Treatment of hematologic disorders

Details Treatment of hematologic disorders Treatment of hematologic disorders

1998-11-13

2003-05-06

Chan, Christina (Department: 1644)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

C424S577000, C435S372000

Reexamination Certificate

active

06558662

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the treatment of hematologic disorders, e.g., disorders characterized by unwanted cells of hematopoietic origin, e.g., hematologic cancers.
Bone marrow transplantation (BMT) has yet to realize its full potential for the treatment of hematologic malignancies. A major obstacle to further advancement is graft-versus-host disease (GVHD), which has been prevented by removing T cells from the donor marrow. Unfortunately, T cell depletion has been associated with increased rates of engraftment failure and leukemic relapse. Despite improvements in pharmacologic GVHD prophylaxis, severe acute and chronic GVHD are still major complications of HLA-matched sibling bone marrow transplantation. Immunosuppressive drugs used for GVHD prophylaxis may also increase the relapse rate for certain types of leukemia. The patients receiving allogeneic BMT are, nevertheless, a fortunate select group: most patients do not have an HLA-matched sibling or a phenotypically matched unrelated donor, and therefore do not have the option of BMT. Attempts to perform BMT between strongly HLA-mismatched donor-recipient pairs have been associated with a prohibitively high incidence of severe GVHD and of failure of engraftment. Furthermore, a large fraction of leukemias and lymphomas afflict older patients who are more prone to the development of GVHD than are younger persons, and who therefore are not generally considered candidates for BMT, despite the lack of other curative options.
SUMMARY OF THE INVENTION
The inventors have discovered that hematologic disorders, e.g., both neoplastic (hematologic cancers) and non-neoplastic conditions, can be treated by the induction of mixed chimerism in the absence of whole body irradiation (total myeloablation protocols) or other myeloablative treatment. Methods of the invention reduce GVHD, especially GVHD associated with mismatched allogeneic or xenogeneic donor tissue, yet provide significant graft-versus-leukemia (GVL) effect and the like.
Certain embodiments of the subject methods also feature preparative regimens which minimize or eliminate the need for myeloablative treatment, e.g., hematopoietic space-creating irradiation, especially, preparative whole body irradiation.
One aspect of the present invention provides a method for treating a subject having a hematologic disorder comprising: (i) administering a myeloreductive nonmyeloablative treatment to the subject in sufficient amount such that mixed hematopoietic chimerism can be induced in the subject, and (ii) introducing into the subject, allogeneic donor hematopoietic stem cells (donor stem cells) to form chimeric bone marrow in the subject.
In certain embodiments, the myeloreductive treatment includes treating the subject with an immunosuppressant regimen, prior to introduction of the donor stem cells, in an amount sufficient to prevent rejection of the donor stem cells.
Likewise, the method can include a further step of treating the subject with an immunosuppressant regimen, after introduction of the donor stem cells, in an amount sufficient to prevent a graft-versus-host response mediated by the donor stem cells.
Such immunosuppressant regimens can include, independently for pre- and post-transplantation is both are carried out, a treatment of the subject which inactivates and/or depletes host T-lymphocytes and/or natural killer (NK) cells in the subject. For example, the immunosuppressant regimen includes treatment with T cell-depleting anti-CD4 and/or CD8 antibodies, such as anti-thymocyte globulin (ATG), OKT3 (Orthoclone OKT3 monoclonal antibody, Ortho Pharmaceutical Corp), LO-CD2a (U.S. Pat. No. 5,730,979), or Minnesota anti-lymphoblast globulin (MALG). Preferably, the immunosuppressant regimen, both before and after transplantation, includes administration of ATG.
Moreover, the immunosuppressant regimen can include treatment with thymic irradiation. Preferably, the pre-transplantation immunosuppressant conditioning includes administration of ATG and thymic irradiation.
In other embodiments, the immunosuppressant regimen includes treatment with one or more of a macrolide immunosuppressant, azathioprine, steroids (e.g., prednisone, methyl prednisolone), sub-lethal nonmyeloablative irradiation of lymphocyte-containing tissue, or costimulatory blocking agents (e.g., anti-CD40 ligands, CTLA4Ig fusion proteins, see, e.g., Lenschow et al., (1992)
Science
257:789; and Turka et al., (1992)
PNAS
89:11102).
In certain embodiments, the myeloreductive treatment includes treating the subject, prior to introduction of the donor stem cells, with an cytoreductive agent selected from one or more of alkylating agents (e.g., nitrogen mustards [such as mechloretamine], cyclophosphamide, melphalan and chlorambucil), alkyl sulphonates (e.g., busulphan), nitrosoureas (e.g., carmustine, lomustine, semustine and streptozocine), triazenes (e.g., dacarbazine), antimetabolites (e.g., folic acid analogs such as methotrexate), pyrimidine analogs (e.g. fluorouracil and cytarabine), purine analogs (e.g., fludarabine, idarubicin, cytosine arabinoside, mercaptopurine and thioguanine), vinca alkaloids (e.g., vinblastine, vincristine and vendesine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin), dibromomannitol, deoxyspergualine, dimethyl myleran and thiotepa.
Preferably, the myeloreductive treatment includes treating the subject with cyclophosphamide.
Preferably, the pre-transplantation conditioning includes administration of ATG and cyclophosphamide, and thymic irradiation. Preferably the cyclophosphamide, or other cytoreductive agents, are substantially cleared from the patient so as not inhibit proliferation of the transplanted stem cells.
An important use of the subject method is for allogeneic transplantation of donor stem cells which are mismatched, with respect to the subject, at one or more HLA class II antigens.
Another important use of the subject method is for allogeneic transplantation of donor stem cells which are mismatched, with respect to the subject, at two or more HLA antigens (either HLA class I or II or both).
In preferred embodiments, the donor stem cells are provided as allogeneic bone marrow, mobilized peripheral blood cells, or cord blood cells.
The donor stem cells, in some instances, can be expanded ex vivo for transplantation.
In preferred embodiments, the donor stem cells are from the same species as the subject. However, the present application also specifically contemplates that the donor stem cells are xenogeneic stem cells from a different species than the subject. In xenogeneic methods, the subject is a mammal, preferably a primate and more preferably a human. The donor mammal can be, by way of example, a swine, e.g., a miniature swine, or a nonhuman primate. In xenogeneic methods the donor of stem cells and the donor of leukocytes need not be the same individual but can be from different individuals which are MHC matched or highly inbred, e.g., inbred miniature swine which are MHC matched.
In preferred embodiments, the subject is a human, and even more preferably, the subject is a human and donor stem cells are from another human.
The methods of the present invention can be used to treat a wide range of hematologic disorders, including neoplastic proliferation of hematopoetic cells, such as lymphoblastic leukemia, myelogenous leukemia, Hodgkin's lymphoma, Non-Hodgkin's lymphoma and myelodysplastic syndrome. As described herein, the subject method can be used to treat hematologic disorders which are refractory to chemotherapy, such a chemorefactory Non-Hodgkin's lymphoma.
In other embodiments, the subject method can be used to treat hematologic disorders which are non-malignant, such as erythrocyte abnormalities or immune system disorders. For example, the instant method can be used to treat hemoglobinopathies, e.g., sickle cell anemia, aplastic anemia or thalassemia. The subject method also can be used as part of a treatme

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