Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes.

PURPOSE: To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. PATIENTS, MATERIALS, AND METHODS: A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). Results The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P <.005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. CONCLUSION: Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.

Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders.

In this study we investigated telomere restriction fragment (TRF) length in a panel of mature B-cell lymphoproliferative disorders (MBCLDs) and correlated this parameter with histology and histopathogenesis in relation to the germinal center (GC). We assessed 123 MBCLD samples containing 80% or more tumor cells. TRF length was evaluated by Southern blot analysis using a chemiluminescence-based assay. GC status was assessed through screening for stable and ongoing somatic mutations within the immunoglobulin heavy-chain genes. Median TRF length was 6170 bp (range, 1896-11 200 bp) and did not correlate with patient age or sex. TRF length was greater in diffuse large cell lymphoma, Burkitt lymphoma, and follicular lymphoma (medians: 7789 bp, 9471 bp, and 7383 bp, respectively) than in mantle cell lymphoma and chronic lymphocytic leukemia (medians: 3582 bp and 4346 bp, respectively). GC-derived MBCLDs had the longest telomeres, whereas those arising from GC-inexperienced cells had the shortest (P < 10(-9)). We conclude that (1) TRF length in MBCLD is highly heterogeneous; (2) GC-derived tumors have long telomeres, suggesting that minimal telomere erosion occurs during GC-derived lymphomagenesis; and (3) the short TRF lengths of GC-inexperienced MBCLDs indicates that these neoplasms are good candidates for treatment with telomerase inhibitors, a class of molecules currently the subject of extensive preclinical evaluation.

Patients with high-risk aggressive lymphoma treated with frontline intensive chemotherapy and autografting: evidence of marked differences in outcome between patients with age-adjusted International Prognostic Index scores 2 and 3.

BACKGROUND: The goal of the current study was to evaluate the impact of presentation with an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3 on patients with high-risk aggressive lymphoma who are treated with frontline intensive chemotherapy and autografting. METHODS: Sixty-nine consecutive patients (median age, 40 years) with either B-cell (n = 60) or non-B-cell (n = 9) aggressive lymphoma were treated with high-dose sequential (HDS) chemotherapy and peripheral blood progenitor cell (PBPC) autografting. The patients who were examined had poor prognoses, with aaIPI scores of 2 (n = 37) or 3 (n = 32). The original treatment regimen, sequential delivery of cyclophosphamide, methotrexate, and etoposide, followed by PBPC autografting (o-HDS), was used in the first 32 patients; the program was intensified by the addition of a course of high-dose cytosine arabinoside (C-HDS) in the next 37 patients. RESULTS: There were 4 toxicity-related deaths-2 in each aaIPI subgroup (treatment-related mortality, 5.8%). The complete remission rate was significantly higher among patients with an aaIPI score of 2 (n = 32 [86%]) compared with those with an aaIPI score of 3 (n = 13 [41%]; P < 0.001). Patients with an aaIPI score of 2 had significantly better outcomes than did patients with an aaIPI score of 3 in terms of both overall survival (78% vs. 34% at 8 years; P < 0.001) and event-free survival (72% vs. 28% at 8 years; P < 0.001). Similar results were observed when the analysis was limited to the 60 patients with B-cell-derived lymphoma. No significant differences in outcome between patients receiving o-HDS and patients receiving C-HDS were observed. Multivariate analysis demonstrated that an aaIPI score of 3 was the only parameter that was significantly associated with poor overall and event-free survival. CONCLUSIONS: Age-adjusted International Prognostic Index score is applicable to patients with aggressive lymphoma who are treated with frontline intensive chemotherapy and autografting. In addition, upfront use of HDS chemotherapy appears to be beneficial to patients with an aaIPI score of 2 but not to those with an aaIPI score of 3.

High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma: a multicenter study of the intergruppo Italiano Linfomi showing prolonged disease free survival in patients treated at first recurrence.

BACKGROUND: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.