Cesare Guglielmi

Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma

BACKGROUND High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkins lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment. METHOD A total of 215 patients with relapses of non-Hodgkins lymphoma were treated between July 1987 and June 1994. All patients received two courses of conventional chemotherapy. The 109 patients who had a response to chemotherapy were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55 patients). RESULTS The overall rate of response to conventional chemotherapy was 58 percent; among patients with relapses after chemotherapy, the response rate was 64 percent, and among those with relapses during chemotherapy, the response rate was 21 percent. There were three deaths from toxic effects among the patients in the transplantation group, and none among those in the group receiving chemotherapy without transplantation. The two groups did not differ in terms of prognostic factors. The median follow-up time was 63 months. The response rate was 84 percent after bone marrow transplantation and 44 percent after chemotherapy without transplantation. At five years, the rate of event-free survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation (P = 0.001), and the rate of overall survival was 53 and 32 percent, respectively (P = 0.038). CONCLUSIONS As compared with conventional chemotherapy, treatment with high-dose chemotherapy and autologous bone marrow transplantation increases event-free and overall survival in patients with chemotherapy-sensitive non-Hodgkins lymphoma in relapse.

Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases

Acute promyelocytic leukaemia (APL), characterized by a specific PML‐RARα fusion gene resulting from translocation t(15;17) and by a high response rate to differentiation therapy with all‐trans retinoic acid, presents clinical (varying WBC counts, age and treatment outcome), morphological (hypergranular M3 and hypogranular M3V) and molecular (three isoforms of PML breakpoint) heterogeneity.

Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial.

PURPOSE The purpose of this study was to investigate the prognostic value of time to relapse in 188 adult patients with intermediate- or high-grade non-Hodgkins lymphoma (NHL) included on the Parma trial at the time of their first relapse. PATIENTS AND METHODS The median follow-up of these patients is 102 months after registration onto the Parma study. Time to relapse was calculated from initial diagnosis, and a cutoff of 12 months was used to separate 77 patients defined as early relapse from 111 patients defined as late relapse. RESULTS Patients with early and late relapses had significantly different overall response rates to salvage therapy with two courses of dexamethasone, high-dose cytarabine, and cisplatin (DHAP; 40% v 69%; P=.00007) and different 8-year survival rates (13% v 29%; P=.00001). Features at relapse with a negative prognostic value in univariate analysis were higher than normal lactic dehydrogenase (LDH) levels, tumor size greater than 5 cm, Ann Arbor stages III to IV, and Karnofsky score less than 80%. Therefore, multivariate analyses were performed. Time to relapse (P=.001) and LDH levels at relapse (P=.003) had independent prognostic value, whereas tumor size did not reach statistical significance in the logistic model that predicted overall response after two courses of DHAP. The study of prognostic factors for overall survival (OS) and progression-free survival (PFS) confirmed the prognostic value of time to relapse (P < .0001 for OS and P=.005 for PFS) independent of response or treatment after two courses of DHAP. CONCLUSION Time to relapse may be used to stratify patients at time of first relapse of intermediate to high-grade non-Hodgkins lymphoma.

P-VABEC: a prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin's lymphoma.

PURPOSE To evaluate, in a prospective trial, a new combination chemotherapy specifically designed for elderly patients. PATIENTS AND METHODS From October 1988 to December 1990, 60 previously untreated patients older than 60 years of age with aggressive non-Hodgkins lymphoma (NHL) were treated at our institution with a new weekly alternating six-drug chemotherapy regimen, P-VABEC. The schedule consisted of doxorubicin, etoposide, and cyclophosphamide alternated weekly with vincristine and bleomycin. Oral prednisone was administered daily during the entire treatment period. Twenty-six of 60 patients were treated for a total of eight courses and 34 of 60 for 12 courses. RESULTS A total of 45 patients (75%) achieved a complete response (CR), 10 (17%) a partial response (PR), and five (8%) no response. So far, 20 of 45 CR patients have relapsed, four of 10 PR patients have progressed, and three patients have died while in CR. Twenty-eight patients are still alive and responding (22 CRs, six PRs) after a median follow-up of 25 months. The projected overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) rates at 2 years were 64%, 57%, and 55%, respectively. The outcome of patients treated with eight courses was similar to that of those who received 12 courses of P-VABEC in terms of CR rate and actuarial curves of OS, DFS, and EFS. Hematologic toxicity was mild in all patients. CONCLUSION The P-VABEC regimen is active, well tolerated, and one of the briefest first-line chemotherapy regimens so far reported in the treatment of elderly patients with aggressive NHL. However, prospective randomized trials are needed to establish the real advantage of this regimen compared with other standard chemotherapy regimens.

Mediastinal large B‐cell lymphoma: clinical and immunohistological findings in 18 patients treated with different third‐generation regimens

We report on the immunophenotype, clinical findings and response to aggressive chemotherapy of 18 patients with mediastinal large B‐cell lymphoma (MLCL). Cases were collected from a series of 286 high‐grade non‐Hodgkins lymphomas (HG‐NHL) which, in the period September 1988 to August 1991, were enrolled in a prospective multicentre trial designed to compare the MACOP‐B and F‐MACHOP regimens. Immunostaining on frozen sections revealed a previously unrecognized phenotype, i.e. co‐expression of B‐cell (CD19, CD20, CD22, Ig‐associated dimer) and activation‐associated antigens (CD30 and CDw70) in about 60% of MLCL cases; in contrast, the activation‐associated antigens CD25 and Ki‐27 (unclustered) were consistently negative. This peculiar phenotype may reflect a derivation of the tumour from a subset of thymic activated B cells. Clinically, the patients (median age 31 years; F/M ratio 2.6) presented with bulky mediastinal mass (72%) associated with mediastinal syndrome in >50% cases; disease was stage IIA in most cases. All 18 patients received aggressive chemotherapy (F‐MACHOP 11; MACOP‐B 7). Complete response (CR) was achieved in 57.1% of cases treated with MACOP‐B. In contrast, the response of the 11 MLCL treated with F‐MACHOP was poor (CR 18.2%) as compared to that of the 135 HG‐NHL treated with the same regimen during the trial (CR 69.6%). This difference was still statistically significant after adjusting for negative prognostic factors (mediastinal mass > 10 cm plus increased LDH) and suggests that F‐MACHOP might not be the most appropriate regimen for this kind of lymphoma.

Acute lymphoblastic leukaemia occurring as second malignancy : report of the GIMEMA Archive of Adult Acute Leukaemia

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre‐pre‐B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL.

Pathogenetic and clinical implications of Bcl-6 and Bcl-2 gene configuration in nodal diffuse large B-cell lymphomas

Bcl‐6 (LAZ‐3) and Bcl‐2 gene rearrangements have been respectively reported in 20–35 per cent and 10–25 per cent of diffuse large B‐cell lymphomas (DLBCLs). Although these genetic lesions have been associated with different clinical outcomes (i.e., more favourable in Bcl‐6 rearranged cases and poorer in Bcl‐2 rearranged cases), their prognostic significance is still controversial. In the present study, we have investigated by Southern blot analysis the Bcl‐6 and Bcl‐2 gene configuration in a series of 80 lymph nodes involved by well‐characterized DLBCLs, histologically defined according to the REAL and the updated Kiel classifications. The molecular findings have been correlated with the clinical features at presentation and with response to therapy. The majority of cases (57/80=71·2 per cent) had a centroblastic morphology. Bcl‐6 rearrangements were detected in 23/80 cases (28·8 per cent), and were similarly associated with centroblastic (18/57=31·6 per cent) or immunoblastic (3/11=27·3 per cent) histotypes. In contrast, Bcl‐2 was found to be rearranged in only three cases of centroblastic lymphoma (3·8 per cent). No significant differences were found between Bcl‐6 rearranged and germline cases, as far as the clinical features at presentation are concerned. Forty‐one patients, in whom the lymph node biopsy was performed at diagnosis, could be evaluated for response to treatment and clinical outcome. Most of these cases (30/41=73·2 per cent) were nodal DLBCL, without extranodal site involvement. Analysis of the clinical outcome showed no statistically significant differences between Bcl‐6 rearranged and Bcl‐6 germline cases (actuarial overall survival 50 per cent vs. 48 per cent, event‐free survival 45 per cent vs. 46 per cent, at 4 years). These findings confirm that Bcl‐6 rearrangements are the most frequent genetic lesion in DLBCL. The incidence of Bcl‐2 involvement in our series is significantly lower than the figures reported in other studies, mainly from North American countries, probably reflecting heterogeneous patient selection and/or epidemiological variability. Finally, our results suggest that no relevant clinical differences are observed between Bcl‐6 rearranged and Bcl‐6 germline cases, when nodal DLBCLs are considered.

Immunophenotype of adult and childhood acute lymphoblastic leukemia: Changes at first relapse and clinico-prognostic implications

The immunologic features of leukemic cells at the time of 1st hematologic relapse were compared to those obtained at initial diagnosis in 128 patients (69 children and 59 adults) with acute lymphoblastic leukemia (ALL) treated at a single institution. An immunophenotypic change was observed in 59 cases (46%), more frequently in T (20/25) than in B (39/103) lineage ALL (80 vs 38%, P = 0.0008), but with a similar incidence in adults and children. Of these cases, 34 (24 B- and 10 T-ALL) changed at relapse their intralineage subgroup affiliation, although no complete shift from B to T lineage ALL, or vice versa, was observed. The myeloid antigens CD13 and/or CD33 were frequently lost (2/5 cases) or acquired (12/123 cases) at relapse. In 21 cases, the immunophenotype at relapse was more undifferentiated than at diagnosis, while it was more differentiated in 13 cases. Initial treatment intensity or preceding treatment with teniposide did not affect the phenotypic profile at relapse. Complete response (CR) rate to salvage therapy and event-free survival were not influenced by the immunophenotypic shifts, nor by the presence, at relapse, of leukemic cells expressing the myeloid antigens CD13 and/or CD33. Univariate analysis suggested that prognosis after relapse was dependent on the duration of 1st CR, patients’ age and immunophenotype at the time of diagnosis, with a worse outcome for patients with T lineage ALL and for patients with the less differentiated subgroup of B lineage ALL (CD19+ and CD10−). Multivariate analysis showed that only two factors, duration of 1st CR and grade of immunologic differentiation at diagnosis, have independent prognostic value in relapsed ALL.

Outcome of patients developing GVHD after DLI given to treat CML relapse : a study by the Chronic Leukemia Working Party of the EBMT

We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (⩽45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63–75) at 5 years, DLI-related mortality was 11% (95% CI 8–15) and disease-related mortality was 20% (95% CI 16–25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.

p53 over-expression identifies a subset of nodal peripheral T-cell lymphomas with a distinctive biological profile and poor clinical outcome.

Peripheral T‐cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non‐Hodgkins lymphoma cases in Western countries, and also to the paucity of specific molecular‐genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra‐nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21WAF1, BCL‐2 and p‐glycoprotein (MDR‐1 gene product) in a series of 45 cases of nodal peripheral T‐cell lymphomas (PTCL) with ‘high‐grade’ histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over‐expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl‐2 (p<0.01) and less frequent expression of p21WAF1 than p53 negative cases. Mdm2 and p‐glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event‐free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over‐expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21WAF1 and more frequent expression of Bcl‐2, Mdm2 and p‐glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low‐cost method which may provide information of potential clinical and prognostic value in nodal peripheral T‐cell lymphomas. Copyright