Introduction

Safety data presented during the 127th Annual Meeting of the American Neurological Association should further assist neurologists in differentiating subtleties between the interferon beta formulations currently available for treating patients with multiple sclerosis (MS). Emerging evidence indicates that immunomodulatory therapy with interferon beta for relapsing-remitting MS may result in elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.^1-4 Tremlett et al conducted an extensive retrospective review and reported that although treatment with each interferon beta resulted in at least one episode of ALT/AST elevation in a percentage of patients, intramuscular interferon beta-1a once weekly (Avonex) was the only interferon beta associated with a zero incidence of treatment discontinuation.⁵

All immunomodulatory therapy has shown benefits in patients with relapsing-remitting MS by reducing relapses. Some have shown efficacy by improving cognitive functions [Avonex] and slowing disability progression [Avonex and Rebif]. However, there are patients who do not respond adequately to single-agent immunomodulatory treatment. In those patients, neurologists must consider combination therapy. Mitoxantrone (Novantrone) is an agent approved for use in worsening relapsing-remitting, progressive relapsing, and secondary-progressive MS⁶ and may be utilized in combination with interferon beta. However, the combination of a cytotoxic agent with an immunomodulatory agent may have unexpected side effects. Leist et al reported their experience in 54 patients with MS who received the combination and the results indicate that the combination is generally well tolerated.⁷

Long-term efficacy and safety are important factors to consider when selecting an immunomodulatory agent. This report will review these clinically relevant and significant findings to further assist neurologists in selecting appropriate immunomodulatory therapies in achieving the most safe and efficacious outcomes for their MS patients.

Liver Enzyme Elevation during Interferon-β in Clinical Practice: A Comparison of Avonex, Betaseron, and Rebif

Helen L. Tremlett, Jon Porciuncula, K. Ho, E. Yoshida, D. Paty, and J. Oger; Vancouver, British Columbia, Canada

Emerging evidence indicates that immunomodulatory therapy with interferon beta for relapsing-remitting MS may result in elevations of ALT and AST levels.^1-4 To further explore this association, Tremlett and colleagues⁵ conducted a retrospective review of 545 eligible MS patients (540 charts available) from the University of British Columbia Multiple Sclerosis clinic; results were available from 453 (83.9%) patient charts. All patients reviewed had initiated treatment with Avonex 30 mcg once weekly, subcutaneous interferon beta-1b (Betaseron) 250 mcg every other day, or subcutaneous interferon beta-1a (Rebif) 44 mcg or 22 mcg 3 times weekly between July 1, 1995 and May 31, 2001. Patients who had participated in interferon beta clinical trials were excluded from the review. Investigators also explored whether any particular demographic factors, such as age or gender play any role in the susceptibility to liver enzyme elevations in these patients. The mean disease duration was 12.9 ±8.7 years. Mean duration of treatment was 1.8 ±1.3 years.

Enzyme elevations developed and levels peaked in the first 6 months of the treatment with all three agents. However, Rebif 44 mcg 3 times weekly resulted in the largest proportion of patients with elevated values (18.5%) [elevated defined as greater than or equal to twice the upper normal limit], compared with the lowest proportion in the Avonex 30 mcg once weekly group (5.1%) (Table 1). Enzyme levels subsided during the second year of treatment with only Avonex-treated patients' liver enzymes returning to baseline levels at 12-24 months. The Rebif (44 mcg and 22 mcg doses) and Betaseron cohorts continued to exhibit elevated enzymes in 3.5%, 1.9% and 1.8% of patients, respectively. Enzyme elevations were statistically significant compared with baseline values (P<0.0005).

"The data collected on the incidence and patterns of side effects during clinical trials are not always the same as those gathered in real life clinical situations," commented Joel Oger, MD Professor of Neurology, University of British Columbia/Vancouver Hospital & Health Sciences Center, in Vancouver, British Columbia, Canada. Expressing that their data was more precise vis-а-vis a clinical trial, Dr. Oger stated, "The selection of patients was less drastic and factors in patients may be taking other medications besides beta interferons".

Sixty-eight patients (15.1%) developed at least one episode of ALT/AST elevation during treatment with interferon beta (Table 2).

Avonex demonstrated the lowest incidence of elevated liver enzymes (10.5%), whereas the more frequently administered Rebif 44 mcg 3 times weekly resulted in the highest incidence of liver enzyme elevation in 24.4% of patients. Furthermore, no patient treated with intramuscular Avonex discontinued treatment due to liver enzyme elevation as compared with 13 patients treated with subcutaneous Betaseron and Rebif who required treatment discontinuation.

The authors noted that the study found a higher incidence of ALT/AST elevations in clinical practice compared with reported incidence from some clinical trials. Citing well-documented differences in interferon beta structures and formulations, the authors suggested that the total weekly dose and/or dose frequency may have some bearing on the degree of hepatocyte injury and stated that "a once weekly dose and a longer time interval between doses may allow damaged cells to recover". No evidence for specific demographic factors, such as age or gender was found to play a role in the susceptibility to liver enzyme elevations. The study has been expanded to other clinics in British Columbia, Canada.

Safety of Therapy with Mitoxantrone (Novantrone) and Interferon-β1a (Avonex), Interferon-β1b (Betaseron), or Glatiramer Acetate (Copaxone)

Thomas P. Leist, David S. Dougherty, and Bernadette Kalman; Philadelphia, Pennsylvania

Mitoxantrone (Novantrone) is an agent approved for use in worsening relapsing-remitting, progressive relapsing, and secondary-progressive MS⁶ and has been utilized in combination with interferon beta. However, the combination of a cytotoxic agent with an immunomodulatory agent may have unexpected side effects and potentially lead to a pronounced leukopenia. To further explore this association, Leist et al retrospectively evaluated 55 patients who received add-on treatment with Novantrone for worsening relapsing-remitting and secondary progressive MS. Results from that evaluation were presented by Thomas P. Leist, MD, PhD, Assistant Professor of Neurology, Jefferson Medical College and Director of the Multiple Sclerosis Comprehensive Clinical Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.⁷

Fifty-four patients with MS had been treated with either Betaseron 250 mcg every other day (n = 14), Avonex 30 mcg once weekly (n = 21), or Copaxone 20 mg daily (n = 12) for at least 6 months or stopped immunomodulatory treatment (n = 8) before initiating add-on Novantrone therapy.

Novantrone was administered as an intravenous infusion at a dose of 12 mg/m² every 3 months unless dose adjustment was necessary due to neutropenia. Laboratory testing (complete blood count, serum chemistries) was performed before and 10 to 13 days after infusion of Novantrone. In addition to leukopenia, assessments were conducted for neutropenia and cardiotoxicity related to Novantrone.

Novantrone was generally well tolerated. A majority of patients (58%) described transient nausea without emesis lasting from 8 hours to 3 days. Forty-two percent of patients reported subjective transient worsening of fatigue for up to 4 days. There were no significant variations between treatment groups.

Baseline white blood cell (7.4 ±1.4 x 10⁹ cells/L) and neutrophil (4.7 ±0.9 x 10⁹ cells/L) counts were comparable between patients treated with Avonex and Novantrone, Copaxone and Novantrone, and those patients treated with single-agent Novantrone. However, patients on Betaseron and Novantrone therapy had significant reduction of the baseline white cell (4.9 ±1.0 x 10⁹ cells/L) and neutrophil (2.8 ±0.8 x 10⁹ cells/L) counts. The degree of Novantrone-induced leukopenia varied greatly between patients. Eight of 14 patients treated with Betaseron had neutrophil counts below 1.5 x 10⁹ cells/L when measured 10 to 13 days after the first infusion treatment with Novantrone. Eventually, white blood cell and neutrophil counts returned to pre-treatment levels in all patients. Subsequent courses of Novantrone therapy displayed no statistically significant accentuation of medication-induced leukopenia.

After reaching cumulative Novantrone doses of 48 to 60 mg/m², 14 of 16 eligible patients [defined as reaching cumulative dose assessment level] showed no change in ejection fractions as assessed by MUGA (Multiple Gated Acquisition) scans. Two patients had reductions in ejection fraction from 68 to 61% and from 53 to 47%, respectively.

Investigators found no significant hematologic or cardiac safety concerns with combination therapy of Avonex/Novantrone or Copaxone/Novantrone, but pronounced transient leukopenia with Betaseron/Novantrone therapy. It was postulated by researchers that this effect may be directly related to the cytostatic effects of higher and more frequent doses of Betaseron. The results presented justify closer monitoring of patients on combinations of Novantrone and high, frequent doses of Betaseron or Rebif investigators advised.

Conclusion

Results from these studies emphasize the need for continued evaluation of the adverse events associated with immunomodulatory therapies; both as single-agent and in combination therapy with Novantrone. Emerging evidence indicates that immunomodulatory therapy given at higher and more frequent doses may result in liver enzyme elevations to a greater degree than those given less frequently. In that regard, Avonex was the only interferon beta formulation to demonstrate a return to baseline levels after an extended period of treatment. For patients who do not respond satisfactorily to single-agent immunomodulatory therapy, combination therapy with Novantrone is generally well tolerated with no significant hematologic or cardiac concerns whose combination warrants further investigation. Although it was again clear that when used with a more frequently administered interferon beta, more precaution is warranted.

For a chronic disease such as MS, it is particularly important for neurologists to understand the long-term benefits of immunomodulatory agents. After initiation of therapy, patients must remain compliant in taking the medication. Reducing the likelihood of adverse events will help patients achieve compliance and receive the full benefit of therapy.

References

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5. Tremlett HL, Porciuncula J, Ho K, Yoshida E, Paty D, Oger J. Liver enzyme elevation during interferon-β in clinical practice: a comparison of Avonex, Betaseron, and Rebif. Presented at the 127th Annual Meeting of the American Neurological Association, October 13-16, 2002, New York, New York. Abstract 91.
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7. Leist TP, Dougherty DS, Kalman B. Safety of therapy with mitoxantrone (Novantrone) and interferon beta-1a (Avonex), interferon beta-1b (Betaseron), or glatiramer acetate (Copaxone). Presented at the 127th Annual Meeting of the American Neurological Association, October 13-16, 2002, New York, New York. Abstract 215.