Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Literature review and expert opinion on the treatment of high-risk acute myeloid leukemia in patients who are eligible for intensive chemotherapy.

In patients with Acute Myeloid Leukemia (AML), the assessment of disease risk plays a central role in the era of personalized medicine. Indeed, integrating baseline clinical and biological features on a case-by-case basis is not only essential to select which treatment would likely result in a higher probability of achieving complete remission, but also to dynamically customize any subsequent therapeutic intervention. For young high-risk patients with low comorbidities burden and in good general conditions (also called "fit" patients), intensive chemotherapy followed by allogeneic stem cell transplantation still represents the backbone of any therapeutic program. However, with the approval of novel promising agents in both the induction/consolidation and the maintenance setting, the algorithms for the management of AML patients considered eligible for intensive chemotherapy are in constant evolution. In this view, we selected burning issues regarding the identification and management of high-risk AML, aiming to provide practical advice to facilitate their daily clinical management in patients considered eligible for intensive chemotherapy.

Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report the long-term results of the frontline trial with dasatinib and blinatumomab in induction/consolidation (GIMEMA LAL2116, D-ALBA) for adult Philadelphia-positive ALL (Ph+ ALL), which enrolled 63 patients of all ages. At a median follow-up of 53 months, disease-free survival, overall survival, and event-free survival are 75.8%, 80.7%, and 74.6%, respectively. No events have occurred among early molecular responders. A significantly worse outcome was recorded for IKZF1plus patients. Twenty-nine patients-93.1% being in molecular response (ie, complete molecular response or positive nonquantifiable) after dasatinib/blinatumomab-never received chemotherapy/transplant and continued with a tyrosine kinase inhibitor only; 28 patients remain in long-term complete hematologic response (CHR). An allogeneic transplant was carried out in first CHR mainly in patients with persistent minimal residual disease; 83.3% of patients are in continuous CHR. The transplant-related mortality was 12.5% for patients transplanted in first CHR and 13.7% overall. Nine relapses and six deaths have occurred. ABL1 mutations were found in seven cases. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen on the basis of a targeted strategy (dasatinib) and immunotherapy (blinatumomab) is effective in inducing durable long-term hematologic and molecular responses in adult Ph+ ALL, paving the way for a new era in the management of these patients.

Fms -like tyrosine kinase 3 positive acute myeloid leukemia.

PURPOSE OF REVIEW: Fms -like tyrosine kinase 3 (FLT3) mutations are common in newly diagnosed patients with acute myeloid leukemia (AML). They are associated with a high risk of relapse. The identification of FLT3 mutations has important implications for the management of AML. FLT3 inhibitors have shown improved outcomes in FLT3-positive AML when used as a single agent in the salvage setting. However, the combination of inhibitors and chemotherapy in the first-line setting is the real game changer in FLT3mutant AML. The introduction of these drugs has improved the prognosis of FLT3-mutant AML, but the development of resistance is common. There are still many unanswered questions about FLT3-mutant AML. RECENT FINDINGS: This article will analyze recent advances for FLT3-mutant AML, focusing on front-line therapy and post-transplant maintenance. SUMMARY: Novel drug combinations and strategies against FLT3 mutated AML are currently under investigation and will be the focus of future studies. The development of more selective and potent FLT3 inhibitors may further improve outcomes for patients with FLT3-positive AML. Monitoring minimal residual disease and overcoming resistance are key issues for the future.

Safety of Subcutaneous Daratumumab in Anti-CD38 Monoclonal Antibody-Naïve Patients with Plasma Cell Disorders: A Multicenter Real-Life Experience.

BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, is used for treatment of multiple myeloma (MM) and light chain amyloidosis at an intravenous dosage of 16 mg/kg or at a subcutaneous fixed dose of 1800 mg. However, the subcutaneous formulation has only recently been approved in Europe, and real-life data on its safety are still few. OBJECTIVE: In this multicenter retrospective real-life experience, we provided evidence for the safety of subcutaneous daratumumab in plasma cell disorders. PATIENTS AND METHODS: A total of 189 patients diagnosed with MM or light chain amyloidosis were included in this retrospective study, and all subjects were daratumumab-naïve. Primary endpoint was safety of subcutaneous daratumumab, especially for infusion-related reaction (IRR) incidence and severity. All patients received premedication with dexamethasone, paracetamol, and antihistamine, with montelukast usage in 85% of cases. RESULTS: Eight patients (4%) experienced IRRs, mainly of grade I-II, and other frequent toxicities were: hematological (thrombocytopenia, 4%; neutropenia, 5%; lymphopenia, 6%) and non-hematological (pneumonia, 4%; diarrhea, 2%; and cytomegalovirus reactivation, 0.5%). In our multicenter retrospective real-life experience, subcutaneous daratumumab was well-tolerated with an excellent safety profile with a very low (4%) IRR incidence, even in frailer MM patients with severe renal impairment or increased body weight. CONCLUSIONS: Subcutaneous daratumumab was safe in a real-life setting including patients with severe renal failure and advanced disease. However, further studies on larger and prospective cohorts are required to confirm our real-life observations.

Acute myeloid leukemia: Incidence, transplantation and survival through Italian administrative healthcare data.

OBJECTIVE: To identify newly diagnosed patients with acute myeloid leukemia in 2017 treated with intensive chemotherapy or unfit for intensive chemotherapy, and to assess their probability of receiving allogeneic stem cell transplantation and survival, from the Italian National Health Service perspective. PATIENTS AND METHODS: From the Ricerca e Salute database, adults with an in-hospital diagnosis of acute myeloid leukemia (International Classification of Disease-9th version-Clinical Modification code 205.0x) in 2017 (index date), without any identifying acute myeloid leukemia criteria within the preceding year, were selected. Among them, subjects treated with intensive chemotherapy (chemotherapy during an overnight hospitalization) within one year after index date were identified. The remaining were considered unfit for intensive chemotherapy. Gender, age and comorbidities were described. Within the follow-up period, probabilities of in-hospital allogeneic stem cell transplantation and overall survival were assessed through Kaplan Meier analyses. RESULTS: From 4,840,063 beneficiaries of the Italian National Health Service, 368 newly acute myeloid leukemia diagnosed adults (9.0 *100,000) were selected. Males comprised 57%. Mean age was 68±15. There were 197 patients treated with intensive chemotherapy. The remaining 171 unfit for intensive chemotherapy were older (72±14) and with more comorbidities (e.g. hypertension, chronic lung diseases and chronic kidney disease). Only patients treated with intensive chemotherapy underwent an allogeneic stem cell transplantation (41; 33%) during the one year after the index date. Within the first and second follow-up year, respectively: 41.1% and 26.9% of subjects treated with intensive chemotherapy (144) survived (median survival time: 7.8 months); 25.7% and 18.7% of those unfit for intensive chemotherapy (139) survived (1.2 months). Difference was significant (p<0.0001). Within one and two years after transplantation (41 patients), 73.5% and 67.3% of subjects survived, respectively. CONCLUSION: This study, by showing the incidence of acute myeloid leukemia in Italy in 2017, the proportion of patients treated with intensive chemotherapy from the new diagnosis, the use of allogeneic stem cell transplantation and two-year survival, integrated evidence on large and unselected populations and may help to improve treatment strategies of older acute myeloid leukemia patients.

Assessing eligibility for treatment in acute myeloid leukemia in 2023.

INTRODUCTION: Age has historically been considered the main criterion to determine eligibility for intensive chemotherapy in patients with acute myeloid leukemia (AML), but age alone can no longer be considered an absolute indicator in determining which patients should be defined as unfit. Assessment of fitness for a given treatment today serves an important role in tailoring therapeutic options. AREAS COVERED: This review examines the main options used in real life to define eligibility for intensive and nonintensive chemotherapy in patients with AML, with a main focus on the Italian SIE/SIES/GITMO Consensus Criteria. Other published real-life experiences are also reviewed, analyzing the correlation between these criteria and short-term mortality, and thus expected outcomes. EXPERT OPINION: Assessment of fitness is mandatory at diagnosis to tailor treatment to the greatest degree possible, evaluating the patient's individual profile. This is especially relevant when considering the availability of newer, less toxic therapeutic regimens, which have shown promising results in patients with AML who are older or considered unfit for intensive treatment. Fitness assessment is now a fundamental part of AML management and a critical step that can potentially influence outcomes and not just predict them.

In patients with acute myeloid leukemia (AML), age has generally been considered as the main factor to determine if intensive chemotherapy can be carried out (fitness). However, this has been gradually changing in recent years. In addition to age, comorbidities and overall performance status are also important in determining if the patient should undergo intensive chemotherapy and have an important role in tailoring therapeutic options. Consensus criteria to define eligibility for intensive and nonintensive chemotherapy in patients with AML have been proposed, which have been shown to correlate well with expected outcomes. Today, given the evolution of the treatment armamentarium, assessment of a patient's 'fitness' is compulsory to select the most appropriate treatment for each patient.

AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

Cost-effectiveness analysis of gemtuzumab ozogamicin for the treatment of de novo CD33-positive Acute Myeloid Leukaemia (AML) in Italy.

BACKGROUND: Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service. METHODS: For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT). CONCLUSIONS: If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML. TRIAL REGISTRATION: Not applicable.

Incidence, treatment and outcome of central nervous system relapse in adult acute lymphoblastic leukaemia patients treated front-line with paediatric-inspired regimens: A retrospective multicentre Campus ALL study.

Within the Campus ALL network we analyzed the incidence, characteristics, treatment and outcome of a central nervous system (CNS) relapse in 1035 consecutive adult acute lymphoblastic leukemia (ALL) patients treated frontline with pediatric-inspired protocols between 2009 and 2020. Seventy-one patients (6.8%) experienced a CNS recurrence, more frequently in T- (28/278; 10%) than in B-ALL (43/757; 5.7%) (p = 0.017). An early CNS relapse-< 12 months from diagnosis-was observed in 41 patients. In multivariate analysis, risk factors for early CNS relapse included T-cell phenotype (p = <0.001), hyperleucocytosis >100 × 109 /L (p<0.001) and male gender (p = 0.015). Treatment was heterogeneous, including chemotherapy, radiotherapy, intrathecal therapy and novel agents. A complete remission (CR) was obtained in 39 patients (55%) with no differences among strategies. After CR, 26 patients underwent an allogenic transplant, with a significant overall survival benefit compared to non-transplanted patients (p = 0.012). After a median observation of 8 months from CNS relapse, 23 patients (32%) were alive. In multivariate analysis, the time to CNS relapse was the strongest predictor of a lower 2-year post-relapse survival (p<0.001). In conclusion, in adult ALL the outcome after a CNS relapse remains very poor. Effective CNS prophylaxis remains the best approach and allogenic transplant should be pursued when possible.

Efficacy and safety of belantamab-mafodotin in triple-refractory multiple myeloma patients: A multicentric real-life experience.

Belantamab-mafodotin is an innovative and selective treatment for multi-refractory/relapsed multiple myeloma (MM) patients; however, available real-life experiences on efficacy and safety are limited. In this real-world multicentric retrospective study, we enrolled 28 MM patients treated in four Hematology units of Campania region, Italy, who received a median of six treatment lines prior to belantamab-mafodotin. The overall response rate (ORR) was 40% (complete remission, CR, 11%; very good partial remission, VGPR, 11%; and partial remission, PR, 18%), with a median progression-free survival (PFS) and overall survival (OS) of 3 and 8 months, respectively. One of the most frequent drug-related adverse events was keratopathy observed in nine (32%) patients, leading to therapy discontinuation in only three (11%) of them. Moreover, 22 out of 28 total patients who were treated with at least two administrations achieved an ORR of 50% (CR, 14%; VGPR, 14%; and PR, 22%) with a median PFS and OS of 5 and 11 months, respectively. In conclusion, our multicentric study confirmed efficacy and safety of belantamab-mafodotin in triple-refractory MM patients even in the real-life setting.

MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?

The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of anti-leukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/"unfit" to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclax-based combinations.

Diagnostic Workup of Acute Myeloid Leukemia: What Is Really Necessary? An Italian Survey.

Acute myeloid leukemia (AML) is a heterogeneous disease with a wide variety of clinical presentations, morphological features, and immunophenotypes. The diagnostic approaches to AML that are adopted in Italy have been explored using an online Delphi-based process to expand the global discussion on mandatory tests for the correct diagnosis and, consequently, for optimal management of AML in clinical practice. The final results of the panel of Italian hematologists involved in this work highlight the importance of genetic evaluation for classification and risk stratification and firmly establish that karyotyping, fluorescence in situ hybridization in cases with non-evaluable karyotype, and molecular tests must be performed in every case of AML, regardless of age. Obtaining clinically relevant genetic data at diagnosis is the basis for the success of patient-tailored therapy. The Italian specialists also confirm the role of multidisciplinary diagnostics for AML, now mandatory and expected to become more important in the future context of "precision" medicine.

Drug treatment options for acute promyelocytic leukemia.

INTRODUCTION: Until the late 1980s, acute promyelocytic leukemia (APL) was the most rapidly fatal leukemia; however, nowadays, it is a curable disease with survival rates exceeding 90-95%. The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript PML-RARα responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The story of APL represents a pioneering model for the development of precision medicine and curative chemotherapy-free approaches for acute leukemia. AREA COVERED: The authors examine the major advances in the treatment of patients with APL focusing on three different eras: 1) the pre-ATRA era; 2) the ATRA era; 3) the ATO era. EXPERT OPINION: The combination of ATRA and ATO is effective and curative for the majority of APL patients. It has been approved for low/intermediate risk cases while an experimental trial with a minimal addition of chemotherapy for high-risk ones is ongoing. Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.

The changing landscape for patients with relapsed/refractory acute myeloid leukaemia.

PURPOSE OF REVIEW: The treatment of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) has been an unequal challenge for many decades. Although significant progress has been made in the discovery of the mechanisms underlying the molecular pathogenesis of the disease, more than 50% of AML patients still die, mostly from relapsed disease. Currently, the only potential curative option for patients with R/R AML remains allogeneic bone marrow transplantation in second complete remission, which is far being easy to achieve, mainly for patients with primary induction failure or older than 65 years. The purpose of this review is to discuss recent advances in the management of patients with R/R AML, with particular emphasis to new therapeutic options that are replacing conventional salvage chemotherapy. RECENT FINDINGS: The development of new agents selectively targeting molecular abnormalities offer more effective and less toxic alternative to chemotherapy, potentially useful as a bridge to allogeneic stem cell transplantation in second complete remission. SUMMARY: The recent approval of new drugs for R/R is transforming the paradigm of care we have relied on for the past 50 years. Ongoing clinical trials will tell us how bright is the future for R/R AML patients.

Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study.

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients obtained a response to HMA (CR, PR, or CRi), while 26% showed a stable disease (SD); 50% of patients experienced progressive disease. Median OS was 6.5 months. OS in patients with de novo AML was 6.1 months, while OS in patients with secondary AML (sAML) was 12.3 months (p = 0.037). Median OS after HMA in patients with SD as best response to HMA was similar to median OS in patients with response to HMA (10.6 months vs. 13 months). On multivariate analysis, OS difference between patients who obtained a response versus patients who did not was significant (p = 0.0037). OS difference in sAML was significantly better than in de novo AML (p < 0.00001). HMA showed a remarkable efficacy in terms of response rate and OS in a subgroup of patients (sAMLs), historically characterized by a poor outcome. Therefore, 5Azacitidine and decitabine may represent a good clinical option in a selected patient population with relapsed or refractory AML, unsuitable for allo-HSCT.