The impact of initial treatment of advanced stage indolent lymphoma on the risk of transformation.

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: June 4, 2006

Presenter: A.J.Al-Tourah
Presenter's Affiliation: BC Cancer Agency Fraser Valley Centre, Surrey, BC, Canada
Type of Session: Keynote


  • Follicular lymphoma is an indolent Non-Hodgkin's lymphoma that usually presents in an advanced stage.
  • Follicular lymphomas usually express CD20, a B-cell marker.
  • Transformation is defined as the development of aggressive lymphoma in patients with indolent lymphoma.
  • The FLIPI categorizes patients into low, intermediate, and high risk groups based on 5 prognostic indicators (age, stage, LDH, hemoglobin, # of extranodal sites).
  • High LDH, advanced stage, and high FLIPI at diagnosis are predictive for future transformation.
  • The impact of initial treatment on the risk of transformation is unknown.
  • Published series on this topic have included heterogeneous patient populations.

Materials and Methods

  • The BC Cancer Agency Lymphoid Cancer Database records full clinical and follow-up data on all patients with lymphoma managed at the BC Cancer Agency.
  • A retrospective study of the incidence and outcome of transformed lymphoma was performed.
  • 698 patients were identified.
  • Patient cohorts from consecutive phase III trials that were included in the retrospective study were identified for this analysis.
  • Patients were ages 16 to 60.
  • Patients could not have a previous diagnosis of cancer.
  • Histology had to be indolent lymphoma (follicular, small lymphocytic, or lymphoplasmacytic).
  • Patients had to present with advanced stage disease (stage III/IV, or I/II with B symptoms and/or bulky disease >10cm).
  • The diagnosis of transformation was either made with pathologic confirmation or using suspicious clinical markers such as rapid localized nodal growth, sudden rise in LDH (2X baseline), unusual extranodal involvement, or hypercalcemia.
  • The first study in the database used BPVACOP (bleomycin, cisplatin, etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone) with involved field radiation to original nodal sites (n=140).
  • The second study in the database used combination alkylator/purine analog (cyclophosphamide - cladrabine or fludarabine and prednisone) (n=120).
  • For this analysis, these two groups of study patients were compared.
  • However, these two groups only represented 2 of the 8 strategies for initial treatment identified in this database: BPVACOP + radiation, alkylator + purine analogue, observation, radiation, alkylating agent, purine analog, CHOP, and rituximab.
  • The two groups were fairly well balanced in terms of demographic and disease related factors.


  • 26 (18%) patients in the BPVACOP+RT study developed transformation; 16 were biopsy confirmed.
  • 32 (27%) patients in the alkylator/purine study developed transformation; 18 were biopsy confirmed.
  • The 5 year risk of transformation for the BPVACOP+RT patients was 9% compared to 24% for the alkylator/purine patients (p<0.0095).
  • The 10 year absolute risk of transformation for the BPVACOP+RT group was 1.5% compared to 3% for the alkylator/purine patients (p<0.0095).
  • The 5 year overall survival for all transformed patients was 19%.
  • There was no difference seen in overall survival after transformation by initial treatment regimen (p=0.4).
  • There was no difference seen in overall survival by choice of initial regimen.
  • Patients with transformation based on clinical versus histologic criteria did not differ in their outcomes.

Author's Conclusions

  • The use of an anthracycline based regimen as initial treatment of advanced stage indolent lymphoma is associated with a marked reduction in the risk of transformation compared to an alkylator/purine combination.
  • No impact on the overall survival of indolent lymphoma was observed.

Clinical/Scientific Implications

The authors presented a retrospective analysis of patients treated for advanced stage indolent lymphoma. The analysis really only focused on patients who received one of two separate regimens, and was thus comprised of 260 patients. It is difficult to make strong conclusions using these methods. Why weren't the other patients included in the analysis? The fact that only 260 of 698 patients were analyzed weakens this study.

Curiously, the patients who received the BPVACOP+RT had a lower chance of transformation than the alkylator/purine patients, but the two groups had no difference in overall survival. Does this mean that the alkylator/purine patients were salvaged more effectively? Or did more of the BPVACOP+RT patients die as a result of therapy? The authors do not present enough data to answer these important questions.

The claim that an antracycline based regimen reduces the risk of transformation compared to alkylator/purine combination is somewhat misleading. Yes the BPVACOP+RT group included an anthracycline, but it also included lots of other potent therapies (cisplatin, etoposide, radiation). How do we know it is the anthracycline that made the difference and not one of the other drugs? We cannot ever know the answer to this question based on this analysis.

Finally, there are a number of new therapeutic agents used for indolent lymphoma that appear quite effective without causing significant toxicity (rituximab, Bexaar). This study will not change the way that patients are treated for advanced stage indolent lymphoma, and it unlikely to convince many doctors that BPVACOP+RT is the preferred regimen for this disease. The only way to prove the superiority of a regimen is to study it in a randomized clinical trial.