Risk-assessment in diffuse large cell lymphoma at first relapse. A study by the Italian Intergroup for Lymphomas.

BACKGROUND AND OBJECTIVES: Our aim was to identify risk factors in adults with diffuse large cell lymphoma at first relapse. DESIGN AND METHODS: We studied 474 patients observed at 45 centers in Italy. Median time from diagnosis to relapse was 395 days, median age at relapse was 55 years and median follow-up from relapse was 3.3 years. Salvage therapy consisted of polychemotherapy in 79% of patients, monochemotherapy and/or radiotherapy and/or surgery alone in 16%, and palliative therapy in 5%. Salvage treatment was intensified with high-dose chemotherapy + stem cell transplant in 20% of patients. OS and PFS were compared by sex, International Prognostic Index at diagnosis, histology, B/T phenotype, initial treatment, salvage therapy, and features at relapse: time from diagnosis, LDH, stage, performance status and bone marrow involvement. Cox models, adjusted for salvage therapy, were performed with factors related to overall survival (OS) and progression-free survival (PFS). RESULTS: Overall response (complete + partial) was 63%, OS at 3 years 35% and PFS at 3 years 26%. Relapse within 12 months from diagnosis, elevated serum lactic dehydrogenase (LDH), advanced stage and poor performance status were independent adverse factors for OS and PFS. The cumulative number of adverse factors is proposed as prognostic index for DLCL at first relapse since it identifies risk groups (p<0.0001) and has been validated (p=0.01). Moreover, it predicts OS and PFS in the selected group of patients with a responsive relapse (p<0.0001). INTERPRETATION AND CONCLUSION: Delay from initial diagnosis, LDH, stage and performance status at relapse should be balanced in comparative studies of salvage therapy of adults with DLCL. Patients with more than 2 adverse factors are one third of all cases and deserve more effective salvage treatments.

The risk of second malignant tumors and its consequences for the overall survival of Hodgkin's disease patients and for the choice of their treatment at presentation: analysis of a series of 1524 cases consecutively treated at the Florence University Hospital.

PURPOSE: To quantify the incidence of second malignant tumors (SMT) as a whole and that of second "solid" tumors (SST) and leukemia (L) in a large series of 1524 Hodgkin's disease (HD) patients (pts) treated at the Florence University Hospital (UFH); to define the clinical and therapeutic features possibly related with SMT occurrence; to evaluate the consequences of SMT for the overall survival of the series studied and for the choice of the treatment of HD at presentation. METHODS AND MATERIALS: From 1960 to 1991, 1524 pts with HD, Clinical Stage (CS) I--IV have been treated at the UFH. Overall treatment consisted of radiation alone (RT, 36%), chemotherapy alone (CHT, 21%), or both (RT + CHT, 43%). The cumulative probability (CP) of SMT, SST, and L was calculated for the whole series and for the different clinical and therapeutic subgroups, and the results compared with uni- and multivariate analysis ("internal" comparison, IC). Standardized incidence ratios (SIR) for different SMT types (estimated on the basis of gender, age, period specific incidence rates of the general population) have been also calculated ("external" comparison, EC). The impact of the SMT-related mortality on the survival of the entire series has been estimated. RESULTS: A 14.9% 20-year CP of SMT was registered, along with a SIR of 2.04 (95% confidence interval [CI]: 1.2--2.5). Both IC and EC showed a statistically significant relationship between L incidence and treatment with CHT, alone or in combination with RT. A significant excess of breast cancers has been observed in RT-treated patients with longer follow-up (SIR, 2.9); an excess of other common SST (lung, non-Hodgkin's lymphomas) is evident in pts treated with either RT, RT + CHT, or CHT. The actuarial long-term survival of the series would have been better of about 3%, in absence of the SMT mortality possibly due to HD treatment, which is almost equally divided between patients treated with RT alone, CHT alone, and RT + CHT. CONCLUSIONS: SMT represent an important late event in HD long-term survivors. The relationship between L and treatment with CHT seems to be the most clearly defined. The effect of SMT on the survival of the entire series, although not negligible, does not seem to justify by itself substantial alterations in the current standards for the treatment of HD at presentation.

Treatment of large cell lymphoma with the Fi2 regimen (doxorubicin, vincristine, cyclophosphamide, bleomycin and prednisone): 25-year experience.

The CHOP protocol is the reference treatment for large cell lymphomas, but several other schemes of different intensity have recently been studied with controversial clinical findings. We report here the results obtained at our institution with a CHOP-like regimen called Firenze 2 (Fi2), which is characterised by an original scheduling of chemotherapy administration. A total of 225 patients, who were diagnosed from 1974 to 1996, were included in this retrospective study. All patients received the Fi2 regimen as a first-line intervention. One-hundred and sixty-two (72%) achieved complete remission; the overall survival at 120 months was 51% with a disease-free survival of 67% (median follow-up = 78 months). The survival curve showed a stable plateau of 42% after 16 years, which remained stable for further 4 years. In a multivariate survival analysis, achievement of complete remission (p<0.001) and IPI index of 0 or 1 (p=0.05) were significantly associated with a better survival. Overall, the outcome of our patients was similar to that reported by others, but the distinguishing feature of our study is the very long follow-up of the patients. Our study confirms that first generation regimens are effective and can cure a substantial proportion of patients. The long-term results of our study are helpful to retrospectively identify high-risk patients whose prognosis is poor and who can be candidates for more aggressive schemes of chemotherapy.

Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi.

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P <. 0001). The model was also predictive (P =.0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.

Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role.

We investigated the pathogenetic relevance of hepatitis C virus (HCV) infection in mixed cryoglobulinemia (MC) with or without complicating B-cell Non-Hodgkin's lymphoma (NHL) in comparison with other immunological and lymphoproliferative disorders. The following groups of patients were studied: A) 25 patients with MC in 7 cases evolved into B-cell NHL; B) 25 healthy subjects; C) 22 patients with different systemic immune diseases; D) 24 patients with chronic HCV infection without MC; E) 25 patients with B-cell idiopathic NHL. Methods used included: i) Polymerase chain reaction (PCR) for HCV RNA detection in serum and peripheral blood mononuclear cells (PBMC) (uncultured or mitogen-stimulated); ii) Branched DNA (b-DNA) for HCV RNA quantification; iii) HCV genotyping by genotype-specific primers localized in the core region and by hybridization of amplification products of the 5' untranslated region (5'UTR), obtained with universal primers, using genotype-specific probes. Serum anti-HCV and HCV RNA were detected in 88% and 73% of MC patients, respectively, and in a significantly lower percentage of healthy controls and patients with autoimmune diseases. HCV RNA concentration was significantly lower in supernatants than in corresponding whole sera (p < 0.001). Plus-strand HCV RNA was detected in 81% of peripheral blood mononuclear cell (PBMC) samples and minus-strand in the majority of fresh or mitogen stimulated cells. All MC patients with NHL had HCV RNA sequences in PBMC. HCV genotype 2a/III was detected in MC patients with a prevalence that was significantly higher than in HCV infected patients without MC. Surprisingly, HCV markers (anti-HCV and/or HCV RNA) were found in 32% of patients with idiopathic NHL. These data suggest that HCV infection is involved in the pathogenesis of MC through both direct participation in the immune complex related vasculitis and by triggering the lymphoproliferative disorder underlying the disease. This latter disorder seems to be related to HCV lymphotropism which could also be responsible for the evolution of MC to malignant lymphoma. This study also suggests that HCV infection may be involved in the pathogenesis of idiopathic B-cell NHL through a similar pathogenetic mechanism.

A new protocol (MiCEP) for the treatment of intermediate or high-grade non-Hodgkin's lymphoma in the elderly.

Age has proved to be an important prognostic factor in patients with advanced non-Hodgkin lymphoma (NHL) and these patients require intensive and extensive therapy. Dose-reduction and therapy attenuation have reduced treatment-related toxicity, but have also decreased therapeutic efficacy. Between January 1990 and December 1992, 41 previously untreated patients, 65 years with stage 2-4 intermediate- or high-grade NHL were treated with a new therapeutic scheme which included Mitoxantrone, Etoposide, Cyclophosphamide and Prednisone (MiCEP). Twenty-eight patients achieved a complete remission, ten patients partial remission (overall response rate of 93%) and two cases were resistant. The overall survival was 66% with a median follow-up of 24 months from diagnosis: three patients relapsed after a median period of 7 months. The relapse-free survival was 92% after a median follow-up of 18 months. Blood and other organ toxicity was acceptable and 12% of patients experienced a grade 4 (WHO) neutropenia. In conclusion, MiCEP was effective in inducing a good remission rate with moderate toxic effects in elderly patients with intermediate- or high-grade NHL and appears to be a useful combination to use in this group of patients.

Combined surgery and chemotherapy in primary gastric non-Hodgkin's lymphoma: a retrospective study in sixty-six patients.

Sixty-six consecutive patients with primary gastric non-Hodgkin's lymphoma are reported. All patients underwent surgery which consisted of radical resection in 23 patients (36%) and partial or palliative excision in the remaining 43 cases (36 and 7 respectively). Three patients died before starting chemotherapy, two refused the treatment and 61 completed the postoperative chemotherapeutic programme. We analysed this group of patients in order to assess the efficacy of chemotherapy following surgery. Chemotherapy included either CVP or the original protocols from our institution. Excluding patients who underwent radical resection, postoperative chemotherapy induced complete remission in 87% of the remaining 39 patients. After a median follow-up of 84 months (range 6-216), the 10-year cause-specific survival was 90% with a stable curve plateau after about 25 months. The survival was only influenced by response to therapy (p < 0.0001). The disease-free survival for patients who were not radically resected was 93%. We encountered only two relapses after 15 and 32 months. One of these was local and the other systemic. Our results indicate that chemotherapy following surgery induces long-term remission and survival in primary gastric lymphoma and in particular improves remission and survival, in stage II. In our opinion, surgery may also be fundamental for the treatment of gastric lymphoma in the majority of cases.

Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study.

PURPOSE: To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkin's disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT. PATIENTS AND METHODS: From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkin's disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44). RESULTS: All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02). CONCLUSION: We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.

Phase II cooperative study with a new alkylating drug, PTT-119, in the treatment of non-Hodgkin's lymphomas.

In a phase II cooperative study involving eleven Italian haematological units, the efficacy and toxicity of a new alkylating compound, PTT-119, was evaluated in 53 patients with non-Hodgkin's lymphoma (NHL). Forty-five of the patients had been previously treated with various regimens of chemotherapy, the remaining eight were at the onset of the disease. PTT-119 was scheduled at 3.0 mg/kg every three weeks for a minimum of three administrations. Seven patients achieved a complete remission (CR), 19 a partial remission (PR); the overall response rate was 49%. The median duration of response was 6 months. Most frequent adverse effects were alopecia, nausea and vomiting and phlebitis due to the drug infusion. Myelosuppression was severe only in patients with bone marrow involvement or who were heavily pretreated. No liver, cardiac or renal toxicity was recorded. These data indicate that PTT-119 is an effective drug in the treatment of NHL; the matter of its non-cross-resistance with other alkylating compounds warrants further studies.

CD4 + T Cells from Lymph Nodes Involved by Hodgkin's Disease Showing Response in Autologous Mixed Lymphocyte Reaction, are Polyclonal.

Thirteen CD4 + T cell clones (TCCs) showing autologous mixed lymphocyte reaction (AMLR) and 12 CD4 + AMLR-negative TCCs derived from involved lymph nodes (LN) of 4 untreated patients with newly-diagnosed Hodgkin's disease (HD) were analyzed for some functional activities and for T cell receptor (TCR) gamma and beta gene rearrangement The majority of the AMLR-positive-, but only two AMLR-negative TCCs showed cytolytic potential when assayed by a lectin-dependent assay. In addition, the proportion of clones able to produce interleukin 2 (IL-2) was higher among AMLR-positive- than AMLR-negative TCCs and the amount of IL-2 synthesized by AMLR-positive TCCs was significantly greater than that of AMLR-negative TCCs. In contrast, no difference in the profile of interleukin 4 (IL-4) and interferon-gamma (IFN-γ) production between AMLR-positive- and AMLR-negative TCCs was detected When AMLR-positive TCCs were analysed for their TCR beta and gamma gene rearrangements, a highly heterogeneous pattern was found. More importantly, TCCs derived from the same donor and displaying the same kind of TCR beta and gamma gene rearrangement showed different patterns of rearrangements, suggesting that CD4 + cells from LN involved by HD, displaying such an unusual functional profile, are polyclonal.

Clinical data and therapeutic approach in elderly patients with Hodgkin's disease.

The present study was undertaken to investigate the clinico pathologic features of Hodgkin's disease in a series of 114 elderly patients (age greater than 60 yrs), with particular reference to prognosis and treatment. Mixed cellularity (63.2%) was the most frequent histologic subtype. Clinical presentation was characterized by superficial lymphadenopathy (92%) and the presence of general symptoms (40.4%); mediastinal involvement was observed in 16.6% of cases; 17.5% of patients had a primitive infradiaphragmatic presentation. Thirty-eight patients were treated with radiotherapy alone (33.4%), 69 with chemotherapy alone (60.5%), while 7 received combined treatment. Complete remission was obtained in 85 patients (74.6%), 25 of whom relapsed. Elderly patients had an overall 5-year survival rate of 61.8% (considering only disease progression as a cause of death). Proportional-hazard multi variate statistics showed that survival was strongly influenced by the achievement of complete remission (P less than 0.001) and stage (P = 0.011). The achievement of complete remission was also significantly linked to the presence of constitutional symptoms, advanced stage and age greater than 70 yrs, as demonstrated by discriminant statistical analysis. The actuarial incidence of second cancer (28.7% at 15 yrs) was slightly higher than that previously reported in younger patients. Overall, our data indicate that the treatment of elderly patients with Hodgkin's disease should be aimed at achieving a cure, using the same therapeutic modalities commonly employed in younger subjects.

Combined surgery and chemotherapy for the treatment of primary gastrointestinal intermediate- or high-grade non-Hodgkin's lymphomas.

Fifty-five consecutive patients with primary gastrointestinal intermediate or high grade non-Hodgkin's lymphoma were analysed to assess the efficacy of chemotherapy following surgical tumour resection. Histological subtypes were high grade (n = 18), intermediate grade (n = 36) and unclassified (n = 1). The majority of patients had gastric presentation (71%) and localised disease (84%). Surgery consisted of radical resection in 25 patients (45%) and partial or palliative excision in the remaining cases (22 and 8 respectively). Four subjects died within 3 months of surgery, two patients refused adjuvant chemotherapy and 49 completed the postoperative chemotherapeutic programme. Chemotherapy included either Fi2/74 (adriamycin + vincristine + bleomycin + cyclophosphamide + prednisone) or Fi3/74 (adriamycin + VM26 + bleomycin + cyclophosphamide + prednisone). Excluding the group who underwent radical tumour resection, postoperative chemotherapy induced complete remission in 81% of the remaining 30 patients. The 10-year cause-specific survival for the 53 treated patients was 76% (median follow-up 58 months) with a stable curve plateau after 80 months. Proportional-hazard multivariate statistics showed that survival was influenced by type of surgical resection (P less than 0.05) and stage (P less than 0.05), whereas age, sex and histological subtype were not influential. Our data indicate that chemotherapy following surgical resection of gastrointestinal lesion induces long-term remission in primary gastrointestinal lymphomas.

MOPP chemotherapy versus extended-field radiotherapy in the management of pathological stages I-IIA Hodgkin's disease.

In order to assess whether mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (CT), which is less expensive and more easily available than radiotherapy (RT), is at least as effective as RT in terms of cure rate and has less iatrogenic damage, 89 consecutive patients with Hodgkin's disease (HD) (pathological stage I-IIA) were randomly allocated to receive mantle plus lumbar bar RT (36-45 Gy) or CT (six courses of MOPP). Forty-five patients were entered in the RT group and 44 in the CT group. The median follow-up was 60 months. Complete remission (CR) was obtained in all patients in the RT group and in 40 of 44 patients in the CT group. Overall survival (OS) and disease-free survival (DFS) were, respectively, 87.2% and 72.7% in the CT group and 93.5% and 74% in the RT group. Survival probability of relapsing patients was 76% for the patients in the RT group and 45% in the CT group. Treatment-related complications were more severe in the CT group as compared with the RT group.

High numbers of CD4+ T cells showing abnormal recognition of DR antigens in lymphoid organs involved by Hodgkin's disease.

Purified T lymphocytes (E rosetting cells) isolated from the involved lymphoid organs (lymph nodes and spleen) of five patients with Hodgkin's disease (HD) were cloned under culture conditions (phytohemagglutinin plus interleukin-2) that allow clonal expansion of most T lymphocytes. A total number of 104 CD4+ T cell clones so obtained were tested for their ability to proliferate in response to autologous mitomycin-treated non-T cells. About half of these clones but none of 234 CD4+ T cell clones derived from normal lymphoid tissues or peripheral blood displayed a proliferative response to autologous stimulators. When clones proliferating in autologous mixed lymphocyte reaction (AMLR) were assessed for their ability to respond in allogeneic MLR (allo-MLR), most of them were found to exhibit consistent proliferation in response to more than one haplotype. Both the AMLR and the allo-MLR by HD clones were inhibited by adding monoclonal antibodies (MoAbs) reactive with monomorphic determinants of major histocompatibility complex (MHC) class II (DR) antigens to the cultures, whereas MoAbs reactive with MHC class I antigens were without effect. These studies suggest that lymphoid organs involved by HD contain high proportions of CD4 T cells showing abnormal recognition of DR antigens. These unusual cells may play an important role in the pathogenetic mechanisms occurring in HD.