Giuseppe Visani’s research while affiliated with Azienda Ospedaliera Marche Nord and other places
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Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event – free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 – 15.2) and OS was 40.0% (95%CI, 36.4 – 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 – 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 – 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 – 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 – 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.
The bone marrow microenvironment (BMM) has highly specialized anatomical characteristics that provide a sanctuary place for hematopoietic stem cells (HSCs) that allow appropriate proliferation, maintenance, and self-renewal capacity. Several cell types contribute to the constitution and function of the bone marrow niche. Interestingly, uncovering the secrets of BMM and its interaction with HSCs in health paved the road for research aiming at better understanding the concept of leukemic stem cells (LSCs) and their altered niche. In fact, they share many signals that are responsible for interactions between LSCs and the bone marrow niche, due to several biological similarities between LSCs and HSCs. On the other hand, LSCs differ from HSCs in their abnormal activation of important signaling pathways that regulate survival, proliferation, drug resistance, invasion, and spread. Targeting these altered niches can help in better treatment choices for hematological malignancies and bone marrow disorders in general and acute myeloid leukemia (AML) in particular. Moreover, targeting those niches may help in decreasing the emergence of drug resistance and lower the relapse rate. In this article, the authors reviewed the most recent literature on bone marrow niches and their relations with either normal HSCs and AML cells/LSC, by focusing on pathogenetic and therapeutic implications.
Introduction. The outcome of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved in the last decade, due with the introduction in the clinical practice of tyrosine kinase inhibitors (TKIs). A further improvement has been obtained with the use of blinatumomab as a consolidation strategy in newly diagnosed patients. We previously designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA); the preliminary results showed that after 2 cycles of blinatumomab (primary endpoint), molecular responses were achieved in 60% of cases and that, with a median follow-up of 18 months, overall survival (OS) and disease (DFS) were 95% and 88% (Foà et al, NEJM 2020). An updated follow-up at 53 months (Foà et al, under revision and ASH 2023) confirmed the favorable long-term outcomes with OS and DFS of 75.8% and 80.7%, respectively. A total of 9 relapses occurred. The median time to relapse was 4.4 months (1.9-25.8); 4 were at the central nervous system (CNS). To further improve the outcome of these patients, we designed a phase III trial (GIMEMA ALL2820) in which in the experimental arm dasatinib was substituted with ponatinib, followed - in the consolidation phase - by at least 2 cycles of blinatumomab. The trial is currently enrolling.
Aims. To compare the efficacy of the combination of ponatinib followed by blinatumomab with that reported with dasatinib followed by blinatumomab for the management of newly diagnosed adult Ph+ ALL patients.
Patients and Methods. From September 2021 to July 2023, 74 patients have been enrolled in the experimental arm, based on ponatinib followed by at least 2 cycles of blinatumomab; the induction period has been reduced from 85 to 70 days and the dose of ponatinib was either 45 mg or 30 mg, according to patient's age. A dose reduction to 30 mg was foreseen by day 28 of induction, regardless of age, to avoid unacceptable toxicities. Furthermore, CNS prophylaxis was strengthened with a total of 15 medicated lumbar punctures and triple intrathecal therapy (methotrexate, aracytin and steroids) was administered. Finally, transplant allocation was not left to investigator's choice, but it was established according to biological features (minimal residual disease and presence of the IKZF1 plu s genotype).
Results. Median age was 57 years (range 20-80), with 31% of patients being older than 65 years; 51% were males, the median white blood count (WBC) was 12 x10 9/l (1-207 x10 9/l). The p190 fusion protein was detected in 75.6% of cases, the p210 in 21.6% and p190/p210 in 2.7%. The IKZF1 plus genotype was detected in 33% of cases. The median follow-up is 6.1 months (0 - 20.3). Of the 74 patients enrolled, 16 were still receiving induction treatment and have therefore been excluded from the present analysis, and 40 have received ≥2 cycles of blinatumomab. Regarding the induction phase, 55 of 58 patients (95%) achieved a complete hematologic remission (CHR), while 3 patients (5%) died in induction (a 77-year-old woman for unknown causes, a 68-year-old man for an intestinal occlusion and a 52-year-old man due to pneumonia). A molecular response (including both MRD negative and positive non-quantifiable (PNQ) cases) was obtained in 21/55 cases (38.2%). By the end of the consolidation phase, of the 40 evaluable patients 25 (62.5%). achieved a molecular response. So far, a single patient has relapsed (WBC at onset 121 x10 9/l and a IKZF1 plus genotype) after 3 months from CHR: at relapse, this case harbored a T3151 mutation (Sanger sequencing and digital droplet PCR at diagnosis were wild type). At recurrence, CD19 expression was maintained.
Conclusions. The preliminary analysis of the GIMEMA ALL2820 trial proved the feasibility of this ponatinib-blinatumomab induction consolidation strategy for newly diagnosed Ph+ ALL of all ages, with a 95% CHR rate. Molecular responses at the end of induction are slightly superior in the current trial (38.2% vs 29% in the D-ALBA study), whereas they are virtually equivalent after 2 cycles of blinatumomab (62.5% vs 60% in in the D-ALBA). So far, the benefit of the current protocol appears to rely on a lower relapse rate, with only 1 relapse being observed to date, while in the same time period 3 relapses were documented with the dasatinib-blinatumomab combination. Further details will be provided.
We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m ² and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II–IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III–IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo ( P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% ( P = 0.6), 73% versus 76% ( P = 0.5), and 54% versus 53% ( P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.
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.
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by progressive bone marrow sclerosis, extra-medullary hematopoiesis, and possible transformation to acute leukemia. In the last decade, the molecular pathogenesis of the disease has been largely uncovered. Particularly, genetic and genomic studies have provided evidence of deregulated oncogenes in PMF as well as in other MPNs. However, the mechanisms through which transformation to either the myeloid or lymphoid blastic phase remain obscure. Particularly, it is still debated whether the disease has origins in a multi-potent hematopoietic stem cells or instead in a commissioned myeloid progenitor. In this study, we aimed to shed light upon this issue by using next generation sequencing (NGS) to study both myeloid and lymphoid cells as well as matched non-neoplastic DNA of PMF patients. Whole exome sequencing revealed that most somatic mutations were the same between myeloid and lymphoid cells, such findings being confirmed by Sanger sequencing. Particularly, we found 126/146 SNVs to be the e same (including JAK2V617F), indicating that most genetic events likely to contribute to disease pathogenesis occurred in a non-commissioned precursor. In contrast, only 9/27 InDels were similar, suggesting that this type of lesion contributed instead to disease progression, occurring at more differentiated stages, or maybe just represented “passenger” lesions, not contributing at all to disease pathogenesis. In conclusion, we showed for the first time that genetic lesions characteristic of PMF occur at an early stage of hematopoietic stem cell differentiation, this being in line with the possible transformation of the disease in either myeloid or lymphoid acute leukemia.
The prognosis of adult acute lymphoblastic leukemia (ALL) is variable but more often dismal. Indeed, its clinical management is challenging, current therapies inducing complete remission in 65–90% of cases, but only 30–40% of patients being cured. The major determinant of treatment failure is relapse; consequently, measurement of residual leukemic blast (minimal residual disease, MRD) has become a powerful independent prognostic indicator in adults. Numerous evidences have also supported the clinical relevance of MRD assessment for risk class assignment and treatment selection. MRD can be virtually evaluated in all ALL patients using different technologies, such as polymerase chain reaction amplification of fusion transcripts and clonal rearrangements of antigen receptor genes, flow cytometric study of leukemic immunophenotypes and, the most recent, high throughput sequencing (HTS). In this review, the authors focused on the latest developments on MRD monitoring with emphasis on the use of HTS, as well as on the clinical impact of MRD monitoring.
COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between February 25, 2020 and February 1, 2021. Median age was 70 years (range 38-94) with male preponderance (60.1%). Approximately half of patients (n=127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n=176). Overall, after a median follow-up of 42 days (IQR 24-96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (February 25, 2020 - June 22, 2020) and second wave (June 23, 2020 - February 1, 2021), respectively (p=0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03-3.24, p=0.04), age over than 70 years (HR 2.23, 95% CI 1.23-4.05, p=0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04-2.84, p=0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62-12.33, p<0.0001; critical: HR 15.99, 95% CI 6.93-36.90, p<0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters. This article is protected by copyright. All rights reserved.
... 9 Mosna et al. now confirm in a larger, international cohort that CBF-AML in older patients, including patients ≥70 years, is chemo-sensitive and almost as likely to respond to an anthracycline and cytarabine induction as CBF-AML in younger patients, specifically when an anthracycline is delivered. 1 Although older patients with CBF-AML achieve CR with similar frequency to younger patients, Mosna et al. confirm that overall survival (OS) is inferior. 1 The French AML Intergroup study of older CBF-AML patients reported a 5-year OS of 31%. 9 In comparison, the German AML Intergroup reported a 5-year OS of 65%-74% among younger patients aged 16-60 with CBF-AML. 10 With a median follow-up of 53.5 months, Mosna et al. reported a 5-year OS of 44%; patients ≥70 years had inferior 5-year OS (33%) compared to patients <70 years (48%, p=0.006). ...
... It should be underlined that blinatumomab in association with a TKI (dasatinib and ponatinib) has been associated with increased rates of CMR 1,2,13,14 . This will eventually lead to a greater number of patients who could attempt TKI discontinuation. ...
... Approximately 30% of AML patients harbor Flt3 mutations. There is an urgent need to develop kinase inhibitors to combat these mutations [49]. Several Flt3 small molecular inhibitors have been approved for the treatment of AML, such as midostaurin, quizartinib, and gilteritinib. ...
... Detailed survival and feasibility data specific to this subgroup as well as a specification of T-cell depletion were not provided [29]. A recent EBMT analysis underpins these results for patients with AML in remission and further demonstrates a similar efficacy to the TBF regimen [30]. ...
... В настоящий момент как в научной, так и клинической практике диагностику пациентов с Ph-негативными МПН методом NGS проводят с использованием различных индивидуальных и коммерческих панелей генов [9][10][11][12]. В нашем исследовании впервые мутационный статус пациентов с Ph-негативными МПН изучен с помощью персонализированной панели из 118 генов. ...
... The dataset includes 3,256 images of peripheral blood smears (PBS) collected from 89 individuals who were suspected to have ALL. Within the group classified as malignant, three lymphoblast subgroups are recognized: Early Pre-B, Pre-B, and Pro-B [11]. Shown in Figure 1. ...
... Several new-generation MDM2 inhibitors have been developed, including RG7388 [32], HDM201 [33], AMG232 [34], DS-3032 [35], ASTX295 [36], and MI-77301 [37], which have been shown to reduce cancer cell viability and proliferation in preclinical models, including leukemia and lymphoma cells [38][39][40][41][42][43][44]. Most of these compounds are also currently being evaluated in clinical trials, both as monotherapies [45,46] and in combination therapies [47][48][49][50]. These non-genotoxic compounds bind specifically to the p53-binding pocket of MDM2 [51], stabilizing p53 and activating the p53 pathway. ...
... possibly justifying the peculiar survival disadvantage compared to other hematological neoplasms. Notably, in large multicentric studies, patients with advanced age and CLL-directed treatment were at increased risk of death following COVID-19.11,12 Study findings are limited by the unavailability of data from 2021 to 2022. ...
... Despite the improved genetic understanding of AML, excluding the M3 subtype, some of these studies have overlooked the effect of patient age. Younger patients with non-M3 AML represent a distinct group with specific needs and minimal survival improvement (33). Therefore, our present research primarily focused on discussing non-M3 AML in younger patients. ...
... Idelalisib, a selective inhibitor of the delta isoform, was the first PI3Ki developed for the treatment of FL. In the European phase II DELTA study, idelalisib demonstrated the highest efficacy to date in r/r/ FL patients, with a median treatment duration of 10 mo (range 1-43) and an overall response rate of 73% [65]. ...