Pegylated recombinant interferon alpha-2b vs recombinant ... - Nature

Leukemia (2004) 18, 309–315 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $25.00 www.nature.com/leu

Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study M Michallet1, F Maloisel2, M Delain3, A Hellmann4, A Rosas5, RT Silver6 and C Tendler7, for the PEG-Intron CML Study Group8 1 Hoˆpital Edouard Herriot, Lyon, France; 2Hoˆpital Hautepierre, Strasbourg, France; 3Hoˆpital Bretonneau, Tours, France; 4Medical University of Gdansk, Gdansk, Poland; 5Centro Mexico Nacional La Raza Instituto Mexicano del Seguro Social, Mexico City, Mexico; 6New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA; and 7Schering-Plough, Kenilworth, NJ, USA

Recombinant interferon alpha-2b (rIFN-a2b) is an effective therapy for chronic-phase chronic myelogenous leukemia (CML). Polyethylene glycol-modified rIFN-a2b is a novel formulation with a serum half-life (B40 h) compatible with onceweekly dosing. This open-label, noninferiority trial randomized 344 newly diagnosed CML patients: 171 received subcutaneous pegylated rIFN-a2b (6 lg/kg/week); 173 received rIFN-a2b (5 million International Units/m2/day). Primary efficacy end point was the 12-month major cytogenetic response (MCR) rate (o35% Philadelphia chromosome-positive cells). Modified efficacy analysis included all MCRs 412 months, except for patients discontinuing treatment after 6 months and achieving an MCR on other salvage therapy. The MCR rates were 23% for pegylated rIFN-a2b vs 28% for rIFN-a2b in the primary efficacy analysis and 26 vs 28% in the prospectively modified efficacy analysis. However, a significant imbalance in baseline hematocrit (HCT), a significant predictor of cytogenetic response (P ¼ 0.0001), was discovered: 51 (30%) patients treated with pegylated rIFN-a2b had low HCT (o33%) vs 33 (19%) rIFN-a2btreated patients. Among patients with HCT 433%, the MCR rate was 33 vs 31%. The adverse event profile of weekly pegylated rIFN-a2b was comparable to daily rIFN-a2b. Once-weekly pegylated rIFN-a2b is an active agent for the treatment of newly diagnosed CML with an efficacy and safety profile similar to daily rIFN-a2b, although statistical noninferiority was not demonstrated. Leukemia (2004) 18, 309–315. doi:10.1038/sj.leu.2403217 Published online 4 December 2003 Keywords: chronic phase; chronic myelogenous leukemia; PEG Introns; pegylated recombinant interferon alpha-2b

Introduction Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder involving neoplastic proliferation of pluripotent myeloid stem cells. Several large clinical trials have shown that daily administration of recombinant interferon alpha (rIFN-a) is effective in the treatment of Philadelphia chromosome-positive (Ph þ ) chronic-phase CML, achieving sustained cytogenetic responses and improving survival compared with standard chemotherapy.1–6 Some studies have shown that daily dosing of rIFN-a at 5 million International Units (MIU)/m2 is more effective than lower doses or three times weekly dosing;7,8 therefore, patient compliance with the daily rIFN-a regimen is a key factor for achieving clinical benefit. However, due to the requirement for frequent subcutaneous injections and due to the significant side effects associated with rIFN-a therapy, this regimen is sometimes not tolerated.7,8 Correspondence: M Michallet, Hoˆpital Edouard Herriot, Pavillon E, Place d’Arsonval, 69437 Lyon, Cedex 03, France; Fax: þ 33 47 211 7303; E-mail: [email protected] 8 See appendix for participating investigators Received 14 April 2003; accepted 13 October 2003; Published online 4 December 2003

A pegylated form of recombinant interferon alpha-2b (rIFNa2b), PEG Introns (Schering-Plough Corporation, Kenilworth, NJ, USA), was developed, which contains a single polyethylene glycol moiety (12 000 Da average molecular weight). Pegylated rIFN-a2b exhibits decreased clearance, increased area under the curve, and a significantly longer half-life (B10-fold greater) than rIFN-a2b, and is compatible with weekly dosing.9 An increased area under the curve in combination with prolonged tumor exposure to rIFN-a2b may be more critical than peak rIFN-a2b serum levels for mediating an antileukemic effect.8 In a phase I study in CML patients, pegylated rIFN-a2b at doses up to 6.0 mg/ kg/week was well tolerated, demonstrated clinical activity in patients who failed rIFN-a2b therapy, and was more convenient than daily rIFN-a2b treatment.10 Based on these data, a randomized phase III trial was conducted to determine the efficacy and safety of weekly pegylated rIFN-a2b compared with daily rIFN-a2b in newly diagnosed patients with Ph þ chronicphase CML.

Patients and methods

Patients Patients were eligible if they were diagnosed with Ph þ chronicphase CML within 3 months before study enrollment, were between 18 and 70 years of age, and had an Eastern Cooperative Oncology Group performance status of o2, a baseline platelet count 450 000/oml, hemoglobin 49.0 g/dl, and a white blood cell (WBC) count 42000 cells/ml but o50 000 cells/ml. Pretreatment with hydroxyurea and allopurinol was allowed as needed before randomization until the WBC count was o50 000 cells/ml. Eligible patients were required to have an adequate liver function (serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, serum bilirubin o2 times the upper limits of normal), an adequate renal function (serum creatinine o2.0 mg/dl), and an adequate cardiac function. Patients were ineligible if they presented with accelerated-phase CML (defined as 415% peripheral blood myeloblasts, 420% peripheral blood basophils, 430% peripheral blood myeloblasts plus promyelocytes, or platelets 4100 000/ml, unrelated to therapy) or blastic-phase CML (defined as 430% myeloblasts in peripheral blood or bone marrow). Patients were ineligible if they were planning to receive a bone marrow transplantation within 12 months after enrollment, had received prior therapy for CML (except for hydroxyurea and allopurinol), or had a history of a neuropsychiatric disorder requiring hospitalization. All patients provided informed written consent, and this study complied with the ethical standards of the local institutional review boards of each study center and with the Helsinki Declaration of 1975, as revised in 1983.

Peg Introns in chronic-phase CML M Michallet et al

310

Treatment Patients were randomized to receive pegylated rIFN-a2b (6.0 mg/ kg/week) or rIFN-a2b (5 MIU/m2/day) by subcutaneous injection. The first dose of study drug was administered within 7 days of randomization. All patients received 500–1000 mg acetaminophen 30 min before study drug administration. Patients were treated for a minimum of 6 months or until disease progression, unacceptable toxicity, or patient request for discontinuation occurred. Patients who failed to achieve a complete hematologic response (CHR) after 6 months were allowed to pursue other treatments and were considered treatment failures in the primary protocol-defined analysis. After 1 year of treatment, patients with a minor cytogenetic response (o90% Ph þ ) could continue treatment for an additional 12 months or until disease progression. Dose reduction was permitted for the management of treatment-related toxicity: 25% for the first occurrence of grade 2 neurologic toxicity or grade 3 nonhematologic or hematologic toxicity; 50% for the first occurrence of grade 3 neurologic toxicity, for the second occurrence of grade 2 neurologic toxicity or for the second occurrence of grade 3 nonhematologic or hematologic toxicity. Once the pegylated rIFN-a2b or rIFNa2b dose was reduced for either nonhematologic or neurologic toxicity, no subsequent dose escalations were permitted. However, for dose reductions based on leukopenia or thrombocytopenia, dose escalation (ie one dose level) was permitted when the WBC recovered to 44.0 109/l and the platelet count recovered to 4100 109/l.

Response and safety assessments The primary protocol-defined end point was the major cytogenetic response (MCR) rate (o35% Ph þ cells) at 12 months. Secondary end points included hematologic response rate at 3, 6, and 12 months; cytogenetic response rate at 6 months; and an assessment of the safety and impact on healthrelated quality of life (HQL). Cytogenetic response was defined by the degree of suppression of Ph þ cells in bone marrow aspirate samples as analyzed at one of two designated central cytogenetics laboratories. Complete (no Ph þ cells) and partial (1–34% Ph þ cells) cytogenetic responses were considered in the determination of the MCR rate (a minimum of 10 metaphases were required for sample adequacy). If the sample sent to the central lab was unsatisfactory for cytogenetic analysis, results from a qualified local cytogenetic laboratory were accepted. If both the central and local cytogenetic analyses were unsatisfactory, alternative approaches including fluorescent in situ hybridization or repeat bone marrow aspiration (up to 15 months on treatment) were used to determine each patient’s cytogenetic response at 12 months. For complete hematologic remission, a patient must have met all of the following criteria for a minimum of 28 days: WBC o10 000 cells/ml, platelets o450 000/ml, normal differential count in peripheral blood, and no palpable spleen. In the intentto-treat protocol-specified efficacy analysis, patients lacking a CHR at 6 months were considered cytogenetic failures regardless of their response at 12 months. A prospectively modified efficacy analysis included all MCRs 412 months. This analysis included patients who may not have had a CHR at 6 months but remained on study treatment and subsequently achieved an MCR. In this analysis, patients who achieved a CHR at 6 months but discontinued treatment soon Leukemia

thereafter and achieved an MCR on other effective antileukemic therapy were considered treatment failures. Quality of life was measured using a health-related quality-oflife questionnaire that consisted of the EORTC Quality of Life Questionnaire-C30 (version 2.0),11 the INTRONs A side-effect module,6 and an additional question with respect to how often patients were bothered by treatment. Toxicities were graded according to the National Cancer Institute’s Common Toxicity Criteria. Safety and tolerability were assessed by clinical observation and routine laboratory methods. Patients were monitored for toxicity weekly from weeks 1 to 11, monthly from weeks 12 to 52, then every 3 months until discontinuation. A thyroid function test was performed every 3 months starting at week 12 until treatment discontinuation.

Statistics This study was prospectively powered to demonstrate noninferiority of pegylated rIFN-a2b compared with rIFN-a2b. With a sample size of 150 patients per group (300 total), the study had a power of 80% at a 5% level of significance to demonstrate noninferiority (assuming a 20% MCR rate for rIFN-a2b and 30% for pegylated rIFN-a2b). Noninferiority required that the lower boundary of the 95% confidence interval (CI) for the odds ratio (pegylated rIFN-a2b:rIFN-a2b) for the probability of achieving an MCR did not fall below 0.8. The Cochran Mantel–Haenszel test was used for the primary efficacy analysis (cytogenetic response at 12 months) and secondary end points (cytogenetic response at 6 months and hematologic response at 3, 6, and 12 months) on an intent-to-treat basis. All baseline demographic characteristics were analyzed in the logistic regression analysis. At the time the study was initiated, the Sokal score was the standard approach used to define risk groups before randomization. However, we used the Hasford score in the regression analysis because it had become a more acceptable criterion for defining risk groups at the time the analysis was performed. Overall survival was analyzed using the log-rank statistic. Survival rates were estimated using the Kaplan–Meier method.12 Hazard ratios and corresponding 95% CIs were calculated using Cox’s proportional-hazards model.

Results

Patient characteristics A total of 344 patients with newly diagnosed chronic-phase CML were enrolled (171 received pegylated rIFN-a2b; 173 received rIFN-a2b) between August 1998 and November 1999. A minority of patients received hydroxyurea to control their WBC count before randomization. Baseline patient and disease characteristics at randomization are shown in Table 1. Treatment groups were well balanced with respect to patient demographic and baseline disease characteristics, with the exception of hematocrit (HCT). A significantly larger proportion of patients randomized to pegylated rIFN-a2b had an HCT o33% compared with the rIFN-a2b group (30% in the pegylated rIFN-a2b group compared with 19% in the rIFN-a2b group; P ¼ 0.02, w2 test). The median administered dose for the entire patient population was approximately 5 mg/kg/week (range, 0.08–6.52 mg/kg/ week) for pegylated rIFN-a2b (intended dose: 6 mg/kg/week) and 27 MIU/m2/week (range, 4.83–26.71 MIU/m2/week) for rIFN-


a2b (intended dose: 35 MIU/m2/week). In all, 105 (61%) patients in the pegylated rIFN-a2b group and 108 (62%) patients in the rIFN-a2b completed 1 year of treatment. The major reasons for early discontinuation of study treatment were adverse events (31 patients treated with pegylated rIFN-a2b and 26 treated with rIFN-a2b) and disease progression/recurrence (14 patients treated with pegylated rIFN-a2b and six treated with rIFN-a2b).

Response As shown in Table 2, cytogenetic response rates were comparable between treatment groups. Based on the protocolTable 1

311 defined primary efficacy analysis, 39 of 171 (23%) patients treated with pegylated rIFN-a2b and 48 of 173 (28%) patients treated with rIFN-a2b achieved an MCR. However, this did not meet the criteria for noninferiority. The odds ratio was 0.79 (95% CI: 0.48–1.29). In the prospectively modified efficacy analysis, 45 (26%) patients treated with pegylated rIFN-a2b had an MCR compared with 49 (28%) patients treated with rIFNa2b. However, this also did not meet the criteria for noninferiority (odds ratio: 0.93; 95% CI: 0.57–1.50). Of these MCRs, 17 (10%) patients in each treatment group had a complete response and 28 (16%) patients in the pegylated rIFN-a2b group vs 32 (19%) in the rIFN-a2b group had partial responses. Hematologic and cytogenetic response rates at 6

Patient characteristics

Characteristic

Pegylated rIFN-a2b (n ¼ 171)

rIFN-a2b (n ¼ 173)

44 (26) 127 (74) 53.0 (20–76)

56 (32) 117 (68) 53.0 (20–80)

Age (years) o45, n (%) 445, n (%) Median (range) Sex, n (%) Male Female Race Caucasian Hispanic Other Patients with splenomegaly, n (%) Patients with circulating blast cells, n (%) Blood cell counts, mean7s.d. WBCs 109/l Platelets 109/l Hemoglobin (g/l), mean7s.d. HCT, n (%) o33%a 433% Sokal score, n (%) Low (o0.8) Intermediate (0.8–1.2) High (41.2)

96 (56) 75 (44)

106 (61) 67 (39)

142 (83) 18 (11) 11 (6)

142 (82) 17 (10) 14 (8)

86 (50) 86 (50)

77 (45) 81 (47)

25.0722.2 451.97298.9

28.0729.3 461.27336.4

124.3717.4

128.1717.8

51 (30) 120 (70)

33 (19)b 140 (81)

58 (34) 75 (44) 38 (22)

65 (38) 72 (42) 36 (21)

rIFN-a2b ¼ recombinant interferon alpha-2b; s.d. ¼ standard deviation; WBC ¼ white blood cell; HCT ¼ hematocrit. a Defined as clinical anemia. b Statistically significant difference (P ¼ 0.02, w2 test). Table 2

Cytogenetic responses by treatment group (intent-to-treat population) Patients, n (%)

Efficacy analysis

Pegylated rIFN-a2b, (n ¼ 171)

rIFN-a2b, (n ¼ 173)

Odds ratio

95% CI

13 (8) 26 (15) 39 (23)

13 (8) 35 (20) 48 (28)

0.79

(0.48–1.29)

17 (10) 28 (16) 45 (26)

17 (10) 32 (19) 49 (28)

0.93

(0.57–1.50)

a

Protocol defined Completeb Partialc Total d

Modified Completeb Partialc Total

rIFN-a2b ¼ recombinant interferon alpha-2b; CI ¼ confidence interval. a Cytogenetic response at 12 months. b 0% Ph+. c 1–34% Ph+. d Cytogenetic response at or beyond 12 months. Leukemia


312 months were similar between treatment groups: 91 (53%) patients treated with pegylated rIFN-a2b and 98 (57%) patients treated with rIFN-a2b had a CHR, and 26 (15%) patients in each treatment group achieved an MCR at 6 months. These results demonstrated that pegylated rIFN-a2b was clinically comparable to rIFN-a2b in both the protocol-defined and prospectively modified efficacy analyses but failed to demonstrate statistical noninferiority.

Subset analysis of response A logistic regression analysis of all baseline demographic variables was performed to identify prognostic factors that may have affected the outcome of this study. In this analysis, HCT, age, and Hasford score13 were found to be significant predictors of MCR, and low HCT (o33%) was highly correlated with a poorer response (P ¼ 0.0001). This was relevant to the outcome of this study because of the imbalance in baseline HCT. The proportion of patients with HCT o33% was significantly higher in the pegylated rIFN-a2b group (Table 1) compared with the rIFN-a2b group (30 vs 19%, respectively; P ¼ 0.02). Therefore, cytogenetic response rates were reanalyzed by baseline HCT. In the subset of patients with HCT o33% (poor prognostic subgroup), the MCR rate was lower in both treatment groups than in the overall patient population (Figure 1). MCR rates in this subgroup were 12% (six of 51 patients) in the pegylated rIFN-a2b group compared with 15% (five of 33 patients) in the rIFN-a2b group. Among patients with HCT 433% (good prognostic subgroup), the MCR rate for pegylated rIFN-a2b was 33% (39 of 120 patients) compared with 31% (44 of 140 patients) in the rIFN-a2b group (odds ratio: 1.09; 95% CI: 0.65–1.84).

Safety Pegylated rIFN-a2b was safe and well tolerated. The most frequently reported adverse events are summarized by treatment Table 3

Figure 1

Analysis of MCR rates by baseline HCT.

group in Table 3. The most commonly reported adverse events were fever and headache. The most commonly reported grade 3/4 adverse events were fever and thrombocytopenia. Injectionsite reactions were more commonly observed in the pegylated rIFN-a2b group (42 vs 17%). However, these adverse events were generally mild to moderate in severity. Only one patient treated with pegylated rIFN-a2b experienced a grade 3 injection-site reaction, and the episode did not result in treatment discontinuation. Laboratory abnormalities were similar between the two treatment groups, and the majority of changes were grade 1 or 2. Grade 3 decreases in WBC, neutrophils, and platelets were indicative of an antileukemic treatment effect and were similar for both treatment groups. Elevations in alanine transaminase, aspartate transaminase, and total bilirubin were within the expected range for this patient population, and there were no

Most frequently reported adverse events by treatment group (45% grade 3/4) Patients, n (%) Any grade

Adverse event Fever Headache Rigors Anorexia Fatigue Myalgia Nausea Diarrhea Arthralgia Asthenia Musculoskeletal pain Back pain Weight decrease Depression Hepatic enzymes increased

Pegylated rIFN-a2b (n ¼ 171) 140 134 118 114 105 105 109 104 92 96 82 79 83 64 13

Hematologic Thrombocytopenia Leukopenia Neutropenia rIFN-a2b ¼ recombinant interferon alpha-2b. Leukemia

(82) (78) (69) (67) (61) (61) (64) (61) (54) (56) (48) (46) (49) (37) (8)

43 (25) 19 (11) 14 (8)

Grade 3/4 rIFN-a2b (n ¼ 173) 134 129 109 100 109 109 103 89 84 80 83 82 69 54 12

(77) (75) (63) (58) (63) (63) (60) (51) (49) (46) (48) (47) (40) (31) (7)

46 (27) 19 (11) 14 (8)

Pegylated rIFN-a2b (n ¼ 171) 26 15 5 8 21 5 6 10 13 11 17 11 8 13 9

(15) (9) (3) (5) (12) (3) (4) (6) (8) (6) (10) (6) (5) (8) (5)

21 (12) 7 (4) 7 (4)

rIFN-a2b (n ¼ 173) 23 10 8 13 23 11 9 8 11 14 10 9 15 11 11

(13) (6) (5) (8) (13) (6) (5) (5) (6) (8) (6) (5) (9) (6) (6)

24 (14) 10 (6) 9 (5)


313 reports of grade 4 hepatic laboratory abnormalities in either treatment group. Grade 3 hepatic laboratory abnormalities were uncommon. Grade 3 alanine transaminase or aspartate transaminase increases occurred in 17 (10%) and 15 (9%) patients treated with pegylated rIFN-a2b and 11 (6%) and 11 (6%) patients treated with rIFN-a2b, respectively. Serum neutralizing antibodies were not detected in patients treated with pegylated rIFN-a2b. Discontinuation because of adverse events occurred in 27 and 21% of patients in the pegylated rIFN-a2b and rIFN-a2b groups, respectively. The most frequently reported adverse events leading to discontinuation are summarized in Table 4. Discontinuations because of depression, fatigue, headache, asthenia, and diarrhea occurred slightly more often in patients treated with rIFN-a2b compared with pegylated rIFN-a2b, whereas chest pain and thrombocytopenia more often resulted in discontinuation of pegylated rIFN-a2b. In addition, the HQL analysis indicated that the impact of treatment with pegylated rIFN-a2b on HQL was comparable to that of rIFN-a2b; no significant differences were observed between groups (data not shown). In all, 17 patients treated with pegylated rIFN-a2b and 15 patients treated with rIFN-a2b died during the study. The Kaplan–Meier survival analysis (Figure 2) was limited by the small number of deaths at a median follow-up of approximately

Table 4 Discontinuations because of frequently reported adverse events (42% per treatment group) Patients, n (%) Adverse event Depression Fatigue Asthenia Headache Weight decrease Chest pain Thrombocytopenia Diarrhea Total

Pegylated rIFN-a2b (n ¼ 171) rIFN-a2b (n ¼ 173) 7 4 3 1 4 3 3

(4) (2) (2) (o1) (2) (2) (2) 0

46 (27)

9 8 4 5 1

(5) (5) (2) (3) (o1) 0 0 3 (2)

37 (21)

rIFN-a2b ¼ recombinant interferon alpha-2b.

Figure 2 Kaplan–Meier estimate of survival in patients treated with pegylated rIFN-a2b (n ¼ 171) and rIFN-a2b (n ¼ 173). rIFNa2b ¼ recombinant interferon alpha-2b.

1.3 years; the hazard ratio was 0.859 (95% CI: 0.43–1.72). Disease progression was the major cause of death, resulting in 20 of 32 deaths, and 18 deaths caused by disease progression occurred 430 days after the patient discontinued study drug. The remaining deaths resulted from adverse events primarily unrelated to treatment.

Discussion This phase III study was initiated to determine the efficacy and safety of pegylated rIFN-a2b compared with rIFN-a2b in the treatment of patients with newly diagnosed chronic-phase CML. The primary goal of this study was to perform a head-to-head comparison to determine if pegylated rIFN-a2b resulted in an increased MCR rate compared with rIFN-a2b without the added complexities of other agents such as Ara C, based on the evidence that higher doses of rIFN-a2b are associated with improved MCR rates.7,8 Based on the observed linear pharmacokinetics of pegylated rIFN-a2b,9 it was hypothesized that pegylated rIFN-a2b could be delivered at a substantially greater exposure level than could be achieved with conventional rIFNa2b. A comparison of observed area under the curve data from a multidose, dose-ranging study in patients with chronic hepatitis C suggested that pegylated rIFN-a2b at a dose of 1.5 mg/kg/week yielded equivalent exposure as 45 MIU/week rIFN-a2b.14 A dose of 6.0 mg/kg/week was chosen for the current study based on phase I data, indicating that pegylated rIFN-a2b up to 6.0 mg/ kg/week was well tolerated and demonstrated clinical activity in patients with CML who failed rIFN-a2b therapy.10 In the current study, in addition to the protocol-defined primary end point, which included only MCRs occurring within 12 months of therapy, a modified primary end point (defined before study unblinding) was used to assess the MCR rate beyond 12 months. An international panel of CML experts agreed that the modified efficacy end point provided a more clinically relevant analysis than the protocol-defined end point. Although statistical noninferiority of pegylated rIFN-a2b was not demonstrated, based on either the protocol-defined or modified efficacy analysis, once-weekly pegylated rIFN-a2b (6.0 mg/kg/ week) yielded an MCR rate that was clinically comparable to that achieved with rIFN-a2b. However, because the strict statistical criteria for noninferiority were not met, one cannot rule out the possibility that pegylated rIFN-a2b may be slightly inferior to rIFN-a2b. Interestingly, a disproportionate number of patients with an HCT o33% (ie clinically anemic) were randomized to receive pegylated rIFN-a2b compared with rIFN-a2b (30 vs 19%, respectively), and this statistically significant imbalance may have biased the results in favor of rIFN-a2b. Baseline HCT was identified as the most significant predictor of MCR (P ¼ 0.0001) in a logistic regression analysis. Similar results have been reported in other CML studies.13,15,16 Hasford et al13 reported that hemoglobin was a significant (Po0.0001) predictor of survival. In a study of imatinib mesylate in 532 patients with late chronic-phase CML who failed treatment with rIFN-a, a multivariate analysis showed that hemoglobin o12 g/dl (comparable with HCT o33%) was an independent prognostic factor for cytogenetic response.16 A subset analysis of MCR rate by baseline HCT revealed that among patients with HCT o33%, rIFN-a2b yielded a higher MCR rate (15 vs 12% with pegylated rIFN-a2b), but among patients with HCT 433%, pegylated rIFN-a2b yielded an MCR rate equivalent to rIFN-a2b (33 vs 31%, respectively). Thus, the significantly larger proportion of patients with low HCT randomized to pegylated rIFN-a2b may Leukemia


314 account for the lower MCR rate compared with rIFN-a2b in the overall analysis. For the two-thirds of patients with normal HCT, pegylated rIFN-a2b was as effective as rIFN-a2b. Moreover, the MCR rate observed in this study was consistent with that reported in the literature for patients with early chronic-phase CML treated with single-agent rIFN-a2b.1,17,18 Pegylated rIFN-a2b was also shown to be safe and well tolerated at a dose of 6 mg/kg/week and exhibited a safety profile similar to rIFN-a2b with long-term use. Furthermore, the adverse event profile was generally similar to that reported previously for pegylated rIFN-a2b and rIFN-a2b.1,2,10 The most common adverse events in both groups were flu-like symptoms such as fever, headache, rigors, and fatigue. Discontinuations because of adverse events were slightly higher in the pegylated rIFN-a2b group compared with rIFN-a2b (27 vs 21%). However, the slightly higher discontinuation rate in the pegylated rIFN-a2b group did not result from a general increase in toxicity, and there was no a substantial increase in any particular adverse event in the pegylated rIFN-a2b group that led to discontinuation. Most events were reported by 1–3 patients (o2%). In both treatment groups, the most commonly reported reasons for discontinuations because of adverse events were depression, fatigue, headache, and diarrhea, which more often resulted in discontinuation of rIFN-a2b therapy, whereas chest pain and thrombocytopenia more often resulted in discontinuation of pegylated rIFN-a2b. Based on the slightly higher discontinuation rate in the pegylated rIFN-a2b group, the selected dose in this study may have been too high. Lower doses might allow for longer treatment duration while producing a similar rate of response in patients with CML. Although numerous studies suggest that high-dose rIFN-a2b (5 MIU/m2/day) yields higher response rates than low-dose regimens (3 MIU/m2/day), a recent randomized study with rIFN-a2b has reported numerically similar MCR rate with low- vs high-dose rIFN-a2b (Shepherd P et al. Blood 2001; 98: 727a). In summary, convenient weekly dosing with 6 mg/kg/week pegylated rIFN-a2b demonstrated a clinically comparable response rate and safety profile compared with a standard daily dose of rIFN-a2b, but the goal of improving efficacy by increasing rIFN-a2b exposure was not achieved. Imbalance in baseline HCT may explain the trend towards a better MCR rate with rIFN-a2b. Future studies are warranted to investigate pegylated rIFN-a2b in combination with other antileukemic agents (eg cytarabine or imatinib) in the treatment of chronicphase CML.

References 1 Kantarjian HM, Smith TL, O’Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 1995; 122: 254–261. 2 The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long-term follow-up of the Italian trial of interferonalpha versus conventional chemotherapy in chronic myeloid leukemia. Blood 1998; 92: 1541–1548. 3 Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood 1994; 84: 4064–4077. 4 Tura S, Baccarani M, Zuffa E, Russo D, Fanin R, Zaccaria A et al. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 1994; 330: 820–825. Leukemia

5 Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet 1995; 345: 1392–1397. 6 Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Kuramoto A et al. A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 1995; 86: 906–916. 7 Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood 1993; 82: 691–703. 8 Kantarjian HM, O’Brien S, Anderlini P, Talpaz M. Treatment of chronic myelogenous leukemia: current status and investigational options. Blood 1996; 87: 3069–3081. 9 Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000; 68: 556–567. 10 Talpaz M, O’Brien S, Rose E, Gupta S, Shan J, Cortes J et al. Phase 1 study of polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 2001; 98: 1708–1713. 11 Osoba D, Aaronson N, Zee B, Sprangers M, te Velde A. Modification of the EORTC QLQ-C30 (version 2.0) based on content validity and reliability testing in large samples of patients with cancer. The Study Group on Quality of Life of the EORTC and the Symptom Control and Quality of Life Committees of the NCI of Canada Clinical Trials Group. Qual Life Res 1997; 6: 103–108. 12 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 13 Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998; 90: 850–858. 14 Bukowski R, Tendler C, Cutler D, Rose E, Laughlin MM, Statkevich P. Treating cancer with PEG intron. Pharmacokinetic profile and dosing guidelines for an improved interferon alfa-2b formulation. Cancer 2002; 95: 389–396. 15 Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–3539. 16 Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652. 17 Ozer H, George S, Schiffer C, Rao K, Rao P, Wurster-Hill D et al. Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study. Blood 1993; 82: 2975–2984. 18 Mahon FX, Montastruc M, Faberes C, Reiffers J. Predicting complete cytogenetic response in chronic myelogenous leukemia patients treated with recombinant interferon alpha. Blood 1994; 84: 3592–3594.

Appendix Listing of PEG-Intron CML Study Group including ScheringPlough Research Institute: Esther Rose and Helen Yeardley; Argentina: Gustavo Kusminsky; Austria: Marianne Bernhart, Gunther Gastl; Australia: Anthony Dodds, R Lindeman; Belgium: Marc Boogaerts, Louise Debusscher, Andre Efira, Michee´le Rauis; Canada: Robert Belanger, Janis Bormanis, Guy Cantin, Donna Forrest, Michael Kovacs, Pierre Laneuville, Jeffrey H Lipton, Pedro Lopez, Robert Turner; Chile: Alejandro


315 Majlis; Columbia: Rodolfo Gomez; Denmark: Hans Karle; Finland: Tuomo Honkanen, Kalevi Oksanen; France: Frederic Bauduer, Agnes Buzyn-Veil, Sylvie Castaigne, Martine Delain, Bernard Desablens, Alain Devidas, Francois Guilhot, Denis Guyotat, Frederick Maloisel, Mauricette Michallet, Joseph Reiffers, Jean-Franccois Rossi, Philippe Rousselot, Philippe Solal-Celigny, Jean-Jaques Sotto, Michel Tulliez; Germany: Walter E Aulitzky, Olaf Brudler, Gerhard Ehninger, Ruediger Hehlmann, Christoph Huber, Christian Peschel, Peter Von Wussow; Greece: Nikolaos Anagnostopoulos, Maria Bakiris; Guatemala: Cesar Vettorazzi; Italy: Sergio Amadori, Achille Ambrosetti, Michele Baccarani, Carlo Bernasconi, Giovanna Rege Cambrin, Antonio Capaldi, Gianluigi Castoldi, Pietro Citarrella, Anna D’Emilio, Rosario Giustolisi, Luigi Gugliotta, Pietro Leoni, Anna Marina Liberati, Vincenzo Liso, Patrizio Mazza, Enrica Morra, Gianantonio Rosti, Bruno Rotoli, Ettore Volpe, Alfonso Zaccaria; Mexico: Jose Gonzalez-Llaven; Sweden: Magnus Bjorkholm, Olle Linder, Per Ljungman, Claes Malm, Stig Rodjer, Bengt Simonsson; The Netherlands: Gerrit Johan Ossenkoppele; Norway: Anders Waage; Poland: Anna

Dmoszynska, Maria Podolak-Dawidziak, Tadeusz Robak, Aleksander Skotnicki; Portugal: Jorge Coutinho, Ines Nolasco, Gabriel Tamagnini; South Africa: Lydia Fourie, FC Slabber, N Novitsky; Spain: Consuelo Canizo, Francisco Cervantes, Juan Luis Steegmann; United Kingdom: Naim Akhtar, Saad Adar AlIshmail, David Bareford, Helen Frances Barker, D Chan, James Chang, Dominic John Culligan, JG Erskine, C Hatton, P Hillmen, R Kaczmarski, SJ Kelly, PR Kelsey, JA Lui Yin, DW Milligan, AC Newlands, A Pagliuca, H Parry, M Potter, S Rassam, Sarah Willoughby, B Woodcock; Uruguay: Martha Nese; United States of America: David Bodensteiner, Timothy Brotherton, Delvyn C Case, Gary Cohen, Laurence Elias, Stephanie Elkins, John Feigert, Eric Feldman, Stephanie Gregory, Gary Gross, Robert Hirsch, John Hunter, Ahmad Jajeh, Matt Kalaycio, Ali Khojasteh, Jurgen Kogler, Phil Kuebler, Roger M Lyons, Kenneth Manning, Ann Mohrbacher, Robert O’Donnell, Joel Policzer, Mark Rarick, Allan Saven, Gary Schiller, Larry Schlabach, Andrew Schneider, Karen Seiter, Kevin Troy, Estil A Vance, Allen Yeilding, Furhan Yunus; Venezuela: Angela Rodriguez-M.

Leukemia