Title: CML Therapy
United States Patent: 6,362,162
Inventors: Rybak; Mary Ellen (Waren, NJ); Rose; Esther Helen
Assignee: Schering Corporation (Kenilworth, NJ)
Appl. No.: 545311
Filed: April 7, 2000
Methods for treating treatment-naive as well as treatment-experienced
patients having CML to achieve at least a partial cytogenetic response
involving administering a therapeutically effective amount of pegylated
interferon-alpha, e.g., pegylated interferon alpha-2b as monotherapy or in
association with a therapeutically effective amount of Ara-C are
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 PEG12000 -interferon alpha 2b. The
phrases "12,000 molecular weight polyethylene glycol conjugated
interferon alpha" and "PEG12000 -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 PEG12000 -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 PEG12000 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
PEG12000 attached. The PEG12000 -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 be formulated with a suitable buffer, e.g.,
Tris-HCl, acetate or phosphate such as dibasic sodium phosphate/monobasic
sodium phosphate buffer, and pharmaceutically acceptable excipients (e.g.,
sucrose), carriers (e.g. human serum albumin), toxicity agents (e.g. NaCl),
preservatives (e.g. thimerosol, cresol or benylalcohol), and surfactants
(e.g. tween or polysorabates) in sterile water for injection. The
pegylated interferon alpha-may be stored as lyophilized powders under a
refrigeration at 2o - 8oC. The reconstituted aqueous
solutions are stable when stored between 20o and 8oC.
and used within 24 hours of reconstitution. See for example U.S. Pat. Nos.
4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueous solutions
may also be stored in prefilled, multi-dose syringes such as those useful
for delivery of drugs such as insulin. Typical suitable syringes include
systems comprising a prefilled vial attached to a pen-type syringe such as
the NOVOLET Novo Pen available from Novo Nordisk, as well as prefilled,
pen-type syringes which allow easy self-injection by the user. Other
syringe systems include a pen-type syringe comprising a glass cartridge
containing a diluent and lyophilized pegylated interferon alpha powder in
a separate compartment.
CML (chronic myelogenous leukemia) is a clonal myeloproliferative disorder
which is a neoplastic proliferation of the pluripotential stem cell. In
CML, the leukemic cells retain some ability to differentiate. Hence, at
the time CML is diagnosed, the white cell count in CML may range from
10,000 to >200,000 cells/mm3 with 90% of the cells in the
granulocyte series. Hematocrit, hemoglobin and platelet counts are usually
normal although the platelet count and number of basophils may be
increased. CML was the first cancer to be associated with a specific
cytogenetic abnormality, the Philadelphia chromosome (Ph1), a
reciprocal translocation involving chromosomes 22 and 9. A segment of the
long arm of chromosome 9 which contains the c-abl oncogene is translocated
to the q11 position on chromosome 22 within a specified segment designated
as the breakpoint cluster region (bcr). This results in a new gene, bcr/abl,
on chromosome 22 within an associated abnormal messenger RNA, which can be
detected by RT-PCR (reverse transcriptase polymerase chain reaction), and
an abnormal protein product. A bcr/abl gene rearrangement is the major
pathogenic mechanism underlying the development of CML.
The term "cytogenic response" as used herein means a reduction
or elimination of Philadelphia chromosone-positive cells ("Ph1
+cells") in the bone marrow. A complete cytogenetic response means
there are no Ph1 +cells; a major cytogenetic response means there are
about 1 to about 34% of such cells i.e. <about 35% Ph1 +cells.
Minor response means about 35 to about 90% of such cells and treatment
failure about 91 to about 100% of such cells i.e., >about 90% Ph1
+cells). Clinicans have suggested that achievement of a major cytogenic
response i.e. <about 35% of Ph+cells in the bone marrow after 1 year of
CML therapy is predictive of long-term survival.
The term "patients having chronic myelogenous leukemia or CML"
as used herein means any patient having CML and includes treatment-naive
patients as well as treatment-experienced patients as well as patients in
the chronic phase of CML.
The term "treatment-naive patients" as used herein means
patients with CML--including newly-diagnosed CML patients--who have never
been treated with any chemotherapeutic drugs, including but not limited
to, e.g., busulfan("BU"), hydroxyurea("HU"),
Homoharringtonine ("HHT"), cytarabine("Ara-C"),
Idadubicin("I"), Etoposide("E") or chemotherapeutic
drug combinations, e.g., 1+Ara-C+E, i.e., "ICE" as well as any
interferon, including but not limited to interferon alpha, or pegylated
The term "treatment-experienced patients as used herein means those
patients who have initiated some form of chemotherapeutic drug therapy
including, but not limited to chemotherapeutic drug, e.g.,
busulfan("BU"), hydroxyurea("HU"), Homoharringtonine
("HHT"), cytarabine("Ara-C"), Idadubicin("I"),
Etoposide("E") or chemotherapeutic drug combinations, e.g.,
The term "hematologic response" as used herein means an
improvement in the WBC, and platelets.
A complete hematologic response means a WBC of less than 10,000 per
microliter and a platelet count of less than 450,000 per microliter and
normal differential in peripheral blood, and no palpable spleen.
A partial hematologic response means a WBC of fewer than about 20,000 per
microliter, or at least about a 50% reduction in the WBC baseline
In a preferred embodiment of the present invention, hydroxyurea is
administered to CML patients prior to initiation of pegylated interferon
alpha, and preferably about two weeks up to about three months prior to
initiation of pegylated interferon alpha.
Pegylated interferon-alpha formulations are not effective when
administered orally, so the preferred method of administering the
pegylated interferon-alpha is parenterally, preferably by subcutaneous,
IV, or IM, injection. Of course, other types of administration of both
medicaments, as they become available are contemplated, such as by nasal
spray, transdermally, by suppository, by sustained release dosage form,
and by pulmonary inhalation. Any form of administration will work so long
as the proper dosages are delivered without destroying the active
Claim 1 of 20 Claims
What is claimed is:
1. 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.
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