Italian Physicians' Perceptions about the Role of Asciminib in Later Lines Chronic Myeloid Leukemia in Clinical Practice: A GIMEMA Survey

Unmet needs remain in later lines chronic myeloid leukemia (CML): the response rate and the overall survival of resistant patients in the chronic phase who changed a second-generation TKI in the second line with another TKI with similar action are usually poor, while the off-target toxicities and the potential development of mutations increase. The recent approval of asciminib, a STAMP inhibitor, in the third line, has the potential to soon change the therapeutic algorithm for this subset of patients. Here, we report the results of a GIMEMA survey assessing the number of patients currently treated in the third line in Italy, the current approach in later lines by Italian physicians, and the future role of this drug according to the reason to switch to asciminib (resistance and/or intolerance), as well as the perceptions about the future position of this agent

Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial

Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov 64NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP1 cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P<.0001). PBC<1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC .1.5 (PBChigh, n = 96) and 43.6% of patients with PBC 641.5 (PBClow, n = 55) achieved CR after single-course induction (P<.0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P 5 .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy

Capture-Based Next-Generation Sequencing Improves the Identification of Immunoglobulin/T-Cell Receptor Clonal Markers and Gene Mutations in Adult Acute Lymphoblastic Leukemia Patients Lacking Molecular Probes

The monitoring of minimal residual disease (MRD) in Philadelphia-negative acute lymphoblastic leukemia (ALL) requires the identification at diagnosis of immunoglobulin/T-cell receptor (Ig/TCR) rearrangements as clonality markers. Aiming to simplify and possibly improve the patients’ initial screening, we designed a capture-based next-generation sequencing (NGS) panel combining the Ig/TCR rearrangement detection with the profiling of relevant leukemia-related genes. The validation of the assay on well-characterized samples allowed us to identify all the known Ig/TCR rearrangements as well as additional clonalities, including rare rearrangements characterized by uncommon combinations of variable, diversity, and joining (V-D-J) gene segments, oligoclonal rearrangements, and low represented clones. Upon validation, the capture NGS approach allowed us to identify Ig/TCR clonal markers in 87% of a retrospective cohort (MRD-unknown within the Northern Italy Leukemia Group (NILG)-ALL 09/00 clinical trial) and in 83% of newly-diagnosed ALL cases in which conventional method failed, thus proving its prospective applicability. Finally, we identified gene variants in 94.7% of patients analyzed for mutational status with the same implemented capture assay. The prospective application of this technology could simplify clonality assessment and improve standard assay development for leukemia monitoring, as well as provide information about the mutational status of selected leukemia-related genes, potentially representing new prognostic elements, MRD markers, and targets for specific therapies

Molecular Detection of Minimal Residual Disease before Allogeneic Stem Cell Transplantation Predicts a High Incidence of Early Relapse in Adult Patients with NPM1 Positive Acute Myeloid Leukemia

We analyzed the impact of alloHSCT in a single center cohort of 89 newly diagnosed NPM1mut AML patients, consecutively treated according to the Northern Italy Leukemia Group protocol 02/06 [NCT00495287]. After two consolidation cycles, the detection of measurable residual disease (MRD) by RQ-PCR was strongly associated with an inferior three-year overall survival (OS, 45% versus 84%, p = 0.001) and disease-free survival (DFS, 44% versus 76%, p = 0.006). In MRD-negative patients, post-remissional consolidation with alloHSCT did not provide a significant additional benefit over a conventional chemotherapy in terms of overall survival [OS, 89% (95% CI 71–100%) versus 81% (95% CI 64–100%), p = 0.59] and disease-free survival [DFS, 80% (95% CI 59–100%) versus 75% (95% CI 56–99%), p = 0.87]. On the contrary, in patients with persistent MRD positivity, the three-year OS and DFS were improved in patients receiving an alloHSCT compared to those allocated to conventional chemotherapy (OS, 52% versus 31%, p = 0.45 and DFS, 50% versus 17%, p = 0.31, respectively). However, in this group of patients, the benefit of alloHSCT was still hampered by a high incidence of leukemia relapse during the first year after transplantation (43%, 95% CI 25–60%). Consolidative alloHSCT improves outcomes compared to standard chemotherapy in patients with persistent NPM1mut MRD positivity, but in these high-risk patients, the significant incidence of leukemia relapse must be tackled by post-transplant preemptive treatments

MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therap