Elisabetta Abruzzese

Background: Maternal and fetal outcomes in patients with chronic myeloproliferative neoplasms (MPN) can be suboptimal unless a preventive strategy is finely tuned, however, direct evidence is scarce.GoalsEuropean LeukemiaNet addressed this unmet need by starting an evidence-based multidisciplinary project devoted to systematic evidence review and robust recommendations. Methods: An international panel of 18 hematologists, 1 gynecologist and 1 pharmacologist was convened from Europe, Canada and US. The panel prioritized and selected 7 core clinical questions which underwent proper analysis according to the GRADE method. A systematic review of direct and indirect evidence was completed for each question. Three meta-analyses assessed the effect of JAK2V617F mutation, aspirin (ASA), interferon-alpha (IFN) upon live birth (LB) rate. A patient representative was invited to review the full report and provide specific comments. Results: Almost 3,000 pregnancies in MPN patients were described in published studies. The meta-analysis of systematically reviewed studies showed that JAK2V617F mutation was associated with a significantly lower LB rate (OR 0.61; 95% CI 0.40-0.92), while ASA (OR 1.60; 95% CI 1.30-1.96) and IFN (OR 4.05; 95% CI 1.35-12.11) significantly improved the LB rate. Based on moderate quality direct evidence, the panel agreed on 2 strong evidence-based recommendations. Based on sparse direct evidence and mostly indirect evidence, the panel also agreed on 9 good practice recommendations and 15 remarks. Conclusions: Based on the protective effect of ASA and IFN regarding LB rate, low-dose ASA is recommended to all MPN pregnant women and IFN can be started in women planning pregnancy or currently pregnant, where the pregnancy is considered high-risk according to disease or patient related risk factors. The risk of pregnancy complications should be carefully assessed and monitored in MPN fertile women willing to become pregnant.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM); however, a substantial proportion of patients eventually experience disease relapse despite an initial response. This review provides a brief overview of CAR-T cell therapy, including its manufacturing process and associated toxicities, before examining the biological mechanisms underlying post-CAR-T relapse in B-ALL, NHL—particularly large B-cell lymphoma (LBCL)—and MM. We critically review current and emerging strategies to prevent and manage relapse. Strategies for relapse prevention primarily include consolidation approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), maintenance with targeted agents (e.g., tyrosine kinase inhibitors in Philadelphia chromosome-positive B-ALL), and CAR-T cell reinfusion, whereas relapse management is disease-specific and increasingly incorporates novel therapeutic agents, including bispecific antibodies (BsAbs) and other targeted therapies. However, current evidence remains largely preliminary and is limited by the paucity of randomized prospective trials.

Background: Optimizing tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) requires careful consideration of patient quality of life (QoL), which significantly influences treatment adherence and long-term outcomes. Long-term treatment can be associated with persistent symptoms that may negatively impact QoL, adherence, and patient satisfaction. This nationwide Italian survey explored patient experiences, treatment patterns, and factors influencing clinical decision-making in CML, with the aim of better understanding unmet needs and potential barriers to optimal care. Methods: We conducted a cross-sectional survey involving 146 adult patients with CML. A structured questionnaire, developed collaboratively by hematologists and patient association representatives, assessed patient-reported outcomes (PROs), treatment-related burden, and care satisfaction. Analyses were descriptive and exploratory. Results: Despite the availability of effective therapies, a substantial proportion of patients reported impaired QoL due to both disease and treatment-related factors. While most patients reported overall satisfactory QoL, 26% described low or very low QoL. The burden was particularly evident in specific patient subgroups and in later lines of therapy, reflecting a significant physical and psychological impact of CML and its management. Fatigue, weakness, and muscle pain were the most frequently reported symptoms, often persistent and affecting daily functioning. Female patients reported a higher symptom burden and greater psychological distress compared to males. Despite high overall satisfaction with healthcare professionals, relevant unmet needs were identified, particularly regarding information on supportive services, long-term disease management, and fertility-related issues. Treatment-related adverse events were common and frequently chronic, suggesting a substantial cumulative burden over time. Conclusions: Despite the effectiveness of TKIs, patients with CML continue to experience a meaningful and multidimensional burden, particularly in later treatment lines and specific subgroups. These findings highlight the importance of greater attention to patient-centered management in CML, with treatment decisions carefully balancing the benefits and limitations of available therapeutic options to optimize both clinical outcomes and quality of life.

Background: Since the advent of imatinib, more potent next-generation tyrosine kinase inhibitors (TKIs) and asciminib have expanded therapeutic options for chronic myeloid leukemia (CML). Treatment-free remission (TFR) is an important goal in CML management, but only ~30% of patients can achieve it, leaving many on lifelong therapy. TKIs are usually used in escalating order of potency, but in patients ineligible for or failing TFR, “downgrading” to safer, lower-potency agents may be advantageous. Methods: We analyzed this strategy in 157 patients across 29 Italian CML Campus centres. Data were collected via e-forms in July 2024. Prognostic scores at diagnosis did not influence downgrading. Results: The most downgraded TKIs were nilotinib (47%) and dasatinib (37%). Imatinib was the most frequent target agent (69.7%), followed by nilotinib and bosutinib. The majority underwent downgrading during first-line therapy and most after prior dose de-escalation. Adverse events were the leading reason for downgrading (79%). Notably, in 52.6% of cases, molecular responses improved afterwards. Twenty-one patients subsequently attempted TFR, with 17 (81%) remaining treatment-free at a median follow-up of 22 months. Conclusions: These results show that, beyond the known role of de-escalation, downgrading represents a new, feasible approach to maintaining long-term control, limiting toxicity and costs, and favouring TFR.

Background: Momelotinib, a JAK1 / JAK2 / ACVR1 inhibitor, is approved for treating myelofibrosis with splenomegaly, symptoms, and moderate‐to‐severe anemia. Evidence on its real‐world effectiveness after ruxolitinib failure is limited. Methods: This study retrospectively analyzed 221 patients who received momelotinib after ruxolitinib failure by assessing spleen, symptom, and anemia responses, safety, and survival. Logistic regression analyses identified the responses’ predictors. Results: Before momelotinib initiation, all patients had received ruxolitinib for a median of 31.5 months and discontinued as a result of resistance (29.9%), intolerance (48.0%), or both (22.1%). At baseline, all patients started at full dose; 97.3% presented with cytopenia, 34.8% presented with large splenomegaly, and 43.9% were highly symptomatic. Most patients (74.7%) switched from ruxolitinib stop to momelotinib within 2 months without tapering, whereas 18.1% waited over a year. After a median exposure of 8.2 months, adverse events occurred in 35.7% of patients, which prompted dose reductions or permanent discontinuation in 12.7% and 19.9% of cases, respectively. At 6 months, 30.0% achieved ≥50% spleen length reduction (SR50), with higher responses in those with prior SR50 to ruxolitinib and shorter transition intervals. Symptom and anemia responses occurred in 39.2% and 63.4% of cases, respectively. After a median follow‐up of 10.3 months, 11 patients (5.0%) progressed to blast phase, and 37 patients (16.7%) died. Two‐year overall and progression‐free survival (including death and blast phase transformation) were 60.9% and 59.0%, respectively. Conclusions: Momelotinib demonstrated meaningful clinical benefit and acceptable safety in cytopenic patients pretreated with ruxolitinib, which supports its role after ruxolitinib failure.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, extramedullary hematopoiesis (particularly symptomatic splenomegaly), constitutional symptoms, progressive cytopenias, and, in a subset of patients, leukemic transformation. The advent of the JAK1/2 inhibitor ruxolitinib has revolutionized the management of MF, substantially improving splenomegaly, symptom burden, and, in some settings, overall survival. However, a substantial percentage of patients fail to achieve sustained benefit, are intolerant, or become refractory; real-world and clinical trial data indicate that approximately half of treated patients discontinue ruxolitinib treatment within 3 years and up to approximately 75% within 5 years, with poor outcomes after discontinuation (median survival in several series is approximately 12–14 months). In recent years, several new small molecules that act beyond the JAK-STAT axis have emerged in clinical development. These include agents targeting telomerase (imetelstat), epigenetic regulation via BET inhibition (pelabresib/CPI-0610), the MDM2-p53 axis (navtemadlin/KRT-232), erythroid maturation and the bone marrow microenvironment (luspatercept), PI3K signaling (parsaclisib), and PIM inhibitors (nuvisertib). Early clinical data show promising results for symptom and splenic control in specific settings and, importantly, suggest potential disease-modifying activity (improvements in marrow fibrosis and molecular responses) for some compounds. This review summarizes the biological rationale, key clinical data (efficacy and safety), ongoing randomized trials, and remaining knowledge gaps for these non-JAK small molecules in MF and offers practical considerations for integrating them into contemporary treatment algorithms.

Ruxolitinib (RUX), a JAK1/2 inhibitor, demonstrated treatment benefits for myelofibrosis (MF) in intermediate‐1 (Int‐1)–risk patients with a significant disease burden; however, the evidence is scarce. This interim analysis investigated the efficacy and safety of ruxolitinib in patients with Int‐1‐risk MF. ROMEI, a multicenter, observational, prospective study, enrolled 508 adult patients with MF receiving ruxolitinib according to approved indications. The present interim analysis was focused on 107 eligible patients in the Int‐1‐risk group. Primary endpoints included changes in symptoms response and health‐related quality of life scores. Secondary endpoints included spleen response evaluation, overall survival, and safety including dosing pattern and dose interruptions. Among the 107 Int‐1‐risk patients with a median age of 63 years, 65.5% were highly symptomatic (total symptoms score: ≥ 20), while the spleen was palpable at ≥ 5 cm and ≥ 10 cm in 74% and 27% of patients, respectively, with baseline EuroQol visual analogue scale (EQ‐VAS) score of 65.1 ± 19.4. After RUX treatment, 42.1% and 43.9% of patients demonstrated a symptom response at 24 and 48 weeks, while 38.9% and 46.8% showed a spleen response at 24 and 48 weeks, respectively. EQ‐VAS increased to 71.8 ± 16.3 at 24 weeks and 69.3 ± 19.2 at 48 weeks. Furthermore, 11.2% and 25.2% of patients reported temporary and permanent discontinuation, respectively with no new adverse events reported. The interim analysis showed that ruxolitinib provided clinical benefits, a manageable safety profile, and improved quality of life for Int‐1‐risk subgroup patients with frequent and sustained responses with acceptable toxicity.

The Janus kinase (JAK) inhibitor ruxolitinib is a standard first-line therapy for patients with symptomatic and/or intermediate- to high-risk myelofibrosis (MF). However, the majority of patients discontinue ruxolitinib within 5 years of initiation, mainly due to lack or loss of response and/or therapy-related cytopenias. Additional treatments are needed to improve long-term outcomes, including overall survival (OS). Momelotinib, a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated benefits in reducing anemia and improving symptoms and spleen size in 3 phase 3 trials of patients with intermediate- to high-risk MF (SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM). These studies also provide data on patients who received momelotinib after discontinuing ruxolitinib. In the absence of long-term head-to-head comparisons of momelotinib and other treatments after discontinuation of ruxolitinib, the present study compared OS in patients with ruxolitinib-experienced MF from the momelotinib phase 3 trials vs. those treated with best available therapy (BAT) after ruxolitinib from the RUX-MF retrospective real-world study. The comparison was performed using an unanchored matching-adjusted indirect comparison (MAIC). Additionally, an MAIC of OS was conducted in an anemic subgroup (hemoglobin < 10 g/dL). After adjustment for cross-trial differences, the MAIC results showed a favorable trend for momelotinib vs. BAT, both in the overall population and in the anemic subgroup, with hazard ratios < 1 across all analytical scenarios and all population-matching models with an effective sample size of ≥ 20. This study is a key addition to current evidence surrounding OS post ruxolitinib and highlights the benefit of momelotinib in this setting.