[Show abstract][Hide abstract] ABSTRACT: Nilotinib (NIL) is approved for the first-line treatment of CML based on the results of the ENESTnd study that demonstrated a higher efficacy compared to imatinib (IM). However, there are concerns on the vascular toxicity of NIL, disclosed by an increased rate of cardiovascular adverse events (CVAEs) with respect to imatinib. For this reason, we investigated the CVAEs in 2 studies of the GIMEMA CML WP that included NIL as first-line treatment of CML: the GIMEMA CML 0307 trial (73 pts; NIL
400 mg BID), and the GIMEMA CML 0408 trial (123 pts; 3-months alternating regime of NIL 400 mg BID and IM 400 mg QD). The median age at CML diagnosis of all 196 pts was 55 (18-84) years; 59 (30%) pts were ≥65 years; 52% were males; cardiovascular risk factors (CVRF: hypertension, dyslipidemia, diabetes, BMI ≥30, and prior ischemic disease) were present in 74 (38%) pts (median 1, range 1-4). There were no significant differences between the pts characteristics in the 2 studies. The
median f-up was 61 months. Nineteen CVAEs occurred in 17 (8.6%) pts: 7 acute myocardial infarctions (MI); 5 PAODs; 2 carotid stenosis, 2 aortic atherosclerosis, 1 stroke, 1 unstable angina, and 1 stable angina (1 patient had 1 PAOD, 1 stroke, and 1 MI). In pts with CVAEs, the median age at CML diagnosis was 67 (43-84 years), and the median interval from CML
diagnosis to CVAE was 38(1-76) months. Out of the 17 pts with CVAEs, 53% were males; 70% were ≥65 years at CML diagnosis; 76% had at least 1 CVRF, and 65% were treated with NIL alone. All pts but one (who died at 90 years for congestive heart failure post MI) are alive. Treatment of CVAEs included coronary angioplasty in 5 pts, lower limb amputation in 2 pts, and peripheral vascular surgery in 2 pts; all other pts received medical treatment; 12/17 pts permanently discontinued NIL. In univariate analysis, the occurrence of CVAEs was associated with age≥65 years (12/59[20%] vs 5/137[3.6%]; p=0.0004), the presence of at least one CVRF (13/74[18%] vs 4/122[3.3%]; p=0.001), and the monotherapy with NIL (11/73[15%] vs 6/123[4.8%]; p=0.018). CVAEs occurred at a significant rate in pts treated with NIL-based regimes, and in particularly in pts ≥65 years and/or with CVRF. Noteworthy, the alternating schedule of NIL and IM resulted in a lower incidence of CVAEs compared to NIL monotherapy. Thus, considering the morbidity associated to CVAEs, the risk/benefit ratio of NIL monotherapy should be
carefully evaluated in selected groups of patients.
[Show abstract][Hide abstract] ABSTRACT: Background: The treatment-free remission (TFR) is an emerging treatment goal in CML and a sustained deep molecular response (DMR, MR4 or better) is a pre-requisite to achieve TFR. The 5-year update from the ENESTnd trial showed a superiority of NIL over IM in terms of achievement of DMR, but differences concerning the stability of DMR have not
been reported yet. Independent studies are important to confirm and to extend the results of company-sponsored trials.
Aims: To assess the efficacy of NIL as first-line treatment in terms of achievement of DMR and stability of DMR.
Methods: Phase 3b study conducted by the GIMEMA CML WP (NCT01535391). Primary endpoint: MR4 at 24 months. Key secondary endpoints: kinetics of molecular response and stability of DMR. Starting NIL dose: 300 mg BID (dose escalation to 400 mg BID for ELN 2009 suboptimal response or failure). Molecular response assessed in GIMEMA standardized molecular laboratories (Labnet network): MR4 and MR4.5, according to EUTOS 2015 definitions; sustained MR4 or MR4.5, MR4 or MR4.5 for at least 1 year with at least 3 evaluable analysis. All the analysis were performed according to the ITT principle. Results: 130 CML patients in early chronic phase have been enrolled: median age, 50 (18-85) years; high risk patients, 22% (Sokal), 6% (Euro) and 8% (EUTOS); CCA in Ph+ cells at baseline, 5%; median follow-up, 29 (24-37) months. At the last contact the patients still on treatment with NIL were 100/130, 77%, while 30/130 patients, 23%, permanently interrupted the study drug: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% TFR, 5% other reasons. At 3 months, 80% of patients had BCR-ABL transcript levels <10%; at 6 months, 78% of patients had BCR-ABL transcript levels <1%. The major molecular response rates at 12 and 24 months were 57% and 65%, respectively. The rates of MR4 at 6, 12, 18 and 24 months were 12%, 28, 31% and 46%, respectively. Seventy-six patients (58%) achieved a MR4 at least once; the patients with a sustained MR4 were 39/76 (51%, or 30% of the total). The rates of MR4.5 at 6, 12, 18 and 24 months were 2%, 7%, 11% and 17%, respectively. Eleven patients (8%) achieved a sustained MR4.5. All the patients are still alive.
Conclusions: After 2 to 3 years of treatment, 30% and 8% of all the enrolled patients were in stable MR 4.0 and in stable MR4.5, respectively. It is likely that a longer treatment time is required to bring more patients to treatment free remission.
[Show abstract][Hide abstract] ABSTRACT: For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine-kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died, and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (lower than or equal to 10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but since 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also due to second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.Leukemia accepted article preview online, 19 June 2015. doi:10.1038/leu.2015.152.
Full-text · Article · Jun 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage.
Patients and methods:
To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period.
Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011).
The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome.
Clinical trial numbers:
NCT00510926, NCT00514488, NCT00769327, NCT00481052.
Full-text · Article · Oct 2014 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. Here we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukemias.
By using the GRADE (Grades of Recommendations, Assessment, Development, and Evaluation) system we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues.
Six courses of CHOP or CHOEP chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while L-asparaginase containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong).
In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas (PTCLs) receiving conventional treatment have a poor clinical outcome. We conducted a phase II study to evaluate the feasibility and efficacy of chemo-immunotherapy in young (60 years old, Clin A study) and elderly (>60 and 75 years old, Clin B study) patients with newly diagnosed PTCL. Clin A patients (n=61) received two courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-21 with alemtuzumab (AL, 30 mg) followed by two courses of high-dose chemotherapy. On the basis of donor availability, patients in response received allogeneic (allo) or autologous (auto) stem cell transplantation (SCT). Clin B patients (n=25) received six courses of CHOP-21 and AL (10 mg). Clin A responding patients were 38 of 61 (62%) and received alloSCT (n=23) or autoSCT (n=14); one complete remission (CR) patient was not transplanted. At a median follow-up of 40 months, the 4-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) rates were 49, 44 and 65%, respectively. In Clin B study, the response rate was 72%. At a median follow-up of 48 months, the 4-year OS, PFS and DFS rates were 31, 26 and 44%, respectively. In conclusion, front-line alloSCT or autoSCT is effective in prolonging DFS in young patients; AL in elderly improved response with no survival benefit.Leukemia advance online publication, 25 March 2014; doi:10.1038/leu.2014.79.
No preview · Article · Feb 2014 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Regulatory T-cells (Tregs) constitute a small subset of cells involved in antitumour immunity and are generally increased in patients with chronic lymphocytic leukemia (CLL). No data is available on Tregs in monoclonal B-cell lymphocytosis (MBL), a disease entity characterized by less than 5000/microL circulating clonal B-cells in absence of other features of lymphoproliferative disorders. We used multicolour flow cytometry to evaluate the number of circulating Tregs in 56 patients with "clinical" MBL, 74 patients with previously untreated CLL and 40 healthy subjects. MBL patients showed a lower absolute number of Tregs, compared to CLL patients, but slightly higher than controls. Moreover, the absolute cell number of Tregs directly correlated both with more advanced Rai/Binet clinical stages and peripheral blood B-cell lymphocytosis. Of note, the absolute number of Tregs was found lower in MBL patients than in CLL patients staged as 0/A Rai/Binet. The study showed that Treg increase gradually from normal subjects to "clinical" MBL patients and are significantly higher in CLL patients as compared to MBL patients. Moreover, a significant direct relationship was found between higher Treg values and a higher tumor burden expressed by B-lymphocytosis or more advanced clinical stages. In light of this data, MBL seems to be a preliminary phase preceding CLL. The progressive increase of Treg numbers might contribute both to the clinical evolution of MBL to overt CLL and to CLL progression.
No preview · Article · Oct 2011 · International journal of immunopathology and pharmacology
[Show abstract][Hide abstract] ABSTRACT: The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.
No preview · Article · Jul 2011 · International journal of immunopathology and pharmacology
[Show abstract][Hide abstract] ABSTRACT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000- 4000 newborns. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland, all conditions indicated as "thyroid dysgenesis" (TD). A higher prevalence of congenital heart diseases has been documented in children with CH compared to the general population. This association suggests a possible pathogenic role of genes involved in both heart and thyroid development. Among these, it can be included Isl1, a transcription factor containing a LIM homeodomain that is expressed in both thyroid and heart during morphogenesis.
In the present study, we investigate the role of ISL1 in the pathogenesis of TD.
By single stranded conformational polymorphism, we screened for mutations the entire ISL1 coding sequence in 96 patients with TD and in 96 normal controls.
No mutations have been found in patients and controls.
Our data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients.
No preview · Article · Nov 2010 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: Invasive fungal infections (IFIs) still pose major challenges in allogeneic hematopoietic SCT (HSCT), and effective antifungal prophylaxis remains a matter of debate. The aim of this retrospective study was to evaluate the toxicity and the impact of aerosolized deoxycholate amphotericin B (aero-d-AmB) on respiratory tract IFIs (airways IFIs) in a homogeneous cohort of allogeneic HSCT patients, transplanted at one institution. Since 1999, 102 consecutive patients were transplanted from matched related (N = 71) or unrelated donor (MUD). Aero-d-AmB was administered for a median time of 16 days (range 2-45), in addition to systemic antifungal prophylaxis. Prolonged administration was neither associated with increased severe bacterial infections, nor with severe adverse events. In 16 patients in whom aero-d-AmB was delivered for less than 8 days, due to worsened clinical conditions or poor compliance, proven or probable airways IFIs were diagnosed in three cases (one mucormycosis and one fusariosis and one probable aspergillosis), whereas in 84 patients receiving aero-d-AmB for ≥ 8 days, one possible and one probable aspergillosis were diagnosed. A shortened administration (< 8 days) of aero-d-AmB was therefore associated with an increased risk of both total airways IFIs (P = 0.027) and proven/probable IFIs (P = 0.012). At multivariate analysis prolonged aero-d-AmB administration retained an independent protective effect on airways IFIs (P = 0.026) whereas a MUD transplant was associated with a borderline increase of IFIs risk (P=0.052). Overall, 95.1% of patients did not experience airways IFIs and no patient died due to IFIs. In this cohort of patients, prolonged aero-d-AmB seems to have a role in preventing respiratory tract IFIs, but a randomized controlled trial is recommended to verify the impact of this prophylaxis in the setting of allogeneic HSCT.
Full-text · Article · Apr 2010 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Background. Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in derma fibroblasts. There are two major subsets of SSc, the diffuse cutaneous systemic sclerosis (dSSc) and the limited cutaneous systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well characterized system of serine-proteases involved in several pathologic processes, has been investigated in SSc fibroblasts. Methods. The expression of the components of the PA system, including uPA, its receptor (uPAR) and its type-1 and type-2 inhibitors (PAI-1 and PAI-2) was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. SSc fibroblasts adhesion to vitronectin (VN) was examined by cell adhesion assays. Results. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions, as compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc and dSSc lesions in from not affected areas, as compared to normal controls. Conclusions. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of cytokines and metalloproteases with the accumulation of extra-cellular matrix components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up-regulation in the not-affected areas.
No preview · Article · Jan 2010 · Rivista Italiana della Medicina di Laboratorio
[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc) is characterized by excessive fibrosis throughout the body. There are two major subsets of SSc, diffuse cutaneous Systemic sclerosis (dSSc) and limited cutaneous Systemic sclerosis (lSSc). Fibroblasts play a key role in SSc. The expression and function of the urokinase (uPA)-mediated plasminogen activation (PA) system, a well-characterized system of serine-proteases involved in several pathological processes, has been investigated in SSc fibroblasts. The expression of the components of the PA system, including uPA, its type-1 and type-2 inhibitors (PAI-1 and PAI-2) and its receptor (uPAR), was examined by Western blot in fibroblasts from patients affected by limited and diffuse forms of SSc. uPA and PAI-1 secretion increased only in fibroblasts from lSSc lesions compared to normal fibroblasts. PAI-2 levels were decreased in fibroblasts from both SSc forms. Interestingly, fibroblasts from areas not adjacent to the lesions (not-affected) of the diffuse form showed reduced levels of PAI-1 and increased uPAR expression. Adhesion experiments showed reduced adherence to VN of fibroblasts from lSSc lesions and from non-affected areas of the diffuse form, as compared to normal controls. These results suggest a role for uPA and PAI-1 in the lSSc form, likely related to the activation of latent forms of cytokines and to the accumulation of ECM components, whereas a role for uPAR can be hypothesized in the evolvement of the diffuse form, based on its up-regulation in the non-affected areas.
No preview · Article · Nov 2009 · International journal of immunopathology and pharmacology
[Show abstract][Hide abstract] ABSTRACT: In 80-85% of cases, congenital hypothyroidism is associated with thyroid dysgenesis (TD), but only in a small percentage of cases mutations in thyroid transcription factors (NKX2.1, PAX8, FOXE1, and NKX2.5) have been associated with the disease. Several studies demonstrated that the activity of the transcription factors can be modulated by the interaction with other proteins, such as coactivators and co-repressors, and TAZ (transcriptional co-activator with PDZ-binding motif or WWTR1) is a co-activator interacting with both NKX2.1 and PAX8. In the present study we investigate the role of TAZ in the pathogenesis of TD.
By Single Stranded Conformational Polymorphism, we screened the entire TAZ coding sequence for mutations in 96 patients with TD and in 96 normal controls.
No mutations were found in patients and controls, but we found several polymorphisms in both groups. No significant differences could be demonstrated in the prevalence of the mutations between patients and controls.
Our data indicate that TAZ mutations are not a cause of TD in the series of patients studied.
No preview · Article · Apr 2009 · Journal of endocrinological investigation