Publications by authors named "Francesca Elice"

22 Publications

  • Page 1 of 1

Logistics of an advanced therapy medicinal product during COVID-19 pandemic in Italy: successful delivery of mesenchymal stromal cells in dry ice.

J Transl Med 2020 11 30;18(1):451. Epub 2020 Nov 30.

Haematology Unit, Vicenza Hospital, Vicenza, Italy.

Background: During the coronavirus disease-2019 (COVID-19) pandemic, Italian hospitals faced the most daunting challenges of their recent history, and only essential therapeutic interventions were feasible. From March to April 2020, the Laboratory of Advanced Cellular Therapies (Vicenza, Italy) received requests to treat a patient with severe COVID-19 and a patient with acute graft-versus-host disease with umbilical cord-derived mesenchymal stromal cells (UC-MSCs). Access to clinics was restricted due to the risk of contagion. Transport of UC-MSCs in liquid nitrogen was unmanageable, leaving shipment in dry ice as the only option.

Methods: We assessed effects of the transition from liquid nitrogen to dry ice on cell viability; apoptosis; phenotype; proliferation; immunomodulation; and clonogenesis; and validated dry ice-based transport of UC-MSCs to clinics.

Results: Our results showed no differences in cell functionality related to the two storage conditions, and demonstrated the preservation of immunomodulatory and clonogenic potentials in dry ice. UC-MSCs were successfully delivered to points-of-care, enabling favourable clinical outcomes.

Conclusions: This experience underscores the flexibility of a public cell factory in its adaptation of the logistics of an advanced therapy medicinal product during a public health crisis. Alternative supply chains should be evaluated for other cell products to guarantee delivery during catastrophes.
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http://dx.doi.org/10.1186/s12967-020-02625-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702210PMC
November 2020

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.

Lancet Haematol 2020 Dec;7(12):e861-e873

Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Azienda Ospedaliero-Universitaria di Bologna, Università di Bologna, Bologna, Italy. Electronic address:

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/m 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<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group.

Interpretation: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.

Funding: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.
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http://dx.doi.org/10.1016/S2352-3026(20)30323-9DOI Listing
December 2020

Evaluation of lymphocytes inactivation by extracorporeal photopheresis using tetrazolium salt based-assay.

Transfus Apher Sci 2015 Oct 27;53(2):242-5. Epub 2015 May 27.

Department of Cellular Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy. Electronic address:

Extracorporeal photopheresis (ECP) is accepted as a second-line therapy for the treatment of acute and chronic steroid-refractory graft versus host disease (GvHD), cutaneous T-cell lymphoma and solid organ transplantation. ECP should be validated: we compared in parallel apoptosis and proliferation analysis of patient lymphocytes treated with 8-MOP ECP using respectively Annexin V/7-aminoactinomycin D (7-AAD) and CFSE with a tetrazolium salt (WST-1) method. Using WST-1 assay we found a significant decrement (p < 0.01) of metabolic activity at 4 days between ECP-treated and untreated cells. This finding was confirmed by the significant decrease of cell proliferation and increase of cell death observed by CFSE and 7AAD-Annexin V, respectively. Accordingly, once validated against a reference method, WST-1 could represent a rapid and easy assay for routinely quality control of ECP.
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http://dx.doi.org/10.1016/j.transci.2015.05.004DOI Listing
October 2015

Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study.

Am J Hematol 2014 Dec 17;89(12):1085-91. Epub 2014 Sep 17.

"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy.

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
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http://dx.doi.org/10.1002/ajh.23835DOI Listing
December 2014

Side effects of anti-angiogenic drugs.

Thromb Res 2012 Apr;129 Suppl 1:S50-3

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Anti-angiogenic drugs and in particular anti-vascular endothelial growth factor (VEGF) agents have entered the clinical armamentarium against cancer. New unexpected toxicities have emerged. The incidence and the severity of these toxicities have a great variability in the different studies. Among them, bleeding is one of the most severe and difficult to manage. Bevacizumab retains the highest frequency of bleeding complications, in particular epistaxis, hemoptysis and gastrointestinal bleeding. Although a higher incidence of severe hemorrhages has not been consistently demonstrated during the treatment with bevacizumab, mild bleeding episodes appear clearly increased in the experimental arm of most trials. Cases of severe pulmonary hemorrhage were reported in patients with lung cancer; these events occurred mainly intra-tumor and were significantly associated with squamous cell histology. Trials with other small-molecule tyrosine kinase inhibitors like sunitinib or sorafenib showed an overall lower rate of bleeding complications, but still significantly higher than the control arm in many cases. The mechanisms of bleeding induced by anti-VEGF agents are complex and not yet fully clarified: the main hypothesis is that VEGF could promote endothelial cell survival and integrity in the adult vasculature and its inhibition may decrease the renewal capacity of damaged endothelial cells. Management of bleeding in patients treated with anti-VEGF agents is a challenging task because this complication is at least in part inherent to the efficacy of the drug and because there is also an increased risk of thrombosis, both arterial and venous. So far, only few preliminary data are available on a strategy to prevent hemorrhage and thrombotic event.
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http://dx.doi.org/10.1016/S0049-3848(12)70016-6DOI Listing
April 2012

Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial.

J Clin Oncol 2011 Mar 31;29(8):986-93. Epub 2011 Jan 31.

University of Torino, Azienda Ospedaliero-Universitaria San Giovanni Battista, Torino, Italy.

Purpose: In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens.

Patients And Methods: A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment.

Results: Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded.

Conclusion: In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.
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http://dx.doi.org/10.1200/JCO.2010.31.6844DOI Listing
March 2011

Thrombotic events in patients with cancer receiving antiangiogenesis agents.

J Clin Oncol 2009 Oct 24;27(29):4865-73. Epub 2009 Aug 24.

University of Utah, Division of Hematology, Blood/Marrow Transplant and Myeloma Program, Salt Lake City, UT, USA.

Tumor-associated neoangiogenesis has recently become a suitable target for antineoplastic drug development. In this overview, we discuss specific drug-associated hemostatic complications, the already known pathogenetic mechanisms involved, and the effect of varying antithrombotic strategies. Multiple agents with angiogenic inhibitory capacity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib, and sirolimus) have obtained US Food and Drug Administration approval, and many others have entered clinical trials. Arterial and venous thromboembolism and hemorrhage have emerged as significant toxicities associated with the use of angiogenesis inhibitors. We present a detailed analysis of the literature on thrombotic complication of antiangiogenic drugs. Close attention to hemostatic complications during antiangiogenic treatment is warranted. Further studies are required to better understand the pathophysiologic mechanisms involved and to define a safe prophylactic strategy.
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http://dx.doi.org/10.1200/JCO.2009.22.3875DOI Listing
October 2009

Thrombosis associated with angiogenesis inhibitors.

Best Pract Res Clin Haematol 2009 Mar;22(1):115-28

Department of Cell Therapy and Haematology, San Bortolo Hospital, Via Rodolfi 37, 36100 Vicenza, Italy.

Recent advances in the understanding of the pathogenesis of cancer have led to the introduction of a variety of biological agents with novel mechanisms of action into clinical trials and even into clinical practice. In particular, tumour-associated neoangiogenesis has become a major target for this new class of antineoplastic agents. Five anti-angiogenic agents (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use, and many others have entered clinical trials. Many new biological agents with anti-angiogenic properties appear to be associated with an increased risk for thrombosis and, paradoxically, bleeding. Although the mechanisms underlying the increased thromboembolic risk remain ill defined, the main hypothesis is that perturbation of tumour-associated endothelial cells can switch the endothelium from a naturally anticoagulant surface to a prothrombotic surface, thus mediating the activation of systemic coagulation in cancer patients, who are already more susceptible to thromboembolism due to their underlying disease. The toxicity profile differs between the anti-angiogenic agents. Thalidomide, lenalidomide, semaxibin (SU5416) and prinomastat have produced more venous thromboembolic complications, whereas bevacizumab, sunitinib, sorafenib and ZD6126 have been associated with a higher risk of arterial thromboembolism and, in particular, myocardial ischaemia. The observation of these vascular toxicities suggests the need to establish, in randomized clinical trials, the usefulness of thrombosis prophylaxis when anti-angiogenic agents are used in cancer patients, especially when associated with chemotherapy. In addition, careful reporting of haemostatic complications during treatment with new anti-angiogenic drugs is warranted.
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http://dx.doi.org/10.1016/j.beha.2009.01.001DOI Listing
March 2009

Hemostatic complications of angiogenesis inhibitors in cancer patients.

Am J Hematol 2008 Nov;83(11):862-70

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.
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http://dx.doi.org/10.1002/ajh.21277DOI Listing
November 2008

Predictive value of alkaline phosphatase for response and time to progression in bortezomib-treated multiple myeloma patients.

Am J Hematol 2007 Sep;82(9):831-3

The Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Myeloma bone disease is characterized by osteolytic destruction associated with suppressed osteoblastic activity. Using data from the APEX (Richardson et al., N Engl J Med 2005;352:2487-2498) study, we have assessed the relationship of changes in alkaline phosphatase (ALP) levels during bortezomib therapy with response and time to progression on this therapy. The percentage of ALP increments in responders (complete and partial response) and nonresponders was analyzed at different thresholds and time points. For all bortezomib-treated patients enrolled in the trial (N = 333), at least a 25% increase in ALP from the baseline at 6 week was the most powerful predictor of treatment response (P < 0.0001) and time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in ALP (P = 0.01). Markers of osteoblastic activation may predict quality and duration of response in multiple myeloma. In addition, our data suggest that bone anabolism could inhibit myeloma growth.
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http://dx.doi.org/10.1002/ajh.20961DOI Listing
September 2007

Hemostatic dysfunction in paraproteinemias and amyloidosis.

Semin Thromb Hemost 2007 Jun;33(4):339-49

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Thrombotic and hemorrhagic complications frequently have been observed in patients with monoclonal gammopathy, Waldenström macroglobulinemia, amyloidosis, multiple myeloma (MM), and myeloma. Chemotherapy in combination with the use of antiangiogenic agents can further enhance the risk of cardiovascular complications. A malignancy-associated thrombophilic state (in particular, cytokine-induced high levels of factor VIII and von Willebrand factor) can also explain the high rate of thrombosis reported in these patients. Impaired fibrinolysis and a transient downregulation of the protein C system are recently discovered pathogenetic mechanisms. At diagnosis, when the highest VTE risk is present, baseline coagulation tests such activated protein C resistance may be helpful to identify patients who can benefit the most from anticoagulation; with the emerging evidence of a positive effect on survival of low molecular weight heparin, prospective trials are needed in this group of diseases.
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http://dx.doi.org/10.1055/s-2007-976169DOI Listing
June 2007

Thrombosis in multiple myeloma.

Expert Rev Anticancer Ther 2007 Mar;7(3):307-15

Myeloma Institute, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 776, Little Rock, Arkansas 72205, USA.

Multiple myeloma, as with other malignancies, has been associated with the development of venous thromboembolic events. Chemotherapy or steroids in combination with antiangiogenic agents can further enhance this risk. The identification of measurable factors associated with this prothrombotic state could help in the selection of patients who need antithrombotic prophylaxis. Malignancy-associated thrombophilic state, paraprotein-specific mechanisms and treatment-induced changes can explain the high rate of thrombosis in this cancer population. While the release of inflammatory cytokines induces high levels of factor VIII, von Willebrand factor and downregulate the protein C system, elevated plasma immunoglobulin can impair fibrinolysis. Strategies of thromboprophylaxis with low molecular weight heparin, warfarin or aspirin in patients treated with thalidomide/chemotherapy or lenalidomide and dexamethasone have shown efficacy. Early data indicate that the effect of low molecular weight heparin on multiple myeloma is not confined to the anticoagulant effect but could extend to survival; a similar positive trend in overall survival has also been reported in patients treated with aspirin.
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http://dx.doi.org/10.1586/14737140.7.3.307DOI Listing
March 2007

Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.

Br J Haematol 2006 Aug;134(4):399-405

Department of Haematology, San Bortolo Hospital, Vicenza, Italy.

Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE). APCR was determined in 1178 myeloma patients using an activated partial thromboplastin time-based resistance assay in the presence of excess of factor V-deficient plasma; polymerase chain reaction amplification of genomic DNA was used to detect factor V Leiden mutation. A total of 109 patients were found to have abnormal APCR and one-third of them were carriers for the mutation. With a median follow-up of 40 months, the presence of aAPCR was associated with a significantly increased risk of thrombosis (P < or = 0.001). APCR was measured again after treatment in 31 patients with abnormal baseline values and had normalised in 30 of them. This study indicates that aAPCR is the most common single transitory baseline coagulation abnormality associated with VTE in myeloma patients.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06208.xDOI Listing
August 2006

Prolonged overall survival with second on-demand autologous transplant in multiple myeloma.

Am J Hematol 2006 Jun;81(6):426-31

Department of Hematology, San Bortolo Hospital, Vicenza, Italy.

Between August 1993 and March 2003, 130 consecutive multiple myeloma (MM) patients eligible for high-dose treatment were offered a program including up-front autologous stem cell transplantation (ASCT) after conditioning with 200 mg/m(2) melphalan followed by a second ASCT in case of relapse or progression. A total of 107 (82%) patients completed the first ASCT. The best response obtained after ASCT was complete response (CR) 23%, very good partial response (VGPR) 28%, partial response (PR) 42%, and minimal response (MR) 7%. Median overall survival (OS) and event-free survival (EFS) were 65.4 and 27.7 months, respectively. Relapse or progression occurred in 70 patients; 26 received a second ASCT (with a median time of 20.4 months from first ASCT). A major response (> or =PR) was obtained in 69% of these patients. Median OS and EFS after the second ASCT were 38.1 and 14.8 months. Treatment-related mortality was 1.9% after the first ASCT but no deaths occurred after the second. Our experience suggests that elective up-front single ASCT followed by second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients.
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http://dx.doi.org/10.1002/ajh.20641DOI Listing
June 2006

Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study.

Blood 2006 May 29;107(9):3463-8. Epub 2005 Dec 29.

Division of Hematology, Ospedale Niguarda, Piazza Ospedale Maggiore 3, 20162-Milano, Italy.

Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD(816)) was associated with a high white blood cell count at diagnosis (median, 29.60 x 10(9)/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD(816) mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT(-)) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD(816) (n = 7) and the c-KIT(-) patients. These findings indicate that c-KIT TKD(816) mutation has a negative impact on the outcome of AML with t(8;21).
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http://dx.doi.org/10.1182/blood-2005-09-3640DOI Listing
May 2006

Immunomodulatory drugs in multiple myeloma.

Expert Opin Investig Drugs 2005 Nov;14(11):1411-8

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Immunomodulatory drugs (IMiDs) are thalidomide analogues that retain the direct anticancer cytotoxic and immunological activity of their parent compound, but with a different toxicity profile. In vitro studies show that IMiDs have a more potent antitumour effect than thalidomide on multiple myeloma (MM) cell lines. This activity is mediated by multiple mechanisms: direct antiproliferative effect; inhibition of angiogenesis due to reduced IL-6 and vascular endothelial growth factor secretion; inhibition of cytokines production, especially TNF-alpha; and stimulation of T-cell activity. Two IMiDs, CC-5013 and CC-4047, have been tested in clinical trials in MM patients with progressive or refractory disease, and one trial is ongoing in newly diagnosed MM patients. Observed toxicities include thrombocytopoenia, neutropoenia and cardiovascular events, but no significant neurotoxicity has been reported. Partial responses (> or = 50% reduction in M-protein) ranged from 20 to 71% in different studies depending on the pretreatment status of the patients. The combination of IMiDs with dexamethasone may be beneficial.
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http://dx.doi.org/10.1517/13543784.14.11.1411DOI Listing
November 2005

Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma.

Br J Haematol 2005 Oct;131(1):71-3

The Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

The prompt response to bortezomib observed in a 63-year-old woman with multiple myeloma was associated with a significant increase in alkaline phosphatase (ALP). After similar elevations were noted in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels were analysed in two large bortezomib trials. A statistically significant elevation of ALP from baseline was observed in responding patients (complete and partial responders) within three cycles of therapy. The rise in ALP after bortezomib in three patients was explained by a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in myeloma is closely associated with osteoblastic activation.
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http://dx.doi.org/10.1111/j.1365-2141.2005.05733.xDOI Listing
October 2005

Recombinant human erythropoietin and the risk of thrombosis in patients receiving thalidomide for multiple myeloma.

Haematologica 2004 Sep;89(9):1141-2

Among 199 patients treated with thalidomide for multiple myeloma, four thromboses occurred in 49 cases during erythropoietin therapy (prevalence 8.1%; annual rate 7.25%), and another 14 events occurred in patients not on erythropoietin (9.3%; 7.56%). Thus, erythropoietin would seem not to increase the risk of thrombosis of myeloma patients receiving thalidomide.
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September 2004

KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication.

Haematologica 2004 Aug;89(8):920-5

Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Italy.

Background And Objectives: Mutations of KIT receptor tyrosine kinase are involved in the constitutive activation and development of human hematologic malignancies. Gain-of-function mutations in the second intracellular kinase domain (TK2) and in the juxtamembrane domain are described in patients with core binding factor acute myeloid leukemia (CBFL) and are associated with leukocytosis. We evaluated the incidence of KIT mutation in 52 adult patients with de novo CBFL and in 49 FLT3/ITD-negative childhood patients with de novo acute myeloid leukemia (AML), excluding cases of acute promyelocytic leukemia.

Design And Methods: In order to analyze the role of KIT in CBFL we examined the KIT mutations in 52 adult CBFL, including 15 previously reported patients, and in 49 non-APL childhood AML patients using sensitive detection methods. We correlated our findings with the presence of trisomy 4 and investigated the relationship of the extra chromosome 4 with KIT mutations.

Results: Several kinds of gain-of-function KIT mutations were found in 24 of the 52 (46.1%) adult CBFL cases and 6 of the 49 (12.2%) non-APL childhood AML patients. KIT mutations were detected in 4 of the 8 adult patients and one childhood AML case bearing trisomy of chromosome 4 as either the sole cytogenetic aberration or a karyotypic aberration additional to t(8;21). In three of the trisomy 4 cases we demonstrated that trisomy 4 leads to duplication of the KIT mutated allele.

Interpretation And Conclusions: These results underline that the KIT gene is activated in AML characterized by distinct cytogenetic and molecular genetic patterns and represents the most frequently mutated target in adult CBFL.
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August 2004

Thalidomide and thrombosis.

Pathophysiol Haemost Thromb 2003 ;33 Suppl 1:15-8

Department of Hematology, San Bortolo Hospital, Vicenza, Italy.

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http://dx.doi.org/10.1159/000073282DOI Listing
May 2004

Fluorescent polymerase chain reaction and capillary electrophoresis for IgH rearrangement and minimal residual disease evaluation in multiple myeloma.

Haematologica 2002 Nov;87(11):1157-64

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Background And Objectives: Several polymerase chain reaction (PCR)-based techniques for tracking minimal residual disease (MRD) in B-lymphoproliferative disorders have been recently proposed. These procedures show significant variation in sensitivity and specificity. We describe an alternative assay based on fluorescent PCR combined with capillary electrophoresis and GeneScan analysis, to identify the monoclonal immunoglobulin heavy chain (IgH) rearrangement in multiple myeloma (MM) and to provide a semi-quantitative evaluation of MRD by limiting dilutions.

Design And Methods: Different sets of family specific primers derived from the leader region and from the framework-1 of IgH were used, with a unique reverse fluorescent primer JH. The malignant clone was identified by GeneScan and sequenced. Two tumor primers, mapping in the complementarity determining regions CDRII and CDRIII, were designed for each patient. A comparison between the nested-PCR approach and direct fluorescent PCR was performed for three patients in complete clinical remission after autologous or allogeneic bone marrow transplantation.

Results: Thirty-six consecutive patients with MM were screened and monoclonality was identified in about 70% of the cases. Molecular MRD evaluation was performed in 18 patients using tumor primers. This method allowed identification of 1 neoplastic cell among 10(4)-10(6) normal cells. In three cases, negative by nested-PCR and agarose gel electrophoresis, gene scanning showed persistence of the neoplastic clone, despite the negativity of the immunofixation.

Interpretation And Conclusions: Capillary electrophoresis of fluorescent fragments with gene scanning provides a simple, rapid and reproducible method to detect IgH rearrangement and to evaluate MRD. Furthermore, the sensitivity reached is up to 1 log higher than that of the conventional approach with nested-PCR, even though two steps of specificity are maintained.
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November 2002