Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis

Figures & data

Table I. Characteristics of controlled ESA trials conducted in patients with lymphoproliferative malignancies that reported mortality data.

		Number of patients analyzed
Study publication	Disease*	ESA (n = 1558)	Control (n = 1308)	Duration of study	Duration of follow-up	ESA administered	ESA target	Hct or Hb enrollment criteria	Age of patients, years	Baseline Hct or Hb	Chemotherapy
Rose et al., 1994 [32]^†‡	CLL	142	79	12 weeks	Not done	EA 150 U/kg or placebo 3 times weekly	Hct 38%	Hct < 32%	Not reported	Mean Hct: ESA 27.5%; control 27.7%	Not reported
Pangalis et al., 1995 [28]^†‡	B-cell CLL	33	12	3 months	Not done	EA 150 U/kg (to max. of 300 U/kg) or placebo 3 times weekly	Hct 38%	Hct < 32%	Median 66	Mean Hct 28%	On chemotherapy for ≥ 4 weeks; planned chemotherapy ≥ 3 more months
Cazzola et al., 1995^‡ [24]	MM, low- or intermediate-grade NHL, CLL	117	29	8 weeks	Not done	EA fixed dose of 1000, 2000, 5000 or 10 000 U daily or untreated control	Not stated; primary endpoint was percent increase in Hb/week	Hb ≤ 11 g/dL	Median: ESA 63–68 (4 treatment groups); control 68	Mean Hb: ESA 9.3–9.4 g/dL (4 treatment groups); control 9.5 g/dL	Patients on chemotherapy during study: 76–83% (4 ESA treatment groups); control 83%
Österborg et al., 1996 [7]^§	NHL, MM	95	49	24 weeks	Not done	EA 2000 or 10 000 U daily until target Hb reached, or untreated control	Hb 11 g/dL	Hb < 10 g/dL	Median: ESA 65–66 (2 treatment groups); control 64	Median Hb: ESA 8.0 g/dL; control 8.1 g/dL	88% received chemotherapy during study
Dammacco et al., 2001^‡ [25]	MM	69	76	12 weeks	Not done	EA 150–300 U/kg or placebo 3 times weekly	Hb 12 g/dL	Hb < 11 g/dL	Median: ESA 67; control 65	Median Hb: ESA 9.6 g/dL; control 9.7 g/dL	Chemotherapy for ≥ 6 months before study entry
Hedenus et al., 2002^‡ [31]	HD, NHL, CLL, MM	55	11	12 weeks	4 weeks	DA 1.0, 2.25 or 4.5 µg/kg or placebo once weekly for 12 weeks	Hb 12 g/dL	Hb ≤ 11 g/dL	Median: ESA 64–70 (3 treatment groups); control 63	Mean Hb: ESA 9.4–9.7 g/dL (3 treatment groups); control 9.5 g/dL	≥ 12 weeks of chemotherapy planned
Hedenus et al., 2003, 2005^‡ [10,17]	NHL, HD, CLL, MM	174	170	12 weeks	ESA: median 25 months; control: median 33 months	DA 2.25–4.5 µg/kg or placebo once weekly	Hb 12 g/dL	Hb ≤ 11 g/dL	Mean: ESA 65; control 65	Mean Hb: ESA 9.6 g/dL; control 9.5 g/dL	≥ 12 weeks of chemotherapy planned
Österborg et al., 2002, 2005 [27,34]	Low-grade NHL, CLL, MM	170	173	16 weeks	Median 28 months	EB 150–300 IU/kg or placebo 3 times weekly	Hb 13 g/dL	Hb < 10 g/dL	Median: ESA 63; control 64	Mean Hb: ESA 9.2 g/dL; control 9.3 g/dL	≥ 4 months of chemotherapy planned
Engert et al., 2010^‡ [29]	Advanced HD	648	655	During chemotherapy and up to 6 months thereafter	Up to 4 years	EA 40 000 U or placebo weekly	Hb 13 g/dL during chemotherapy; Hb 12 g/dL 6 weeks after chemotherapy	None	Median: ESA 34; control 34	Mean Hb > 12 g/dL; ESA 57%; control 56%	Chemotherapy during study
Cabanillas et al., 2012^‡ [26]	ALL, lymphoblastic or Burkitt lymphoma	55	54	6 cycles of chemotherapy	Up to 3 years	EA 40 000–60 000 U or control weekly; not blinded	Hb 10 g/dL	Hb ≤ 10 g/dL	Median: ESA 39; control 42	Mean Hb: ESA 9.0 g/dL; control 8.9 g/dL	Chemotherapy during study

ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; DA, darbepoetin alfa; EA, epoetin alfa; EB, epoetin beta; ESA, erythropoiesis-stimulating agent; HD, Hodgkin disease; Hb, hemoglobin; Hct, hematocrit; MM, multiple myeloma; NHL, non-Hodgkin lymphoma.

*All studies were conducted in patients receiving chemotherapy.

^†Meta-analysis includes unpublished data from Amgen Inc. or Janssen Products LP databases.

^‡Reanalyzed using as-randomized data from company databases.

^§Numbers of patients are from the Cochrane 2006 meta-analysis [16] and include data not published in the original Österborg 1996 report. The Österborg 1996 study was included in a meta-analysis of epoetin beta studies reported by Aapro et al. in 2006 [35], with 4 weeks of follow-up beyond the period reported in the original publication [7]. Because the Aapro report [35] did not include the numbers or percentages of patients who died or had disease progression in individual studies, its data for the Österborg 1996 study could not be included in this meta-analysis.

Figure 1. Study-level meta-analysis of mortality in randomized controlled trials of patients with lymphoproliferative malignancies receiving erythropoiesis-stimulating agents (ESAs) or controls, including odds ratio for death using a random-effects model and results of a risk difference analysis. *The Österborg 1996 study was included in a meta-analysis of epoetin beta studies reported by Aapro et al. in 2006 [35], with 4 weeks of follow-up beyond the period reported in the original 1996 publication [7]. Aapro et al. reported that the hazard ratio for overall survival was 1.02 (95% CI, 0.55–2.05). Because the Aapro report did not include the numbers or percentages of patients who died, its data for the Österborg 1996 study could not be included in this meta-analysis.

Figure 2. Study-level meta-analysis of disease progression in patients with lymphoproliferative malignancies receiving erythropoiesis-stimulating agents (ESAs) or controls; odds ratio for disease progression using a random-effects model. *In the Österborg 1996 and 2005 studies [7,27], disease progression was based on tumor response assessment. ^†The Österborg 1996 study was included in a meta-analysis of epoetin beta studies reported by Aapro et al. in 2006 [35], with 4 weeks of follow-up beyond the period reported in the original 1996 publication [7]. Aapro et al. [35] reported that the hazard ratio for disease progression was 1.43 (95% CI, 0.72–2.86). Because the Aapro report did not include the numbers or percentages of patients with disease progression, its data for the Österborg 1996 study could not be included in this meta-analysis.

Figure 3. Proportion of patients (%) who received transfusions in studies of patients with lymphoproliferative malignancies receiving erythropoiesis-stimulating agents (ESAs) or controls in randomized controlled trials. n represents the number of patients for whom transfusion data were available in each study.

Table II. Thromboembolic or cardiovascular events reported* in studies included in meta-analysis of patients with lymphoproliferative malignancies.

	Myocardial infarction/coronary artery disorder		Venous thromboembolism/thrombosis		Cerebrovascular accident		Heart failure
Study	ESA	Control	ESA	Control	ESA	Control	ESA	Control	Other/notes
Rose et al., 1994 [32]									Not reported
Pangalis et al., 1995 [28]									No side effects observed
Cazzola et al., 1995 [24]									No increased incidence of thromboembolic events observed in ESA group vs. controls
Österborg et al., 1996 [7]			3 (3%)^§	0 (0%)			5 (5%)^†	2 (4%)^†
Dammacco et al., 2001 [25]
Hedenus et al., 2002 [31]^‡	2 (4%)	0 (0%)	4 (7%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Hedenus et al., 2003 [10]^‡	2 (1%)	5 (3%)	11 (6%)	7 (4%)	1 (< 1%)	0 (0%)	2 (1%)	5 (3%)
Österborg et al., 2002 and 2005 [27,34]			≥ 1^§	Not reported					No specific event rates reported; one ESA patient died on-study of pulmonary embolus
Engert et al., 2010 [29]									Total rate of thromboembolic events: 10.1%, OR 1.2 (95% CI, 0.7–1.9)
Cabanillas et al., 2012 [26]			5 (9%)	2 (4%)					Difference not statistically significant

CI, confidence interval; ESA, erythropoiesis-stimulating agent; OR, odds ratio.

*Empty cells indicate no data available.

^†Fatal heart failure.

^‡Data from Amgen Inc. databases.

^§Pulmonary embolism.

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