Publications by authors named "Lucia Mastrullo"

18 Publications

  • Page 1 of 1

Is re-challenge still an option as salvage therapy in multiple myeloma? The case of REal-life BOrtezomib re-Use as secoND treatment for relapsed patients exposed frontline to bortezomib-based therapies (the REBOUND Study).

Ann Hematol 2019 Feb 23;98(2):361-367. Epub 2018 Oct 23.

Haematology Unit, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15 months, while median PFS2 was 55 months. With a median follow-up of 56 months, overall survival was 94 months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.
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http://dx.doi.org/10.1007/s00277-018-3524-1DOI Listing
February 2019

Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma.

Oncotarget 2018 May 4;9(34):23443-23450. Epub 2018 May 4.

Unit of Hematology, University of Padova, Padova, Italy.

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.
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http://dx.doi.org/10.18632/oncotarget.25215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955107PMC
May 2018

Combined use of free light chain and heavy/light chain ratios allow diagnosis and monitoring of patients with monoclonal gammopathies: Experience of a single institute, with three exemplar case reports.

Oncol Lett 2016 Oct 5;12(4):2363-2370. Epub 2016 Aug 5.

Complex Operative Unit of Hematology, San Gennaro Hospital, Naples 1 Local Health Center, I-80135 Naples, Italy.

Monoclonal gammopathies are characterized by serum monoclonal component (MC) plus an intact immunoglobulin and a free light chain (FLC), or a combination of both. The measurement of FLC with Freelite is the standard practice recommended by International Myeloma Working Group guidelines. Recently, Hevylite heavy/light chains (HLC) assays were introduced to specifically target junctional epitopes between the heavy and light chains of intact immunoglobulins, allowing the independent quantification of the involved (MC) and uninvolved (polyclonal immunoglobulin background) HLC isotype. Between January 2012 and March 2014, 90 patients were examined: 49 multiple myeloma (MM), 6 smoldering MM (SMM) and 35 monoclonal gammopathy of undetermined significance (MGUS). Of these 90 patients, 300 samples were collected at different times. The diagnostic and monitoring contribution of Hevylite A and G assays was assessed in all 90 patients examined. Additionally, 3 representative cases were selected. The Hevylite absolute values and ratio demonstrated high sensitivity and specificity with respect to serum protein electrophoresis and serum immunofixation. The combined use of Hevylite A and G with Freelite was particularly useful in dubious cases with more than one MC or with co-migrating components, as well as in the course of monitoring to assess the independent change of FLC and HLC, possibly reflecting the presence of clonal heterogeneity in the cohort. From this study, it can be concluded that FLC and HLC are independent, useful markers to monitor the MC and to assess with greater specificity and sensitivity the effect of therapy, thereby providing clinical support. Further studies are required to assess the prognostic potential of Hevylite in MGUS and SMM.
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http://dx.doi.org/10.3892/ol.2016.4965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038391PMC
October 2016

Personal history and quality of life in chronic myeloid leukemia patients: a cross-sectional study using narrative medicine and quantitative analysis.

Support Care Cancer 2016 11 3;24(11):4487-93. Epub 2016 Jun 3.

Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161, Rome, Italy.

Background: Tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients diagnosed with chronic myeloid leukemia (CML). Several reports indicated the advantage of continue long-term adherence associated with positive outcome. Therefore, it is important to better understand from the patient's standpoint the experience of living with the disease and the related treatment.

Objectives: In this study, quantitative analysis and narrative medicine were combined to get insights on this issue in a population of 257 patients with CML in chronic phase treated with TKIs (43 % men, with a median age of 58 years, 27 % aged 31-50 years), followed for a median time of 5 years. Sixty-one percent of patients enrolled were treated in first line, whereas 37 % were treated in second line.

Results: The results showed more positive perceptions and acceptance in males compared to females, without impact of disease on relationships. Level of positive acceptance was more evident in elderly compared to younger patients, with a close connection with median time from diagnosis. Overall, female patients reported negative perceptions and an impact of disease on family daily living. The majority of patients understood the importance of continue adherence to treatment, with 27 % resulting less adherent (60 % for forgetfulness), even if well informed and supported by his/her physician.

Discussion And Conclusions: Narrative medicine, in association to quantitative analysis, can help physicians to understand needs of their patients in order to improve communication.
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http://dx.doi.org/10.1007/s00520-016-3286-zDOI Listing
November 2016

Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials.

Eur J Cancer 2016 06 27;60:154-65. Epub 2016 Apr 27.

Hematology Unit, Department of Onco-Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy.

Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2016.03.069DOI Listing
June 2016

Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms.

Leuk Res 2016 07 7;46:18-25. Epub 2016 Apr 7.

Cellular Biotechnologies and Hematology Dept., University "La Sapienza", Roma, Italy.

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes >10×10(9)/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up.
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http://dx.doi.org/10.1016/j.leukres.2016.04.004DOI Listing
July 2016

Prognostic role of translocator protein and oxidative stress markers in chronic lymphocytic leukemia patients treated with bendamustine plus rituximab.

Oncol Lett 2015 Mar 19;9(3):1327-1332. Epub 2014 Dec 19.

Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples I-80138, Italy.

Principally located in the outer mitochondrial membrane, the translocator protein (TSPO) is an 18-kDa transmembrane protein that is a key component of the mitochondrial permeability transition pore. TSPO is associated with a number of biological processes, including apoptosis, the regulation of cellular proliferation, porphyrin transport and heme biosynthesis, immunomodulation, anion transport and the regulation of steroidogenesis. Thus, numerous studies have proposed TSPO as a promising target for novel therapeutic agents, particularly for the treatment of cancer. In the present study, the response of 30 consecutive chronic lymphocytic leukemia (CLL) patients to bendamustine and rituximab treatment was evaluated according to TSPO expression levels. Furthermore, thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO) levels, as well as caspase-3 activity were determined. Compared with the lymphocytes of healthy donors, the 30 consecutive CLL patients exhibited increased TSPO expression levels, decreased TBARS and NO levels and reduced caspase-3 activity. Six months after the treatment commenced, the TSPO/mitochondria ratio resembled that of the healthy controls in 24/30 CLL patients. In addition, an increase in TBARS and NO levels, two markers of oxidative stress, and a potentiation of caspase-3 activity in all responder patients was observed. Notably, the six patients who appeared to be resistant to treatment also displayed higher TSPO levels, and lower caspase-3 activity and TBARS levels. These data indicate that TSPO expression may be a molecular prognostic factor in CLL patients.
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http://dx.doi.org/10.3892/ol.2014.2817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315100PMC
March 2015

Transfusion-dependent low-risk myelodysplastic patients receiving deferasirox: Long-term follow-up.

Oncol Lett 2013 Dec 10;6(6):1774-1778. Epub 2013 Oct 10.

Hematology Division, P.O. San Gennaro ASL NA1 Centro, Naples I-80136, Italy.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis that results in peripheral cytopenias. Anemia is the most common symptom of MDS and the majority of patients become transfusion-dependent with the risk of iron overload, which may lead to cardiac, hepatic and endocrine complications. Deferasirox is an orally available iron chelator administered once-daily in transfusion-dependent patients with various chronic anemias. Its efficacy has been established in controlled clinical trials. In the present study, we describe our experience with 55 consecutive MDS patients [International Prognostic Scoring System risk score of low (n=32) or intermediate-1 (n=23)] treated with deferasirox in a routine clinical setting following Consensus Guidelines on Iron Chelation Therapy. According to WHO classifications, patients had refractory anemia (n=30), refractory anemia with ringed sideroblasts (n=16), refractory cytopenia with multilineage dysplasia (n=8) or refractory cytopenia with multilineage dysplasia and ringed sideroblasts (n=1). The median monthly transfusion requirement at baseline was 3 units. Patients received a starting dosage of 10 mg/kg/day, subsequently titrated according to serum ferritin (SF) levels which were measured monthly. Safety assessment included monitoring of liver and renal parameters and recording adverse events (AE) during treatment. At the baseline, the mean ± SD SF level was 2,362±172 ng/ml and after 24 months, the mean ± SD decrease in SF was 1,679±209 ng/ml. Sixteen patients had sustained hematological improvement meeting International Working Group 2006 criteria. One patient became transfusion-independent. No severe AE were reported. In conclusion, deferasirox therapy was effective and safe in reducing transfusional iron overload and it reduces transfusion requirement in a subset of patients.
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http://dx.doi.org/10.3892/ol.2013.1617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834329PMC
December 2013

Identification and molecular characterization of a novel 55-kb deletion recurrent in southern Italy: the Italian (G) γ((A) γδβ)°-thalassemia.

Eur J Haematol 2013 Mar 14;90(3):214-9. Epub 2013 Feb 14.

Istituto di Genetica e Biofisica Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, Napoli, Italy.

Objectives: To characterize the molecular basis of a β-thalassemia defect in subjects with mild microcytosis associated with normal Hb A2 and increased levels of Hb F.

Methods: Six subjects from three apparently unrelated families from Campania (southern Italy) have been investigated using DNA restriction analysis, inverse PCR, cloning, sequencing, multiplex ligation-dependent probe amplification (MLPA), quantitative real-time PCR, and gap-PCR.

Results: We have identified a novel 55-kb β-globin gene cluster deletion in three unrelated families: the Italian (G) γ((A) γδβ)°-thalassemia. This deletion removes most of the β-globin cluster. The 5' breakpoint was within the (A) γ-globin exon 2, and the 3' breakpoint was within a 160-bp palindrome: the breakpoint-flanking regions present a microhomology (5'-TGGG-3') that, together with the palindromic structure, may have contributed to the recombination.

Conclusions: Large deletions of β-globin gene cluster are usually found in single families. Here, we report about the novel Italian (G) γ((A) γδβ)°-thalassemia we have found in three families. Twenty years ago, the characterization of the first family was challenging, whereas that of the other families has taken advantage of nowadays techniques. The relatively high frequency of this novel deletion in southern Italy suggests that it should be tested, together with the Sicilian (δβ)°-thalassemia, in Italian and Mediterranean families with microcytosis, normal Hb A2, and increased Hb F levels.
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http://dx.doi.org/10.1111/ejh.12066DOI Listing
March 2013

Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy.

Br J Haematol 2011 Sep 28;154(5):579-89. Epub 2011 Jun 28.

Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione G. Pascale, IRCCS, Naples, Italy.

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15·6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P=0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08786.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258483PMC
September 2011

Non-pegylated liposomal doxorubicin (Myocet®) in patients with poor-risk aggressive B-cell non-Hodgkin lymphoma.

Leuk Lymphoma 2011 Jul 25;52(7):1222-9. Epub 2011 May 25.

Hematology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

The incidence of non-Hodgkin lymphomas increases with age. Non-pegylated liposomal formulations of doxorubicin (Myocet®) reduce systemic and cardiac toxicity especially in the elderly, who often have cardiac diseases. We treated 80 patients (mean age 70.9 years) with poor-risk diffuse large B-cell lymphoma with the R-COMP 21 regimen (Myocet® 50 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), rituximab 375 mg/m(2), prednisone 100 mg/day). In all, 82.5% and 13.7% patients showed complete and partial responses, respectively. Sixty-two of the 80 patients are alive and disease-free (77.5%), while 3/80 are alive with active disease and 15 patients (18.7%) have died (median follow-up: 31 months). The estimated probability of overall survival at 12/24 months from admission was 93.5/87.3%, respectively. There were no therapy-related cardiac events and the ejection fraction improved (from 51.6 ± 6.9% to 54.2 ± 3.9%). Grade 3-4 neutropenia occurred in 22% of patients. We concluded that Myocet® shows both efficacy and tolerability, mainly at the cardiac level.
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http://dx.doi.org/10.3109/10428194.2011.572321DOI Listing
July 2011

Genotype-phenotype relationship of the δ-thalassemia and Hb A(2) variants: observation of 52 genotypes.

Hemoglobin 2010 ;34(5):407-23

Istituto di Genetica e Biofisica Adriano Buzzati-Traverso, CNR, Napoli, Italia.

The increase of Hb A(2) (α2δ2) beyond the upper limit [2.0-2.2/3.3-3.4% of the total hemoglobin (Hb)] is an invaluable tool in the hematological screening of β-thalassemia (β-thal) carriers. Factors decreasing Hb A(2) percentages can hinder correct diagnosis. In order to analyze the genotype-phenotype relationship, we characterized δ-, β- and α-globin genotypes in 190 families where the probands had Hb A(2) values of ≤2.0% or were β-thal heterozygotes with normal Hb A(2) levels. Hb A(2) was measured with cation exchange high performance liquid chromatography (HPLC). Mutations were detected with allele-specific methods or DNA sequencing; two multiplex-ARMS (amplification refractory mutation system) assays were set up. The molecular basis underlying the decrease in Hb A(2) was extremely heterogeneous. Nineteen δ-globin alleles (Hb A(2)-S.N. Garganico was new) were detected; their interaction with α- or β-globin alleles (10 and eight, respectively) led us to observe 52 genotypes in 261 carriers. The type of δ-globin mutations, the relative genotypes, the interaction with α(0)-thal traits, are the most important factors in decreasing the Hb A(2) percentage. These results are extremely useful in addressing the molecular diagnosis of hemoglobinopathies and thalassemias.
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http://dx.doi.org/10.3109/03630269.2010.511586DOI Listing
March 2011

Acute promyelocytic leukemia in patients aged over 60 years: multicenter experience of 34 consecutive unselected patients.

Anticancer Res 2010 Mar;30(3):967-71

Via Nicolò Piccinni 6, 80128, Napoli, Italy.

Treatment of acute promyelocytic leukemia (APL) has evolved over recent years, resulting in a cure rate of 75-80%. However, the prognosis of older patients with APL remains poorer as compared to young adults because of substantial morbidity of either induction or consolidation therapy. We describe therapeutic results in a series of 34 consecutive APL patients aged over 60 years, with particular emphasis on those patients managed outside of clinical trials because of comorbidities at diagnosis. All patients were programmed to receive the GIMEMA AIDA protocol, based on all transretinoic acid as induction followed by chemotherapy as consolidation. The median age was 70 years. Twenty-three patients (68%) received the protocol, while 11 (32%) were given a personalized approach. The median age was 69 years for patients on protocol as opposed to 75 years for the remaining ones (p=0.02). Six patients (18%) died within two days of diagnosis; among these, only one was on the AIDA protocol. Overall, complete response (CR) was achieved in 68% of cases; the CR rate was 74% for patients on the protocol as opposed to 54 % for those not. The most frequent cause of death was cerebral hemorrhage. Patients accrued into the GIMEMA AIDA protocol achieved longer survival (median not reached vs. 10 months, p=0.03). In conclusion, our data demonstrate that at least 30% of older APL patients are not eligible to accrual in multicenter trials; furthermore, in this subset, the possibility of early death is substantial. However, when CR is achieved, a personalized consolidation approach can be adopted with the possibility of achieving long-term disease control.
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March 2010

Rituximab to treat chronic lymphoproliferative disorder-associated pure red cell aplasia.

Eur J Haematol 2009 Mar 20;82(3):235-9. Epub 2008 Nov 20.

Hematology and Stem Cell Transplantation Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.

We report four patients (mean age 65 yr; range 40-77 yr) affected by acquired pure red cell aplasia (PRCA) complicating chronic lymphoid disorders and treated with anti-CD20 monoclonal antibody rituximab. Three out of four patients were given packed red cell transfusion. Steroids and recombinant erythropoietin (r-Epo) were also administered as first-line therapy without response. After a mean time of 57 d (range 23-62 d) from PRCA diagnosis, all patients received rituximab at a dosage of 375 mg/m(2)/wk for four consecutive weeks. First injection side effects of rituximab were minimal. All patients showed an increase in hemoglobin levels in response to rituximab, in one patient just after the first dose, in another patient after the second and in two other patients after the third dose. Three patients (75%) were considered in complete remission (CR) and one patient (25%) in partial remission 4 wk after the last rituximab infusion, despite a CR was obtained later (16 wk following the beginning of the therapy). Finally, at the last follow-up (mean 18.5 months, range 2-60 months), all patients were alive and in continue CR. Despite very limited in number, these results suggest that rituximab is very effective in the treatment of PRCA complicating B-cell chronic lymphoproliferative disorders.
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http://dx.doi.org/10.1111/j.1600-0609.2008.01187.xDOI Listing
March 2009

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients.

Ann Hematol 2009 Feb 16;88(2):151-8. Epub 2008 Aug 16.

Hematology, Università Federico II, Naples, Italy.

A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.
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http://dx.doi.org/10.1007/s00277-008-0571-zDOI Listing
February 2009

Molecular evidences of single mutational events followed by recurrent crossing-overs in the common delta-globin alleles in the Mediterranean area.

Gene 2008 Feb 14;410(1):129-38. Epub 2007 Dec 14.

Istituto di Genetica e Biofisica Adriano Buzzati Traverso, CNR, Naples, Italy.

The human delta-globin gene (HBD) is one of the beta-like globin genes expressed in adults. In the Mediterranean countries the carriers of delta-thalassemia defects or Hb A2-variants are >1% and about 40/70 known alleles have been found in families with this ethnic origin. The scope of this study was to investigate the variability of the gene and of the chromosomal background in order to highlight the origin and spreading of the delta-globin gene alleles in the Mediterranean area. We carried out the characterization of the delta-globin gene alleles and of RFLP-haplotypes, SNPs and one microsatellite associated with them in 231 carriers originating principally from East Sicily. Seventeen alleles were identified, of which five were new. The chromosomes associated with mutated alleles from unrelated carriers were 158; the allele Hb A2-Yialousa accounted for about 75% of relative frequency, Hb A2-Mitsero for about 8%. The alleles were associated with RFLP 5'-haplotypes "- - - -" or "+ - + +", prevalent in the Mediterranean area, except Hb A2-Mitsero associated with the 5'-haplotype "Benin" "- - - +" and the Hb A2' associated with "+ - - +", both of African origin. Each allele showed linkage with one haplotype with these exceptions. The Hb A2-Yialousa showed heterogeneity of the 5'-haplotype in 2/58 chromosomes; the Hb A2-Mitsero showed SNPs and (A)gamma-microsatellite typical of a "Benin" haplotype found associated with the Hb C and Hb S chromosomes; the Hb A2-Yialousa (14/58 chromosomes), Hb A2-Mitsero, Hb A2-Pylos, Hb A2-Fitzroy showed heterogeneity in the 3'-haplotypes and beta-globin gene SNPs. The Hb A2-Coburg was found associated with the haplotype "+ - + +/+ +" different from that already reported "- - - -/+ -". With the exception of this last allele, the linkage of each mutation with a core of RFLPs or SNPs around or inside the delta-globin locus suggested the unicentric origin of the mutations followed by recurrent recombination events causing the chromosomal background heterogeneity.
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http://dx.doi.org/10.1016/j.gene.2007.12.004DOI Listing
February 2008

Epidemiology of the delta globin alleles in southern Italy shows complex molecular, genetic, and phenotypic features.

Hum Mutat 2002 Nov;20(5):358-67

Istituto di Genetica e Biofisica Adriano Buzzati Traverso, Napoli, Italy.

We characterized mutations and haplotypes of the delta-globin gene (HBD, MIM# 142000) in two regions of southern Italy. Mutations were discovered by screening for individuals with Hb A2<2%. In Basilicata, about 10,000 students were screened and 53 carriers in 43 unrelated families were diagnosed; in Campania, cases were referred through a routine thalassemia counseling service. Twelve alleles were detected. Four were novel variants [Hb A2-Metaponto (g.238C>A), Hb A2-Campania (g.302C>A), Hb A2-Lucania (g.393C>G), and Hb A2-Capri (g.443G>T)]. Hb A2-Lucania was not inherited but had arisen in the propositus. Two were novel mutations in the noncoding regions: the substitutions IVS2+6T>A, presumably affecting the splicing, and g.-126A>T in the GATA motif presumably affecting transcription. All novel alleles were found associated with haplotypes common in the Mediterranean area. The remaining six were alleles already described. The Hb A2-Yialousa (g.82G>T) was the most prevalent (42/63 families). Recurrent homologous crossing-over events have, most likely, linked this allele to Haplotypes IX (24 families), IV (10 families), or III (seven families). The ratio of Haplotypes IX:IV:III was about the same in the two regions. The rare allele Hb A2-NYU (g.39T>A) was found in 11 families from Basilicata associated with Haplotype I. All the 11 families lived in a restricted area extending from the Ionian Coast for 15 km along the Angri and Sinni Rivers. A founder effect most probably gave origin to this isolated group. The remaining four alleles were rare: the 7.2-kb deletion Corfù type (HBD g.-5946_1262del), Hb A2-Mitsero (g.14C>T), Hb A2-Etolia (g.385T>C), Hb A2-Coburg (g.1376G>A). Correlation between genotype and phenotype was established in 103 carriers.
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http://dx.doi.org/10.1002/humu.10132DOI Listing
November 2002