Giuseppe Irrera

Pegfilgrastim compared with filgrastim after high‐dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients

Abstract:u2002 We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high‐dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty‐seven consecutive patients were randomly assigned to receive a single 6u2003mg dose of Pegfilgrastim on day 1 post‐transplant (nu2003=u200318 patients) vs. daily subcutaneous injections of Filgrastim 5u2003μg/kg (nu2003=u200319 patients) starting on day 5 post‐transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6u2003d, respectively (Pu2003=u2003ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, Pu2003=u20030.003) and duration of febrile neutropenia (1.5u2003d vs. 4u2003d, Pu2003=u20030.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytesu2003×u2003109u2003L on day 15 (6.0 vs. 2.7, Pu2003=u20030.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects.

Bone Marrow Failure Associated with Herpesvirus 8 Infection in a Patient Undergoing Autologous Peripheral Blood Stem Cell Transplantation

We describe a fatal case of human herpesvirus 8-associated bone marrow failure in a patient who had received intense treatment for Hodgkin lymphoma and was undergoing bone marrow transplantation. Bone marrow failure was resistant to antiviral treatment and a second infusion of autologous stem cells. Human herpesvirus 8 infection continues to be a major concern in transplant recipients in critical condition.

Low tolerance and high toxicity of thalidomide as maintenance therapy after double autologous stem cell transplant in multiple myeloma patients

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression‐free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post‐transplantation period as maintenance therapy was tested in 17 pts at a dose of 100u2003mg/d starting between 3 and 5u2003months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13u2003months (range: 3–26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow‐up of 36u2003months (range: 10–59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent.

Incremental – Adaptive – Knowledge Based – Learning for Informative Rules Extraction in Classification Analysis of aGvHD

Acute graft-versus-host disease (aGvHD) is a serious systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) that occurs when alloreactive donor-derived T cells recognize host-recipient antigens as foreign. The early events leading to GvHD seem to occur very soon, presumably within hours from the graft infusion. Therefore, when the first signs of aGvHD clinically manifest, the disease has been ongoing for several days at the cellular level, and the inflammatory cytokine cascade is fully activated. So, it comes as no surprise that to identify biomarker signatures for approaching this very complex task is a critical issue. In the past, we have already approached it through joint molecular and computational analyses of gene expression data proposing a computational framework for this disease. Notwithstanding this, there aren’t in literature quantitative measurements able to identify patterns or rules from these biomarkers or from aGvHD data, thus this is the first work about the issue. In this paper first we have applied different feature selection techniques, combined with different classifiers to detect the aGvHD at onset of clinical signs, then we have focused on the aGvHD scenario and in the knowledge discovery issue of the classification techniques used in the computational framework.

Wernicke's encephalopathy after allogeneic stem cell transplantation.

Wernickes encephalopathy is an acute neuropsychiatric condition due to thiamine deficiency frequently associated with chronic alcohol abuse. We describe 2 cases of patients who experienced acute Wernickes encephalopathy after allogeneic stem cell transplantation associated with the use of commercial total parental nutrition. Early diagnosis with magnetic resonance imaging and timely treatment with thiamine resulted in rapid resolution of clinical and radiological signs. In conclusion, the prolonged use of commercial total parental nutrition formulas must be supplemented with thiamine in the form of intramuscularly administered multivitamins.

Administration of recombinant human erythropoietin alpha before autologous stem cell transplantation reduces transfusion requirement in multiple myeloma patients

Recombinant human erythropoietin administered after peripheral blood stem cell transplantation (PBSCT) has been ineffective for the treatment of anemia. We administered recombinant human erythropoietin alpha (rHuEPO) prior to high-dose therapy after peripheral blood stem cell (PBSC) collection to evaluate its efficacy on transfusion requirements and hematological parameters during the post-transplant aplastic phase. Twenty-two multiple myeloma patients (EPO-MM) were included in the trial to receive rHuEPO 10,000xa0IU subcutaneous daily starting 30 days before PBSCT. Forty hemoglobin (Hb)-matched patients who had not received rHuEPO before transplant were retrospectively selected (Ctr-MM) for comparative data. None of the patients received transfusions at study entry. All but one patient responded to rHuEPO. However, no significant differences in Hb levels were obtained between the two groups at the time of transplantation. At nadir, the EPO-MM cases had a significantly higher Hb level (median 10xa0g/dl versus 7.6xa0g/d; p=0.001). Consequently, less than 20% of EPO-MM patients required packed red blood cell (PRBC) transfusions compared to more than half the Ctr-MM patients (p=0.007). Furthermore, the number of PRBC transfusions performed in the EPO-MM group was significantly lower (median 0 versus 1; p=0.008). Independently of Hb levels at PBSCT, rHuEPO therapy was significantly associated with a lower risk of transfusion requirement. In conclusion, rHuEPO is shown to be effective when administered prior to high-dose therapy in MM.

Differences in transplant-related complications between hematologic malignancies and solid tumors receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation

Multiple factors contribute to transplant-related complications after high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, including conditioning regimens, number of infused stem cells and clinical characteristics of patient at transplant. We compared the transplant-related complications of 141 patients affected with hematological malignancies with those of 109 patients with solid tumors. The total number of peripheral blood stem cell transplantations performed was 339. High-dose chemotherapy mainly consisted of melphalan-, busulphan- or thiotepa-based regimens. Despite the equal number of infused CD34+ cells, patients with a hematological malignancy showed a slower absolute neutrophil count (days to neutrophils >0.5 x 109/L, 10.6 ± 3.6 for hematological malignancies versus 9.1 ± 1.2 for solid tumors, P <0.0001) and platelet recovery (days to platelets >20 x 109/L, 16.4 ± 9.8 for hematological malignancies versus 12.3 ± 4.1 for solid tumors, P <0.0001) than patients with a solid tumor. A significantly higher requirement of red blood cell (3.3 ± 4.1 versus 2.0 ± 1.9, P <0.0029) and platelet units (7.5_± 10.4 versus 4.2 ± 3.4, P <0.0001) was observed for hematological malignancies than for solid tumors. Five graft failures were documented exclusively in patients with a hematological malignancy. Moreover, such patients displayed a longer duration of mucositis (P <0.0028) and hospital stay (P <0.0001), but no difference was observed in terms of febrile episodes. Transplant-related mortality was similar between the two groups. In conclusion, patients with a hematological malignancy overall have more complications than those with a solid tumor.

Utility of the clinical practice of admnistering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors treated with G-csf for mobilization of peripheral blood stem cells

The aim of the study was to verify the utility of the clinical practice of administering thrombophilic screening and antithrombotic prophylaxis with low-molecular-weight heparin to healthy donors receiving granulocyte colony-stimulating factor to mobilize peripheral blood stem cells. Thrombophilia screening comprised of testing for factor V Leiden G1691A, prothrombin G20210A, the thermolabile variant (C677T) of the methylene tetrahydrofolate reductase gene, protein C, protein S, factor VIII and homocysteine plasmatic levels, antithrombin III activity, and acquired activated protein C resistance. We investigated prospectively 72 white Italian healthy donors, 39 men and 33 women, with a median age of 42 years (range, 18-65). Five donors (6.9%) were heterozygous carriers of Factor V Leiden G1691A; two healthy donors had the heterozygous prothrombin G20210A gene mutation; C677T mutation in the methylene tetrahydrofolate reductase gene was present in 34 (47.2%) donors in heterozygous and in 7 donors (9.7%) in homozygous. Acquired activated protein C resistance was revealed in 8 donors of the study (11.1%). The protein C plasmatic level was decreased in 3 donors (4.2%); the protein S level was decreased in 7 donors (9.7%). An elevated factor VIII dosage was shown in 10 donors (13.9%) and hyperhomocysteinemia in 9 donors (12.5%). Concentration of antithrombin III was in the normal range for all study group donors. The factor V Leiden mutation was combined with the heterozygous prothrombin G20210A in 2 cases and with protein S deficiency in one case; 2 healthy donors presented an associated deficiency of protein C and protein S. Although none of these healthy subjects had a previous history of thrombosis, low-molecular-weight heparin was administered to all donors during granulocyte colony-stimulating factor administration to prevent thrombotic events. No donor experienced short or long-term thrombotic diseases after a median follow-up of 29.2 months. Our data do not support this clinical practice because there is no evidence that the combination of granulocyte colony-stimulating factor to previous hypercoagulable conditions results in thrombotic events.

Knowledge Discovery and Risk Prediction for Chronic Diseases: An Integrated Approach

A novel ontology based type 2 diabetes risk analysis system framework is described, which allows the creation of global knowledge representation (ontology) and personalized modeling for a decision support system. A computerized model focusing on organizing knowledge related to three chronic diseases and genes has been developed in an ontological representation that is able to identify interrelationships for the ontology-based personalized risk evaluation for chronic diseases. The personalized modeling is a process of model creation for a single person, based on their personal data and the information available in the ontology. A transductive neuro-fuzzy inference system with weighted data normalization is used to evaluate personalized risk for chronic disease. This approach aims to provide support for further discovery through the integration of the ontological representation to build an expert system in order to pinpoint genes of interest and relevant diet components.