Long term results of a randomized study performed by Intergruppo Italiano Linfomi comparing Mini-CEOP vs P-VEBEC in elderly patients with diffuse large B-cell lymphoma.

The Intergruppo Italiano Linfomi started, in 1996, a randomized trial for the initial treatment of elderly patients (older than 65 years) with Diffuse Large B-Cell Lymphoma (B-DLCL) comparing 6 courses of Mini-CEOP vs 8 weeks of P-VEBEC chemotherapy. Study objectives were survival, response and Quality of Life (QoL). Two hundred and thirty-two patients were evaluable for final analysis. Complete Response (CR) and Overall Response Rates (ORR) were 54% vs 66% (p = 0.107) and 90% vs 78% (p = 0.021) for P-VEBEC and Mini-CEOP, respectively. With a median follow-up of 72 months, the 5-year Overall Survival (OS), Relapse Free Survival (RFS), and Failure Free Survival (FFS) were 32%, 52%, and 21%, respectively. Subjects achieving a CR showed improvement of QoL regardless of treatment arm. Both Mini-CEOP and P-VEBEC determined a similar outcome for elderly patients with B-DLCL, with a third of patients alive after more than 6 years of follow-up. Both regimens can be considered equally for combination treatment with anti-CD20 monoclonal antibody.

Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group.

PURPOSE: To determine clinical features and patterns of outcome of primary testicular diffuse large B-cell lymphomas (DLCL). PATIENTS AND METHODS: A retrospective international survey of 373 patients with primary testicular DLCL. RESULTS: Most patients presented with localized disease (stage I to II), and the median age at diagnosis was 66 years (range, 19 to 91 years). Anthracycline-based chemotherapy was administered to 255 patients (68%), and prophylactic intrathecal chemotherapy was given to 68 patients (18%); 133 patients (36%) received prophylactic scrotal radiotherapy. Median overall survival was 4.8 years, and median progression-free survival was 4 years. The survival curves showed no clear evidence of a substantial proportion of cured patients. A favorable international prognostic index score (IPI), no B-symptoms, the use of anthracyclines, and prophylactic scrotal radiotherapy were significantly associated with longer survival at multivariate analysis. However, even for patients with stage I disease and good-risk IPI, the outcome seems worse than what was reported for DLCL at other sites. At a median follow-up of 7.6 years, 195 patients (52%) had relapsed. Extranodal recurrence was reported in 140 cases. Relapses in CNS were detected in 56 patients (15%) up to 10 years after presentation. A continuous risk of recurrence in the contralateral testis was seen in patients not receiving scrotal radiotherapy. CONCLUSION: Testicular DLCL is characterized by a particularly high risk of extranodal relapse even in cases with localized disease at diagnosis. Anthracycline-based chemotherapy, CNS prophylaxis, and contralateral testicular irradiation seem to improve the outcome. Their efficacy is under evaluation in a prospective clinical trial.

[Symmetric multiple lipomatosis. A case report with an unusual onset]. / Lipomatosi multipla simmetrica. Descrizione di un caso clinico con inusuale insorgenza.

The authors report a case of symmetric multiple lipomatosis in a young woman with chronic liver disease caused by previous alcohol abuse whose onset occurred three years after the suspension of the toxic agent. The introduction includes a review of the latest literature, focusing in particular on the most probable etiopathogenetic causes, the most common clinical presentations and therapeutics choices. After a description of this particular case, the authors discuss the unusual presentation of the syndrome caused by the rapid onset of lipid accumulation a long time after the suspension of alcohol abuse.

EBVD and alternating MOPP/EBVD with or without localized field radiotherapy in advanced or unfavorably presenting Hodgkin's disease.

PATIENTS AND METHODS: Ninety-five patients with previously untreated, advanced or unfavorably presenting Hodgkin's disease were recruited in ten centers. Twenty-five patients with stage II-A-bulky disease received four courses of EBVD (epirubicin, bleomycin, vinblastine, dacarbazine) plus involved field radiotherapy (Group 1); 24 patients in stage I-B, II-B and III-A received 6 courses of EBVD (11 of them also received radiotherapy on bulky localizations (Group 2); 46 patients in stage III-AS > or = 3 nodes, III-B and IV received MOPP/EBVD 4 + 4 courses (Group 3). RESULTS: Eighty patients (84%) achieved CR, eight patients (8%) a PR, five patients did not respond and two progressed during therapy. CRs were achieved by 23/25 patients (92%) in Group 1, 21/24 (87%) in Group 2 and 36/46 (78%) in Group 3. The mean duration of follow-up was 33.3 months (range 5-69). There were three deaths from directly treatment-related causes. Twelve patients suffered chronic toxicity, including six who suffered lung toxicity and two who developed secondary myelodysplasia. CONCLUSIONS: The results achieved in this co-operative study are similar to those reported by most single-Institution trials and those with adriamycin-containing regimens. Long-term toxicity deserves careful consideration.

Single-institution results of autologous bone marrow transplantation in acute myeloid leukemia.

BACKGROUND: Current results of autologous bone marrow transplantation (ABMT) suggest that this procedure may prolong disease-free survival (DFS) in patients with acute myeloid leukemia (AML). MATERIALS AND METHODS: Over the last ten years, 29 AML patients received unpurged autologous bone marrow (BM) after a conditioning regimen including Ara-C (3 g/m2/12h, days -9, -8), CTX (60 mg/kg/day, days -6, -5) and TBI (3.33 Gy/day, days -3 through -1). In 21 patients, ABMT was performed as late intensification after first CR. Eight more relapsing patients were autografted after the achievement of second CR. RESULTS: Three patients died from transplant-related complications. In the remaining patients, mean times to WBC and platelet recovery were, respectively, 23 days (range 13-55) and 55 days (range 22-790). Follow-up for censored patients ranged from 1 to 120 months. Relapse occurred in 7 patients (5 in first and 2 in second CR). Overall 5-year DFS and event-free survival (EFS) chances were, respectively, 67.3% and 60%, with no statistically significant differences between first (DFS = 67.3%, EFS = 60.3%) and second CR (DFS = 68.6%, EFS = 60%). DISCUSSION: Apart from obvious selection biases, our study suggests that outcome in first CR AML patients is improved by ABMT. Long-term DFS and EFS are clearly better than when conventional post-remission chemotherapies are used. The greater antileukemic potential of ABMT is further underlined by the results in patients autografted in second CR, when conventional chemotherapy is almost never curative.

Idarubicin in the therapy of acute myeloid leukemia: final analysis in 57 previously untreated patients.

Fifty-seven previously untreated adult acute myeloid leukemia patients received idarubicin (IDA) in sequential combination with cytarabine as induction therapy; post-remission treatment included two courses of IDA and cytarabine alternating with two courses of VP-16 and cytarabine. As late intensification, patients received either high-dose cytarabine or, in 10 cases, autologous bone marrow transplantation. Complete remission (CR) was achieved in 48 patients (84.2%), 41 after one induction course and seven after two courses. Median length of disease-free survival (DFS) was 26 months. Univariate analysis did not identify any of the investigated variables as having prognostic significance in predicting DFS. On the other hand, patients achieving CR after one induction course had a better DFS than those requiring two courses. Furthermore, the analysis of DFS slightly favors autologous bone marrow transplantation. In conclusion, the antileukemic activity of the present IDA protocol is testified by the high CR rate and by the possibility of minimizing the role of prognostic factors. The better outcome of patients achieving CR after one induction course further supports the opinion that the intensity of the induction treatment, offered by an agent as potent as IDA, might significantly influence DFS.

Long-term results of autologous bone marrow transplantation in adult acute lymphoblastic leukemia.

Autologous bone marrow transplantation (BMT) is widely performed in both adult and high-risk pediatric acute lymphoblastic leukemia (ALL). Nevertheless, there is still a lack of definitive data concerning its real effectiveness in prolonging the survival of these patients. Between 1984 and 1992, 20 ALL patients in first, second and third complete remission (CR) underwent autografting in the BMT Unit of the University of Milan. This series included 3 children in CR after one or more hematological relapses while all the other patients were adult. Autologous bone marrow was harvested during the same disease phase as that in which the autologous BMT was performed. The conditioning regimen included high-dose Ara-C, cyclophosphamide and TBI 1000 cGy. Successful engraftment occurred in all patients; no early deaths or deaths in CR were recorded, making disease-free survival and event-free survival (EFS) curves superimposable. The overall chance of EFS at 72 months was 41%: 57% for patients in first CR, 53% for patients autografted after one or more isolated meningeal relapse, 14% for patients autografted after one or more hematological relapse. The present data do not provide any evidence to support a role for autologous BMT in prolonging EFS in first CR ALL patients. Nevertheless, the results after meningeal relapse seem to be favourable when compared with the disappointing prospects of these patients after conventional chemotherapy. The EFS after hematological relapse revealed by this study does not significantly differ from that reported in the majority of other studies: the efficacy of autologous BMT in these ALL patients is doubtful.

Allogeneic bone marrow transplantation for myelodysplastic syndromes of childhood: report of three children with refractory anemia with excess of blasts in transformation and review of the literature.

Myelodisplastic syndromes (MDS) in childhood deserve a negative prognosis even though disease-free survival has been obtained in 20% of cases by using aggressive chemotherapy. We describe three children with refractory anemia with excess of blasts in transformation (RAEB-T) who underwent bone marrow transplantation (BMT). We also reviewed 21 additional cases (median age was 8 years) with primary MDS recently reported in the literature with the aim of clarifying the role of BMT in treating these patients. Twelve of the 24 children were long-term survivors and free from disease at a median time of 1,320 days (range 302-2,340). There were five relapses, two graft failures, two early deaths (one VOD, one severe GVHD), and three late deaths (two respiratory diseases, one severe GVHD). We didn't find any correlation between karyotype and outcome. In conclusion, so far BMT seems to be the most valid treatment of childhood primary MDS. However, since the major causes of failure were regimen-related toxicity or recurrence of the disease after BMT, it must be pointed out that, when a compatible donor even unrelated is available, BMT for childhood MDS should be given as soon as possible or at any rate prior to blastic crisis.

Use of high-dose cytarabine in autologous bone marrow transplantation in acute myeloid leukemia.

Autologous bone marrow transplantation is widely used as late intensification therapy for patients with AML in remission without an HLA identical donor or who are older than 40-45 years. We report our experience in 21 AML patients in 1st or 2nd CR transplanted with a regimen including HD-ARA-C in addition to Cyclophosphamide (CY) and TBI. The median age was 32 years (3-50). Fourteen patients were transplanted in 1st CR and 7 in 2nd CR. In all but one patient BM harvesting and ABMT were done in the same remission status and after at least 3 courses of consolidation therapy. Two patients (9.5%) died from treatment related toxicity on Day +15 and Day +31. The median time to reach 1000 WBC and 50,000 platelets per cmm was 23 (13-55) and 55 (22-790) days respectively. Only 4 (21%) of the 19 evaluable patients (median observation time of 32 months) relapsed, at 3, 8, 18 and 26 months from ABMT. The projected event free survival curve shows survival of 67% at 96 months with a relapse rate of 26%.

Abnormal Neutrophil Chemotaxis after Successful Bone Marrow Transplantation.

Twenty patients with self-sustaining hematopoiesis were evaluated for neutrophil functions and bone marrow histology 7 to 34 months after bone marrow transplantation (BMT) (7 allogeneic, 13 autologous) performed for acute leukemia in complete remission (11 patients), Hodgkin's lymphoma (2 patients), chronic myeloid leukemia (6 patients) or severe aplastic anemia (1 patient). The chemotactic response toward zymosan-treated serum was severely depressed (<35% of normal) in peripheral neutrophils of 11 patients (2 allogeneic and 9 autologous BMT) and moderately defective (35-70% of normal) in 5 others (2 allogeneic and 3 autologous BMT). On the other hand, phagocytic activity, activation of the metabolic burst and surface expression of CD11/CD18 molecules were within normal limits or moderately increased. The chemotactic defect was independent of age, sex, conditioning regimen and the time period after marrow infusion. The incidence of defective chemotaxis was much greater in patients receiving an autologous BMT (92% of the patients) than in those who had an allogeneic BMT (57% of the patients). Simultaneous bone marrow biopsy studies showed significant stromal alterations in most of our patients; since the bone marrow microenvironment plays an essential role in the process of blood cell formation and release, these observations suggest that defective neutrophil chemotaxis may well serve as a marker of abnormal post-transplant hematopoiesis.

Autologous bone marrow transplantation in acute leukemia.

We evaluated the therapeutic efficacy of autologous bone marrow transplantation (ABMT) in 49 patients with acute leukemia, using ex-vivo-treated marrow with mafosfamide. This report summarizes data collected from 8 italian centers, involving 27 cases with acute lymphoid leukemia (ALL) and 22 cases with acute nonlymphoid leukemia (ANLL). The analysis of the results shows that the disease-free survival of ALL and ANLL are similar (45 and 52%, respectively) and no significant difference can be demonstrated between patients transplanted in CR1 or CR2, although there is a trend in favor of ABMT in CR1.

Diagnosis and treatment of fungal infections in patients with hematologic malignancies.

A diagnosis of deep-seated mycosis was made in 54 patients with hematologic malignancies, severe neutropenia and fever, based on a set of clinical and laboratory criteria. Standardized antifungal treatment was started in 31 patients who seven days after onset of fever had not responded to antibiotics; the fungal infection was cured in 13, all of whom had a simultaneous remission of neutropenia, whereas the other 18 who did not respond to antifungal treatment, all had a falling or static neutrophil count. None of the 23 patients who were given no or inadequate antifungal treatment survived regardless of the neutrophil count and/or phase of the hematologic disease. We discuss the suitability of utilizing empirical criteria for a diagnosis of disseminated fungal infection as a basis for starting antifungal therapy in this type of patient.

Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia.

Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu-type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

Clinical stage and immunological findings in chronic lymphocytic leukemia.

The total and T-lymphocyte counts, different types of lymphocytic surface immunoglobulins and levels of serum immunoglobulins were studied in 112 consecutive patients with chronic lymphocytic leukemia in order to investigate possible correlations between the immunological picture and the different stages according to the staging criteria recently proposed by Binet et al. Patients were also subdivided according to the form of their disease, "indolent" or "active", and correlations with the immunological picture investigated. The total lymphocyte count showed a significantly increasing trend through the three different stage (p less than 0.01), and it was higher in the "active" than in the "indolent" disease (p less than 0.01). Also the number of T-lymphocytes increased in the "active" forms (p less than 0.01). No statistically significant correlations were observed between the different surface immunoglobulin subclasses and the clinical pattern. As regard the various classes of serum immunoglobulins, the number of patients, with a reduction of at least one of the classes tended to increase with worsening of the clinical stage.

Plasma and urine cyclic nucleotide levels in patients with acute and chronic leukemia.

Plasma and urine levels of cyclic adenosine 3',5'-monophosphate (cAMP) and of cyclic guanosine 3',5'-monophosphate (cGMP) were measured in 35 normal subjects, in 24 patients with nonneoplastic diseases (iron deficiency anemia, peptic ulcer, and cholelithiasis), and in 50 leukemic patients. The leukemic group included patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. All patients were recently diagnosed and untreated, except for 5 patients with blastic transformation of chronic myelogenous leukemia who had been previously treated. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with nonneoplastic diseases. In leukemic patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly elevated. There were no significant differences in cGMP values between the various types of leukemia. After starting treatment, plasma cyclic nucleotide levels were periodically measured in 21 of the patients with acute leukemia; cGMP levels were normalized in all the 16 subjects who attained complete remission, whereas both cAMP and cGMP levels were apparently unaffected in the patients who did not respond to treatment. This suggests that plasma or urine cGMP could be used as an additional parameter to monitor the patient's response to treatment.