Real-world use of blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice : results from the NEUF study

Altres ajuts: Amgen (Europe) GmbHThis retrospective observational study (NEUF) included adult patients with B-cell acute lymphoblastic leukemia (B-cell ALL) who had received blinatumomab for the treatment of minimal residual disease-positive (MRD+) or relapsed/refractory (R/R) B-cell ALL via an expanded access program (EAP). Patients were eligible if blinatumomab was initiated via the EAP between January 2014 and June 2017. Patients were followed from blinatumomab initiation until death, entry into a clinical trial, the end of follow-up, or the end of the study period (December 31, 2017), whichever occurred first. Of the 249 adult patients included, 109 were MRD+ (83 Philadelphia chromosome-negative [Ph−] and 26 Philadelphia chromosome-positive [Ph+]) and 140 had a diagnosis of R/R B-cell ALL (106 Ph− and 34 Ph+). In the MRD+ group, within the first cycle of blinatumomab treatment, 93% (n = 49/53) of Ph− and 64% (n = 7/11) of Ph+ patients with evaluable MRD achieved an MRD response (MRD <0.01%). Median overall survival (OS) was not reached over a median follow-up time of 18.5 months (Ph−, 18.8 [range: 5.1-34.8] months; Ph+, 16.5 [range: 1.8-31.6] months). In the R/R group, within two cycles of blinatumomab, 51% of Ph− and 41% of Ph+ patients achieved complete hematologic remission (CR/CRh/CRi), and 83% of Ph− and 67% of Ph+ MRD-evaluable patients in CR/CRh/CRi achieved an MRD response. Median (95% confidence interval) OS was 12.2 (7.3-24.2) months in the R/R Ph− subgroup and 16.3 (5.3-not estimated) months in the R/R Ph+ subgroup. This large, real-world data set of adults with B-cell ALL treated with blinatumomab confirms efficacy outcomes from published studies

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults

BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.)

ABSORBABLE ADHESIVE FOR LAPAROSCOPIC APPLICATIONS

One of the main problems of abdominal prosthetic surgery is the mesh fixation. Surfaces able to adhere promptly and strongly on wet biological tissue may represent an effective alternative to the conventional prosthesis fixation. Our VIDEO proposes the application of the nature inspired micro- or nano-patterned adhesive surfaces. We realized the intervention with 2 trocar in treated group vs 3 trocar in control group on pig model and operating time in the treated was 10’vs 60’in control group.ClinicalTrials.gov Identifier: NCT02137018 https://register.clinicaltrials.gov prot. C26A10HCNR, founding of 35000€ Prof Lucio D'Ilario, Prof. Andrea Martinelli, Dott. Massimo Chiaretti , prot letter 0003306 project n° 304P25, interfaculty Chemistry Dep, General Surgery Paride Stefanini Dep. http://www.uniroma1.it Location National Health Institute (ISS Istituto Superiore di Sanità), Viale Regina Elena 299 Rome, Roma, Italy, 00161 "BP as a New Device for Surgery and Solid Cancer and Hematopoietic System Tumors Treatment. Effects of BP Implantation" (DM159) ClinicalTrials.gov Protocol and Results Registration System (PRS) Receipt Release Date: 12/30/2014 The objective of this project is to obtain results that can direct the search for the ultimate realization of a prosthetic device for use in abdominal surgery. Will be conducted systematic experiments in 30 New Zealand female rabbits (R1-R30), weighting about 3000 g (Harlan Laboratories)

Buckypaper as absorbable adhesive for surgical applications

FONANZIAMENTO pROGETTO DI RICERCA INTERFACOLTA' dIP pARIDE sTEFANINI Chirurgia Generale e Dip di Chimica Anno 2010 prot C26A10HCNR per 5333€ di 35000€TOPICS: Biotecnologia ed innovazioni tecnologiche. Le proposte italiane nella ricerca. BUCKYPAPER AS ABSORBABLE ADHESIVE FOR SURGICAL APPLICATIONS Massimo Chiaretti(1), Andrea Martinelli(2), Giovanna Angela Carru(3), Fabio Procacciante(1), Lucio D’Ilario(2), Emanuela D’Amore(4), Alessandra Maria Chiaretti(5), Fabio Faiola(6) and Paola Consentino(7). (1)Department of General Surgery “Paride Stefanini”, Sapienza University of Rome, Viale del Policlinico 155, Rome, 00161 (Italy) (2)Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, Rome, 00185 (Italy) (3)Policlinico Umberto I Hospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 - Rome (Italy) (4)National Health Institute, Viale Regina Elena 299, 00161 - Rome (Italy) (5)Biologic Sciences Faculty, University of Rome, P.le Aldo Moro 5, Rome, 00185 (Italy) (6)Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161 (Italy) (7)Appialab Srl V. Latina, 286 00179 Rome (+39) 067825111www.appialab.it E-mail: [email protected] Keywords: buckypaper, carbon nanotubes, medical application, abdominal surgery, wet adhesion absorbable adhesive device. Introduction: The adhesion of a surface on a biological tissue represents an important scientific and technological issue which excites the interest of many researchers. One of the main problems related to the abdominal prosthetic surgery is the mesh fixation. On the one hand suture line tension, mesh separation or displacement, improper and blind application of metal tacks and staples in laparoscopy surgery are the main causes of complications, including seroma, postoperative pain and recurrence[6-9]. On the other hand, the use of human fibrin as glue between the prosthesis and the damaged tissue, although it has become a well-established surgical procedure, presents possible risks associated to the transmission of unknown diseases related to the use of human blood-derived materials [9]. Moreover, it was observed that an increased incidence of postoperative seroma is associated to the use of fibrin glue for mesh fixation[10]. Surfaces able to adhere promptly and strongly on wet biological tissue may represent an effective alternative to the conventional prosthesis fixation methods. This study proposes the application of the nature inspired micro- or nano-patterned adhesive surfaces, by exploiting the scaling effect, according to which the adhesion strength can be enhanced through the reduction of interface adhesive contact size. We experimented evidences on the potential applicability on wet biological tissue of the Buckypaper (BP) as an adhesive tape: BP is a self-standing felt composed of entangled multi-walled carbon nanotubes. In vitro bench surgery mechanical peeling and shear adhesion tests and In vivo tests If compared to other commercial tested prosthesis meshes, BP shows a stronger adhesion, only on wet tissues. much better than both self-gripping commercial mesh and fibrin-glue non-gripping meshes and fabrics. Prompted by these results, we implanted BP in rabbits, to assess its effectiveness as adhesive absorbable prosthetic device and its biocompatibility. After 35 days from the operation we observed that no rabbit behavioral alteration occurred; the BP samples preserved their position in the implantation site and mechanical adhesion was enhanced. This is indicative of no toxicity, good integration and slow reabsorption of the synthetic material into the surrounding tissue without eliciting adverse reactions. Materials and Methods. Operated New Zeeland 3000g female rabbits (R1-R4) did not show mortality or morbidity, no significant neurovegetative or behavioral differences in comparison with the no operated control R5. Results and Discussion. Body weight monitoring graph do not showed any significant difference. The Hematoxilin and Eeosin (H&amp;E) stained implant section reported BP surface fragmentation, shows the formation of a capsule of loose fibrous tissue, consisting of fibroblasts and collagen fibers, indicative of a weak inflammation reaction., the necroscopy examination of R2 showed that the implanted PP favors a cicatrisation process, the mesh appearing wrapped in the inflammatory reaction. In R4, the no sutured incision, tighten by the BP strep, was normally closed and healed. On the smooth BP surface facing the abdominal cavity, explanted from R3, a scarcely adherent neo-formed protein fibrous carpet, about 5 mm thick, may be observed in scansion electronic microscope (SEM). Conclusions: by peeling and shear mechanical tests, a strong BP adhesion on wet biological tissue was measured. In view of a possible application as adhesive absorbable tape in surgery, preliminary in vivo experiments were carried out on rabbit model. Necroscopical and histological investigations enlighten that 35 days after the implantation, the BP elicits minimal adverse tissue response, and when exposed to the peritoneal cavity, no adhesion of omentum or intestinal loops was observed. Nanometric carbon nanotube aggregates, deriving from the surface BP fragmentation, were phagocytised by macrophages and observed in Bowman's urinary space. The assessment of the BP debris, possible toxicity or confinement or metabolism and accumulation or excretion mechanism needs further studies. However, we believe that the results here reported can be used to propose the BP as a new wet absorbable adhesive tape to fix prosthetic materials. References 1. L. Liu, W. Ma, Z. Zhang,Small 2011, 7, 1504 2. M. Chiaretti, G. Mazzanti, S. Bosco, S. Bellucci, A. Cucina, F. Le Foche, G. A. Carru, S. Mastrangelo, A. Di Sotto, R. Masciangelo, A. M. Chiaretti, C. Balasubramanian, G. De Bellis, F. Micciulla, N. Porta, G. Deriu, A. Tiberia, J. Phys.: Condens. Matter 2008,20, 474203 3. A. Di Sotto, M. Chiaretti, G. A. Carru, S. Bellucci, G. Mazzanti, Toxicol. Lett. 2009, 184, 192 4. S. Bellucci, M. Chiaretti, A. Cucina, G.A. Carru,A.I. Chiaretti, Nanomedicine 2009, 4, 531 5. a) The mean equivalent radius was evaluated by wicking tests carried out in water, assuming a water contact angle of about 80°; b) G. Callegari, I. Tyomkin, K. G. Kornev, A.V. Neimark, Y-L. Hsieh, J. Colloid Interface Sci.2011, 353, 290 6. B. P. Jacob, N. J. Hogle, E. Durak, T. Kim, D. L. Fowler, Surg. Endosc. 2007, 21, 629 7. J. R. Eriksen, J. I. Bech, D. Linnemann, J. Rosemberg, Hernia 2008, 12, 483 8. W. B. Gaertner, M. E. Bonsack, J. P. Delaney, Hernia 2010, 14, 375 9. S. Olmi, A. Addis, C. Domeneghini, A. Scaini, E. Croce, Hernia. 2007, 11, 211 10. S. Bellucci, M. Chiaretti, P. Onorato,F. Rossella, M. S. Grandi, P. Galinetto, I. Sacco,F. Micciulla, Nanomedicine 2010, 5, 209 11. massimochiaretti.wordpress.co

Repeated infusions of escalating doses of expanded and activated autologous natural killer cells in minimal residual disease-positive Ph+ acute lymphoblastic leukemia patients. A GIMEMA phase 1 trial

not avalilabl

Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial

: Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). The GIMEMA LAL1913 trial tested a modified regimen adding pegaspargase 2000 IU/m2 to courses 1, 2, 5 and 6 of an eight-block protocol for patients 18-65 years, with dose reductions in patients &gt;55 years. Responders were risk-stratified to allogeneic hematopoietic stem cell transplantation (HCT) or maintenance according to clinical characteristics and minimal residual disease (MRD). Out of 203 study patients (median age 39.8 years, 68.5% B-lineage), 185 (91%) achieved a complete remission (CR). The 3-year overall survival (OS), event-free (EFS) and disease-free (DFS) survival rates were 66.7% (95% confidence intervals, 64.4-60.1%), 57.7% (51.0-65.3%) and 63.3% (56.3-71.1%), respectively, fulfilling the primary study endpoint of a 2-year DFS &gt;55%. While by intention-to-treat DFS was 74% and 50% in the chemotherapy (n=94) and HCT (n=91) assigment cohorts, a time-dependent analysis proved the value of HCT in eligible patients (DFS HCT 70% vs. no HCT 26%, P&lt;0.0001). In multivariate analysis, age and MRD (n=151) were independent prognostic factors associated with DFS rates of 86% (age less/equal to 40/MRD-negative, n=66), 65% (age &gt;40/MRD-negative, n=48), 64% (age less/equal to 40/MRD-positive, n=17) and 25% (age &gt;40/MRD-positive, n=20) (P&lt;0.0001). Grade 2/greater pegaspargase toxicity was mainly observed at course 1 (41 episodes in 32 patients), contributing to induction death in 2 patients, but was rare and milder thereafter. This pegarspargase-containing risk-oriented program was feasible and improved outcome of Ph- ALL/LL patients up to 65 years in a multicenter national setting. ClinicalTrials.gov #NCT02067143

Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimal residual disease-oriented GIMEMA LAL1913

Early recognition of Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) cases could impact on the management and outcome of this subset of B-lineage ALL. In order to assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the "BCR/ABL1-like predictor" - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission rate was significantly lower in Ph-like compared to non-Phlike cases (74.1% vs. 91.5%, P=0.044); ii) at time point 2, decisional for transplant allocation, 52.9% of Ph-like cases versus 20% of non-Ph-like were MRD-positive (P=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at time point 2 (P=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs. 66.2%, P=0.005 and 45.5% vs. 72.3%, P=0.062, respectively). This study documents that Ph-like patients have a lower complete remission rate, event-free survival and disease-free survival, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies. Clinicaltrials gov. Identifier: 02067143