Introduction Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based mainly on evaluation of patient's ...characteristics and clinical expectations. To avoid long term adverse events or potential drug interactions, elderly patients may start CML treatment with a frontline reduced dose of TKI (RD-TKI). Aim To analyse outcome of CP-CML patients aged over 65 years in a large and unselected cohort treated with RD-TKI. Methods We retrospectively evaluated 747 patients from 1/2012 to 12/2019 at 36 Hematology Centres participating at the “Campus CML” project. Results Clinical features for the whole cohort according to frontline TKI initial dose are reported in Table 1. Among all patients, 605 (81%) were treated with standard dose (SD) while the remaining 142 (19%) with reduced dose (RD). As to frontline TKI, 579 patients (77%) received IM and 158 (23%) a 2G-TKI (DAS n=78, 49%; NIL n=80, 51%). Of the 142 RD-TKI, 122 (85.9%) started with IM, 14 (9.9%) with DAS and 6 (4.2%) with NIL. Median RD was 100 mg for IM (range 100-300), 20 mg for DAS (range 20-50) and 250 mg for NIL (range 150-300). RD-TKI was mainly reported in IM treated patients (p=0.018), in elderly (p<0.001) and in patients with comorbidities, in particular diabetes (p=0.005) and ischemic heart disease (p=0.039). Number of concomitant drugs was also significantly associated with RD-TKI (p<0.001) probably to avoid drug interactions and subsequent toxicity. In detail, among RD-TKI, 41.1% of patients was treated with more than five concomitant drugs. Sokal score did not impact on TKI starting dose. No differences emerged between SD-TKI and RD-TKI in terms of haematological or extra-haematological toxicity. TKI frontline dose was not associated with difference in resistance, nor primary neither secondary resistance. Progression to blastic phase was reported in 1.2% of the whole population, none of which in RD-TKI. At 12 months no differences were noted in terms of achievement of major molecular response (MMR), obtained in 22.4% of SD-TKI treated patients and in 19% of RD-TKI treated patients. RD-TKI had inferior probability of deep molecular response (DMR) achievement (p=0.003), reported in 12.6% of patients. No differences were reported in 12-months cumulative rate of permanent discontinuation for any cause and for primary resistance between SD-TKI and RD-TKI as reported in Figure 1. Conclusions RD-TKI was a frontline treatment strategy used mainly in frail elderly patients, with more comorbidities and concomitant therapies. RD-TKI did not impact on primary resistance leading to TKI switch. While no differences were reported in the rate of MMR, the rate of 12-months DMR achievement was inferior in RD-TKI, but this result need to be confirmed with longer follow-up.
Introduction Median age at diagnosis in patients with Chronic Myeloid Leukemia (CML) is about 60 years: only few data are available in younger subjects at present. Aim To analyze initial features, ...choice of frontline Tyrosine-Kinase Inhibitor (TKI) and early adverse events leading to permanent TKI discontinuation in the first 12 months from TKI start in newly diagnosed subjects aged ≤ 40 years in a large and unselected real-life cohort of CML patients. Methods We retrospectively evaluated 1963 patients newly diagnosed from 1/2012 to 12/2019 at 38 Hematology Centers in Italy participating at the “Campus CML” project: according to age at diagnosis, 302 were ≤ 40 years Younger Patients (YP), 900 were > 45 < 65 years Intermediate Aged Patients (IAP) and 761 were ≥ 65 years Elderly Patients (EP). Results Clinical features, frontline TKI and causes of early TKI discontinuation according to age at diagnosis are reported in the Table 1. As to baseline clinical features, YP had significantly higher WBC count, lower Hb levels and higher rate of spleen enlargement: moreover, as expected, low-risk Sokal score was more common and rate of concomitant diseases/number of concomitant drugs lower in YP. As to frontline TKI, 96 YP (31.1%) received imatinib (IM) and 206 (68.9%) a 2G-TKI dasatinib (DAS) n=60, 19.9%; nilotinib (NIL) n=144, 47.6%: choice of 2G-TKI as frontline treatment was significantly more common in YP compared to both IAP and EP (p < 0.001). Causes of permanent frontline TKI discontinuation during the first 12 months of treatment according to age at diagnosis are reported in the Table 1: among YP, 45 (14.9%) discontinued frontline TKI treatment due to hematologic toxicity (5 cases, 1.6%), extra-hematologic toxicity (11 cases, 3.7%), primary resistance (24 cases, 8.0%), secondary resistance (2 cases, 0.6%) or evolution in blastic phase (BP) (3 cases, 1.0%). Cumulative incidence of permanent discontinuation at 12 months was 14.6% (95%CI 10.7 - 18.5) in YP compared to 16.9% (95%CI 14.3 - 19.2) in IAP (p=0.388) and 24.0% (95%CI 20.9 - 27.1) in EP (p < 0.001) (Figure 1): considering only permanent TKI discontinuation due to treatment resistance (primary resistance + secondary resistance + evolution in BP), no difference was observed according to age at diagnosis 9.6% (95%CI 6.3 - 12.9) in YP versus 10.2% (95%CI 8.2 - 12.2) in IAP versus 11.8% (95%CI 9.6 - 14.0) in EP, p=0.589. Conclusions Our data highlight the following peculiar clinical features at baseline and during the first year of treatment in YP with CML compared with IAP and EP: a delayed diagnosis, outlined by higher WBC count and rate of spleen enlargement; an expected choice of 2G-TKI as frontline treatment in the real-life, even if about one third of them was still treated with IM; a lower incidence of early frontline TKI permanent discontinuation compared to EP but not IAP, mainly due to toxic causes and not related to resistance. Data on early molecular response and further evaluations at 24 and 36 months are warranted to complete present analysis.
Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase ...inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32–72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.
: Spontaneous coronary artery dissection (SCAD) is a rare and poorly understood cause of acute coronary syndrome in relatively young patients. Nowadays, the optimal treatment of SCAD is uncertain. A ...conservative approach seems to be preferable, but in particular conditions, an invasive strategy is necessary. The poor rate of procedural success, the high risk of procedural complications and the uncertain long and mid-term results make the interventional treatment of SCAD a challenge. We report a case of a young male patient presenting with SCAD successfully treated with a sirolimus-eluting self-expanding coronary stent. To our knowledge, the use of self-expanding coronary stent for SCAD has never been described yet and we discuss about the rationale of a possible larger use in clinical practice.
The growing world population coupled with longer human life expectancy warrants the need for better medical implant development. Recent advances in lithographic techniques have opened the door to a ...variety of approaches to tackle the aforementioned issue. However, several scientific hurdles must be overcome before patients can use fully synthetic and effective implants.Identifying the optimal material, porosity, and mechanical properties of the scaffold to induce cell functionality are key obstacles. Limitations in established fabrication techniques have hindered the ability to fully understand cell behavior on 3D substrates. 3D printing is limited to feature sizes that are at least one order of magnitude larger than a single cell (~10μm); electrospinning is able to yield features that are on the same scale as cells, but its stochastic nature leads to scaffolds with poor mechanical properties; salt leeching doesn’t allow for control of pore size and distribution which have detrimental effects on nutrient diffusion and cell ingrowth, thereby thwarting the formation of functional tissue.Much effort has been made to create a suitable platform for regenerating a relatively less complex organ, such as bone, yet the inability to fully understand cell mechanics on 3D scaffolds has curbed the fabrication of effective bone implants.The first part of this thesis focuses on the suitability of nanoarchitected materials as 3D platforms for bone-tissue growth. We employed two-photon lithography to create polymeric and hydroxyapatite-coated 3D nanolattices to explore scaffold biocompatibility and material effects on osteoblast attachment and growth. Our experiments showed that the unit cell geometry, tetrakaidekahedron, and size, 25μm, were adequate for cell attachment and infiltration, which are hallmark signs of biocompatibility. Our study also corroborated previous findings that mammalian cells respond differently to different materials that they come in contact with. To isolate structural effects, we fabricated nanolattices coated with a uniform 20nm-thick outermost layer of TiO2. These nanolattices, which had fixed porosity and unit cell size (25μm) while they varied in structural stiffness (~2-9MPa) were used to explore the influence of scaffold properties on the viability of osteoblasts in a microenvironment similar to that of natural bone. Upon growing osteogenic cells on the nanolattices, significant cell attachment and presence of various calcium phosphate species, which are commonly found in natural bone, were observed. These findings suggest that 3-dimensional nano-architected materials can be used as effective scaffolds for bone cell growth and proliferation.The second part of the thesis investigates the effects of nanolattice structural stiffness and loading conditions on osteoblast behavior. We fabricated nanolattices with stiffness ranging from ~0.7MPa to 100MPa. Experiments done by seeding osteoblast-like cells on these nanolattices revealed that both stress fiber concentration and bioapatite deposition were higher on the most compliant nanolattice, (0.7 MPa) by ~20% and ~40% respectively. These results provide insights into cell behavior in 3D microenvironments which can lead to a better understanding of stress shielding at the cellular level. Preventing stress shielding by creating scaffolds with structural stiffness and porosity that enhances osteoblasts activity could lead to the creation of effective implants with improved mechanical stability which ultimately improves osteointegration.
Checkpoint inhibitors have significantly changed the prognosis of patients with relapsing refractory classical Hodgkin’s lymphoma (cHL), demonstrating excellent results in heavily pretreated ...patients. However, there is still limited data on the real-world experience with PD-1 inhibitors in cHL. Within the context of the Apulian hematological network (Rete Ematologica Pugliese, REP), we performed a retrospective, multicenter analysis of 66 patients with relapsing refractory cHL who had received PD-1 inhibitors in the non-trial setting. Forty-three patients (65%) were treated with nivolumab and 23 (35%) with pembrolizumab. Thirty-one (47%) and 8 (12%) patients underwent autologous or allogeneic stem cell transplantation prior to checkpoint inhibitor therapy, respectively. The median number of lines of treatment attempted prior to PD-1 inhibitor therapy was 4 (range, 3 to 7). All patients had received brentuximab vedotin prior to checkpoint inhibitor therapy. The overall response rate to PD-1 inhibitors therapy was 70% (47% complete remission (CR) and 23% partial remission (PR)). Twenty-four immune-related adverse events (19 (80%) grades 1–2; 5 (20%) grades 3–4) were documented (4 gastrointestinal, 4 hepatic, 6 fever, 4 hematological, 3 dermatological, 3 allergic rhinitis). Toxicity resolved in all patients, and there were no deaths attributed to checkpoint inhibitor therapy. After a median follow-up of 26 months (range 3–72 months), 54 patients (82%) are alive, and 12 (18%) died. The cause of death was attributed to disease progression in 9 patients and sepsis in 3 patients. After PD-1 inhibitor therapy, 22 patients (33%) relapsed or progressed. The overall survival and progression-free survival at 5 years were 65% and 54%, respectively. This study confirms the efficacy and tolerability of PD-1 inhibitor therapy in relapsed refractory cHL in a real-world setting, demonstrating similar clinical outcomes and toxicity profiles compared to clinical studies.
Introduction: therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in ...Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice.
Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib.
Results: median age at diagnosis was 59.9 years interquartile range (IQR) 47.1 - 71.7, with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively.
Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start.
As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged <45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p<0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC >100,000/mm3 vs 38.2% if WBC <100,000/mm3; p<0.001), lower Hb (53.8% if Hb <10 g/dl vs 41.9 if Hb >10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p<0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for >5 drugs, respectively (p<0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p<0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age > 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications.
Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib.
Display omitted
Breccia:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.
Introduction Treatment of chronic phase (CP) chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) proved to be almost equally effective in young and elderly patients. Three TKIs, ...imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based on a combined evaluation of patient's characteristics and expectations, with age usually playing a prominent role. However, to date, few data are available on patterns of TKI selection in very elderly patients.
Aim To analyse the use of frontline TKI therapy in a large and unselected cohort of very elderly CP-CML patients
Methods We retrospectively evaluated 332 patients aged ≥75 year diagnosed from 1/2012 to 12/2019 at 36 Hematology Centres participating at the “Campus CML” project.
Results Clinical features at diagnosis for the whole cohort and according to frontline TKI are reported in Table 1. As to frontline TKI, 285 patients (85.8%) received IM and 47 (14.2%) a 2G-TKI (DAS n=28, 59.5%; NIL n=19, 40.5%). Of the 285 IM-treated patients, 192 (67.3%) started with standard dose (400 mg/day) and 93 (32.7%) with a reduced dose (300 mg/day n=64, 22.5%; <300 mg/day n=29, 10.2%). Among the 47 patients starting a 2G-TKIs, 35 (74.4%) received standard dose and 12 (25.6%) a reduced dose (NIL <600 mg/day n=3; DAS 80 mg/day n=4 and 50 mg/day n=5). There were no differences between patients treated with imatinib or 2G-TKI (Table 1); only a previous cerebrovascular event was reported in a significantly higher rate of IM-treated patients. It is however evident that the distinct toxicity profiles of NIL and DAS had an impact on TKI choice as, for example, no patient with diabetes or ischemic heart disease received NIL.
Following widespread introduction of generic IM in Italy in early 2018, patients were divided in 2 groups: among 238 patients diagnosed from 2012 to 2017, 198 (83.1%) received IM and 40 (16.9%) a 2G-TKI, while patients diagnosed in 2018-2019 were treated with IM in 87/94 (92.5%) cases and with a 2G-TKI in 7 (7.5%) cases only (p=0.028).
Conclusions IM remains the frontline drug of choice in very elderly CML patients, and this trend seems to increase after the introduction of the generic formulation. However, 2G-TKI are used in a small but sizeable group of patients, without a clear correlation with baseline CML features, thus probably reflecting a physician's evaluation of patient's fitness and/or expectation. Efficacy and safety of initial reduced TKIs doses in the setting of very elderly patients warrant further analyses.
Display omitted
Latagliata: Novartis: Honoraria; BMS Cellgene: Honoraria; Pfizer: Honoraria. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Iurlo: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Abruzzese: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.
PDF