony Stimulating Factor ◽  
Randomized Controlled ◽  
All Cause Mortality ◽  
Chemotherapy Dose ◽  
To Receive ◽  
Stimulating Factor

Abstract Abstract 3100 Poster Board III-37 Background The risk of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) is increased following prior exposure to cytotoxic cancer chemotherapy and radiation therapy. A few retrospective studies have suggested a potential risk for AML/MDS in cancer patients also receiving granulocyte colony-stimulating factor (G-CSF). A systematic review and meta-analysis of randomized controlled clinical trials (RCTs) in patients receiving cancer chemotherapy ± initial G-CSF support was conducted to evaluate the risk of AML/MDS and impact on all-cause mortality. Methods Electronic databases including Medline, EMBASE, Cochrane Library and meeting proceedings were searched. Eligible studies included RCTs of solid tumor or lymphoma patients receiving chemotherapy ± initial G-CSF and ≥2 years follow-up reporting AML/MDS or second malignancies. Dual blinded data extraction was performed. After evaluating for heterogeneity, relative risk (RR) and absolute risk (AR) difference [95% confidence limits] were estimated by the method of Mantel and Haenszel. Results In the 25 eligible RCTs, 6,058 patients were randomized to receive chemotherapy with and 6,746 without G-CSF support. Mean and median follow-up in all studies were 60 and 53 months, respectively. Among 23 RCTs reporting AML/MDS, 22 cases (0.36%) were reported in control- and 43 (0.79%) in G-CSF-treated patients. The RR and AR increase for AML/MDS in G-CSF-supported patients was 1.92 [1.19, 3.07; P=.007] and 0.41% [0.10%, 0.72%; P=.009], respectively. A trend suggesting publication bias was observed for AML/MDS consistent with an underreporting of small negative studies based on funnel plot asymmetry [Egger's regression intercept, P=.039]. No significant difference in reported AML/MDS was found based on source of study funding with RR for AML/MDS for industry and non-industry funded studies of 2.57 and 1.71, respectively. Trends toward greater risk of AML/MDS with higher cumulative chemotherapy dose were observed but none reached statistical significance. Mortality was reported in all 25 trials occurring in 1,845 patients randomized to receive G-CSF and in 2,099 controls. The RR and AR decrease for mortality in G-CSF-supported patients were 0.897 [0.857, 0.938; P<.0001] and 3.40% [2.01%, 4.80%; P<.0001], respectively. Greater RR reduction for mortality was seen for larger study sample size [P=.05]. Greater RR reduction for mortality was also observed with increasing planned [P=.016] as well as greater delivered relative [P=.015] and absolute [P=.027] chemotherapy dose intensity in patients receiving initial G-CSF support compared to controls. Conclusions Risk of AML/MDS is increased while all-cause mortality is decreased in patients receiving G-CSF-supported chemotherapy. Greater reductions in risk for all cause mortality were observed in larger studies and with greater planned and delivered chemotherapy dose intensity. Disclosures Lyman: Amgen: Research Funding, Speakers Bureau. Crawford:Amgen: Consultancy. Kuderer:Amgen: Husband receives research support. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

Standard Versus Dose-Intensified Chemotherapy with Granulocyte Colony-Stimulating Factor for Malignant Lymphoma: Evaluation of Risk for Acute Myeloid Leukemia or Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2390-2390 ◽  
Author(s):  
Gary H. Lyman ◽  
David C. Dale ◽  
Debra Wolff ◽  
Eva Culakova ◽  
Nicole M. Kuderer ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Myeloid Leukemia ◽  
Retrospective Studies ◽  
Meta Analysis ◽  
Dose Intensity ◽  
Granulocyte Colony Stimulating Factor ◽  
Randomized Controlled ◽  
Chemotherapy Dose ◽  
Intensified Chemotherapy ◽  
Stimulating Factor

Abstract Background: Retrospective studies have reported inconsistent results concerning risk of acute myeloid leukemia or myelodysplastic syndrome (t-ML) in cancer patients receiving granulocyte colony-stimulating factor (G-CSF) along with systemic chemotherapy. In order to further evaluate any potential impact of chemotherapy with G-CSF support on overall survival (OS) and risk of t-ML in malignant lymphoma, a systematic review and subsequent meta-analysis of prospective, randomized controlled clinical trials were conducted. Methods: Electronic databases including Medline, EMBASE, BIOSIS and the Cochrane Library were searched through August 2008 identifying 5885 articles for initial screening. Eligibility criteria included studies of adult patients with non-myeloid malignancies receiving chemotherapy (CT) with or without G-CSF with at least 2 years of follow-up. Of the 136 potentially eligible publications identified, 8 were from prospective, randomized, controlled trials (RCTs) in adult patients with non-Hodgkin’s lymphoma (7) or Hodgkin’s disease (1). Excluded reports consisted of retrospective studies, duplicate reports, studies with no control group or studies involving stem cell transplantation. Study outcomes included all secondary malignancies, t-ML, OS and delivered chemotherapy dose intensity. Meta-analyses were based on the method of Mantel and Haenszel with summary estimates and 95% CIs for both relative risk (RR) and absolute risk difference (ARD;%). Results: In 8 RCTs, a total of 4089 patients were randomized to receive CT with G-CSF support (n=2032) versus no G-CSF (n=2057). In 5 of the 8 trials, dose intensified or dose dense CT was given in the G-CSF arms compared to standard CT without initial G-CSF. Initial CT dose and schedule were the same in the remaining 3 trials although each reported significantly greater overall delivered dose intensity in the G-CSF arm. No signficant heterogeneity was observed for the primary outcomes. Among 6 reporting RCTs, secondary malignancies occurred in 36 patients in the G-CSF arms versus 35 patients in control arms. T-ML was reported in 15 patients randomized to G-CSF compared to 6 in control patients [RR=2.30; 0.95–5.58; ARD = 0.6%; −0.1%–1.3%; p=.06]. In all 8 studies, patients receiving G-CSF received significantly greater chemotherapy dose intensity compared to controls. Among patients randomized to G-CSF support, a statistically significant increase in OS [RR=0.87; 0.81–0.94; ARD = −5.0%; −7.7%–−2.3%; p&lt;.0001] was observed. Conclusions: A meta-analysis based on an extensive search of the literature demonstrated that intensified chemotherapy with G-CSF support in malignant lymphoma resulted in a significant improvement in OS despite a non-significant trend toward an increase in t-ML. There were insufficient data to definitively examine the independent roles of G-CSF versus dose intensified chemotherapy on risk of t-ML.

Use of Recombinant Human Granulocyte Colony-Stimulating Factor to Increase Chemotherapy Dose-Intensity: A Randomized Trial in Very High-Risk Childhood Acute Lymphoblastic Leukemia

2000 ◽  
Vol 18 (7) ◽  
pp. 1517-1524 ◽  
Author(s):  
G. Michel ◽  
J. Landman-Parker ◽  
M.F. Auclerc ◽  
C. Mathey ◽  
T. Leblanc ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Chemotherapy Dose ◽  
Stimulating Factor ◽  
Very High ◽  
Chemotherapy Dose Intensity

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 × 109/L and platelet count was > 100 × 109/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non–G-CSF group (mean ± 95% confidence interval, 105 ± 5% v 91 ± 4%; P < .001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

Granulocyte Colony-Stimulating Factor (G-CSF) Treatment of Childhood Acute Myeloid Leukemias That Overexpress the Differentiation-Defective G-CSF Receptor Isoform IV Is Associated With a Higher Incidence of Relapse

2010 ◽  
Vol 28 (15) ◽  
pp. 2591-2597 ◽  
Author(s):  
Stephanie Ehlers ◽  
Christin Herbst ◽  
Martin Zimmermann ◽  
Nicole Scharn ◽  
Manuela Germeshausen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Children And Adolescents ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Cell Surface Expression ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Acute Myeloid ◽  
Factor G

Purpose This prospective, multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Muenster (AML-BFM) 98 study randomly tested the ability of granulocyte colony-stimulating factor (G-CSF) to reduce infectious complications and to improve outcomes in children and adolescents with acute myeloid leukemia (AML). However, a trend toward an increased incidence of relapses in the standard-risk (SR) group after G-CSF treatment was observed. Patients and Methods Of 154 SR patients in the AML-BFM 98 cohort, 50 patients were tested for G-CSF receptor (G-CSFR) RNA isoform I and IV expression, G-CSFR cell surface expression, and acquired mutations in the G-CSFR gene. Results In patients randomly assigned to receive G-CSF after induction, 16 patients overexpressing the G-CSFR isoform IV showed an increased 5-year cumulative incidence of relapse (50% ± 13%) compared with 14 patients with low-level isoform IV expression (14% ± 10%; log-rank P = .04). The level of G-CSFR isoform IV had no significant effect in patients not receiving G-CSF (P = .19). Multivariate analyses of the G-CSF–treated subgroup, including the parameters G-CSFR isoform IV overexpression, sex, and favorable cytogenetics as covariables, revealed the prognostic relevance of G-CSFR isoform IV overexpression for 5-year event-free survival (P = .031) and the 5-year cumulative incidence of relapse (P = .049). Conclusion Our results demonstrate that children and adolescents with AMLs that overexpress the differentiation-defective G-CSFR isoform IV respond to G-CSF administration after induction, but with a significantly higher incidence of relapse.

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