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Franco Mandelli

Publications and source records attributed to Franco Mandelli.

At least 19 recordsLinked to original sources
PubMed2007

Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol.

Thirty elderly (> 60 years) Philadelphia chromosome-positive (Ph(+)) patients with acute lymphoblastic leukemia (ALL) received imatinib, 800 mg daily, associated to steroids without further chemotherapy as frontline treatment. Median age was 69 years (range, 61-83 years). Twenty-nine patients were evaluable for response and all of them obtained a hematologic complete remission, with a median BCR-ABL reduction of 2.9 and 2.0 logs in p190(+) and p210(+) cases, respectively. Most of the induction treatment did not require admission of the patients. No major toxicities occurred and the treatment was well tolerated. Median survival from diagnosis was 20 months. This study shows that elderly Ph(+) patients with ALL-often considered eligible only for palliative treatment strategies-may benefit from an imatinib-steroids protocol, which does not require chemotherapy nor a long hospitalization, is feasible, highly active, and associated with a good quality of life.

Aged↗
PubMed2006

Late relapses in acute promyelocytic leukaemia.

From January 1988 to December 1997, among 53 acute promyelocytic leukaemia patients in 1st complete remission (CR) after 5 years from diagnosis, we observed 5 late relapses (9.4%) after 60, 61, 71, 101 and 155 months from diagnosis; 3 of those late relapses (7.7%) occurred among 39 patients previously treated with all-trans-retinoic acid. An involvement of the mastoid occurred in 3/5 patients (60%), compared with 2/32 patients (6.3%) at an early relapse (p < 0.02). As to the treatment of the late relapse, 1 patient received all-trans-retinoic acid alone followed by allogeneic transplantation and 4 patients were treated according to the GIMEMA 0191 protocol. All patients achieved a 2nd CR and are still alive: 4 in the 2nd molecular CR after 6, 33, 34 and 115 months; 1 relapsed after 15 months and is now in the 3rd CR. In conclusion, a late relapse occurred in a sizeable fraction of acute promyelocytic leukaemia patients: the high rate of ear involvement might be explained considering the ear as a 'disease sanctuary'.

Adolescent↗
PubMed2006

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.

In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.

Adolescent↗
PubMed2006

Identification of risk factors in atypical chronic myeloid leukemia.

In the WHO classification atypical chronic myeloid leukemia (CML) has been considered as a new distinct clinical entity included in the category of mixed myeloproliferative/myelodysplastic disorders. Little is known about this uncommon disease, whose incidence is about of one-two cases every 100 cases of Ph-positive CML. We analyzed our series of 55 patients diagnosed as having aCML, with the aim of identifying clinical factors of possible prognostic value on survival and acute transformation.

Aged↗
PubMed2006

Sudden blast crisis in patients with Philadelphia chromosome-positive chronic myeloid leukemia who achieved complete cytogenetic remission after imatinib therapy.

BACKGROUND: Most patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase (CP) who receive treatment with imatinib achieve complete cytogenetic remission (CCR), which is correlated tightly with long-term progression-free survival. In these patients, the occurrence of blastic crisis (BC) is rare, and its clinical biologic characteristics are not well known. METHODS: Among 164 patients who received imatinib and were followed for a median of 35 months, 11 patients (6.7%) developed a BC; this was sudden (i.e., it occurred within 3 months of a documented CCR) in 6 patients (54.5%). Those patients were analyzed with respect to their clinical and biologic features and were compared with previous reports. RESULTS: At the time of diagnosis, there were 3 low-risk patients and 3 intermediate-risk patients; 4 patients had received pretreatment with interferon, and 2 patients received only imatinib. The median CP was 18 months, and the median duration of imatinib therapy was 7 months. The median time to CCR was 3 months, and the median time from CCR to BC was 4 months. BC phenotype was lymphoid in 2 patients, myeloid in 3 patients (including 2 patients who had extramedullary localization), and biclonal in 1 patient. Karyotype evolution was detected in 4 patients, whereas a Ph-positive/Ph-negative mosaicism was evident in all 6 patients. One patient presented an M351T mutation. The overall median survival was 3 months. CONCLUSIONS: Sudden BC generally is an uncommon phenomenon that may be relatively frequent in patients with CML who receive imatinib. Clinical and biologic features also seem to characterize this peculiar type of abrupt disease evolution, which intervenes in patients' response to this drug. Close monitoring of disease markers and full disease eradication are warranted.

Adult↗
PubMed2006

Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia.

Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (>or=50 microg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.

Antineoplastic Agents↗
PubMed2006

Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification.

Because of a lack of specific clonality markers, information on lineage involvement and cell of origin of acute myeloid leukemia with normal karyotype (AML-NK), is missing. Because Nucleophosmin (NPM) gene is frequently mutated in AML-NK and causes aberrant NPM cytoplasmic localization (NPMc+), it was used as an AML lineage clonality marker. Clonal NPM exon 12 mutations were detected in myeloid, monocytic, erythroid, and megakaryocytic cells but not in fibroblasts or endothelia that were laser-microdissected from 3 patients with NPMc+ AML. Aberrant cytoplasmic expression of mutated NPM proteins was identified with anti-NPM antibodies in 2 or more myeloid hemopoietic cell lineages in 99 (61.5%) of 161 of NPMc+ AML paraffin-embedded bone marrow biopsies; lymphoid involvement was excluded in 3 investigated cases. These findings suggest that NPMc+ AML derives from either a common myeloid or earlier progenitor. Immunohistochemical studies show that varying combinations and ratios of NPMc+ leukemic cells from distinct lineages are responsible for heterogeneity within each French-American-British (FAB) classification type and for NPMc+ AML falling into different FAB categories. These findings question the value of FAB criteria in subdividing the WHO category of "AML not otherwise characterized" and suggest that, for clinical use, NPMc+ AML be provisionally regarded as a separate AML with prognostic significance.

Biomarkers, Tumor↗
PubMed2006

Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia.

Nucleophosmin (NPM) exon-12 mutations occur in 50% to 60% of adult acute myeloid leukemia (AML) with normal karyotype and are predictors of favorable prognosis. We evaluated bone marrow or peripheral blood samples from 450 adult patients with AML of the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto)/AML12 EORTC (European Organization for Research and Treatment of Cancer) trial to (1) search for new exon-12 NPM mutations; (2) determine whether NPM immunostaining on paraffin-embedded biopsies predicts NPM mutations; and (3) investigate altered nucleocytoplasmic NPM traffic in primary AML cells. Fourteen NPM mutations, including 8 new variants, were identified. All 200 AML cases expressing cytoplasmic NPM (NPMc(+) AML) carried NPM mutations. None of the 250 cases with nucleus-restricted NPM (NPMc(-) AML) was mutated. At the C-terminus, NPM leukemic mutants carried mutations of only tryptophan 290 or of both tryptophans 288 and 290 and a new nuclear export signal (NES) motif, which appear to underlie their nuclear export. The specific Crm1/exportin-1 inhibitor leptomycin-B relocated NPM mutants from cytoplasm to nucleus of primary NPMc(+) AML cells, demonstrating that nuclear export is NES dependent. NPM mutants bound and recruited wild-type NPM into leukemic cell cytoplasm. Because alterations at C-terminus of leukemic NPM mutants are similar, immunohistochemistry detects all exon-12 NPM mutations and is a valuable, inexpensive tool in the diagnostic-prognostic work-up of patients with AML with normal karyotype.

Active Transport, Cell Nucleus↗
PubMed2006

Impact of international collaboration on the prognosis of childhood acute promyelocytic leukemia in Iraq.

The promotion of an operational network between hospitals and medical schools in Iraq and in Western countries is a primary humanitarian objective of international collaboration. As a consequence of a collaborative project between the Al Mansour Hospital for Pediatrics in Baghdad and the Pediatric Unit of Hematology of "La Sapienza" University, in Rome, in October 2003 a specific all-trans-retinoic acid-based protocol was designed in order to offer a modern therapeutic program for the management of Iraqi children with acute promyelocytic leukemia, adapted to the severe local difficulties. The preliminary encouraging results represent a substantial improvement over the earlier experience in childhood acute promyelocytic leukemia in Iraq.

Adolescent↗
PubMed2006

The role of BCR/ABL isoforms in the presentation and outcome of patients with Philadelphia-positive acute lymphoblastic leukemia: a seven-year update of the GIMEMA 0496 trial.

To verify the potential clinical and prognostic value of BCR/ABL isoforms, we analyzed 101 consecutive adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in the GIMEMA 0496 trial between October 1996 and December 1999. A p190 or p210 with or without p190 BCR/ABL transcript was documented in 59 (58.5%) and 42 cases (41.5%), respectively. At diagnosis, a white cell count <16 x 10(9)/L and a higher level of CD34 and CD33 expression were associated with the p190 BCR/ABL transcript (p<0.05, p=0.009 and p=0.03, respectively). A complete remission was achieved in 62/92 (67.4%) patients, while 16/92 (17.4%) were resistant and 14/92 (15.2%) died of therapy-related complications. Fifty-two patients underwent intensive re-induction treatment, which was followed by stem cell transplant consolidation in the 36 in persistent complete remission (allogeneic = 20 patients; autologous = 16 patients). Response rates to induction therapies were similar in the two BCR/ABL isoform groups. By contrast, the p190 emerged as the only independent prognostic factor favorably affecting the 5-year overall survival and disease-free survival rates (p=0.008 and p=0.02, respectively).

Adult↗
PubMed2006

Home care management of patients affected by hematologic malignancies: a review.

Home care (HC) has an increasingly expanding role in the global management of patients affected by hematologic malignancies. Integrated strategies, including causal-targeted and supportive treatments according to hematologic expertise and a holistic approach inspired by the philosophy and practice of palliative medicine, may allow suitable management and the possibility for most patients to stay at home. Physical, social and psychological needs of patients are likely to vary according to the course of their disease and the treatments they are receiving. Therefore, consideration should be given to different models of care and how to tackle patients' diverse needs, as outlined by reported experiences which claimed that HC can provide appropriate solutions not only for terminally and chronically ill patients but also for those in other phases of disease. According to these studies and to our own experience, when appropriate measures and structured operating models are adopted, HC results in a safe, effective and economically realistic alternative to traditional in-hospital treatment. Therefore, all efforts should be made to overcome budget and administrative barriers and to ensure a more widespread use of this model of care.

Disease Management↗
PubMed2006

Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia.

The aim of this multicenter GIMEMA study was to correlate autoimmune complications (AIC) in B-cell chronic lymphocytic leukemia (B-CLL) with stage and therapy. Autoimmune hemolytic anemia (129/194 cases) and autoimmune thrombocytopenia (35/194 cases) were typically present in advanced and multi-treated disease. Age over the median, stage C and first and second line therapy were identified as independent risk factors by multivariate analysis. In contrast, non-hematologic AIC (30/194 cases) and the presence of serological markers of autoimmunity were mostly observed in early B-CLL, suggesting different pathogenic mechanisms underlying hematologic and non-hematologic autoimmune phenomena in B-CLL.

Aged↗
PubMed2005

Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation.

PURPOSE: To characterize gene expression signatures in acute lymphocytic leukemia (ALL) cells associated with known genotypic abnormalities in adult patients. EXPERIMENTAL DESIGN: Gene expression profiles from 128 adult patients with newly diagnosed ALL were characterized using high-density oligonucleotide microarrays. All patients were enrolled in the Italian GIMEMA multicenter clinical trial 0496 and samples had >90% leukemic cells. Uniform phenotypic, cytogenetic, and molecular data were also available for all cases. RESULTS: T-lineage ALL was characterized by a homogeneous gene expression pattern, whereas several subgroups of B-lineage ALL were evident. Within B-lineage ALL, distinct signatures were associated with ALL1/AF4 and E2A/PBX1 gene rearrangements. Expression profiles associated with ALL1/AF4 and E2A/PBX1 are similar in adults and children. BCR/ABL+ gene expression pattern was more heterogeneous and was most similar to ALL without known molecular rearrangements. We also identified a set of 83 genes that were highly expressed in leukemia blasts from patients without known molecular abnormalities who subsequently relapsed following therapy. Supervised analysis of kinase genes revealed a high-level FLT3 expression in a subset of cases without molecular rearrangements. Two other kinases (PRKCB1 and DDR1) were highly expressed in cases without molecular rearrangements, as well as in BCR/ABL-positive ALL. CONCLUSIONS: Genomic signatures are associated with phenotypically and molecularly well defined subgroups of adult ALL. Genomic profiling also identifies genes associated with poor outcome in cases without molecular aberrations and specific genes that may be new therapeutic targets in adult ALL.

Adolescent↗
PubMed2005

Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-3 study.

The role of glycosylated recombinant human granulocyte colony-stimulating factor (G-CSF) in the induction treatment of older adults with acute myeloid leukemia (AML) is still uncertain. In this trial, a total of 722 patients with newly diagnosed AML, median age 68 years, were randomized into 4 treatment arms: (A) no G-CSF; (B) G-CSF during chemotherapy; (C) G-CSF after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes; and (D) G-CSF during and after chemotherapy. The complete remission (CR) rate was 48.9% in group A, 52.2% in group B, 48.3% in group C, and 64.4% in group D. Analysis according to the 2 x 2 factorial design indicated that the CR rate was significantly higher in patients who received G-CSF during chemotherapy (58.3% for groups B + D vs 48.6% for groups A + C; P = .009), whereas no significant difference was observed between groups A + B and C + D (50.6% vs 56.4%, P = .12). In terms of overall survival, no significant differences were observed between the various groups. Patients who received G-CSF after chemotherapy had a shorter time to neutrophil recovery (median, 20 vs 25 days; P < .001) and a shorter hospitalization (mean, 27.2 vs 29.7 days; P < .001). We conclude that although priming with G-CSF can improve the CR rate, the use of G-CSF during and/or after chemotherapy has no effect on the long-term outcome of AML in older patients.

Acute Disease↗
PubMed2005

Myelodysplastic syndromes in patients under 50 years old: a single institution experience.

We report on our experience relating to 62 patients with myelodysplastic syndrome (MDS) aged less than 50 years, seen at our Institution and conservatively treated from July 1983 to December 2000. Patients demographics and clinical features at diagnosis were analysed for their prognostic value on survival and on risk of transformation to acute leukaemia. The median age at diagnosis was 43 years (range 21-50). According to FAB criteria there were 30 patients with refractory anaemia (RA), 3 with refractory anaemia with ringed sideroblasts (RARS), 18 with refractory anaemia with excess of blasts (RAEB), 6 with refractory anaemia with excess of blasts in transformation (RAEB-t) and 5 with chronic myelomonocytic leukaemia (CMML). Fifty patients had evaluable cytogenetic analysis: the most frequent karyotypic change was trisomy of chromosome 8 (10%), followed by monosomy 7 (6%); partial chromosome deletions and translocations were also common abnormalities, occurring on the whole in 16% of patients. At a median follow-up of 15 months 19 patients (31%) progressed to acute myeloid leukaemia (AML). From univariate analysis we identified some features, which appeared to be predictive of outcome and risk of transformation to AML. Age above 40 years (p = 0.002) and high risk according to IPSS score (p = 0.002) were found to be predictive for a shorter survival; FAB grouping (p = 0.0001), percentage > 5% of blasts in the bone marrow (p = 0.001) and high risk by IPSS score (p = 0.0003) were found to be predictive for a higher risk of transformation to AML. Presenting features in young MDS patients may identify subjects at higher risk of unfavourable outcome.

Adult↗
PubMed2005

Treatment of 72 newly diagnosed Waldenstrom macroglobulinemia cases with oral melphalan, cyclophosphamide, and prednisone: results and cost analysis.

BACKGROUND: Current treatment regimens for Waldenstrom macroglobulinemia (WM) are based on the use of oral alkylating agents. Recently, however, other more costly agents have been proposed for the treatment of WM. In the current study, the authors report on results obtained using oral melphalan, cyclophosphamide, and prednisone (MCP) to treat 72 patients with WM, and they compare these results (and the associated costs) with those observed using more aggressive protocols. METHODS: Between July 1973 and April 2002, the authors documented overexpression of the immunoglobulin M paraprotein in 317 consecutive patients. Of these, 100 had newly diagnosed WM, and the 72 who were symptomatic were treated using the MCP protocol. Response rate, overall survival (OS), response duration, freedom from progression (FFP), event-free survival (EFS) duration, toxicity, and cost per course in Euro and U.S. dollars were evaluated for patients receiving this regimen. RESULTS: Seventy-one of 72 patients (99%) were evaluable. Of these patients, 55 (77%) achieved a response; 7 others (10%) experienced disease stabilization, and the remaining 9 (13%) experienced disease progression. After a median follow-up of 72 months (range, 3-195 months), the median durations of EFS, FFP, response, and OS were 47, 55, 64, and 66 months, respectively. No World Health Organization Grade III or IV toxicities were observed, and side effects were limited to transient nausea, emesis, and mild neutropenia. The cost per course of the MCP regimen was $16, similar to that of standard protocols involving chlorambucil and much less than that of more aggressive protocols (price range, $91-11091) proposed for the treatment of WM. CONCLUSIONS: Like chlorambucil-based protocols, the MCP regimen is a cost-effective and safe option for the treatment of patients with WM. Furthermore, the results obtained do not appear to be inferior to those yielded by more expensive, aggressive, and toxic intravenous protocols.

Administration, Oral↗
PubMed2005

GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children.

The role of all-trans retinoic acid (ATRA) in pediatric acute promyelocytic leukemia (APL) is the topic of several ongoing studies. The results of the Italian pediatric experience with the multicentric Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)-Italian Pediatric Hematology and Oncology Group (AIEOP) "AIDA" (ATRA and idarubicin) trial are presented. Of the 983 patients with APL enrolled in this protocol between January 1993 and June 2000, 124 (13%) had younger than 18 years. Treatment consisted of ATRA and idarubicin induction followed by 3 polychemotherapy consolidation courses. Molecular response by reverse transcriptase-polymerase chain reaction (RT-PCR) was assessed after consolidation and patients who were PCR- were randomized for different maintenances. One hundred and seven children were eligible and evaluable for induction: 103 (96%) achieved a hematologically complete remission. Overt ATRA syndrome was observed in 2 patients and pseudotumor cerebri was observed in 10 patients. Ninety-four patients were evaluable for RT-PCR analysis at the end of consolidation: 91 (97%) proved PCR+ and 3 PCR-. The overall survival and event-free survival (EFS) are 89% (95% confidence interval [c.i.]: 83%-95%) and 76% (c.i.: 65%-85%), respectively, at more than 10 years. A white blood cell (WBC) count at diagnosis of greater than 10 x 10(9)/L had a significant impact on EFS (59% vs 83% at 10 years). These results highlight the efficacy and feasibility of the AIDA protocol in the pediatric APL population.

Adolescent↗