Oncologist. The. Symptom Management and Supportive Care

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1 The Oncologist Symptom Management and Supportive Care A Randomized, Open-Label, Multicenter Trial of Immediate Versus Delayed Intervention with Darbepoetin Alfa for Chemotherapy-Induced Anemia VEENA CHARU, a BRUCE SAIDMAN, b ALI BEN-JACOB, c GLEN R. JUSTICE, d AJIT S. MANIAM, a DIANNE TOMITA, e GREG ROSSI, e TIMOTHY REARDEN, f JOHN GLASPY g a Pacific Cancer Medical Center, Anaheim, California, USA; b Medical Oncology Associates, Kingston, Pennsylvania, USA; c Cache Valley Cancer Treatment and Research Center, Logan, Utah, USA; d Pacific Coast Hematology Oncology Medical, Fountain Valley, California, USA; e Amgen Inc., Thousand Oaks, California, USA; f Hematology Oncology Consultants, St. Louis, Missouri, USA; g Department of Medicine-Hematology and Oncology, University of California, Los Angeles School of Medicine, Los Angeles, California, USA Key Words. Chemotherapy Anemia Darbepoetin alfa Hemoglobin Cancer Disclosure: This research was supported by Amgen Inc. (Study , ClinicalTrials.gov Identifier: NCT ). V.C., D.T., and G.R. own stock in Amgen. T.R. has acted as a consultant to Amgen. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. ABSTRACT The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 g every 3 weeks) to maintain hemoglobin levels >10g/dl in patients with CIA (hemoglobin >10.5 g/dl and <12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to <10 g/dl). In 201 evaluable patients, there was a significant difference between the two groups in the Kaplan Meier proportion of patients with a hemoglobin decrease to <10g/dl during weeks 1 13 (test period) (primary endpoint): 29% for immediate-intervention patients versus 65% for observation patients. Sixty-four patients in the observation group received darbepoetin alfa (delayedintervention subgroup). The Kaplan Meier proportion of patients who received transfusions was lower in the immediate-intervention group than in the delayed-intervention subgroup (14% versus 31% for the test period; 17% versus 36% over the whole study). The target hemoglobin level (>11 g/dl) was achieved by a higher percentage of patients (crude percentage) in less time in the immediate-intervention group (94% in 2 weeks) than in the delayed-intervention subgroup (73% in 6 weeks); hemoglobin endpoints for the delayed-intervention subgroup were calculated from recalibrated study week 1 (the date patients first received darbepoetin alfa). For both groups, a higher mean change in hemoglobin from baseline led to a greater improvement in Functional Assessment of Cancer Therapy Fatigue scores. In conclusion, immediate intervention resulted in a significantly lower proportion of patients who expe- Correspondence: John Glaspy, M.D., M.P.H., Department of Medicine-Hematology and Oncology, University of California, Los Angeles School of Medicine, Box , Suite 550, 100 Medical Plaza, Los Angeles, California 90095, USA. Telephone: ; Fax: ; jglaspy@mednet.ucla.edu Received February 21, 2007; accepted for publication August 28, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 1254 Immediate vs Delayed Intervention with Darbepoetin Alfa rienced a decline in hemoglobin, lower requirement for transfusions, and greater proportion of patients achieving and maintaining the target hemoglobin level. The Oncologist 2007;12: INTRODUCTION Chemotherapy-induced anemia (CIA) is a common side effect of myelosuppressive chemotherapy [1] and is associated with a number of debilitating symptoms that have a profound effect on health-related quality of life (HRQoL) [2]. Treatment of CIA with erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and darbepoetin alfa increases hemoglobin levels, thus reducing the requirement for RBC transfusions and improving HRQoL [3 9]. Three evidence-based clinical practice guidelines have been established to assist physicians in their management of patients with CIA: (a) The American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) issued joint guidelines that recommend initiating erythropoietic therapy when hemoglobin levels fall to 10 g/dl (intervention when hemoglobin is above 10 g/dl is left to the discretion of the physician) with a target hemoglobin level at or near 12 g/dl [10]; (b) the National Comprehensive Cancer Network recommends treating with ESAs once hemoglobin levels are 11 g/dl, with an optimal target hemoglobin level of g/dl [11]; and (c) the European Organization for Research and Treatment of Cancer recommends initiating treatment when the hemoglobin level is between 9 and 11 g/dl, with a target range of g/dl [12]. The recommended hemoglobin concentration at which to initiate erythropoietic therapy in patients with CIA varies between 9 and 11 g/dl; thus, some patients may develop more severe anemia before they are treated with erythropoietic agents (the National Cancer Institute or World Health Organization define mild anemia as hemoglobin 10 g/dl or g/dl, and moderate anemia as 8 10 g/dl or g/dl [1]). Results of clinical studies suggest that there are clinical benefits associated with the initiation of erythropoietic therapy in patients with mild anemia [7, 9, 13 16]. In two of these studies, the proportion of patients who received transfusions was approximately 50% lower if they were treated with darbepoetin alfa when their hemoglobin was 10 g/dl compared with patients who were treated when their hemoglobin was 10 g/dl [7, 16]. Here, we present the results of a prospective, randomized, open-label, multicenter study designed to assess the potential benefits of immediate (on-time) intervention with darbepoetin alfa administered as a fixed dose of 300 g every 3 weeks (Q3W) to patients with CIA. This trial is based on a design suggested by the ASH/ASCO guideline committee [10] and comprises two arms: patients who received darbepoetin alfa throughout the study (immediate-intervention group) and patients who were monitored using a waitand-watch approach (observation group) until their hemoglobin declined to 10 g/dl, at which time they received darbepoetin alfa (delayed-intervention subgroup). We evaluated the effects of immediate intervention versus a wait and watch approach and immediate intervention versus delayed intervention on transfusion requirements, achievement of the target hemoglobin level 11 g/dl, and maintenance of hemoglobin concentration within the range of g/dl recommended by evidence-based guidelines [10 12]. PATIENTS AND METHODS Patient Population Two hundred four patients were enrolled and randomized from 28 centers in the U.S. Institutional review board approval and written informed consent were obtained before screening procedures or study medications were administered. Inclusion criteria included patients 18 years with nonmyeloid malignancies (including lymphocytic leukemia) with anemia (hemoglobin 10.5 g/dl but 12.0 g/dl) as a result of cancer and chemotherapy, at least eight additional weeks of planned cyclic chemotherapy, and a Karnofsky Performance Status score of 50%. Exclusion criteria comprised a history of anemia resulting from hematologic disorders other than CIA, diagnosis of acute myelogenous or chronic myelogenous leukemia or myelodysplastic syndromes, a history of cardiac conditions, active bleeding, pure red cell aplasia, treatment with any erythropoietic agent within 2 weeks before screening, a transfusion within 4 weeks of screening, inadequate iron stores (transferrin saturation 15% and ferritin 10 ng/l), and an antibody response to any erythropoietic agent. Study Drug Human serum albumin-free (polysorbate) darbepoetin alfa (Aranesp ) was manufactured, packaged, and distributed by Amgen Inc. (Thousand Oaks, CA) and provided in single-use vials as a clear, colorless, sterile protein solution containing 325 or 500 g/ml.

3 Charu, Saidman, Ben-Jacob et al Study Design This was an open-label study wherein eligible patients with anemia were randomly allocated in a 1:1 ratio to one of two groups: the immediate-intervention group or the observation group; the observation group received darbepoetin alfa only if their hemoglobin concentration decreased to 10 g/dl. The randomization list was generated by the Amgen biostatistics department. Randomization was central across all centers and was not stratified. Site personnel were to contact the contract research organization within 4 days of the expected first day of the study to both provide the required data and obtain group assignment and randomization information. Patients in the immediate-intervention group received darbepoetin alfa (300 g Q3W) starting within 4 days after randomization (the start of week 1), for up to 22 weeks. If a patient s hemoglobin level decreased to 10 g/dl at any time after week 4, the dose was to be escalated to 500 g Q3W. Patients in the observation group were not to receive darbepoetin alfa unless their hemoglobin level decreased to 10 g/dl during the study, at which time they were treated with darbepoetin alfa at a dose of 300 g Q3W (delayedintervention subgroup). If patients in the delayed-intervention subgroup did not reach a hemoglobin level 10 g/dl after two doses, or their hemoglobin level decreased to 9 g/dl, they could have their dose increased to 500 g Q3W. For all patients, darbepoetin alfa was temporarily withheld if hemoglobin exceeded 13 g/dl, and was resumed at the previous dose once hemoglobin was 13 g/dl. The test period was defined as weeks 1 13 and is the primary time frame used for the analysis of efficacy variables. This time frame is consistent with the duration of previous studies, thus allowing for a comparison among studies. For patients in the immediate-intervention group, the treatment period was up to 22 weeks. For patients in the observation group, the length of treatment was up to 21 weeks and was expected to depend on whether or not the patient received darbepoetin alfa. Patients had a follow-up visit 1 week after the end of treatment. For patients in the delayed-intervention subgroup, treatment week 1 was defined as the first week they received darbepoetin alfa and, in general, corresponds to the first week following a hemoglobin decline to 10 g/dl. All laboratory tests were done before administration of darbepoetin alfa. Patients may have received transfusions and iron supplementation according to the institutions guidelines and at the investigators discretion. Study Endpoints The primary endpoint was the proportion of patients with a hemoglobin decrease to 10 g/dl during the test period. Secondary endpoints included the mean change in hemoglobin level from baseline, the proportion of patients who received transfusions, and patient-reported outcomes assessed using the Functional Assessment of Cancer Therapy Fatigue (FACT-F) subscale. Exploratory analyses evaluated the ability of patients in both groups to achieve a hemoglobin level 11 g/dl and maintain a hemoglobin concentration within the target range of g/dl recommended by evidence-based guidelines [10 12]. Patient Safety Adverse events occurring during the study were summarized by system organ class and preferred term according to the MedDRA dictionary (version 9) [17]. Serum samples were collected to assess antibody formation after completing darbepoetin alfa administration. Statistical Analysis The planned sample size of 200 patients was selected to detect a 33% difference in the proportion of patients with a hemoglobin level 10 g/dl during the test period in the immediate-intervention group relative to the observation group, with 90% power using a two-sided continuity corrected 2 test at a nominal significance level of The proportion of patients with hemoglobin 10 g/dl during the test period was estimated by subtracting the Kaplan Meier (KM) estimate of the survival function at the time of the last observed hemoglobin drop from 1; approximate 95% confidence intervals (CIs) were calculated using Greenwood s estimate of the variance, assuming a normal distribution of the survival function. Hemoglobin levels over the study period were calculated using two approaches. The first approach ensured all randomized and treated patients were included in the analysis, wherein missing hemoglobin values were imputed using the last-value-carried-forward approach. Hemoglobin values recorded within 28 days of an RBC transfusion were also considered missing and imputed using the pretransfusion value. For patients in the observation group who received darbepoetin alfa, the last hemoglobin value prior to initiating darbepoetin alfa treatment was carried forward to the end of the study. A sensitivity analysis, wherein hemoglobin values were not imputed (available data approach), was also done. For the delayed-intervention subgroup, week 1 was recalibrated as the date patients received their first dose of darbepoetin alfa; hemoglobin endpoints for this group were calculated from the recalibrated date. Weeks prior to the recalibrated date are presented as negative treatment weeks. The incidence of transfusions and time to target hemo-

4 1256 Immediate vs Delayed Intervention with Darbepoetin Alfa Figure 1. Patient disposition. globin level were estimated using the KM method. Changes in FACT-F scores were calculated using available data, and mean changes in FACT-F scores were calculated for each incremental change in hemoglobin concentration ( 0, 0 2, and 2 g/dl) from baseline to the end of study. RESULTS Study Population The study was conducted between November 19, 2002 and October 16, The Consolidated Standards of Reporting Trials diagram illustrating patient disposition is presented in Figure 1. The primary analysis set included 99 patients from the immediate-intervention group who received at least one dose of darbepoetin alfa and 102 patients from the observation group. Sixty-four patients (63%) in the observation group received darbepoetin alfa because their hemoglobin level dropped to 10 g/dl (delayed-intervention subgroup). Fifty-four patients (19 in the immediate-intervention group and 35 in the observation group) died or withdrew from the study before the planned study completion (Fig. 1). In general, reasons for not completing the study were similar in the two groups. Baseline demographics, disease characteristics, and laboratory values (including baseline hemoglobin) were generally similar in the two groups (Table 1). Most patients were women, with a slightly higher percentage in the immediate-intervention group than in the observation group. The most common tumor types were breast, lung, and gastrointestinal. The mean FACT-F scores at baseline were slightly higher in patients in the immediate-intervention group than in patients in the observation group (Table 1). Clinical Outcomes for the Immediate-Intervention Versus Observation Groups During weeks 1 13, the KM percentage of patients who experienced a hemoglobin drop to 10 g/dl was significantly lower (p.0001) for the immediate-intervention group (29%; 95% CI, 19% 38%) than for the observation group (65%; 95% CI, 55% 75%) (Fig. 2). The median time to a hemoglobin concentration 10 g/dl in the observation group was 7 (95% CI, 5 10) weeks. As 50% of patients in the immediate-intervention group experienced a hemoglobin drop to 10 g/dl during weeks 1 13, no estimate for the median time to achieve this endpoint could be calculated. Similar differences between the two groups were also observed at week 22 (32%; 95% CI, 22% 41% and 70%; 95% CI, 61% 80%, respectively). For patients in the immediate-intervention group, hemoglobin levels steadily increased during weeks 1 13 (Fig. 3A). Thereafter, the dose titration rules, which required

5 Charu, Saidman, Ben-Jacob et al Table 1. Patient demographics and baseline characteristics Figure 2. Time to hemoglobin decline to 10 g/dl for patients in the immediate-intervention and observation groups. The 95% confidence intervals (CIs) were determined from the last noncensored time point and are displayed at weeks 13 and 22. ** indicates significance at p Immediate-intervention group (n 99) Observation group a (n 102) Women, n (%) 59 (60) 70 (69) Race, n (%) White 84 (85) 83 (81) Black 10 (10) 13 (13) Other 5 (5) 6 (6) Age (years), mean (SD) 63.2 (10.9) 63.7 (12.2) Primary tumor type, n (%) Breast 27 (27) 31 (30) Lung 20 (20) 26 (25) Gastrointestinal 24 (24) 18 (18) Genitourinary 7 (7) 8 (8) Hematologic b 9 (9) 10 (10) Gynecologic 7 (7) 4 (4) Other c 5 (5) 5 (5) Hemoglobin d (g/dl), mean (SD) n 11.1 (0.7) (0.6) 101 Hemoglobin within 28 days of transfusion, n (%) 2 (2) 0 (0) Hemoglobin missing, n (%) 0 (0) 1 (1) TSAT, median (min, max) n 19.0% (6.0, 305.0) % (4.0, 271.6) 99 Ferritin (ng/l), median (min, max) n 209 (8.1, 1338) (8, 71,000) 99 FACT-F scores, mean (SD) n 31.6 (11.7) (12.8) 86 a Includes patients who received darbepoetin alfa (delayed-intervention subgroup). b Includes chronic lymphocytic leukemia, non-hodgkin s lymphoma, Hodgkin s disease, and multiple myeloma. c Includes other tumors and squamous cell head/neck cancer. d Last available hemoglobin measurement from 7 days before study day 1 through study day 1 (in the absence of any transfusions within 28 days). Abbreviations: FACT-F, Functional Assessment of Cancer Therapy Fatigue; SD, standard deviation; TSAT, transferrin saturation. dose withholding when hemoglobin was 13 g/dl, successfully maintained the mean hemoglobin level at approximately 12 g/dl for the remainder of the 22-week study period (Fig. 3A). In the observation group, the mean hemoglobin concentration declined over the course of the study (patients in this group who received darbepoetin alfa were censored when their hemoglobin level dropped to 10 g/dl; Fig. 3A). During the test period, there was an apparent trend toward more patients receiving transfusions in the observation group (includes patients who were treated or not treated with darbepoetin alfa; KM percentage, 22%; 95% CI, 13% 30%) than in the immediate-intervention group (14%; 95% CI, 7% 20%) (Fig. 3B). Throughout the 22- week study period, 26% (95% CI, 16% 35%) of patients in the observation group received transfusions compared with 17% (95% CI, 9% 25%) in the immediate-intervention group (Fig. 3B). The mean hemoglobin level at the time of receiving a transfusion was 8.9 (95% CI, ) g/dl in the immediate-intervention group compared with 9.0 (95% CI, ) g/dl in the observation group;

6 1258 Immediate vs Delayed Intervention with Darbepoetin Alfa Figure 3. Clinical outcomes. (A) Mean hemoglobin concentration during the study for the immediate-intervention and observation groups (LVCF approach). For the observation group, the last hemoglobin value prior to receiving darbepoetin alfa was carried forward to the end of the study. (B): Percentage of patients who received transfusions (KM method). Patients in the observation group include those who received darbepoetin alfa. (C): Mean hemoglobin concentration during the study for the immediateintervention group and delayed-intervention subgroup (available data). Week 1 is the week during which the first dose of the study drug was given. (D): KM percentage of patients who received transfusions. The shaded area in (A) and (C) represents the target hemoglobin level (11 13 g/dl). Abbreviations: CI, confidence interval; KM, Kaplan Meier; LVCF, last value carried forward. thus, there appeared to be no obvious bias in the decision to administer transfusions based on study group randomization. The effect of declining hemoglobin level on FACT-F scores was not investigated because many patients in the observation group had initiated darbepoetin alfa therapy by the time of the first postbaseline fatigue assessment (week 13). Effect of Delayed Intervention on Clinical Outcomes Of the 101 patients randomized to the observation group, 64 (63%) received darbepoetin alfa therapy following a decline in hemoglobin concentration to 10 g/dl. The median time to a hemoglobin concentration 10 g/dl for patients in this delayed-intervention subgroup was 4.5 (95% CI, ) weeks. Before initiation of darbepoetin alfa therapy, the mean hemoglobin concentration of patients in the delayed-intervention subgroup decreased from 11.2 (standard deviation [SD], 0.6) g/dl at baseline to 9.5 (SD, 0.5) g/dl at the time of their first dose of darbepoetin alfa. After the initiation of darbepoetin alfa therapy, hemoglobin levels recovered, with a mean increase of 0.9 (95% CI, ) g/dl after 4 weeks (week 5) and 1.6 (95% CI, ) g/dl after 12 weeks (week 13) (Fig. 3C). These data were calculated from the recalibrated date (week 1 is the date patients received their first dose of darbepoetin alfa); thus, data prior to treatment week 1 represent the drop in hemoglobin in this group before they received darbepoetin alfa. The sample size is not constant because patients could have received darbepoetin alfa 1 week after their hemoglobin dropped to 10 g/dl. Allowing patients hemoglobin levels to drop to 10

7 Charu, Saidman, Ben-Jacob et al g/dl before treatment with darbepoetin alfa resulted in a higher incidence of transfusions; for patients who were treated with darbepoetin alfa, the percentage who received transfusions in the immediate-intervention group (14%; 95% CI, 7% 20%) was less than half that in the delayedintervention subgroup (31%; 95% CI, 19% 42%) (Fig. 3D) during weeks A twofold difference in transfusion requirements was also observed over the entire treatment period (Fig. 3D). Change in FACT-F Scores An exploratory analysis was performed to determine the change in FACT-F scores from baseline to the end of study by change in hemoglobin from baseline to the end of study. Hemoglobin categories were: 0 g/dl, that is, a decline in hemoglobin from baseline; 0 to 2 g/dl, that is, a stable or moderate increase in hemoglobin compared with baseline; and 2 g/dl, that is, a clinically significant increase in hemoglobin from baseline. Patients in the immediate-intervention group and delayed-intervention subgroup had similar mean changes in FACT-F scores: those whose hemoglobin declined from baseline had a decrease in FACT-F scores, those who had a change in hemoglobin from baseline of 0 to 2 g/dl had a small mean increase in FACT-F scores, and those who experienced a hemoglobin change of 2 g/dl had a clinically meaningful ( 3 points [18]) improvement in fatigue (Fig. 4). Achievement and Maintenance of Hemoglobin Within the Target Range We performed an exploratory analysis to evaluate if patients were able to achieve a hemoglobin level 11 g/dl and maintain a hemoglobin within the range of g/dl recommended by evidence-based guidelines [10 12]. During the entire study, a higher percentage of patients in the immediate-intervention group (94% [crude percent]) achieved a hemoglobin level 11 g/dl compared with the observation group (88% [crude percent]); the time taken to achieve the target hemoglobin was the same (2 weeks) (Table 2). Of those patients in the delayed-intervention subgroup, 73% achieved the target hemoglobin level in a median time of 6 weeks (Table 2). The mean hemoglobin concentration after achieving the target level was higher for patients in the immediate-intervention group than for patients in the observation group and patients in the delayed-intervention subgroup, and a higher percentage of patients in the immediate-intervention group maintained their hemoglobin concentration in the range of g/dl (Table 2). Figure 4. Change in FACT-F scores by change in hemoglobin category for patients receiving immediate or delayed intervention. Change in hemoglobin was measured from baseline to EOTP. Abbreviations: CI, confidence interval; EOTP, end of treatment period; FACT-F, Functional Assessment of Cancer Therapy Fatigue. Darbepoetin Alfa Use Dose escalation was required in 22 patients (22%) in the immediate-intervention group compared with 20 (31%) in the delayed-intervention subgroup. Dose withholding because of hemoglobin exceeding 13 g/dl occurred in 45 patients (45%) in the immediate-intervention group compared with 14 (22%) in the delayed-intervention subgroup. Consequently, the mean weekly dose was statistically significantly lower (p.0014) in the immediate-intervention group (95.3 g; 95% CI, g) compared with the delayed-intervention subgroup (109.2 g; 95% CI, g). Patient Safety The numbers and types of adverse events reported by patients are summarized in Table 3. There was a higher incidence of serious adverse events (SAEs) in the immediate-intervention group and the delayed-intervention subgroup than in patients who never received darbepoetin alfa. The most common SAEs were: febrile neutropenia (3% in the immediate-intervention group and 11% in the delayed-intervention subgroup), pneumonia (4% in the immediate-intervention group, 8% in the delayed-intervention subgroup, and 3% in untreated patients), and dehydration (3% in the immediate-intervention group and 9% in the delayed-intervention subgroup). Two patients in the immediate-intervention group reported deep vein thrombosis

8 1260 Immediate vs Delayed Intervention with Darbepoetin Alfa Table 2. Patients achieving and maintaining the target hemoglobin range Immediate-intervention group (n 99) Observation group (n 102) Delayed-intervention subgroup a,b (n 64) Patients achieving target hemoglobin 94 (89 99) 97 c 88 (81 94) 96 c 73 (61 84) 64 c of 11 g/dl, crude percent (95% CI) n Time (weeks) to target hemoglobin, 2 (NA to NA) d 97 2 (2 3) 96 6 (4 7) e 64 KM median (95% CI) n Hemoglobin (g/dl) after achieving 12.0 ( ) ( ) ( ) 54 target, f mean (95% CI) n Percentage of patients maintaining hemoglobin after achieving target, f n (%) 11 g/dl 14 (14) 27 (27) 26 (14) g/dl 65 (66) 52 (51) 27 (42) 13 g/dl 11 (11) 3 (3) 1 (2) a For those patients who received darbepoetin alfa in the observation group. b Hemoglobin endpoints for this group were calculated based on the date a patient received their first dose of darbepoetin alfa, which was recalibrated as study week 1. c Patients who had hemoglobin and dosing data after achieving target hemoglobin. d All patients in the immediate-treatment group achieved the target hemoglobin range after the first dose of darbepoetin alfa. e Study week after initial hemoglobin drop to 10 g/dl. f For patients who had at least one hemoglobin level 11 g/dl. Abbreviations: CI, confidence interval; KM, Kaplan Meier. Table 3. Patient safety Adverse event category, n (%) Immediate intervention (n 99) Observation Delayed intervention a (n 64) Not treated b (n 38) Adverse events 88 (89) 56 (88) 27 (71) Treatment-related adverse events 6 (6) 3 (5) 1 (3) Serious adverse events 30 (30) 29 (45) 8 (21) Serious treatment-related adverse events 1 (1) 1 (2) 0 (0) Adverse events of historical interest 21 (21.2) 9 (14.1) 7 (18.4) Cardiovascular and thromboembolic events 16 (16.2) 5 (7.8) 2 (5.3) Arrhythmias 3 (3) 2 (3.1) 1 (2.6) Cerebrovascular accident 1 (1) 1 (1.6) 0 (0) Congestive heart failure 4 (4) 1 (1.6) 0 (0) Myocardial infarction/coronary artery 2 (2) 0 (0) 1 (2.6) disorders Embolism/thrombosis 10 (10.1) 2 (3.1) 0 (0) Seizure 1 (1) 0 (0) 1 (2.6) Hypertension 2 (2) 1 (1.6) 0 (0) Immune system disorders 1 (1) 0 (0) 0 (0) Neoplasms benign, malignant, and unspecified 6 (6.1) 3 (4.7) 4 (10.5) (including cysts and polyps) Deaths on study or within 30 days of end of study 6 (6.1) 5 (7.8) 2 (5.3) a Patients who received darbepoetin alfa. These patients may have experienced an adverse event before they received darbepoetin alfa. b Patients who never received darbepoetin alfa.

9 Charu, Saidman, Ben-Jacob et al not considered related to the study drug by the treating physician. One patient in the immediate-intervention group reported a treatment-related thrombotic event (deep vein thrombosis). Two patients reported treatment-related SAEs: one patient in the immediate-intervention group experienced atrial fibrillation, and one patient in the delayedintervention subgroup reported peripheral swelling and limb pain. Thirteen patients died during the study or within 30 days following the study: six patients (6.1%) in the immediateintervention group (four from cancer, one from respiratory failure, and one from cardiac failure), five (7.8%) in the delayed-intervention subgroup (three from cancer, one from cardiac arrest, one from dyspnea), and two (5.3%) untreated patients (one from cancer and one from small intestinal obstruction). One patient randomized to the immediate-intervention group died before receiving darbepoetin alfa. Three patients who died of cancer within 30 days following the end-of-study visit were documented as leaving the study for reasons other than death (Fig. 1). Adverse events of historical interest are listed in Table 3. Thromboembolic events were reported by 10.1%, 3.1%, and 0% of patients in the immediate-intervention group, delayed-intervention subgroup, and untreated patients, respectively. There was no evidence that neutralizing antibodies to darbepoetin alfa developed in any patient during the study. DISCUSSION The results of this study suggest that there are clinical benefits associated with initiating treatment with darbepoetin alfa before patients hemoglobin levels fall to 10 g/dl (immediate [on-time] intervention). Patients with mild anemia (hemoglobin 10.5 g/dl and 12.0 g/dl) who were treated immediately with darbepoetin alfa were significantly less likely (p.001) to experience a decline in hemoglobin levels to 10 g/dl (primary endpoint) than those who did not receive treatment. Although this study was powered to address only the difference in the primary endpoint between the two treatment groups, analysis of the secondary endpoints provided evidence that supports the use of an immediate-intervention strategy in patients with mild anemia: a lower proportion of patients who received immediate intervention had transfusions, a higher percentage of these patients achieved the target hemoglobin level ( 11 g/dl) and maintained a hemoglobin level within the range of g/dl, and the time to achieve the target hemoglobin level was shorter than in patients whose treatment was delayed until after their hemoglobin level declined to 10 g/dl. Sixty-five percent of patients in the observation group experienced a hemoglobin drop to 10 g/dl in weeks 1 13; 70% over the entire treatment period. Unfortunately, we were unable to assess the effect of falling hemoglobin levels on symptoms of fatigue because these patients were treated with darbepoetin alfa as soon as their hemoglobin level dropped to 10 g/dl. However, when changes in FACT-F scores from baseline to the end of study were analyzed by change in hemoglobin over the same time period, patients in the delayed-intervention subgroup and immediate-intervention group who experienced a change in hemoglobin of 2 g/dl had similar and clinically meaningful ( 3-point change [18]) improvements in FACT-F scores. This association is consistent with the conclusions of a previous study that suggested a direct and positive relationship between hemoglobin concentration and HRQoL [19]. Since completion of this trial, other studies have been published suggesting a clinical benefit associated with treating CIA patients with ESAs before they develop more severe anemia. A combined analysis of data from five clinical trials, which included data presented in abstract form from the present study, indicated a significantly lower relative risk for transfusions in patients treated immediately compared with those whose treatment was delayed [20]. Similar to the present study, patients with non-small cell lung cancer treated with epoetin alfa before their hemoglobin dropped to 10 g/dl had fewer transfusions than those receiving delayed treatment [21], and in a large trial of 1,501 patients administered darbepoetin alfa Q3W, patients with a baseline hemoglobin level 10 g/dl received fewer transfusions than those with a baseline hemoglobin level 10 g/dl (12% versus 28%; from week 5 to the end of study) [22]. Also, a higher percentage of patients with a baseline hemoglobin level 10 g/dl achieved the target hemoglobin level in less time than patients with a baseline hemoglobin level 10 g/dl (87% in 3 weeks versus 66% in 9 weeks) [22]. The incidence of thromboembolic events in the immediate-intervention group observed in the present study (10.1%) is similar to that observed in a similar early intervention study with epoetin alfa (11.1% [23]). In both these studies, the incidence of thromboembolic events was higher than that observed in the observation group. The rates of thromboembolic events observed in a patient-level pooled analysis of previous studies in CIA with darbepoetin alfa were 7.4% in the darbepoetin alfa group (n 7,661) and 4.5% in the control group (n 1,014) (Amgen, Inc., data on file). Two recently published meta-analyses also noted a higher frequency of thromboembolic events in patients treated with ESAs than in controls [24] [25]. The risk for thromboembolic events is addressed in ESA product labels. In the present study, there were no thromboembolic events

10 1262 Immediate vs Delayed Intervention with Darbepoetin Alfa in the group not treated with darbepoetin alfa, probably because of the small sample size: as noted above, the observed frequency of these events in control groups of previous darbepoetin alfa trials was 4.5% (Amgen, Inc., data on file). Recent results from a number of clinical trials have raised concerns that treatment with ESAs may be associated with shorter survival in patients with cancer. However, four of these studies, two in patients with locally advanced head and neck cancer [26, 27], one in metastatic breast cancer [28], and one in metastatic non-small cell lung cancer [29], were in unapproved indications and used target hemoglobin levels (up to 15.5 g/dl) that are higher than the currently recommended threshold of 13 g/dl. Also, in a placebo-controlled trial of darbepoetin alfa in patients with advanced cancer not receiving chemotherapy or radiotherapy (an unapproved indication), there was a significant difference in survival in favor of placebo [30]. These potential risks were recently updated in the current labels for ESAs as a boxed warning and were the focus of the 2007 Oncology Drug Advisory Committee meeting convened by the U.S. Food and Drug Administration to discuss the use of ESAs in patients with cancer. In the present study, our dosing strategy maintained hemoglobin levels within a range (11 13 g/dl) that prevented increases in hemoglobin above concentrations that are associated with safety concerns. No difference in REFERENCES 1 Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 1999;91: Stasi R, Abriani L, Beccaglia P et al. Cancer-related fatigue: Evolving concepts in evaluation and treatment. Cancer 2003;98: Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15: Glaspy JA, Jadeja JS, Justice G et al. Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer 2002;87: Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16: Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;19: Vadhan-Raj S, Mirtsching B, Charu V et al. Assessment of hematologic effects and fatigue in cancer patients with chemotherapy-induced anemia given darbepoetin alfa every two weeks. J Support Oncol 2003;1: Littlewood TJ, Bajetta E, Nortier JW et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19: mortality was observed between the two treatment algorithms in this study, but as active treatment with darbepoetin alfa occurred in both arms, no conclusions about the impact of ESAs on survival can be made. In conclusion, immediate intervention with darbepoetin alfa (300 g Q3W) in patients receiving chemotherapy resulted in a significantly lower proportion of patients who experienced a decline in hemoglobin, lower requirement for RBC transfusions, and higher proportion of patients who achieved a hemoglobin level 11 g/dl and maintained it within the range recommended by evidence-based guidelines. These results may have important implications for the management of patients with CIA in clinical practice and may also reduce the cost of treatment by reducing the number of RBC transfusions and the average weekly dose of darbepoetin alfa required to achieve and maintain the target hemoglobin range. ACKNOWLEDGMENTS The authors would like to acknowledge Joseph Murray, M.S., and Ben Frierson, M.B.A., for assistance with the statistical analysis; Danica Katz, M.A., for her assistance with the clinical trial; and Kathryn Boorer, Ph.D., and Steven Sholly, Ph.D., for assistance with writing the manuscript. 9 Vansteenkiste J, Pirker R, Massuti B et al. Double-blind, placebocontrolled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94: Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;20: Rodgers GM. NCCN Practice Guidelines in Oncology: Cancer and treatment-related anemia, National Comprehensive Cancer Network. Available at Accessed June 1, Bokemeyer C, Aapro MS, Courdi A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40: Bamias A, Aravantinos G, Kalofonos C et al. Prevention of anemia in patients with solid tumors receiving platinum-based chemotherapy by recombinant human erythropoietin (rhuepo): A prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group. Oncology 2003;64: Del Mastro L, Venturini M, Lionetto R et al. Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapyinduced anemia. J Clin Oncol 1997;15: Thatcher N, De Campos ES, Bell DR et al. Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999;80:

11 Charu, Saidman, Ben-Jacob et al Vansteenkiste J, Tomita D, Rossi G et al. Darbepoetin alfa in lung cancer patients on chemotherapy: A retrospective comparison of outcomes in patients with mild versus moderate-to-severe anaemia at baseline. Support Care Cancer 2004;12: Tremmel L, Scarpone L. Using MedDRA for adverse events in cancer trials: Experience, caveats, and advice. Drug Inf J 2001;35: Cella D, Eton DT, Lai JS et al. Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage 2002;24: Crawford J, Cella D, Cleeland CS et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95: Lyman GH, Glaspy J. Are there clinical benefits with early erythropoietic intervention for chemotherapy-induced anemia? A systematic review. Cancer 2006;106: Crawford J, Robert F, Perry MC et al. A randomized trial comparing immediate versus delayed treatment of anemia with once-weekly epoetin alfa in patients with non-small cell lung cancer scheduled to receive first-line chemotherapy. J Thorac Oncol 2007;2: Boccia R, Malik IA, Raja V et al. Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia. The Oncologist 2006;11: Straus DJ, Testa MA, Sarokhan BJ et al. Quality-of-life and health benefits of early treatment of mild anemia: A randomized trial of epoetin alfa in patients receiving chemotherapy for hematologic malignancies. Cancer 2006; 107: Ross SD, Allen IE, Henry DH et al. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: A systematic review of the literature. Clin Ther 2006;28: Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98: Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 2003;362: Overgaard J, Hoff CM, Sand Hansen H et al. Randomized study of the importance of Novel Erythropoiesis Stimulating Protein (Aranesp ) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC) The Danish Head and Neck Cancer Group (DAHANCA 10) randomized trial. 14th European Cancer Conference, Barcelona, Spain, September 23 27, Abstract 6LB. 28 Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 2005;23: Wright JR, Ung YC, Julian JA et al. Randomized, double-blind, placebocontrolled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25: Glaspy J, Smith R, Aapro M et al. Results from a phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. American Association for Cancer Research, Los Angeles, CA, April 14 18, Abstract LB-3.