Abstract 879 As previously reported, dose-escalated first-line therapy with autoSCT as conducted in the GCLLSG CLL3 protocol is a feasible and effective therapy option for younger patients with poor-risk CLL. Purpose of the present analysis was to study the impact of FISH karyotype according to the hierarchical model, and of IGHV mutational status on progression-free (PFS) and overall survival (OS) in this trial. Trial design and patients: The protocol comprised optional cytoreduction with CHOP, fludarabine, or FC; PBSC mobilization using the Dexa-BEAM regimen; and myeloablative therapy with TBI/CY followed by reinfusion of purged (CD34+) stem cells. Inclusion criteria were age <61 years, stage Binet B/C or poor-risk stage A as defined by short lymphocyte doubling time plus elevated TK, and one line of pretreatment or less. From December 1996 through September 2002, 216 patients were registered with the protocol. As 47 cases had to be excluded due to screening failure (n=21), withdrawn consent (n=19) or other reasons (n=7), 169 patients were eligible for the current analysis. Male to female ratio was 5:1 and the median age at diagnosis was 51 years (range 27-60). Results: SCT was performed in 131 patients (78%) at a median time of 17 months (range 4-159) after initial diagnosis, whereas 38 patients did not proceed to SCT due to mobilization failure (n=14), disease progression (n=4), early death (n=3), patients preference (n=6), or unknown reasons (n=11). At a median follow-up of 99 months (range 4-137) after initiation of first cytoreductive therapy within the protocol, median OS of all 169 patients was 10.5 years, with 10.5 years for those treated with and 6.1 years for those treated without autoSCT, yielding a hazard ratio of 0.26 (95% CI 0.13-0.54; p<.0001). Median PFS was 6.3 years, with 6.8 years for those treated with and 4.8 years for those treated without autoSCT (HR 0.39; 95% CI 0.23-0.67; p=0.0007). The 10-year incidence rate of t-MDS/ t-AML was 9% (1-18%). Diagnostic samples for assessment of the IGHV mutational status were available for 143 of 169 patients (85%). An unfavorable (unmutated of V3-21-containing) IGHV rearrangement was present in 104 patients (73%). Compared to the 39 patients with favorable IGHV, those with unfavorable VH had significantly worse PFS and OS (median PFS 5.1 years vs not reached, hazard ratio (HR) 2.47 (1.56-3.92), p=0.0001; median OS 9.1 years vs not reached, HR 2.0 (1.14-3.68), p=0.017). FISH was possible in 160 patients (95%) with results as follows: del 17p- 4 patients (3%), del 11q- without del 17p 40 patients (25%), trisomy 12 without del 17p- and del 11q- 20 patients (13%), del 13q- as sole abnormality 48 patients (30%), other karyotypes 20 patients (13%), normal karyotype 28 patients (17%). All 4 patients with del 17p- showed progressive disease after Dexa-BEAM mobilization and did not proceed to autoSCT. Whereas PFS (p <0.0001) and OS (p <0.0001) thus was strongly reduced in the 4 patients with del 17p-, no significant differences between the other subsets became evident: median PFS 1.0 years (del 17p-), 5.9 years (del 11q), 4.8 years (+12), 7.5 years (del 13q-), 7.7 years (normal); median OS 1.5 years (del 17p-), 10.5 years (del 11q-), not reached (+12), not reached (del 13q-), 10.3 years (normal). Conclusions: Unmutated IGHV remains an adverse prognostic factor after dose-escalated first-line therapy with autoSCT. In contrast, this strategy may overcome the unfavorable impact of the FISH karyotype del 11q- seen with conventional therapy. Disclosures: Hopfinger: Roche: Honoraria. Schmitz:Roche: Honoraria, Research Funding. Stilgenbauer:BayerScheringAG: Honoraria, Research Funding.

To assess retrospectively the results of long-term combined chemotherapy and radiotherapy of patients 70 years of older, taking into account the international non-Hodgkin lymphoma (NHL) prognostic index of Shipp as well as the dose-intensity.Of 303 patients treated for aggressive NHL 100 were aged 70 years or more (median age 76 years). Localized stages I or II were present in 56, advanced stages III or IV in 44, and 38 had extranodal tumours. 92 patients were given multiple-drug chemotherapy according to the CHOP or COP BIAM protocols (n = 89 and 3, respectively), followed by single large-field or "involved field" radiotherapy with the aim of consolidation (n = 49) or cure (n = 26).Recurrence-free and total survival probabilities were 32% and 30%, respectively. 54 patients with stages I or II survived 10 years, but only six survived just 4 years with stages III or IV. There were five treatment-associated deaths.Combined chemo- and radiotherapy can achieve long-term remission in most even elderly patients with localized stages of aggressive NHL.

In a twelve-year period (1980-1992) 23 patients (9 men, 14 women; mean age 65 [25-82] years) with malignant non-Hodgkin lymphoma of the stomach, in localized stage I or II (Ann Arbor classification), were given chemo- and radiotherapy without preceding operation. The results were compared with those of a group of 34 patients (19 men, 15 women; mean age 55 [17-77] years) who had been admitted during the same period, having first been treated by surgical resection and most of them additionally by chemo- and/or radiotherapy. Three not previously operated patients with inadequate response to chemotherapy subsequently underwent laparotomy and remained in remission after further treatment. There was in each group one fatal recurrence. Five-year total probability of survival in the operated and non-operated groups was 90% and 92%, respectively; five-year total recurrence-free probability was 88% and 86%, respectively. There were no cases of severe bleeding or perforation. These results demonstrate that conservative management of localized gastric lymphoma by combined chemo- and radiotherapy does not bring about a rise in recurrence rate and does not seem to be inferior to surgical treatment.

The World Health Organization (WHO) lymphoma classification recognises anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoma (AIL) and peripheral T-cell lymphoma, unspecified (PTCU) as nodal mature T-cell lymphomas. Little is known about long-term outcome and prognostic factors of these diseases. A retrospective analysis on 125 patients with ALCL, AIL or PTCU was performed to evaluate outcome parameters, taking into account histological subtype and the International Prognostic Index (IPI). Median age was 54 years (range 17-90 years). Complete remission (CR) was achieved in 51% of patients. Five-year overall survival (OS) was 43%, and 5-year relapse-free survival was 69%. Five-year OS was 61% for ALCL, 45% for PTCU and 28% for AIL. With regard to the IPI, 5-year OS was 74%, 49%, 21% and 6% for the low, low-intermediate, high-intermediate and high risk groups, respectively. In the multivariate analysis, the IPI but not the histological subtype significantly predicted survival. To a large extent, the IPI score explains the differences in survival between histological subtypes of nodal mature T-cell lymphomas. The IPI may therefore be used for risk stratification in clinical trials to identify patients who would benefit most from new treatment strategies, such as high-dose chemotherapy followed by stem cell or bone marrow transplantation.

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.

A phase III, randomized, double-blind, placebo-controlled, multi-center trial was conducted in order to compare the incidence of microbiologically defined infections occurring after high-dose chemotherapy (HDT) and ASCT in 98 patients given lenograstim (Granocyte®) and 94 patients given placebo after transplantation. Hematopoietic recovery, the use of i.v. antibiotics, the numbers of red blood cell and platelet transfusions, the days spent in hospital, and the days on parenteral nutrition were also compared. The incidence of infections until neutrophil recovery was significantly less in patients who received lenograstim after HDT and ASCT as compared to patients who received placebo (66 of 98 vs 86 of 94 patients, P<0.001). Lenograstim also significantly reduced the use of i.v. antibiotics (P<0.001) and the median duration of i.v. antibiotic treatment (8 days vs 10 days, P=0.04), improved neutrophil recovery (absolute neutrophil count >0.5 × 109/l: 11 days vs 15 days, P<0.001) and reduced the number of days spent in hospital (15 days vs 17 days, P<0.001). The administration of lenograstim after HDT and ASCT significantly reduces the incidence of microbiologically defined infections until neutrophil recovery. It also leads to less use of antibiotics and earlier discharge from hospital.

The study was initiated to assess the safety and effectiveness of primary chemotherapy (CHT) followed by radiotherapy (RT) compared to surgery prior to CHT and/or RT in the management of localized gastric lymphoma. Ninety-two patients treated between 1985 and 2000 were included in a retrospective analysis. Sixty patients received primary CHT followed by extended field or involved field RT. Thirty-two patients had undergone primary surgery prior to referral and were treated with curative or consolidative CHT and/or RT. CHT was carried out according to the CHOP or COP-Blam protocol. Median age was 60 years (29-85). Forty patients had tumor stage IE, 36 II1E and 16 II2E (Musshoff classification). MALT histology was present in 25, diffuse large-cell in 62, lymphoplasmocytic in 4 cases and follicular histology in 1 case. Five-year disease-specific survival was 93% both after primary CHT and after primary surgery (P = 0.8). Five-year relapse-free survival was 91% and 93%, respectively (P = 0.7). No patient experienced gastric perforation or bleeding during CHT. Primary CHT of localized gastric lymphoma is associated with a low risk of treatment-related complications. Survival was similar compared to patients initially treated with surgery. To avoid long-term sequelae after gastric resection, primary CHT is recommended as standard initial treatment in localized gastric lymphoma.

To evaluate the efficacy and toxicity of two different etoposide dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning regimen followed by stem cell transplantation in patients with acute myeloid leukemia (AML).

Background: Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear.Methods: Seven hundred and eighty-three newly diagnosed AML patients treated in the German SHG-AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission-rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers.Results: With a median follow-up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox-regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients less than or equal to 60 years.Conclusions: Immunophenotyping is not only helpful for diagnosis but is of independent significance for prognosis, and may be useful for risk stratification in AML patients. (C) 2003 Wiley-Liss, Inc.

The aim of this retrospective single institution study was to investigate the long-term outcome of sequential chemotherapy (CHT) and radiotherapy (RT) in patients >/= 70 years old, considering the International Prognostic Index (IPI) for high-grade non-Hodgkin's lymphoma (NHL) and comorbidity. The study involved 106 patients aged 70 years and above, treated between 1986 and 1998, for diffuse large B-cell NHL (DLBCL); 57% had localized disease (stage I or II) and 43% had advanced disease (stage III or IV). All patients received four to six cycles of CHOP (cyclophosphamide, hydroxy-daunorubicin, oncovin, prednisone) CHT at 14-21 d intervals, followed in 69 cases by extended-field or involved-field RT. Complete response rate was 65%; overall survival probability at 5 years was 41% in all stages. Five-year survival was 62% in patients with localized and 12% in advanced disease. There were 3% treatment-related deaths. The 5-year survival rate was 70% in patients with IPI low risk, 46% with low-intermediate risk, 28% with high-intermediate risk and 0% with high risk. Patients with cardiac problems and advanced disease were more susceptible to treatment-related toxicity. Patients with hypertension showed a high rate of vinca alkaloid-associated polyneuropathy. Most patients with localized DLBCL achieved long-term remission after CHT and RT regimens despite advanced age and frequent comorbidities. Advanced disease increased the risk for treatment-related complications and efficacy of treatment seemed limited.

. Autologous stem cell transplantation (SCT) is widely used as salvage treatment for patients with relapsed follicular lymphoma (FL). Although SCT can induce prolonged remissions, it does not appear to be curative in the vast majority of patients. The purpose of this study was to investigate if incorporation of SCT into first-line therapy can improve its efficacy. Fifty-five patients underwent sequential high-dose therapy as up-front ( n =33) or salvage treatment ( n =22) for advanced stage FL at our institution. Treatment consisted of intensive chemotherapy with dexamethasone, carmustine (BCNU), etoposide, cytarabine, and melphalan (Dexa-BEAM) for mobilization of peripheral stem cells and reduction of tumor load, followed by one of three different myeloablative regimens and SCT. With a median follow-up of 4 years, projected event-free survival (EFS) and overall survival (OS) at 4 years post transplant was 59% and 84%, respectively, with no evidence of plateau in the survival curves. By univariate and multivariate analysis weighing age, sex, stage, BM and extranodal involvement, timing of transplant, ex vivo purging, and conditioning regimen [total body irradiation (TBI) vs non-TBI], the only significant factor predicting for superior EFS and OS was up-front vs salvage transplant (4-year EFS 76% vs 38%, p =0.02; 4-year OS 92% vs 73%, p =0.033). However, when calculated from diagnosis, EFS and OS of the up-front and salvage groups were virtually identical, implying that the longer survival post SCT in the up-front group was completely compensated by the longer interval between diagnosis and transplant in the salvage group. Median OS from diagnosis was 13.5 years. Except for one case of anaplastic large cell lymphoma, secondary neoplasms have not occurred to date. In conclusion, our data indicate that SCT might improve the prognosis of patients with disseminated FL, although it is probably not curative even if applied early during the course of the disease. The optimum timing of SCT remains to be determined by the ongoing randomized multicenter trial of the German Low-grade Lymphoma Study Group. The impact of radiotherapy on the success of SCT does not seem to be as essential as originally believed.