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Chronic myeloid leukemia (CML) is caused by BCRABL1 in a cell with the biological potential, intrinsic or acquired, to cause leukemia. This cell is commonly termed the CML leukemia stem cell (LSC). In humans a CML LSC is operationally-defined by ≥1 in vitro or in vivo assays of human leukemia cells transferred to immune-deficient mice. Results of these assays are sometimes discordant. There is also the unproved assumption that biological features of a CML LSC are stable. These considerations make accurate and precise identification of a CML LSC difficult or impossible. In this review, we consider biological features of CML LSCs defined by these assays. We also consider whether CML LSCs are susceptible to targeting by tyrosine kinase inhibitors (TKIs) and other drugs, and whether elimination of CML LSCs is needed to achieve therapy-free remission or cure CML.

The FLT3-ITD mutation is a critical prognostic marker in acute myeloid leukemia (AML) and recent clinical trials demonstrate that FLT3-based measurable residual disease (MRD) is both prognostic and predictive, guiding therapeutic interventions in intensive and post-transplant settings. Conventional detection methods lack the sensitivity required for effective MRD monitoring. We developed a patient-specific droplet digital PCR (ddPCR) approach achieving analytical sensitivity of 10−5 (0.001%) for FLT3-ITD quantification. In our cohort, ddPCR enabled longitudinal monitoring of clonal dynamics, allowing the detection of re-emerging FLT3-ITD clones months before hematologic relapse and earlier than standard capillary electrophoresis. Notably, 25% of patients who relapsed as FLT3-ITD positive despite being classified as FLT3-negative at diagnosis harbored detectable microclones when retrospectively analyzed by ddPCR, suggesting that FLT3-ITD-positive relapse frequently originates from pre-existing subclones below conventional detection thresholds. These findings challenge current diagnostic classification and may influence risk stratification and treatment decisions, particularly regarding FLT3 inhibitor eligibility. While ddPCR is limited to tracking known dominant clones, it represents a practical, cost-effective solution for high-sensitivity MRD surveillance. In the era of targeted FLT3 therapies, integrating sensitive molecular monitoring into routine AML management may enable timely therapeutic adjustments and improve patient outcomes.

Ravulizumab is a second-generation C5i engineered from eculizumab to achieve immediate, complete, and sustained inhibition of terminal complement activity in PNH. The REACTION observational cohort study describes the effectiveness and tolerability of ravulizumab in Italian patients who were previously treated with eculizumab. Eighty-one PNH patients were enrolled in this study. The primary endpoint was the percentage change in lactate dehydrogenase (LDH) from baseline to the end of observation (52 weeks follow-up). Among secondary endpoints, transfusion avoidance, breakthrough hemolysis (BTH) and patients’ quality of life (QoL) were evaluated. The median (25–75 percentiles) percentage change in LDH at 52 weeks follow-up was -2.6 (-11.5–13.4) U/L, with 92.3% of the patients presenting LDH within or < 1.5 × upper limit of normal (ULN). Overall, 20 (25.0%) patients required transfusion during the eculizumab period and 15 (18.8%) during the ravulizumab. Seven BTH events were observed, 5 during eculizumab period and 2 (triggered by other medical conditions) during ravulizumab, suggesting the reduction of pharmacokinetic BTH during ravulizumab treatment. EORTC-QLQ-C30 and FACIT-Fatigue scores were similar to the general population, and patients’ preference indicated ravulizumab as the favorite treatment. The REACTION study confirmed the effectiveness of ravulizumab in maintaining stable disease and hemolysis control in the real-world setting. Clinical trial registration. NCT05274633, 02-Mar-2022.

Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the de novo pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting in human activity.

The adoption of pediatric-inspired regimens for the treatment of Ph-negative acute lymphoblastic leukemia (ALL) in adults has improved prognosis. However, the feasibility of these intensive regimens in older patients is limited, due to the increased incidence of therapy-related side effects, including those related to asparaginase. In this sub-analysis carried out by the Campus ALL network, 90 ALL patients aged 55 or more (median age 59 years) homogeneously treated in real-life according to the GIMEMA LAL1913 program, were analyzed to evaluate the feasibility and tolerability of pegaspargase (PEG-ASP) treatment. Among the 90 patients analyzed, 86 (96%) received PEG-ASP at least in one of the first two courses (C1-C2) of chemotherapy and were evaluated for toxicity and outcome. In detail, 51 patients received PEG-ASP in both courses and 35 in either C1 or C2. The most common adverse event was hepatic toxicity (HT), with 38% of patients experiencing any grade of HT at C1 (HT grade ≥ 3, 19%) and 23% at C2 (HT grade ≥ 3, 9%). Additionally, HT at C1 was the primary reason for withholding PEG-ASP at C2. Coagulopathy was the second most frequent toxicity (any grade of toxicity in 26% of patients at C1 and in 20% at C2). No deaths directly related to PEG-ASP therapy were reported. The CR rate after C1 and C3 was 94% and 93%, respectively. MRD negativity rate was 40% and 68%, respectively. The OS and DFS probability at 3 years was 54% and 47%, respectively. PEG-ASP administration in older ALL patients is feasible, but HT is a concern, being the major cause of PEG-ASP interruption. Therefore, a dose adjustment, according to age and concomitant comorbidities, is advisable to balance PEG-ASP efficacy with its toxicity.

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy.

Background: Richter syndrome (RS) represents a major unmet need in the lymphoma field, being refractory to chemoimmunotherapy and targeted agents. The BCL-2 inhibitor venetoclax in combination with dose-adjusted EPOCH-R chemoimmunotherapy showed promising efficacy in patients affected by RS. However, responses were not durable, suggesting the need for further treatment optimization. Methods: Here, we report two cases of RS achieving long-term complete remission with intensified chemoimmunotherapy (Rituximab-G-MALL B-ALL/NHL2002 regimen) plus venetoclax induction, followed by haploidentical hematopoietic stem cell transplant (allo-HSCT). Venetoclax was given continuously for 14 consecutive days after every Rituximab-G-MALL cycle in off-label use. An accelerated venetoclax rump-up schedule was used in both patients to reach the maximal dose. Maximal venetoclax dose was 300 mg and 400 mg in patient 1 and patient 2, respectively. Results: The combined treatment was well tolerated, with no major infective complications or non-hematological toxicities. In both patients, immunosuppression was discontinued within day 180 after transplant with no graft-versus-host-disease flares. Both patients are alive and in continuous complete remission after 60 and 72 months following allo-HSCT. Conclusions: This report supports the feasibility of a combination treatment with BCL-2 inhibitors and intensive chemoimmunotherapy as a bridge to allo-HSCT in RS.

Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011–12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46–68%) and 53% (95% CI, 45–61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.

The immunophenotype is a key element to classify B-cell Non-Hodgkin Lymphomas (B-NHL); while it is routinely obtained through immunohistochemistry, the use of flow cytometry (FC) could bear several advantages. However, few FC laboratories can rely on a long-standing practical experience, and the literature in support is still limited; as a result, the use of FC is generally restricted to the analysis of lymphomas with bone marrow or peripheral blood involvement. In this work, we applied machine learning to our database of 1465 B-NHL samples from different sources, building four artificial predictive systems which could classify B-NHL in up to nine of the most common clinico-pathological entities. Our best model shows an overall accuracy of 92.68%, a mean sensitivity of 88.54% and a mean specificity of 98.77%. Beyond the clinical applicability, our models demonstrate (i) the strong discriminatory power of MIB1 and Bcl2, whose integration in the predictive model significantly increased the performance of the algorithm; (ii) the potential usefulness of some non-canonical markers in categorizing B-NHL; and (iii) that FC markers should not be described as strictly positive or negative according to fixed thresholds, but they rather correlate with different B-NHL depending on their level of expression.