About Lymphoma > Transformation

Last update: 10/25/2016

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TOPIC SEARCH: Google Scholar Auto Transplant treatment for transformed lymphoma

CLINICAL TRIALS for Transformed Lymphoma: Untreated | Relapsed | Not Transplant

What is Transformation?

Indolent lymphomas generally grow slowly, can sometimes remain stable for a long while, or can even regress spontaneously.  However, sometimes a more aggressive cell emerges from the population of indolent cells (which soon outnumber the indolent cells) leading to symptoms and the need to treat.  This change in the behavior of the lymphoma is called transformation.

Follicular lymphomas are more prone to transformation to more aggressive clones than other indolent types. 
A follicular lymphoma can transform to: 

	Grade 3 - a greater proportion of large to small cells
	Diffuse Large B-cell lymphoma - so-called histologic transformation to a diffuse growth pattern
	Aggressive B-cell lymphoma with features of Burkitt lymphoma,
	Lymphoblastoid lymphoma (more rarely)     Adapted from article by Jonathan W. Said, M.D. www.nature.com

Transformation is suspected or indicated by how it behaves (clinical) or by evaluation of a biopsy as described in the following report, ASH 2012: Rates and Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource

Transformation is often "defined as refractory/recurrent disease with either
a) biopsy-confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or
b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). "
 

Clinical versus histologic criteria for transformation: 

The following clinical changes raise suspicion of transformation: 

	Rapid growth or discordant (uneven) growth between various disease sites.
	Sudden rise in LDH (2X baseline)
	Unusual extranodal involvement (eg, liver, bone, muscle, brain) - excluding bone marrow
	New and persistent onset of b-symptoms
	New hypercalcemia (elevated calcium levels in blood) - a "rare presenting feature"
	PET imaging: The majority of transformations have a high SUV (standard uptake value).    Transformation should be suspected in indolent lymphoma with very high SUVs. Biopsies should be directed to the site of greatest FDG avidity (uptake).

What is histologic transformation to DLBCL?  

Image showing diffuse versus follicular growth pattern within the lymphoma - nodular versus diffuse. Click image or go to source:  www.med-ed.virginia.edu 

The transformation is almost certainly the result of additional genetic mutations that cause the cells to divide more rapidly. The diagnosis is based on changes in the growth of the cells from follicular (nodular) to a diffuse growth pattern ... resembling de novo DLBCL.

"DLBCL can be classified as de novo, that is, without a previous history of an indolent lymphoma,
or as secondary transformed DLBCL emanating from an indolent lymphoma most commonly follicular lymphoma.  [The latter commonly referred to as "histologic transformation to DLBCL"]

The distinction between transformed and de novo DLBCL is based on the morphological (by appearance) demonstration of a low malignancy grade lymphoma such as follicular lymphoma either before or simultaneous to the DLBCL.

However, it is not known whether some apparently de novo DLBCL could in fact represent transformed cases where the component of low-grade malignancy is no longer detectable. The demonstration of a t(14;18) rearrangement in a significant proportion of de novo DLBCL gives some support for this hypothesis." ⁸

How does it arise?

Genetics of Follicular Lymphoma Transformation - supports divergent evolution from a common mutated precursor http://bit.ly/1tO4OWm  Full text PDF

The first finding of our study is that, although all FL-tFL sample pairs have a clear clonal relationship, the dominant tFL clone arises in most patients from a mutated CPC (common precursor cell) through the acquisition of independent genetic events, consistent with divergent evolution.

The existence of this CPC cannot be physically demonstrated, but it can be postulated on the basis of the presence of a set of lesions that are shared between FL and tFL, and is consistent with previous studies based on the analysis of the rearranged Ig genes (Carlotti et al., 2009) as well as with recent work on FL progression (Green et al., 2013).

Comment:  These finding may influence the approach to treating follicular lymphoma ... suggesting the need to target also the common precursor cell if treatment is to have a potential for cure.

Resources:

	2016: Poor outcomes for histologically transformed follicular lymphoma warrant use of salvage HSCT http://bit.ly/2e7T0wT
	ASH Ed.: The incidence, natural history, biology, and treatment of transformed lymphomas
	Best Pract Res Clin Haematol. 2011, Lossos, Gascoyne: Transformation of Follicular Lymphoma http://1.usa.gov/1aAZSwo "The clinical presentation at the time of higher-grade transformation is variable. Consequently, higher-grade transformation should be suspected in every FL patient at the time of disease progression or relapse. It is often heralded by rapid and commonly discordant growth of localized lymph nodes that may be associated with pain, appearance of unusual extranodal involvement (e.g. central nervous system, liver and bone), sudden and excessive rise in levels of LDH or development of new B symptoms that can be observed in 30 to 56% of patients. New onset hypercalcemia can also be detected[15], but this is a rare manifestation of FL transformation."
	BJH (correspondence): Improving survival in patients with transformed B cell non Hodgkin lymphoma: consolidation with Zevalin-BEAM and autologous stem cell transplantation
	Clinical Trials for Transformed lymphoma:   For Previously Untreated  | For previously treated | For previously untreated and not SCT
	Stem cell mimicry: key to lymphoma transformation? http://bit.ly/2bTkKc

Frequently Asked Questions:

When an indolent lymphoma transforms only some of the malignant cells become aggressive. Generally, the goal of therapy is to cure the transformed cells, but the indolent cells may survive this therapy.

	A transformation of CLL is called Richter's syndrome, which is less common than the so-called histologic transformation of follicular lymphoma.
	When the growth rate becomes rapid, some experts recommend treating it as if it was a histological transformation, whether it has been confirmed by biopsy or not. Consider that a biopsy is only a small sample of what exists, so only on positive finding is conclusion ... there could be transformed cells in another area.
	It seems that no single test is conclusive for transformation, with the exception of a positive finding from a biopsy.  That is, there can sometimes be clinically apparent instances of transformation despite unsuspicious LDH, PET values, etc.
	If the clinical behavior of the indolent lymphoma becomes aggressive the approach to treatment changes. You typically treat with intent to cure the transformed (aggressive) component, as you would a de novo (primary) aggressive lymphoma (NCCN 2011).

The Diagnosis of Histological Transformation: 
 

Pathologic confirmation from a tissue sample - a biopsy finding of diffuse large B-cell or Burkitt-like lymphoma according to WHO criteria Adapted from oncolink.org | PubMed | PMID 18838711 | Cancer.gov

What causes transformation? 

Genes are the "recipes" for proteins that determine cell behavior. The lymphoma cells can acquire additional genetic mutations that alter the growth rate, growth pattern, and sometimes sensitivity to treatment. When it's a confirmed  histological transformation, the change is apparent as a new growth pattern: diffuse instead of nodular. 

Transformation of indolent lymphoma to faster growing (aggressive) grade of the disease is 
common during the course of the disease.  

"Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. 

Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type. 

Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. 

"Histologic conversions should be treated with the regimens described in the Aggressive, Recurrent Adult Non-Hodgkin's Lymphoma section of this summary. The durability of the second remission may be short, and clinical trials, should be considered." Cancer.gov  

Articles: Risk factors and Mechanisms

	Risk Factors for Early Transformation of Follicular Lymphoma: Report From the National LymphoCare Study (NLCS) http://bit.ly/5KN44N
	Technical: Transformation of follicular lymphoma to DLBCL proceeds by distinct oncogenic mechanisms http://bit.ly/8Sx0e1
	Determinants of the optimal first-line therapy for follicular lymphoma: A decision analysis http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932442/   cites this report: Population-based analysis of incidence and outcome of transformed NHL. http://www.ncbi.nlm.nih.gov/pubmed/18838711 when saying: "In the largest population-based series of 600 patients, the annual risk of transformation was estimated to be 3% per year, and the median survival after transformation was 1.7 years [13]. In subset analysis (denominator not specified), the annual risk of transformation after anthracycline/radiation-based therapy was 1.5%, compared to 3% after alkylator/purine-based therapy.

What is the risk of histologic transformation
of indolent lymphoma to DLBCL?   


The risk of this event ranging from 16% to 60% depending on the source and definition of transformation.¹   
The answer depends on how you ask the question, the time period, and who you ask:

	The risk of histologic transformation (HT) by 10 years was 28%.  1
	Transformation to more aggressive large cell lymphoma occurs in 25-60% of pts with FL 4
	Rate of Transform

at 10 Yr 28%

at 15 Yr 37%

Click chart to enlarge it
 Source: hememalignancies.com  pdf   

In the News:

	2016, June: Risk Factors and Outcomes for Patients With Follicular Lymphoma Who Had Histologic Transformation (HT) After Response to First-Line Immunochemotherapy (rituxan-chemo) in the PRIMA Trial PDF full report  An important report with some surprising (to me) findings, such as CR response (judge by imaging) is not associated with a decreased risk of histologic transformation (HT) at recurrence, but early relapse is -- as is presentation in a new area. The encouraging news is that this risk is low overall (among all who responded to r-chemo) at about 2% and that only 22% relapsed within 6 years (if I have it right); and that this is 1% less than incidence of HT previously reported ... perhaps an indication that Rituxan decreases the risk of HT. Among those who relapse early (within 1 year), 36% had HT (among those who had a biopsy to determine this). Persons with HT can benefit from high dose chemo with auto transplant; but no advantage was seen for auto SCT for those with relapse to non-transformed (regular) FL. Among these persons (relapsed to regular FL), only 10% had radioimmunotherapy compared to 33% auto SCT. Will this finding lead to more RIT and less auto SCT for first relapse to regular FL? An important take-home point is that a biopsy at relapse is highly recommended to inform next treatment on relapse of FL after first line R-chemo (immuno-chemotherapy) KarlS
	Nov 2015: *Clinical Onc 2015 Ann S. LaCasce: How I Manage: Transformed Follicular Lymphoma http://bit.ly/1MGviFw Dr. LaCasce provides a nice overview and encouraging update on this topic
	Aug 2015: Blood Journal | Cell-of-origin of transformed follicular lymphoma http://bit.ly/1fGoVnS We report that the expression of IRF4 is an independent predictor of early transformation (hazard ratio 13.3, P < .001). We also show that composite histology at the time of transformation predicts favourable prognosis.
	Blood 2015: Casulo, Burack, Friedberg Transformed follicular non-Hodgkin lymphoma http://bit.ly/149RgNW HT (Histologic Transformed FL) is an important cause of morbidity and mortality in patients with FL. Given the biological heterogeneity of HT, and the relative rarity of the event, it is unlikely we will have prospective, randomized trials to guide management of this complication. However, anticipating rapid translation of genomic insights into clinical practice, the implementation of targeted DNA sequencing approaches, and a plethora of novel, targeted therapeutic agents in development, we look forward to a day soon when a molecularly defined, precision therapy approach will replace our current empiricism in the approach to HT.
	Blood 2014: Transformed follicular non Hodgkin lymphoma http://bit.ly/1Gwptn4 Technical in large sections, but also contains therapeutic approaches of importance to patients - and encouraging news on improved outcomes in the Rituxan era.
	Blood 2013: Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma. http://1.usa.gov/KiijNG Could help to guide treatment decisions one day if validated.
	ASCO Post, 2012: : Predictors and Treatment for Transformed Lymphoma: Current Paradigms http://bit.ly/12V268Z  "To date, it is unclear whether early treatment vs a “watch and wait” strategy has any impact on the risk of transformation. Most studies suggest there is no change in risk.
	ASCO POST, May 2013:  Role of Stem Cell Transplantation in [transformed] Follicular Lymphoma ascopost.com By James O. Armitage, MD | May 15, 2013, Volume 4, Issue 8 My experience has been that patients who present with a transformation to diffuse large B-cell lymphoma and have composite low-grade follicular lymphoma can often be “cured” of the high-grade lymphoma with regimens like CHOP-R. However, for patients with transformation that occurs after previous treatment for follicular lymphoma, the results with further standard chemotherapy/chemoimmunotherapy have not been satisfactory, and these patients should be offered transplantation if they respond to salvage chemoimmunotherapy. The results by Villa and colleagues suggest that for most patients, autologous transplantation is likely to lead to the best outcome. Dr. Armitage is Joe Shapiro Professor of Medicine and Professor and Chair of Oncology, University of Nebraska Medical School, Omaha.
	ASCO POST, May 2013: Autologous Stem Cell Transplant Improves Survival in Transformed Follicular Lymphoma  ascopost.com  This retrospective cohort study included 172 patients aged 18 to 65 years with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patients undergoing transplant were those treated with autologous or allogeneic transplantation between 1994 and 2010 at transplant centers in Canada. A separate comparison group of patients receiving rituximab-containing chemotherapy alone was identified using the British Columbia Cancer Agency Centre for Lymphoid Cancer Database.
	ASCO 2013: Changes in the tumor microenvironment associated with transformation in follicular lymphoma.

	*Blood 2013: Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma. http://1.usa.gov/KiijNG Could help to guide treatment decisions one day if validated.
	ASCO Post, 2012: : Predictors and Treatment for Transformed Lymphoma: Current Paradigms http://bit.ly/12V268Z  "To date, it is unclear whether early treatment vs a “watch and wait” strategy has any impact on the risk of transformation. Most studies suggest there is no change in risk.
	ASCO POST, May 2013:  Role of Stem Cell Transplantation in [transformed] Follicular Lymphoma ascopost.com By James O. Armitage, MD | May 15, 2013, Volume 4, Issue 8 My experience has been that patients who present with a transformation to diffuse large B-cell lymphoma and have composite low-grade follicular lymphoma can often be “cured” of the high-grade lymphoma with regimens like CHOP-R. However, for patients with transformation that occurs after previous treatment for follicular lymphoma, the results with further standard chemotherapy/chemoimmunotherapy have not been satisfactory, and these patients should be offered transplantation if they respond to salvage chemoimmunotherapy. The results by Villa and colleagues suggest that for most patients, autologous transplantation is likely to lead to the best outcome. Dr. Armitage is Joe Shapiro Professor of Medicine and Professor and Chair of Oncology, University of Nebraska Medical School, Omaha.
	ASCO POST, May 2013: Autologous Stem Cell Transplant Improves Survival in Transformed Follicular Lymphoma  ascopost.com  This retrospective cohort study included 172 patients aged 18 to 65 years with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patients undergoing transplant were those treated with autologous or allogeneic transplantation between 1994 and 2010 at transplant centers in Canada. A separate comparison group of patients receiving rituximab-containing chemotherapy alone was identified using the British Columbia Cancer Agency Centre for Lymphoid Cancer Database.
	ASCO 2013: Changes in the tumor microenvironment associated with transformation in follicular lymphoma.

OUTCOME REPORTS

	ASH 2012: Rates and Outcomes of Follicular Lymphoma Transformation in the Rituximab Era: A Report From the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource
	ASH Ed: The incidence, natural history, biology, and treatment of transformed lymphomas
	An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma   http://annonc.oxfordjournals.org/content/22/7/1622.short   "The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for Transformed Lymphoma (TL). "
	Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma ASH 2009
	High rate of survival in transformed lymphoma after autologous stem cell  transplant: pathologic analysis and comparison with de novo diffuse large  B-cell lymphoma.  http://www.ncbi.nlm.nih.gov/pubmed/19672775

n = 56 "select" patients with transformed lymphoma (25) or de novo DLBCL (25)

Comment: encouraging news given the prognosis of transformed lymphoma, but the study is small (n = 25 transformed) and the participants  were selected by investigators using unspecified criteria ... key factors such as age and having chemo-sensitive disease, untreated/previously treated, etc. were not described in the abstract.

	Population-based analysis of incidence and outcome of transformed NHL. Al-Tourah AJ, Gill KK, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ,  Sehn LH, Shenkier TN, Gascoyne RD, Connors JM. J Clin Oncol. 2008 Nov 10;26(32):5165-9. Epub 2008 Oct 6. PMID: 18838711  n =  600 patients with newly diagnosed FL met the inclusion criteria. Conclusion: The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years.  Advanced stage at diagnosis is predictive of future transformation.  Clinically diagnosed transformation* has an equal impact on outcome as biopsy proven transformation. "advanced stage (III, IV, or I/II with B symptoms or bulky disease)  was predictive for the development of transformation (P.002)." Patients with limited extent transformation had a significantly better  survival with a 5-year post-transformation survival of 66%.  [supporting careful, regularly scheduled monitoring; timely reporting of symptoms by patients] Patients requiring multiple courses of therapy appear to be at significantly higher risk of transformation Confounder: 87% of this population were not treated with R-based chemo at transformation (before introduction of Rituxan) Patient selection: 1986 - 2001
	Transformation of follicular lymphoma: prognostic factors and effect on survival  ASCO Conclusions: prognostic factors for TF include lack of CR, elevated LDH, and B symptoms. TF is associated with a higher risk of death than FH without TF at first and subsequent relapses; however, time to TF does not affect long term survival.
	The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological  subtype are the most important factors to predict histological transformation in  follicular lymphoma  PDF  Conclusion: FLIPI and histology were the most important variables predicting HT. Upon HT,  only patients achieving CR (complete response) reached prolonged survival,  thus emphasizing the need for effective therapies once this event occurs.
	Feasibility of allogeneic stem cell transplantation for follicular lymphoma undergoing  transformation to diffuse large B-cell lymphoma.   Leuk Lymphoma. 2008 Oct;49(10):1893-8. PMID: 18949613  n = 8 patients with histologically confirmed transformation to diffuse large B-cell lymphoma underwent HSCT at our institution. The median age was 56 years (range 44-63 years). Allogeneic HSCT appears feasible in patients with transformed FL and is associated with acceptable treatment-related mortality and low relapse rates.
	The impact of initial treatment of advanced stage indolent lymphoma on the  risk of transformation  ascopubs.org  n = 698 patients with indolent NHL, no prior treatment, age16–60 y and advanced stage disease  (III/ IV or I/ II with B symptoms or bulky disease 10cm).  "Conclusion: The use of an anthracycline-based regimen as initial treatment for advanced stage indolent NHL is associated with a marked reduction in the risk of future transformation."

Background Articles

1. Risk and Clinical Implications of Transformation of Follicular Lymphoma to 
   Diffuse Large B-cell Lymphoma  jco.org 
   
   Purpose: To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in
   patients with follicular lymphoma (FL).
   
   Patients and Methods: From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew’s Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. 
   
   Results:  The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P  .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P  .04) scores at diagnosis. 
   
   Expectant management [watchful waiting]  (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P  .008). Older age (P .005), low hemoglobin level (P  .03), high lactate dehydrogenase (P = .0001), and high-risk FLIPI (P = .01) or IPI (P=  .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. 
   
   The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P .0001) and a shorter survival from progression (P = .0001) than did those in whom it was not diagnosed.
    
   Conclusion: Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival.
   There may be a subgroup of patients in whom HT does not occur..

2. Transformation of follicular lymphoma: prognostic factors and effect on survival ASCO.org
   
   Prognostic factors for transformation (TF) include lack of CR, elevated LDH, and B symptoms. 
   
   TF is associated with a higher risk of death than follicular lymphoma without TF at first and subsequent relapses; however, time to TF does not affect long term survival

3. Biology and Management of Histologic Transformation of Indolent Lymphoma  asheducationbook.org 
   
   "...chemotherapy is generally of limited benefit, although a subset of patients are long-term survivors following high-dose therapy and autologous stem cell transplantation. The use of radioimmunotherapy and new agents targeting specific lesions or aberrant pathways may impact on the management of these aggressive diseases."

4. Transformation of follicular lymphoma to diffuse large-cell lymphoma: 
    
   Alternative patterns with increased or decreased expression of c- myc and 
   its regulated genes - SUMC   PDF | HTML 
   
   Histological transformation is a pivotal event in the natural history of cancers, typically coincident with more aggressive clinical behavior. Follicular lymphoma (FL) is often a precursor to a more aggressive lymphoma. 
    
   ... Transformation to more aggressive large cell lymphoma occurs in 25–60% of patients with FL (3, 4).

5. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated 
   with a heterogeneous set of DNA copy number and gene expression alterations  bloodjournal.org
   
   "Follicle center lymphoma (FCL) is one of the most common types of lymphoma, comprising 
   about 40% of adult non-Hodgkin lymphomas (NHLs) in Western populations.¹  
   
   It is characterized by a relatively indolent clinical course and long survival, but it is currently incurable.² FCL transforms to a more aggressive lymphoma in 25%-60% of patients, an event that represents the outgrowth of a more malignant sub-clone. 
   
   Transformation is usually associated with a rapidly progressive clinical course, refractoriness to treatment, and short survival.^2,3 Several secondary genetic abnormalities have been associated with this histological transformation of FCL, ...  However, these alterations are each observed in only a subset of transformed lymphomas, suggesting that the process of histological transformation can occur by multiple different mechanisms."

6. Indolent, Recurring Non-Hodgkin's Lymphoma  Cancer.gov 

7. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma  annonc.oxfordjournals.org 
   
   Background: Histological transformation (HT) is a well-known event in patients with follicular lymphoma (FL) conferring an unfavorable prognosis. The aim of the study was to analyze incidence and risk factors for HT in a large series of FL patients.
   
   Patients and methods: 276 patients (median age: 54 years; M139/F137) diagnosed with FL (42% grade 1, 51% 2, 7% 3) in a single institution were studied. Initial treatment consisted of combined chemotherapy in most cases. Median survival was 11.3 years. Main clinic and biological variables were assessed for HT and survival. Results: 30 of 276 patients (11%) presented HT after a median follow-up of 6.5 years, with a risk of 15% and 22% at 10 and at 15 years, respectively. All HT corresponded to diffuse large B-cell lymphoma (DLBCL). Grade 3 histology, nodal areas >4, increased LDH and b2-microglobulin, and high-risk IPI and FLIPI were associated with HT. 
   
   In multivariate analysis, grade 3 histology and FLIPI retained prognostic significance. Only FLIPI predicted HT in grade 1–2 patients. 28 patients received salvage treatment for HT, with a CR rate of 52%. Median survival from transformation was 1.2 years, with 6/13 CR patients being alive >5 years after HT. 
   
   Conclusion: FLIPI and histology were the most important variables predicting HT. Upon HT, only patients achieving CR reached prolonged survival, thus emphasizing the need for effective therapies once this event occurs. 
   

8. Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma 
   
   www.nature.com pdf  
   
   Follicular lymphoma is commonly transformed to a more aggressive diffuse large B-cell lymphoma (DLBCL). 
   
   In order to molecularly characterize this histiological and clinical transformation, comparative genomic hybridization was applied on 23 follicular lymphoma and 35 transformed DLBCL tumors from a total of 30 patients. 
   
   The results were also compared with our published findings in de novo DLBCL. Copy number changes were detected in 70% of follicular lymphoma and in 97% of transformed DLBCL. 
   
   In follicular lymphoma, the  most common alterations were þ18q21 (33%), þXq25–26 (28%), þ1q31–32 (23%), and 17p (23%), whereas transformed DLBCL most frequently exhibited þXq25–26 (36%), þ12q15 (29%), þ7pter-q22 (25%), þ8q21 (21%), and 6q16–21(25%). 
   
   Transformed DLBCL showed significantly more alterations as compared to follicular lymphoma (P¼0.0001), and the alterations 6q16–21 and þ7pter-q22 were only found in transformed DLBCL but not in follicular lymphoma (P¼0.02). 
   
   Alterations involving þ13q22 were significantly less frequent, whereas 4q13–21 was more common in transformed as compared to de novo DLBCL (P¼0.01 and P¼0.02, respectively). Clinical progression from follicular lymphoma to transformed DLBCL is on the genetic level associated with acquirement of increasing number of genomic copy number changes, with non-random involvement of specific target regions. 
   
   The findings support diverse genetic background between transformed and de novo DLBCL. 

   Modern Pathology (2007) 20, 63–75. doi:10.1038/modpathol.3800708; published online 29 September 2006
    

9. Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene  bloodjournal.hematologylibrary.org

   Izidore S. Lossos and Ronald Levy
   
   Our results show that transformation of FCL to DLBCL is associated with accumulation of new mutations in the 5' noncoding regulatory region of the BCL-6 gene, that by deregulation of the BCL-6 gene expression may play a role in lymphoma transformation.

10. Genetic Reconstruction of Follicular Lymphoma Evolutions: S Mutations Studies Suggest Two Progression Patterns, Early Direct or Late from FL Stem Cells  abstracts2view.com 
    
    In conclusion, our results suggest that there may be at least two different patterns of progression in FL. 
    
    The first could be a direct and rapid evolution from the dominant subclone, explaining the stability of the mutations. 
    
    The second, which could potentially happen after many years of clinical remission, could instead be indirect, from a clonally related and often earlier t(14;18) positive subclone probably arising from a different compartment.

11. Progression of follicular large cell lymphoma to Burkitt's lymphoma.
     PubMed Related articles

12. PubMed: Atypical burkitt's lymphoma transforming from follicular lymphoma
    
     

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Incidence & Risk Factors

	The impact of initial treatment of advanced stage indolent lymphoma on the risk of transformation  ascopubs.org  n = 698 patients with indolent NHL, no prior treatment, age16–60 y and advanced stage disease (III/ IV or I/ II with B symptoms or bulky disease 10cm).  "Conclusion: The use of an anthracycline-based regimen as initial treatment for advanced stage indolent NHL is associated with a marked reduction in the risk of future transformation."
	Risk and Clinical implications of Transformation of Follicular Lymphoma to Diffuse Large B-cell Lymphoma (Single Center Experience)  JCO.org  " From January 1972 to December 1999, 325 patients with FL were treated at St Bartholomew’s Hospital (London, United Kingdom; Table 1). The diagnosis of transformation was made in 88 patients at a median of 3 years (range, 0.1 to 16.2 years). Among these 88 patients, 14 transformed before initiation of any therapy (two within 3 months of diagnosis) and 10 during initial therapy. ... The risk of transformation by 5, 10, and 15 years was 17% (95% CI,13%to 22%), 28% (95%CI,23%to 34%), and 37%(95%CI,30% to 44%), respectively.  Histological Transformation (HT) was not observed after 16.2 years of follow up, the rate of transformation remaining at 39% from that point onward (Fig 1). Patients undergoing expectant management at diagnosis (watchful waiting) had a higher risk of transformation than did those treated immediately (P  .008).  Advanced stage (III to IV) at diagnosis was associated with a higher risk of transformation (P  .02).  Both the FLIPI (P .01) and the IPI (P .04) scores at diagnosis predicted for the risk of HT  The log-rank test showed a trend for a higher risk of transformation in patients with a high LDH/HBD level at diagnosis (5-year risk,28% 17%;P.08) and for those with grade 3a FL (38% at 5 years  20% for grade 1 and 10% for grade 2; P  .09). "
	The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma (Single Center experience)  annonc.oxfordjournals.org Incidence: "30 of 276 patients (11%) presented HT after a median follow-up of 6.5 years, with a risk of 15% and 22% at 10 and at 15 years, respectively. All HT corresponded to diffuse large B-cell lymphoma (DLBCL). "  Risk factors:  "Grade 3 histology, nodal areas >4, increased LDH and b2-microglobulin, and high-risk IPI and FLIPI were associated with HT. In multivariate analysis, grade 3 histology and FLIPI retained prognostic significance. Only FLIPI predicted HT in grade 1–2 patients."
	Gene-Expression and Immunohistochemical Study of Specific T-Cell Subsets and Accessory Cell Types in the Transformation and Prognosis of Follicular Lymphoma. J Clin Oncol. 2007 Jan 2; PMID: 17200149 | Related articles
	The International Prognostic Index predicts outcome after histological transformation of low-grade non-Hodgkin lymphoma. Leuk Lymphoma. 2006 Sep;47(9):1794-9. PMID: 17064990
	Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol. 2005 Sep 10;23(26):6358-63. Review. PMID: 16155020
	A Proteomic Approach to Discovery of Candidate Proteins Involved in the Transformation of Follicular Lymphoma  ASH 2005
	Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995.  Full Text
	Transformed lymphoma: an Achilles' heel of non-Hodgkin's lymphoma.  Bone Marrow Transplant. 2003 Apr;31(7):531-7. Review. PMID: 12692617 | Related articles
	Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol. 1997 Apr;15(4):1587-94. PMID: 9193357 | Related
	Follicular lymphoma: prognostic factors for response and survival - Journal of Clinical Oncology, Vol 4, 1470-1480  abstract
	International Prognostic Index (IPI) Predicts Outcome after Histological Transformation of Low Grade Non-Hodgkin Lymphoma.  Reader-friendly
	Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol. 1995 Jul;13(7):1726-33. PMID: 7602362  PubMed | Related
	Histological conversion of follicular lymphoma with structural alterations of t(14;18) and immunoglobin genes. Leukemia. 1995 Oct;9(10):1748-55. PMID: 7564520  PubMed | Related abstracts   "About half of the patients with follicular lymphoma will develop an aggressive B cell lymphoma with morphological changes in growth pattern and cellular morphology."
	Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with  fludarabine- rituximab- containing regimens: natural history- or therapy-related complication? Eur J Haematol. 2002 Feb;68(2):80-3. PMID: 12038452  PubMed | Related
	Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood. 1994 Aug 15;84(4):1043-9. PMID: 8049424  PubMed | Related
	Acute liver failure as initial manifestation of low-grade non-Hodgkin's lymphoma transformation into large-cell lymphoma. Leuk Lymphoma. 2001 Jul;42(3):555-9. PMID: 11699425  PubMed | Related
	Transformation of follicular lymphoma: prognostic factors and effect on survival Year: 2002  Abstract No: 1129 "Conclusions: prognostic factors for Transformation  include lack of CR (complete response), elevated LDH, and B symptoms. Transformation is associated with a higher risk of death than indolent Follicular without transformation at first and subsequent relapses; however, time to transformation  does not affect long term survival."
	An autopsy study of histologic progression in non-Hodgkin's lymphomas. 192 cases from the National Cancer Institute. Cancer. 1983 Aug 1;52(3):393-8. PMID: 6344979  PubMed | Related

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Diagnosis

The Tumor Microenvironment Measured by Flow Cytometry Predicts Overall Survival (OS) and Transformation Risk (TR) in Follicular Lymphoma. Session Type: Poster Session, Board #584-II  ASH 2006  "The proportion of CD8+ T cells relative to the total T cells and the number of residual, non-neoplastic B cells were both predictors of OS. Importantly, both predict, independently of the IPI, the risk of transformation. These biomarkers are easily measured and may be used to better stratify patients, choose initial treatment options and predict transformation risk in patients with FL." Majority of Transformed Lymphomas Have High SUVs on PET Scanning Similar To Diffuse Large B Cell Lymphoma (DLBCL)  ASH 2006

Fine-needle aspiration in non-Hodgkin lymphoma: evaluation of cell size by cytomorphology and flow cytometry. Am J Clin Pathol. 2002 Jun;117(6):880-8. PMID: 12047139  PubMed | Related abstracts

"These data suggest that although outcome after HT is generally poor, a subset of patients can present prolonged OS. Moreover, it also stresses that obtaining CR with salvage therapy is a crucial event, in agreement with previously published series" 

Also see 

Treatments for Refractory Lymphomas

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Treatment Considerations

Reports consistently show that achieving a complete response (CR) is essential to long term survival (PMID: 16940035)  

How that is best achieved depends on many factors and so you must consult with your oncologist, preferably a lymphoma expert, on which of the many protocols are most appropriate to your age, treatment history, performance, and so on.  

It appears that patients with no initial therapy, or who have achieved a CR from initial therapy, have a more favorable prognosis.  

What is most often prescribed for transformed follicular is CHOP-R, but reports indicate that Bendamustine and radioimmunotherapy (RIT) can also be effective against transformed disease.   

NEWS:

Lenalidomide (LEN) in patients with transformed lymphoma: Results from a large international phase II study (NHL-003).  http://bit.ly/a234dx

"LEN has promising clinical activity and achieves durable responses in patients with TL. Also, it may be necessary to consider the original histology when setting a course of therapy for patients with TL. Further studies are needed in this hard-to-treat population."

ClinicalTrials.gov:
Studies for transformed lymphoma: Untreated  | Relapsed | Not Transplant

Note: there's no sure-fire way to query ClinicalTrials.gov to find trials that are open to patients with transformed lymphoma. Some trials exclude patients with this status, others include in the CONDITION field, but many studies don't specify one way or the other.  Here are three such studies that may be open and reasonable tries for relapsed transformed FL - that are not transplant:

* Testing DCDT2980S OR DCDS4501A (antibody - drug conjugates) WITH Rituxan http://1.usa.gov/SppweO

* Testing: ABT-199 WITH Bendamustine-Rituximab http://1.usa.gov/10StJaU

* Testing: Everolimus WITH Rituxan maintenance AFTER High-dose Consolidative Therapy http://1.usa.gov/V8CeiG

Questions you might ask:  

	What protocol would you recommend if the lymphoma is not chemosensitive?
	Is following chemotherapy with Radioimmunotherapy (bexxar / zevalin) indicated?
	Is it advisable to use PET to determine response to treatment early, so you can change the protocol if needed as early as possible?
	Is high dose therapy with stem cell rescue indicated?
	What clinical trial protocols look promising for transformed lymphoma?
	What is the rationale for the recommended treatment?

The most important first step is to consult a lymphoma expert (not a general oncologist) about which of the many options you have that are most appropriate for you.  Be sure to bring a friend or loved one to the consult and to write down your questions in advance.

Treatment Reports

	Pivotal Study of Iodine I 131 Tositumomab for Chemotherapy-Refractory Low-Grade or Transformed Low-Grade B-Cell Non-Hodgkin’s Lymphomas http://jco.ascopubs.org
	Randomized Controlled Trial of Zevalin Versus Rituximab Immunotherapy for Patients With Relapsed or Refractory Low-Grade, Follicular, or Transformed B-Cell NHL http://bit.ly/aoKHyQ
	Multicenter Phase II Study of Bexxar for Chemotherapy-Relapsed/Refractory Low-Grade and Transformed Low-Grade B-Cell NHL http://bit.ly/aX3cZf 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 antibodies.
	Bexxar and Transformed disease?  ASCO  | Full text  http://theoncologist.alphamedpress.org/cgi/content/full/9/2/160
	Zevalin and Transformed disease?  ASCO
	The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation (HT) in follicular lymphoma (Single Center Experience)  annonc.oxfordjournals.org Surviving HT:  Six patients presented prolonged survival over five years after HT (5.6+, 7+, 9.2+, 11.2+, 15+ and 18.8+ years).  Early stage (I–II) (P = 0.02), ambulatory performance status (£1) (P = 0.028), and intermediate/low or low IPI score (<3) (P = 0.0046), all at the time of transformation, correlated with longer survival after HT.  In addition, the response to salvage therapy was very important to predict survival after HT (5 years survival of 43% versus 0% for patients reaching CR (complete response) versus no CR, respectively; P = 0.0001).  No differences in terms of survival from transformation were seen between the seven patients who underwent intensification with autologous stem-cell transplantation and those that for a variety of reasons were not autografted.
	Risk and Clinical Implications of [Histologic] Transformation (HT) of Follicular Lymphoma to  Diffuse Large B-cell Lymphoma (Single Center Experience)  jco.org  Of note, up to six patients have presented prolonged survival over five years after HT. All of them had achieved CR (complete response) after salvage therapy, which included an autologous transplantation in only one case.  These data suggest that although outcome after HT is generally poor, a subset of patients can present prolonged OS. Moreover, it also stresses that obtaining CR with salvage therapy is a crucial event, in agreement with previously published series [14].
	Meet the Professors - a provocative discussion among experts regarding first treatment options for  advanced follicular lymphoma, including indications of transformation  meettheprofessors.com
	High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma:  a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001.  PuMed
	Deregulation of the Insulin-Like Growth Factor Type 1 Receptor (IGF-1R) in Transformed Follicular Lymphomas: Implications for Novel Therapy.   ASH 2006   The take-home point is that insulin-like growth factor receptors were found to be expressed on transformed FL cells, but not the FL cells of origin. Antibodies to target these receptors are under development for other cancers providing the opportunity and rationale to test these antibodies on transformed fNHL.
	Auto-transplants for histologically transformed follicular non-Hodgkin's lymphoma  related abstracts
	Aggressive NHL: Oncology Board Review Manual  yr 2000 PDF
	Overview Aggressive Non-Hodgkin's Lymphomas  Lymphoma InfoNet
	High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: a study of 27 patients from a single centre. Ann Oncol. 1998 Aug;9(8):865-9. PMID: 9789609  PubMed
	Autologous peripheral blood progenitor cell transplantation for transformed diffuse large-cell lymphoma. Clin Lymphoma. 2000 Dec;1(3):226-31; discussion 232-3. PMID: 11707835  PubMed
	Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant. 1999;5(4):262-8. PMID: 10465106  PubMed
	Rituximab-EPOCH - an Effective Salvage Regime for Relapsed, Refractory, or Transformed B-Cell Lymphoma. Results of a Phase II Study. Year: 2001  Abstract No: 1157
	Treatment of Intermediate-and High-Grade Non-Hodgkin's Lymphoma U-M Comprehensive Cancer Center
	The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma  PDF  Conclusion: FLIPI and histology were the most important variables predicting HT. Upon HT, only patients achieving CR (complete response) reached prolonged survival, thus emphasizing the need for effective therapies once this event occurs.
	Revlimid (R) Demonstrates Activity against Relapsed/Refractory Aggressive NHL marketwatch.com According to the publication, of 49 patients eligible for response evaluation in the study, an objective response was observed in 35 percent, with 12 percent exhibiting a complete or unconfirmed complete response. Activity was also seen in other lymphoma subtypes, including diffuse large b-cell, follicular grade 3 and transformed.

Transformation from follicular to Diffuse Large Cell Lymphoma
(DLCL)

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Transformed Follicular Lymphoma

"Some cases of DLBCL may arise from follicular lymphoma (an indolent lymphoma) or from chronic lymphocytic leukemia. The latter is known as a Richter’s transformation.  Both of these transformations are generally associated with worse short- and long-term outcomes after therapy." - Aggressive NHL: Oncology Board Review Manual  yr 2000 PDF | PDF-help

	p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993 Oct 15;82(8):2289-95. PMID: 8400281  PubMed
	Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8886-91. PMID: 12077300  PubMed | PDF

Non-follicular 
Transformations

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CLL and Blast Phase?

A: Yes. But it's a little bit different. The equivalent for indolent lymphomas is that most of them have a tendency, some more than others, to undergo histological transformation to a more aggressive disease. So that reflects clonal evolution, where a clone that gets additional hits. Once these things become tumors or become lymphomas, they become independent of normal regulatory pathways. They have a higher tendency to accumulate and to survive additional hits. And so what happens over time is that when our normal cells get genetic hits, our cells have huge amounts of surveillance pathways to kill those cells. Those cells die. Otherwise, we would be popping up with tumors all the time. 

Because our genetic code probably gets hit constantly. You know, our body fixes them or the cells commit suicide through the apoptotic pathway. Tumor cells have a much higher tendency of, number one, not transcribing their code correctly. And number two, not committing suicide when the hit happened. So when you have an indolent process, a chronic process, that you have for years and years and years, over time it's just natural that you're going to get clonal evolution. A clone that gets a hit that gives it a proliferative advantage. And something's going to pop up. And that's what happens in CLL when it undergoes a blastic transformation. In any of the lymphomas, they undergo a large cell transformation.  www.cancer.gov

• Richter’s transformation (DLBCL) can arise from CLL - 
  Aggressive NHL: Oncology Board Review Manual  yr 2000 PDF

MALT/Marginal Zone

	New: High-grade transformation in splenic marginal zone lymphoma with circulating villous lymphocytes: the site of transformation influences response to therapy and prognosis. Br J Haematol. 2008 Jul 30. PMID: 18671706
	Progression to large B-cell lymphoma in splenic marginal zone lymphoma: a description of a series of 12 cases. Am J Surg Pathol. 2001 Oct;25(10):1268-76. PMID: 11688461  PubMed
	Primary digestive Richter's syndrome. Mod Pathol. 2001 May;14(5):452-7. PMID: 11353056  PubMed | More
	Histological grading with clinical relevance in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recent Results Cancer Res. 2000;156:27-32. Review. PMID: 10802860 | Related articles