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Title:  Treatment of chronic myelogenous leukemia, resistant or intolerant to ST1571, involving homoharringtonine alone or combined with other agents
United States Patent: 
6,987,103
Issued: 
January 17, 2006
Inventors: 
Robin; Jean-Pierre (Charlottesville, VA); Mahon; François-Xavier (Bordeaux, FR); Maisonneuve; Hervé (La Roche sur Yon, FR); Maloisel; Frederick (Illkirch Graffenstaden, FR); Blanchard; Julie (Rouillon, FR)
Assignee:
 Stragen Pharma S.A. (Geneva, CH)
Appl. No.: 
397267
Filed: 
March 27, 2003


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The present invention concerns a method of treating chronic myelogenous leukemia, a related myeloproliferative disorder or a Ph-positive acute lymphocytic leukemia in a subject animal, comprising:

  • (a) selecting or identifying an animal suffering from chronic myelogenous leukemia or a related myeloproliferative disorder and showing resistance or intolerance to treatment with STI571; and
  • (b) administering to the animal homoharringtonine.

In a preferred embodiment, the animal is a human being.

Description of the Invention

The invention relates to methods for treating subjects suffering from chronic myelogenous leukemia which is resistant or intolerant to treatment with STI571, involving treating the subjects with homoharringtonine alone or combined with STI571 and/or other antileukemic agents.

Chronic myelogenous leukemia (CML) is a mycloproliferative disease which strikes about 4,500 new cases per year in the U.S. or in Europe. The median survival of this disease is around 3 years without treatment. Since the introduction of standard therapy by interferon alpha (INF) the median survival of this leukemia reaches about 7 years. However when patients become resistant to interferon, progression to acute phases occurs. Until these recent years there were only a few drugs able to induce a new remission. [Ref 1-5] Homoharringtonine, an alkaloid isolated from the genus Cephalotaxus [Ref 1, 2, 6, 7] and more recently STI571, a synthetic product, are recent drugs able to give a new remission to patients resistant to INF. Moreover STI571 was recently approved in the U.S. as major therapy of CML.

STI571 is becoming the standard of therapy for CML; recent clinical studies indicate that good results are obtained in patients with chronic phase CML: >90% of complete hematologic response, including 50% of cytogenetic response. However, limited result are seen in accelerated phase (<40%), and poor efficacy is obtained in blastic phase (<10% of complete bematologic response) including very transient remission. [Ref 8] In addition, after 15 months on STI571, we recently found that actuarial risk of progression to accelerated phase or blastic phase was higher than 30% [Ref 9] (unpublished results). To overcome these therapeutic limitations, combinations of STI571 with existing standard therapy based on INFs (including new form of TNF such as PEG INF) were recently tried. Preliminary analysis of these combinations indicates that addition of TNF or PEG INF does not change really the efficacy of each drug given alone. [Ref 9] (unpublished results)

There is therefore a need for improved methods of treating CML which provide longer term remission. In view of the limitations of STI571, there is a need for therapies providing improved results in the treatment of accelerated phase CML and blastic phase.

It was recently published that STI571 and homoharringtonine combination exhibit additive or synergistic cytotoxic effect in vitro, [Ref 10-13] which allows their clinical use as combination. In another preliminary study, it was indicated that homoharringtonine exhibits activity in a standard myeloid cell line made resistant in vitro to STI571.

We discovered recently that cells coming from patients with chronic myelogenous leukemia resistant to STI571, exhibited a good sensibility to homoharringtonine. [14] (unpublished results). We also found that patients resistant or intolerant to STI571 exhibit hematologic response to homoharringtonine, and furthermore that this response is sometimes transient (Robin J P et al., unpublished results). This finding could be explained by the rapid appearance of new malignant clones in which an alternate mechanism of apoptosis inhibition was "found" by a mutation-selection process of leukemic cells.

Further support for such a mechanism can be found in recent articles which indicate that the two drugs induce a release of the inhibition of caspase (a key molecular signal in the triggering of apoptosis) according two different alternative pathways:

  • First, for homoharringtonine, independent of reactive oxygen species (ROS) generation; [Ref 15]
  • Second, for STI, ROS dependent; [Ref 16]

In addition, Ara-C, a fourth agent currently combined with both INF, homoharringtonine and more recently STI571, induce apoptosis according to a ROS dependent mechanism [Ref 17]. (Some findings indicate that interferon alpha cytotoxicity would act according to a ROS dependent mechanism [Ref 18]).

This indicates that homoharringtonine may be use as new treatment of patients resistant to CML but also that standard methods of treatment which includes removing the existing resistant therapy and replace it by the new putatively active one should by improved.

The present invention is based on the discovery that the treatment of CML using the combination of STI571 and homoharringtonine resulted in improved treatment outcomes, and that treatment with homoharringtonine results in effective treatment of CML which is resistant or intolerant to STI571. The invention is also based on the discovery that treatment of CML using first STI571 and then homoharringtonine in the absence of STI571 may lead to a transient response.

The invention provides a novel method of treatment of patients with chronic myelogenous leukemia, other related myeloproliferative diseases and Ph-positive acute lymphocytic leukemia involving homoharringtonine based therapy in order to overcome primary or secondary resistance and/or intolerance to STI571, and able to induce or to improve hematologic response and/or cytogenetic response and, eventually, survival, with a mild non hematologic toxicity. Homoharringtonine is preferably combined with one or more other antileukemic agents including STI571 itself. In other embodiments, homoharringtonine is combined simultaneously with one or more other antileukemic agents including STI571 itself which is continued. In other aspects, homoharringtonine can be combined sequentially with one or more other antileukemic agents, optionally including STI571 itself which is continued. In other aspects of these methods, homoharringtonine can be combined sequentially by addition to existing STI571 therapy including in patients who lost their response to or who failed to respond to this agent in using the following steps (a) to (d), optionally (e): (a) patients with chronic myelogenous leukemia, eventually resistant to standard interferon alpha therapy, are treated by STI571 (400 to 800 mg daily, permanently) until a complete cytogenetic response (for de novo patients) or at least a complete hematologic response (for all other more advanced phases) are obtained, (b) in these partially STI571-resistant patients, STI571 is not removed but only reduced to 300 to 400 mg daily, in those of patients who failed to have or lost their complete cytogenetic or hematologic response, (c) homoharringtonine is administered subcutaneously and/or intravenously or/and orally, at dose 0.25 to 5 mg/m2 preferably at dose 2.5 mg/m2, preferably for 2 to 14 days per 28-day cycle, (d) finally homoharringtonine dose and/or STI571 are adjusted according to cytopenia and/or side effects; and (e) optionally, subcutaneous or intravenous or oral nucleoside synergistic with homoharringtonine, preferably cytarabine may be simultaneously or sequentially added to homoharringtonine.

The present invention concerns a method of treating chronic myelogenous leukemia, a related myeloproliferative disorder or a Ph-positive acute lymphocytic leukemia in a subject animal, comprising:

  • (a) selecting or identifying an animal suffering from chronic myelogenous leukemia or a related myeloproliferative disorder and showing resistance or intolerance to treatment with STI571; and
  • (b) administering to the animal homoharringtonine.

The present invention further relates to a method of treating chronic myelogenous leukemia or a related myeloproliferative disorder in a subject animal, comprising (a) selecting or identifying an animal suffering from chronic myelogenous leukemia or a related myeloproliferative disorder or Ph-positive acute lymphocytic leukemia and showing resistance or intolerance to treatment with STI571; and (b) administering to the animal homoharringtonine in an amount effective to inhibit proliferation of myeloid cells. In certain embodiments, homoharringtonine and STI571 and/or other antileukemic agents are administered in combinations more preferably homoharringtonine is added to a therapeutic regimen comprising STI571 without discontinuing the STI571 treatment. In other embodiments homoharringtonine and STI571 and/or other antileukemic agents are administered in a sequential treatment.

In a preferred embodiment, the homoharringtonine is combined with one or more other antileukemic agents including STI571. Preferably, homoharringtonine is combined simultaneously with one or more other antileukemic agents including STI571. More preferably, homoharringtonine is combined simultaneously with one or more other antileukemic agents including STI571, wherein STI571 is continued from previous treatment.

In another preferred embodiment, homoharringtonine is combined sequentially with one or more other antileukemic agents. Preferably, homoharringtonine is combined sequentially with one or more other antileukemic agents including STI571 itself which is continued.

The present invention also embodies a method for inhibiting proliferation of a hyperproliferative myeloid cell, as well as to a method of treating CML or a related myeloproliferative disorder in a subject animal, comprising: a) contacting said cell with or administering to said animal STI571; and b) contacting said cell with, or administering to said animal, homoharringtonine. Accordingly, the invention also relates to a method of preventing resistance to STI571, in a subject animal suffering from CML or a related myeloproliferative disorder. In further preferred embodiments, the methods of the invention further comprise treating said hyperproliferative myeloid cell or animal with one or more other therapeutic antileukemic compounds, preferably in sequential treatment. Several examples of suitable compounds are further mentioned herein. The STI571 and homoharringtonine will preferably be administered in an amount effective to inhibit proliferation of myeloid cells.

Therefore, the present invention concerns also a method of treatment, wherein homoharringtonine is combined sequentially by addition to existing STI571 therapy, including in patients who lost their response to or who failed to respond to STI571, comprising the following steps (a) to (d), and optionally (e):

  • (a) administering to patients with chronic myelogenous leukemia, optionally resistant to standard interferon alpha therapy, STI571 (preferably at 400 to 800 mg daily, permanently) until a complete cytogenetic response (preferably for de novo patients) or at least a complete hematologic response (preferably for all other more advanced phases) is obtained,
  • (b) in these partially STI571-resistant patients, reducing to 300 to 400 mg daily but not removing STI571 treatment, in those patients who failed to have or lost their complete cytogenetic or hematologic response,
  • (c) administering homoharringtonine subcutaneously and/or intravenously or/and orally, at dose 0.25 to 5 mg/m2, preferably at dose 2.5 mg/m2, preferably for 2 to 14 days per 28-day cycle;
  • (d) adjusting the homoharringtonine dose and/or STI571 dose according to cytopenia and/or side effects;
  • (e) optionally, subcutaneously or intravenously administering an oral nucleoside synergistic with homoharringtonine, wherein said oral nucleoside may be added simultaneously or sequentially to homoharringtonine.

In a preferred embodiment, said oral nucleoside in step (c) is cytarabine, wherein cytarabine may be added simultaneously or sequentially to homoharringtonine.

In another embodiment, the present invention concerns a method for inhibiting proliferation of a hyperproliferative myeloid cell resistant to STI571, comprising:

  • a) contacting the cell with STI571; and
  • b) contacting the cell with homoharringtonine,
  • wherein STI571 and homoharringtonine are provided in an amount effective to inhibit proliferation of said myeloid cell.

In a further embodiment, the present invention concerns a method of treating chronic myelogenous leukemia, a related myeloproliferative disorder or a Ph-positive acute lymphocytic leukemia in a subject animal:

  • a) administering to the animal in a first course of treatment STI571, wherein said CML or disorder displays resistance and/or intolerance to STI571;
  • b) administering to the animal in a second course of treatment a combination of homoharringtonine and STI571 in an amount effective to inhibit proliferation of myeloid cells.


The (hyperproliferative) myeloid cell or myeloproliferative disorder will preferably be characterized as being resistant and/or intolerance to STI571, that is, STI571 when not combined with homoharringtonine. Preferably the efficacy of the therapy is enhanced through synergistic effects of STI571 and homoharringtonine.

Preferably the treatment of the present invention is able to overcome resistance and/or intolerance to STI571.

More preferably said treatment induces a hematologic response, and/or a cytogenetic response and/or survival, with weak non-hematologic toxicity.

In a preferred embodiment the efficacy of the therapy is enhanced through synergistic effects of STI571 and homoharringtonine.

Preferably, the other antileukemic agents are interferon alpha and/or one or more nucleosides and/or a farnesyl transferase inhibitor (FTI).

More preferably, the other antileukemic agent is interferon alpha or PEG-interferon.

More preferably, the other antileukemic agent is a nucleoside. More preferably, the nucleosides are cytarabine (Ara-C) and/or decitabine and/or troxacytabine. More preferably, the nucleoside is cytarabine (Ara-C).

More preferably, the other antileukemic agent is a farnesyl transferase inhibitor (FTI).

More preferably, the other agents are a combination of interferon alpha and cytarabine.

In a preferred embodiment, the animal treated by the treatment of the present invention is a human being.

The present invention also concern the use of Homoharringtonine with other chemotherapeutic agent, in particular STI571, as a combined preparation for simultaneous, separate or sequential use in CML therapy or for treating a related myeloproliferative disorder, advantageously for treating CML or a related myeloproliferative disorder in an animal, advantageously a human being, showing resistance or intolerance to treatment with STI571.

As mentioned, STI571 and homoharringtonine can be administered during the same course or cycle of treatment. In one embodiment they can be coadministered, optionally substantially simultaneously, optionally as a single pharmaceutical composition. The methods of the invention may also involve the administration of STI571 and homoharringtonine to an animal such as a human patient who has not been previously treated with STI571. Preferably, however, the STI571 and homoharringtonine are administered to an animal which has undergone a first course or cycle of therapy for the treatment of the myeloproliferative disorder. In related aspects, the inventions also comprise methods of treatments where more than one course of therapy is carried out. Included is a method of treating CML or a related myeloproliferative disorder or Ph-positive acute lymphocytic leukemia in a subject animal comprising: a) administering to the animal in a first course or cycle of treatment STI571; and b) administering to the animal in a second course or cycle of treatment a combination of homoharringtonine STI571 in an amount effective to inhibit proliferation of the cell. Generally this method will be used when said subject shows resistance or intolerance to treatment with STI571 in the first course or cycle of treatment.

Said other antileukemic agents that can be used in therapeutic combinations of the invention with homoharringtonine may include interferon alpha (including interferon alpha or PEG-interferon) and/or one or more nucleosides (including cytarabine (Ara-C) and/or decitabine and/or troxacytabine) and/or a farnesyl transferase inhibitor (FTI). In preferred embodiments of the methods of treatment, the other agents are a combination of interferon alpha and cytarabine.

While reference is generally made to STI571 which is currently commercially available as an approved pharmaceutical product, and for which particularly surprising results were obtained using the methods of the invention, it will be appreciated that the invention also applies to other related agents, including other protein kinase inhibitors, more preferably protein tyrosine kinase inhibitors such as Bcr-Abl kinase inhibitors, or more preferably other compounds of the 2-phenylaminopyrimidine type.

Advantageously, Homoharringtonine is administrated by subcutaneous administration such as described in the patent application U.S. Ser. No. 09/801,751 which is incorporated by reference. Advantageously, Homoharringtonine is administrated in the form of a salt such as described in the patent application U.S. Ser. No. 09/801,751.
 

Claim 1 of 25 Claims

1. A method of treating chronic myelogenous leukemia, a related myeloproliferative disorder or a Ph-positive acute lymphocytic leukemia in a subject animal, comprising:

(a) selecting or identifying an animal suffering from chronic myelogenous leukemia or a related myeloproliferative disorder and showing resistance or intolerance to treatment with STI571; and

(b) administering to the animal homoharringtonine.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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