U.S. patent application number 10/440186 was filed with the patent office on 2003-11-06 for combination therapies for b-cell lynphomas comprising administration of anti-cd20 antibody.
This patent application is currently assigned to IDEC Pharmaceuticals Corporation. Invention is credited to Grillo-Lopez, Antonio J..
Application Number | 20030206903 10/440186 |
Document ID | / |
Family ID | 22256115 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030206903 |
Kind Code |
A1 |
Grillo-Lopez, Antonio J. |
November 6, 2003 |
Combination therapies for B-cell lynphomas comprising
administration of anti-CD20 antibody
Abstract
New combined therapeutic regimens for treatment of B-cell
lymphomas are disclosed which comprise in particular administration
of anti-CD20 antibodies to patients having low-, intermediate- or
high-grade non-Hodgkins lymphomas.
Inventors: |
Grillo-Lopez, Antonio J.;
(Rancho Santa Fe, CA) |
Correspondence
Address: |
PILLSBURY WINTHROP, LLP
P.O. BOX 10500
MCLEAN
VA
22102
US
|
Assignee: |
IDEC Pharmaceuticals
Corporation
|
Family ID: |
22256115 |
Appl. No.: |
10/440186 |
Filed: |
May 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10440186 |
May 19, 2003 |
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10196732 |
Jul 17, 2002 |
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10196732 |
Jul 17, 2002 |
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09372202 |
Aug 11, 1999 |
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6455043 |
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60096190 |
Aug 11, 1998 |
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Current U.S.
Class: |
424/144.1 |
Current CPC
Class: |
A61K 31/475 20130101;
A61P 43/00 20180101; A61K 51/1069 20130101; A61K 2039/545 20130101;
A61K 38/2013 20130101; A61K 31/573 20130101; A61K 38/212 20130101;
A61K 51/1027 20130101; C07K 16/2887 20130101; A61K 38/193 20130101;
A61K 39/39541 20130101; A61K 2039/505 20130101; C02F 2307/02
20130101; C02F 1/003 20130101; C07K 2317/24 20130101; C07K 2317/56
20130101; A61P 37/00 20180101; A61K 39/39558 20130101; C07K 16/3061
20130101; A61K 31/675 20130101; A61K 31/704 20130101; A61P 35/00
20180101; A61P 35/04 20180101; C07K 2317/77 20130101; A61K 38/217
20130101; A61P 35/02 20180101; A61K 39/39541 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/144.1 |
International
Class: |
A61K 039/395 |
Claims
What is claimed:
1. A method for treating relapsed B-cell lymphoma comprising
administering to a patient having relapsed the B-cell lymphoma a
therapeutically effective amount of an anti-CD20 antibody.
2. The method of claim 1, wherein said patient was treated
previously with an anti-CD20 antibody.
3. The method of claim 1, wherein said patient previously underwent
a bone marrow or stem cell transplantation.
4. The method of claim 1, wherein said patient previously underwent
radiotherapy.
5. The method of claim 1, wherein said patient previously underwent
chemotherapy for said B-cell lymphoma.
6. The method of claim 5, wherein said chemotherapy is selected
from the group consisting of CHOP, ICE, Mitozantrone, Cytarabine,
DVP, ATRA, Idarubicin, hoelzer chemotherapy regime, La La
chemotherapy regime, ABVD, CEOP, 2-CdA, FLAG & IDA with or
without subsequent G-CSF treatment), VAD, M & P, C-Weekly,
ABCM, MOPP and DHAP.
7. A method for treating a subject having B-cell lymphoma, which
subject has not exhibited appreciable tumor remission or regression
after administration of a chimeric anti-CD20 antibody, comprising
administering to said patient a radiolabeled anti-CD20
antibody.
8. The method of claim 7, wherein said radiolabeled anti-CD20
antibody is administered from about one week to about two years
after said administration of said chimeric anti-CD20 antibody.
9. The method of claim 8, wherein said radiolabeled anti-CD20
antibody is administered from about one week to about nine months
after said administration of said chimeric anti-CD20 antibody.
10. The method of claim 1, wherein said anti-CD20 antibody is a
chimeric anti-CD20 antibody.
11. The method of claim 10, wherein said chimeric antibody is C2B8
(Rituximab.RTM.).
12. A method for treating B-cell lymphoma comprising administering
a synergistic therapeutic combination comprising at least one
anti-CD20 antibody and at least one cytokine, wherein the
therapeutic effect is better than the additive effects of either
therapy administered alone.
13. The method of claim 12, wherein said at least one cytokine is
selected from the group consisting of alpha interferon, gamma
interferon, IL-2, GM-CSF and G-CSF.
14. The method of claim 13, wherein said anti-CD20 antibody and
said alpha interferon, gamma interferon, IL-2, GM-CSF or G-CSF is
administered sequentially, in either order, or in combination.
15. The method of claim 12, wherein said anti-CD20 antibody is a
chimeric antibody.
16. The method of claim 15, wherein said chimeric anti-CD20
antibody is C2B8 (Rituximab.RTM.).
17. A method for treating B-cell lymphoma comprising administering
to a patient a therapeutically effective amount of anti-CD20
antibody before, during or subsequent to a chemotherapeutic
regimen.
18. The method of claim 17, wherein said chemotherapy regimen is
selected from the group consisting of CHOP, ICE, Mitozantrone,
Cytarabine, DVP, ATRA, Idarubicin, hoelzer chemotherapy regime, La
La chemotherapy regime, ABVD, CEOP, 2-CdA, FLAG & IDA with or
without subsequent G-CSF treatment), VAD, M & P, C-Weekly,
ABCM, MOPP and DHAP.
19. The method of claim 17, wherein said anti-CD20 antibody is a
chimeric antibody.
20. The method of claim 19, wherein said chimeric antibody is C2B8
(Rituximab.RTM.).
21. A method for treating B-cell lymphoma comprising administering
to a patient a therapeutically effective amount of an anti-CD20
antibody before, during or subsequent to a bone marrow or stem cell
transplant.
22. The method of claim 21, wherein said anti-CD20 antibody is a
chimeric anti-CD20 antibody.
23. The method of claim 22, wherein said chimeric anti-CD20
antibody is C2B8 (Rituximab.RTM.).
24. A method of reducing residual CD20+ tumor cells in bone marrow
or stem cells before or after myeloablative therapy by
administering to a patient an anti-CD20 antibody.
25. The method of claim 24, wherein said anti-CD20 antibody is a
chimeric anti-CD20 antibody.
26. The method of claim 25, wherein said chimeric anti-CD20
antibody is C2B8 (Rituximab.RTM.).
27. The method of claim 1, wherein said B-cell lymphoma is selected
from the group consisting of low grade/follicular non-Hodgkin's
lymphoma (NHL), small lymphocytic (SL) NHL, intermediate
grade/follicular NHL, intermediate grade diffuse NHL, chronic
lymphocytic leukemia (CLL), high grade immunoblastic NHL, high
grade lymphoblastic NHL, high grade small non-cleaved cell NHL,
bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma and
Waldenstrom's Macroglobulinemia.
28. The method of claim 12, wherein said B-cell lymphoma is
selected from the group consisting of low grade/follicular
non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL,
intermediate grade/follicular NHL, intermediate grade diffuse NHL,
chronic lymphocytic leukemia (CLL), high grade immunoblastic NHL,
high grade lymphoblastic NHL, high grade small non-cleaved cell
NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma
and Waldenstrom's Macroglobulinemia.
29. The method of claim 17, wherein said B-cell lymphoma is
selected from the group consisting of low grade/follicular
non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL,
intermediate grade/follicular NHL, intermediate grade diffuse NHL,
chronic lymphocytic leukemia (CLL), high grade immunoblastic NHL,
high grade lymphoblastic NHL, high grade small non-cleaved cell
NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma
and Waldenstrom's Macroglobulinemia.
30. The method of claim 21, wherein said B-cell lymphoma is
selected from the group consisting of low grade/follicular
non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL,
intermediate grade/follicular NHL, intermediate grade diffuse NHL,
chronic lymphocytic leukemia (CLL), high grade immunoblastic NHL,
high grade lymphoblastic NHL, high grade small non-cleaved cell
NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma
and Waldenstrom's Macroglobulinemia.
31. The method of claim 24, wherein said B-cell lymphoma is
selected from the group consisting of low grade/follicular
non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL,
intermediate grade/follicular NHL, intermediate grade diffuse NHL,
chronic lymphocytic leukemia (CLL), high grade immunoblastic NHL,
high grade lymphoblastic NHL, high grade small non-cleaved cell
NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma
and Waldenstrom's Macroglobulinemia.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application take priority from Provisional Application
No. 60/096,180, filed on Aug. 11, 1998; the entire content of which
is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to the use of anti-CD20 antibodies or
fragments thereof in the treatment of B-cell lymphomas,
particularly the use of such antibodies and fragments in combined
therapeutic regimens.
BACKGROUND OF THE INVENTION
[0003] The use of antibodies to the CD20 antigen as diagnostic
and/or therapeutic agents for B-cell lymphoma has previously been
reported. CD20 is a useful marker or target for B-cell lymphomas as
this antigen is expressed at very high densities on the surface of
malignant B-cells, i.e., B-cells wherein unabated proliferation can
lead to B-cell lymphomas.
[0004] CD20 or Bp35 is a B-lymphocyte-restricted differentiation
antigen that is expressed during early pre-B-cell development and
remains until plasma cell differentiation. It is believed by some
that the CD20 molecule may regulate a step in the B-cell activation
process which is required for cell cycle initiation and
differentiation. Moreover, as noted, CD20 is usually expressed at
very high levels on neoplastic ("tumor") B-cells. The CD20 antigen
is appealing for targeted therapy, because it does not shed,
modulate, or internalize.
[0005] Previous reported therapies involving anti-CD20 antibodies
have involved the administration of a therapeutic anti-CD20
antibody either alone or in conjunction with a second radiolabeled
anti-CD20 antibody, or a chemotherapeutic agent.
[0006] In fact the Food and Drug Administration has approved the
therapeutic use of one such anti-CD20 antibody, Rituxan.RTM., for
use in relapsed and previously treated low-grade non-Hodgkin's
lymphoma (NHL). Also, the use of Rituxan.RTM. in combination with a
radiolabeled murine anti-CD20 antibody has been suggested for the
treatment of B-cell lymphoma.
[0007] However, while anti-CD20 antibodies and, in particular,
Rituxan.RTM. (U.S.; in Britain, MabThera.RTM.; in general
Rituximab.RTM.), have been reported to be effective for treatment
of B-cell lymphomas, such as non-Hodgkin's lymphoma, the treated
patients are often subject to disease relapse. Therefore, it would
be beneficial if more effective treatment regimens could be
developed. More specifically, it would be advantageous if anti-CD20
antibodies had a beneficial effect in combination with other
lymphoma treatments, and if new combined therapeutic regimens could
be developed to lessen the likelihood or frequency of relapse.
Also, it would be helpful if current treatment protocols for B-cell
lymphoma were improved whereby patients with lymphomas which are
refractory to other treatment methods could be treated with
chimeric or radiolabeled anti-CD20 antibodies. It would also be
helpful if treatment with anti-CD20 antibodies, particularly in
combination with other treatments, could be used as therapy for
other types of lymphoma besides low grade, follicular non-Hodgkins
lymphoma (NHL).
SUMMARY OF THE INVENTION
[0008] The present invention discloses combined therapeutic
treatments for B-cell lymphomas, and reports the benefits of
treating relapsed or refractory B-cell lymphomas with chimeric and
radiolabeled anti-CD20 antibodies. In particular, it has been found
that treatment with anti-CD20 antibody provides a beneficial
synergistic effect when administered in combination with cytokines,
radiotherapy, myeloablative therapy, or chemotherapy. Surprisingly,
patients who had prior bone marrow or stem cell transplantation had
an unexpected increase in the over-all response rate when compared
with patients with no prior therapy.
DETAILED DESCRIPTION OF THE INVENTION
[0009] This invention encompasses combined therapeutic regimens for
the treatment of B-cell lymphomas. In general, such methods include
a method for treating relapsed B-cell lymphoma, where a patient
having prior treatment for lymphoma has relapsed and is
administered a therapeutically effective amount of a chimeric
anti-CD20 antibody. Such prior treatments can include, for example,
previous treatment with anti-CD20 antibodies, treatments which
included a bone marrow or stem cell transplantation, radiotherapy
and chemotherapy. The previous chemotherapy may be selected from a
wide group of chemotherapeutic agents and combination regimens,
including CHOP, ICE, Mitozantrone, Cytarabine, DVP, ATRA,
Idarubicin, hoelzer chemotherapy regime, La La chemotherapy regime,
ABVD, CEOP, 2-CdA, FLAG & IDA with or without subsequent G-CSF
treatment), VAD, M & P, C-Weekly, ABCM, MOPP and DHAP.
[0010] Also included in the methods of the invention are methods
for treating a subject having B-cell lymphoma wherein the subject
is refractory for other therapeutic treatments, including all those
listed above, i.e., treatment with chimeric anti-CD20 antibody,
treatments which included a bone marrow or stem cell
transplantation, radiotherapy and chemotherapy. In particular,
encompassed are methods of treating a patient who has not exhibited
appreciable tumor remission or regression after administration of a
chimeric anti-CD20 antibody, comprising administering to said
patient a radiolabeled anti-CD20 antibody.
[0011] In particular, the methods of treating a patient with a
radiolabeled antibody after a chimeric antibody are performed
whereby the radiolabeled anti-CD20 antibody is administered from
about one week to about two years after said administration of said
chimeric anti-CD20 antibody. More particularly, the radiolabeled
anti-CD20 antibody is administered from about one week to about
nine months after said administration of said chimeric anti-CD20
antibody.
[0012] While any anti-CD20 antibodies can be used for the methods
of the present invention, a preferred chimeric antibody is C2B8
(IDEC Pharmaceuticals, Rituximab.RTM.). A preferred radiolabeled
antibody is Y2B8, which is a murine antibody labeled with
yttrium-90 (.sup.90Y). However, antibodies with other radiolabels
may be used, particularly those labeled with a beta or alpha
isotope. Anti-CD19 antibodies may also be used.
[0013] One of skill in the art would know the parameters for
choosing a particular type of anti-CD20 antibody. For instance,
chimeric and humanized antibodies are beneficial for decreased
immunogenicity, and for facilitating antibody effector mediated
immune reactions via the human constant region domains. Murine and
other mammalian antibodies, in contrast, are beneficial for
delivering a radiolabel to the tumor cell, as such antibodies
generally have a decreased half-life in vivo.
[0014] Antibody treatments performed initially to which patients
are refractory or have relapsed may include initial treatments with
chimeric antibodies or mammalian antibodies. Also encompassed are
initial treatments with other antibodies, including anti-CD19
antibodies and anti-Lym antibodies, and treatments with antibodies
labeled with cytotoxic moieties, such as toxins, and radiolabels,
e.g., Oncolym.RTM. (Techniclone) or Bexxar (Coulter).
[0015] It should be clear that the combined therapeutic regimens of
the present invention can be performed whereby said therapies are
given simultaneously, i.e., the anti-CD20 antibody is administered
concurrently or within the same time frame (i.e., the therapies are
going on concurrently, but the agents are not administered
precisely at the same time). The anti-CD20 antibodies of the
present invention may also be administered prior to or subsequent
to the other therapies. Sequential administration may be performed
regardless of whether the patient responds to the first therapy to
decrease the possibility of remission or relapse.
[0016] The combined therapies of the present invention include a
method for treating B-cell lymphoma comprising administering at
least one chimeric anti-CD20 antibody and at least one cytokine. In
particular, the invention includes a method for treating B-cell
lymphoma comprising administering a synergistic therapeutic
combination comprising at least one anti-CD20 antibody and at least
one cytokine, wherein the therapeutic effect is better than the
additive effects of either therapy administered alone. Preferred
cytokines are selected from the group consisting of alpha
interferon, gamma interferon, IL-2, GM-CSF and G-CSF. Again, the
anti-CD20 antibody and the cytokine(s) may be administered
sequentially, in either order, or in combination.
[0017] Also included in the present invention is a method for
treating B-cell lymphoma comprising administering to a patient a
therapeutically effective amount of a chimeric anti-CD20 antibody
before, during or subsequent to a chemotherapeutic regimen. Such a
chemotherapy regimen may be selected from the group consisting of,
at the very least, CHOP, ICE, Mitozantrone, Cytarabine, DVP, ATRA,
Idarubicin, hoelzer chemotherapy regime, La La chemotherapy regime,
ABVD, CEOP, 2-CdA, FLAG & IDA with or without subsequent G-CSF
treatment), VAD, M & P, C-Weekly, ABCM, MOPP and DHAP.
[0018] Also encompassed are methods for treating B-cell lymphoma
comprising administering to a patient a therapeutically effective
amount of a chimeric anti-CD20 antibody before, during or
subsequent to a bone marrow or peripheral stem cell transplant.
Such bone marrow transplant may also be accompanied by other
therapeutic regimens such as chemotherapy. The antibodies of the
present invention may also be used in a method of reducing residual
CD20+ tumor cells in bone marrow or stem cells before or after
myeloablative therapy by administering to a patient a chimeric
anti-CD20 antibody. It may also be possible to use such antibodies
in vitro to induce apoptosis of tumor cells and reduce or cure bone
marrow or stem cell preparations of residual tumor cells before
they are infused back into the patient.
[0019] It should be understood that stem cell transplants may be
allogeneic or autologous. If the transplant is allogeneic, i.e.,
from another person, the disclosed therapeutic regimens may include
treatments with immunosuppressive drugs before administration of
the anti-CD20 antibodies. Coadministration of other drugs designed
to enhance acceptance of the transplant and stimulate the
production and differentiation of immune cells is also
contemplated. For instance, it has been shown that administration
of GM-CSF to marrow transplant recipients promotes the development
of specific bone marrow cells which in turn produces circulating
infection-fighting neutrophils, and increased the survival rate of
marrow transplant recipients.
[0020] The methods of the present invention may be used to treat a
variety of B-cell lymphomas, including low grade/follicular
non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL,
intermediate grade/follicular NHL, intermediate grade diffuse NHL,
high grade immunoblastic NHL, high grade lymphoblastic NHL, high
grade small non-cleaved cell NHL, bulky disease NHL and
Waldenstrom's Macroglobulinemia. It should be clear to those of
skill in the art that these lymphomas will often have different
names due to changing systems of classification, and that patients
having lymphomas classified under different names may also benefit
from the combined therapeutic regimens of the present
invention.
[0021] For instance, a recent classification system proposed by
European and American pathologists is called the Revised European
American Lymphoma (REAL) Classification. This classification system
recognizes Mantle cell lymphoma and Marginal cell lymphoma among
other peripheral B-cell neoplasms, and separates some
classifications into grades based on cytology, i.e., small cell,
mixed small and large, large cell. It will be understood that all
such classified lymphomas may benefit from the combined therapies
of the present invention.
[0022] The U.S. National Cancer Institute (NCI) has in turn divided
some of the REAL classes into more clinically useful "indolent" or
"aggressive" lymphoma designations. Indolent lymphomas include
follicular cell lymphomas, separated into cytology "grades,"
diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia
(CLL), lymphoplasmacytoid/Waldenstrom's Macroglobulinemia, Marginal
zone lymphoma and Hairy cell leukemia. Aggressive lymphomas include
diffuse mixed and large cell lymphoma, Burkitt's lymphoma/diffuse
small non-cleaved cell lymphoma, Lymphoblastic lymphoma, Mantle
cell lymphoma and AIDS-related lymphoma. These lymphomas may also
benefit from the combined therapeutic regimens of the present
invention.
[0023] Non-Hodgkin's lymphoma has also been classified on the basis
of "grade" based on other disease characteristics including
low-grade, intermediate-grade and high-grade lymphomas. Low-grade
lymphoma usually presents as a nodal disease, and is often indolent
or slow-growing. Intermediate- and high-grade disease usually
presents as a much more aggressive disease with large extranodal
bulky tumors. Intermediate- and high-grade disease, as well as low
grade NHL, may benefit from the combined therapeutic regimens of
the present invention.
[0024] The Ann Arbor classification system is also commonly used
for patients with NHL. In this system, stages I, II, III, and IV of
adult NHL can be classified into A and B categories depending on
whether the patient has well-defined generalized symptoms (B) or
not (A). The B designation is given to patients with the following
symptoms: unexplained loss of more than 10% body weight in the 6
months prior to diagnosis, unexplained fever with temperatures
above 38.degree. C. and drenching night sweats. Occasionally,
specialized staging systems are used:
[0025] Stage I--involvement of a single lymph node region or
localized involvement of a single extralymphatic organ or site.
[0026] Stage II--involvement of two or more lymph node regions on
the same side of the diaphragm or localized involvement of a single
associated extralymphatic organ or site and its regional lymph
nodes with or without other lymph node regions on the same side of
the diaphragm.
[0027] Stage III--involvement of lymph node regions on both sides
of the diaphragm, possibly accompanying localized involvement of an
extralymphatic organ or site, involvement of the spleen, or
both.
[0028] Stage IV--disseminated (multifocal) involvement of 1 or more
extralymphatic sites with or without associated lymph node
involvement or isolated extralymphatic organ involvement with
distant (non-regional) nodal involvement.
[0029] For further details, see The International Non-Hodgkin's
Lymphoma Prognostic Factors Project: A predictive model for
aggressive non-Hodgkin's lymphoma. New England J. Med. 329(14):
987-994 (1993).
[0030] Preferred antibodies, dosage regimens and particular
combinations of therapy will now be illustrated by way of the
following exemplary data.
[0031] Rituximab.RTM. and Y2B8
[0032] Non-Hodgkin's lymphoma (NHL) affects approximately 250,000
people in the United States. The majority of patients with NHL are
not cured by chemotherapy, radiotherapy, or high-dose treatment
with autologous bone marrow (ABMT) or peripheral blood stem cell
(PBSC) support.
[0033] Approximately 80% of non-Hodgkin's lymphomas are B-cell
malignancies and >95% of these express the CD20 antigen on the
cell surface. This antigen is an attractive target for
immunotherapy because it is found exclusively on B-cells, and not
on hematopoietic stem cells, pro-B-cells, normal plasma cells, or
other normal tissues. It is not shed from the cell surface and does
not modulate upon antibody binding (1).
[0034] Rituximab.RTM. is one of a new generation of monoclonal
antibodies developed to overcome limitations encountered with
murine antibodies, including short half-life, limited ability to
stimulate human effector functions, and immunogenicity (2,3).
[0035] Rituximab.RTM. is a genetically engineered monoclonal
antibody with murine light- and heavy-chain variable regions and
human gamma I heavy-chain and kappa light-chain constant regions.
The chimeric antibody is composed of two heavy chains of 451 amino
acids and two light chains of 213 amino acids and has an
approximate molecular weight of 145 kD. Rituximab.RTM. is more
effective than its murine parent in fixing complement and mediating
ADCC, and it mediates CDC in the presence of human complement (4).
The antibody inhibits cell growth in the B-cell lines FL-18, Ramos,
and Raji, sensitizes chemoresistant human lymphoma cell lines to
diphtheria toxin, ricin, CDDP, doxorubicin, and etoposide, and
induces apoptosis in the DHL-4 human B-cell lymphoma line in a
dose-dependent manner (5). In humans, the half-life of the antibody
is approximately 60 hours after the first infusion and increases
with each dose to 174 hours after the fourth infusion. The
immunogenicity of the antibody is low; of 355 patients in seven
clinical studies, only three (<1%) had a detectable
anti-chimeric antibody (HACA) response.
[0036] Rituximab.RTM. was genetically engineered using the murine
2B8 antibody. The 2B8 antibody has also been conjugated to
different radiolabels for diagnostic and therapeutic purposes. To
this end, copending application Ser. Nos. 08/475,813, 08/475,815
and 08/478,967, herein incorporated by reference in their entirety,
disclose radiolabeled anti-CD20 conjugates for diagnostic "imaging"
of B-cell lymphoma tumors before administration of therapeutic
antibody. "In2B8" conjugate comprises a murine monoclonal antibody,
2B8, specific to human CD20 antigen, that is attached to
Indium[111] (.sup.111In) via a bifunctional chelator, i.e., MX-DTPA
(diethylene-triaminepentaacetic acid), which comprises a 1:1
mixture of 1-isothiocyanatobenzyl-3-methyl-DTPA and
1-methyl-3-isothiocyanatobenzyl-DTPA. Indium-[111] is selected as a
diagnostic radionuclide because it emits gamma radiation and finds
prior usage as an imaging agent.
[0037] Patents relating to chelators and chelator conjugates are
known in the art. For instance, U.S. Pat. No. 4,831,175 of Gansow
is directed to polysubstituted diethylenetriaminepentaacetic acid
chelates and protein conjugates containing the same, and methods
for their preparation. U.S. Pat. Nos. 5,099,069, 5,246,692,
5,286,850, and 5,124,471 of Gansow also relate to polysubstituted
DTPA chelates. These patents are incorporated herein in their
entirety.
[0038] The specific bifunctional chelator used to facilitate
chelation in application Ser. Nos. 08/475,813, 08/475,815 and
08/478,967 was selected as it possesses high affinity for trivalent
metals, and provides for increased tumor-to-non-tumor ratios,
decreased bone uptake, and greater in vivo retention of
radionuclide at target sites, i.e., B-cell lymphoma tumor sites.
However, other bifunctional chelators are known in the art and may
also be beneficial in tumor therapy.
[0039] Also disclosed in application Ser. Nos. 08/475,813,
08/475,815 and 08/478,967 are radiolabeled therapeutic antibodies
for the targeting and destruction of B-cell lymphomas and tumor
cells. In particular, the Y2B8 conjugate comprises the same
anti-human CD20 murine monoclonal antibody, 2B8, attached to
yttrium-[90] (.sup.90Y) via the same bifunctional chelator. This
radionuclide was selected for therapy for several reasons. The 64
hour half-life of .sup.90Y is long enough to allow antibody
accumulation by the tumor and, unlike e.g. .sup.131i, it is a pure
beta emitter of high energy with no accompanying gamma irradiation
in its decay, with a range of 100 to 1000 cell diameters. The
minimal amount of penetrating radiation allows for outpatient
administration of .sup.90Y-labeled antibodies. Furthermore,
internalization of labeled antibodies is not required for cell
killing, and the local emission of ionizing radiation should be
lethal for adjacent tumor cells lacking the target antigen.
[0040] Because the .sup.90Y radionuclide was attached to the 2B8
antibody using the same bifunctional chelator molecule MX-DTPA, the
Y2B8 conjugate possesses the same advantages discussed above, e.g.,
increased retention of radionuclide at a target site (tumor).
However, unlike .sup.111In, it cannot be used for imaging purposes
due to the lack of gamma radiation associated therewith. Thus, a
diagnostic "imaging" radionuclide, such as .sup.111In, can be used
for determining the location and relative size of a tumor prior to
and/or following administration of therapeutic chimeric or
.sup.90Y-labeled antibodies in the combined regimens of the
invention. Additionally, indium-labeled antibody enables dosimetric
assessment to be made.
[0041] Depending on the intended use of the antibody, i.e., as a
diagnostic or therapeutic reagent, other radiolabels are known in
the art and have been used for similar purposes. For instance,
radionuclides which have been used in clinical diagnosis include
.sup.131I, .sup.125I, .sup.123I, .sup.99Tc, .sup.67Ga, as well as
.sup.111In. Antibodies have also been labeled with a variety of
radionuclides for potential use in targeted immunotherapy (Peirersz
et al. (1987) The use of monoclonal antibody conjugates for the
diagnosis and treatment of cancer. Immunol. Cell Biol. 65:
111-125). These radionuclides include .sup.188Re and .sup.186Re as
well as .sup.90Y, and to a lesser extent .sup.199Au and .sup.67Cu.
I-(131) has also been used for therapeutic purposes. U.S. Pat. No.
5,460,785 provides a listing of such radioisotopes and is herein
incorporated by reference.
[0042] As reported in copending application Ser. Nos. 08/475,813,
08/475,815 and 08/478,967, administration of the radiolabeled Y2B8
conjugate, as well as unlabeled chimeric anti-CD20 antibody,
resulted in significant tumor reduction in mice harboring a B-cell
lymphoblastic tumor. Moreover, human clinical trials reported
therein showed significant B-cell depletion in lymphoma patients
infused with chimeric anti-CD20 antibody. In fact, chimeric 2B8 has
recently been heralded the nation's first FDA-approved anti-cancer
monoclonal antibody under the name of Rituxan.RTM.. Thus, at least
one chimeric anti-CD20 antibody has been shown to demonstrate
therapeutic efficacy in the treatment of B-cell lymphoma.
[0043] In addition, U.S. application Ser. No. 08/475,813, herein
incorporated by reference, discloses sequential administration of
Rituxan.RTM., a chimeric anti-CD20, with both or either
indium-labeled or yttrium-labeled murine monoclonal antibody.
Although the radiolabeled antibodies used in these combined
therapies are murine antibodies, initial treatment with chimeric
anti-CD20 sufficiently depletes the B-cell population such that the
HAMA response is decreased, thereby facilitating a combined
therapeutic and diagnostic regimen.
[0044] Thus, in this context of combined immunotherapy, murine
antibodies may find particular utility as diagnostic reagents.
Moreover, it was shown in U.S. application Ser. No. 08/475,813 that
a therapeutically effective dosage of the yttrium-labeled anti-CD20
antibody following administration of Rituxan.RTM. is sufficient to
(a) clear any remaining peripheral blood B-cells not cleared by the
chimeric anti-CD20 antibody; (b) begin B-cell depletion from lymph
nodes; or (c) begin B-cell depletion from other tissues.
[0045] Thus, conjugation of radiolabels to cancer therapeutic
antibodies provides a valuable clinical tool which may be used to
assess the potential therapeutic efficacy of such antibodies,
create diagnostic reagents to monitor the progress of treatment,
and devise additional therapeutic reagents which may be used to
enhance the initial tumor-killing potential of the chimeric
antibody. Given the proven efficacy of an anti-CD20 antibody in the
treatment of non-Hodgkin's lymphoma, and the known sensitivity of
lymphocytes to radioactivity, it would be highly advantageous for
such chimeric and radiolabeled therapeutic antibodies to find use
in combined therapeutic regimens which decrease the frequency of
relapsed or refractory non-Hodgkin's lymphoma. In addition, it
would be beneficial if such combined therapeutic regimens found use
in the treatment of other B-cell lymphomas.
[0046] Low-Grade ir Follicular NHL
[0047] Single-Agent Studies with Relapsed or Refractory NHL
[0048] FDA approval of Rituxinmab.RTM. was based on five
single-agent studies primarily in patients with low-grade or
follicular NHL. An early Phase I study of single Rituximab.RTM.
infusions ranging from 10-500 mg/m.sup.2 demonstrated that the
maximum tolerated dose had not been reached; however, the length of
infusion time at the highest dose was not considered feasible for
outpatient therapy. The ORR in 15 patients was 13% (Table
1)(6).
1TABLE 1 Rituximab .RTM.: Summary of Efficacy Results Median Median
DR TIP Study Description Indication N* ORR CR PR (months) (months)
References Phase I/II, Single-Dose Relapsed B-Cell Lymphoma 15 2
(13%) 0 (0%) 2 (13%) NA{cube root} 8.1 6 Single Agent Phase I/II,
Multiple-Dose Relapsed Low-, Intermediate-, 34 17 (50%) 3 (9%) 14
(41%) 8.6 10.2 7 Dose-Ranging and High-Grade Lymphotna Phase II;
Multiple-Dose Newly Diagnosed and Relapsed 38 38 (100%) 22 (58%) 16
(42%) 35.3+ 36.7+ 21, 22 Combined with CHOP Low-Grade or Follicular
B-Cell Lymphoma Phase III, Multiple-Dose Relapsed Low-Grade or 151
76 (50%) 9 (6%) 67 (44%) 11.6 13.2 8, 9 Single-Agent Follicular
B-Cell Lymphoma Phase II, Multiple-Dose Relapsed Low-Grade or 35 21
(60%) 5 (14%) 16 (46%) 13.4+ 19.4+ 13 Single-Agent Follicular
B-Cell Lymphoma Phase II, Multiple-Dose, Relapsed Low-Grade or 38
17 (45%) 4 (11%) 13 (34%) 22.3+ 25.2+ 29 Combined with Interferon
Follicular B-Cell Lymphoma Phase II, Multiple-Dose, Relapsed
Low-Grade or 28 12 (43%) 1 (4%) 11 (39%) 5.9 8.1 14 Single-Agent
Follicular B-Cell Lymphoma, Bulky Disease Phase II, Multiple-Dose,
Relapsed Low-Grade or 57 23 (40%) 6 (11%) 17 (29%) 15.0+ 16.7+ 19,
20 Single-Agent Follicular B-Cell Lymphoma, Retreatment Phase II,
Multiple-Dose Previously Untreated 30 29 (96%) 19 (63%) 10 (33%)
11+ 17+ 34 Combined with CHOP Intermediate- or High-Grade Modality
Lymphoma Phase II, Alternative Multiple Intermediate- or High-Grade
B- 54 17 (32%) 5 (9%) 12 (22%) NA.dagger. 8.2+ 33 Dosing Cell
Lymphoma *N = number of evaluable patients .dagger.Not
available
[0049] In Phase I of a Phase I/II dose-ranging study, patients
received 125-375 mg/m.sup.2 administered as four weekly infusions.
No dose-related toxicities were demonstrated, and 375 mg/m.sup.2
was chosen as the Phase II dose. Tumor regressions were observed in
17 of 37 (46%) patients who received this dose, including 3 (8%)
complete responses (CR) and 14 (38%) partial responses PR (7).
[0050] A subsequent single-arm pivotal study of Rituximab.RTM.
infused at 375 mg/m.sup.2 weekly times four was conducted in 166
patients with relapsed or refractory, low-grade or follicular NHL
(International Working Formulation [IWF] Types A-D and REAL
classification, small lymphocytic lymphoma, Follicular center,
follicular Grades I, II, III (8)). Patients with tumor masses
>10 cm or with >5000 lymphocytes/.mu.L in the peripheral
blood were excluded from this study. The median age was 58 years
(105 men and 61 women) and the median number of prior treatments
was three. Bone marrow involvement was present in 56% of 149
patients evaluated. Forty-five percent had .gtoreq.2 extranodal
sites and 41% had bulky disease (.gtoreq.5 cm).
[0051] Complete response required the regression of all lymph nodes
to <1.times.1 cm.sup.2 demonstrated on two occasions at least 28
days apart on neck chest, abdomen, and pelvic CT scans, resolution
of all symptoms and signs of lymphoma, and normalization of bone
marrow, liver, and spleen. Partial response required a .gtoreq.50%
decrease in the sum of the products of perpendicular measurements
of lesions without any evidence of progressive disease for at least
28 days. Patients who did not achieve a CR or PR were considered
non-responders, even if a net decrease (>50%) of measurable
disease was observed. Time to progression was measured from the
first infusion until progression.
[0052] The overall response rate (ORR) was 48% with a 6% CR and a
42% PR rate (8). The median time to progression (TTP) for
responders was 13.2 months and the median duration of response (DR)
was 11.6 months. Twenty-two of 80 (28%) responders remain in
ongoing remission at 20.9+ to 32.9+ months (9).
[0053] Administration of Rituximab.RTM. resulted in a rapid and
sustained depletion of B-cells. Circulating B-cells were depleted
within the first three doses with sustained depletion for up to six
to nine months post-treatment in 83% of patients. Median B-cell
levels returned to normal by 12 months following treatment.
Although median NK cell counts remained unchanged, a positive
correlation was observed between higher absolute NK cell counts at
baseline and response to Rituximab.RTM. (10).
[0054] Several baseline prognostic factors were analyzed to
determine their correlation to response. Significantly, in 23
patients relapsed after ABMT or PBSC, the ORR was 78% versus 43% in
patients who did not undergo prior high-dose therapy (p<0.01).
In a multivariate analysis, the ORR was higher in patients with
follicular NHL as compared with small lymphocytic lymphoma (58% vs.
12%, p<0.01), and higher in patients with chemosensitive relapse
as compared with chemoresistant relapse (53% vs. 36%, p=0.06). No
effect on response rate was associated with: age >60 years,
extranodal disease, prior anthracycline therapy, or bone marrow
involvement.
[0055] A statistically significant correlation was found between
the median serum antibody concentration and response at multiple
time points during treatment and follow up (11).
[0056] Serum levels of antibody were higher in patients with
follicular NHL compared with small lymphocytic lymphoma. Mean serum
antibody was also inversely correlated with measurements of tumor
bulk and with the number of circulating B-cells at baseline. The
association of lower serum antibody concentrations with higher
numbers of circulating NHL cells and with higher tumor bulk suggest
that the main mode of antibody clearance is to tumor cells. The
association of high serum antibody concentrations with response and
lower tumor bulk or circulating cells suggests that higher or more
doses of Rituximab.RTM. may be necessary to induce responses in
some subsets of patients, such as those with bulky disease.
[0057] Nevertheless, responses were seen with Rituximab.RTM. in 43%
of patients with tumors >5 cm and in 35% of patients with tumors
>7 cm, suggesting that treatment of patients with bulky disease
with Rituximab.RTM. is feasible. This is surprising considering it
was long thought that antibody therapy is not conducive to treating
bulky disease due to the compact nature of the tumors.
[0058] In a study conducted in Japan (12), patients with relapsed
B-cell lymphoma were treated with either 250 mg/m.sup.2 (N=4) or
375 mg/m.sup.2 (N=8) of Rituximab.RTM. weekly times four. Of 11
evaluable patients, 8 had follicular NHL, 2 had diffuse large-cell
NHL, and one had mantle-cell lymphoma. Two of the 11 had a CR and 5
had a PR for an ORR of 64%; all responders had follicular
histology.
[0059] Because Rituximab.RTM. serum levels and response were
positively correlated in previous studies, a Phase II study of
eight weekly doses of 375 mg/m.sup.2 Rituximab.RTM.t was conducted
in low-grade or follicular NHL patients. The ORR was 60% in
evaluable patients, with a 14% CR and a 46% PR rate. Median values
for TTP in responders and DR were 13.4+ months and 19.4+ months,
respectively (13). Though it is difficult to compare across
studies, it appears that TTP and DR may be improved by using more
doses.
[0060] Contrary to early assumptions about antibody therapy being
useful only in micrometastatic disease, Rituximab.RTM. is quite
active in high bulk disease. In a separate study, 31 patients with
relapsed or refractory, bulky low-grade NHL (single lesion of
>10 cm in diameter) received 375 mg/m.sup.2 Rituximab.RTM. as
four weekly infusions. Twelve of 28 evaluable patients (43%)
demonstrated a CR (1, 4%) or PR (11, 39%) (14).
[0061] Waldenstrom's Macroglobulinemia
[0062] Waldenstrom's Macroglobulinemia (WM) is a malignancy wherein
B lymphocytes secrete excessive amounts of IgM antibodies. WM
usually occurs in people over sixty, but has been detected in
adults in their early thirties. WM today is considered a rare
incurable indolent malignancy, which has in the past been treated
by plasmaphoresis to reduce serum viscosity. Chemotherapeutic drugs
such as an alkylating agent and a corticosteroid are often
prescribed. The most recommended drug for WM has been Leustatin
(2CdA).
[0063] A report on seven patients with Waldenstrom's
macroglobulinemia where the patients were treated with
Rituximab.RTM. (375 mg/m.sup.2 weekly times 4)(15) noted responses
in 4 (57%) of patients. Median progression-free survival was 8
months (range 3-27+months). Thus, Rituximab.RTM. should be useful
in combined therapeutic protocols, particularly with
chemotherapeutic reagents such as 2CdA.
[0064] Chronic Lymphocytic Leukemia (CLL)
[0065] CLL is the liquid (leukemic) equivalent of small lymphocytic
lymphoma (SLL). Patients with SLL had lower serum levels and a
lower response rate when treated with the standard dose of
Rituximab.RTM. than patients with other low-grade NHL subtypes.
This is probably due to the very high levels of circulating tumor
cells in patients with CLL, and because malignant cells involved in
CLL are thought to have reduced levels of expression of CD20 on the
cell surface.
[0066] Nevertheless, the present inventors have discovered that
hematologic malignancies such as CLL may be treated with
Rituximab.RTM.. A recent clinical study evaluated treatment of CLL
patients at higher doses of Rituximab.RTM. (16). All patients
receive a first dose of 375 mg/m.sup.3 to minimize
infusion-relapsed side effects. Subsequent weekly dosages (3)
remained the same but were given at an increased dose level.
Sixteen patients have been treated at dosages of 500-1500
mg/m.sup.3. Medium age was 66 years (range, 25-78). Eighty-one
percent had end-stage III-IV disease. Medium white blood cell count
was 40.times.10.sup.9/L (range, 4-200), Hgb 11.6 g/dl (range,
7.7-14.7), platelets 75.times.10.sup.9/L (range, 16-160), median
.beta..sub.2 immunoglobulin was 4.5 mg/L (range, 3.1-9.2). Median
numbers of prior therapies was 2.5 (range 1-9). Sixty percent of
patients were refractory to treatment. Two patients developed
severe hypertension with the first dose (375 mg/m.sup.3); another
one received further therapy. Toxicity at subsequent escalated
dosages has been mild although no patient at the 1500 mg/m.sup.3
dose level has been fully evaluated. Eight patients have completed
therapy (4 at 500 mg/m.sup.3, 3 at 650 mg/m.sup.3, 1 at 825
mg/m.sup.3). One patient treated at 560 mg/m.sup.3 achieved full
remission. One patient has progressive lympocytosis on treatment
and all other patients had reduction in peripheral blood
lymphocytosis but less effect on lymph nodes. Dose escalation
studies are ongoing.
[0067] Another approach to improving response in CLL patients is to
upregulate the CD20 antigen using cytokines. In an in vitro study,
mononuclear cells from CLL patients were incubated for 24 hours
with various cytokines. Flow cytometry results showed significant
up-regulation by IL-4, GM-CSF, and TNF-alpha (17). In fact, recent
data suggests that the upregulation of CD20 observed on CLL cells
may be limited to tumor cells (Venogopal et al. Poster--PanPacific
Lymphoma meeting, June 1999. Cytokine-induced upregulation of CD20
antigen expression in chronic lymphocytic leukemia (CLL) cells may
be limited to tumor cells). Preliminary data also suggest that
interferon alpha also upregulates CD20 on CLL cells after only 24
hours when applied at a concentration of 500 to 1000 U/ml.
[0068] Thus, by administering certain cytokines to CLL patients
prior to or concurrently with administration of Rituximab.RTM., the
expression of CD20 on the surface of malignant B-cells may be
upregulated, thereby rendering CD20, as well as other cell surface
markers such as CD 19, a more attractive target for immunotherapy.
A collaborative study has been initiated to test for optimal
cytokine doses for CD20 upregulation in vivo. The study protocol
involves treating ten patients initially with GM-CSF at 250
mcg/m.sup.2 SQ QD.times.3, ten patients with IL-4 mcg/kg SQ
QD.times.3, and ten patients with G-CSF at 5 mcg/kg SQ QD.times.3.
Mononuclear cells will be separated by Ficon Hypaque centrifugation
for apoptotic studies to determine if upregulation of CD20
translates to enhanced killing of tumor cells by
Rituximab.RTM..
[0069] Antibody treatment of CLL can be combined with other
conventional chemotherapeutic treatments known to be useful for the
treatment of CLL. The most frequently used single agent for CLL is
chlorambucil (leukeran), given either as 0.1 mg/kg daily or 0.4 to
1.0 mg/kg every 4 weeks. Chlorambucil is often combined with oral
prednisone (30 to 100 mg/m.sup.2/d), which is useful in the
management of autoimmune cytopenias. Cyclophosphamide is an
alternative to chlorambucil, the usual dose being 1-2 g/m.sup.2
every 3-4 weeks together with vincristine and steroids (e.g., COP
regimen).
[0070] Various drug combinations have been used for CLL, including
COP (cyclophosphamide, Oncovin, and prednisone), and CHOP (these
three drugs plus doxorubicin). Fludarabine has shown an effect in
the treatment of CLL, and gave an ORR of 50% in a group of patients
treated with 25-30 mg/m.sup.2/d every 3-4 weeks.
http://www.cancernetwork.com. Although some patients have been
shown to be refractory for fludarabine. Such patients may also be
resistant to 2-CdA because often, patients who are refractory to
fludarabine are also refractory to 2-CDA (O'Brien et al. N. Engl.
J. Med. 330: 319-322 (1994)).
[0071] Hence, anti-CD20 antibody therapy will be particularly
useful for patients who are refractory or who have relapsed after
treatment with chemotherapeutic drugs. Rituximab.RTM. therapy may
also be combined with radiotherapy in these patients. TBI with a
low fraction size of 15 cGy to total doses of 75 to 150 cGy has
been shown to be effective in about one-third of patients.
[0072] A Phase II trial is currently being conducted by CALGB in
CLL patients. Rituximab.RTM. and fludarabine are administered
concurrently, followed by Rituximab.RTM.D consolidation versus
fludarabine induction followed by Rituximab.RTM..
[0073] Rituximab.RTM. with Myeloablative Therapy
[0074] Myeloablative therapy has yielded responses in indolent
lymphomas; however, residual tumor cells may remain despite
high-dose therapy and the PBSC reinfused may contain tumor cells.
Rituximab.RTM. is being used before stem cell mobilization and
after transplant to reduce residual CD20+ tumor cells and
contamination of the bone marrow or stem cells harvested. Interim
results demonstrated that no CD20+ cells were detectable in
harvested cells. Eighteen of 24 patients achieved engraftment and
the treatment was well tolerated. PCR testing is ongoing to
evaluate residual tumor cells (18).
[0075] Retreatment of Relapsed Low-Grade NHL with
Rituximab.RTM.
[0076] A trial evaluating retreatment of 53 patients who had
responded to Rituximab.RTM. and later relapsed has been reported
(19). Seven of 56 evaluable patients (13%) obtained a CR and 16 a
PR (29%), for an ORR of 42%. Four patients who had a second
response received a third treatment; 3 of these responded.
[0077] After treatment with two courses of Rituximab.RTM., one
patient's tumor, initially classified as follicular, small cleaved
cell NHL, no longer expressed the CD20 antigen and was unresponsive
to Rituximab.RTM. at the time of transformation to diffuse,
large-cell NHL (20).
[0078] Thus, while retreatment with Rituximab.RTM. is effective for
treating patients who have relapsed after prior treatment with
Rituximab.RTM., there may be an increased incidence of CD20-tumor
cells after secondary treatment. This observation supports the
utility of the combined therapeutic treatment regimens described
herein.
[0079] Combination of Rituximab.RTM. and CHOP Chemotherapy for
Low-Grade NHL
[0080] Chemotherapy with cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP) is an effective first-line
therapy for low-grade or follicular NHL. Though initial response
rates are high, relapse eventually occurs and subsequent
chemotherapy regimens produce remissions with shorter durations. A
Phase II trial was initiated to evaluate the combination of CHOP
and Rituximab.RTM. (21) in newly diagnosed and relapsed low-grade
or follicular NHL because their mechanisms of action are not
cross-resistant, and Rituximab.RTM. is synergistic with certain
cytotoxic drugs, including doxorubicin (5).
[0081] Twenty-nine of 38 patients received no prior anticancer
therapy. CHOP was administered at standard doses every three weeks
for six cycles with six infusions of Rituximab.RTM. (375
mg/m.sup.2). Rituximab.RTM. infusions 1 and 2 were administered on
Days 1 and 6 before the first CHOP cycle, which started on Day 8.
Rituximab.RTM. infusions 3 and 4 were given 2 days before the third
and fifth CHOP cycles, respectively, and infusions 5 and 6 were
given on Days 134 and 141, respectively, after the sixth CHOP
cycle.
[0082] In this combination study, 100% of the 38 patients treated
responded (CR, 58%; PR, 42%). Of 35 evaluable patients who
completed treatment, there were 63% CR, and 37% PR (21). Median DR
is 35.3+ months with median progression-free survival not reached
after a median observation time of 36.7+ months. Twenty patients
are still in remission after 36+ months to 53.4+ months (22). This
DR is impressive even for first-line treatment, and 24% of this
trial population had relapsed after chemotherapy.
[0083] In a study to be conducted by CALGB, 40 patients with
low-grade NHL will receive Rituximab.RTM. weekly times 8 and oral
cyclophosphamide daily starting on Day 8. Twenty patients will
receive Rituximab.RTM. alone for 8 weekly doses.
[0084] A Phase III study conducted by ECOG in patients with
low-grade NHL is comparing the combination of cyclophosphamide and
fludarabine (Ann A) with standard CVP therapy (Arm B). In the
randomization to Arm A or Arm B, patients are stratified by age,
tumor burden, histology, and B symptoms. Responders in both arms
will undergo a second randomization to Rituximab.RTM. maintenance
therapy (375 mg/m.sup.2 weekly times 4 every 6 months for 2 years
(Arm C) or to observation (Arm D).
[0085] Combination of Rituximab.RTM. with Cytokines
[0086] Rituximab.RTM. Plus Interferon Alpha
[0087] Interferon is a cytokine involved in modulating the immune
system (23). Mechanisms by which interferon may increase the
effectiveness of antibodies include the potentiation of antigen
expression (24), increased targeting of antibodies into tumors
(25,26), and enhanced cytotoxicity of immunotoxins (27).
[0088] In a combination trial, interferon-alpha (Roferon-A), a
cytokine with a single-agent clinical activity in NHL (28), and
Rituximab.RTM. were given to patients with relapsed low-grade or
follicular NHL. Interferon-alpha (2.5 or 5 MIU) was administered
subcutaneously, three times weekly for 12 weeks. Rituximab.RTM. was
administered by IV infusion weekly for four doses (375 mg/m.sup.2)
starting on the fifth week of treatment. The ORR was 45% (17/38
patients); 11% had a CR and 34% had a PR. Kaplan-Meier estimates of
the median DR and TTP in responders were 22.3+ and 25.2+ months,
respectively (29). Previous combination studies of interferon-alpha
and chemotherapeutic regimens containing anthracyclines yielded
prolonged time to progression, but did not consistently increase
response or survival rates (30-32). These early results suggest
that the combination of Rituximab.RTM. and interferon-alpha may
prolong the time to progression relative to Rituximab.RTM.
alone.
[0089] Rituximab.RTM. Plus G-CSF
[0090] In a separate study, Rituximab.RTM. and G-CSF are being
evaluated in relapsed low-grade NHL. It has been demonstrated in
vitro as well as in vivo in healthy volunteers that G-CSF, via its
effect on myeloid precursor cells, induces FcRI-positive
neutrophils that are capable of functioning as effector cells in
ADCC. Therefor, a Phase I/II study was initiated to evaluate the
toxicity and efficacy of the combined treatment.
[0091] Both in Phase I and Phase II, patients were administered a
standard dose of G-CSF (5 .mu.g/kg/day) administered for three
days, starting 2 days before administration of Rituximab.RTM..
Phase I consisted of a dose escalation of Rituximab.RTM. (125, 250,
or 375 mg/m.sup.2 weekly.times.4). Early results in 9 patients
evaluated so far yielded an ORR of 67% (44% CR, 22% PR) with minor
toxicity in 8 of the 9 patients (33). The most frequent adverse
events were fever (4/8 patients), rhinitis (4/8), chills (3/8) and
headaches (3/8), which were comparable to the adverse events
observed previously in administration of Rituximab.RTM. alone. The
Phase II part of the study has been initiated, which will examine
the efficacy of the combination of G-CSF and 375 mg/m.sup.2
Rituximab.RTM..times.4.
[0092] Rituximab.RTM. Plus IL-2
[0093] High-dose therapy with autologous peripheral blood stem
cells (PBSC) or bone marrow (BM) rescue has been used to treat NHL,
however success remains limited by the high risk of relapse, which
is 50-80%. In an effort to improve durable remissions
post-transplant, immunotherapy including high dose and low dose
therapy with IL-2 has been studied in a number of treatment
centers. Such studies have suggested that IL-2 therapy does
demonstrate early post-transplant anti-Tumor activity.
[0094] Initially following autologous transplant, patients display
delayed immune reconstitution which potentially results in
diminished immune-mediated tumor eradication (43, 44). Indeed, it
has been shown that both CD$+ T cells and cytotoxic CD8+ T cells
are depressed (45-49). In vitro assays have demonstrated a profound
suppression of T cell cytolytic and proliferative responses as well
as decreased production of IL-2 in response to mitogens and soluble
antigens. However, soluble IL-2 is able to restore these immune
responses suggesting that immune cells in patients after autologous
transplant are capable of responding to exogenous L-2 (47).
Peripheral blood NK activity also remains lower following BMT than
control values and the NK activity is also augmented by addition of
exogenous IL-2 (49). These data suggest that administration of IL-2
to patients shortly after stem cell transplant may enhance immune
responsiveness at a critical period when tumor burden is minimal
and when immune responsiveness in the absence of IL-2 is
lacking.
[0095] For instance, Caligiuru et al. have shown that IL-2
(Hoffman-LaRoche) administered at 0.45.times.10.sup.6 U/M.sup.2/day
by 24 hour CIV for 12 weeks was able to expand the absolute number
of CD56 bright NK cells (50-52). This regimen was administered to
non-transplant patients in the outpatient setting with little
toxicity.
[0096] Animal models have shown that non-LAK inducing low doses of
1L-2 dramatically enhances anti-tumor activity when administered
with tumor-specific T effector cells (53). In addition, Soiffer et
al. (54) administered low doses of IL-2 to 13 autologous BMT or T
cell depleted allogeneic BMT recipients undergoing treatment for
relapsed leukemia or lymphoma. Enhanced immunological
responsiveness was demonstrated in the laboratory with a 5- to
40-fold increase in circulating CD56 bright CD16+ CD3- NK cells.
Moreover, this low dose regimen of IL-2 resulted in augmented in
vitro killing of the NK targets K562. When Soiffer et al. (55)
updated the outcome of 29 allogeneic BMT patients who received low
dose IL-2, they found superior survival for these patients (70%)
compared to histological controls (30%, p=0.41).
[0097] Lauria et al. (56) treated 11 patients with high grade NHL
at a median of 42 days after ABMT with IL-2 at a dose of
2.times.10.sup.6 IU/m.sup.2 qod for two weeks and then
3.times.10.sup.6 IU/m.sup.2 twice a week for a year. Phenotypic
analysis showed a persistent and significant (p=0.001) increase in
the proportion and absolute number of total lymphocytes and
especially of both CD 16 and CD56 NK cells after 6 months of
therapy. None of the patients progressed with a median follow-up of
twenty-two months (range 10-42 months) after starting therapy. In
addition, two patients with residual disease after ABMT, one in the
liver and second in the lymph nodes, obtained a complete response
after 7 and 10 months of IL-2 therapy.
[0098] Vey et al. (57) treated 25 patients with refractory or
relapsed HD (11 patients) and NHL (14 patients) with low dose IL-2.
48% of the patients had resistant disease at transplant and 84%
achieved CR after ABMT. IL-2 was started at a mean of 54 days after
transplant and consisted of a first cycle of 5 days followed by 4
cycles of 2 days every other week. Patients received a mean of
160.times.10.sup.6 IU/m2 of IL-2. After a five year follow-up, the
probability of survival and DFS is 72% (HD 73% and NHL 70%) and 45%
(HD 36% and NHL 48%).
[0099] A group at the Fred Hutchinson Cancer Research Center
(FHCRC) has recently found that low dose IL-2 therapy was
well-tolerated in the outpatient setting, and that remissions in
patients treated with low dose IL-2 tended to be longer than
without IL-2 treatment. IL-2 therapy was associated with an
increase in the number of certain populations of immune cells,
including CD8+ CD69+ cells; CD16+ CD8+ cells; CD16+ CD69+ cells;
CD16+ CD56+ cells; CD16+ CD122+ cells; CD16+ Dr+ cells; and CD8+
CD56+ cells. There was also an increase in the expression of lytic
activity against the timor targets K562 and Daudi, with a median of
5.9-fold and 6.5-fold increase, respectively. Relapses, when they
occurred, occurred at a median of 17.8 months after transplant, and
therefor remissions were reported to be characteristically longer
than what was historically seen in transplant recipients without
IL-2 therapy.
[0100] Given the encouraging data gathered from single therapy
studies with IL-2 on ABMT transplant recipients, it seemed
reasonable to combine IL-2 therapy with Rituximab.RTM. post
transplant, given that Rituximab's biological activity appears to
be mediated through ADCC and complement-mediated lytic activity.
Thus, a Phase I trial has been initiated in collaboration with the
FHCRC to evaluate the safety and potential efficacy of a combined
therapeutic regimen.
[0101] A separate Phase II study is also being performed to
evaluate the efficacy and the incidence of HACA formation in
patients receiving low-dose IL-2 and Rituxan.RTM.. A specific
objective of this study is to assess whether ADCC is enhanced by in
vivo exposure to IL-2 and whether ADCC activity correlates with
clinical response. Inclusion criteria for patients are
histologically confirmed stage 1I-IV low-grade, follicular B-cell
or mantle cell ylmphoma. Mantle cell lymphoma, for the purposes of
this clinical study, is defined as CD5+, CD23- (if available)
and/or bcl-1+ by immunohistochemistry. Patients who did not respond
to or have relapsed following their first treatment with a standard
therapy, i.e., chemotherapy, radiotherapy, ABMT and/or
immunotherapy, are eligible.
[0102] Rituximab.RTM. Plus GM-CSF for the Treatment of Relapsed Low
Grade or Follicular B-Cell Lymphoma
[0103] Two separate Phase II trials have also been initiated to
test the efficacy of combined treatment with Rituximab.RTM. and
GM-CSF. One study involves 40 patients with relapsed low grade
B-cell lymphoma, and comprises administering Rituximab.RTM. at 375
mg/m.sup.2 weekly.times.4 (d. 1, 8, 15, 22) and GM-CSF (Leukine,
Immunex) at 250 mcg sc three times weekly for 8 weeks, starting one
hour before the first dose of Rituximab.RTM.. This study will be
used to evaluate the clinical efficacy (overall response rate
(ORR), overall complete response rate, time to progression and
failure-free survival) of the combined therapeutic regimen, to
characterize the safety (qualitative, quantitative, duration and
reversibility of adverse events) of the combined therapy, and to
determine the effects of the combined therapy on relevant
lymphocyte subsets and cytokines. The second study plans to also
monitor immunologic parameters to assess the mechanism of killing
(complement C3 and C4, CH50, flow cytometry for CD3, CD4, CD8, CD
16, CD19 and CD56 and ADCC assay).
[0104] Rituximab.RTM. Plus Gamma-Interferon
[0105] Gamma-interferon may also be useful in combined therapy with
Rituximab.RTM. for treating patients with low-grade or higher-grade
lymphomas. It is has recently been found that gamma-interferon
upregulates CD20 expression on multiple myeloma (MM) patient plasma
cells, patient B-cells, as well as on normal donor B-cells (Treon
et al., Lugano, 1999). In fact, Treon and colleagues have shown
that gamma-interferon augments binding of these cells to
Rituximab.RTM.. Induction of CD20 expression on plasma cells
occurred in a dose dependent manner, with upregulation seen with as
little as 1 U/ml of interferon gamma. A plateau occurred at 100
U/ml at 48 hours. Thus, gamma-interferon may also be beneficial
when administered in combination with Rituximab.RTM..
[0106] Intermediate-Grade and High-Grade NHL
[0107] Single-Agent Studies
[0108] In a study conducted in Europe and Australia, alternative
dosing schedules were evaluated in 54 relapsed or refractory
intermediate- or high-grade NHL patients (34). Rituximab.RTM. was
infused at 375 mg/m.sup.2 weekly for 8 doses or at 375 mg/m2 once
followed by 500 mg/m.sup.2 weekly for 7 doses. The ORR was 31%; (CR
9%, PR 22%) no significant difference between the dosing regimens
was observed. Patients with diffuse large-cell lymphoma (N=30) had
an ORR of 37% and those with mantle-cell lymphoma (N=12) had an ORR
of 33%.
[0109] Combination of Rituximab.RTM. and CHOP Chemotherapy
[0110] In another study, 31 patients with intermediate- or
high-grade NHL (19 females, 12 males, median age 49) received
Rituximab.RTM. on Day 1 of each of six 21-day cycles of CHOP (35).
Of 30 evaluable patients, there were 19 CR (63%) and 10 PR (33%),
for an ORR of 96%. This regimen was considered well tolerated and
may result in higher response rates than with Rituximab.RTM. or
CHOP alone.
[0111] The NCI Division of Cancer Treatment and Diagnosis is
collaborating with IDEC Pharmaceuticals Corporation to explore
Rituximab.RTM. treatment in other indications. A Phase II trial of
CHOP versus CHOP and Rituximab.RTM. is being conducted by ECOG,
CALGB, and SWOG in older patients (>60 years) with mixed,
diffuse large cell, and immunoblastic large cell histology NHL
(N=630 planned). This study includes a secondary randomization to
maintenance with Rituximab.RTM. versus non-maintenance.
[0112] A Phase III trial of Rituximab.RTM. and CHOP in 40 patients
with previously untreated mantle-cell lymphoma is also ongoing at
the Dana Farber Institute. Rituximab.RTM. is administered on Day 1
and CHOP is given on Days 1-3 every 21 days for 6 cycles. Accrual
for this study has been completed. A Phase II trial of CHOP
followed by Rituximab.RTM. in newly diagnosed follicular lymphoma
conducted by SWOG has also been completed. Results of these two
trials are being analyzed.
[0113] A Phase II trial of CHOP and Rituximab.RTM. versus CHOP
alone in HIV-related NHL conducted by the AIDS Malignancy
Consortium is ongoing; 120 patients are planned.
[0114] Rituximab.RTM. after Myeloablative Therapy Relapse
[0115] Rituximab.RTM. has shown promising early results in patients
with relapsed intermediate-grade NHL after high-dose therapy with
autologous PBSC support. Six of seven patients responded (1 CR and
5 PR) and one patient had stable disease; therapy was well
tolerated (36).
[0116] Safety Experience
[0117] Adverse events and clinical laboratory data from 315
patients in the five single-agent U.S. studies were combined to
provide a safety profile of Rituximab.RTM. in patients with
low-grade or follicular NHL. The majority of adverse events were
infusion-related and occurred with decreasing frequency after the
first infusion. The most common infusion-related events were fever
(49%), chills (32%), nausea (18%), fatigue (16%), headache (14%),
angioedema (13%), pruritus (10%), and occasionally, hypotension
(10%) and bronchospasm (8%). During the treatment period (up to 30
days following the last dose), 10% of patients experienced Grade 3
or 4 adverse events, which were primarily infusion-related or
hematologic. Thrombocytopenia (<50,000 platelets/mm.sup.3)
occurred in 1.3% of patients, neutropenia (<1000/mm.sup.3)
occurred in 1.9%, and anemia (<8 gm/dL) occurred in 1.0%.
Although Rituximab.RTM. induced B-cell depletion in 70%-80% of
patients, abnormally decreased serum immunoglobulins were observed
in a minority of patients and the incidence of infection did not
appear to be increased.
[0118] Hypotension requiring interruption of the Rituximab.RTM.
infusion occurred in 10% of patients and was Grade 3 or 4 in 1%.
Angioedema was reported in 13% of patients and was considered
serious in one patient. Bronchospasm occurred in 8% of patients; 2%
were treated with bronchodilators. A single report of bronchiolitis
obliterans was noted. Most patients experienced no further
infusion-related toxicities by the second and subsequent infusions.
The percentage of patients reporting adverse events upon
retreatment was similar to that reported following the first course
(14).
[0119] Four patients developed arrhythmias during Rituximab.RTM.
infusion. One of the four discontinued treatment because of
ventricular tachycardia and supraventricular tachycardias. The
other three patients experienced trigeminy (N=1) and irregular
pulse (N=2) and did not require discontinuation of therapy. Angina
was reported during infusion and myocardial infarction occurred
four days post-infusion in one subject with a prior history of
myocardial infarction.
[0120] The overall incidence of adverse events and Grade 3 and 4
adverse events was higher in patients with bulky disease than in
patients with non-bulky disease. The incidence of dizziness,
neutropenia, thrombocytopenia, myalgia, anemia, and chest pain was
higher in patients with lesions >10 cm. The incidence of Grade 3
or 4 neutropenia, anemia, hypotension, and dyspnea was also higher
in patients with bulky disease compared with patients with lesions
<10 cm (19).
[0121] Since FDA approval of Rituximab.RTM. for treatment of
relapsed or refractory low-grade or follicular NHL in 1997, an
estimated 17,000 patients have been treated. In May, 1998,
descriptions of eight post-marketing reports of severe
infusion-related adverse events associated with the use of
Rituximab.RTM. that resulted in fatal outcomes were summarized. In
seven of the eight fatalities, severe symptoms occurred during the
first Rituximab.RTM. infusion. The cause of death was not reported
or remains unknown for two of the eight cases. Severe respiratory
events, including hypoxia, pulmonary infiltrates, or adult
respiratory distress syndrome contributed to six of the eight
reported deaths. One patient had a pretreatment lymphocyte count of
600,000/mm.sup.3; another, a creatinine of 8; a third, a
respiratory rate of 40; and a fourth, pancytopenia. Patients with a
high tumor burden or with a high number of circulating malignant
cells may be at higher risk and these patients should be monitored
closely throughout each infusion.
[0122] Most of the adverse events recently described were
previously observed in Rituximab.RTM. clinical studies. One notable
exception is an infusion-related syndrome associated with rapid
tumor lysis, that was reported in six patients with high numbers of
circulating tumor cells (37,38). This syndrome was characterized by
fever, rigors, bronchospasm with associated hypoxemia, a rapid
decline in peripheral lymphocytes, laboratory evidence of tumor
destruction, and transient, severe thrombocytopenia. These patients
had diagnoses of B-prolymphocytic leukemia (N=2), chronic
lymphocytic leukemia (N=2), mantle-cell lymphoma (N=1), or
transformed NHL (N=1); all had elevated circulating lymphocytes,
bulky adenopathy, and organomegaly. Although five of these six
patients required hospitalization, symptoms resolved and subsequent
Rituximab.RTM. treatments were well tolerated; the last patient
refused further therapy and died of progressive disease two weeks
later.
[0123] In a separate report of seven patients with CLL and one
patient with mantle-cell lymphoma, tumor lysis syndrome was
observed after the first Rituximab.RTM. infusion in those patients
with lymphocyte counts >10.times.10.sup.9L (39).
[0124] Radioimmunotherapy with .sup.90Yttrium-Labeled Anti-CD20
Antibody in Combination with Rituximab.RTM.
[0125] Another therapeutic approach to NHL under evaluation is a
radiolabeled anti-CD20 antibody (IDEC-Y2B8) in combination with
Rituximab.RTM.. IDEC-Y2B8 (.sup.90Y-ibritumomab tiuxetan) is a
murine IgG.sub.1 kappa anti-CD20 antibody conjugated to .sup.90Y
via a chelator, MX-DTPA, which is covalently bound to the antibody.
Rituximab.RTM. (250 mg/m2) is administered prior to IDEC-Y2B8 to
deplete peripheral B lymphocytes and improve biodistribution of the
radiolabeled antibody.
[0126] In a recently reported Phase I/II study (40-42), patients
with low-grade NHL (N=34), intermediate-grade NHL (N=14), or
mantle-cell lymphoma (N=3) were treated with IDEC-Y2B8. The median
age was 60, 71% were male, and 96% were Caucasian. Of 51 patients
with relapsed or refractory NHL, 34 (67%) responded to single doses
of 0.2, 0.3, or 0.4 mCi/kg of IDEC-Y2B8. The ORR was 82% (28/34)
for patients with low-grade or follicular NHL and was 43% (6/14)
for patients with intermediate-grade lymphoma. No patients with
mantle-cell disease responded.
[0127] A Phase III randomized study comparing IDEC-Y2B8 with
Rituximab.RTM. (375 mg/m.sup.2 weekly times 4) for treatment of
low-grade follicular or transformed NHL patients is ongoing.
Another Phase III trial is also being conducted in patients with
relapsed NHL who are refractory to Rituximab.RTM..
SUMMARY
[0128] In the absence of curative therapy for NHL, the objective of
treatment is to achieve control of the disease for a meaningful
duration and provide relief of tumor-related symptoms without undue
toxicity. Treatment with Rituximab.RTM. is a brief, 22-day
outpatient therapy with limited adverse events in most patients. In
clinical studies, 50% of evaluable relapsed or chemotherapy
refractory low-grade or follicular NHL patients achieved complete
or partial responses. These responses were durable without
maintenance therapy; the median TTP for responders was 13.2 months
and the median DR was 11.6 months in the pivotal study.
[0129] Rituximab.RTM. is approved as a safe and effective treatment
for patients with relapsed low-grade or follicular B-cell NHL. It
has significant clinical activity, a novel mechanism of action, and
compares favorably with alternative therapies in response rate and
response duration. Completion of ongoing studies will verify the
role of alternative Rituximab.RTM. regimens and Rituximab.RTM. in
the treatment of other CD20+ B-lymphocyte malignancies.
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