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Curti A.,University of Bologna | Ruggeri L.,University of Perugia | D'Addio A.,Hematology Unit | Bontadini A.,S. Orsola Malpighi University Hospital | And 14 more authors.
Blood | Year: 2011

Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56 +CD3 - natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor-ligand mismatched donors after fludarabine/ cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 10 6/Kg. T cells were < 10 5/Kg. No NK cell-related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799. © 2011 by The American Society of Hematology.

Visani G.,Hematology and Hematopoietic Stem Cell Transplant Center | Sapienza M.R.,University of Bologna | Isidori A.,Hematology and Hematopoietic Stem Cell Transplant Center | Tripodo C.,University of Palermo | And 15 more authors.
PLoS ONE | Year: 2011

The molecular pathogenesis of primary mielofibrosis (PMF) is still largely unknown. Recently, single-nucleotide polymorphism arrays (SNP-A) allowed for genome-wide profiling of copy-number alterations and acquired uniparental disomy (aUPD) at high-resolution. In this study we analyzed 20 PMF patients using the Genome-Wide Human SNP Array 6.0 in order to identify novel recurrent genomic abnormalities. We observed a complex karyotype in all cases, detecting all the previously reported lesions (del(5q), del(20q), del(13q), +8, aUPD at 9p24 and abnormalities on chromosome 1). In addition, we identified several novel cryptic lesions. In particular, we found a recurrent alteration involving cytoband 20p13 in 55% of patients. We defined a minimal affected region (MAR), an amplification of 9,911 base-pair (bp) overlapping the SIRPB1 gene locus. Noteworthy, by extending the analysis to the adjacent areas, the cytoband was overall affected in 95% of cases. Remarkably, these results were confirmed by real-time PCR and validated in silico in a large independent series of myeloproliferative diseases. Finally, by immunohistochemistry we found that SIRPB1 was over-expressed in the bone marrow of PMF patients carrying 20p13 amplification. In conclusion, we identified a novel highly recurrent genomic lesion in PMF patients, which definitely warrant further functional and clinical characterization. © 2011 Visani et al.

Visani G.,Hematology and Hematopoietic Stem Cell Transplant Center | Isidori A.,Hematology and Hematopoietic Stem Cell Transplant Center
Expert Opinion on Pharmacotherapy | Year: 2014

The therapeutic armamentarium of chronic myeloid leukemia (CML) has been considerably improved after the introduction of first- and second-generation tyrosine-kinase inhibitors (TKIs). Accordingly, the natural history of the diseases has changed, and patients in complete molecular response now have the same life expectancy of their healthy coetaneous. Notwithstanding these results, ∼ 20-30% of patients do not respond optimally to TKIs therapy, and most of these patients are potential candidates to progress toward the accelerated or blastic phase of the disease. Unfortunately, patients who become resistant to both first- and second-generation TKIs develop BCR-ABL kinase domain mutations, against which TKIs have extremely low cross-activity. In particular, none of the TKIs, with the exception of ponatinib, has significant activity against T315 mutation, which is estimated to be present in ∼ 15-20% of patients carrying BCR-ABL mutations. The use of omacetaxine mepesuccinate/homoharringtonine for the treatment of TKI-resistant CML patients regained interest due to its mechanism of action independent of binding to the ATP-binding pocket. Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure. © 2014 Informa UK, Ltd.

Pagano L.,Catholic University | Valentini C.G.,Catholic University | de Stefano V.,Catholic University | Venditti A.,University of Rome Tor Vergata | And 13 more authors.
Annals of Oncology | Year: 2011

Background: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. Patients and methods: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). Results: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. Conclusions: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Russo D.,University of Brescia | Malagola M.,University of Brescia | Skert C.,University of Brescia | Cancelli V.,University of Brescia | And 33 more authors.
Blood Cancer Journal | Year: 2015

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ≥65 years in optimal and stable response with ≥2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response. © 2015, Nature Publishing Group. All rights reserved.

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