Clinical Trials With Erythropoietic Proteins

Trials conducted with rHuEPO and darbepoetin alfa have shown that exogenous rHuEPO and darbepoetin alfa can reduce transfusion requirements or increse in Hct in patients with CLL. Only one of the trials (29) required a low baseline EPO value as part of the entrance criteria (Table 4).

2.2.1. Randomized Trials

Rose et al. (30) conducted a randomized, double-blind, placebo-controlled trial of epoetin alfa in 221 anemic patients with CLL. Patients had advanced disease (Rai stage intermediate) with Hct < 32%, and were randomized to receive epoetin alfa 150 U/kg three times/wk sc (n = 141) or placebo (n = 80) for up to 12 wk. Hct values were measured at baseline and weekly while on study. Quality of life (QOL) (as measured by a self-administered questionnaire addressing energy, physical/social/cognitive role function, and mental health) was assessed at baseline and after 6 and 12 wk of treatment. Treatment groups were balanced for baseline demographics. (Baseline Hct was 27.4% in the treated group vs 27.8% in the control group.) The mean final Hct increased by 5.7 percentage points in the epoetin alfa-treated group and 1.5 percentage points in the placebo group (p < 0.0001). Approximately 50% of the epoetin alfa group had a Hct change > 6 points over baseline value, unrelated to transfusion, compared with 15% of the control group (p < 0.0001). Overall, approx 30% of the epoetin alfa group and 5% of the placebo group achieved Hct > 38, unrelated to transfusion (p < 0.0001). Group differences favoring the epoetin alfa patients were found for the energy scores on the QOL questionnaire (p < 0.05). Patients who achieved an Hct > 38% had significant improvements in all aspects of the QOL questionnaire (p < 0.01 to p <

Erythropoietin Activity in Randomized Trials in Anemic, Chronic Lymphocytic Leukemia Patients

Ref. Erythropoietin

CLL patients (no.)

Entry criteria

Definition of response



p value

30 Epoetin alfa (150 U/kg

n = 221 (141 treated,

Hct < 32%

Increase in Hct > 6 points

~ 50%



3x wk for 12 wks)

80 control)

from baseline

Increase in Hct >38%

~ 30%



29 Epoetin beta (150 U/kg

n = 125

Hb < 10 g/dL

Increase in Hb > 2 g/dL




3x wk for 16 wk,

and "low"

from baseline

dose escalation

serum EPO

permitted after wk 4)

Improvement in FACT QOL

14.8 ± 28

8.7 ± 28.9


scale at 16 wk

31 Darbepoetin alfa (1, 2.25

n = 11 evaluable

Hb < 11 g/dL

Increase in Hb > 2 g/dL

1 U/kg (1/2 N/A)



or 4.5 U/kg 1x wk

(2 placebo, 2,1,

from baseline

2.25 U/kg d 1


for 12 wk)

and 6 at the 1,2.25 and 4.5 U/kg/wk doses)

4.5 U/kg Dose response: 1 U/kg (1/2 N/A) 2.25 U/kg (0/1) 4.5 U/kg (3/6)

32 Epoetin alpha (150 U/kg

n = 9 (6 epoetin alfa,

Hct < 32%

Complete response

6/6 responses

0/3 responses


3x wk for 12 wk, then

3 placebo)

= Hct > 38%

(wk 12)

wk 12

12 wk of open-label

drug—dose escalation

permitted after wk 12)

Partial response = Hct > 6 pts from baseline

8/9 responses (wk 24)

Abbreviations: Hb, hemoglobin; N/A, not applicable; Hct, hematocrit; FACT, Functional Assessment of Cancer Therapy; QOL, quality of life. * See Table 2 for definition of "low"serum EPO used.

Abbreviations: Hb, hemoglobin; N/A, not applicable; Hct, hematocrit; FACT, Functional Assessment of Cancer Therapy; QOL, quality of life. * See Table 2 for definition of "low"serum EPO used.

0.0004). In addition, the need for transfusions was significantly reduced in the epoetin alfa group.

The results of this study have been confirmed in several other randomized trials (Table 4). Österberg et al. (29) conducted a double-blind, randomized, placebo-controlled trial of epoetin beta in 343 transfusion-dependent patients with hematologic malignancies (Hb concentration < 10 g/dL) with low serum EPO concentrations. The study was stratified for patients with NHL (n = 106), CLL (n = 126), or multiple myeloma (n = 117). CLL patients were randomized to receive 150 U/kg of epoetin beta sc three times week or placebo for 16 wk. The epoetin beta dose was increased to 300 U/kg three times/wk if no signs of response were observed after 4 wk. Patients were prescreened for low serum EPO concentrations (relative EPO deficiency; see Table 2 for definitions). Hb concentrations were measured at baseline and throughout the study. QOL assessments were done at baseline and at wk 4, 8, 12, and 16 using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire. The primary endpoint of the study was transfusion-free survival during wk 5 to 16.

The cumulative Hb response rate (defined as a 2-g/dL increase in Hb concentration from baseline) in patients receiving epoetin beta was statistically significantly higher than among placebo patients (63% vs 26%, p < 0.0001). Patients receiving epoetin beta in the trial had statistically significant risk reductions of approx 40% in both transfusionfree survival and severe anemia-free survival (p = 0.02 and 0.03, respectively). For all patients in the study, a statistically significant increase in FACT-An scores was observed among epoetin beta patients relative to placebo patients at wk 12 and 16 (p < 0.05). Regression analysis of the epoetin beta patients evaluating the week-16 Hb concentration and the change in FACT-An over the course of the study demonstrated a statistically significant correlation on the basis of log-linear relationships regression (r = 0.3167, p = 0.001), but the between-patient variability was considerable.

Hedenus et al. (31) conducted a randomized, double-blind, placebo-controlled dose-finding study of darbepoetin alfa in 66 anemic patients with lymphoproliferative malignancies. Anemia was defined as Hb concentration < 11 g/dL. Twelve patients with CLL were randomized within the study: two placebo, two to 1.0 U/kg/wk, one to 225 U/kg/wk, and seven to 4.5 U/kg/wk. No dose increases were allowed during the study. Eleven patients were evaluable for efficacy. Darbepoetin alfa or placebo was administered once a week sc for 12 wk. Hb response was defined as a 2-g/dL increase from the baseline value, and concentrations were measured weekly during the study. For all patients in the study, the proportion of patients achieving an Hb response increased with the darbepoetin alfa dose (from 45% in the 1-U/kg/wk cohort to 62% in the 4.5-U/kg/wk cohort) and was significantly higher for the darbepoetin alfa patients than for placebo patients (p < 0.01). Hb responses were observed among CLL patients at a frequency that did not differ from other tumor types by covariate analysis.

Pangalis et al. (32) conducted a randomized, closed-label trial of 12 wk of epoetin alfa (n = 6) or placebo (n = 3) in anemic CLL patients (defined as Hct < 32%). Patients were then enrolled in an open-label phase of the study for 12 additional weeks during which all patients received epoetin alfa. During the closed phase, epoetin alfa was administered at 150 U/kg three times/wk. During the open-label phase, increments of 50 U/kg were allowed to a maximum of 300 U/kg if response was slow or unsatisfactory. Complete responses (Hct > 38%) were achieved in 5/9 patients, and partial responses (increase of >6 points from baseline) in 3/9 patients. Dose escalation was required in 2/7 responding patients. Patients who received placebo during the closed-label phase of the study showed no evidence of improvement.

2.2.2. Clinical Utilization Issues

Siakantaris et al. (33) evaluated the necessity of maintenance therapy in patients who achieved a response to epoetin alfa. The study enrolled 33 patients with chronic lymphoproliferative disorders, among whom were 22 patients with B-CLL. Patients were anemic at entry (Hct < 32%) and were treated with 150 U/kg epoetin alfa three times/wk sc for 12 wk. After 6 wk, escalation of the epoetin alfa doses was permitted in 50-U/kg increments (to a maximum of 300 U/kg three times/wk) for unsatisfactory responses. Unsatisfactory response was defined as an Hct increase from baseline < 2 points. The overall response was determined at wk 12. At that time, 50% of the responding patients received maintenance therapy with epoetin alfa 150 U/kg/wk sc, and the remaining responding patients were discontinued.

At wk 12, 11/22 CLL patients had a complete response (i.e., Hct > 38%), and 6 achieved a partial response (i.e., >6 point increase in Hct from baseline). All responding patients who received maintenance therapy continued to respond (8/8), whereas responding patients who discontinued epoetin alfa relapsed at a median of 2 mo (9/9). The median follow-up time of the maintenance phase was 12 mo. Thus, continued maintenance therapy appears to be necessary to maintain responses to rHuEPO therapy in patients with CLL.

In both the Rai and Binet staging systems, severe anemia (Hb concentration < 11 g/dL and Hct < 33% in Rai, and Hb concentration < 10 g/dL in Binet) is associated with poor prognosis and is part of the definition of an advanced-stage patient. The National Cancer Institute (NCI) guidelines for management of CLL state that B-CLL patients with Hb concentration < 10 g/dL are candidates for chemotherapy (22). Studies have reported that the response to rHuEPO in CLL patients results in the "downstaging" of patients (32,33). Pangalis et al. (34) conducted a study to evaluate the clinical impact of the downstaging of CLL patients by improvement of disease-related anemia. The primary endpoint was whether increasing the Hct in patients could postpone the need for cytotoxic therapy and prolong survival.

For this study, 32 consecutive patients with B-CLL diagnosed with Rai stage III (intermediate) or IV (advanced) were eligible to enroll into an epoetin alfa treatment protocol if anemia developed (anemia was defined as Hct < 32% on two occasions 2 wk apart). Of the 32 patients, 11 were anemic at diagnosis, and 14 developed anemia during follow-up (median: 53.5 mo), for a total of 25 study patients with disease-related anemia. Of the 25 patients, 15 had no prior or concurrent chemotherapy, 9 had received prior chemotherapy but had been discontinued for at least 3 mo, and 1 received chlorambucil during the study.

Treatment involved an induction phase with epoetin alfa 150 U/kg three times/wk sc, for a maximum period of 12 wk. If response was slow after 4 wk (Hct increase < 6 points from baseline), the dose was increased in 50-U/kg increments to a maximum of 300 U/kg three times/wk. After the induction period, all responding patients were converted to maintenance therapy with 150 U/kg epoetin alfa sc weekly. After 12 wk of sustained responses on the maintenance schedule, the dosing interval was increased from 7 to 10 d.

The primary endpoint of the study was time to cytotoxic chemotherapy. Blood counts were evaluated every 2 wk during induction and every 4 wk thereafter. In cases of disease progression, cytotoxic therapy was initiated. Complete Hct responses (Hct > 38%) were observed in 18/25 patients. Partial Hct responses (>6-point increase from baseline) were observed in 2 additional patients, for an overall response rate of 80% (20/25). Eighteen/20 responding patients had sustained responses at a median of >30.8 mo. The remaining two patients died of infection while still responding to epoetin alfa. Dose escalation of epoetin alfa to 300 U/kg occurred in seven nonresponding patients, two of whom went on to achieve a complete response.

After induction, responding patients were restaged using Rai criteria. This resulted in the downstaging of 19/20 responding patients from Rai stage III to Rai stage 0 (n = 6), stage I (n = 9), or stage II (n = 4). In the one patient in whom "downstaging" did not occur, anemia was corrected but thrombocytopenia persisted. Disease progression was observed in 4/20 responding patients, triggering initiation of cytotoxic chemotherapy. In addition, one patient developed autoimmune hemolysis, requiring corticosteroids. The 15 remaining patients (11/13 previously untreated and 4/7 previously treated) remained free of antileukemic therapy at a median of 31+ mo. Neither the median time to leukemic therapy nor the median overall survival had been reached at the time of publication. The probability of response to epoetin alfa was decreased in patients with CLL who had increased pretreatment serum EPO concentrations, and among patients with lymphadenopathy and splenomegaly. The probability of response was independent of the extent or pattern of bone marrow infiltration.

As the authors of the study noted, the clinical trial did not prove that exogenous EPO exerts an effect on the biologic course of B-CLL, but it does raise the issue of whether anemia is a suitable criteria for B-CLL staging.

Exogenous EPO have been well tolerated and safe in all clinical trials reported to date in CLL (27-34). Most adverse events were attributed to the underlying malignancies or antitumor therapy and were reported with equal frequency for the erythropoietic and placebo cohorts. Transient skin reaction at the injection sites were the most common rHuEPO-related toxicity.

Two consensus papers were published in 2002 with specific recommendations for the management of disease-related anemia (i.e., multiple myeloma and CLL) with exogenous EPO. These reviews contain critical and extensive analyses of the existing literature and have specific recommendations with regard to patient management (35,36).

0 0

Post a comment