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Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin's Lymphoma

Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin's Lymphoma

ABSTRACT: The field of radioimmunotherapy for the treatment of non-Hodgkin's lymphoma (NHL) has advanced significantly over the past decade, and several radioimmunoconjugates are being tested in clinical trials. Two of these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeled tositumomab (Bexxar). Other agents target either CD22 (Y-90 epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1), respectively. In February 2002, Y-90-labeled ibritumomab tiuxetan became the first radioimmunoconjugate to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Tositumomab/I-131 tositumomab was approved in June 2003. Thus, two radioimmunoconjugates have been approved for the treatment of NHL. Both agents, when administered as a single dose, have produced impressive tumor response rates with an acceptable toxicity profile. The main side effect is reversible myelosuppression. Radioimmunotherapy produces overall response rates of approximately 80% in patients with low-grade lymphomas, and 25% to 30% of patients achieve a complete remission. Lower response rates (approximately 40%) have been reported in patients with large-cell lymphomas. This review discusses the clinical trials of radioimmunotherapeutic agents for NHL that demonstrated their safety and efficacy and outlines the current status of these agents.

The rationale for the development
of radioimmunotherapy is
based on the knowledge that
non-Hodgkin's lymphoma (NHL) is
sensitive to external-beam irradiation.
The goal of linking a radionucleotide
to an antibody is to deliver a focused
field of radiation to the cell population
that the antibody targets, while
sparing nearby normal organs. The
cytotoxicity of these agents occurs
through the direct effect of the antibody
(such as antibody-dependent
cellular cytotoxicity), as well as the
effects of the ionizing radiation.

An ideal target antigen for radioimmunotherapy
is one that is expressed
on tumor cells but not on
normal cells, and is not internalized
or shed from the cell surface. The
currently available radioimmunconjugates
target the surface antigens
CD20, as in the case of tositumomab/
iodine-131 (I-131)-labeled tositumomab
(Bexxar) and yttrium-90 (Y-90)-
labeled ibritumomab tiuxetan
(Zevalin)[1]; CD22, as in the case of
epratuzumab (hLL2 [LymphoCide]);
and human leukocyte antigen (HLA)-
DR, as in the case of Lym-1.

The efficacy of a radioimmunoconjugate
is dependent on several factors:
(1) the type of antibody used
(murine, humanized) along with its
specificity, affinity, and mechanism
of action; (2) the properties of the
antigen being targeted (some antigens
are shed into the circulation or internalized);
(3) the emission properties
of the radionuclide and its stability
and pathways of metabolism and excretion;
(4) the histology of the tumor
being targeted (low-grade NHL showing
a higher overall response rate than
large-cell NHL); (5) the size, site, radiosensitivity,
and vascularization of
the target tumor; and (6) factors such
as bone marrow, other normal organ
functions, and the number and type of
prior therapies.[2,3]

Initial studies used polyclonal antibodies,[
4] but the antibodies currently
used for radioimmunotherapy are
either monoclonal, murine, or human.[
2] The administration of a cold
antibody prior to the radiolabeled antibody
has been shown to improve
tumor-to-normal organ biodistribution
and deplete normal B cells.[5] The
antibodies used in I-131 tositumomab
and Y-90-labeled ibritumomab tiuxetan
to deliver radiation are murine in
origin. In Y-90-labeled ibritumomab
tiuxetan, the cold antibody used as a
predose is rituximab (Rituxan), whereas
in I-131 tositumomab it is tositumomab.
Epratuzumab is an example
of a humanized antibody being used
for radioimmunotherapy.

At present, the two main radionucleotides
used in clinical radioimmunotherapy
are Y-90 and I-131.
Copper-67 (Cu-67) is also available
and has been used in a limited number
of studies. The I-131-labeled antibodies
are gamma emitters and can
be used for imaging and dosimetry.
Y-90-labeled antibodies are beta emitters
and cannot be used for imaging;
thus, indium-111 (In-111) is used for
tumor imaging and dosimetry as a
surrogate for Y-90. The differences
between these two agents that affect
their clinical use are outlined in Tables
1 and 2. The properties of these
radiolabels potentially could be used
to individualize therapy, but to date,
this strategy has not been studied.[2]

Clinical trials of anti-CD20 radioimmunotherapy
(I-131 tositumomab
and Y-90-labeled ibritumomab tiuxetan)
designed to assess efficacy and
safety were limited to patients with
relapsed disease, excellent bone marrow,
and normal organ function. Exclusion
criteria included central
nervous system lymphoma, human
immunodeficiency virus (HIV) infection
or HIV-related NHL or chronic
lymphoctic leukemia (CLL), pleural
or peritoneal fluid positive for lymphoma,
or known myelodysplasia.[1]

Ibritumomab TiuxetanCharacteristics
Ibritumomab is a murine anti-
CD20 antibody attached to tiuxetan,
an MX-DTPA linker-chelator, to form
Y-90-labeled ibritumomab tiuxetan.
Ibritumomab is the murine parent of
the anti-CD20 antibody from which
the human chimeric antibody rituximab
was engineered. In February
2002, it became the first radioimmunotherapy
to be approved by the US
Food and Drug Administration (FDA)
for the treatment of cancer.

For dosimetry and tumor imaging,
ibritumomab tiuxetan is reacted with
In-11; for therapy, it is linked with
Y-90. With the use of In-111-labeled
ibritumomab tiuxetan, images of the
tumor and normal organs are produced
for dosimetry and biodistribution studies.[
6] The therapeutic dose of Y-90-
labeled ibritumomab tiuxetan is
determined by the patient's weight
and baseline platelet count. If the
platelet count is normal, the recommended
dose is 0.4 mCi/kg; if the
platelet count is between 100 and
150,000 cells/mm3, the dose is
0.3 mCi/kg. For patients who weigh
≥ 80 kg, the dose is capped at 32 mCi.
Patients are given rituximab at
250 mg/m2 and 5 mCi of In-111-
labeled ibritumomab tiuxetan on day 1
followed by tumor imaging over the
next few days. At least two to three
images are required by the FDA to
ensure normal biodistribution. On
day 8, patients receive another dose
of rituximab followed by Y-90-
labeled ibritumomab tiuxetan.[5,7]

The safety data accumulated from
studies of Y-90-labeled ibritumomab
tiuxetan have shown that myelosuppression
is the most common side effect,
with 27% to 30% of patients
experiencing grade 4 neutropenia and
about 10% experiencing grade 4
thrombocytopenia.[7] However, only
7.6% of patients were hospitalized
with infections, and physicians need
to be aware of the delayed nadir
counts; unlike chemotherapy, platelet
counts usually nadir about 7 to
9 weeks following therapy.[7,8]

Clinical Trials

  • Phase I Trials-Two phase I trials
    of Y-90-labeled ibritumomab tiuxetan
    were performed. The first trial
    used cold ibritumomab as the predose
    and enrolled patients with relapsed
    low- or intermediate-CD20-positive
    B-cell NHL.[5] Stem cells were harvested
    from the peripheral blood or
    marrow of all patients prior to treatment
    with Y-90-labeled ibritumomab
    tiuxetan. The overall response rate was
    79%, with complete remissions in
    36% and partial remissions in 43%.
    Two patients (both had received
    50 mCi of Y-90-labeled ibritumomab
    tiuxetan) required reinfusion of stem
    cells. A comparison of two sets of In-
    111-labeled ibritumomab tiuxetan
    images showed that predosing with
    cold antibody improved the biodistribution
    of Y-90-labeled ibritumomab
    tiuxetan.

    The second phase I study tested
    the use of rituximab rather than cold
    murine ibritumomab before administration
    of Y-90-labeled ibritumomab
    tiuxetan to determine the maximum
    tolerated dose of the radiolabeled an-
    tibody without stem cell support.[7]
    Rituximab was used to lower the risk
    of human antimurine antibody
    (HAMA) and to potentially add
    efficacy. A total of 51 previously
    treated patients were enrolled. The
    optimal rituximab dose was found to
    be 250 mg/m/2, although higher doses
    were not studied. Y-90-labeled ibritumomab
    tiuxetan doses ranged from
    0.2 to 0.4 mCi/kg; no higher doses
    were used, given the risk of substantial
    myelosuppression and because
    stem cells were not collected prior to
    administration of the radiolabeled
    antibody. The overall response rate
    was 67%, and 26% achieved a complete
    remission. Patients with lowgrade
    NHL had a higher response
    rate (82%) than did patients with
    large-cell NHL (43%).

  • Phase II Trials-A phase II trial
    using 0.3 mCi/kg of Y-90-labeled
    ibritumomab tiuxetan was conducted
    in 30 patients who were previously
    treated with chemotherapy and had
    low platelet counts (100,000 to
    149,000 * 106/L). The overall response
    rate was 83%, with 43%
    achieving a complete remission. The
    most common toxicity was reversible
    myelosuppression.[9]
  • Trials Comparing Ibritumomab
    Tiuxetan With Rituximab
    -In a pivotal
    study comparing the efficacy of
    Y-90-labeled ibritumomab tiuxetan vs
    rituximab, 143 patients with relapsed
    NHL and no prior rituximab therapy
    were randomized to receive the radiolabeled
    antibody or rituximab.[8] Patients
    received either 0.4 mCi/kg
    (maximum: 32 mCi) of Y-90 ibritumomab
    tiuxetan or rituximab at
    375 mg/kg/wk * 4. Those randomized
    to Y-90 ibritumomab tiuxetan
    had an overall response rate of 80%
    and a complete remission rate of 30%,
    compared to 56% and 16%, respectively,
    in the rituximab arm.

    Another study tested the effect of
    Y-90-labeled ibritumomab tiuxetan
    after rituximab therapy had failed.[10]
    Among the 54 patients who were treated
    with the radiolabeled antibody at
    0.4 mCi/kg, the overall response rate
    was 74%, with 15% achieving a complete
    remission.

Therapy After
Radioimmunotherapy

Unfortunately, about 70% of patients
will relapse after a single dose
of Y-90 ibritumomab tiuxetan, requiring
additional treatment. To address
the question of tolerability of subsequent
therapy, investigators studied
58 patients who had relapsed after
treatment with 0.4 mCi/kg of Y-90
ibritumomab tiuxetan.[11] Peripheral
stem cell collection was feasible in
these patients, and all recipients of
autologous transplantation achieved
adequate engraftment. Growth factor
support with chemotherapy was required
in 28%, and two patients received
reduced doses of chemotherapy
because of persistent cytopenias.

Safety
A report on the safety of Y-90-
labeled ibritumomab tiuxetan in 349
patients treated in five studies[12] and
followed for up to 4 years or until
disease progression showed that the
main toxicity was myelosuppression,
with nadir counts occurring at 7 to 9
weeks for a duration of approximately
1 to 4 weeks. Patients with bone
marrow involvement by NHL had a
significantly greater incidence of
grade 4 hematologic toxicity, and the
greater the bone marrow involvement,
the higher the incidence of grade 4
myelosuppression. Grade 1/2 infusion-
related toxicities were associated
with rituximab, and no further
reactions were noted when Y-90-
labeled ibritumomab tiuxetan was
administered.

Myelodysplasia or acute myelogenous
leukemia was reported in 1% of
patients after 8 to 34 months of therapy.
However, all of these patients had
received prior alkylating agents. The
HAMA rate was less than 1%, compared
to 8% to 10% for I-131 tositumomab.
The clinical implications of
a positive HAMA (and whether it will
eventually resolve) are unclear at this
time.

TositumomabCharacteristics
Tositumomab is an IgG2a murine
monoclonal antibody directed against
CD20 that is radiolabeled with I-131
to form I-131 tositumomab. The FDA
approved tositumomab/I-131 tositumomab
in June 2003. As described
previously, I-131 tositumomab can be
used for dosimetry and treatment because
it emits both gamma and beta
radiation.[13] Dosimetry is used to
calculate the therapeutic dose of
I-131 tositumomab for each patient,[
14] which varies with differences
in body mass, tumor burden,
metabolism, and renal excretion of
I-131.[14-16] The therapeutic dose is
administered within 7 to 14 days of
the dosimetric dose and consists of
450 mg of tositumomab followed by
a 20-minute infusion of the patientspecific
dose of I-131 tositumomab.
Because of the concentration of iodine
in the thyroid, a saturated solution
of potassium iodide (SSKI,
Lugol's solution) is started 1 day before
tositumomab and is continued
for 2 weeks after the therapeutic dose
is given.

The side effects of I-131 tositumomab[
17] include a transient flu-like
syndrome that may develop after infusion;
toxicity during infusion is uncommon.
The incidence of HAMA is
about 10%. Reversible myelosuppression
is the most common adverse
event, with 16% of patients experiencing
grade 4 neutropenia for a median
duration of 11 days. The platelet
count nadirs about 32 days after I-131
tositumomab administration, and approximately
2% of patients develop
grade 4 thrombocytopenia for a median
duration of 14 days.

Similar to the experience with
Y-90-labeled ibritumomab tiuxetan,
patients with bone marrow involvement
by NHL had a higher incidence
of hematologic toxicity (21% vs 12%
grade 4 neutropenia). In addition, patients
previously treated with chemotherapy
had a 21% incidence of grade
4 neutropenia, compared to 5% among
those with no prior chemotherapy.
Myelodysplasia has developed in a
small number of patients treated with
I-131 tositumomab.[18] However, all
these patients had been previously
treated with chemotherapy, and to
date, no treated patients who did not
receive prior chemotherapy have
developed myelodysplastic syndrome.[
19]

Clinical Trials

  • Phase I Trials-The phase I trial
    of I-131 tositumomab was designed
    to determine the dose that could be
    administered without stem cell support.[
    16,20,21] The dose-limiting toxicity
    was myelosuppression, and the
    maximum tolerated dose was 75 cGy
    to the whole body. A 475-mg dose of
    cold tositumomab was given before
    the dosimetric and therapeutic doses
    of the radiolabeled antibody. The
    overall response rate in this phase I/II
    trial was 71% (42/59) with a 34%
    (20/59) complete remission rate. Patients
    with low-grade or transformed
    NHL had an overall response rate of
    83%, compared to 41% in those with
    intermediate-grade NHL.

    To address the concern about myelosuppression,
    another phase I trial
    was conducted in which I-131 tositumomab
    administration was followed
    by an infusion of stem cells.[22] A total
    of 43 patients were enrolled and
    their stem cells harvested before they
    received I-131 tositumomab. Of these
    patients, 19 were able to receive the
    therapeutic dose of I-131 tositumomab,
    followed 12 to 18 days later (after
    radioactivity ceased) by stem cell
    reinfusion. Neutrophil recovery occurred
    after a median of 23 days, and
    platelet recovery to 20,000 cells/mm3
    after a median of 22 days. HAMA was
    detected in 16% of patients. The overall
    response rate was 95%, with 84%
    achieving a complete remission.

  • Phase II Trials-A phase II trial
    was conducted in 47 patients with
    relapsed low-grade or transformed
    NHL. All patients had previously been
    treated with a median of four chemotherapy
    regimens.[23] Depending on
    their baseline platelet count, they were
    given either 75 cGy to the whole body
    (those with a platelet count > 150,000
    cells/mm3) or 65 cGy (those with a
    platelet count between 100,000 and
    150,000 cells/mm3). The overall response
    rate was 57%, and 32%
    achieved a complete remission. At last
    follow-up, six patients remained in
    complete remission for durations of
    26.9+ to 33.8+ months.

    After the phase I trial of I-131 tositumomab
    followed by stem cell infusion,
    a phase II study that enrolled 25
    patients was conducted using the same
    protocol.[24,25] The overall response
    rate was 86%, with a 76% complete
    remission rate. The study was then
    expanded to combine I-131 tositumomab
    with cyclophosphamide (Cytoxan,
    Neosar) and etoposide followed
    by autologous stem cell support.[26]
    This protocol demonstrated that the
    combination of radioimmunotherapy
    and chemotherapy could be safely
    administered to patients; estimated
    overall and progression-free survival
    rates at 2 years were 83% and 68%,
    respectively. A similar study performed
    in patients with mantle cell
    lymphoma showed a 91% tumor response
    rate, with overall and progression-
    free survival rates at 3 years of
    93% and 61%, respectively.[27]

  • I-131 Tositumomab Radioimmunotherapy
    vs Chemotherapy
    -A
    pivotal trial with I-131 tositumomab
    compared radioimmunotherapy to
    chemotherapy.[18] The trial was designed
    to compare the overall response
    rates associated with I-131 tositumomab
    and the last chemotherapy regimen
    the patient had received. The
    overall response rate was 65% for
    I-131 tositumomab, with a 17% complete
    remission rate, compared to 28%
    and 3%, respectively, for chemotherapy.
    A longer duration of response was
    seen in 78% of patients treated with
    I-131 tositumomab vs 22% of patients
    in the chemotherapy arm. The median
    duration of response for I-131 tositumomab
    was 6.5 months, compared
    with 3.4 months for chemotherapy.

    Another important finding in this
    study was that the overall response
    rate in patients with low-grade NHL
    was 81%, with 19% achieving a complete
    remission, compared to a 39%
    overall response rate and 13% complete
    remission rate in patients with
    transformed histology.

  • I-131 Tositumomab vs Cold Tositumomab-
    A study comparing cold
    tositumomab to I-131 tositumomab
    in 78 patients with relapsed low-grade
    and transformed NHL demonstrated
    an overall response rate of 67% (33%
    complete remission) in the I-131 tositumomab
    arm, compared to 28% (8%
    complete remission) in the cold tositumomab
    arm.[28] The 19 patients
    with disease progression in the cold
    tositumomab arm were subsequently
    treated with I-131 tositumomab; 17
    (89%) responded, with 42% achieving
    a complete remission.
  • I-131 Tositumomab vs Rituximab-
    I-131 tositumomab has also
    been tested in patients previously exposed
    to rituximab. This is an important
    issue because many patients
    receive rituximab early in the course
    of their disease.[29] The study treated
    38 patients, of which 88% were
    refractory to rituximab, 68% had received
    at least four prior chemotherapy
    regimens, and 32% had marrow
    involvement. Responses were
    achieved in 58% of patients, with a
    21% complete remission rate. Among
    patients refractory to rituximab, the
    overall response rate was 57%, with a
    14% complete remission rate.
  • Other Studies of I-131 Tositumomab-
    Patients with transformed
    large-cell NHL who are not eligible
    for stem cell transplantation are difficult
    to cure. A retrospective study addressing
    this group analyzed 71
    patients with transformed NHL treated
    with I-131 tositumomab.[30] Many
    of these patients had poor prognostic
    factors (International Prognostic Index
    of 3 in 52%, elevated lactate dehydrogenase
    in 57%, bulky disease in
    70%). The overall response rate was
    39%, with a 25% complete remission
    rate; five patients remain in remission
    beyond 40 months.

    The experience with re-treatment
    with I-131 tositumomab is limited. A
    report of 13 patients re-treated with
    I-131 tositumomab showed an overall
    response rate of 62% with a 31%
    complete remission rate.[31] None of
    the patients developed grade 4 hematologic
    toxicity.

    The only study that evaluated radioimmunotherapy
    in previously untreated
    patients was conducted by
    Kaminski et al.[32] This study enrolled
    76 patients with advanced follicular
    lymphoma, of which 63% had
    bone marrow involvement by NHL.
    The overall response rate was 95%,
    with a 74% complete remission rate.
    The 5-year progression-free survival
    rate for all patients was 62.3%, and
    patients who achieved a complete remission
    had a longer progression-free
    survival. The major toxicities included
    HAMA in 63% of patients and
    hypothyroidism in 7%. To date, none
    of the patients have developed myelodysplastic
    syndrome. The high incidence
    of HAMA in this study (as
    opposed to a 10% incidence in studies
    with previously treated patients) is
    most likely related to the competency
    of the immune system in previously
    untreated patients. Whether the presence
    of HAMA has an impact on
    future treatment with I-131 tositumomab
    is unknown. It is possible that,
    with time, the HAMA response will
    disappear.

    Prior to FDA approval and outside
    of a formal clinical trial, a study enrolled
    368 patients with relapsed lowgrade
    or transformed NHL in 53
    community and academic sites.[33]
    The overall response rate was 58%,
    with 27% achieving a complete remission.
    The overall response rate
    among rituximab failures was 47%,
    with a 19% complete remission rate.

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