Rationale for continued study of
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
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
patients. (See RIT
is given in therapeutic steps
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.
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
(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
properties of RIT
- Zevalin is an FDA
approved RIT for indolent lymphoma
- RIT has unique properties:
It takes about 1 week to give it, compared to
many months of chemotherapy.
It's the only non-chemotherapy-based approach
with a high rate of durable remissions
It's an important choice for patients:
- who must continue to work through
or shortly after treatment
- who cannot tolerate
chemotherapy, because of advanced age, or specific comorbidities
- who may prefer to limit the on-treatment side effects
specific to chemotherapy
nausea, neuropathy, hair loss, gastric, and gastric and mucositis
mechanisms of action
When radio-labeled antibody binds to tumor cells it can cause tumor
Apoptosis - programmed cell death triggered by the
Complement-dependent cytotoxicity (CDC) - where antibody fixes
complement that kills the tumor cells
Antibody-dependent cellular cytotoxicity (ADCC) - where effector
cells (immune cells) kill the tumor cells
Ionizing radiation from the radioisotope damages the tumor cells,
leading to cell death
Vaccine-like effect - leading to adaptive immunity against cells
that may survive initial treatment
Other RIT Topics
Radioimmunotherapy Background Articles
Radioimmunotherapy with tositumomab and iodine-131 tositumomab
Radioimmunotherapy of Lymphoma: Ahead of Its Time or Past Its
Tim Martin Illidge,
School of Cancer and Imaging Sciences, Manchester Academic
Health Sciences, University of Manchester, Manchester, United
"As we look to the future, few things are certain, but we can be
sure that there will continue to be increasing numbers of
patients with follicular lymphoma who are refractory to both
chemotherapy and rituximab. For the latter group, there are
compelling data that RIT can play an important role in both
chemotherapy- and rituximab refractory disease, leading to high
response rates with durable remissions."
Radioimmunotherapy review article
"Currently in the United States, RIT is mainly
used in the salvage setting; however, emerging data suggest that
to enhance patient benefit, RIT should be administered earlier
in the treatment of follicular lymphoma. In an analysis of 1,177
patients treated with 131I-tositumomab, the ORR, CR rate, and
duration of response decreased as the number of prior therapies
Rationale for Consolidation to Improve Progression-Free
Survival in Patients with Non-Hodgkin's Lymphoma: A Review of the
"With the higher CR rates and
longer Progression Free Survival (PFS) times observed in patients
with FL and DLBCL, as well as encouraging early data
from MZL and MCL consolidation trials, RIT appears to
have an important role in the treatment of patients
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
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
Randomized Controlled Trial of Zevalin Versus Rituximab
Immunotherapy for Patients With Relapsed or Refractory
Low-Grade, Follicular, or Transformed B-Cell NHL
Multicenter Phase II Study of Bexxar for
Chemotherapy-Relapsed/Refractory Low-Grade and Transformed
Low-Grade B-Cell NHL
Forty-five of 47 patients were treated with a single
dosimetric and therapeutic dose. Twenty-seven patients (57%)
had a response. The response rate was similar in patients
with low-grade (57%) or transformed low-grade (60%)
NHL. The median duration of response was 9.9 months.
Fifteen patients (32%) achieved a complete response
(CR; 10 CRs and five clinical CRs), including five
patients (50%) with transformed low-grade NHL. The
median duration of CR was 19.9 months, and six patients
have an ongoing CR. Treatment was well tolerated, with the
principal toxicity being hematologic. The most common
nonhematologic toxicities that were considered to be
possibly related to the treatment included mild to
moderate fatigue (32%), nausea (30%), fever (26%),
vomiting (15%), infection (13%), pruritus (13%), and
rash (13%). Additionally, one patient developed human-antimouse
Potential Benefits and
Risks: RIT Studies:
approved indications for RIT: "for the treatment of relapsed
or refractory low grade, follicular, or transformed B-cell
non-Hodgkin's lymphoma (NHL)."
Comparing Risks of RIT-based
therapy with Chemo-Rituxan-based therapy?
RIT, like all cancer treatments, has risks which should be
carefully considered when making treatment decisions.
should be noted that it's not possible to avoid treatment risk
(even delaying therapy has risks) and chemotherapy-based
protocols can have risks similar to RIT.
At present it's not known which approach
to treating indolent lymphomas is better (on average) for survival - an endpoint that FDA considers the only reliable measure for comparison because it accounts for both known and unknown positive and adverse effects.
risk we take cannot be separated from the potential reward
or from clinical necessity. When you sprint to escape an aggressive bear you increase the risk of breaking a leg, or having a cardiac event
... Similarly, how appropriate the risks we assume when selecting a therapy depends on the clinical circumstances and the goal of treatment.
Ultimately, only well-controlled studies with sufficient follow up will
help to determine which treatment approach provides the better chance for optimal clinical benefit, and most likely - given the variation in the disease and patients - the optimal therapy for any person
varies and will involve some chance.
the reports below indicate RIT is perhaps
the most potent agent we have at this time for indolent b-cell
lymphomas, but it also has risks, such as low platelet counts,
infections, bleeding, and myelodysplastic
syndromes (MDS), and also hypothyroidism
for bexxar. Noting that the latency
(time it takes to develop and present) for MDS - a serious
potential complication - can be quite
long. However, it should be noted that the risk of MDS also
exists for chemotherapy-based protocols.
studies have evaluated the risk for myelodysplastic
syndrome (MDS) and acute myeloid leukemia following RIT
with either 90Y-ibritumomab or 131I-tositumomab. These
retrospective analyses of large numbers of patients both
showed that RIT did not produce a higher risk for MDS in
comparison with similar patient populations treated with
multiple chemotherapies alone [90, 91]. MDS has rarely
been observed in patients treated upfront with RIT using
131I-tositumomab alone .
- Radiolabeled and
Native Antibodies and the Prospect of Cure of
for technical safety information Bexxar
your conversation with your doctor about risks and benefits, you
might also inquire about what future therapies may be precluded
(made no longer available) by use of RIT and what specific clinical factors
(such as age, areas of involvement, previous therapies) may increase or reduce risk
as described in the following technical paper.
* Prediction of Hematologic Toxicity After Radioimmunotherapy with I-Labeled
* Subsequent therapy can be administered after
tositumomab and iodine I-131 tositumomab
for non-Hodgkin lymphoma. Cancer. 2005 Dec 16; PMID:
* Re-Treatment With I-131 Tositumomab in Patients With
Non-Hodgkin's Lymphoma Who Had Previously Responded to I-131
* Specific Regimen Influences Risk
of Myelodysplasia After Lymphoma Treatment BloodJournal
Stem Cells for Transplant in Non-Hodgkin's Lymphoma Patients
Is Still Possible After Treatment with Bexxar news.cornell.edu
See also Factors that
Influence Treatment Decisions
A reason RIT is considered a vital therapy is that it is the
first treatment proven to reverse the pattern of decreasing
response and duration of response in indolent lymphomas. 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.
following abstract describes the pattern of relapse for follicular
lymphomas with standard therapy:
Subsequent Therapy Results in Diminishing Response Rate and
Duration of Response in Low Grade or Transformed Low Grade
"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
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."
In the News:
ASH Paper, 2013: A Randomized Phase II Study
Comparing Consolidation With a Single Dose Of <sup>90</Sup>y
Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With
Rituximab (R) For Two Years In Patients With Newly Diagnosed
Follicular Lymphoma (FL) Responding To R-CHOP.
Preliminary Results At 36 Months From Randomization
Patients with FL can have long
time of survival, but disease progression typically occurs 3-5
years after initial treatment. Consolidation with Z after
initial therapy has shown to improve progression-free survival
(PFS) mainly in the pre-R era, whereas maintenance with R also
has demonstrated a substantial benefit in terms of PFS in
patients treated with immunochemotherapy.
In this setting, the Spanish intergroup PETHEMA/GELTAMO/GELCAB
started a randomized phase 2 trial in order to compare the use
of consolidation with Z vs. R maintenance in patients with FL
responding to R-CHOP. From June 2008 to July 2010, 146 patients
(66M/80F; median age, 55 years) were enrolled from 25 Spanish
institutions in the randomized phase 2 trial ZAR2007
Main inclusion criteria were: FL grade 1, 2 or 3a, age 18-75
years, stages II-IV and need of treatment according to modified
GELF criteria. Patients with FL grade 3b or transformed to DLBCL
... The number of patients in PR after R-CHOP who reached CR
during maintenance were 14 of 28 (50%) and 12 of 26 (46%) for
arms A and B, respectively.
Two patients developed transformation to DLBCL at 8 (arm A) and
39 months (arm B) after randomization. During the maintenance
period, patients receiving Z showed grade 3-4 neutropenia in 6
of 63 cases and grade 3-4 thrombocytopenia in 5 of 63, whereas
these figures were 1 of 61 and 0 of 61 (p=0.05) for patients in
arm B, respectively. No unexpected late toxicities have been
Five patients have died during the follow-up due to the
progression of lymphoma in all cases, with no differences
between the arms (36-month OS, 98% vs. 95% for arms A and B,
respectively). In conclusion, in patients with FL in response
after R-CHOP, maintenance with R was superior to consolidation
with Z in terms of PFS, with no differences in OS with the
Advocate comment: That
Rituxan competes with Zevalin for binding to cd20 could work
against Zevalin in this study design - where induction included
4 cycles of Rituxan. In the FIT study (leading to approval
of Zevalin for this use) the induction therapy often did not
include Rituxan. KarlS
Zevalin Consolidation of First Remission in
Advanced-Stage Follicular Non-Hodgkin Lymphoma: Median Follow-Up
of 7.3 Years From the International, Randomized, Phase III
First-Line Indolent Trial”
Could Extend Survival in Some Patients with Advanced Lymphoma -
The ASCO Post
Update: Bexxar® Provides Years of Lasting Activity as Initial Therapy
* Overall survival at 10 years was 86%.
* Anticancer responses were achieved in 95% of patients.
* A complete disappearance of detectable cancer (complete
was achieved in 75% of patients.
* The median time for cancer progression among patients who
a complete remission was 9.2 years.
Radio-Immunotherapy with Bexxar Produces
Durable Remissions in Patients
with Late Stage Low Grade Non-Hodgkin's
Trans Am Clin Climatol Assoc. 2004;115:255-72.
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.
for relapsed or refractory B-cell non-Hodgkin
updated results and long-term follow-up of the University of
Blood. 2000 Aug 15;96(4):1259-66.
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
and safety of Bexxar in B-cell
lymphoma, progressive after Rituxan.
J Clin Oncol. 2005 Feb 1;23(4):712-9. Epub 2004 Dec 21.
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 =
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.
novel radioimmunotherapy for the treatment of low-grade
and transformed low-grade
Oncologist. 2004;9(2):160-72. Review.
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.
and scientific overview of tositumomab (Zevalin)
and iodine I 131 tositumomab (Bexxar).
Semin Oncol. 2003 Apr;30(2 Suppl 4):22-30. Review. PMID:
"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"
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.
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.
radioimmunotherapy produces high response rates and durable
in patients with previously treated B-cell
Clin Lymphoma. 2004 Sep;5(2):98-101.
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.
responses after ibritumomab tiuxetan radioimmunotherapy (Zevalin)
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.
"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.
Radioimmunotherapy: FIT to be applied? Randomized study shows
improved PFS by 2 yrs in follicular lymphoma when given as
consolidation for chemotherapy Medscape.com
( login req.)
n = The trial compared a single Zevalin treatment
with observation in 414 patients with advanced (stage 3 or 4)
follicular lymphoma who had achieved partial or complete remission
after first-line chemotherapy. The choice of which chemotherapy
regimen to use for induction was left to the physicians' discretion,
and various combinations were used, including CVP, CHP, fludarabine,
chlorambucil, and rituximab.
Contraindications for use of RIT
Some of these "cutoffs"
may have changed since
Bone marrow biopsy
marrow (<15% cellularity)
of bone marrow precursors
NOTE: The bone marrow findings must be within 30 days
Impaired bone marrow
reserves as indicted by:
myeloablative therapies with ABM or PBSC transplantation
< 100,000 cells/mm3 (or perhaps < 50,000 for Zevalin)
ANC (Neutrophil Count (Absolute))
< 1,500 cells/mm3
History of failed
stem cell collection
Known type I
hypersensitivity or anaphylactic reactions to murine (mouse)
or to any component of the therapeutic regimen
test - test required for women of child-bearing age.
Serum Creatinine >
1.5 X the upper limit of normal
beam radiation involving >25% of the active bone marrow
Pregnancy and continuing breast feeding
Children and adolescents under 18 years of age
Prior bone marrow or stem cell transplantation
(this is being studied)
Adapted from: interactive.snm.org
FDA Label describing use for
RIT for the Elderly?
Bexxar is an Effective and Well Tolerated Therapy in Elderly Patients with
CONCLUSION: Bexxar was efficacious and well tolerated in this population of elderly patients with NHL. Due to physiologic changes in the elderly, conventional chemotherapy may require dose-attenuation; however, Bexxar therapy provides pt-optimized dosing so that the same TBD is given for all age groups. This novel therapy provides a therapeutic choice for pts who may have limited therapeutic options.
Consider RIT? ...
When might RIT be appropriate ... indicated ... deserving of full consideration?
approved indications for RIT: "for the treatment of relapsed
or refractory low grade,
follicular, or transformed B-cell
non-Hodgkin's lymphoma (NHL)."
our brochure on this topic: RIT.pdf
Important: Treatment decisions are complex and require input from well-trained, experienced lymphoma specialists. All therapies have risks and outcomes will vary. Please discuss the risks and benefits of all reasonable therapies when consulting your physician. Items below marked with * indicate investigational uses. See Locating
RIT-Based Clinical Trials.
As first primary treatment, perhaps as an alternative to chemotherapy, particularly if chemotherapy is not indicated for you. *
As consolidation therapy? *
Consolidation therapy is a treatment given shortly after another treatment with the goal of improving on the response. (Also called sequential therapy.)
As second primary treatment, particularly following a short or insufficient response to prior treatment?
A primary treatment is one that is given with intent to achieve a significant and long lasting response, as opposed to palliative therapy where the goal might be to relieve symptoms.
When you have relapsed from prior treatment, and the goal of your next therapy is to achieve a durable complete remission.
As an alternative to stem cell transplantation (SCT), particularly if SCT is indicated, but not suitable for you because of age or other factors. *
As part of the conditioning therapy of stem cell transplantation? *
As an alternative to maintenance Rituxan
Maintenance is the regularly scheduled administration of Rituxan with the goal of maintaining the response to prior induction treatment.
When transformation is suspected and you are not a candidate for SCT, or combination chemotherapy, such as CHOP-Rituxan?
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
some clinical centers.
Non-clinical factors that
may influence underutilization of RIT
Lack of awareness
potential of RIT to result in higher remission
rates and duration of remission among patients and some
When insurance carriers
do not cover treatment out of network/area,
and the patient's treating physician does not offer nuclear
A conflict of interest
(mostly unintended) that occurs when physicians cannot
offer the full range of therapies within their local practice.
When the potential risks
of RIT are overestimated or not fully understood
by patients and physicians.
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
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
Therefore, if you have bulky disease, you may want to consider
prior to use of RIT,
as lower tumor burden is associated with better and more durable outcomes (O. Press).
However, use of chemotherapy shortly before RIT could also
increase risks of RIT
Pretreatment might also include stem cell harvesting.
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
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
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:
HD chemo - (with harvesting), sequenced with RIT versus
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
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
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
may be indicated to eliminate this complicating factor.
other types of lymphoma?