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

1Hoˆpital Edouard Herriot, Lyon, ; 2Hoˆpital Hautepierre, Strasbourg, France; 3Hoˆpital Bretonneau, Tours, France; 4Medical University of Gdansk, Gdansk, ; 5Centro 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 A pegylated form of recombinant interferon alpha-2b (rIFN- therapy for chronic-phase chronic myelogenous leukemia a2b), PEG Introns (Schering-Plough Corporation, Kenilworth, (CML). Polyethylene glycol-modified rIFN-a2b is a novel for- mulation with a serum half-life (B40 h) compatible with once- NJ, USA), was developed, which contains a single polyethylene weekly dosing. This open-label, noninferiority trial randomized glycol moiety (12 000 Da average molecular weight). Pegylated 344 newly diagnosed CML patients: 171 received subcutaneous rIFN-a2b exhibits decreased clearance, increased area under the pegylated rIFN-a2b (6 lg/kg/week); 173 received rIFN-a2b (5 curve, and a significantly longer half-life (B10-fold greater) than 2 million International Units/m /day). Primary efficacy end point rIFN-a2b, and is compatible with weekly dosing.9 An increased was the 12-month major cytogenetic response (MCR) rate area under the curve in combination with prolonged tumor ( 35% Philadelphia chromosome-positive cells). Modified o exposure to rIFN-a2b may be more critical than peak rIFN-a2b efficacy analysis included all MCRs 412 months, except for 8 patients discontinuing treatment after 6 months and achieving serum levels for mediating an antileukemic effect. In a phase I an MCR on other salvage therapy. The MCR rates were 23% for study in CML patients, pegylated rIFN-a2b at doses up to 6.0 mg/ pegylated rIFN-a2b vs 28% for rIFN-a2b in the primary efficacy kg/week was well tolerated, demonstrated clinical activity in analysis and 26 vs 28% in the prospectively modified efficacy patients who failed rIFN-a2b therapy, and was more convenient analysis. However, a significant imbalance in baseline hemato- than daily rIFN-a2b treatment.10 Based on these data, a crit (HCT), a significant predictor of cytogenetic response randomized phase III trial was conducted to determine the (P ¼ 0.0001), was discovered: 51 (30%) patients treated with pegylated rIFN-a2b had low HCT ( 33%) vs 33 (19%) rIFN-a2b- efficacy and safety of weekly pegylated rIFN-a2b compared with o þ treated patients. Among patients with HCT 433%, the MCR rate daily rIFN-a2b in newly diagnosed patients with Ph chronic- was 33 vs 31%. The adverse event profile of weekly pegylated phase CML. 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 Patients and methods demonstrated. Leukemia (2004) 18, 309–315. doi:10.1038/sj.leu.2403217 Patients Published online 4 December 2003 Keywords: chronic phase; chronic myelogenous leukemia; PEG þ Introns; pegylated recombinant interferon alpha-2b Patients were eligible if they were diagnosed with Ph chronic- phase 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 Introduction cell (WBC) count 42000 cells/ml but o50 000 cells/ml. Pre- treatment with hydroxyurea and allopurinol was allowed as Chronic myelogenous leukemia (CML) is a clonal myeloproli- needed before randomization until the WBC count was ferative disorder involving neoplastic proliferation of pluripotent o50 000 cells/ml. Eligible patients were required to have an myeloid stem cells. Several large clinical trials have shown that adequate liver function (serum glutamic-oxaloacetic transami- daily administration of recombinant interferon alpha (rIFN-a)is nase, serum glutamic-pyruvic transaminase, serum bilirubin o2 effective in the treatment of Philadelphia chromosome-positive þ times the upper limits of normal), an adequate renal function (Ph ) chronic-phase CML, achieving sustained cytogenetic (serum creatinine o2.0 mg/dl), and an adequate cardiac responses and improving survival compared with standard 1–6 function. Patients were ineligible if they presented with chemotherapy. Some studies have shown that daily dosing 4 2 accelerated-phase CML (defined as 15% peripheral blood of rIFN-a at 5 million International Units (MIU)/m is more 4 4 7,8 myeloblasts, 20% peripheral blood basophils, 30% periph- effective than lower doses or three times weekly dosing; eral blood myeloblasts plus promyelocytes, or platelets therefore, patient compliance with the daily rIFN-a regimen is a 4100 000/ml, unrelated to therapy) or blastic-phase CML key factor for achieving clinical benefit. However, due to the (defined as 430% myeloblasts in peripheral blood or bone requirement for frequent subcutaneous injections and due to the marrow). Patients were ineligible if they were planning to significant side effects associated with rIFN-a therapy, this 7,8 receive a bone marrow transplantation within 12 months after regimen is sometimes not tolerated. enrollment, had received prior therapy for CML (except for hydroxyurea and allopurinol), or had a history of a neuropsy- Correspondence: M Michallet, Hoˆpital Edouard Herriot, Pavillon E, chiatric disorder requiring hospitalization. All patients provided þ Place d’Arsonval, 69437 Lyon, Cedex 03, France; Fax: 33 47 211 informed written consent, and this study complied with the 7303; E-mail: [email protected] 8See appendix for participating investigators ethical standards of the local institutional review boards of each Received 14 April 2003; accepted 13 October 2003; Published online study center and with the Helsinki Declaration of 1975, as 4 December 2003 revised in 1983. Peg Introns in chronic-phase CML M Michallet et al 310 Treatment thereafter and achieved an MCR on other effective antileukemic therapy were considered treatment failures. Patients were randomized to receive pegylated rIFN-a2b (6.0 mg/ Quality of life was measured using a health-related quality-of- kg/week) or rIFN-a2b (5 MIU/m2/day) by subcutaneous injec- life questionnaire that consisted of the EORTC Quality of Life tion. The first dose of study drug was administered within 7 days Questionnaire-C30 (version 2.0),11 the INTRONs A side-effect of randomization. All patients received 500–1000 mg acetami- module,6 and an additional question with respect to how often nophen 30 min before study drug administration. Patients were patients were bothered by treatment. treated for a minimum of 6 months or until disease progression, Toxicities were graded according to the National Cancer unacceptable toxicity, or patient request for discontinuation Institute’s Common Toxicity Criteria. Safety and tolerability occurred. Patients who failed to achieve a complete hematolo- were assessed by clinical observation and routine laboratory gic response (CHR) after 6 months were allowed to pursue other methods. Patients were monitored for toxicity weekly from treatments and were considered treatment failures in the primary weeks 1 to 11, monthly from weeks 12 to 52, then every 3 protocol-defined analysis. After 1 year of treatment, patients months until discontinuation. A thyroid function test was with a minor cytogenetic response (o90% Ph þ ) could continue performed every 3 months starting at week 12 until treatment treatment for an additional 12 months or until disease discontinuation. progression. Dose reduction was permitted for the management of treatment-related toxicity: 25% for the first occurrence of grade Statistics 2 neurologic toxicity or grade 3 nonhematologic or hematologic toxicity; 50% for the first occurrence of grade 3 neurologic This study was prospectively powered to demonstrate noninfer- toxicity, for the second occurrence of grade 2 neurologic iority of pegylated rIFN-a2b compared with rIFN-a2b. With a toxicity or for the second occurrence of grade 3 nonhematologic sample size of 150 patients per group (300 total), the study had a or hematologic toxicity. Once the pegylated rIFN-a2b or rIFN- power of 80% at a 5% level of significance to demonstrate a2b dose was reduced for either nonhematologic or neurologic noninferiority (assuming a 20% MCR rate for rIFN-a2b and 30% toxicity, no subsequent dose escalations were permitted. for pegylated rIFN-a2b). Noninferiority required that the lower However, for dose reductions based on leukopenia or thrombo- boundary of the 95% confidence interval (CI) for the odds ratio cytopenia, dose escalation (ie one dose level) was permitted (pegylated rIFN-a2b:rIFN-a2b) for the probability of achieving when the WBC recovered to 44.0 Â 109/l and the platelet count an MCR did not fall below 0.8. The Cochran Mantel–Haenszel recovered to 4100 Â 109/l. 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 Response and safety assessments characteristics were analyzed in the logistic regression analysis. At the time the study was initiated, the Sokal score was the The primary protocol-defined end point was the major standard approach used to define risk groups before randomiza- cytogenetic response (MCR) rate (o35% Ph þ cells) at 12 tion. However, we used the Hasford score in the regression months. Secondary end points included hematologic response analysis because it had become a more acceptable criterion for rate at 3, 6, and 12 months; cytogenetic response rate at 6 defining risk groups at the time the analysis was performed. months; and an assessment of the safety and impact on health- Overall survival was analyzed using the log-rank statistic. related quality of life (HQL). Cytogenetic response was defined Survival rates were estimated using the Kaplan–Meier method.12 by the degree of suppression of Ph þ cells in bone marrow Hazard ratios and corresponding 95% CIs were calculated using aspirate samples as analyzed at one of two designated central Cox’s proportional-hazards model. 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 Results metaphases were required for sample adequacy). If the sample sent to the central lab was unsatisfactory for cytogenetic Patient characteristics analysis, results from a qualified local cytogenetic laboratory were accepted. If both the central and local cytogenetic A total of 344 patients with newly diagnosed chronic-phase analyses were unsatisfactory, alternative approaches including CML were enrolled (171 received pegylated rIFN-a2b; 173 fluorescent in situ hybridization or repeat bone marrow received rIFN-a2b) between August 1998 and November 1999. aspiration (up to 15 months on treatment) were used to A minority of patients received hydroxyurea to control their determine each patient’s cytogenetic response at 12 months. WBC count before randomization. Baseline patient and disease For complete hematologic remission, a patient must have met characteristics at randomization are shown in Table 1. Treat- all of the following criteria for a minimum of 28 days: WBC ment groups were well balanced with respect to patient o10 000 cells/ml, platelets o450 000/ml, normal differential demographic and baseline disease characteristics, with the count in peripheral blood, and no palpable spleen. In the intent- exception of hematocrit (HCT). A significantly larger proportion to-treat protocol-specified efficacy analysis, patients lacking a of patients randomized to pegylated rIFN-a2b had an HCT CHR at 6 months were considered cytogenetic failures regard- o33% compared with the rIFN-a2b group (30% in the less of their response at 12 months. pegylated rIFN-a2b group compared with 19% in the rIFN-a2b A prospectively modified efficacy analysis included all MCRs group; P ¼ 0.02, w2 test). 412 months. This analysis included patients who may not have The median administered dose for the entire patient popula- had a CHR at 6 months but remained on study treatment and tion was approximately 5 mg/kg/week (range, 0.08–6.52 mg/kg/ subsequently achieved an MCR. In this analysis, patients who week) for pegylated rIFN-a2b (intended dose: 6 mg/kg/week) and achieved a CHR at 6 months but discontinued treatment soon 27 MIU/m2/week (range, 4.83–26.71 MIU/m2/week) for rIFN-

Leukemia Peg Introns in chronic-phase CML M Michallet et al 311 a2b (intended dose: 35 MIU/m2/week). In all, 105 (61%) patients defined primary efficacy analysis, 39 of 171 (23%) patients in the pegylated rIFN-a2b group and 108 (62%) patients in the treated with pegylated rIFN-a2b and 48 of 173 (28%) patients rIFN-a2b completed 1 year of treatment. The major reasons for treated with rIFN-a2b achieved an MCR. However, this did not early discontinuation of study treatment were adverse events (31 meet the criteria for noninferiority. The odds ratio was 0.79 patients treated with pegylated rIFN-a2b and 26 treated with (95% CI: 0.48–1.29). In the prospectively modified efficacy rIFN-a2b) and disease progression/recurrence (14 patients analysis, 45 (26%) patients treated with pegylated rIFN-a2b had treated with pegylated rIFN-a2b and six treated with rIFN-a2b). an MCR compared with 49 (28%) patients treated with rIFN- a2b. However, this also did not meet the criteria for noninferiority (odds ratio: 0.93; 95% CI: 0.57–1.50). Of these Response MCRs, 17 (10%) patients in each treatment group had a complete response and 28 (16%) patients in the pegylated As shown in Table 2, cytogenetic response rates were rIFN-a2b group vs 32 (19%) in the rIFN-a2b group had partial comparable between treatment groups. Based on the protocol- responses. Hematologic and cytogenetic response rates at 6

Table 1 Patient characteristics

Characteristic Pegylated rIFN-a2b (n ¼ 171) rIFN-a2b (n ¼ 173)

Age (years) o45, n (%) 44 (26) 56 (32) 445, n (%) 127 (74) 117 (68) Median (range) 53.0 (20–76) 53.0 (20–80)

Sex, n (%) Male 96 (56) 106 (61) Female 75 (44) 67 (39)

Race Caucasian 142 (83) 142 (82) Hispanic 18 (11) 17 (10) Other 11 (6) 14 (8)

Patients with splenomegaly, n (%) 86 (50) 77 (45) Patients with circulating blast cells, n (%) 86 (50) 81 (47) Blood cell counts, mean7s.d. WBCs  109/l 25.0722.2 28.0729.3 Platelets  109/l 451.97298.9 461.27336.4

Hemoglobin (g/l), mean7s.d. 124.3717.4 128.1717.8 HCT, n (%) o33%a 51 (30) 33 (19)b 433% 120 (70) 140 (81)

Sokal score, n (%) Low (o0.8) 58 (34) 65 (38) Intermediate (0.8–1.2) 75 (44) 72 (42) High (41.2) 38 (22) 36 (21) rIFN-a2b ¼ recombinant interferon alpha-2b; s.d. ¼ standard deviation; WBC ¼ white blood cell; HCT ¼ hematocrit. aDefined as clinical anemia. bStatistically 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

Protocol defineda Completeb 13 (8) 13 (8) Partialc 26 (15) 35 (20) Total 39 (23) 48 (28) 0.79 (0.48–1.29)

Modifiedd Completeb 17 (10) 17 (10) Partialc 28 (16) 32 (19) Total 45 (26) 49 (28) 0.93 (0.57–1.50) rIFN-a2b ¼ recombinant interferon alpha-2b; CI ¼ confidence interval. aCytogenetic response at 12 months. b0% Ph+. c1–34% Ph+. dCytogenetic response at or beyond 12 months.

Leukemia Peg Introns in chronic-phase CML M Michallet et al 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 compar- able 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 Figure 1 Analysis of MCR rates by baseline HCT. 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 reana- group in Table 3. The most commonly reported adverse events lyzed by baseline HCT. In the subset of patients with HCT were fever and headache. The most commonly reported grade o33% (poor prognostic subgroup), the MCR rate was lower in 3/4 adverse events were fever and thrombocytopenia. Injection- both treatment groups than in the overall patient population site reactions were more commonly observed in the pegylated (Figure 1). MCR rates in this subgroup were 12% (six of 51 rIFN-a2b group (42 vs 17%). However, these adverse events patients) in the pegylated rIFN-a2b group compared with 15% were generally mild to moderate in severity. Only one patient (five of 33 patients) in the rIFN-a2b group. Among patients with treated with pegylated rIFN-a2b experienced a grade 3 HCT 433% (good prognostic subgroup), the MCR rate for injection-site reaction, and the episode did not result in pegylated rIFN-a2b was 33% (39 of 120 patients) compared treatment discontinuation. with 31% (44 of 140 patients) in the rIFN-a2b group (odds ratio: Laboratory abnormalities were similar between the two 1.09; 95% CI: 0.65–1.84). treatment groups, and the majority of changes were grade 1 or 2. Grade 3 decreases in WBC, neutrophils, and platelets were Safety indicative of an antileukemic treatment effect and were similar for both treatment groups. Elevations in alanine transaminase, Pegylated rIFN-a2b was safe and well tolerated. The most aspartate transaminase, and total bilirubin were within the frequently reported adverse events are summarized by treatment expected range for this patient population, and there were no

Table 3 Most frequently reported adverse events by treatment group (45% grade 3/4)

Patients, n (%)

Any grade Grade 3/4

Adverse event Pegylated rIFN-a2b (n ¼ 171) rIFN-a2b (n ¼ 173) Pegylated rIFN-a2b (n ¼ 171) rIFN-a2b (n ¼ 173)

Fever 140 (82) 134 (77) 26 (15) 23 (13) Headache 134 (78) 129 (75) 15 (9) 10 (6) Rigors 118 (69) 109 (63) 5 (3) 8 (5) Anorexia 114 (67) 100 (58) 8 (5) 13 (8) Fatigue 105 (61) 109 (63) 21 (12) 23 (13) Myalgia 105 (61) 109 (63) 5 (3) 11 (6) Nausea 109 (64) 103 (60) 6 (4) 9 (5) Diarrhea 104 (61) 89 (51) 10 (6) 8 (5) Arthralgia 92 (54) 84 (49) 13 (8) 11 (6) Asthenia 96 (56) 80 (46) 11 (6) 14 (8) Musculoskeletal pain 82 (48) 83 (48) 17 (10) 10 (6) Back pain 79 (46) 82 (47) 11 (6) 9 (5) Weight decrease 83 (49) 69 (40) 8 (5) 15 (9) Depression 64 (37) 54 (31) 13 (8) 11 (6) Hepatic enzymes increased 13 (8) 12 (7) 9 (5) 11 (6)

Hematologic Thrombocytopenia 43 (25) 46 (27) 21 (12) 24 (14) Leukopenia 19 (11) 19 (11) 7 (4) 10 (6) Neutropenia 14 (8) 14 (8) 7 (4) 9 (5) rIFN-a2b ¼ recombinant interferon alpha-2b.

Leukemia Peg Introns in chronic-phase CML M Michallet et al 313 reports of grade 4 hepatic laboratory abnormalities in either 1.3 years; the hazard ratio was 0.859 (95% CI: 0.43–1.72). treatment group. Grade 3 hepatic laboratory abnormalities were Disease progression was the major cause of death, resulting in uncommon. Grade 3 alanine transaminase or aspartate transa- 20 of 32 deaths, and 18 deaths caused by disease progression minase increases occurred in 17 (10%) and 15 (9%) patients occurred 430 days after the patient discontinued study drug. treated with pegylated rIFN-a2b and 11 (6%) and 11 (6%) The remaining deaths resulted from adverse events primarily patients treated with rIFN-a2b, respectively. Serum neutralizing unrelated to treatment. antibodies were not detected in patients treated with pegylated rIFN-a2b. Discontinuation because of adverse events occurred in 27 and Discussion 21% of patients in the pegylated rIFN-a2b and rIFN-a2b groups, respectively. The most frequently reported adverse events This phase III study was initiated to determine the efficacy and leading to discontinuation are summarized in Table 4. Dis- safety of pegylated rIFN-a2b compared with rIFN-a2b in the continuations because of depression, fatigue, headache, asthe- treatment of patients with newly diagnosed chronic-phase CML. nia, and diarrhea occurred slightly more often in patients treated The primary goal of this study was to perform a head-to-head with rIFN-a2b compared with pegylated rIFN-a2b, whereas comparison to determine if pegylated rIFN-a2b resulted in an chest pain and thrombocytopenia more often resulted in increased MCR rate compared with rIFN-a2b without the added discontinuation of pegylated rIFN-a2b. In addition, the HQL complexities of other agents such as Ara C, based on the analysis indicated that the impact of treatment with pegylated evidence that higher doses of rIFN-a2b are associated with rIFN-a2b on HQL was comparable to that of rIFN-a2b; no improved MCR rates.7,8 Based on the observed linear pharma- significant differences were observed between groups (data not cokinetics of pegylated rIFN-a2b,9 it was hypothesized that shown). pegylated rIFN-a2b could be delivered at a substantially greater In all, 17 patients treated with pegylated rIFN-a2b and 15 exposure level than could be achieved with conventional rIFN- patients treated with rIFN-a2b died during the study. The a2b. A comparison of observed area under the curve data from a Kaplan–Meier survival analysis (Figure 2) was limited by the multidose, dose-ranging study in patients with chronic hepatitis small number of deaths at a median follow-up of approximately 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/ Table 4 Discontinuations because of frequently reported adverse kg/week was well tolerated and demonstrated clinical activity in events (42% per treatment group) patients with CML who failed rIFN-a2b therapy.10 In the current study, in addition to the protocol-defined Patients, n (%) primary end point, which included only MCRs occurring within 12 months of therapy, a modified primary end point (defined Adverse event Pegylated rIFN-a2b (n 171) rIFN-a2b (n 173) ¼ ¼ before study unblinding) was used to assess the MCR rate Depression 7 (4) 9 (5) beyond 12 months. An international panel of CML experts Fatigue 4 (2) 8 (5) agreed that the modified efficacy end point provided a more Asthenia 3 (2) 4 (2) clinically relevant analysis than the protocol-defined end point. Headache 1 (o1) 5 (3) Although statistical noninferiority of pegylated rIFN-a2b was not Weight decrease 4 (2) 1 (o1) demonstrated, based on either the protocol-defined or modified Chest pain 3 (2) 0 Thrombocytopenia 3 (2) 0 efficacy analysis, once-weekly pegylated rIFN-a2b (6.0 mg/kg/ Diarrhea 0 3 (2) week) yielded an MCR rate that was clinically comparable to that achieved with rIFN-a2b. However, because the strict Total 46 (27) 37 (21) statistical criteria for noninferiority were not met, one cannot rIFN-a2b ¼ recombinant interferon alpha-2b. 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 multi- variate 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 Figure 2 Kaplan–Meier estimate of survival in patients treated rIFN-a2b yielded an MCR rate equivalent to rIFN-a2b (33 vs with pegylated rIFN-a2b (n ¼ 171) and rIFN-a2b (n ¼ 173). rIFN- 31%, respectively). Thus, the significantly larger proportion of a2b ¼ recombinant interferon alpha-2b. patients with low HCT randomized to pegylated rIFN-a2b may

Leukemia Peg Introns in chronic-phase CML M Michallet et al 314 account for the lower MCR rate compared with rIFN-a2b in the 5 Allan NC, Richards SM, Shepherd PC. UK Medical Research overall analysis. For the two-thirds of patients with normal HCT, Council randomised, multicentre trial of interferon-alpha n1 for pegylated rIFN-a2b was as effective as rIFN-a2b. Moreover, the chronic myeloid leukaemia: improved survival irrespective of MCR rate observed in this study was consistent with that cytogenetic response. The UK Medical Research Council’s Work- ing Parties for Therapeutic Trials in Adult Leukaemia. Lancet 1995; reported in the literature for patients with early chronic-phase 345: 1392–1397. 1,17,18 CML treated with single-agent rIFN-a2b. 6 Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Pegylated rIFN-a2b was also shown to be safe and well Kuramoto A et al. A randomized trial comparing interferon-alpha tolerated at a dose of 6 mg/kg/week and exhibited a safety profile with busulfan for newly diagnosed chronic myelogenous leukemia similar to rIFN-a2b with long-term use. Furthermore, the adverse in chronic phase. Blood 1995; 86: 906–916. event profile was generally similar to that reported previously for 7 Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. 1,2,10 Chronic myelogenous leukemia: a concise update. Blood 1993; pegylated rIFN-a2b and rIFN-a2b. The most common 82: 691–703. adverse events in both groups were flu-like symptoms such as 8 Kantarjian HM, O’Brien S, Anderlini P, Talpaz M. Treatment of fever, headache, rigors, and fatigue. Discontinuations because chronic myelogenous leukemia: current status and investigational of adverse events were slightly higher in the pegylated rIFN-a2b options. Blood 1996; 87: 3069–3081. group compared with rIFN-a2b (27 vs 21%). However, the 9 Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK slightly higher discontinuation rate in the pegylated rIFN-a2b et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmaco- dynamics, safety, and preliminary efficacy data. Hepatitis C group did not result from a general increase in toxicity, and Intervention Therapy Group. Clin Pharmacol Ther 2000; 68: there was no a substantial increase in any particular adverse 556–567. event in the pegylated rIFN-a2b group that led to discontinua- 10 Talpaz M, O’Brien S, Rose E, Gupta S, Shan J, Cortes J et al. Phase tion. Most events were reported by 1–3 patients (o2%). In both 1 study of polyethylene glycol formulation of interferon alpha-2B treatment groups, the most commonly reported reasons for (Schering 54031) in Philadelphia chromosome-positive chronic discontinuations because of adverse events were depression, myelogenous leukemia. Blood 2001; 98: 1708–1713. 11 Osoba D, Aaronson N, Zee B, Sprangers M, te Velde A. fatigue, headache, and diarrhea, which more often resulted in Modification of the EORTC QLQ-C30 (version 2.0) based on discontinuation of rIFN-a2b therapy, whereas chest pain and content validity and reliability testing in large samples of patients thrombocytopenia more often resulted in discontinuation of with cancer. The Study Group on Quality of Life of the EORTC and pegylated rIFN-a2b. the Symptom Control and Quality of Life Committees of the NCI of Based on the slightly higher discontinuation rate in the Canada Clinical Trials Group. Qual Life Res 1997; 6: 103–108. pegylated rIFN-a2b group, the selected dose in this study may 12 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. have been too high. Lower doses might allow for longer 13 Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, treatment duration while producing a similar rate of response in Kluin-Nelemans JC et al. A new prognostic score for survival of patients with CML. Although numerous studies suggest that patients with chronic myeloid leukemia treated with interferon high-dose rIFN-a2b (5 MIU/m2/day) yields higher response rates alfa. Writing Committee for the Collaborative CML Prognostic than low-dose regimens (3 MIU/m2/day), a recent randomized Factors Project Group. J Natl Cancer Inst 1998; 90: 850–858. study with rIFN-a2b has reported numerically similar MCR rate 14 Bukowski R, Tendler C, Cutler D, Rose E, Laughlin MM, Statkevich P. Treating cancer with PEG intron. Pharmacokinetic profile and with low- vs high-dose rIFN-a2b (Shepherd P et al. Blood 2001; dosing guidelines for an improved interferon alfa-2b formulation. 98: 727a). Cancer 2002; 95: 389–396. In summary, convenient weekly dosing with 6 mg/kg/week 15 Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, pegylated rIFN-a2b demonstrated a clinically comparable Ottmann OG et al. Imatinib induces hematologic and cytogenetic response rate and safety profile compared with a standard daily responses in patients with chronic myelogenous leukemia in dose of rIFN-a2b, but the goal of improving efficacy by myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–3539. increasing rIFN-a2b exposure was not achieved. Imbalance in 16 Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, baseline HCT may explain the trend towards a better MCR rate Gambacorti-Passerini C et al. Hematologic and cytogenetic with rIFN-a2b. Future studies are warranted to investigate responses to imatinib mesylate in chronic myelogenous leukemia. pegylated rIFN-a2b in combination with other antileukemic N Engl J Med 2002; 346: 645–652. agents (eg cytarabine or imatinib) in the treatment of chronic- 17 Ozer H, George S, Schiffer C, Rao K, Rao P, Wurster-Hill D et al. phase CML. Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leuke- mia: effect on remission duration and survival: Cancer and References 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 1 Kantarjian HM, Smith TL, O’Brien S, Beran M, Pierce S, Talpaz M. patients treated with recombinant interferon alpha. Blood 1994; Prolonged survival in chronic myelogenous leukemia after 84: 3592–3594. 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 interferon- Appendix alpha versus conventional chemotherapy in chronic myeloid leukemia. Blood 1998; 92: 1541–1548. 3 Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld Listing of PEG-Intron CML Study Group including Schering- DK et al. Randomized comparison of interferon-alpha with Plough Research Institute: Esther Rose and Helen Yeardley; busulfan and hydroxyurea in chronic myelogenous leukemia. Argentina: Gustavo Kusminsky; Austria: Marianne Bernhart, The German CML Study Group. Blood 1994; 84: 4064–4077. Gunther Gastl; Australia: Anthony Dodds, R Lindeman; Bel- 4 Tura S, Baccarani M, Zuffa E, Russo D, Fanin R, Zaccaria A et al. gium: Marc Boogaerts, Louise Debusscher, Andre Efira, Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Michee´le Rauis; Canada: Robert Belanger, Janis Bormanis, Cooperative Study Group on Chronic Myeloid Leukemia. N Engl Guy Cantin, Donna Forrest, Michael Kovacs, Pierre Laneuville, J Med 1994; 330: 820–825. Jeffrey H Lipton, Pedro Lopez, Robert Turner; Chile: Alejandro

Leukemia Peg Introns in chronic-phase CML M Michallet et al 315 Majlis; Columbia: Rodolfo Gomez; Denmark: Hans Karle; Dmoszynska, Maria Podolak-Dawidziak, Tadeusz Robak, Alek- Finland: Tuomo Honkanen, Kalevi Oksanen; France: Frederic sander Skotnicki; Portugal: Jorge Coutinho, Ines Nolasco, Bauduer, Agnes Buzyn-Veil, Sylvie Castaigne, Martine Delain, Gabriel Tamagnini; South Africa: Lydia Fourie, FC Slabber, N Bernard Desablens, Alain Devidas, Francois Guilhot, Denis Novitsky; : Consuelo Canizo, Francisco Cervantes, Juan Guyotat, Frederick Maloisel, Mauricette Michallet, Joseph Luis Steegmann; : Naim Akhtar, Saad Adar Al- Reiffers, Jean-Franccois Rossi, Philippe Rousselot, Philippe Ishmail, David Bareford, Helen Frances Barker, D Chan, James Solal-Celigny, Jean-Jaques Sotto, Michel Tulliez; : Chang, Dominic John Culligan, JG Erskine, C Hatton, P Hillmen, Walter E Aulitzky, Olaf Brudler, Gerhard Ehninger, Ruediger R Kaczmarski, SJ Kelly, PR Kelsey, JA Lui Yin, DW Milligan, AC Hehlmann, Christoph Huber, Christian Peschel, Peter Von Newlands, A Pagliuca, H Parry, M Potter, S Rassam, Sarah Wussow; Greece: Nikolaos Anagnostopoulos, Maria Bakiris; Willoughby, B Woodcock; Uruguay: Martha Nese; United : Cesar Vettorazzi; : Sergio Amadori, Achille States of America: David Bodensteiner, Timothy Brotherton, Ambrosetti, Michele Baccarani, Carlo Bernasconi, Giovanna Delvyn C Case, Gary Cohen, Laurence Elias, Stephanie Elkins, Rege Cambrin, Antonio Capaldi, Gianluigi Castoldi, Pietro John Feigert, Eric Feldman, Stephanie Gregory, Gary Gross, Citarrella, Anna D’Emilio, Rosario Giustolisi, Luigi Gugliotta, Robert Hirsch, John Hunter, Ahmad Jajeh, Matt Kalaycio, Pietro Leoni, Anna Marina Liberati, Vincenzo Liso, Patrizio Ali Khojasteh, Jurgen Kogler, Phil Kuebler, Roger M Lyons, Mazza, Enrica Morra, Gianantonio Rosti, Bruno Rotoli, Ettore Kenneth Manning, Ann Mohrbacher, Robert O’Donnell, Joel Volpe, Alfonso Zaccaria; Mexico: Jose Gonzalez-Llaven; Policzer, Mark Rarick, Allan Saven, Gary Schiller, Larry Sweden: Magnus Bjorkholm, Olle Linder, Per Ljungman, Claes Schlabach, Andrew Schneider, Karen Seiter, Kevin Troy, Estil Malm, Stig Rodjer, Bengt Simonsson; The : Gerrit A Vance, Allen Yeilding, Furhan Yunus; Venezuela: Angela Johan Ossenkoppele; : Anders Waage; Poland: Anna Rodriguez-M.

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