Ming Sheng Lee

Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25 Years of Treatment Experience at The University of Texas M.D. Anderson Cancer Center

PURPOSE Advanced-stage follicular lymphoma is considered incurable. The pace of improvements in treatment has been slow. This article analyzes five sequential cohorts of patients with stage IV follicular lymphoma treated between 1972 and 2002. METHODS Five consecutive studies (two were randomized trials) involving 580 patients were analyzed for overall survival (OS), failure-free survival (FFS), and survival after first relapse. A proportional hazards analysis, and subset analyses using the follicular lymphoma international prognostic index (FLIPI) score were performed. Treatment regimens included: cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin (CHOP-Bleo); CHOP-Bleo followed by interferon alfa (IFN-alpha); a rotation of three regimens (alternating triple therapy), followed by IFN-alpha; fludarabine, mitoxantrone, dexamethasone (FND) followed by IFN-alpha; and FND plus delayed versus concurrent rituximab followed by IFN-alpha. RESULTS Improvements in 5-year OS (from 64% to 95%) and FFS (from 29% to 60%) indicate steady progress, perhaps partly due to more effective salvage therapies, but the FFS data also indicate improved front-line therapies; these observations held true after controlling for differences in prognostic factors among the cohorts. The FLIPI model adds rigor to and facilitates comparisons among the different cohorts. An unexpected finding in this study was a trend toward an apparent FFS plateau. CONCLUSION Evolving therapy, including the incorporation of biologic agents, has led to stepwise significant outcome improvements for patients with advanced-stage follicular lymphoma. The apparent plateau in the FFS curve, starting approximately 8 to 10 years from the beginning of treatment, raises the issue of the potential curability of these patients.

The significance of molecular response of follicular lymphoma to central lymphatic irradiation as measured by polymerase chain reaction for t(14;18)(q32;q21).

BACKGROUND More than 80% of the patients with follicular lymphoma have a characteristic chromosomal translocation, t(14;18)(q32;q21), at the major breakpoint region (MBR) or minor cluster region (MCR) involving the bcl-2 oncogene. This study was undertaken to assess the significance of the molecular response rate measured by the polymerase chain reaction (PCR) evidence of translocation among patients with Stage I to III follicular lymphoma treated with central lymphatic irradiation (CLI). METHODS AND MATERIALS Thirty-three patients with Stage I-III follicular lymphoma were treated with CLI on a prospective protocol. Bone marrow and peripheral blood samples were obtained before CLI for PCR analysis of t(14;18)(q32; q21). PCR-positive patients were followed by PCR analysis at regular intervals during and after CLI, and the results were correlated with clinical outcome. The following pretreatment factors were also investigated for their relationship to relapse and molecular response: gender, age, lactate dehydrogenase (LDH) and beta-2 microglobulin (beta2M) levels, Ann Arbor stage, and International Prognostic Index (IPI) for malignant lymphoma. RESULTS The subjects were 19 men and 14 women, with a median age of 52 years (range 30-69), who started CLI between January 1993 and February 1998. Median follow-up was 44 months (range 12-67), and all but 2 patients were still alive at the last follow-up. Four patients were Stage IA, 8 were Stage IIA, 19 were Stage IIIA, and 2 were Stage IIIB. Two patients had abnormal LDH levels (> 618 U/dL) and 7 patients had abnormal beta2M levels (> 2 mg/dL). Nine patients had IPI = 0, 16 had IPI = 1, and 8 had IPI = 2. All patients achieved complete response (CR). Twelve patients have relapsed to date. The median overall time to relapse was 54 months. The actuarial proportion of patients free from relapse at 3 years was 87% (95% confidence interval [CI] 69-95%). A total of 287 PCR results were available, 64 from bone marrow and 223 from peripheral blood. Pretreatment PCR data were available for 27 patients, of whom 21 were positive and 3 were unambiguously negative (in blood and bone marrow for both MBR and MCR). For the 19 PCR positive patients for whom we had post-treatment results, there was a clear and steady decreasing trend toward loss of PCR positivity (49% positive for bone marrow and 32% positive for peripheral blood at 3 years). There was a clear trend for increasing PCR positivity with increasing IPI: 10% for IPI = 0, 31% for IPI = 1, and 63% for IPI = 2 at 3 years for blood. The same trend was also observed for bone marrow. The IPI was the only statistically significant predictor for relapse with a relapse-free survival of 91% at 3 years for IPI < 2 and 75% for IPI = 2 (p = 0.024, log-rank test). CONCLUSION Molecular response to CLI occurs gradually over years. High IPI is a negative predictor for molecular response and relapse-free survival.

Molecular response of follicular lymphoma to cyclophosphamide, doxorubicin, vincristine, prednisone C(H)OP or COP-based therapy as measured by polymerase chain reaction evidence of translocation (14;18)(q32;q21).

PURPOSEExisting data suggest that conventional C(H)OP (cyclophospha-mide, doxorubicin, vincristine, prednisone) regimen may not be intensive enough to achieve molecular response, as measured by polymerase chain reaction (PCR) evidence of translocation (14;18)(q32;q21) for follicular lymphoma. This study was undertaken to study the molecular response rate of follicular lymphoma to C(H)OP-based therapy and to analyze prognostic factors for molecular response. PATIENTS AND METHODSTwenty patients with pretreatment PCR evidence of t(14;18)(q32;q21) and at least one posttreatment PCR analysis after the initiation of the treatment with C(H)OP with or without radiation therapy constituted the basis for this analysis. The random effects logistic model was used to analyze the data. The following factors were investigated for their relationship to molecular response: gender, age, β2-microglobulin, use of radiation therapy, Ann Arbor stage, and International Prognostic Index for malignant lymphoma. RESULTSMedian follow-up was 56 months (range, 23–153 months). A total of 135 PCR results were available, 33 from bone marrow and 102 from peripheral blood. Overall, there was a clear and steady decreasing trend toward loss of PCR positivity with increasing time after treatment. By univariate analysis, stage ≥3, stage = 4, International Prognostic Index ≥2, and no radiation therapy were adverse factors for molecular response. On multivariate analysis, Ann Arbor stage IV and no radiation therapy were independent risk factors for PCR positivity, both for the peripheral blood data analyzed alone and for all data combined. DISCUSSIONIt is possible to achieve molecular response with C(H)OP with or without radiation therapy in patients with follicular lymphoma. Response rate depends on the Ann Arbor stage and radiation therapy.