Histologic Progression of Follicular Lymphoma: Efficacy of High-Dose Therapy and Autologous Bone Marrow Transplant
Abstract & Commentary
Source: Friedberg JW, et al. Biol Blood Marrow Transplant 1999:5;262.
About 20-25% of all lymphomas are follicular lymphomas and the majority of these cancers present with disseminated disease. As they are derived from follicular center B cells, they have a tendency to undergo mutations in their immunoglobulin genes, and increasingly it appears that this genetic instability affects other genes as well. Follicular lymphoma may remain indolent in its clinical growth for a number of years, but up to 90% of patients dying with a diagnosis of follicular lymphoma have experienced histologic transformation from a follicular pattern of growth to a diffuse pattern of growth.1
And when the pattern of growth changes, so too does the natural history.2,3 Patients with histologic transformation of follicular lym- phoma to diffuse large B-cell lymphoma have a median survival of 6-8 months.4
Efforts to treat transformed diffuse large-cell lymphoma in a fashion similar to de novo diffuse large-cell lymphoma have generally found that some patients may achieve durable remissions, but the frequency of successful treatment is lower with transformed than with de novo patients. Recently, Friedberg and colleagues from the Dana-Farber Cancer Institute reported on the use of high-dose therapy and autologous bone marrow transplantation in 27 patients with transformed lymphoma.
Twenty-one of the reported patients had an original diagnosis of follicular lymphoma and six had Richter’s transformation from chronic lymphocytic leukemia. Age ranged from 29 to 58 years, median 44 years. Median time of histologic transformation from diagnosis was three years (range, 6 months-15 years). All patients received conventional dose therapy to reduce tumor bulk to lymph node masses less than 2 cm and bone marrow involvement of less than 20% of the marrow space. The preparative regimen was cyclophosphamide (60 mg/kg) given daily twice followed by three days of hyperfractioned total body radiation therapy.
There were no acute treatment-related deaths, although four patients developed secondary myelodysplasia or acute leukemia and three of these patients died. Twelve patients (44%) are alive and free of disease a median of three years after treatment. Eleven patients (41%) experienced disease progression after treatment and nine of these patients have died.
Outcome was analyzed for the influence of a variety of prognostic factors. Interestingly, patients who had undergone histologic transformation within 18 months of diagnosis had a significantly better treatment outcome than those who had a longer period of indolent lymphoma before progression. Five-year disease-free survival was 62% for early transformers compared to 31% for those whose transformation occurred more than 18 months after diagnosis. Overall survival at five years was 80% for the early transformers and 31% for the late transformers.
COMMENTARY
Histologic transformation of follicular lymphoma appears to occur as a consequence of accumulation of genetic damage. The new tumor is a genetically altered version of the original tumor in the vast majority of cases.
New cytogenetic lesions affecting chromosomes 6p, 17p, and 9p are particularly common after histologic transformation and alterations in the function of the p53 gene on chromosome 17p and the cyclin-dependent kinase inhibitors, p15 and p16 on chromosome 9p are thought to be involved in the accelerated growth.5-7 It is unclear how these tumors differ in molecular terms from the de novo diffuse large B-cell lymphomas that they resemble microscopically; however, whatever the differences, the result appears to be a greater likelihood of drug resistance.
The results reported by Friedberg et al suggest that perhaps as many as half of the patients who undergo histologic transformation from an indolent to a diffuse aggressive lymphoma are curable with high-dose therapy and autologous bone marrow transplantation. This fraction is similar to the fraction of patients with relapsed diffuse large cell lymphoma that may be curable by this modality. The extremely poor outcome from the use of CHOP in patients with histologic transformation combined with the relatively greater success of the high-dose therapy approach makes it reasonable to consider high-dose therapy approaches as the treatment of choice in patients with histologic transformation.
The apparent influence of time to transformation on treatment outcome in this study is a surprise. Friedberg et al attempted to ascertain if there were significant differences in the amount of prior therapy given to the early vs. the late transformers. However, this variable did not appear to explain the observed differences. It would be of enormous interest to compare the genetic lesions in early vs. late transformers to try to better understand if there are molecular predictors of response to therapy in this setting.
References
1. Garvin AJ, et al. Cancer 1983;52:393-398.
2. Hubbard SM, et al. Blood 1982;59:258-264.
3. Acker B, et al. J Clin Oncol 1983;1:11-16.
4. Armitage JO, et al. Cancer Treat Rep 1981;65:413-418.
5. Tilly H, et al. Blood 1994;84:1043-1049.
6. Sander CA, et al. Blood 1993;82:4,1994-2004.
7. Elenitoba-Johnson KS, et al. Blood 1998;91:4677-4685.
Which statement is true regarding histologic transformation of follicular lymphoma?
a. It is a rare occurrence in patients with follicular lymphoma.
b. It happens commonly but does not affect the natural history of the disease.
c. It is readily treatable with CHOP.
d. It represents the emergence of a second malignant neoplasm unrelated to the first.
e. About half of patients may be cured with high-dose therapy and bone marrow transplant.
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