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.

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.

The Role of Anti-CD33 for the Treatment of Acute Myeloid Leukemia – Systematic Review and Meta-Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1521-1521
Author(s):  
Ronit Gurion ◽  
Anat Gafter-Gvili ◽  
Ron Ram ◽  
Liat Vidal ◽  
Pia Raanani ◽  
...  
Keyword(s):  
Systematic Review ◽  
Acute Myeloid Leukemia ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
All Cause Mortality ◽  
Acute Myeloid

Abstract Abstract 1521 The treatment for acute myeloid leukemia (AML) has not changed dramatically for the last 20 years. Anti-CD33 monoclonal antibody therapy, the most prominent of which is gemtuzumab ozogamicin (GO), has been used over the last decade, in order to improve the results of patients with AML. It has been studied in a variety of contexts; at induction, consolidation and as re-induction after disease relapse. Several randomized controlled trials have evaluated the addition of anti-CD33 to chemotherapy as compared to chemotherapy alone for the treatment of AML. Systematic review and meta-analysis of randomized controlled trials comparing addition of anti-CD33 to chemotherapy with chemotherapy alone in patients with AML, for either induction or post-remission therapy. Patients under 18 years old or those with acute promyelocytic leukemia were excluded. The Cochrane Library, MEDLINE, conference proceedings and references were searched until July 2012. Two reviewers appraised the quality of trials and extracted data. Outcomes assessed were: all-cause mortality at 30 days, all-cause mortality at the end of follow up, complete response and relapse rate. Relative risks (RR) were estimated and pooled. Our search yielded 11 included trials, five of them published as abstracts, including 5239 patients. Most trials assessed GO and two trials assessed lintuzumab as the anti-CD33 agent. Dose and schedule differed between trials. Eight trials examined the effect of anti-CD33 in the induction setting: six assessed the addition of anti-CD33 to intensive induction (daunorubicin and cytarabine based) and two used low dose cytarabine in elderly patients. Three trials examined the addition of anti-CD33 in the post remission setting (one as consolidation, one as maintenance and one after relapse). When analyzing the addition of anti-CD33 in all settings together, there was no difference in all-cause mortality at 30 days or at the end of follow up between chemotherapy with anti-CD33 and chemotherapy alone (RR 1.15 [95% CI, 0.96–1.37, 7 trials], RR 0.96 [95% CI, 0.92–1.00, 8 trials] respectively). In the subgroup of favorable and intermediate risk AML, the addition of anti-CD33 had no effect on all-cause mortality, RR 0.94 (95% CI, 0.87–1.02, 3 trials)], however when analyzing the subgroup of favorable risk patients only, mortality was significantly reduced with the use of anti-CD33 (RR 0.60, 95% CI, 0.42–0.85, 2 trials). Treatment with anti-CD33 had no effect on complete remission rate, RR 1.05 (95% CI 0.96–1.14, 7 trials). Yet, it significantly reduced relapse rate, RR 0.90 (95% CI 0.84–0.96, 4 trials). There was not enough data to evaluate the incidence of veno-occlusive disease. In conclusion, the addition of anti-CD33 to chemotherapy significantly decreased relapse rate, with no effect on all cause mortality. Yet, in the favorable risk subgroup, the use of anti-CD33 significantly reduced mortality. Further research is needed to confirm the beneficial effect in the favorable risk AML patients. Disclosures: No relevant conflicts of interest to declare.

Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1430-1436 ◽  
Author(s):  
R Pettengell ◽  
H Gurney ◽  
JA Radford ◽  
DP Deakin ◽  
R James ◽  
...  
Keyword(s):  
Relative Risk ◽  
Controlled Trial ◽  
Dose Intensity ◽  
Cytotoxic Chemotherapy ◽  
Control Group ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Weekly Chemotherapy ◽  
To Receive ◽  
Stimulating Factor

Abstract The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia, infection, and cytotoxic chemotherapy administration was studied in a randomized trial in patients receiving intensive weekly chemotherapy for non-Hodgkinxybs lymphoma (NHL). Eighty patients (aged 16 to 71 years) with high-grade NHL (Kiel) of any stage were randomized to receive VAPEC-B chemotherapy alone (39 patients) or with G-CSF administered as a daily subcutaneous dose of 230 micrograms/m2 (41 patients). Prophylactic ketoconazole and cotrimoxazole were administered to all patients throughout treatment. The protocol specified identical dose modification and antibiotic treatment criteria bor both groups. Neutropenia (absolute neutrophil count [ANC] less than 1.0 x 10(9)/L) occurred in 15 of 41 (37%) of the G-CSF-treated patients and in 33 of 39 (85%) of the controls, giving a relative risk for control patients of 2.31 (95% confidence interval [CI], [1.51, 3.54]; P = .00001). Fever (greater than or equal to 37.5 degrees C) with neutropenia (ANC less than 1.0 x 10(9)/L) occurred in 9 of 41 (22%) of the G-CSF group and in 17 of 39 (44%) of the controls (relative risk for control, 2.26; 95% CI [1.01, 5.06]; P = .04). There were fewer treatment delays, with shorter duration (P = .01) in patients receiving G-CSF. Chemotherapy doses were reduced in 4 of 41 (10%) of the G-CSF patients and 13 of 39 (33%) of the controls (P = .01). The dose intensity of cytotoxic chemotherapy was significantly increased in patients receiving G-CSF (median of 95% in G-CSF group compared with 83% in control patients). Three vascular deaths occurred in the G-CSF group. Delays in the control group most commonly resulted from neutropenia (19 patients, compared with 2 patients in the G-CSF-treated group, P = .000007). Severe mucositis was the major dose-limiting toxicity in G-CSF-treated patients, but did not occur more frequently than in controls (15 patients in each group). Overall, patients randomized to receive G-CSF achieved a greater dose intensity than control patients, but this did not result in significant differences in drug toxicity (other than neutropenia), intravenous antibiotic usage, or hospitalization between the two groups.

Priming with Granulocyte-Colony Stimulating Factor Did Not Improve Outcome in a Randomized Study of Elderly Acute Myeloid Leukemia but Increased Induction Mortality.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1980-1980 ◽  
Author(s):  
Gesine Bug ◽  
Steffen Koschmieder ◽  
Juergen Krauter ◽  
Stefanie Wiebe ◽  
Carla Hannig ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Randomized Study ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Secondary Aml ◽  
To Receive ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Introduction: In acute myeloid leukemia (AML), granulocyte-colony stimulating factor (G-CSF) has been used in combination with induction chemotherapy to improve complete remission rates (CR) by sensitization of leukemic cells. This randomized prospective oligocenter study was designed to assess whether two induction cycles given simultaneously with and followed by G-CSF (G-CSFpriming) was superior to G-CSF administered only after induction (G-CSFpost) with regard to CR and disease-free survival (DFS) in patients older than 60 years. Secondary objectives were comparison of this concept in de novo versus secondary AML and to examine the feasibility of autologous stem cell transplantation (ASCT) as late consolidation. Methods: Overall, 183 eligible pts (median age 67 yrs) were randomly assigned to receive G-CSF starting on the day before (n=91) or after chemotherapy (n=92) during two induction cycles consisting of idarubicin, cytarabine and etoposide (IdAV). The two treatment groups were evenly matched with respect to age, diagnosis and cytogenetic risk factors. G-CSF was given as daily s.c. injection at 5μg/kg. Pts achieving a CR were scheduled to receive early consolidation chemotherapy with fludarabine, cytarabine, idarubicin plus G-CSF (mini-FlagIda) and peripheral blood stem cell (PBSC) harvest, followed by ASCT as late consolidation. Pts lacking PBSC due to mobilization failure were optionally treated with a second cycle of mini-FlagIda as late consolidation. Results: After induction chemotherapy, 118 out of 183 pts (64%) achieved CR. Response was not different in the G-CSFpost vs. G-CSFpriming group (70% vs. 59%, p=0.148). Recovery of neutrophils was similar in both groups after cycle 1 (21.8 vs. 20.5 days) and cycle 2 (14.9 vs. 16.3 days). Notably, G-CSF priming resulted in a significantly increased mortality in induction 1 (25% vs. 9%, p=0.003) associated with a higher rate of severe mucositis and infectious complications. The probability of OS and DFS at 5 years was 16% and 20%, resp., with no significant differences between the induction groups. With a median follow up of 26 months (range, 5–77), 77 out of 118 complete responders have relapsed and 7 died while in CR. Patients with de novo AML had a significantly better OS than those with secondary AML (17 vs. 11 months, p<0.001). Unfavorable cytogenetics were associated with a poor median OS (7 vs. 15 months, p<0.001). Following mini-FlagIda I, collection of at least 2x10E6 CD34+ PBSC/kg was feasible in 35 of 67 pts in whom mobilization of CD34+ cells was monitored. Late consolidation with ASCT (n=19) was not superior to mini-FlagIda II (n=16, DFS 24 vs. 27 months). Conclusions: In this randomized study with elderly AML patients, G-CSF priming did not result in an increased CR rate and was associated with higher induction mortality, but OS was not influenced. We demonstrated feasibility of ASCT in patients up to the age of 70 years, which was not superior to chemotherapy consolidation.

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