CML Therapy

Details CML Therapy CML Therapy

2000-04-07

2002-03-26

Pryor, Alton (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

Reexamination Certificate

active

06362162

ABSTRACT:

Throughout this disclosure, various publications, patents and patent applications are referenced. The disclosures of these publications, patents and patent applications are herein incorporated by reference
BACKGROUND OF THE INVENTION
This invention relates to an improved therapy for treating patients having chronic myelocytic leukemia (“CML”) by administering a therapeutically effective dose of pegylated interferon-alpha for a time sufficient to achieve at least a partial cytogenetic response.
Guilhot, F. et al. disclosed in
N. Engl. J. Med
., 1997, Volume 337, pages 223-229 that the combination of interferon alpha-2b and cytarabine increased the rate of major cytogenetic response and prolonged survival in patients in the chronic phase of CML. It must be noted that daily injections of interferon alpha-2b were required to achieve these results. In addition, interferon alpha-2b has many side effects that a substantial number of patients find unacceptable, and patient compliance with the daily injections of interferon alpha-2b has become a problem. Allogenic bone marrow transplantation (“BMT”) may be an alternative for CML patients with HLA-identical siblings. However, many patients are clearly too old or lack suitable donors and thus BMT is ruled out for most of these patients. (See the Editorial by Goldman, John M. in
N. Engl. J. Med
. 1997 volume 337, pages 270-271.) Accordingly, there is a need for an improved therapy for treating patients having CML.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a patient having chronic myelogenous leukemia which comprises administering to such a patient a therapeutically effective dose of pegylated interferon alpha for a time period sufficient to effect at least a partial cytogenetic response.
The present invention also provides a method of treating a patient having chronic phase chronic myelogenous leukemia which comprises administering to said patient an effective amount of pegylated interferon-alpha once a week for a time period sufficient to effect at least a partial cytogenetic response.
The present invention further provides a method of a patient having chronic phase of chronic myelogenous leukemia which comprises administering to such a patient about 4.5 micrograms/kg to about 9.0 micrograms/kg of pegylated interferon alpha-2b once a week for a time period sufficient to effect at least a partial cytogenetic response.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved method of treating patients with CML-especially those in the chronic phase of CML. The improved method provides a safer and more efficacious and tolerable treatment for CML by use of weekly injections of pegylated interferon alpha alone or in combination with chemotherapeutic agents such as cytarabine. The CML patients include those newly diagnosed with this disease as well as those patients intolerant or resistant to interferon alpha. Normally, hydroxyurea is given as needed to the CML patients before initiation of the method of the present invention to reduce the leukocyte count. Treatment with pegylated interferon alpha in accordance with the present invention will continue for a minimum of six months, and preferably for at least twelve months unless there is clinical evidence of disease progression, unacceptable toxicity or the patient requests that the therapy be discontinued.
When the pegylated interferon-alpha administered is a pegylated interferon alpha-2b, the therapeutically effective amount of pegylated interferon alpha-2b administered is in the range of about 4.5 to about 9.0 micrograms per kilogram of pegylated interferon alpha-2b administered once a week (QW), preferably about 4.5 to about 6.5 micrograms per kilogram of pegylated interferon alpha-2b administered once a week, more preferably about 5.5 to about 6.5 micrograms per kilogram of pegylated interferon alpha-2b administered once a week, and most preferably about 6.0 micrograms per kilogram of pegylated interferon alpha-2b administered once a week.
When the pegylated interferon-alpha administered is a pegylated interferon alpha-2a, the therapeutically effective amount of pegylated interferon alpha-2a administered is in the range of about 50 micrograms to about 500 micrograms once a week(“QW”), preferably about 200 micrograms to about 250 micrograms QW.
The term “pegylated interferon alpha” as used herein means polyethylene glycol modified conjugates of interferon alpha, preferably interferon alpha-2a and -2b. The preferred polyethylene-glycol-interferon alpha-2b conjugate is PEG
12000
-interferon alpha 2b. The phrases “12,000 molecular weight polyethylene glycol conjugated interferon alpha” and “PEG
12000
-IFN alpha” as used herein mean conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 12000.
The preferred PEG
12000
-interferon alpha-2b is prepared by attaching a PEG polymer to the epsilon amino group of a lysine residue in the IFN alpha-2b molecule. A single PEG
12000
molecule is conjugated to free amino groups on an IFN alpha-2b molecule via a urethane linkage. This conjugate is characterized by the molecular weight of PEG
12000
attached. The PEG
12000
-IFN alpha-2b conjugate is formulated as a lyophilized powder for injection. The objective of conjugation of IFN alpha with PEG is to improve the delivery of the protein by significantly prolonging its plasma half-life, and thereby provide protracted activity of IFN alpha.
The term “interferon-alpha” as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Typical suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J., recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.J., recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-n1, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain, or a consensus alpha interferon such as those described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 or 9 thereof) and the specific product available from Amgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename. The use of interferon alpha-2a or alpha-2b is preferred. Since interferon alpha-2b, among all interferons, has the broadest approval throughout the world for treating chronic hepatitis C infection, it is most preferred. The manufacture of interferon alpha-2b is described in U.S. Pat. No. 4,530,901.
Other interferon alpha conjugates can be prepared by coupling an interferon alpha to a water-soluble polymer. A non-limiting list of such polymers include other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof. As an alternative to polyalkylene oxide-based polymers, effectively non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like can be used. Such interferon alpha-polymer conjugates are described in U.S. Pat. No. 4,766,106, U.S. Pat. No. 4,917,888, European Patent Application No. 0 236 987, European Patent Application Nos. 0 510 356, 0 593 868 and 0 809 996(pegylated interferon alpha-2a) and International Publication No. WO 95/13090.
Pharmaceutical composition of pegylated interferon alpha-suitable for parenteral administration may b

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