Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis

none36Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosisopenPalandri F.; Palumbo G.A.; Elli E.M.; Polverelli N.; Benevolo G.; Martino B.; Abruzzese E.; Tiribelli M.; Tieghi A.; Latagliata R.; Cavazzini F.; Bergamaschi M.; Binotto G.; Crugnola M.; Isidori A.; Caocci G.; Heidel F.; Pugliese N.; Bosi C.; Bartoletti D.; Auteri G.; Cattaneo D.; Scaffidi L.; Trawinska M.M.; Stella R.; Ciantia F.; Pane F.; Cuneo A.; Krampera M.; Semenzato G.; Lemoli R.M.; Iurlo A.; Vianelli N.; Cavo M.; Breccia M.; Bonifacio M.Palandri, F.; Palumbo, G. A.; Elli, E. M.; Polverelli, N.; Benevolo, G.; Martino, B.; Abruzzese, E.; Tiribelli, M.; Tieghi, A.; Latagliata, R.; Cavazzini, F.; Bergamaschi, M.; Binotto, G.; Crugnola, M.; Isidori, A.; Caocci, G.; Heidel, F.; Pugliese, N.; Bosi, C.; Bartoletti, D.; Auteri, G.; Cattaneo, D.; Scaffidi, L.; Trawinska, M. M.; Stella, R.; Ciantia, F.; Pane, F.; Cuneo, A.; Krampera, M.; Semenzato, G.; Lemoli, R. M.; Iurlo, A.; Vianelli, N.; Cavo, M.; Breccia, M.; Bonifacio, M

Low low-density lipoprotein (LDL), cholesterol and triglycerides plasma levels are associated with reduced risk of arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life. A Campus CML study

36noopenopenCaocci G.; Mulas O.; Capodanno I.; Abruzzese E.; Iurlo A.; Luciano L.; Albano F.; Annunziata M.; Tiribelli M.; Bonifacio M.; Galimberti S.; Castagnetti F.; Sgherza N.; Stagno F.; Gozzini A.; Orlandi E.M.; Luzi D.; Binotto G.; Pregno P.; Fozza C.; Efficace F.; Simula M.P.; Trawinska M.M.; Cattaneo D.; De Gregorio F.; Attolico I.; Stella R.; Scaffidi L.; Barate C.; Gugliotta G.; Scalzulli E.; Elena C.; Pirillo F.; Foa R.; Breccia M.; Nasa G.L.Caocci, G.; Mulas, O.; Capodanno, I.; Abruzzese, E.; Iurlo, A.; Luciano, L.; Albano, F.; Annunziata, M.; Tiribelli, M.; Bonifacio, M.; Galimberti, S.; Castagnetti, F.; Sgherza, N.; Stagno, F.; Gozzini, A.; Orlandi, E. M.; Luzi, D.; Binotto, G.; Pregno, P.; Fozza, C.; Efficace, F.; Simula, M. P.; Trawinska, M. M.; Cattaneo, D.; De Gregorio, F.; Attolico, I.; Stella, R.; Scaffidi, L.; Barate, C.; Gugliotta, G.; Scalzulli, E.; Elena, C.; Pirillo, F.; Foa, R.; Breccia, M.; Nasa, G. L

Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia.

none25We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806.noneRusso D; Martinelli G; Malagola M; Skert C; Soverini S; Iacobucci I; De Vivo A; Testoni N; Castagnetti F; Gugliotta G; Turri D; Bergamaschi M; Pregno P; Pungolino E; Stagno F; Breccia M; Martino B; Intermesoli T; Fava C; Abruzzese E; Tiribelli M; Bigazzi C; Cesana BM; Rosti G; Baccarani M.Russo D; Martinelli G; Malagola M; Skert C; Soverini S; Iacobucci I; De Vivo A; Testoni N; Castagnetti F; Gugliotta G; Turri D; Bergamaschi M; Pregno P; Pungolino E; Stagno F; Breccia M; Martino B; Intermesoli T; Fava C; Abruzzese E; Tiribelli M; Bigazzi C; Cesana BM; Rosti G; Baccarani M

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

open25noSecond-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a "real-life" setting. We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a "real-life" setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.openTiribelli, Mario*; Bonifacio, Massimiliano; Binotto, Gianni; Iurlo, Alessandra; Cibien, Francesca; Maino, Elena; Guella, Anna; Festini, Gianluca; Minotto, Claudia; De Biasi, Ercole; De Marchi, Federico; Scaffidi, Luigi; Frison, Luca; Bucelli, Cristina; Medeot, Marta; Calistri, Elisabetta; Sancetta, Rosaria; Stulle, Manuela; Orofino, Nicola; Krampera, Mauro; Gherlinzoni, Filippo; Semenzato, Gianpietro; Pizzolo, Giovanni; Ambrosetti, Achille; Fanin, RenatoTiribelli, Mario; Bonifacio, Massimiliano; Binotto, Gianni; Iurlo, Alessandra; Cibien, Francesca; Maino, Elena; Guella, Anna; Festini, Gianluca; Minotto, Claudia; De Biasi, Ercole; De Marchi, Federico; Scaffidi, Luigi; Frison, Luca; Bucelli, Cristina; Medeot, Marta; Calistri, Elisabetta; Sancetta, Rosaria; Stulle, Manuela; Orofino, Nicola; Krampera, Mauro; Gherlinzoni, Filippo; Semenzato, Gianpietro; Pizzolo, Giovanni; Ambrosetti, Achille; Fanin, Renat

The significance of early warning in chronic myeloid leukemia

We have read with great interest the manuscript by Eskazan and colleagues entitled \u201cCritical appraisal of European LeukemiaNet (ELN) 2013 recommendations for the management of chronic myeloid leukemia: is it early for a warning?\u201d. After a revision of the relatively limited literature, the Authors conclude that there are still no solid data to suggest a switch of therapy in patients with warning signs and that long-term survival remains a highly significant endpoint in CML patients. While we generally agree with these thoughts, we would like to stress a couple of additional points on the issue of ELN 2013 \u2013 defined \u201cwarning\u201d. The ELN recommendations defines warning as less than partial cytogenetic response (PCyR) and/or BCR-ABL1 >10% (according to the International Scale \u2013 IS) at 3 months, less than complete cytogenetic response (CCyR) and/or BCR-ABL1 >1%IS at 6 months, and BCR-ABL1 >0.1% IS, i.e. no major molecular response (MMR) at 12 months. So, at the first two time-points, conventionally considered as \u201cearly\u201d, both cytogenetic and molecular status define response, while at 12 months only BCR-ABL1 level >0.1 to 1%IS identifies warning patients, as anything less than CCyR is regarded as a failure. Our group analyzed the outcome of 216 CML patients treated with front-line standard dose (400 mg/day) imatinib with discordant cytogenetic and molecular responses at 3 and 6 months. Patients with even a single warning sign at 3 months (i.e. no PCyR or BCR-ABL1 >10%IS) had a significantly lower chance to obtain a subsequent CCyR (37% compared to 85% in patients with concordant optimal cytogenetic and molecular responses) and worse failure-free survival (FFS) (39% vs 81% at 48 months). Similarly, a warning sign at 6 months identified patients less prone to attain a MMR at 12 months (17% vs 82% in concordantly optimal patients) and with worse FFS (62% vs 88%). In our experience, most discordant patients had a \u201cmolecular warning\u201d, as 15/17 discordant at 3 months were in PCyR or better but with BCR-ABL1 transcript >10%IS and at 6 months 20/25 discordant were in CCyR with BCR-ABL1 >1%IS. This finding is an indirect confirmation of the importance of a BCR-ABL1 transcript level <10%IS at 3 months (now defined \u201cearly molecular response\u201d, EMR) as a positive predictor of long-term outcome, as reported by different studies. Despite EMR is gaining ground as a factor for an early switch of therapy, as suggested by NCCN guidelines, some reports indicate, in line with ELN recommendations, to consider also the 6-month cytogenetic or molecular status to assess a two-point evaluation of response to TKI therapy. The MDACC group analyzed the outcome of 453 CML patients treated with different TKIs, finding that 19 out of 44 patients (43%) not achieving major (i.e. optimal) cytogenetic response (MCyR) at 3 months obtained this response at 6 months and had an outcome comparable to patients achieving an earlier MCyR [8]. A Canadian study reviewed 320 patients receiving imatinib therapy with 3 and 6 month BCR-ABL1 transcript levels available, reporting that patients not achieving an EMR at 3 months but with BCR-ABL1 transcript <1% at 6 months (n=18) had similar FFS, progression-free survival (PFS) and overall survival (OS) compared to patients in EMR (n=184). Taken together, these data suggest that cytogenetic and molecular response at 6 months can identify a subgroup with favorable outcome among patients \u201cwarning\u201d at 3 months. However, considering patients with cytogenetic and/or molecular warning at 3 months in our series (n=41), only 2 had a subsequent optimal cytogenetic and molecular response at 6 months (unpublished). Moreover, we found that the rates of warning responses at 3 and 6 months were higher in cases with b2a2 BCR-ABL1 transcript type compared to those with b3a2 variant (32% vs 24% at 3 months and 31% vs 12% at 6 months, respectively). If there is still debate on the practical significance of a warning at 3 or 6 months, even less consensus and significantly less data are about the meaning of a late (i.e. at 12 months) warning. Starting from their database of 483 patients treated with four different TKI strategies, colleagues at MDACC found no benefit, in term of survival, in patients achieving MMR while in CCyR, even if their landmark analysis was performed at 18 and 24 months, and not at the 12-months timepoint. A landmark analysis of PFS and OS on the bases of molecular response at 12 months of imatinib performed in 128 patients from our database did not find any difference between patients in MMR or not (personal data, unpublished). Concordantly, a Spanish group showed that, in 198 patients treated with standard-dose imatinib and in CCyR without MMR at 12 months, a switch to a second-generation TKI was associated with a higher probability of subsequently major and deep molecular response, but no advantage in terms of PFS and OS and higher rates of discontinuation for adverse events, compared to patients continuing imatinib. Hopefully, more information on the therapeutic approach to \u201cwarning\u201d patients will come from an upcoming study of the GIMEMA Working Party on CML study aimed to evaluate efficacy of nilotinib frontline versus imatinib followed by switch to nilotinib in the case of absence of ELN-defined optimal response at 3, 6 or 12 months

Rethinking Health Recommender Systems for Active Aging: An Autonomy-Based Ethical Analysis

Health Recommender Systems are promising Articial-Intelligence-based tools endowing healthy lifestyles and therapy adherence in healthcare and medicine. Among the most supported areas, it is worth mentioning active aging. However, current HRS supporting AA raise ethical challenges that still need to be properly formalized and explored. This study proposes to rethink HRS for AA through an autonomy-based ethical analysis. In particular, a brief overview of the HRS' technical aspects allows us to shed light on the ethical risks and challenges they might raise on individuals' well-being as they age. Moreover, the study proposes a categorization, understanding, and possible preventive/mitigation actions for the elicited risks and challenges through rethinking the AI ethics core principle of autonomy. Finally, elaborating on autonomy-related ethical theories, the paper proposes an autonomy-based ethical framework and how it can foster the development of autonomy-enabling HRS for AA

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study

31noBackground: Intermittent treatment with TKIs is an option for the great majority (70%–80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0) and to improve Health Related Quality of Life (HRQoL). Results: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0/MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients’ HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001). Conclusions: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR3.0/MR4.0 in 81% of the patients during the first 12–24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR3.0 regained the MR3.0 and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.openopenMalagola M.; Iurlo A.; Abruzzese E.; Bonifacio M.; Stagno F.; Binotto G.; D'Adda M.; Lunghi M.; Crugnola M.; Ferrari M.L.; Lunghi F.; Castagnetti F.; Rosti G.; Lemoli R.M.; Sancetta R.; Coppi M.R.; Corsetti M.T.; Rege Cambrin G.; Romano A.; Tiribelli M.; Russo Rossi A.; Russo S.; Aprile L.; Gandolfi L.; Farina M.; Bernardi S.; Polverelli N.; Roccaro A.M.; De Vivo A.; Baccarani M.; Russo D.Malagola, M.; Iurlo, A.; Abruzzese, E.; Bonifacio, M.; Stagno, F.; Binotto, G.; D'Adda, M.; Lunghi, M.; Crugnola, M.; Ferrari, M. L.; Lunghi, F.; Castagnetti, F.; Rosti, G.; Lemoli, R. M.; Sancetta, R.; Coppi, M. R.; Corsetti, M. T.; Rege Cambrin, G.; Romano, A.; Tiribelli, M.; Russo Rossi, A.; Russo, S.; Aprile, L.; Gandolfi, L.; Farina, M.; Bernardi, S.; Polverelli, N.; Roccaro, A. M.; De Vivo, A.; Baccarani, M.; Russo, D

Moral and Legal Autonomy in the Era of Artificial Intelligence

The ethical principle of autonomy is one of the core principles in the field of applied ethics, from bioethics to ethics of artificial intelligence (AI). In this paper, we pursue an ethical inquiry into how AI systems can affect human autonomy according to a moral and legal perspective, that is, both in its moral dimension (as implicit endorsement) as well as in its legal one (as explicit consent). More specifically, after having defined the concept of individual autonomy from a moral and juridical standpoint as the human normative power of self-determination both in the moral sphere and in the legal one, and thus, better substantiating the AI ethics principle of autonomy as currently adopted in the field, we show how the design of novel AI systems, such as machine-learning and deep-learning algorithms, that widely rule the functioning of digital information and communication technology (ICT), can negatively affect both the preconditions of our moral and legal autonomy, by suspending intrinsic consent that individuals can express in order to endorse external information as a true motive of their choices and actions, as well as bypassing the legal conditions for a valid consent, as the external manifestation of the individual legal autonomy. We conclude by highlighting the ethical implications and risks of such phenomenon and proposing ethical and legal design practices to prevent or mitigate them

The cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulated by the expression level of MRP1 but not MDR1

In vitro and in vivo studies have demonstrated that UCB (unconjugated bilirubin) is neurotoxic. Although previous studies suggested that both MRP1 (multidrug resistance-associated protein 1) and MDR1 (multidrug resistance protein 1) may protect cells against accumulation of UCB, direct comparison of their role in UCB transport was never performed. To this end, we used an inducible siRNA (small interfering RNA) expression system to silence the expression of MRP1 and MDR1 in human neuroblastoma SH-SY5Y cells. The effects of in vitro exposure to clinicallyrelevant levels of unbound UCB were compared between unsilenced (control) cells and cells with similar reductions in the expression of MRP1 or MDR1, documented by RT\u2013PCR (reverse transcription\u2013PCR) (mRNA), immunoblotting (protein), and for MDR1, the enhanced net uptake of a specific fluorescent substrate. Cytotoxicity was assessed by the MTT [3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl-2H-tetrazolium bromide] test. MRP1-deficient cells accumulated significantly more UCB and suffered greater cytotoxicity than controls. By contrast, MDR1-deficient cells exhibited UCB uptake and cytotoxicity comparable with controls. At intermediate levels of silencing, the increased susceptibility to UCB toxicity closely correlated with the decrease in the expression of MRP1, but not of MDR1. These data support the concept that limitation of cellular UCB accumulation, due to UCB export mediated by MRP1, but not MDR1, plays an important role in preventing bilirubin encephalopathy in the newborn