Note: Descriptions are shown in the official language in which they were submitted.
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Treatment of Patients having Non-Hodgkins Lymphoma
with Bone Marrow Involvement with Anti-CD20 Antibodies
Field of the Invention
The present invention relates to a method of
reducing the number of cancerous B cells in the bone
marrow of a patient having a B cell lymphoma prior to
radioimmunotherapy comprising administration of an anti-
CD20 antibody. Combined therapeutic methods of treating
a patient having lymphoma with associated bone marrow
involvement are also encompassed.
Background of the Invention
Radioimmunotherapy of B cell lymphoma is limited by
marrow involvement, i.e., infiltration of the bone
marrow by cancerous B lymphocytes. This complicates
radioimmunotherapy in two regards: (1) antibody binding
;to diseased cells in the marrow will deliver a dose of
radiation to the marrow thereby causing unwanted
myelosuppression; and (2) marrow crowding of normal
cells and progenitors will weaken healthy marrow
reserves so that patients may actually be closer to
grade 3 or 4 cytopenias than would be the case in
patients without marrow involvement. In either case,
the patient may be less tolerant to radioimmunotherapy,
e.g., with B cell depleting antibody conjugated to a
radioisotope such as 9°Y or 1311. As a consequence,
patients with greater than 25% bone marrow involvement
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are generally excluded from treatment with
radioimmunotherapy.
As found by Wiseman and colleagues, the clinical
parameters of baseline platelet counts and degree of
bone marrow involvement are accurate predictors of
hematologic toxicity in patients with low-grade
follicular non-Hodgkins lymphoma undergoing therapy with
Y2B8, a murine anti-CD20 antibody conjugated to 9°Y. For
instance, eight percent of patients (2/25) without bone
marrow involvement developed Grade 4 thrombocytopenia
vs. 25% (1/4) of those with 0.1-5% bone marrow
involvement, 45% (5/11) of those with 5-20% involvement,
and 100% (6/6) with 20-25% involvement (Wiseman et al.
IDEC-Y2B8 radioimmunotherapy: baseline bone marrow
involvement and platelet count are better predictors of
hematologic toxicity than dosimetry. Blood 1998
Supplement November, 92(10): 417a (1721) Poster Board #/
Session: 393-III).
It would be useful to develop methods of reducing
the marrow involvement in patients with non-Hodgkin's
lymphoma such that these patients may benefit from new
radioimmunotherapies, thereby providing another avenue
of treatment and decreasing the chance of relapse. The
present invention provides such methods.
Summary of the Invention
The present invention relates to methods of
treating patients having B cell lymphoma accompanied by
bone marrow involvement comprising administering a
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monoclonal antibody or fragment thereof such that said
bone marrow involvement is reduced or alleviated.
Specifically, the invention encompasses methods of
reducing the number of cancerous B cells in the bone
marrow of a patient having non-Hodgkin's lymphoma prior
to radioimmunotherapy comprising administering to said
patient an effective amount of a therapeutic antibody.
The methods are also useful for reducing bone marrow
involvement prior to administration of antibodies
labeled with cytotoxic moieties such as toxins, or any
immunotherapeutic which could damage healthy bone marrow
progenitors by virtue of their location in the vicinity
of targeted cells which have infiltrated the bone
marrow.
Preferably, anti-CD20 antibodies are used, although
antibodies to other B cell surface markers may also be
used, e.g., anti-CD19 antibodies. The cell surface
protein which is targeted should have the
characteristics of being expressed mainly on cancerous B
cells and not generally on normal cells or B cell
precursors, and preferably does not shed, internalize or
modulate upon being bound by antibody.
The term antibody "fragments" includes any
therapeutically effective portion or derivative of a
therapeutic antibody, which is effective to bind to the
intended target and produce the intended result.
Included are Fab2 fragments, Fab fragments, Fv fragments,
domain-deleted antibodies, etc. Preferably, the
antibodies used in the present invention are human,
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chimeric or humanized antibodies, such that the
antibodies contain human constant region domains capable
of stimulating human effector functions. A preferred
antibody is the chimeric anti-CD20 antibody, Rituximab°
(marketed as Rituxan° in the U.S. and Mabthera° in
Britain).
The patients who will most benefit from the present
invention will be patients who have greater than 25%
bone marrow involvement before being treated with the
disclosed immunotherapy. Such patients may be
identified by prior diagnostic imaging using antibodies
radiolabeled with gamma-emitting isotopes such as 1'lln.
Such patients may also be identified following bone
marrow biopsy.
According to a study by Wiseman et al., such
patients have a very high chance of developing
thrombocytopenia due to radioimmunotherapy. However, as
the chance of developing such an adverse reaction
following radioimmunotherapy increases depending on the
extent of bone marrow involvement, any patient with any
level of bone marrow involvement will benefit from the
present invention in that they will benefit from a
decreased risk of radioimmunotherapy-induced
thrombocytopenia following the disclosed treatment.
The dosages to be used in the present invention may
vary depending on the patient, the extent of bone marrow
involvement, and the antibody used. Chimeric anti-CD20
antibody such as Rituximab~ may be administered at a
dosage of at least about 50 mg/m2 weekly for at least 4
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weeks. A preferred dosage regimen is about 375 mg/m2
weekly for four weeks.
Because the purpose of the methods of the present
invention is to decrease the bone marrow involvement in
patients with lymphoma preparing to undergo
radioimmunotherapy, the treatment methods of the present
invention naturally encompass treatment with a
radiolabeled antibody subsequent to purging of the
marrow., The radiolabeled antibody may also be directed
to any B cell surface marker which is found generally on
cancerous cells and not normal cells. Preferably, the
radiolabeled antibody is an anti-CD20 antibody.
Preferred radiolabels are beta emitting isotopes
such as 9°Y or 1311, but any radioisotope may be used so
long as it may be effectively conjugated to the
antibody, it has a relatively short decay range, and it
succeeds in killing nearby cells, i.e., the cells to
which it is targeted. A preferred radiolabeled anti-
;CD20 antibody is Y2B8.
A patient should generally be treated within one
week after administration of the depleting antibody, so
long as they are not severely cytopenic, e.9., platelets
<150,000. If the patient is cytopenic following
treatment with the depleting antibody, recovery should
be allowed to occur, e.g. nadir AGC >1000 or platelets
>150,000, before radioimmunotherapy. In cases where
cell recovery in the peripheral blood and/or bone marrow
is permitted to occur, more depleting antibody may be
administered directly before immunotherapy. Such a
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secondary dosage may be administered, for example, at
about 250 mg/m2 for about two weeks directly before or
overlapping with radioimmunotherapy.
Dosages of radiolabeled antibodies will also vary
depending on the patient, the antibody specificity,
half-life, stability, etc., and of course, the extent of
disease. Radiolabeled anti-CD20 antibodies like Y2B8
are administered at a dosage of about 0.1 to 0.5 mCi/kg.
It. should be clear that the treatment methods
disclosed herein may be combined with other known
treatment methods such as chemotherapy or radiotherapy.
Bone marrow or peripheral blood stem cells may be
harvested from said patient subsequent to treatment with
anti-CD20 antibody and prior to treatment with said
radiolabeled antibody in order to effect autologous bone
marrow or stem cell transplantation after radiotherapy.
It may also be useful to treat patients with
cytokines in order to upregulate the expression of CD20
;or other target protein on the surface of cancerous B
cells prior to administration of the depleting antibody
or the radiolabeled antibody. For upregulation of CD20,
cytokines useful for this purpose are IL-4, GM-CSF and
TNF-alpha. Cytokines may also be administered
simultaneously with or prior to or subsequent to
administration of the depleting antibody or radiolabeled
antibody in order to stimulate immune effector
functions. Cytokines useful for this purpose include
interferon alpha, GM-CSF and G-CSF.
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Chemotherapeutic regimens may be used to supplement
the therapies disclosed herein, and may be administered
simultaneously with or sequentially in any order with
administration of said radiolabeled antibody. The
chemotherapy regimen may be 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 withp.ut subsequent G-CSF treatment), VAD, M & P, C-
Weekly, ABCM, MOPP and DHAP. A preferred
chemotherapeutic regimen is CHOP.
The methods of the present invention may be used to
treat a variety of B cell lymphomas but are particularly
useful wherein said B cell lymphoma is non-Hodgkin's
lymphoma (NHL). Rituximab~ has already been approved
for the treatment of low-grade-follicular NHL, but the
present inventors have surprisingly found that
Rituximab~ is also beneficial for the treatment of
intermediate- and high-grade NHL, including bulky
disease. Accordingly, the lymphomas which are treatable
by the methods of the present invention include 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 noncleaved cell NHL,
bulky disease NHL, mantle cell lymphoma, AIDS-related
lymphoma and Waldenstrom's Macroglobulinemia, so long as
such lymphomas are accompanied by bone marrow
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involvement which complicates the availability of
radioimmunotherapy.
Exemplary treatment conditions will now be
illustrated by way of the following data.
Radioimmunotherapv of Relapsed or Refractory Non-
Hodgkin's Lymphoma (NHL): Y2B8 Phase I/ II 9°Y Trial
This Phase I/II trial included 58 r2lapsed or
refractpry NHL patients, median age 60, 43% bone marrow
involvement, 60% bulky lesions > 5 cm (White et al.
Poster Presentation at VII International Conference on
Malignant Lymphoma, Lugano, Switzerland. Annals of
Oncology Suppl. 3 (1999) 10:64(215)). All patients had
dosimetry by gamma camera measurements and by serial
urine and blood sampling following administration of 5
mCi of 111In-labeled antibody In2B8. Prior to imaging
and therapy, Rituximab° was used to clear peripheral B-
cells and optimize radiolabeled antibody distribution.
One week later, Y2B8 (0.2, 0.3 or 0.4 mCi/kg) was
administered to Group 2 & 3 patients. No bone marrow or
stem cell harvest was performed.
Results:
The MTD was 0.4 mCi/kg (0.3 mCi/kg for patients
with mild thrombocytopenia). Adverse events were mainly
hematologic, transient and reversible. Overall, 5
patients (10%) developed nadir platelet counts
<10,000/mm3 and 14 patients (28%) developed nadir AGC
<500. Three patients (6%) acquired infections requiring
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hospitalization over a one year observation period.
Only 2% developed HAMA/HACA. Mean serum immunoglobulins
remained normal over a one year observation period. The
ORR was 67% (26% CR and 41% PR) in all histologies and
82% for patients with low-grade NHL. The median TTP was
12.9+ months for responders, and the duration of
response was 11.7+ months as projected by Kaplan Meier
methodology. In patients with baseline splenomegaly,
4/8 (50%) patients responded compared to 74% (29/39)
without splenomegaly (p= 0.1761). Two clinical
parameters, baseline platelet counts and degree of bone
marrow involvement in baseline biopsy, were better at
predicting severity of hematologic toxicity than
dosimetry parameters.
