Tolerability and efficacy of pegylated interferon-α-2a in combination with imatinib for patients with chronic-phase chronic myeloid leukemia

Authors


  • The promoter of the SPIRIT trial is the University Hospital of Poitiers.

Abstract

BACKGROUND

The pegylated form of interferon-α-2a (PegIFNa2a) in combination with imatinib has demonstrated a molecular improvement in patients with chronic-phase chronic myeloid leukemia. However, to the authors' knowledge, the appropriate dose of PegIFNa2a has not been established to date.

METHODS

In the French SPIRIT trial, the authors compared 2 initial doses of PegIFNa2a, taking into account an amendment that recommended reducing that dose from 90 μg/week to 45 μg/week because of toxicities. Accordingly, 2 subgroups of patients were identified: the PegIFN90 group (171 patients who were treated with the 90-μg/week dose) and the PegIFN45 group (50 patients who were treated with the 45-μg/week dose). Both groups were compared for toxicity and efficacy.

RESULTS

PegIFNa2a at a dose of 90 μg/week resulted in a rate of 54% of grade 3 to 4 hematologic toxicity compared with 27% with the dose of 45 μg/week (P < .001), leading to discontinuation rates of 40% and 10%, respectively, before 6 months. The dose reduction did not significantly affect the efficacy of the combination. By 12 months, the cumulative molecular response rates (ie, BCR-ABL/abl ≤ 0.01 [IS: molecular responses graded as molecular response 4 (MR4)]) were 14% and 25%, respectively, for the subgroup treated with imatinib at a dose of 400 mg and the PegIFN90 subgroup. After the amendment, the MR4 rates were 10% and 28%, respectively, for the subgroup treated with imatinib at the 400-mg dose and PegIFN45 subgroup (P < .0001).

CONCLUSIONS

The results of the current study demonstrate that in combination with imatinib, the efficient dose of PegIFNa2a appears to be 45 μg/week. Cancer 2013;119:4284–4289. © 2013 American Cancer Society.

INTRODUCTION

Interferon (IFN)-based regimens were the gold standard in the treatment of patients with chronic-phase chronic myeloid leukemia (CP CML)[1] before the introduction of imatinib.[2]

The phase 3 International Randomized Study of Interferon and STI571 (IRIS) was a trial comparing imatinib at a dose of 400 mg daily with interferon-α (IFNa) plus low-dose cytarabine, and demonstrated that imatinib was better tolerated.[3, 4] In addition, imatinib induced higher complete hematological response and complete cytogenetic response rates that resulted in longer progression-free survival than IFNa. In addition, a comparison with IFNa-treated historical controls indicated a significant survival advantage with imatinib.[5] Thus, imatinib was registered for the first-line therapy for patients with CP CML.

Despite the advent of a second generation of tyrosine kinase inhibitors (TKIs) that have led to significantly improved molecular responses and a decreased rate of disease progression,[6, 7] imatinib may still play a role in the frontline treatment of patients with CP CML. To improve on the results obtained with imatinib, various groups have explored the combination of imatinib with pegylated forms of IFNa-2a (PegIFNa2a) or INFa-2b (PegIFNa2b).[8-10]

However, to the best of our knowledge, the appropriate dose of PegIFNa in these strategies has not been clearly established. The initial planned dose of 90 μg/week of PegIFNa2a in the French SPIRIT trial resulted in a substantial rate of treatment discontinuation because of toxicity. Thus, to improve the tolerability of the combination, the initial dose of PegIFNa was reduced to 45 μg/week. The current analysis focused on the tolerability and efficacy of the reduced dose of PegIFNa compared with the initial planned dose of 90 μg/week.

MATERIALS AND METHODS

Study Design

The SPIRIT trial is a multicenter, open-label, prospective trial designed to compare 4 treatment arms: imatinib at a dose of 400 mg daily versus imatinib at a dose of 600 mg daily versus imatinib at a dose of 400 mg daily plus cytarabine versus imatinib at a dose of 400 mg daily plus PegIFNa2a at an initial dose of 90 μg/week. An interim analysis of the first 634 patients based on a molecular response (MR) (ie, MR4 = BCR-ABL/ABL ratio of ≤ 0.01) (α = 85%; β = 10%) at 1 year from randomization has been planned to select the best experimental arm for further comparison with imatinib at a dose of 400 mg. The rate of MR4 at 12 months was significantly higher with the combination of imatinib at a dose of 400 mg and PegIFNa2a (30%; 95% confidence interval [95% CI], 23%-37%) compared with imatinib at a dose of 400 mg alone (14%; 95% CI, 9%-21%) (P = .001). At 24 months, the corresponding rates of MR4 were 38% (95% CI, 30%-46%) and 21% (95% CI, 15%-28%), respectively (P = .001). Major molecular responses (MMRs) and undetectable molecular residual disease were also most frequent with the combination of imatinib and PegIFNa2a.[8] Based on these results and as recommended by the Independent Data and Safety Monitoring Board, the CML French Group stopped accrual into the treatment arms of imatinib at a dose of 600 mg and imatinib at a dose of 400 mg plus cytarabine and additional patients were randomized within the treatment arm of imatinib at a dose of 400 mg and PegIFNa2a plus cytarabine arms.

Although the combination arm with PegIFNa2a resulted in significantly higher rate of MRs, a high degree of hematologic toxicity was also recorded.[8] For this reason, an amendment was proposed to reduce the initiating dose of PegIFNa2a to 45 μg/week. In December 2010, the closing date of accrual to the SPIRIT trial, 789 patients were included, 221 of whom were assigned to receive imatinib plus PegIFNa and 223 of whom were assigned to imatinib at a dose of 400 mg monotherapy.

The endpoints reported herein are rates of MR, safety, and tolerability. Molecular biology was centralized and blood samples were collected before the initiation of the assigned treatment and every 3 months thereafter. Adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). A MMR was defined as a decrease in the ratio of BCR-ABL transcripts to ABL transcripts of < 0.1% (corresponding to a reduction of 3 log units from the standardized baseline level). A MR4 was defined as a decrease in the ratio of BCR-ABL transcripts to ABL transcripts of ≤ 0.01% (corresponding to a reduction of 4 log units from the standardized baseline level [ie MR4]).[11]

All patients provided written consent before randomization. The trial was conducted in accordance with the Declaration of Helsinki and the study protocol was reviewed and approved by the ethics committee of the Poitou-Charentes area (registered at Clinical trial.gov: NCT00219739).

Patient Characteristics and Treatment

Considering the date of the amendment as August 2009, 2 subsets of patients were identified. Before the amendment, 171 patients received PegIFNa2a at the dose of 90 μg/week (PegIFN90 group) whereas after the amendment, 50 patients were included with a dose of 45 μg weekly (PegIFN45 group). There was no significant difference in patient distribution noted according to age (median age of 51 years and 48 years, respectively, for the PegIFN90 and PegIFN45 groups), sex ratio (1.9 in both groups), and distribution according to Sokal risk score (low risk, 38% and 52%, respectively; intermediate risk, 40% and 36%, respectively; and high risk, 22% and 12%, respectively, for the PegIFN90 and PegIFN45 groups).

During the second part of the protocol, the initial PegIFNa2a dose was 45 μg administered once a week. After 2 months of treatment with the combination of PegIFNa2a at a dose of 45 μg plus imatinib at a dose of 400 mg, the weekly dose of PegIFNa2a could be increased to 90 μg per weekly injection if the leukocyte count was consistently > 3000/mm2, the neutrophil count was consistently > 1500/mm2, and the platelet count was consistently > 100,000/mm2, and if nonhematological tolerance permitted it. It was estimated that of the 2 antileukemia agents, imatinib was likely the most effective. We therefore attempted to prescribe it continuously during the protocol.

RESULTS

Tolerability and Compliance

The most predominant adverse event was hematologic toxicity, mainly neutropenia (Table 1). However, grade 3 to 4 neutropenia, which had accounted for 54% of the toxicities noted with the PegIFN90 treatment, was significantly reduced after the amendment (27% with PegIFN45; P < .001). The dose reduction was found to have no significant impact on the other adverse events. It is interesting to note that the neuropsychiatric syndrome was overestimated in Table 1 because it encompasses depression, chronic fatigue, and insomnia. However, the recognized depression accounts for 2% to 3%. The better tolerability noted with PegIFN45 allowed for longer delivery of PegIFNa2a in this subgroup of patients. Indeed, in this latter subgroup, only 10% of patients permanently discontinued PegIFNa2a before 6 months compared with 40% in the PegIFN90 subgroup. No patients permanently withdrew from treatment with imatinib during this same period of time because of toxicity.

Table 1. Rates of Main AEs Occurring With the 2 Initiating Doses (PegIFN90 and PegIFN45) in Combination With Imatiniba
ToxicityAE With PegIFN90 (n = 171)AE with PegIFN45 (n = 50)
All Grades, %Grade 1-2, %Grades 3-4, %All Grades, %Grades 1-2, %Grades 3-4, %
  1. Abbreviations: AE, adverse event; PegIFN45, pegylated form of interferon-α-2a at a dose of 45 µg weekly; PegIFN90, pegylated form of interferon-α-2a at a dose of 90 µg weekly.

  2. a

    Adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Hematologic toxicity681454452827
Flu-like syndrome752422
Skin toxicity725220
Neuropsychiatric syndrome954624
Liver toxicity10.50.5624
Other312624

Treatment Doses and Management of the Patients

During the first 52 weeks from randomization, the median weekly doses of PegIFNa2a before and after the amendment were 51 μg and 40 μg, respectively. The median dose of imatinib was similar before and after the amendment. The management of the patients did not differ after the amendment. According to the trial, it was permissible to increase the dose of PegIFNa2a to a weekly injection of 90 μg for patients assigned to the PegIFN45 group. During the trial, 4 patients increased their dose for only a short period of time and returned to the 45-μg/week dose because of hematological and liver toxicities.

Efficacy

Figures 1 and 2{FIGS 1 and 2} show the cumulative incidence of MMR and MR4 rates by 12 months.

Figure 1.

Cumulative incidence of major molecular responses is shown. Rates were estimated by the cumulative incidence function. IM400 indicates imatinib at a dose of 400 mg daily; PegIFN90, pegylated interferon-α-2a at a dose of 90 μg/week; Ba, before the amendment; PegIFN45, pegylated interferon-α-2a at a dose of 45 μg/week; Aa, after the amendment.

The MMR rates at 6 months were 36.3% (95% CI, 29.1%-49.3%) and 36% (95% CI, 22.0%-50.8%), respectively, before and after the amendment. The corresponding MR4 rates at 6 months were 9.9% (95% CI, 5.9%-15.4%) and 10% (95% CI, 3.3%-21.8%), respectively. Finally for 222 patients, imatinib at a dose of 400 mg alone resulted in fewer responses at 6 months, with an MMR and MR4 rate of 19.3% (95% CI, 14.3%-25.0%) and 5.8% (95% CI, 3.1%-0.7%), respectively.

By 12 months, the cumulative MMR rates for patients receiving imatinib at a dose of 400 mg and those receiving PegIFN90 were 36% and 54%, respectively (P < .001 overall). These differences remained highly significant after the amendment, with the response rates being 38% and 60%, respectively, for the subgroups receiving imatinib at a dose of 400 mg and PegIFN45 (P < .0001 overall) (Fig. 1).

The cumulative MR4 rates were also found to be significantly higher with the combination arms compared with the monotherapy arms. By 12 months, the cumulative MR4 rates were 14% and 25%, respectively, for imatinib at a dose of 400 mg and PegIFN90 (P < .0001 overall). After the amendment, the MR4 rates were 10% and 28%, respectively, for imatinib at 400 mg and PegIFN45 and remained statistically significantly different (P < .0001 overall) (Fig. 2). When the MMR and MR4 response rates by 12 months were adjusted on the Sokal risk score, the results were still significant (P < .0001). It is interesting to note that no statistically significant difference was observed in the progression-free survival rate within the 2 subgroups.

Figure 2.

The cumulative incidence of molecular responses graded as MR4 is shown. Rates were estimated using the cumulative incidence function. IM400 indicates imatinib at a dose of 400 mg daily; PegIFN90, pegylated interferon-α-2a at a dose of 90 μg/week; Ba, before the amendment; PegIFN45, pegylated interferon-α-2a at a dose of 45 μg/week; Aa, after the amendment.

DISCUSSION

CML has long been regarded as a leukemia that could be one of the most accessible to immunotherapy and therefore IFN appears to be a reasonable therapeutic approach in the context of immunoreactivity. IFN is an immunomodulating agent that has demonstrated activity in CML for selected groups of patients who achieved durable cytogenetic responses. However, despite these clinical responses, the use of IFN has been limited because of unacceptable toxicity. Moreover, the recent success of TKIs such as imatinib, dasatinib, and nilotinib has completely changed the therapeutic strategy for patients with CML. However, there are clinical and laboratory data indicating that TKIs given alone are not curable treatment for patients with CML.[12-15] Because of the immunological and cellular effects of IFN and its activity in normal and leukemic stem cells,[16, 17] the reintroduction of IFN in the therapeutic management of patients with CML is currently under study.[18-20] Toxicity is one factor among others than can hamper the efficacy of a drug because it impairs adherence to the treatment.[20, 21] The combination of a 40-kilodalton molecule of polyethylene glycol connected to IFNa2a or 2b allows for the formation of a new type of IFN with improved properties of absorption and prolonged effects, which allow the injection to be administered once a week. In a study demonstrating the superiority of PegIFNa2a, it was suggested that the starting dose of PegIFNa as a single agent should be 180 μg/week.[22] In the French SPIRIT trial, despite the initial dose of PegIFNa2a of 90 μg weekly before the amendment, hematologic toxicity was recorded within the PegIFNa arm (68% of patients with toxicities of all grades, including 54% with grade 3-grade 4), leading to a rate of40% of permanent discontinuation of PegIFNa. A relation between the dose of PegIFNa and toxicity was also established in 2 other studies combining imatinib and PegIFNa2b. In the phase 2 Italian GIMEMA single-arm study, the intended doses of PegIFNa2b of 50 μg/week, 100 μg/week, and 150 μg/week in combination with imatinib were too high and resulted in PegIFNa being discontinued before 12 months in 60% of the 76 patients enrolled.[9] The Nordic trial[10] randomized patients to imatinib plus PegIFNa2b (n = 56 patients) versus imatinib alone (n = 56 patients) after the achievement of a complete hematologic response with imatinib at a dose of 400 mg daily. In this study, the grade 3 to 4 neutropenia prompted an amendment that recommended reducing the initial planned dose from 50 μg/week to 30 μg/week. According to tolerability, this latter dose could be increased to 50 μg/week or further reduced to 15 μg/week. Permanent discontinuation of PegIFNa2b occurred in 61% of patients before 38 weeks. The median administered dose of PegIFNa2b was 42 μg/week in 22 patients who did not discontinue the treatment. This median dose is close to what was observed in the current study with PegIFNa2a before the amendment (51 μg/week) and after the amendment (40 μg/week). It is interesting to note that in the GIMEMA study, the average dose of PegIFNa2b was 33 μg/week. It was suggested in the SPIRIT trial[8] that the duration of treatment with PegIFNa could affect the rates of MMR. Among patients who had been treated for < 4 months with PegIFNa, the rate of MMR was 48% versus 82% for those who received PegIFNa2a for > 12 months. Likewise, in the Nordic study, the MMR rates increased significantly with the duration of PegIFNa2b administration: when administered for < 12 weeks, the MMR rate was 67% versus 91% when the agent was administered for > 12 weeks.[10] In the current study, the low dose of 45 μg/week allowed for the longer delivery of PegIFNa2a at the time of the analysis, with 90% of patients receiving the drug for at least 6 months, eventually resulting in the same rate of MMR and MR4 compared with the starting dose of 90 μg/week. Within the limitation of this small number of patients, the data from the current study appear to support the use of PegIFNa2a at a dose of 45 μg/week when combined with imatinib.

Conclusions

In the 4 European study groups that have reported on IFN in combination with imatinib to date, only PegIFNa2a and PegIFNa2b were found to have an additional impact on the treatment of patients with CML.[8-10, 19] Based on the data reported herein, we conclude that the starting dose of PegIFNa2a of 45 μg weekly is more appropriate when it is combined with imatinib at a dose of 400 mg/day.

This low dose is two times less toxic, although as effective compared with the higher starting dose in combination with imatinib. In the long run, it is expected that the entailed longer delivery will result in a higher rate of undetectable residual disease.

FUNDING SUPPORT

The SPIRIT trial is supported by grants (Programme Hospitalier de Recherche Clinique 2003, 2006, and 2011) from the French Minister of Health as well as grants from Novartis and Roche Pharma.

CONFLICT OF INTEREST DISCLOSURES

Dr. Rousselot has received grants from and is a member of the advisory boards of Bristol-Myers Squibb and Novartis. He has also received travel support from Bristol-Myers Squibb to the 54th ASH Annual Meeting and Exposition, held December 8 to 11, 2012 in Atlanta, Georgia. Dr. Rea is a member of the boards of Bristol-Myers Squibb, Novartis, Teva, Ariad, and Pfizer and is a member of the Speakers' Bureau for Bristol-Myers Squibb and Novartis. Dr. Legros is a member of the boards of Pfizer, Novartis, and Bristol-Myers Squibb and has received a grant from Novartis. Dr. Nicolini has received a grant from Novartis, and has received a consulting fee or honorarium from Novartis, Bristol-Myers Squibb, and Ariad. In addition, he has received fees for participating in review activities from and is a member of the boards of Novartis, Teva, Bristol-Myers Squibb, Ariad, and Pfizer; has acted as a consultant for Novartis, Ariad, and Teva; and has acted as a member of the Speakers' Bureau for Novartis. Dr. Mahon has received grants from Novartis and Bristol-Myers Squibb. Dr. Guilhot has received grants from the French Minister of Health, Novartis, and Roche Pharma and has acted as a consultant for Pfizer, Bristol-Myers Squibb, Novartis, and Ariad.

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