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In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

The proliferation patterns of bone marrow cells from 16 cases of acute nonlymphatic leukemia (ANLL) and 13 of dysmyelopoietic syndromes were analyzed with DNA-flow cytometry. In order to reduce the contamination by nonproliferating peripheral blood cells, all aspirates were submitted to a density centrifugation step. DNA content measurements were performed with a PHYWE ICP 22 flow system apparatus. The distribution of cells in the cell cycle phases was calculated by means of an automated fitting procedure. No significant difference between the cell cycle distribution in ANLL and dysmyelopoietic syndromes was detectable. No relationship was observed between the size of the S phase compartment and the percentage of blasts in the original samples. Aspirates from ANLL were also cultured in vitro in liquid phase on dialysis membranes. A clear relationship was observed between the size of the phase compartment and in vitro cell growth since, with the exception of one case, all samples with less than 11% cells in S phase failed to proliferate in vitro. The proliferation profile of ANLL cells after 10 days in culture was similar to that of the original samples.

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.

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 (

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.

The aim of this study was to evaluate quality of life (QOL) in a group of elderly patients (65 years) with aggressive non-Hodgkin's lymphoma (NHL) treated with chemotherapy regimens containing anthracyclines.QOL was evaluated in a population of elderly patients with aggressive NHL enrolled in a phase III clinical trial run by the Intergruppo Italiano Linfomi (IIL) from 1996 to 1999 to compare two different anthracycline-containing regimens (mini-CEOP vs P-VEBEC). The EORTC-QLQ-C30 questionnaire, which has already been validated in oncology, was used. The questionnaire was administered at the time of diagnosis, half way through the chemotherapy and at the time of restaging.Ninety-one patients completed pre-therapy and post-therapy questionnaires and they are the subject of this report. Baseline QOL assessment showed a strong correlation of poor values of QOL with anemia and high risk according to the International Prognostic Index (IPI). At the end of treatment no functional scales showed worse values. A significant improvement was observed for pain (p=0.003), appetite (p=0.006), sleep (p=0.015) and global health (p=0.027). Considering only the 50 patients who achieved a complete remission (CR), an improvement was also recorded for emotional state (p=0.10), role (p=0.05), constipation (p=0.04) and global QOL (p=0.05).The EORTC-QLQ-C30 is feasible even in a population of elderly patients, in whom it had never been tested before. The improvement of QOL at the end of the treatment demonstrated that the symptoms of the disease have a greater negative influence on the patient's life than do the side effects of the therapy.

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-ASor = 3 nodes, III-B and IV received MOPP/EBVD 4 + 4 courses (Group 3).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.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.

Second complete remission (CR) can be achieved in more than 50% of relapsing patients with acute myelogenous (AML) and lymphoblastic leukemia (ALL); however, in spite of this relatively favourable CR rate, only a scant proportion of these patients experience long-term disease-free survival [1,2]. Various strategies have been designed in order to improve the above figure. Allogeneic (BMT) and autologous bone marrow transplantation (ABMT) appear to be therapeutic choices which could offer a significant advantage in terms of event free survival (EFS) [3,4].

Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute's Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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.

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. © 1993 Wiley-Liss, Inc.

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%.

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.

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.

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.

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.

Media conditioned with viable rat and calf spleen lymphocytes were seen to be able to inhibit 3H-thymidine uptake by rat thymocytes and the mitogenic response of human lymphocytes to PHA but not bone marrow cells proliferation. The inhibitor appeared to have a molecular weight greater than 50,000 daltons, as determined by Amicon Diaflo ultrafiltration. Media conditioned with rat granulocytes had a similar tissue specific but species non-specific inhibitory action. Also human leukemic cells appeared able to produce in vitro an inhibitor of cell proliferation when a certain degree of differentiation was present.

The bone marrow karyotype was studied in 17 patients affected by refractory anemia with excess of blasts (RAEB). A cytogenetic finding common to nearly all the cases is hypodiploidy, present in even quite high percentages. In 3 patients were identified the same interstitial deletion of the long arm of a chromosome 5, present in a percentage varying between 30% and 65%. The presence of this chromosomal anomaly appears to correspond to a slower development of the illness and transformation into acute leukemia seems rare or delayed.

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytaBOM) for patients with intermediate or high grade non-Hodgkin lymphomas (G, H and K according to the Working Formulation), was tested by the Gruppo Cooperativo Lombardo to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimen in a cooperative group setting. Among 64 previously untreated patients, aged between 20 and 71 years, 7 had stage IB-IIB, 12 had stage IIIA-B, 45 (67%) had stage IVA-B. There were 44 complete remissions (CRs) (69%) and 14 partial remissions (22%); the difference between patients in stage I-II-III (84% complete remissions) and those in stage IV (62% complete remissions) was statistically significant. The median length of follow up was 20 months (range 1-60 months), with 56% of patients alive at 60 months and 53% of CRs patients free of disease at 60 months. Patients in stage I-II-III have the best survival and disease free survival compared to stage IV, 87% versus 42% and 72% versus 32% respectively (both with high statistical significance). Grade 3-4 (WHO) haematological toxicity was observed in 39% of patients, with 3 septic deaths. Two more patients died with chemotherapy related toxicity (1 stroke and 1 acute renal insufficiency). Administration of ProMACE-CytaBOM is a feasible and safe regimen although it presents moderate toxicity. ProMACE-CytaBOM may represent improved treatment for aggressive lymphomas, in terms of duration of response and survival, but a longer follow up is needed.

The presence of circulating immune complexes (CIC) was evaluated in 60 untreated patients with chronic lymphocytic leukaemia with the polyethylene-glycol precipitation assay. The mean values of optical density (OD) in patients' sera was 0.161 +/- 0.121 compared with control values of 0.082 +/- 0.045 (P less than 0.001). Sera of 16 patients gave OD values higher than 0.172 (mean of controls plus 2 SD) and were considered positive for the presence of CIC. Using the new staging proposed by Binet for CLL we did not find any correlation between presence of CIC and stage of the disease. On the contrary, it was possible to correlate the presence of CIC with the stability of the disease: CIC were found in only 2 of the 22 patients (9.1%) with progressive disease but in 10 of the 30 patients (33.3%) with stable disease (P less than 0.05). CIC were present in 12 of the 38 patients in whom the only surface immunoglobulins present were IgM, but in only 1 of the 14 patients in whom both IgM and IgD were contemporaneously present on the lymphocyte surface. No correlations were found between levels of serum immunoglobulins and presence of CIC.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Background: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) primarily presenting on the skin is an extremely rare entity with only sporadic cases reported in the literature. Methods: We here report an extraordinary case of primary cutaneous THRLBCL with self-healing and 24 months of follow-up. Results: The lesion was a dermohypodermal/subcutaneous circumscribed ulcerated nodosity. Histological examination with immunohistochemical, molecular analysis and comparative genomic hybridization were performed. A complete staging was negative for secondary involvement. Conclusion: Our case is remarkable because it is the second well-documented primary cutaneous THRLBCL in which we observed a complete self-regression of skin lesions without recurrences or dissemination of the disease. According to the literature, we highlight that the tumoral microenvironment, in our case, could play a relevant role in stopping lymphoma growth. Furthermore, this case supports the observation that THRLBCL primarily presenting on the skin shows an overall good prognosis.