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.

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)

Summary:A high-dose (HD) chemotherapy scheme was designed for the collection of large numbers of peripheral blood progenitor cells (PBPC) in lymphoma patients who were candidates for myeloablative therapy with autograft. The scheme included the sequential administration of HD cyclophosphamide (CY) (7 g/m 2 ) and HD ara-C (2 g/m 2 twice a day for 6 consecutive days), followed by final consolidation with PBPC autograft. PBPC harvests were scheduled following both HD CY and HD ara-C. To minimize hematologic toxicity, small aliquots of PBPC (р3 ؋ 10 6 CD34 + cells/kg) collected following HD CY were reinfused following HD ara-C. The treatment was delivered to 112 patients (median age: 43 years) with lymphoid malignancies (107 non-Hodgkin's lymphoma, four Hodgkin's lymphoma, one amyloidosis); 75 patients were at disease onset, whereas 37 had relapsed or were refractory after first-line conventional therapy. C respectively (P = NS). Thus, the scheme allowed sufficient PBPC collections for autografting in low mobilizer patients; in addition, the scheme could be considered whenever extensive chemotherapy debulking is needed prior to PBPC collection.

Long-term outcome, after first line intensified high-dose sequential (i-HDS) chemotherapy, was evaluated in 46 patients, aged р65 years, with advanced low-grade lymphoma. Seventeen patients had small lymphocytic lymphoma (SLL), 29 had follicular lymphoma (FL), 10 of them with histologic transformation. I-HDS included: (1) tumor debulkying, by 2 APO+2 DHAP courses; (2) sequential administration of high-dose (hd) etoposide, methotrexate, and cyclophosphamide, followed by peripheral blood progenitor cell (PBPC) harvest; (3) hd-mitoxantrone + melphalan with PBPC autograft. Ten FL patients had their PBPC immunologically purged ex vivo. There were two treatment-related deaths; five FL patients had short-lasting response followed by disease progression, five SLL reached a stable PR; overall, 34 patients (74%) reached CR. At a median follow-up of 4.3 years, the estimated 9-year OS and EFS were 84% and 45%, respectively. No significant differences were observed in the OS among patients at low, intermediate or high IPI score, with an estimated OS projection of 95%, 78%, and 75%, respectively. FL had longer survival without evidence of residual disease (9-year EFS: 59%) as compared to SLL patients (8.8-year EFS: 17%); however, both groups had prolonged survival and no need of salvage treatment, as shown by the time to disease progression curve, projected to 66% and 62% for SLL and FL, respectively. The results indicate that hdapproach in low-grade lymphoma: (1) is associated with longer progression-free survival as compared to conventional therapies; (2) may imply higher tumor mass reduction in FL as compared to SLL patients; (3) offers long life expectancy, with potential survival benefits at least for patients at intermediate/high IPI score. Leukemia (2000) 14, 740-747.

The aim of this study was to investigate feasibility, tolerability and efficacy of rituximab-supplemented high-dose sequential chemotherapy (R-HDS) with peripheral blood progenitor cell autografting as frontline or salvage treatment in patients with advanced non-Hodgkin's lymphoma (NHL). Thirty-two patients have been treated: 14 at disease onset and 18 with relapsed or progressive disease. R-HDS regimens included six courses of rituximab. Rituximab was delivered either concurrently with high-dose chemotherapy to exploit the in vivo purging properties of the drug as well as at the end of the treatment plan to target minimal residual disease. All patients treated at disease onset completed their treatment with no life-threatening toxicity, while two toxic deaths due to severe bilateral pneumonia were observed among patients treated due to relapsed or refractory disease. Thirteen of 14 patients treated up-front achieved CR. Among pre-treated patients 10 of 18 achieved CR with better results in patients with relapsed (seven of eight) compared to progressive disease (three of 10). PCR analysis was carried out in indolent lymphoma patients: nine of nine follicular lymphomas and three of six CD5-positive NHL collected PCR-negative peripheral blood progenitor cell harvests. The results of this pilot study show that R-HDS is feasible and effective with acceptable toxicity when used at disease onset. In pretreated patients this treatment also showed promising results, although the risk of severe infections needs to be considered. Leukemia (2001Leukemia ( ) 15, 1941Leukemia ( -1949

Hematological and extrahematological toxicity of high-dose (hd) mitoxantrone (MITO) and melphalan (L-PAM) as conditioning regimen prior to peripheral blood progenitor cell (PBPC) autograft was evaluated in 113 lymphoma patients (87 at disease onset). Autograft was the final part of a hd-sequential (HDS) chemotherapy program, including a debulkying phase (1-2 APO ± 2 DHAP courses) and then sequential administration of hd-cyclophosphamide, methotrexate (or Ara-C) and etoposide, at 10 to 30 day intervals. Autograft phase included: (1) hd-MITO, given at 60 mg/m 2 on day −5; (2) hd-L-PAM, given at 180 mg/m 2 on day −2; (3) PBPC autograft, with a median of 11 × 10 6 CD34 ؉ /kg, or 70 × 10 4 CFU-GM/kg, on day 0. A rapid hematological recovery was observed in most patients, with ANC Ͼ500/L and Plt Ͼ20 000/l values reached at a median of 11 and 10 days since autograft, respectively. The good hemopoietic reconstitution allowed the delivery of consolidation radiotherapy (RT) to bulky sites in 53 out of 57 candidate patients, within 1 to 3 months following autograft; five of these patients required back-up PBPC re-infusion due to severe post-RT pancytopenia. Few severe infectious complications were recorded. There was one single fatal event due to severe pancytopenia following whole abdomen RT. Cardiac toxicity was evaluated as left ventricular ejection fraction (LVEF), monitored by cardiac radionuclide scan. LVEF prior to and after autograft was significantly reduced (median values: 55% vs 46%) in 58 evaluated patients; however, a significant increase to a median value of 50% was observed in 45 patients evaluated at 1 to 3 years since autograft. At a median follow-up of 3.6 years, 92 patients are alive, with a 7-year overall survival projection and 6.7-year failure-free survival projection of 77% and 69%, respectively. We conclude that a conditioning regimen with hd-MITO/L-PAM fits well within the HDS program. It implies good tolerability and reversible cardiotoxicity and it may have contributed to the good long-term outcome observed in this series of patients. Leukemia (2001) 15, 256-263.

BACKGROUNDThe 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).METHODSData 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.RESULTSNinety‐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.CONCLUSIONSThe 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. Cancer 2003;97:2748–59. © 2003 American Cancer Society.DOI 10.1002/cncr.11414

Mobilized peripheral blood progenitor cells (PBPC) are widely employed in the management of adult patients with high-risk non-Hodgkin's lymphoma (NHL), though their use in the elderly has received little attention. This study was mounted to assess the feasibility of the mobilization, harvesting, and reinfusion of PBPC in NHL patients aged >60. Twenty patients (median age: 67, range: 61-80) with poor-prognosis NHL entered the pilot study: nine others were discarded for various reasons. Thus, the program was applicable to 69% of potential candidates. Fourteen patients were at onset and six were being treated for refractory disease or relapses. Mobilization was induced with cyclophosphamide 4 g/m(2), followed by 5 micro g/kg per day granulocyte-colony stimulating factor (G-CSF) s.c. until PBPC collection or hemopoietic recovery. Sixteen patients (80%) displayed some signs of mobilization (CD34+: >5/ micro l). Maximum mobilization varied with median circulating CD34+ cells and colony forming units-granulocyte/macrophage (CFU-GM) peaks of 17.2/ micro l (range: 8.1-210) and 1,650/ml (range: 540-62,900), respectively. A median of two leukaphereses resulted in the harvesting of a median of 6.7x10(6) (range: 0.3-33.6) CD34+/kg and 21.1x10(4) (range: 1.2-209) CFU-GM/kg. Intensified therapy with intermediate-dose melphalan, associated or not with mitoxantrone, was delivered with autologous PBPC support to 13 patients and always resulted in rapid and stable hemopoietic reconstitution. The program was well tolerated and no treatment-related deaths occurred. Twelve patients are still alive with a 5-year survival projection of 59%. In conclusion, the results demonstrate the feasibility of using autologous PBPC to support therapy intensification even in elderly patients.