Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors.

INTRODUCTION: Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach. AREAS COVERED: Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms. EXPERT OPINION: Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.

Neutrophil to lymphocyte ratio in myelofibrosis patients treated with ruxolitinib may predict prognosis and rate of discontinuation.

BACKGROUND: Myelofibrosis (MF) is a clonal Philadelphia chromosome negative myeloproliferative neoplasm (Ph-MPN). MF is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (ruxo) is the-first-in-class Jak1/2 inhibitor approved for treatment of MF, proved to reduce spleen volume and decrease symptom burden. In various malignancies neutrophil-to-lymphocyte ratio (NLR) has been indicated as predictor of progression free survival (PFS) and overall survival (OS). NLR might reflect the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in several neoplasms, including the hematological ones. METHODS: We analyzed a cohort of 140 MF patients treated with ruxo to validate baseline NLR (as a continuous variable and as a cut-off 2) as predictor of OS and of ruxo treatment discontinuation. RESULTS: We found that both baseline NLR as a continuous variable [HR 0.8 (95% CI: 0.7-0.9) (p = .006)] and NLR (<2 vs. ≥2) [HR 3.4 (95% CI: 1.6-7.0) (p = .001)] were significantly associated with OS. Censoring for patients undergone allotransplant, baseline NLR <2 was predictive of an earlier ruxo any-other-cause discontinuation [HR 3.7 (95%CI 1.7-8.3) (p < .001)]. CONCLUSIONS: NLR before starting ruxo treatment may be used as a simple and early predictor of OS and earlier ruxo discontinuation in clinical practice.

Safety and Efficacy of TKIs in very Elderly Patients (≥75 Years) with Chronic Myeloid Leukemia.

BACKGROUND: While the outcomes of chronic phase chronic myeloid leukemia (CP-CML) patients aged over 65 years have been extensively evaluated in real-life experiences, limited data exist for the very elderly population (i.e., aged ≥ 75 years), especially for next-generation tyrosine kinase inhibitors (TKIs). In this retrospective study, we sought to evaluate the safety and efficacy of TKIs in this particular setting of patients. METHODS: We conducted a retrospective analysis of a multicenter cohort of 123 newly diagnosed CP-CML very elderly patients. RESULTS: The median age at diagnosis was 80 years (range: 75-96). In the first line, 86.1% of patients received imatinib, 7.1% dasatinib, 5.6% nilotinib, and 0.81% received bosutinib. A total of 31 patients (25.2%) switched to second-line therapy, nine patients to a third line, and one patient to a fourth line of therapy. Resistance to treatment was the primary reason for switching therapy in both the first (64.5%) and second lines (77.7%). At diagnosis, reduced doses were administered in 36.5% of patients, in 61.2% in the second line, and in all patients in subsequent lines of therapy. In the first-line setting, 71.9% of patients achieved an early molecular response (EMR, i.e., 3-month BCR::ABL1IS < 10%); at 6, 12, and 24 months, MR3 was reached by 35.7%, 55.7%, and 75.0% of patients, respectively, with 16.6%, 35.7%, and 51.7% achieving a deep molecular response (DMR) at the same time points. Treatment-free remission (TFR) was successfully attempted in 11 patients. During the follow-up period, adverse events (AEs) were observed in 78.8% of patients, including 22 cases of cardiovascular AEs. Toxicity grade ≥ 3 was more commonly observed in patients treated with standard doses of TKIs compared to reduced doses (p = 0.033). Overall, the median follow-up was 46.62 months (range: 1.8-206.2), and 43 patients died due to non-CML-related causes. Three patients died due to disease progression to advanced (n = 1) and blastic (n = 2) phases. The 5-year overall survival (OS) for the entire cohort was 71.9% (95% CI: 0.63-0.81), with no significant difference between the patients treated with standard doses of TKIs compared to those treated with reduced doses (p = 0.35). CONCLUSIONS: TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile.

Severe SARS-CoV-2 and subsequent fungal infections after CAR T-cell therapy for relapsed/refractory multiple myeloma: a challenging and happy ending fight.

Chimeric antigen receptor (CAR) T-cells have unveiled a promising therapeutic horizon for relapsed/refractory multiple myeloma (R/R MM). Nevertheless, immune impairment induced by cellular therapies, previous treatments and MM itself could promote infectious events. COVID-19 could evolve into a life-threating infection in R/R MM patients who often have suboptimal responses to SARS-CoV-2 vaccines. Here, we describe a case of severe and long-lasting COVID-19 pneumonia after CAR T-cell therapy for R/R MM requiring a complex clinical management. Long-term infectious complications in MM patients undergoing CAR T-cells should be taken into consideration as they could counteract the efficacy of this new treatment.

Validation of imatinib therapy failure score (IMTF) in chronic phase chronic myeloid leukemia in real life practice.

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival. Aim of our study was to validate this index in a large cohort of patients treated with imatinib.

CCND2 mutations in atypical chronic myeloid leukemia: a report of two cases.

Atypical chronic myeloid leukemia (aCML) is a rare MDS/MPN disease characterized by the absence of BCR::ABL1 rearrangement and well known typical mutations associated with myeloproliferative disorders. Mutational landscape associated with this disease was recently described with frequent involvement of SETBP1 and ETNK1 mutations. CCND2 mutations have not been frequently detected in MPN or MDS/MPN patients. We describe two cases of aCML with two CCND2 mutations in 280 and 281 codons which rapidly develop progressive characteristics, and we reviewed the literature about this unfavorable association, suggesting a role as a new possible marker of aggressive disease.

Case Report: Avelumab and ruxolitinib to manage polycythemia vera and secondary metastatic Merkel cell carcinoma: a possible successful combination.

We describe a case of second primary malignancy in a 65-year-old patient affected by polycythemia vera treated with the JAK 1/2 inhibitor ruxolitinib. The latter is recognized as a risk factor for the onset of non-melanoma skin cancers in many retrospective and perspective studies, but the concomitant use of ruxolitinib with new immunotherapies is very rarely reported, and the safety of this association is still not clear. In our case, ruxolitinib combined with the anti-PD-L1 avelumab demonstrated both safety and efficacy for hematological disease control and underlying carcinoma remission.

Systemic mastocytosis: 2023 update on diagnosis and management in adults.

INTRODUCTION: Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies. AREAS COVERED: The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib. EXPERT OPINION: Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.

Case Report: Infectious prophylaxis in hematological malignancies.

Patients with hematological malignancies and past serological evidence of hepatitis B are at risk for HBV reactivation. In myeloproliferative neoplasms, continuous treatment with the JAK 1/2 inhibitor ruxolitinib confers a moderate risk of reactivation (1-10%); nevertheless, no prospective randomized data are available to strongly recommend HBV prophylaxis in these patients. Here, we report a case of primary myelofibrosis and past serological evidence of HBV infection, treated with ruxolitinib and concomitant lamivudine, developing HBV reactivation due to premature withdrawal of prophylaxis. This case underlines the potential need for persistent HBV prophylaxis in the setting of ruxolitinib treatment.

Utility of procalcitonin and C-reactive protein as predictors of Gram-negative bacteremia in febrile hematological outpatients.

This study was designed to determine the utility of procalcitonin (PCT) and C-reactive protein (CRP) as predictors of Gram-negative bloodstream infection (GN-BSI) in hematological febrile outpatients at the time of the emergency unit admission. Overall, 286 febrile episodes, which included 42 GN-BSI (16%), were considered. PCT levels at patient admission were statistically higher in GNB-BSI when compared to Gram-positive bacteria BSI (median 4.06 ng/ml (range 1.10-25.04) vs 0.88 ng/ml (0.42-10), p<0.03) and to all other fever etiologies. For CRP, differences within fever etiologies were less profound but statistically significant, except for GN-BSIs vs GP BSIs (p=0.4). ROC analysis of PCT showed that an AUC of 0.85 (95%CI 0.79-0.95) discriminated GN-BSI from all other fever etiologies, with a best cut-off of 0.5 ng/ml, a negative predictive value (NPV) of 98%, and a negative likelihood ratio (negLR) of 0.1. ROC analysis of CRP showed an AUC of 0.67 (95%CI 0.53-0.81) with a best cut-off of 6.64 mg/dl, a NPV of 94%, and a negLR of 0.33. This study confirms that 0.5 ng/ml represents the PCT best cut-off to differentiate the cause of fever and rule out a GN-BSI in febrile hematologic outpatients at the time of the emergency unit admission. Therefore, introducing PCT testing could be a valid measure in order to tailor a more precise prompt antimicrobial therapy to the febrile outpatient while waiting for blood culture results.

Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients' vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections-PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments-identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.