Unlocking the potential of synthetic patients for accelerating clinical trials: Results of the first GIMEMA experience on acute myeloid leukemia patients.

Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost-effective methods also enable the development of personalized subject-specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real-world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco-hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

X-ray Investigation of CsPbI3:EuCl3 Infiltrated into Gig-Lox TiO2 Spongy Layers for Perovskite Solar Cells Applications.

In this study, we explore the potential of a blended material comprising CsPbI3:EuCl3 perovskite and Gig-Lox TiO2, a unique transparent spongy material known for its multi-branched porous structure, for application in solar cells. The inclusion of EuCl3 in CsPbI3 serves to stabilize the photoactive γ-phase with a bandgap of 1.75 eV, making it suitable for solar energy conversion in tandem solar cells. Our study applies X-ray-based techniques to investigate the structural properties and interfacial behavior within this blended material, in comparison with a reference perovskite layer deposited on glass. In addition, Spectroscopic ellipsometry is complemented with density functional theory calculations and photoluminescence measurements to elucidate the absorption and radiative emission properties of the blend. Notably, our findings reveal a significant quenching of photoluminescence within the blended material, underscoring the pivotal role of the distributed interfaces in facilitating efficient carrier injection from the CsPbI3:EuCl3 perovskite into the Gig-Lox TiO2 sponge. These findings pave the way for the application of the blend as an Electron Transport Layer (ETL) in semi-transparent perovskite solar cells for tandem and building integrated photovoltaics.

Peripherally inserted central venous catheter for pediatric acute leukemia: A retrospective 11-year single-center experience.

BACKGROUND: Peripherally inserted central catheters (PICCs) are successfully increasingly used in children in onco-hematologic setting. PICC insertion, especially in oncologic patients, can be associated with adverse events (thrombosis, mechanical complications, and infections). Data regarding the use of PICC, as long-term access in pediatric patients with severe hematologic diseases, are still limited. METHODS: We retrospectively evaluated the safety and efficacy of 196 PICC, inserted in 129 pediatric patients with acute leukemia diagnosed and treated at Pediatric Hematology Unit, Sapienza University of Rome. RESULTS: The 196 PICC analyzed were in situ for a median dwell time of 190 days (range 12-898). In 42 children, PICC was inserted twice and in 10, three times or more due to hematopoietic stem cell transplant, disease recurrence, or PICC-related complications. The overall complication rate was 34%: catheter-related bloodstream infections (CRBSI) occurred in 22% of cases after a median time of 97 days; a catheter-related thrombosis (CRT) in 3.5% and mechanical complications in 9% of cases. Premature removal for complications occurred in 30% of PICC. One death from CRBSI was observed. CONCLUSIONS: To our knowledge, this study represents the largest cohort of pediatric patients who have inserted the PICC for acute leukemia. In our experience, PICC was a cheap, safe, and reliable device for long-term intravenous access in children with acute leukemia. This has been possible with the help of dedicated PICC team.

Lead Detection in a Gig-Lox TiO2 Sponge by X-ray Reflectivity.

The importance of lead analysis in environmental matrices becomes increasingly relevant due to the anthropogenic spread of toxic species in nature. Alongside the existing analytical methods to detect lead in a liquid environment, we propose a new dry approach for lead detection and measurement based on its capture from a liquid solution by a solid sponge and subsequent quantification based on X-ray analyses. The detection method exploits the relationship between the electronic density of the solid sponge, which depends on the captured lead, and the critical angle for total reflection of the X-rays. For this purpose, gig-lox TiO2 layers, grown by modified sputtering physical deposition, were implemented for their branched multi-porosity spongy structure that is ideal for capturing lead atoms or other metallic ionic species in a liquid environment. The gig-lox TiO2 layers grown on glass substrates were soaked into aqueous solutions containing different concentrations of Pb, dried after soaking, and finally probed through X-ray reflectivity analyses. It has been found that lead atoms are chemisorbed onto the many available surfaces within the gig-lox TiO2 sponge by establishing stable oxygen bonding. The infiltration of lead into the structure causes an increase in the overall electronic density of the layer and, thus, an increment of its critical angle. Based on the established linear relationship between the amount of lead adsorbed and the augmented critical angle, a standardized quantitative procedure to detect Pb is proposed. The method can be, in principle, applied to other capturing spongy oxides and toxic species.

High rate of durable responses with undetectable minimal residual disease with front-line venetoclax and rituximab in young, fit patients with chronic lymphocytic leukemia and an adverse biological profile: results of the GIMEMA phase II LLC1518 - VERITAS study.

The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.

Childhood acute promyelocytic leukemia in a pediatric cancer referral center in Baghdad, Iraq. Improved results with ATRA extended consolidation.

Modern treatments have dramatically improved the prognosis of childhood acute promyelocytic leukemia (APL). This progress has not yielded equivalent benefit in developing countries, where biological studies and supportive cares are insufficient and often unavailable. Since 2003, an all-trans retinoic (ATRA)-based, risk-adapted protocol was initiated in Baghdad. Patients were defined: high-risk with WBC ≥10 × 109/L and standard-risk with WBC <10 × 109/L. ATRA was included in induction and maintenance and, from 2010, in consolidation. Of 429 pediatric acute myeloid leukemia (September 2003-August 2019), 118 (27.5%) were APL. Six children died before therapy, 4 refused; 94/108 (87%) achieved a remission; 12 (11%) died early and 2 abandoned. The 5-year overall survival and event-free survival are 61.8% and 55.5% for all patients, 51.7% and 43.6% for first protocol, 68.4% and 63.9% for second one. Baseline WBC count was a risk factor for induction mortality; early hemorrhagic death remains a major cause of failure. ATRA extended consolidation improved results.

Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol.

IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19−86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors.

Clinical relevance of an objective flow cytometry approach based on limit of detection and limit of quantification for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial.

Using a multiparametric flow cytometry assay, we assessed the predictive power of a threshold calculated applying the criteria of limit of detection (LOD) and limit of quantitation (LOQ) in adult patients with acute myeloid leukemia. This was a post-hoc analysis of 261 patients enrolled in the GIMEMA AML1310 prospective trial. According to the protocol design, using the predefined measurable residual disease (MRD) threshold of 0.035% bone marrow residual leukemic cells (RLC) calculated on mononuclear cells, 154 (59%) of the 261 patients were negative (MRD <0.035%) and 107 (41%) were positive (MRD ≥0.035%). Using LOD and LOQ, we selected the following categories of patients: (i) LODneg if RLC were below the LOD (74; 28.4%); (ii) LODpos-LOQneg if RLC were between the LOD and LOQ (43; 16.5%); and (iii) LOQpos if RLC were above the LOQ (144; 54.4%). Two-year overall survival of these three categories of patients was 75.4%, 79.8% and 66.4%, respectively (P=0.1197). Given their superimposable outcomes, the LODneg and LODpos-LOQneg categories were combined. Two-year overall survival of LODneg/LODpos-LOQneg patients was 77.0% versus 66.4% of LOQpos individuals (P=0.043). This figure was challenged in univariate analysis (P=0.046, hazard ratio=1.6, 95% confidence interval: 1.01-2.54) which confirmed the independent role of the LOD-LOQ approach in determining overall survival. In the AML1310 protocol, using the threshold of 0.035%, 2-year overall survival of patients with MRD <0.035% and MRD ≥0.035% was 74.5% versus 66.4%, respectively (P=0.3521). In conclusion, the use of the LOD-LOQ method results in more sensitive detection of MRD that, in turn, translates into a more accurate recognition of patients with different outcomes.

ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol.

The 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646.

TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia.

Ibrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutinib maintenance), we investigated the modulation of T-cell cytokine production in 208 peripheral blood paired samples from 71 CLL patients: 71 samples prior to treatment (Day 0, D0) and at day +14 (D14; n=50), at month +8 (M8; 30), +12 (M12; 25), +18 (M18; 22) and +24 (M24; 10) of treatment. We documented a progressive decrease of CD3+CD4+IL-4+ T cells (Th2), that was significant at M8 and at M12 (p=0.019, p=0.002), a relative increase in the CD3+CD4+IFNγ+ T cells (Th1) and a decrease of CD3+CD4+IL-17+ (Th17) cells that was maintained up to M18 (M8 vs D0 p=0.003, M12 vs D0 p=0.003, M18 vs D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14 vs D0 p=0.037, M8 vs D0 p=0.001, M12 vs D0 p=0.005, M18 vs D0 p=0.002). The Th2/Th1 modulation over time was significant only among patients with unmutated IGHV. The Th2/Th1 ratio below a cut-off of 0.088 at M8 was associated with the achievement of a complete response (CR) (p=0.016). Ibrutinib may shape the CLL T-cell profile, limiting Th2 activation and inducing a shift in the Th2/Th1 ratio. The association between the Th2/Th1 ratio decrease and the CR achievement suggests the in vivo generation of a potential host anti-tumor immune activation induced by ibrutinib.

Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group.

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real-life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression-free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0-1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p < 0.01). Treatment breaks ≥14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≥3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations.

In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a 'borderline' (BL) percentage of mutations (i.e. 97-97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL-CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M-CLL (n = 338) and significantly longer than that of UM-CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL-CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL-CLL remained comparable to that of M-CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL-CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL-CLL: n = 47, 4·3%). BL-CLL at diagnosis showed a biological profile comparable to that of M-CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL-CLL is good and similar to that of M-CLL, with the exception of subset #2 cases.