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Considerations at Relapse

Last update: 07/07/2015

For relapsed aggressive lymphoma,
see Treating relapsed DLBCL - review article

Here we provide suggestions on the subject of what to do and consider when you have an indolent lymphoma that has relapsed. The intent is to provide discussion points to assist with the consultation you will have with your doctor.
There are reasons to stay positive -- because there are many effective treatment options when the lymphoma returns, including clinical trials.  The aggressive lymphomas can still be cured; the indolent lymphomas can be managed well.    


Staging will also be done with imaging tests (CT or PET and CT with PET) to see where the lymphoma is, and how far and fast it has progressed since the last treatment.

"While most patients with new lymphadenopathy will have recurrent lymphoma, it is certainly not true for all."  Armitage, MD.

A biopsy is often done to see if what has recurred has changed in any significant way from the original diagnosis. This information can be vital to making informed treatment decisions. For example, it can help your doctors to determine if you have high- or low-risk disease. 

... Pathology experts often advise that the biopsy should be of the largest lymph node that can be safely resected (removed surgically) to maximize the chance of getting representative cells.  A PET scan is sometimes used to guide which node or lesion to biopsy.

Consulting your oncologist ... and if feasible an expert for a second opinion

After you have the pathology and staging information you can begin to make an informed decision.  One important goal being to determine if the lymphoma is high- or low-risk disease and to choose the goal of treatment accordingly.

Prepare for consults by providing information about any symptoms in writing, and by having all pathology and staging information at hand, particularly the latest biopsy and imaging reports and slides, and two copies of your questions (one for you and one for your doctor). 

If possible, bring along trusted loved one to the consult.   See also Optimizing Consults

Factors that determine the approach to treatment include but are not limited to:  


Responsiveness to the initial treatment (treatment sensitive)-
did it lead to a complete response (CR)? 


The duration of response to initial treatment - months/years?

For durable responses, it is sometimes feasible to use the same therapy.


The growth rate before and after treatment? -
is it progressing rapidly/moderately, stable, waxing and waning? 


Is the lymphoma causing symptoms -
fatigue, fever, b-symptoms? 


Is the lymphoma "bulky" - any lymph nodes that are larger than 8 to 10 cm?


The areas of involvement -
is the lymphoma in a region that could affect organ function?


If certain blood counts are low (cytopenias)


Is it responsive to initial treatment -
biologic, single agent, or low dose chemotherapy treatment? 


Pathology findings and blood test markers that my suggest high- or low-risk disease


One's age, fitness, and general health

See also Treatment decisions - for a list of factors that can influence
the goal, the type, or the timing of treatment.

Two basic approaches to treating relapsed indolent lymphoma:
bullet Management - watch & wait, followed by judicious use of lower-toxic biologic or targeted agents* 
and/or chemotherapy agents when treatment is indicated by symptoms,
progressing disease, poor quality of life, low blood counts, or even patient preferences. 

The general idea is to treat a lower-risk lymphoma as a chronic condition, 
to minimize toxicity, and to keep your future options open.  However, you can change to an aggressive approach based on the efficacy of the management approaches or based on changes to the clinical behavior.



Monitoring without treatment (watch and wait)


Rituxan with or without lenalidomide (NCCN guidelines)


Clinical trial using targeted agents


Single-agent chemotherapy, such as Chlorambucil, Cytoxan


Low / metronomic dosing of chemotherapy, such as Low dose oral PEP-C,


Idelalisib (an oral targeted drug)
On July 23, 2014, the U.S. Food and Drug Administration (FDA) approved idelalisib (Zydelig tablets for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.  FDA also granted accelerated approval to idelalisib for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.


One of many clinical trials

Investigational agents with recent encouraging clinical reports for indolent lymphoma
ABT-199  (Venetoclax) (activating apoptosis) Find trials
ACP-196 (targeting btk pathway)  Find trials
Cd19 CAR T-cell therapy (adoptive immunotherapy)  Find trials 
GA-101 (Obinutuzumab), next generation cd20 antibody  Find trials
Lenalidomide (immune modulation and direct activity)  Find trials
Ibrutinib (all - recent approval for CLL; inhibiting btk - on b-cell receptor pathway) Find trials
Ibrutinib for Lymphoma only  Find Trials
Idelalisib GS-1101 formerly CAL101 (inhibiting b-cell receptor pathway)  Find trials
PD1/L antibodies (activates immune system - immune checkpoint blockade)  Find trials 
bullet Curative Approaches / Complete and Durable Response*

Use of combination of drugs or sequential therapy (one type of therapy followed by another) - sometimes at higher doses in order to achieve a durable complete remission, or to cure the aggressive components of the relapsed lymphoma (such as if a transformed lymphoma is suspected or confirmed). 

The objective is to achieve a durable response to therapy, either from personal preference, or because the lymphoma is considered high-risk -- such as the response to the prior therapy was very short and there has been fast progression.

Examples of more aggressive approaches (depending on prior therapy):


Bendamustine + Rituxan (chemo-immunotherapy) with or without
maintenance Rituxan, or consolidation with radioimmunotherapy


CHOP + Rituxan with or without maintenance Rituxan, or consolidation with radioimmunotherapy


Other chemotherapy combinations + Rituxan (chemo-immunotherapy) with or without
maintenance Rituxan, with or without consolidation with radioimmunotherapy -
such as CHOP-R.


Radioimmunotherapy - Zevalin as single agent or following chemotherapy


High-dose chemotherapy with stem cell rescue (from self - autologous, or from donor - allogeneic)
-  an allogeneic type depending on the availability of a donor stem cells that are a good match.


One of many clinical trials  

Evidence-based best practice

Dr. John Leonard, 2009 - Treatment Options in Relapsed, Indolent Non-Hodgkin's Lymphoma - townnews.healthology.com/l
Blood - John G. Gribben, 2007: How I treat indolent lymphoma
Dr. Cheson discusses factors that influence options at relapse for Follicular Lymphomas 
LRF 2006 Education Forum webcast
  Flash format
Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov  
NCCN Clinical Practice Guidelines in Oncology™ Non-Hodgkin's Lymphoma, 2008 www.nccn.org/professionals/physician_gls/PDF/nhl. pdf  - requires free registration.


Treatment decisions - factors that can influence the goal, type, and timing of treatments
2000:  Managing Indolent Lymphomas in Relapse
Working Our Way Through a Plethora of Options  asheducationbook full/2000 

The front-line management of stage IV indolent non-Hodgkin's lymphoma has ranged from the watch-and-wait approach to intensive experimental regimens such as high-dose chemotherapy and bone marrow transplant. With this broad spectrum of regimens to choose from the decision has become a challenging exercise for both patients and oncologists.
Fernando Cabanillas, (Chair), Sandra Horning, Mark Kaminski and Richard Champlin

In this review of the alternative therapies a panel of three expert hemato-oncologists 
each discuss their approach to the management of a 49-year-old patient with 
a relapsed indolent follicular lymphoma. 
2000: Treatment options after relapse of indolent lymphoma  http://tinyurl.com/32jrpx

Dr Leonard, Dr. Coleman, and Dr. O'Conner


Limitations of pathology findings: The pathology reports can have limitations. Sometimes small cleaved indolent behaves aggressively. Sometimes mixed, large, and small cell lymphomas (sometimes called grade 2) behaves indolently.  The clinical behavior can be as important as the diagnostic tests, which do not yet account for all factors that contribute to how the lymphoma will behave.   

Staging: A second scan at two months following relapse could be appropriate to estimate how clinically aggressive the lymphoma is. If the clinical behavior is indolent,  watch & wait might be recommended ... just like many do when originally diagnosed.  It's not uncommon for a relapse to appear abruptly, but then slow down and stabilize.  It can take time to judge the true clinical behavior of the relapsed disease. 

Response to treatment evaluations: "Specifically, assessing response [with PET] may be useful in two possible situations: to evaluate tumor response at the end of a full course of treatment, or to predict tumor response early in the course of a prolonged treatment regimen. In the first instance, early detection of treatment failure may permit a physician to institute a second-line therapeutic approach. In the second instance, accurately predicting treatment failure may allow the physician to substitute an alternative regimen, without subjecting the patient to the toxicity of the full course. "  Peter E. Valk, MD

Keep abreast of clinical trials for agents that have low toxicity and little risk of precluding subsequent treatments.  These may be best tried when treatment is not required -- as an alternative to watch & wait.

If the lymphoma is refractory (resistant) to standard treatments, you might have to consider stronger measures or novel combinations of cancer therapies. Low dose chemo regimens like PEP-C, investigational targeted treatments 

See also
clinical trials and Clinical Trials of Interest however, these are not complete lists of protocols to consider.  Be sure to consult experts in the field.

Know what clinical trials are available and what seems promising and low toxic.  Consult with non-treating lymphoma experts who have intimate knowledge of your disease, treatment history, and all available standard and emerging treatments. Educate yourself about the potential risks and benefits of new approaches.

Honesty. It's important that patient and doctor pay attention to the "messages," or trends of the clinical course of your lymphoma.  Waiting until you get sick or very advanced disease can limit options and work against benefiting optimally from some treatments. 

Talk to your doctor about collecting stem cells before or after the treatments you are considering as a further precaution and use in the future, particularly if you have high-risk disease and stem cell rescue is an option for you down the road because of your age and fitness.

Important note:  Only your doctors have the clinical details necessary to help you to make informed decisions.  But do not limit your horizon to the perspectives of one doctor. It can be helpful to consult outside lymphoma experts as well.  Please do not rely on the anecdotes and theories of patients. 

See also Factors that determine the approach and timing of treatment

Communicating honestly with your doctor and becoming informed about the potential risks and benefits of all the treatments appropriate to your diagnosis are keys to managing lymphoma and treating it effectively in a timely manner.  

Please send us comments or suggestions about these general guidelines. 

Professional input is particularly welcome.  Send comments by clicking .
Disclaimer:  The information 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. 
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