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Biomedical subjects

Michele Baccarani

Publications and source records attributed to Michele Baccarani.

At least 55 records · Page 3Linked to original sources
PubMed2005

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Adult↗
PubMed2005

Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma.

The aim of the present study was to compare thalidomide-dexamethasone (Thal-Dex) and vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous peripheral blood stem-cell (PBSC) transplantation for multiple myeloma (MM). For this purpose, we performed a retrospective matched case-control analysis of 200 patients who entered 2 consecutive studies from 1996 to 2004 and received Thal-Dex (n = 100) or VAD (n = 100) administered for 4 months before collection of PBSCs and autologous transplantation. Matching criteria included age, clinical stage, and serum beta2-microglobulin levels. In comparison with VAD, Thal-Dex resulted in a significantly higher response rate (52% versus 76%, respectively; P < .001) and effected more profound reduction in myeloma cell mass of both immunoglobulin G (IgG; P = .02) and IgA (P = .03) type. More frequent toxicities included nonfatal deep vein thrombosis with Thal-Dex (15%) and granulocytopenia with VAD (12%). In each of the 2 treatment groups, 91% of patients proceeded to PBSC mobilization. The median number of collected CD34+ cells was 7.85 x 10(6)/kg in the Thal-Dex group and 10.5 x 10(6)/kg in the control group. Thal-Dex may be considered an effective and relatively well-tolerated oral alternative to the more complex VAD regimen as front-line therapy for MM patients who are candidates for subsequent autologous transplantation.

Anti-Inflammatory Agents↗
PubMed2005

Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma.

By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH(+) cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH(+) cells in the BM was low (1 BCL2/IgH(+) cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH(+) cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH(+) cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P < .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.

Adult↗
PubMed2005

Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells.

OBJECTIVE: Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. MATERIALS AND METHODS: AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. RESULTS: Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14(-) AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14(-)-derived AML-DCs restored optimal interferon-gamma (IFN-gamma) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14(-) cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14(-)-derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-gamma, thus maintaining a Th1 cytokine profile. CONCLUSION: IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.

Adult↗
PubMed2005

Role of anemia in survival of patients with elderly aggressive non-Hodgkin's lymphoma after chemotherapy.

Baseline anemia is a relevant prognostic factor in the overall population of non-Hodgkin's lymphoma (NHL) patients, and studies focusing on elderly NHL are awaited. We conducted a pooled analysis of a cohort of comparable patients enrolled (1993 - 2001) in three multicenter clinical trials on use of a MACOP-B-like regimen (VNCOP-B) for front-line treatment of elderly aggressive NHL. Models of Cox's proportional hazards regression analysis of prognostic value of pre-/post-treatment hemoglobin values in terms of 5-year overall survival included age, sex, initial tumor staging and response to treatment. Of the 168 patients screened, 16 were excluded due to missing data or lack of 5-year follow-up. In addition to achievement of complete/partial remission (adjusted relative risk [RR], 0.215; p = 0.0001) and advanced stage (II-IV vs. I - II; adjusted RR, 1.55; p = 0.0023), post-treatment hemoglobin values were an independent predictor of survival (adjusted RR per 1-g/dL increment, 0.76; p = 0.0041). In the present analysis, pretreatment hemoglobin values were associated with only marginal risk reduction (adjusted RR per 1-g/dL increment, 0.985; p = 0.049). Post-treatment hemoglobin values appear to provide a strong independent predictor of 5-year survival in elderly aggressive NHL, supporting the potential role of anemia correction in this group of patients.

Aged↗
PubMed2005

Value of oxaliplatin treatment in heavily pretreated patients with non-Hodgkin's lymphoma.

In order to assess the efficacy and toxicity profile of oxaliplatin, a third generation platinum derivate active against several solid tumors, we carried out a study in a group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL). Between August 2003 and May 2004, 19 pretreated patients were enrolled in a phase II trial and were treated with oxaliplatin. The drug was administered intravenously on day 1 of a 21-day schedule, at a dose of 130 mg/m2 for a total of 6 cycles. One (5%) patient achieved complete remission (CR) and 5 patients (27%) had partial response (PR), thus giving an overall response rate of 32%. The patient in CR suffered from an aggressive B NHL. One of the 5 patients in PR had an aggressive B NHL, whereas the remaining 4 had an indolent B NHL. The treatment was well tolerated with minimal hematologic and extrahematologic toxicity. These data suggest and confirm the efficacy and low toxicity of oxaliplatin in the treatment of patients with heavily pretreated NHL. Further trials using oxaliplatin alone or in combination with other conventional drugs are needed.

Aged↗
PubMed2005

Potential pitfalls of 18F-FDG PET in a large series of patients treated for malignant lymphoma: prevalence and scan interpretation.

OBJECTIVE: To evaluate the prevalence and scan interpretation criteria useful in identifying non-tumoural F-FDG focal uptakes (potential pitfalls) in patients who had been previously treated for a malignant lymphoma studied by positron emission tomography (PET). MATERIALS: Nine hundred and ninety-six consecutive PET scans obtained in 706 patients with malignant lymphoma were reviewed. All patients had been previously treated by first-line chemo-radiotherapy, plus surgery when required, and were then studied by FDG PET to investigate suspected recurrence at doubtful or inconclusive conventional radiological imaging (ultrasound, computed tomography, magnetic resonance imaging). PET was obtained with patients in the fasted condition and after i.v. injection of 370 MBq of F-FDG; imaging was acquired 60-90 min later. In patients with focal FDG uptake the final diagnosis was reached on the basis of histological findings or long-term follow-up. RESULTS: Thirty-one of 134 PET scans (23.1%) showing focal FDG uptake were diagnosed as non-tumoural radiotracer uptake, related to the presence of brown fat in seven cases, thymic hyperplasia in five, muscles contraction in four, lymph node unspecific inflammation in four, mediastinal/pulmonary unspecific inflammation in four, gastritis in two, colitis in two, bacterial abscess in one, lactating breast in one, and herpes zoster in one. Each of the above cited situations has been reported in the literature, generally in the form of sporadic reports, as a potential cause of misinterpretation (false positive) in reading a PET scan with the potential for incorrect patient management. An accurate diagnosis in these patients was important for the following therapeutic decision making. CONCLUSIONS: In the whole series of patients with treated malignant lymphoma, the prevalence of non-tumoural FDG focal uptake during follow-up was relatively low (3.1%); conversely, it was relatively high when considering the sub-group of 'positive' PET only (23.1%). The importance of knowing these situations in order to avoid misinterpretation in reading PET scans needs to be emphasized. In this light, an accurate patient's history and a skilful nuclear medicine physician are very important factors. For the same purpose, it is reasonable to think that the use of hybrid PET/CT tomographs could also play an important role in helping to identify non-tumoural FDG focal uptake.

Artifacts↗
PubMed2005

Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias.

Recent studies suggest that the prosurvival signal transduction pathway involving phosphoinositide 3-kinase (PI3K)/Akt can confer an aggressive, apoptosis-resistant phenotype to acute leukaemia cells. We have investigated the effect of modulating this signalling pathway on the sensitivity of leukaemic cell lines (NB-4, CEM, Jurkat, MOLT-4) and acute promyelocytic primary blasts to apoptosis induced by 1 micromol/l As2O3. Whereas parental NB-4 cells did not display any phosphorylated (active) Akt, CEM, Jurkat and MOLT-4 cells exhibited high levels of Akt activation. Consistently, treatment of NB-4 cells with pharmacological inhibitors of the PI3K/Akt pathway (LY294002, wortmannin) did not increase sensitivity of these cells to arsenic trioxide (As2O3), whereas siRNA knock-down of Akt enhanced As2O3-induced apoptosis of CEM, Jurkat and MOLT-4 cells. Overexpression of a constitutively active Akt cDNA rendered NB-4 cells less susceptible to As2O3. Upon prolonged exposure to As2O3, we isolated a NB-4 cell clone that was resistant to As2O3 and displayed high levels of active Akt. LY294002 treatment of acute promyelocytic primary blasts with elevated Akt phosphorylation levels resulted in an increased sensitivity to As2O3. These results may provide a rationale for the development of combined or sequential treatment with PI3K/Akt inhibitors to improve the efficacy of As2O3 on acute leukaemias and also to overcome As2O3 resistance.

Apoptosis↗
PubMed2005

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients.

Fludarabine plus cytarabine (Ara-C) and idarubicin (FLAI) is an effective and well-tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara-C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty-seven patients received FLAI, as the first induction-remission course, and 55 patients received ICE. Post-induction treatment consisted of high-dose Ara-C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara-C) and autologous stem cell transplantation (auto-SCT) or allogeneic (allo)-SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0.01), while death during induction was 2% and 9% respectively. Both haematological (P = 0.002) and non-haematological (P = 0.0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo-SCT. After a median follow-up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti-leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.

Acute Disease↗
PubMed2005

Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma.

OBJECTIVE: Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high-dose therapy. This latter therapeutic approach has risen the concern of side-effects of long-term therapy with this drug. METHODS: We analysed long-term toxicity of 40 patients (27 M, 13 F, median age = 61.5 yr) who received salvage therapy with thalidomide +/- dexamethasone for longer than 12 months (median 15, range 12-44) at our centre. All the patients had achieved at least a stable disease upon treatment with thalidomide alone (200-400 mg/d, n = 20) or thalidomide (200 mg/d) and dexamethasone (40 mg/d for 4 d every 4 wk) (n = 20). RESULTS AND CONCLUSIONS: Neurotoxicity was the most troublesome and frequent toxic effect that was observed after long-term treatment, the incidence averaging 75%. Among these 30 patients symptoms included paraesthesias, tremor and dizziness. Neurotoxicity was grade 1 in six patients (15%); grade 2 in 13 patients (32.5%), thus determining thalidomide dose reduction to 100 mg/d; and grade 3 in 11 patients (27.5%) who had subsequently to interrupt therapy despite their response. Electromyographic study, performed in patients with grade >/=2 neurotoxicity, revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neurotoxicity was not related to cumulative or daily thalidomide dose, but only to the duration of the disease prior to thalidomide treatment, although no patients presented neurological symptoms at study entry. These results suggest that long-term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a peripheral neuropathy.

Adult↗
PubMed2005

Autologous stem cell transplantation for acute myeloid leukemia patients in first complete remission: a 10-year follow-up study of 118 patients.

We assessed the impact of unpurged autologous stem cell transplantation (ASCT) on long-term outcome of 118 patients with acute myeloid leukemia (AML) in first complete remission (CR1). With a median follow-up of 95 months, the 10-year overall survival, disease-free survival and relapse risk are, respectively, 54%, 50% and 46%. De novo AML, the presence of a favorable karyotype and intensification of treatment prior to ASCT are independently associated with clinical outcome by multivariate analysis. Thus, a remarkable proportion of AML patients in CR1 can be cured with high-dose therapy and ASCT.

Acute Disease↗
PubMed2005

Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients. DESIGN AND METHODS: This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection. RESULTS: Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy. INTERPRETATION AND CONCLUSIONS: Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.

Adult↗
PubMed2005

Identification of outcome predictors in diffuse large B-cell lymphoma. Immunohistochemical profiling of homogeneously treated de novo tumors with nodal presentation on tissue micro-arrays.

BACKGROUND AND OBJECTIVES: Patients with diffuse large B-cell lymphoma (DLBCL) could benefit from integration of well-established bioclinical prognostic factors with new tools - such as micro-arrays - exploring aberrant gene and/or protein expression. DESIGN AND METHODS: Tissue micro-arrays (TMA) were constructed for the paraffin blocks of 68 patients with de novo DLBCL with nodal presentation, who underwent MACOP-B and were provided with complete clinical information. TMA were tested with specific antibodies against CD10, CD20, CD30, CD79a, CD138, Bcl-2, Bcl-6, IRF4, and IRTA1. RESULTS: The following phenotypic subclassification was made: a) CD10 +/Bcl-6 + or Bcl-6+/IRF4 +, but Bcl-2-/CD30-/CD138-- suggesting B-cells gathering/leaving the germinal center (group 1; n=36); b) Bcl-2+/CD10-/Bcl-6- and CD30+ or CD138+ corresponding to putative non-germinal center B-cells with features of activation or plasmablastic/plasmacellular differentiation (group 2; n=17); c) CD30-/CD138- with extensive Bcl-2 positivity and variable CD10, Bcl-6 and IRF4 combinations (group 3; n=15). Mean IPI scores were 0.6, 1.9 and 1.1 for groups 1, 2 and 3, respectively (p= 0.001). Complete remission (CR) rates were 89%, 53% and 73% (p= 0.015). The 3-year relapse-free survival (RFS) rates are 86%, 41% and 63% (p=0.001) and 42-month overall survival (OS) rates are 91%, 38% and 66% (p=0.0002). INTERPRETATION AND CONCLUSIONS: The present TMA-based study suggests an immunophenotypic profiling system for patients with de novo DLBCL that seems to provide additional prognostic information and contributes to the existing debate on the identification of suitable immunohistochemical surrogates of gene expression profiling results.

Adult↗
PubMed2005

New tyrosine kinase inhibitors in chronic myeloid leukemia.

The deregulated activity of BCR-ABL tyrosine kinase originating from the t(9;22) chromosomal translocation has been shown to be necessary and sufficient for the transformed phenotype of chronic myeloid leukemia (CML) cells. This peculiarity has paved the way for the development of novel therapies specifically targeting the BCR-ABL gene product. The first BCR-ABL inhibitor to come into use in clinical practice, imatinib mesylate, is now the first-choice treatment for all newly diagnosed CML patients, but the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance. The most common mechanisms of resistance include (i) BCR-ABL overexpression, and (ii) BCR-ABL kinase domain mutations disrupting critical contact points between imatinib and BCR-ABL or inducing a transition to a conformation to which imatinib is unable to bind. Several approaches to overcoming resistance have been studied both in vitro and in vivo. They include dose escalation of imatinib, the combination of imatinib with chemotherapeutic drugs, alternative BCR-ABL inhibitors, and inhibitors of kinases acting downstream of BCR-ABL such as Src kinases. Various novel tyrosine kinase inhibitors (TKI) have been synthesized and have now reached the pre-clinical or clinical phase. This review highlights the development of new TKI as specific molecularly targeted therapy and as the principal mechanisms for overcoming imatinib resistance.

Antineoplastic Agents↗