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Franco Mandelli

Publications and source records attributed to Franco Mandelli.

At least 37 records · Page 2Linked to original sources
PubMed2005

Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

BACKGROUND: Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. METHODS: We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. RESULTS: Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells. CONCLUSIONS: Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy.

Adolescent↗
PubMed2005

A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol.

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.

Adolescent↗
PubMed2005

Clinical features of prognostic significance in myelodysplastic patients with normal karyotype at high risk of transformation.

The International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (MDS) has defined patients with a normal karyotype as a good risk cytogenetic subgroup, but nevertheless a fraction of these patients has a poor outcome similar to that of high risk patients. We retrospectively analysed our series of myelodysplastic patients with normal karyotype observed in a period of 11 years, with the aim of identifying clinical features of possible prognostic significance within this subgroup of patients. Multivariate analysis showed that among clinical scoring systems, the Bournemouth score appears the best prognostic indicator for risk of leukemic transformation, and platelet count <100 x 10(9)/l(-1), presence of haemorrhagic symptoms at time of diagnosis and morphologic FAB classification are the main prognostic factors for prediction of survival. In the absence of genetic abnormalities as detected by conventional cytogenetics or even the more sensitive molecular techniques in MDS, clinical variables could be of help in identifying patients with different prognosis, suitable for risk adapted therapeutic strategies.

Acute Disease↗
PubMed2005

Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment.

Thirty-five patients with Ph+ CML aged more than 60 years were treated with imatinib. Twenty-four patients (group A) were in late chronic phase (CP) and eleven patients (group B) were in accelerated/blastic phase (AP/BP). In group A, complete haematological response (CHR) was achieved by all patients; seventeen patients (70.8%) attained a complete cytogenetic response (CCR), one (4.1%) attained a partial CR, one (4.1%) a minor CR (Ph+ 70%) and five (21%) were resistant (Ph+ 100%), toxicity was mild: seven patients had a transient cytopenia, three a skin reaction, one a moderate oedema and one muscular pain. After a median follow-up of 15 months, 1 patient died in progression and 23 patients are alive (2 in BP and 21 in persisting response). In group B, one patient died after 3 months in aplastic phase from sepsis, three patients were resistant and seven patients (63.7%) achieved CHR; of these, four obtained CCR. After a median follow-up of 17 months, 4 patients have died from progressive disease, 6 are alive; 1 in AP and 5 in CHR (4 of them being in CCR). Present data indicate that imatinib is safe also in elderly with clinical results as good as in younger patients.

Age Factors↗
PubMed2005

A gender-based score system predicts the clinical outcome of patients with early B-cell chronic lymphocytic leukemia.

To facilitate the development of a prognostic model for early B-cell chronic lymphocytic leukemia (CLL), the Gruppo Italiano Malattie EMatologiche Maligne dell'Adulto (GIMEMA) proposes its multi-institutional effort as a working model. In total, 1138 newly diagnosed Binet stage A patients managed over the last 10 years outside the setting of clinical trials according to a "wait and see" policy form the basis of the present study aimed at investigating prognostic variables affecting disease progression, a surrogate endpoint for overall survival. A 3-stage risk system, simply obtained by summing the variables that proved significant in the multivariate analysis (i.e. short lymphocyte doubling time, advanced Rai substage, high peripheral blood lymphocytosis), is proposed. Clear-cut differences in the 10 year progression-free survival (PFS) were observed among patients scoring 0 (low risk), 1 (intermediate risk), 2-3 (high risk): 67.8, 41.0 and 24.8%, respectively (P<0.0001). The results of the Medical Research Council (MRC) suggesting a better clinical outcome for females prompted us to verify such a gender-related difference within our prognostic categories. Because changes in PFS only reflected gender for patients scoring 0 (P=0.04), the following prognostic subgroups are proposed: (1) females scoring 0; (2) males scoring 0; (3) patients scoring 1-3 whatever gender (10 year PFS: 76.2, 61.4 and 37.8%; P<0.00001). Our long-term database provides an adequate patient sample to generate a generalized risk stratification model based on clinical data. The indolent clinical outcome of women with early CLL is also supported by the higher frequency of the immunoglobulin heavy-chain variable (IgVH) mutational status and lower proportion of 17p and 11q deletions found in such a patient subset in the MRC CLL4 trial.

Adult↗
PubMed2004

Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial.

High-dose therapy is an effective standard treatment for multiple myeloma patients. Evidence that intermediate-dose therapy improves survival is limited. At diagnosis, about 70% of patients are older than 65. Intermediate-dose regimen is very well tolerated in older patients. In a multicenter study, 194 patients were randomized to receive at diagnosis either conventional chemotherapy (6 courses of oral melphalan and prednisone [MP]) or intermediate-dose therapy (2 courses of melphalan at 100 mg/m(2) [MEL100]) with stem cell support. Response rate was higher after MEL100. Near-complete remission (nCR) was 6% after MP and 25% after MEL100 (P = .0002). At 3 years, MEL100 increased event-free survival (EFS) from 16% to 37% and overall survival (OS) from 62% to 77% (P < .001). Similar results were observed in patients aged 65 to 70: nCR was 8% after MP and 25% after MEL100 (P = .05); at 3 years, MEL100 improved EFS from 18% to 31% (P = .01) and OS from 58% to 73% (P = .01). Patients aged 65 to 70 had a median OS of 37.2 months (MP) versus 58 months (MEL100). Intermediate-dose melphalan improves response rate, EFS, and OS in myeloma patients, specifically in those aged 65 to 70. It constitutes a more effective first-line regimen than standard treatment for elderly patients.

Aged↗
PubMed2004

Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia.

The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at the molecular level. Of these patients, 8 were experiencing a first, 5 a second, 2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses, and patients achieving a new molecular remission (MR) (ie, negativity of the reverse transcriptase-polymerase chain reaction [RT-PCR] test for PML/RARalpha) received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2 doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3 remaining patients, 1 achieved MR after one GO administration and received no further therapy owing to hepatic toxicity, and 2 showed disease progression during treatment. Quantitative RT-PCR studies showed that responding patients experienced a dramatic decline (at least 2 logs) of the PML/RARalpha transcript after the first GO dose. Of 14 responders, 7 remained in sustained MR for a median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15 months. GO was administered again in 2 patients with relapse, and both obtained a new MR. These data indicate that GO is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.

Adolescent↗
PubMed2004

Clinico-pathological characteristics of myeloid sarcoma at diagnosis and during follow-up: report of 12 cases from a single institution.

The aim of this study was to describe the presenting features, the frequency and outcome of myeloid sarcoma (MS) diagnosed in our Institution from January 1995 to December 2000. Twelve MS were seen and the frequency account for only 2% of all acute myeloid leukemia (AML) patients observed in our department in the same period. Median age was 45 years (range: 4-84). All had been initially misdiagnosed as malignant lymphoma (ML) and a median of 2.9 months (range: 1-6) elapsed between the misdiagnosis and the correct of MS, effectuated in our department. At that time, a bone marrow examination revealed a myelodysplastic condition in seven patients, an infiltration by blast cells >30% in two patients, and normal features in the other three. In the non-leukemic patients a median of 5 months (range: 2-44 months) elapsed between the diagnosis of MS and acute leukemia. In all, 10 patients received intensive treatment. A total of seven patients (70%) achieved MS complete remission (CR). Patients who presented isolated skin localization and received only radiotherapy, obtained a MS-CR, but subsequently developed AML. Only in patients who were treated within 4 months from the initial ML diagnosis we achieved complete remission of both MS and leukemia, whereas in patients who were treated after this time, we obtained a complete disappearance of MS without response at the bone-marrow level, irrespectively of the specific therapy regimen. Median survival time from MS diagnosis was 7 months (range: 1-49 months), and only one patient is still alive, 49 months after bone marrow transplantation. Our data stress the importance of an accurate and prompt identification of this rare form of AML, and suggest that, even in patients with isolated MS, the early administration of AML-like intensive chemotherapy followed by bone marrow transplantation might reduce the risk of subsequently developing systemic disease.

Adolescent↗
PubMed2004

Apoptosis susceptibility and cell-cycle distribution in cells from myelodysplastic syndrome patients: modulatory in-vitro effects of G-CSF and interferon-alpha.

Susceptibility to apoptosis varies in different forms of myelodysplastic syndromes (MDS). Our in vitro study aimed at better defining the cell kinetic profile by investigating whether G-CSF and interferon-alpha (IFNalpha) were capable of controling apoptotic/proliferative mechanisms in RAEB as well as in RAEB-t forms. Apoptosis and cell-cycle distribution were measured in mononuclear and in CD34+ cells from bone marrow samples of 27 MDS patients with RAEB (n = 15) and RAEB-t (n = 12). In selected samples, the in vitro influence of G-CSF and lymphoblastoid (Ly)-IFNalpha on the apoptotic susceptibility and on the cell kinetics of the above MDS populations was evaluated. RAEB samples showed a significantly greater apoptosis than RAEB-t ones, both in mononuclear cells (14.76%+/-8.73 vs. 5.95%+/-3.88, P= 0.0058) and in CD34+ cells (24.66%+/-16.08 vs. 3.96%+/-2.57, P = 0.0007). Short-term cell culture in the presence of G-CSF reduced apoptosis in CD34+ cells in all 4 RAEB samples tested (39.1%+/-40.7 vs. 21.0%+/-23.5, P = n.s.); the percentage of cells in S-phase significantly increased in 3/4 samples (19.90%+/-4.40 vs. 32.40%+/-7.85, P = 0.03). Ly-IFNalpha protected CD34+ cells from apoptosis in 3/4 RAEB samples (25.7%+/-8.06 vs. 10.9%+/-8.8, P = n.s.), but did not modulate cell-cycle distribution. G-CSF and Ly-IFNalpha failed to affect apoptosis and proliferation in RAEB-t. These observations indicate that in RAEB forms increased apoptosis can be efficiently counteracted in most of the samples by both G-CSF and Ly-IFNalpha, suggesting that only in these forms a retained regulatory mechanism on the apoptotic/ proliferative balance may allow therapeutic intervention with apoptotic regulators.

Adult↗
PubMed2004

Prevalence of hepatitis C virus infection in lymphoproliferative diseases other than B-cell non-Hodgkin's lymphoma, and in myeloproliferative diseases: an Italian Multi-Center case-control study.

BACKGROUND AND OBJECTIVES: Infection with hepatitis C virus (HCV) is associated with type II mixed cryoglobulinemia (MC), a lymphoproliferative disorder which, in some patients, evolves into overt B-cell non-Hodgkin's lymphoma (B-NHL). Recently, also the association between HCV infection and B-NHL, which had long been controversial, was confirmed in a large case-control study. Little knowledge is, however, available on possible associations between HCV infection and other lymphoid or myeloid malignancies. The present study was set up in order to investigate this aspect. DESIGN AND METHODS: The study was conducted in hematology departments of ten hospitals in different Italian cities. The cases consisted of consecutive patients with a new diagnosis of T-NHL, Hodgkin's disease (HD), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). The controls were patients in other departments of the same hospitals. HCV infection was investigated by testing for HCV antibodies and HCV-RNA in serum samples. RESULTS: The prevalence of HCV infection was not higher in patients with HD (3.2%, 5 out of 157 cases) or MM (4.7%, 5 out of 107) than in controls. On the other hand, it was consistently higher in T-NHL (13.8%, 4 out of 30), CLL (9.0%, 9 out of 100), ALL (7.6%, 5 out of 54), AML (7.9%, 11 out of 140), and CML (12.2%, 6 out of 49) patients. These patient groups were not, however, large enough to render statistically significant results. INTERPRETATION AND CONCLUSIONS: Our data suggest that HCV infection may be associated not only with B-NHL but also with some other lymphoid and myeloid malignancies.

Acute Disease↗
PubMed2004

Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukemia pathogenesis in the Italian population.

BACKGROUND AND OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and DNA methylation and synthesis. Some genotypes of this highly polymorphic enzyme are associated with decreased activity. Previous studies have suggested that individuals with the MTHFR 677TT, 1298AC and 1298CC have a lower risk of adult acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: In order to test this association we studied the presence of the C677T and A1298C mutant alleles in 174 patients with acute lymphoblastic leukemia and in 110 controls from central Italy. RESULTS: We did not find any association between the different polymorphisms and susceptibility to ALL. In multivariate analysis different genotypes did not show any correlation with the risk of ALL. The adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 0.69 (0.4-1.19) for 677CT versus 677CC wild type, and 0.99 (0.50-1.97) for 677TT versus 677CC. The corresponding values for MTHFR A1298C were 0.93 (0.56-1.53) for 1298AC versus 1298AA wild type and 1.14 (0.36-3.61) for 1298CC versus 1298AA. INTERPRETATION AND CONCLUSIONS: These results do not support the suggestion that populations carrying different genotypes of the two MTHFR polymorphisms, C677T and A1298C, have a different susceptibility to ALL, at least in the Mediterranean area.

Alleles↗
PubMed2004

GIMEMA ALL - Rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: The outcome of adult patients with acute lymphoblastic leukemia (ALL) is discouraging, only about 30% of them becoming long-term survivors. A small fraction of patients are resistant to the first line treatment, while most patients relapse within two years of achieving complete remission (CR). No standard treatment exists for refractory or relapsed patients. The GIMEMA group designed a phase II trial for adult ALL patients with refractory or relapsed disease. DESIGN AND METHODS: Patients aged >15 years with primary refractory or relapsed ALL were eligible for this study. The salvage strategy included a single high dose of idarubicin combined with high dose cytarabine, followed by consolidation therapy leading to a stem cell transplant procedure according to donor availability. RESULTS: From 1998 to 2002, 135 patients were enrolled. Seventy-five patients (55%) achieved CR, including 12 Philadelphia-positive cases; 44 patients had persistent leukemia and 16 died during reinduction. Fifty patients received a stem cell transplant: 19 from an HL-A identical sibling, 16 from an unrelated donor, 7 from a haploidentical relative, 2 received cord blood, and 6 had an autotransplant. The median disease-free and overall survival were both short (5.0 and 6.4 months, respectively); however, after a median follow-up of 40 months, 13 patients are alive, 10 of whom are free of disease (9 transplanted), while 3 are alive with leukemia. INTERPRETATION AND CONCLUSIONS: The treatment induced CR in a high percentage of poor prognosis patients, thus rendering a transplant procedure feasible in most of them. However, significant rates of transplant-related mortality and post-transplant relapse encourage the search for more effective and less toxic conditioning regimens.

Adolescent↗
PubMed2004

Survival of elderly patients with acute myeloid leukemia.

BACKGROUND AND OBJECTIVES: The prognosis of elderly patients with acute myelogenous leukemia (AML) is usually dismal, while the true survival of older patients not included in clinical trials is not known. We retrospectively evaluated the impact on survival of an aggressive versus a non-aggressive approach in 1005 patients aged >60 years registered in the database of the GIMEMA cooperative group. DESIGN AND METHODS: Group A patients (n=621) received aggressive treatment, while group B patients (n=384) underwent non-aggressive therapy. The groups were different for risk factor distribution: the patients in group B had a higher median age, worse performance status (PS) and a higher proportion of previous myelodysplastic disease. RESULTS: The overall median survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At multivariate analysis the following factors were associated with a significantly shorter survival: age >71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95% CI=1.24-1.68), white cell count > 10,000 mL (RR=1.37; 95% CI=1.06-1.75), and heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference in survival was associated with aggressive or non-aggressive treatment (RR=1.1; 95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a white cell count > 10,000/mL showed a significantly better survival when treated aggressively (median survival 7 vs 3 months, p = 0.011). INTERPRETATION AND CONCLUSIONS: Despite an obvious selection of patients with a worse prognosis in group B, the difference in survival between the two groups was marginal. Multivariate analysis failed to demonstrate a significant survival benefit in aggressively treated patients. All these considerations indicate that elderly patients with AML are overall unlikely to benefit from aggressive treatment, so that this should be offered only to selected patients.

Acute Disease↗
PubMed2004

Prognostic factors in myelodysplastic and myeloproliferative types of chronic myelomonocytic leukemia: a retrospective analysis of 83 patients from a single institution.

We analyzed independent prognostic factors associated with survival and risk of evolution to acute leukemia in our series of 83 patients with previously untreated chronic myelomonocytic leukemia (CMML), with the aim of testing the validity of the stratification based on white blood cell (WBC) count, in myeloproliferative and myelodysplastic types of the revisited WHO classification.

Adult↗
PubMed2004

Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups.

BACKGROUND AND OBJECTIVES: Acute myeloid leukemia (AML) in the elderly is associated with low rates of response to conventional chemotherapy and long-term survival, highlighting the need for innovative treatment strategies. Gemtuzumab ozogamicin (GO) is an immunoconjugate that has shown activity in relapsed AML with a favorable safety profile. The aim of this collaborative trial was to assess the feasibility, safety, and antileukemic activity of administering GO followed by conventional chemotherapy as first line therapy in patients aged 61-75 years with AML. DESIGN AND METHODS: Eligible patients received frontline treatment with GO 9 mg/m2 infused intravenously on days 1 and 15. Following response assessment to GO, patients were started on conventional chemotherapy consisting of the MICE regimen (mitoxantrone, cytarabine, etoposide). No further treatment was planned for complete responders. RESULTS: Among the 57 evaluable patients, 38 (67%) completed the entire sequential treatment as planned. The overall response rate to the entire induction sequence was 54.4% (31/57), with complete remission (CR) in 35.1% and complete remission with incomplete platelet recovery (CRp) in 19.3%. Rates of failure due to treatment-related mortality or resistant disease were 14.1% (3 toxic deaths during the GO segment, 5 during MICE) and 29.9%, respectively. An initial response to GO was documented in 20 patients (35.1%), with CR in 22.8% and CRp in 12.3%; 6 additional patients entered a partial remission. Reversible myelosuppression and liver toxicity were the main adverse events during both segments of induction. Frontline GO was associated with modest mucosal and gastrointestinal toxicity, but grade 3-4 pancytopenia was universal and prolonged. Hepatic veno-occlusive disease developed in 3 patients after GO and 2 after MICE, resulting in 4 deaths from liver failure. One-year survival at follow-up was 34%. Twelve patients continue in CR/CRp after a median of 226 days. INTERPRETATION AND CONCLUSIONS: The sequential combination of GO and conventional chemotherapy is a feasible and active treatment strategy for older patients with untreated AML. This novel regimen is now being compared in a phase III trial (AML-17).

Acute Disease↗