Ask Question
Sign Guest book

 
About Lymphoma
| Advocacy & Art | CAM & Life Style | Clinical trials | Doctors & Centers  | Guidelines  at  Diagnosis | How  to   Help  | Research | Side Effects  | Support | Symptoms  | Tests | Treatments


WebCasts

Radioimmunotherapy

  

Radioimmunotherapy: | Bexxar Info | Zevalin Info | Bexxar vs Zevalin | Other Agents

Treatment Overview > Radioimmunotherapy (RIT)

Last update: 05/16/2008

TOPIC SEARCH: PubMed Queries on Radioimmunotherapy: Review | Zevalin | Bexxar

What is RIT? | RIT abstracts | Bulky disease and RIT?When to consider RIT? | Goal of treatment | Clinical Trials 
Outcome Report for RIT
    Bexxar | Centers that Administer Bexxar |  
    Zevalin | Centers that Administer Zevalin   . . . . . . . . . . . . .  .  .  .    Bexxar vs. Zevalin? 

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

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 

Radioimmunotherapy of Cancer  www.ncbi.nlm.nih.gov 

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

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."

Role of Different Frontline Regimens in Achieving Complete Response in Follicular Lymphoma: 
A Meta-Analysis of CR Rate and Its Relation to Hazard Rate for Disease Progression

Session Type: Poster Session, Board #932-II  ASH2006 

"Random effect estimation showed a CRR of 
   37% with CHEMO (95% CI: 18%57%), 
   53% with RCHEMO (34%71%), 
   68% with FLU (49%87%), and 
   79% with RIT (73%85%) 

"The analysis suggests that a higher CRR is correlated with a lower hazard of disease progression. 
These data support the selection of regimens that achieve high CRRs for future trials of initial therapy 
and could provide an additional basis for the design of long-term therapeutic strategies."

CHEMO - chemotherapy combinations without fludarabine
R+/-CHEMO - rituximab as a single-agent or in combination with chemotherapy
FLU - fludarabine as a single-agent or in combination
RIT - Bexxar or Zevalin as  single agents or in combination

Bexxar as initial treatment for follicular lymphoma.
N Engl J Med. 2005 Feb 3;352(5):441-9. Abstract | Full Text

Seventy-six patients with stage III or IV follicular lymphoma ...After a median follow-up of 5.1 years, 
the actuarial 5-year progression-free survival for all patients was  59 percent, with a 
median progression-free survival of 6.1 years
. ...  Of 57 patients who had a complete 
response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no 
patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome 
have been observed.

bexxar-initial_tx.jpg (13092 bytes) click to enlarge chart showing progression free survival 

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?

Important: Treatment decisions are complex
See Factors that Influence Treatment Decisions
 
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?
When you have relapsed from prior treatment, 
and the goal of your next therapy is to achieve a durable complete remission.
When the lymphoma has not responded well (is refractory) to Rituxan?
As an alternative to stem cell transplantation?
As  part of the conditioning therapy of stem cell transplantation? (Ideally in a clinical trial)
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.
When insurance carriers do not cover treatment out of network/area, 
and the patient's treating physician does not offer nuclear medicine.
A conflict of interest (even if 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 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. 
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?

Splenectomy in Non-Hodgkin's lymphoma  ncbi.nlm.nih.gov/books

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.

 

 
Disclaimer:  The information presented on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
Patients Against Lymphoma, Copyright © 2004,  All Rights Reserved.