Improved overall survival with Gemtuzumab Ozogamicin (GO) compared with best supportive care (BSC) in elderly patients with untreated acute myeloid leukemia (AML) not considered fit for intensive chemotherapy: final results from the randomized phase III study (AML-19) of the EORTC and gimema leukemia groups

peer reviewe

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P =.013), Role Functioning (P =.004), and Fatigue (P <.001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P =.005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society

Patient-reported outcomes as independent prognostic factors for survival in oncology:systematic review and meta-analysis

Objectives: Assessment of patient-reported outcomes (PROs) in oncology is of critical importance because it provides unique information that may also predict clinical outcomes. Methods: We conducted a systematic review of prognostic factor studies to examine the prognostic value of PROs for survival in cancer. A systematic literature search was performed in PubMed for studies published between 2013 and 2018. We considered any study, regardless of the research design, that included at least 1 PRO domain in the final multivariable prognostic model. The protocol (EPIPHANY) was published and registered in the International Prospective Register of Systematic Reviews (CRD42018099160). Results: Eligibility criteria selected 138 studies including 158 127 patients, of which 43 studies were randomized, controlled trials. Overall, 120 (87%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies. The EORTC QLQ-C30 questionnaire was the most frequently used measure, and its physical functioning scale (range 0-100) the most frequent independent prognostic PRO, with a pooled hazard ratio estimate of 0.88 per 10-point increase (95% CI 0.84-0.92). Conclusions: There is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. Further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.</p

The Addition of Venetoclax to Induction Chemotherapy in No Low-Risk AML Patients: A Propensity Score-Matched Analysis of the Gimema AML1718 and AML1310 Trials

Venetoclax combined with intensive chemotherapy proved to be safe with promising activity in fit patients with no-low-risk newly diagnosed acute myeloid leukemia (AML), as demonstrated also by an intermediate analysis of the GIMEMA AML1718 trial (NCT03455504). The latter trial, still ongoing, is based on the administration of venetoclax-FLAI to intermediate/high-risk ELN2017 AML and produced a complete remission (CR) rate of 84%, a minimal residual disease (MRD)-negativity rate of 74% and a 12-month Overall Survival (OS) and disease-free survival (DFS) of 75.7% (95%CI: 64.1%, 89.5%) and 80.7% (95%CI: 67.9%, 95.9%), respectively. In order to evaluate the actual advantage of the addition of venetoclax to chemotherapy, the GIMEMA AML1718 was matched to AML1310, which entailed a "3+7"-like induction and a risk-adapted, MRD-directed post-remission transplant allocation (NCT01452646, Venditti et al - Blood 2019). To generate a reliable comparison, AML1718 and AML1310 were matched by using a propensity score and then compared in terms of CR achievement, MRD-negativity and survival outcomes. Patient-level data from GIMEMA AML1718 (n=57) and AML1310 (N=445) with ELN2017 risk classification available were used to conduct a propensity score matching analysis, widely used for reducing the effects of confounding when estimating the effects of treatment on outcomes. Conditional on the propensity score, the distribution of measured variables is expected to be the same in treated (i.e. AML1718) and control (i.e. AML1310) subjects. In the present propensity score model, we included the following variables: age at diagnosis, gender, ELN2017 risk classification and transplant. Different methods for matching were attempted, including 1:1 nearest neighbor, full-matching, optimal matching (1:2, 1:3 and 1:4) and 1:2 genetic matching. The methods employed for assessing balancing were: i) Standardized Mean Difference - Love plot, ii) Empirical cumulative density function, iii) Variance ratio, iv) Empirical QQ-plot. Weights were calculated with probit or logit regression models according to the propensity score method used. Weights obtained from full-matching were used to adjust outcomes (CR, MRD negativity and survival outcomes). No patients were dropped in the full-matching process. A standardized bias score less than 0.25 was used as a criterion for adequate balancing. We used balance tables and Love plots to assess for covariate balance before and after matching. Survival curves were compared by Log-rank test and Restricted Mean Survival Time (RMST) at 12 months. AML1718 and AML1310 cohorts differed in terms of age (median: 54 vs 49 years, p=0.003) and risk category (p&lt; .0001) - since the low risk was not represented in AML1718 trial - and female sex (35% vs 48%, p=0.069), though to a lesser extent. Contrariwise, the percentage of transplanted patients was comparable before matching (49% vs 49%, p=0.96). Being more recent, AML1718 median follow-up was shorter than AML1310 (10.5 vs 75.8 months). Full-matching, 1:2 optimal matching and 1:2 genetic matching produced the best balancing. Table 1 shows the results of the analysis for the unmatched and matched data. After balancing, according to all matching methods, the CR rate observed in the AML1718 was significantly higher than AML1310, as well as MRD-negativity rate. Comparing survival outcomes at 12 months, emerged that, upon matching, OS and DFS estimates of the AML1718 were higher than those of AML1310, though a slight statistical significance was reached only with the optimal matching on DFS (p=0.042). This result was confirmed by a statistically significant difference between the two RMST at 12 months (p=0.036). Despite this, a longer AML1718 follow-up is needed to provide a robust comparison between the two protocols. Our propensity-score analysis showed that combining venetoclax with chemotherapy in newly diagnosed AML patients resulted in improved outcomes in terms of CR rate and MRD-negativity: these achievements are crucial to allow transition to allogenic transplantation in first remission. With regards to survival outcomes, a solid conclusion will be drawn when a longer AML1718 follow-up is available. These preliminary results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy and paves the way to novel combination regimens based on venetoclax

P495: UNLOCKING THE POTENTIAL OF SYNTHETIC PATIENTS FOR ACCELERATING CLINICAL TRIALS: RESULTS OF THE FIRST GIMEMA EXPERIENCE

Background: Artificial intelligence is contributing to improve different medicine areas including clinical trial design. One field that holds a great potential is represented by the use of digital data as an alternative to real ones. The generation of a virtual cohort of patients might be advantageous since an artificial group of patients resembles the real dataset in all the key features but it does not include any identifiable real-patient data, tackling - by a privacy standpoint – the “burden” of collecting data subjects’ consent as well as the shortcomings of common anonymization techniques. Aims: To test the feasibility of this approach and evaluate its potential in clinical trial design, we built an in-silico cohort based on the large dataset of patients enrolled in the GIMEMA AML1310 study (Venditti et al. 2019), which entailed a “3 + 7”-like induction and a risk-adapted, MRD-directed post-remission transplant allocation. Methods: To create the synthetic cohort of patients, a machine learning generative model was constructed from the real individual-level data of the AML1310 study, capturing its patterns and statistical properties. AML1310 enrolled 500 patients (median age 49 years old) in 55 GIMEMA Institutions. All patients were NCCN2009 risk classified and analyzed by morphology, cytogenetics, molecular biology and multiparametric flow cytometry. The subset of 445 patients with ELN2017 risk classification available was used. To this purpose, the R package “synthpop” was used considering a parametric method: for binary data the logistic regression, for a factor with &gt; 2 levels the polytomous logistic regression, for an ordered factor with &gt; 2 levels the ordered polytomous logistic regression. For time to event variables the classification and regression trees method was used. Next, we verified the adherence of the virtual cohort to the original one in terms of age, gender, PS, WBC count, FLT3 and NPM1 mutations, risk category, CR achievement, MRD, transplant rate. Virtual and real cohorts were also compared in terms of survival outcomes. Results: By using the real-patient dataset from the AML1310 trial, a virtual cohort of 850 patients, named synthAML1310, was generated. By comparing the two cohorts, we observed that the clinico-biological characteristics and response evaluations (CR and MRD rates) did not differ significantly. Moreover, as depicted in Figure 1, the curves of OS and DFS were superimposable. Indeed, at 2 years, OS was 57% (52.5%-61.9%) in the original and 59.1% (55.9%-62.6%) in the synthAML1310 cohort. DFS was 55.1% (49.8%-60.9%) in the original and 55.1% (51.3%-59.2%) in the synthetic cohort. Summary/Conclusion: These results demonstrate the success of this approach in producing a virtual dataset that perfectly mimics the original and that, from a “privacy by design” perspective, minimizes the risk of re-identification of patients. Mirroring an AML population treated with a conventional chemotherapeutic approach, synthAML1310 is suitable to represent the control group when testing novel innovative treatments, most likely in an in-silico randomized trial, but also in other settings like propensity score matching analyses in observational studies. Shifting to an in-silico trial would overcome the challenges of randomized trials and it would be beneficial also for patients. since, they would receive only the experimental treatment without being exposed to the “less active“ therapy, thus limiting treatment failures and toxicity. Also, enrolment and the attainment of final results would be faster

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

A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real‐world practice

Given the limited data on the real-life therapeutic use of feline mcdonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML)patients receiving FLT3 inhibitors andwe collected data on the efficacy and safety of these agents. the survey results showed that in the real-life setting the response rate of the 3/7+midostaurin regimen in newly diagnosed FLT3-mutatedAML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. the discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases)

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.)

Patient-reported symptom monitoring and adherence to therapy in patients with newly diagnosed chronic myeloid leukemia

Background: The authors assessed the clinical utility of patient-reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy. Methods: The authors conducted an international prospective study that included patients with newly diagnosed, chronic-phase CML. Before clinical consultation, patients were provided a tablet computer to self-rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self-reported questionnaire. The proportions of optimal responders at 3 and 6&nbsp;months were assessed according to the European LeukemiaNet criteria. Results: Between July 2020 and August 2021, 94 patients with a median age of 57&nbsp;years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6-month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3&nbsp;months and by 61 of 81 patients (75.3%) at 6&nbsp;months. Conclusions: Patient-reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848)