What is radio-immunotherapy (RIT)?
 When your body detects something that does not belong, such as
bacteria (pathogen), one way it eliminates the threat is to produce antibodies
that bind to the protein shapes that are specific to the
pathogen.
RIT agents are man-made antibodies with different radiation components
attached. These antibodies are designed to bind to a protein
shape called CD20, which sticks out of mature B lymphocytes (immune
cells), both malignant and nonmalignant (cancerous and normal).
...
... Importantly, the cd20 shape (or antigen / receptor) is not found on precursor B cells
- immature b-cells which can later mature to replenish the supply of
normal mature b-cells.
RIT is considered a targeted therapy, because the antibodies that
deliver the radiation are specific to one type of cell. RIT is more potent
than unlabeled antibody therapy, such as Rituxan, but it also has
unique potential risks.
Importantly, there is clinical data showing that RIT is very potent and can induce
complete responses that are very durable (measured in years), even in
heavily pretreated
patients. (See RIT
abstracts below.) RIT
is given in therapeutic steps (1)
The initial antibody dose ("cold" or "naked"
antibody) clears the body of normal b-cells so that subsequent
doses will be more focused on tumor cells. (2)
The second "warm" dose has anti-tumor effects, but
also helps calculate the optimal final dose based on uptake of the drug
and individual clearance rates as determined by imaging of the gamma radioactive
element. (3) The final "hot"
dose has has the most potent anti-tumor effects, and is focused on
tumor cells, because prior doses have cleared the body of normal
b-cells.
Possible
mechanisms of radio-immunotherapy tumor killing
When radio-labeled antibody binds to tumor cells it can cause tumor
killing by
(1) Self-killing (apoptosis) - programmed cell death triggered by the
antibody
(2) Complement-dependent cytotoxicity (CDC) - where antibody fixes
complement that kills the tumor cells
(3) Antibody-dependent cellular cytotoxicity (ADCC) - where effector
cells (immune cells) kill the tumor cells
(4) Ionizing radiation from the radioisotope damages the tumor cells,
leading to cell death
(5) Vaccine-like effect - leading to adaptive immunity against cells
that may survive initial treatment
PERSPECTIVE: While your doctor is not
likely to prescribe what he or she cannot offer in their treatment
center, we believe that this should not limit the treatments you
consider. Your doctor's permission is not required in order to consult
outside experts about use of RIT.
Ideally, your local oncologist will help you to determine how appropriate
RIT therapy is for you. We recommend that you consult an
independent lymphoma expert to discuss and evaluate all appropriate therapy options.
ALERT: Economic Interests Threatens Threaten
Proven RIT Cancer Therapy Patient commentary
Radioimmunotherapy Background Articles
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Radioimmunotherapy for
Non-Hodgkin’s Lymphoma clinmedres.org
Arati V. Rao, MD, Gamal Akabani, PhD and David A. Rizzieri, MD |
|
Perspectives on RIT therapy
Robert M. Sharkey, PhD; and David M. Goldenberg, ScD, MD interactive.snm.org |
|
Radioimmunotherapy in the treatment
of low grade b-cell lymphoma cecity.com/nocr/ash2003
pdf |
|
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| Radioimmunotherapy of B-Cell Non-Hodgkin’s
Lymphoma: From Clinical Trials to Clinical Practice
Malik E. Juweid, MD http://jnm.snmjournals.org |
| Novel Concepts in Radioimmunotherapy for
Non-Hodgkin's Lymphoma www.cancernetwork.com
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TOPIC SEARCH Bexxar: Mechanisms PubMed
Outcome ASCO
| Medscape |
PubMed
Safety ASCO
| PubMed
TOPIC SEARCH Zevalin: Mechanisms PubMed
Outcome ASCO
| Medscape |
PubMed
Safety ASCO
| PubMed
RIT reports with a
focus on duration of remissions
Patient
perspective: Durable remissions reduce the need for multiple toxic treatments, which have been found by experts* to result in diminished response rate and duration of response. Furthermore, achieving a durable remission can substantially
improve quality of life independent of symptoms by reducing the anxiety associated with living with active or dormant
disease - particularly when the improved duration of the remissions is measured in years, suggesting a chance of cure.
* Each
Subsequent Therapy Results in Diminishing Response Rate and
Duration of Response in Low Grade or Transformed Low Grade
NHL ASCO
2001
"Evaluation of response and duration of response in these
sixty patients to all prior chemotherapies re-confirmed the
previously published experience showing diminished response and
duration of response with each subsequent chemotherapy.
In this same patient population the duration of response to the
most recent chemotherapy was 4 months. However, upon relapse,
subsequent treatment with Bexxar (a type of RIT) provided a 10
month duration of response (p=<0.001 ). An independent
radiology and oncology review panel confirmed these
findings.
The high incidence of multiple relapses and the enduring decrease
in both response and duration of response to subsequent
therapy further reinforces the need for novel therapies for the
treatment of LG or Transformed LG NHL. New treatment options
are necessary to provide greater clinical benefit evidenced
by both response and duration of response."
Update: Bexxar® Provides Years of Lasting Activity as Initial Therapy in
Follicular Lymphoma patient.cancerconsultants.com
* Overall survival at 10 years was 86%.
* Anticancer responses were achieved in 95% of patients.
* A complete disappearance of detectable cancer (complete
remission) was achieved in 75% of patients.
* The median time for cancer progression among patients who
achieved a complete remission was 9.2 years.
|
Targeted
Radio-Immunotherapy with Bexxar Produces
Durable Remissions in Patients
with Late Stage Low Grade Non-Hodgkin's
Lymphomas.
Trans Am Clin Climatol Assoc. 2004;115:255-72. PMID:
17060972
Response rates were 56% (overall) and 30% (complete). With a
median follow-up of 44.6 months,
30% of the patients achieved a long-term, durable response; median
time to progressive disease
or death was 5 years. |
|
Bexxar
radioimmunotherapy
for relapsed or refractory B-cell non-Hodgkin
lymphoma:
updated results and long-term follow-up of the University of
Michigan experience.
Blood. 2000 Aug 15;96(4):1259-66. PMID:
10942366 | Related
abstracts
For all 42 responders, the median progression-free
survival was 12 months, 20.3 for those with CR.
Seven patients remain in CR 3 to 5.7 years. Sixteen
patients were re-treated after progression;
9 responded and 5 had a CR. Reversible hematologic toxicity was
dose limiting. |
|
Efficacy
and safety of Bexxar in B-cell
lymphoma, progressive after rituximab.
J Clin Oncol. 2005 Feb 1;23(4):712-9. Epub 2004 Dec 21. PMID:
15613695
the OR and CR rates were 86% and 57%. Estimated
3-year Progression Free Survival (PFS) in
this subgroup was 48%, compared with 11% for all others (P =
.002).
Transient grade 3 to 4 marrow toxicity was seen in 50% of
patients. Two patients, one of whom received two subsequent
chemotherapy regimens, developed secondary myelodysplasia.
CONCLUSION: (131)I tositumomab is effective in CD20-positive
lymphoma progressive after rituximab,
with a 65% OR rate and median Progression Free Survival (PFS)
of 24.5 months for responders.
Patients with follicular grade 1 or 2 histology and tumors < or
= 7 cm achieved very high OR and
CR rates, with 48% PFS at 3 years.
|
|
Bexxar:
novel radioimmunotherapy for the treatment of low-grade
and transformed low-grade
non-Hodgkin's lymphoma.
Oncologist. 2004;9(2):160-72. Review. PMID:
15047920
In clinical trials of Bexxar, objective response rates ranged
from 54%-71% in heavily pretreated patients.
In the pivotal trial, the number of patients with a longer
duration of response after treatment with Bexxar
was significantly greater than the number of patients with a
longer duration of response after their
last qualifying chemotherapy regimen. In 76 newly diagnosed
patients, the objective response
rate was 97%, and 63% of patients achieved complete responses. |
|
A clinical
and scientific overview of tositumomab (Zevalin)
and iodine I 131 tositumomab (Bexxar).
Semin Oncol. 2003 Apr;30(2 Suppl 4):22-30. Review. PMID: 12728404
"these studies show that tositumomab and iodine I 131
tositumomab treatment is safe and
induces high response rates and durable remissions in heavily
pretreated patients with
low-grade or transformed low-grade NHL" |
|
Tositumomab
(Zevalin) and iodine-131
tositumomab (Bexxar) produces
durable complete remissions
in a subset of heavily pretreated patients
with low-grade and transformed non-Hodgkin's lymphomas.
J Clin Oncol. 2005 Oct 20;23(30):7565-73. Epub 2005 Sep 26. PMID:
16186600
Response rates in the five trials ranged from 47% to 68%; CR
rates ranged from 20% to 38%.
With a median follow-up of 5.3 years, the 5-year progression-free
survival was 17%.
Eighty-one (32%) of 250 patients had a time to progression of >
or = 1 year
(termed durable response population). For the durable
response population, 44% had not progressed
at > or = 2.5 to > or = 9.5 years and had a median duration
of response of 45.8 months.
The median duration of complete response was not reached. The
durable response population had many
poor prognostic characteristics, including bone marrow involvement
(41%), bulky disease > or = 5 cm (49%),
and transformed histology (23%). Forty-three percent of the
patients had been treated with more than four prior therapies and
36% had not responded to their most recent therapy. |
|
Zevalin
radioimmunotherapy produces high response rates and durable
remissions
in patients with previously treated B-cell
lymphoma.
Clin Lymphoma. 2004 Sep;5(2):98-101. PMID:
15453924 | Related
abstracts
In patients achieving a CR/CRu, the median TTP was 24.7 months
for patients treated
with 90Y ibritumomab tiuxetan compared with 13.2 months for
rituximab-treated patients (P = 0.41),
and ongoing responses of > 5 years have been observed. |
|
Durable
responses after ibritumomab tiuxetan radioimmunotherapy (Zevalin)
for
CD20+ B-cell lymphoma:
long-term follow-up of a phase 1/2 study.
Blood. 2004 Jun 15;103(12):4429-31. Epub 2004 Mar 11. PMID:
15016644
"Nine patients (24% of responding patients) had a TTP
of more than 3 years.
Long-term responders (> 5 years) have been identified." |
|
Leonard JP, Zelenetz AD, Vose JM, et al. Iodine I 131 tositumomab
(Bexxar) for patients with
low grade or
transformed low grade NHL: complete response data.
Blood. 2000;96(suppl 1):728a. Abstract 3148.
Summary data on 251 patients treated on various phase 1 to 3
tositumomab trials from 1990 to 1999.
Those characteristics statistically associated
with a lower probability of achieving CR include
bulky disease, prior chemotherapy, lack of response to last
chemotherapy, and prior radiotherapy.
Nonetheless, CR rates of 30% (confirmed) to 35% (not confirmed)
may be expected in the group
as a whole, with 3-year median duration of CR in those without
confirmed CR and
almost 5 years in those with confirmed CR status. |
Bulky disease and
RIT? (Moved here)
Patient
Perspectives (seeking informed choice)
When might RIT be appropriate ... indicated ... deserving of full consideration?
| As first primary treatment
(ideally in a clinical trial) as an alternative to chemotherapy?
... particularly if chemotherapy is contraindicated or considered
high-risk for you.
|
|
As consolidation*
therapy (ideally in a clinical trials)
* Consolidation therapy is a treatment given shortly after another
treatment with the goal of
improving on the response and duration of response (also called sequential therapy)
|
| As second primary treatment,
particularly following a short response to prior treatment?
|
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When you have relapsed
from prior treatment,
and the goal of your next therapy is
to achieve a durable complete remission.
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| When the lymphoma has not responded well
(is refractory) to Rituxan?
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| As an alternative to stem cell
transplantation?
|
|
As part of the conditioning therapy
of stem cell transplantation? (Ideally in a
clinical trial)
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| As an alternative to
so-called maintenance Rituxan? (Ideally in a
clinical trial)
... particularly if maintenance Rituxan is recommended to stabilize
measurable disease,
but probably not to maintain a complete response to prior
treatment.
|
|
When transformation*
is suspected and you are not a candidate for SCT,
or, perhaps, even if you are?
*Transformation is a change in the indolent lymphoma cells that
leads
to more aggressive clinical behavior and/or resistance to standard
treatment.
|
NOTE: Clearly, the selection of treatment should be based on individual clinical details,
and a realistic assessment of the most appropriate treatment goal. We have
a concern that for non-clinical reasons* RIT is not being considered in the
many clinical centers.
Non-clinical factors that
may influence underutilization of RIT
|
Lack of awareness of the
potential of RIT to result in higher remission
rates and duration of remission among patients and some
oncologists.
|
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When insurance carriers
do not cover treatment out of network/area,
and the patient's treating physician does not offer nuclear
medicine.
|
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A conflict of interest
(even if unintended) that occurs when physicians cannot
offer the full range of therapies within their local practice.
|
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When the potential risks
of RIT are overestimated or not fully understood
by patients and physicians.
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What is the most appropriate
goal of treatment for RIT?
| Our impression is that
RIT is best used when the goal of treatment is to
potentially
cure or obtain
a durable complete remission ... and that may not be as appropriate as
management therapy, because it cannot be given at frequent intervals to control the
disease.
Therefore, if you have bulky disease, you may want to consider
de-bulking
prior to use of RIT,
as lower tumor burden is associated with better and more durable outcomes (O. Press)
See www.lymphomation.org
Pretreatment might also include stem cell harvesting.
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|
Pretreatment (sequential
therapy) can also improve the safety of RIT by
decreasing the % of bone
marrow involvement as described here:
Radioimmunotherapy in the treatment of low grade b-cell lymphoma
www.cecity.com
PDF
|
Please consider the above as ideas and factors that may guide the
discussions with your
doctor and the outside experts you may consult. It should not be regarded as
medical advice.
Questions and Comments for Experts
Comparing Sequential chemo-RIT with autologous SCT? We
believe a study comparing the following protocols would answer an
important clinical question, and would also be of interest to patients
with high-risk lymphomas referred to a transplantation center:
Sequential
HD chemo - (with harvesting), sequenced with RIT versus
Autologous SCT
Importantly, harvesting of stem cells in the
Sequential therapy arm of the study will facilitate subsequent use of
SCT should be needed.
Data on Long-term outcomes: There's a
need to conduct a meta-analysis that describes the potential long term
benefits and risks of RIT across many studies. It appears that
lacking this information, clinical decisions are defaulting to what is
less toxic in the short term and offered at the patient's local
center.
High Dose
RIT as an alternative to SCT? When is high dose (HD) radioimmunotherapy indicated? Can HD radiotherapy be used outside a clinical trial in cases where it is indicated?
Lay comment: One indication for HD RIT seems to be in preparation for stem cell
transplants, especially when conditioning chemotherapy fails to achieve a
remission.
Extranodal disease and RIT: Does mucosal
(gastric MALT) or CNS involvement preclude the use of radioimmunotherapy?
Does spleen involvement
preclude use of radioimmunotherapy?
Residual splenomegaly in a patient who has otherwise successfully
responded in other sites following chemotherapy for lymphoma is
another reason for performing a splenectomy. In these cases, the
procedure may be performed for both diagnostic and therapeutic
reasons; it can determine if the splenomegaly is due to persistent
lymphoma, and should this be true, it can potentially eliminate the
focus of residual disease. A less common indication for splenectomy
that may be seen more frequently in the future is to allow patients to
become eligible for enrollment onto novel treatment protocols. An
example of this is in patients with lymphoma refractory to
conventional chemotherapy who were treated with radioimmunotherapy
using a radiolabelled anti-CD20 antibody.
In some of these patients, splenomegaly was found to complicate
treatment, as the large organ served as an “antigen sink”,
effectively decreasing the dose of radionuclide available to treat
other sites of disease. Thus, pretreatment splenectomy
may be indicated to eliminate this complicating factor.
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57%), 
CHEMO
(34%
