U.S. patent application number 09/256666 was filed with the patent office on 2001-07-05 for combination therapy for lymphoproliferative diseases.
Invention is credited to BYRD, JOHN C., FLINN, IAN W., GREVER, MICHAEL R., WASELENKO, JAMIE K..
Application Number | 20010006974 09/256666 |
Document ID | / |
Family ID | 22973107 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010006974 |
Kind Code |
A1 |
BYRD, JOHN C. ; et
al. |
July 5, 2001 |
COMBINATION THERAPY FOR LYMPHOPROLIFERATIVE DISEASES
Abstract
Disclosed are methods and kits for treating lymphoproliferative
diseases in a host including (co)administering to the host
pentostatin, at least one alkylating agent and at least one
methylated xanthine.
Inventors: |
BYRD, JOHN C.; (BETHESDA,
MD) ; GREVER, MICHAEL R.; (HIGHLAND, MD) ;
FLINN, IAN W.; (LUTHERVILLE, MD) ; WASELENKO, JAMIE
K.; (SAN ANTONIO, TX) |
Correspondence
Address: |
PAUL DAVIS
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Family ID: |
22973107 |
Appl. No.: |
09/256666 |
Filed: |
February 24, 1999 |
Current U.S.
Class: |
514/330 |
Current CPC
Class: |
A61K 33/243 20190101;
A61K 31/565 20130101; A61K 31/55 20130101; A61K 45/06 20130101;
A61K 31/70 20130101; A61K 31/52 20130101; A61K 31/675 20130101;
A61P 35/02 20180101; A61K 33/24 20130101; A61K 31/55 20130101; A61K
31/52 20130101; A61K 31/675 20130101; A61K 31/55 20130101; A61K
31/52 20130101; A61K 31/565 20130101; A61K 31/55 20130101; A61K
31/52 20130101; A61K 31/55 20130101; A61K 31/52 20130101; A61K
31/415 20130101; A61K 31/55 20130101; A61K 31/52 20130101; A61K
31/255 20130101; A61K 31/55 20130101; A61K 31/52 20130101; A61K
31/195 20130101; A61K 31/55 20130101; A61K 31/52 20130101; A61K
31/17 20130101; A61K 31/55 20130101; A61K 31/52 20130101; A61K
31/13 20130101; A61K 31/55 20130101; A61K 2300/00 20130101; A61K
31/565 20130101; A61K 2300/00 20130101; A61K 31/675 20130101; A61K
2300/00 20130101; A61K 33/24 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/330 |
International
Class: |
A61K 031/445; A01N
043/40 |
Claims
What is claimed is:
1. A method of treating lymphoproliferative diseases in a host
comprising (co)administering to the host pentostatin, at least one
alkylating agent and at least one methylated xanthine.
2. The method of claim 1, wherein the at least one alkylating agent
comprises nitrogen mustards; ethyleneimine derivatives; alkyl
sulfonates; nitrosureas; triazines; or metal salts.
3. The method of claim 2, wherein the nitrogen mustards comprise
chlorambucil, cyclophosphamide, ifosamide, estramustine,
mechlorethamine, or melphalan.
4. The method of claim 3, wherein the nitrogen mustard comprises
chlorambucil.
5. The method of claim 2, wherein the ethyleneimine derivatives
comprise triethylenethiophosphoramide.
6. The method of claim 2, wherein the alkyl sulfonates comprise
busulfan.
7. The method of claim 2, wherein the nitrosureas comprise
carmustine, lomustine, or streptozocin.
8. The method of claim 2, wherein the triazines comprise
dacarbazine.
9. The method of claim 2, wherein the metal salts comprise platinum
compounds.
10. The method of claim 8, wherein the platinum compounds comprise
cisplatin, tertplatin, or carboplatin.
11. The method of claim 1, wherein the at least one alkylating
agent is (co)administered in an amount ranging from about 1
mg/m.sup.2 to about a maximum tolerated dosage for the at least one
alkylating agent.
12. The method of claim 1, wherein the at least one alkylating
agent is (co)administered in an amount ranging from about 10
mg/m.sup.2 to about 1000 mg/m.sup.2.
13. The method of claim 12, wherein the at least one alkylating
agent is (co)administered in an amount ranging from about 20
mg/m.sup.2 to about 40 mg/m.sup.2.
14. The method of claim 1, wherein the at least one methylated
xanthine comprises theophylline, caffeine, theobromine, or
paraxanthine.
15. The method of claim 14, wherein the at least one methylated
xanthine comprises theophylline.
16. The method of claim 1, wherein the at least one methylated
xanthine is (co)administered in an amount ranging from about 1
mg/kg to about a maximum tolerated dosage for the at least one
methylated xanthine.
17. The method of claim 1, wherein the at least one methylated
xanthine is (co)administered in an amount ranging from about 1
mg/kg to about 10 mg/kg.
18. The method of claim 17, wherein the at least one methylated
xanthine is (co)administered in an amount ranging from about 2
mg/kg to about 5 mg/kg.
19. The method of claim 18, wherein the at least one methylated
xanthine is (co)administered in a first dose of about 5 mg/kg,
followed by subsequent doses of about 2 to about 3 mg/kg every
about 6 to about 8 hours.
20. The method of claim 1, wherein the pentostatin is
(co)administered in an amount ranging from about 0.1 mg/m.sup.2 to
about a maximum tolerated dosage for pentostatin.
21. The method of claim 1, wherein the pentostatin is
(co)administered in an amount ranging from about 1 mg/m.sup.2 to
about 4 mg/m.sup.2.
22. The method of claim 21, wherein the pentostatin is
(co)administered in an amount ranging from about 2 mg/m.sup.2 to
about 3 mg/m.sup.2.
23. The method of claim 1, wherein the pentostatin is
(co)administered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, intramuscularly,
liposomally, via local delivery by catheter or stent,
subcutaneously, intraadiposally, or intrathecally.
24. The method of claim 23, wherein the pentostatin is
(co)administered intravenously.
25. The method of claim 1, wherein the at least methylated xanthine
is (co)administered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, or intrathecally.
26. The method of claim 24, wherein the methylated xanthine is
(co)administered orally.
27. The method of claim 1, wherein the at least one alkylating
agent is (co)administered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, or intrathecally.
28. The method of claim 27, wherein the alkylating agent is
(co)administered intravenously.
29. The method of claim 1, wherein the lymphoproliferative disease
comprises low-grade lymphoproliferative disorders, chronic
lymphocytic leukemias, cutaneous T cell leukemias, Sezary syndrome,
hairy cell leukemias, lymphomas, Non-Hodgkin's lymphomas, and large
granular lymphocytic leukemias.
30. The method of claim 29, wherein the lymphoproliferative disease
comprises chronic lymphoproliferative diseases.
31. The method of claim 30, wherein the lymphoproliferative disease
comprises cutaneous T cell leukemias.
32. A kit comprising pentostatin, at least one alkylating agent and
at least one methylated xanthine.
33. The kit of claim 32, wherein the at least one alkylating agent
comprises nitrogen mustards.
34. The kit of claim 33, wherein the nitrogen mustards comprise
chlorambucil.
35. The kit of claim 34, wherein the chlorambucil is present in an
amount effective to treat a lymphoproliferative disease in a
host.
36. The kit of claim 32, wherein the at least one methylated
xanthine comprises theophylline.
37. The kit of claim 36, wherein the theophylline is present in an
amount effective to treat a lymphoproliferative disease in a
host.
38. The kit of claim 32, wherein the pentostatin is present in an
amount effective to treat a lymphoproliferative disease in a host.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to methods and kits for treating
lymphoproliferative diseases comprising (co)administering to the
host pentostatin, at least one alkylating agent and at least one
methylated xanthine.
[0003] 2. Description of Related Art
[0004] In spite of the chemosensitivity seen with the initial
treatment of malignant lymphoproliferative diseases, relapse is
uniform and death commonly occurs as a result of disease
progression. One example of this is Chronic Lymphocytic Leukemia
(CLL). CLL is the most common adult leukemia occurring in the
western hemisphere and accounts for 25% of all leukemias. The
extremely indolent natural history of both smoldering and early
stage CLL has left many with the perception that this is a "good
leukemia" that can be ignored until the advanced stage at which
time palliative therapy is acceptable. K. R. Rai et al., Clinical
Staging of Chronic Lymphocytic Leukemia, Blood 46:219-234 (1975);
J. L. Binet et al., A New Prognostic Classification of Chronic
Lymphocytic Leukemia Derived from a Multivariate Survival Analysis,
Cancer 48:198-216 (1981). This document, and all others cited to
herein, are incorporated by reference as if reproduced fully
herein.
[0005] A contrary interpretation of the available data on CLL is
that it is currently an incurable illness with advanced stage
patients having a median survival of 18 months to 3 years. J. S.
Lee et al., Prognosis of Chronic Lymphocytic Leukemia: A
Multivariate Regression Analysis of 325 Untreated Patients, Blood
69:929-936 (1987); E. Montserratt et al., Chronic Lymphocytic
Leukemia: Prognostic Factors and Natural History, Baillieres Clin
Haematol 6:849-866 (1993). For the patient younger than 50 years,
even the diagnosis of early stage CLL shortens expected survival by
an average of 19 years. E. Montserrat et al., Presenting Features
and Prognosis of Chronic Lymphocytic Leukemia in Younger Adults,
Blood 78:1545-1551 (1991).
[0006] Disease frequency and expected death rate derived from the
Surveillance, Epidemiology, and End Results program further
discredit the former paradigm. S. L. Parker et al., Cancer
Statistics, 1997, CA Cancer J Clin 47:5-27 (1997). Approximately
7,400 patients may have been diagnosed with CLL in the United
States during 1997, with 4,300 dying during that same period as a
direct result of this disease. This absolute death rate is several
times that observed in all combined pediatric tumors and similar or
slightly lower than that observed in many adult solid tumors.
[0007] The reasons for the incurability of lymphoproliferative
diseases may stem from intrinsic biologic drug resistance related
to many factors, including inactivation of the p53 tumor suppressor
gene and overexpression of the apoptotic protein bcl-2.
[0008] Bcl-2 overexpression and aberrant p53 function are
frequently observed in low-grade B-cell and T-Cell lymphomas. Tumor
overexpression of bcl-2 protein may be associated with marked
resistance to apoptosis induced by chemotherapy or radiation and
has been associated with a worse outcome. T. Miyashita et al.,
Bcl-2 Oncoprotein Blocks Chemotherapy-induced Apoptosis in a Human
Leukemia Cell Fine, Blood 81:151-157 (1993); L. Sachs et Al.,
Control of Programmed Cell Death in Normal and Leukemic Cells: New
Implications for Therapy, Blood 82:15-21 (1993); 0. Hermine et al.,
Prognositic Significance of Bcl-2 Expression in Aggressive Non-
hodgkin's Lymphoma, Blood 87: 265-272 (1996). Aberrant p53 function
is also associated with both a poor treatment response and inferior
survival in these disorders. K. Dohner et al., p 53 Gene Deletion
Predicts for Poor Survival and Non-response to Therapy with Purine
Analogs in Chronic B-cell Leukemias, Blood 85:1580-1589 (1995); A.
Ichikawa et al., Mutations of the P53 Gene as a Prognostic Factor
in Aggressive B-cell Lymphoma, NEJM 337: 529-34 (1997); E. Wattel
et al., p.sup.53 Mutation Are Associated with Resistance to
Chemotherapy and Short Survival in Hematologic Malignancies, Blood
84: 3148-3157 (1994).
[0009] In the case of CLL in particular, the central decision of
the physician caring for a CLL patient was when to initiate
treatment and what schedule of alkylator therapy to use. Results
from a large French Cooperative Group study comparing immediate
versus delayed chlorambucil therapy in early (Binet A) stage
patients showed an inferior survival rate for the patients who had
an early therapeutic intervention. French Cooperative Group on
Chronic Lymphocytic Leukemia, Effects of Chlorambucil and
Therapeutic Decision in initial Forms of Chronic Lymphocytic
Leukemia (Stage A), Blood 1414-1421 (1990). This unexpected poor
outcome in the patients receiving immediate therapy was partially
attributed to a higher frequency of epithelial malignancies.
[0010] Once therapeutic intervention has been deemed necessary, the
task of deciding what therapy is appropriate for the individual
patient is equally challenging. Conventionally, initial treatment
of patients with symptomatic CLL has often involved therapy with
chlorambucil with or without prednisone. The addition of prednisone
is based on a small 26-patient comparative study of chlorambucil
versus chlorambucil plus prednisone that noted an improved response
rate but similar survival in patients receiving this combination.
T. Han et al., Chlorambucil Versus Combined
Chlorambucil-corticosteroid Therapy in Chronic Lymphocytic
Leukemia, Cancer 31:502-508 (1973).
[0011] Corticosteroids as a single agent have minimal activity
against CLL, predispose the patient to a higher risk of infections,
and may aggravate hyperlymphocytosis. P. A. Kyle et al., Large
Doses of Prednisone and Prednisolone in the Treatment of Malignant
Proliferative Disorders, Ann Intern Med 57:717-731 (1962).
Comparative trials of combination therapy to single-agent
chlorambucil have shown similar or improved response, but no impact
on survival. E. Montserrat et al., Treatment of Chronic Lymphocytic
Leukemia in Advanced Stages, Cancer 56:2369-2375 (1985); The French
Cooperative Group on Chronic Lymphocytic Leukemia, A Randomized
Clinical Trial of Chlorambucil Versus COP in Stage B Chronic
Lymphocytic Leukemia, Blood 75:1422 (1990) (abstr); B. Raphael et
al., Comparison of Chlorambucil and Prednisone Versus
Cyclophosphamide, Vincristine, and Prednisone as Initial Treatment
for Chronic Lymphocytic Leukemia: Long Term Follow-up of the
Eastern Cooperative Oncology Group Randomized Clinical Trial, J
Clin Oncol 9:770-776 (1990).
[0012] In an attempt to improve CLL treatment, physicians have also
turned to the purine analog fludarabine. Results from several large
phase 11 studies led by the M D Anderson Leukemia group and others
in previously treated and untreated CLL patients noted a 31% to
57%, and 78% response rate, respectively. M. R. Grever et al.,
Fludarabine Monophosphate: A Potentially Useful Agent in Chronic
Lymphocytic Leukemia, Nouv Rev Fr Hematol 30:437-459 (1988); M. J.
Keating, Fludarabine Phosphate in the Treatment of Chronic
Lymphocytic Leukemia, Semin Oncol 17:49-62 (1990); M. J. Keating et
al., Fludarabine: A New Agent with Marked Cytoreductive Activity in
Untreated Chronic Lymphocytic Leukemia, J Clin Oncol 9:44-49
(1991).
[0013] Attempts to improve on the outcome of therapy in CLL and
other hematologic malignancies has occurred through rational
combination approaches with utilizing agents with non-overlapping
toxicity. Pre-clinical data (Proc Am Ass Cancer Res 38: 2a, 1997,
Biochem Pharmacol 44: 2220, 1992) suggest synergistic interaction
between DNA damaging agents and the purine analogs or pentostatin.
Based on these data, combination studies with alkylating agents and
one of the purine analogs have been performed. (Leukemia 8:
1290,1994; Leukemia 7: 361,1993; Blood 84s: 383a, 1994). With
respect to fludarabine, these studies demonstrated that
myelosupression was more problematic, and compromised the total
administered dose of each agent. Three phase II designs were
initiated with fludarabine and cyclophosphamide using either
greatly attenuated doses of fludarabine and cyclophosphamide
(Regimen A, Blood 88s: 480a, 1994), somewhat less attenuated doses
of these therapies with filgrastim support (Regimen B, Blood
92s:104a, 1998) and sequential therapy (cyclophosphamide single
agent therapy followed by fludarabine monotherapy(Regimen C, Blood
88s: 481 a, 1996). A summary of response these studies in untreated
patients is shown in Table 1 below.
1 % Complete + Number of % Complete Partial Reg Agents Utilized
Patients Remission Remission A FLU + CY 14 (30)* 93 B FLU + CY +
G-CSF 20 50 100 C FLU Then CY 18 33 89
[0014] Key: Ref-reference; FLU-fludarabine; CY-cyclophosphamide;
*From presentation
[0015] Impressive tumor cytoreduction was noted in all series.
However, the frequency of complete response rate as compared to
that expected with fludarabine monotherapy was not appreciably
increased with the attenuated dose or sequential therapy. In a
separate study, Oken and colleagues combined the less
myelosuppressive agent pentostatin with chlorambucil and prednisone
in untreated CLL patients and noted an overall response rate of
87%, including a 44% complete response rate. (Proc Am Soc Clin
Oncol 17: 6a, 1998) Unlike many of the combination series reported
to date, long term follow-up was available demonstrating a median
response duration that had not reached at greater than 32 months.
Opportunistic infections were problematic in this study, likely as
a consequence of the corticosteroids in the absence of
antimicrobial and antiviral prophylaxis.
[0016] Accordingly, there still remains room for improvement in the
treatment of chronic lymphocytic leukemia, and other
lymphoproliferative diseases. Accordingly, there is a need for
improvement in treating lymphoproliferative diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0017] While precise knowledge of the mechanism of the synergism
due to the combination is not necessary to the practice of the
invention, a brief discussion of the putative mechanism may be
helpful to understanding of the invention. Of course, because
precise knowledge of the mechanism is not necessary to the practice
of the invention, the inventor expressly does not wish to be bound
to any discussion of mechanism present herein.
[0018] Generally speaking, the combination of pentostatin,
alyklating agents, and methylated xanthines appears to be
synergistically more effective in treating lymphoproliferative
diseases than monotherapy of any of the three pharmaceuticals
alone. Several reasons for this might exist. First of all, the
three pharmaceuticals have different putative mechanisms of action,
as is discussed further below. This implies that the dosages of
each of the three pharmaceuticals may be increased to a point where
the total pharmaceutical delivery exceeds the amount that safely
can be given of any one of the pharmaceuticals. Additionally, use
of the inventive combination therapy may tend to reduce the chances
of developing cross-resistance to the various mechanisms of action
of the three pharmaceuticals. Such approaches of combination
therapies (different than these described herein) in the treatment
of other hematologic malignancies has lead to cure in a minority of
patients.
[0019] At this point, a discussion of the individual components of
the inventive combination therapy may be helpful.
[0020] While not wishing to be bound by a particular mechanism or
explanation, it appears that pentostatin may act through the
lymphocyte's adenosine deaminase (ADA) pathways. While ADA is a
ubiquitous enzyme, it is found in higher concentrations in lymphoid
tissue, particularly T-lymphocytes.
[0021] 2'-deoxycoformycin (also referred to as DCF, pentostatin, or
NIPENT) is a nucleoside analog produced by Streptomyces
antibiotics, and has been shown to be a quasi-irreversible
inhibitor of ADA. By favoring the predominance of deoxycytidine
kinase (DCK) over the dephosphorylating enzyme 5-nucleotidase in
lymphocytes it is presumed to induce a preferential accumulation of
deoxyadenosine-5'-triphosphate (dATP). Dighiero, G., "Adverse and
beneficial immunological effects of purine nucleoside analogues,"
Hematol Cell Ther, 38:575-581 (1996).
[0022] In humans, a genetic deficiency of adenosine deaminase may
cause severe combined immunodeficiency. This enzyme is responsible
for deamination of adenosine to inosine and deoxyadenosine to
deoxyinosine in the purine salvage pathway. ADA deficiency is
characterized by a selective lymphopenia of both T and B cells
resulting in reduced cellular and humoral immune capacity, which
may be attributed to the toxic effect of deoxyadenosine
accumulation.
[0023] While the exact nature of the ADA pathway intervention seems
unclear, it may be that pentostatin's inhibition of adenosine
deaminase might mimic an ADA-deficient state. Lack of ADA is
believed to lead to a build up of deoxyadenosine and adenosine
triphosphate in the cell, thus fatally accelerating DNA strand
breaks in the cell.
[0024] Under normal conditions, lymphocytes are continuously
breaking and rejoining DNA. When this physiological process is
accelerated by the effect of excess adenosine triphosphate, it
leads to consumption of NAD for poly-ADP-ribose synthesis. This
polymer is produced from nicotinamide adenosine dinucleotides (NAD)
in a reaction catalyzed by the chromatin-associated
poly(ADP-ribose) synthetase, leading to a depletion of the NAD
content of the cell. This depletion induces a profound alteration
of cellular reducing power, because of lethal ADP and ATP
depletion. The result is programmed cell death through activation
of a Ca++, Mg++, dependent endonuclease.
[0025] At doses of 5 mg/m.sup.2 for 3 consecutive day every 3
weeks, ECOG investigators have been able to show a 32% response
rate in refractory lymphomas using pentostatin as a monotherapy.
Johnson and colleagues found a 30% response rate in patients with
refractory/relapsed B-CLL. Seventeen of 29 of the study patients
had prior treatment with either 2-CDA or fludarabine, thus
suggesting differential efficacy compared to other purine analogs.
Responses seen after treatment with alkylators and other purine
analogs demonstrate possible non-cross-resistance. S. Johnson et
al., Phase In Evaluation of 2'deoxycoformycin (Pentostatin) in a
Five Day Schedule for the Treatment of Relapsed/Refractory Chronic
Lymphocytic Leukemia (CII), Blood: 590a (1996).
[0026] Most conventional alkylating agents are useful in the
practice of this invention. Such alkylating agents include, but are
not limited to nitrogen mustards such as chlorambucil,
cyclophosphamide, ifosamide, estramustine, mechlorethamine, and
melphalan; ethyleneimine derivatives such as
triethylenethiophosphoramide (THIOTEPA7, Immunex Corp.); alkyl
sulfonates such as busulfan; nitrosureas such as carmustine,
lomustine, and streptozocin; triazines such as dacarbazine; metal
salts such as platinum compounds (including cisplatin, tertplatin,
carboplatin, etc.). In a preferable embodiment, the alkylating
agent is a nitrogen mustard. In a more preferable embodiment, the
alkylating agent is chlorambucil.
[0027] As discussed above, alkylating agents possess a different
mechanism of action from pentostatin. Briefly, alkylating agents
tend to induce DNA damage via DNA alkylation and the forming of DNA
cross links.
[0028] In more detail, alkylating agents generally are a diverse
group of compounds capable of forming molecular bonds with nucleic
acids, proteins, and many molecules of low molecular weight.
Alkylating agents are usually either electrophiles or generate
electrophiles in vivo to produce polarized molecules with
positively charged regions. These polarized molecules can then
interact with electron-rich regions of most cellular molecules. The
cytotoxic effect of the alkylating agents appears to relate
primarily to the interaction between the electrophiles and DNA.
This interaction may result in substitution reactions,
cross-linking reactions, or strand-breaking reactions. The net
effect of the alkylating agent's interaction with DNA is to alter
the information coded in the DNA molecule. This alteration results
in inhibition or inaccurate replication of DNA with resultant
mutation or cell death.
[0029] Within the context of the invention, methylated xanthines
refers to methylated xanthines, their derivatives and prodrugs
thereof. In a preferable embodiment, the methylated xanthines
include theophylline, caffeine, theobromine, and paraxanthine. In a
more preferable embodiment, the methylated xanthine is
theophylline. Methylated xanthines have been reported to enhance
the lethal potential of many DNA-damaging agents. J. P. Murnane et
al., Effects of Methylated Xanthines on Mammalian Cells Treated
with Bifunctional Alkylating Agents, Nature 285:326-329 (1980). As
a single agent, methylated xanthines have reduced cytotoxic effects
(Binet et al). Methylated xanthines may be used in the practice of
this invention to enhance the cytotoxic effects of the alkylating
agents and the pentostatin.
[0030] Based upon the observation of absent CLL progression in a
patient receiving the phosphodiesterase inhibitor theophylline, it
was subsequently demonstrated (Br J Haematol 90:957,1995) that
theophylline markedly increased spontaneous apoptosis in CLL
samples studied in vitro. Further investigation of this observation
demonstrated that theophylline given together with chlorambucil
(Blood 88: 2172, 1996) yielded in vitro synergistic apoptosis
toward human CLL cells. The induction of theophylline-induced
apoptosis correlated with an increased intracellular level of cAMP,
a known second signal required for programmed cell death and
down-regulation of bcl-2 which is a known inhibitor or apoptosis in
CLL. (50) A preliminary report (Leukemia 9:2159,1995) noted no
activity utilizing theophylline as a single agent, but its
combination with chlorambucil or cyclophosphamide in
alkylator-refractory CLL yielded responses in 11 of 12
patients.
[0031] The mechanism by which methylated xanthines function remains
unclear. Some investigators believe that they exert their
potentiating effect either by directly inhibiting repair of damage
in DNA or by causing override of the radiation-induced inhibition
of DNA synthesis. S. R. et al., Override of the Radiation-induced
Mitotic Block in Human Tumour Cells by Methylxanthines and its
Relationship to the Potentiation of Cytotoxicity, Int. J. Radiat.
Biol. 57:1105-1112 (1990). There is also evidence that methyl
xanthine compounds can potentiate cytoxocity of chemotherapy in p53
deficient cells through abrogation of the G2 cell cycle checkpoint.
Additionally, methylated xanthine administration may result in
accumulation of intracellular cAMP that activates the apoptosis
cascade. F. Mentz et al., Theophylline Synergies with Chlorambucil
in Inducing Apoptosis of Bchronic Lymphocytic Leukemia Ceffs, Blood
88:2172-2182 (1996). Of course, precise understanding of the
mechanism of action is not necessary to the practice of this
invention.
[0032] Pentostatin may be obtained from commercial suppliers,
including SuperGen, Inc. (San Ramon, Calif.) which supplies
pentostatin under the trademark NIPENT. Alkylating agents and
methylated xanthines according to the invention are available from
commercial suppliers, based upon information present in, for
example, the Physician's Desk Reference. A more preferable
alkylating agent, chlorambucil, is available as LEUKERAN from
Burroughs Wellcome. A preferable methylated xanthine, theophylline,
is available in tablets from Rhone-Poulenc Rorer.
[0033] The alkylating agents according to the invention may be
preferably administered in an amount effective to treat a
lymphoproliferative condition in a host, alone or in combination.
In a more preferable embodiment, the alkylating agents according to
the invention may be administered in an amount ranging from about 1
mg/m.sup.2 to about the maximum tolerated dosage for the alkylating
agent. In a still more preferred embodiment, the alkylating agents
according to the invention may be administered in an amount ranging
from about 10 mg/m.sup.2 to about 1000 mg/m.sup.2. In a yet more
preferred embodiment, the alkylating agents according to the
invention may be administered in an amount ranging from about 20
mg/m.sup.2 to about 40 mg/m.sup.2.
[0034] The methylated xanthines according to the invention may be
preferably administered in an amount effective to treat a
lymphoproliferative condition in a host, alone or in combination.
In a more preferable embodiment, the methylated xanthines according
to the invention may be administered in an amount ranging from
about 1 mg/kg to about the maximum tolerated dosage for the
methylated xanthine. In a still more preferred embodiment, the
methylated xanthines according to the invention may be administered
in an amount ranging from about 1 mg/kg to about 10 mg/kg. In a yet
more preferred embodiment, the methylated xanthines according to
the invention may be administered in an amount ranging from about 2
mg/kg to about 5 mg/kg. In an especially preferred embodiment, the
methylated xanthines according to the invention are administered in
a first dose at 5 mg/kg, followed by subsequent doses of 2-3 mg/kg
every 6-8 hours. The serum level of theopylline will be
approximately 10-20 ug/ml during treatment.
[0035] Pentostatin, according to the invention, may be preferably
administered in an amount effective to treat a lymphoproliferative
condition in a host, alone or in combination. In a more preferable
embodiment, pentostatin according to the invention may be
administered in an amount ranging from about 0.1 mg/m.sup.2 to
about the maximum tolerated dosage for pentostatin. In a still more
preferred embodiment, pentostatin according to the invention may be
administered in an amount ranging from about 1 mg/m.sup.2 to about
4 mg/m.sup.2. In a yet more preferred embodiment, pentostatin
according to the invention may be administered in an amount ranging
from about 2 mg/m.sup.2 to about 3 mg/m.sup.2.
[0036] The alkylating agents, methylated xanthines and pentostatin
according to the invention may be administered by a variety of
routes, and may be administered or coadministered in any
conventional dosage form. Coadministration in the context of this
invention is defined to mean the administration of more than one
therapeutic in the course of a coordinated treatment to achieve an
improved clinical outcome. Such coadministration may also be
coextensive, that is, occurring during overlapping periods of time.
(Co)administration may be taken to mean either coadministration or
administration or both.
[0037] For example, the alkylating agents, methylated xanthines and
pentostatin according to the invention may be administered via a
coordinated cycle of medication. In a preferable embodiment, the
methylated xanthines are administered for nine days, and the
alkylating agents and pentostatin are administered on the eighth
day of the nine day methylated xanthine regimen. In another
preferable embodiment, this nine day cycle is repeated once every
twenty-one days. In a still more preferable embodiment, the nine
day cycle is repeated once every twenty-one days for a maximum of
six cycles.
[0038] The alkylating agents, methylated xanthines and pentostatin
according to the invention may be administered or coadministered in
any conventional dosage form. For example, they may be administered
or coadministered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, or intrathecally. The alkylating agents,
methylated xanthines and pentostatin according to the invention may
also be administered or coadministered in slow release dosage
forms. Furthermore, alkylating agents, methylated xanthines and
pentostatin may be administered or coadministered with conventional
pharmaceutical excipients and additives. As alkyating agents and
pentostatin may induce nausea and vomiting, addition of a serotonin
blocking agent (Kytril or Odansetron) may be considered on the
8.sup.th day. Additionally, as infection may develop while
receiving this therapy in previously treated patients,
consideration of treating with prophylactic antibiotics should be
given.
[0039] A wide variety of lymphoproliferative diseases may be
treated in the practice of this invention, although greatest
efficacy has been observed thus far in B-cell chronic lymphocytic
leukemia (3 of 4 responses for 75% response rate). Such diseases
include, but are not limited to, low-grade lymphoproliferative
disorders, chronic lymphocytic leukemias, cutaneous T cell
leukemias including Sezary, hairy cell leukemias, lymphomas,
Non-Hodgkin's lymphomas, and large granular lymphocytic leukemias,
hairy cell leukemia, splenic lymphoma with vilous lymphocytes,
Waldenstrom's macroglobulinemia and p53 deficient hematologic
malignancy tumors.
[0040] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the spirit or scope of the invention. Thus,
it is intended that the present invention cover the modifications
and variations of this invention provided they come within the
scope of the appended claims and their equivalents. Additionally,
the following examples are appended for the purpose of illustrating
the claimed invention, and should not be construed so as to limit
the scope of the claimed invention.
EXAMPLES
Example 1
[0041] Treatment according to the invention has occurred through an
ongoing phase I clinical trial performed at Walter Reed Army
Medical Center and The Johns Hopkins Oncology Center. In this
study, patients with low-grade lymphoproliferative disorders have
been treated using the combination of theophylline (dosed to a
serum level of 10-20 ug/ml) on days 1-9, pentostatin 2-4 mg/m2 day
8 and chlorambucil 20 mg/m2 day 8. Assessment of in vivo modulation
of bcl-2 (whose over-expression correlates with drug resistance and
poor outcome in CLL) and p27 occurred at the pre-treatment, day 3,
day 8, day 9 and day 15 of treatment.
[0042] Thus far, 14 patients have been enrolled on the clinical
study for whom data are available on 10 related to toxicity and
efficacy of treatment. Specifically, this study has identified the
dose limiting toxicity of this combination approach to be
myelosuppression. Decreased expression of bcl-2 and p27 protein has
been noted in vivo in patients responding to therapy thus
demonstrating a correlation with in vitro and in vivo efficacy and
a potential similar mechanism of action. Responses have been noted
in 3 of 4 CLL patients of whom 1 had fludarabine-refractory disease
for which no effective therapy exists. This combination therapy
appears to be quite active clinically, has a favorable toxicity
profile, and is easily administered to patients in the outpatient
setting as compared to other therapies utilized for the late
treatment of CLL.
Example 2
[0043] An 80-year old man presents with B cell chronic lymphocytic
leukemia. The patient is administered five mg/kg caffeine for a
nine day cycle. On day eight, 2 mg/m.sup.2 pentostatin is
administered intravenously, together with 25 mg/m.sup.2
chlorambucil, also administered intravenously. The nine-day regimen
is repeated once every twenty-one days for a total of six cycles or
until the patient's disease is stabilized or is in remission.
Example 3
[0044] A 26-year old woman presents with adult T-cell
leukemia/lymphoma. The patient is administered seven mg/kg
theophylline for a nine day cycle. On day eight, four Mg/M.sup.2
pentostatin is administered intravenously, together with 35
mg/M.sup.2 chlorambucil, administered PO. The nine-day regimen is
repeated once every twenty-one days for a total of six cycles or
until the patient's disease is stabilized or is in remission.
Example 4
[0045] An 72-year old man presents with B cell Waldenstrom's
macroglobulinemia. The patient is administered five mg/kg
theophylline for a nine day cycle. On day eight, 2 mg/m.sup.2
pentostatin is administered intravenously, together with 20
mg/m.sup.2 chlorambucil administered PO. The nine-day regimen is
repeated once every twenty-one days for a total of six cycles or
until the patient's disease is stabilized or is in remission.
Example 5
[0046] An 70 year old man presents with NHL. The patient is
administered five mg/kg theophylline for a nine day cycle. On day
eight, 2 mg/m.sup.2 pentostatin is administered intravenously,
together with 25 mg/m.sup.2 chlorambucil, administered orally. The
nine-day regimen is repeated once every twenty-one days for a total
of six cycles or until the patient's disease is stabilized or is in
remission.
* * * * *