Different prognosis according to treatment in patients with acute promyelocytic leukemia: How the outcome changed over time.

A comprehensive analysis of 220 patients diagnosed with APL between 1993 and 2022 is here reported. Overall, 214 patients (97.2%) received induction therapy. Complete response (CR) was achieved in 97.4%, 100%, 100%, and 27% of patients treated with AIDA protocol, AIDA + Ara-C, ATRA + ATO, and ATRA monotherapy, respectively. Molecular complete response (CRMRD-) was achieved in 96.8% cases, and 142 patients proceeded to maintenance therapy. Overall, the 3-year and 5-year overall survival (OS) rates were 80.8% (95% CI, 78.1-83.5) and 79.1% (95% CI, 76.4-81.8), respectively. Considering only patients who completed induction and maintenance therapy, the 5-year OS rates were 82.1% (95% CI, 77.5-86.7) for the AIDA0493 cohort, 87.5% (95% CI, 84.4-91.1) for the AIDA2000 cohort, and 100% for the APL0406 cohort (p = 0.044). Additionally, the disease-free survival (DFS) rates were 65.7% (95% CI, 60.4-70.9), 70% (95% CI, 65.8-75.2), and 95.1% (95% CI, 91.7-98.5) (p = 0.016), respectively. Among low and intermediate-risk patients, age > 70 years (p = 0.027) and relapse (p < 0.001) were significantly associated with reduced outcomes. This study contributes to the advancement of our understanding of APL treatment, underscoring the ongoing need for research to enhance outcomes and explore new therapeutic approaches and prognostic factors.

Response Rates and Transplantation Impact in Patients with Relapsed Acute Promyelocytic Leukemia.

BACKGROUND: The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has radically improved the prognosis of acute promyelocytic leukemia (APL), with cure rates above 80%. While relapse occurs in less than 20% of cases, addressing this issue remains challenging. Identifying effective salvage therapies for relapsed APL is crucial to improve patient outcomes. METHODS: A retrospective analysis was performed on a multicentric cohort of 67 APL patients in first relapse, treated in three Italian hematology centers from June 1981 to November 2021. The overall survival (OS) and cumulative incidence of relapse (CIR) were calculated, and predictive factors were assessed using Cox regression models. RESULTS: Overall, 61 patients (91%) received ATO ± ATRA (40.3%), chemo-based regimens (40.3%), or ATRA ± Gemtuzumab ozogamicin (GO) (10.4%). Complete remission (CR) was achieved in 98.2% of patients (molecular CR, n = 71.4%). With a median follow-up time of 54.5 months, the 5-year OS was 73% in the ATO ± ATRA group, 44% in the chemo-based group, and 29% in the ATRA ± GO group (p = 0.035). The 5-year OS rate was also higher for transplant recipients vs. non-recipients within the chemo-based cohort (50% vs. 33%, p = 0.017), but not in the ATO-based cohort (p = 0.12). ATO-based salvage therapy resulted in better OS in both univariate (p = 0.025) and multivariate analyses (p = 0.026). The 2-year CIR was higher in patients without molecular CR vs. patients in molecular CR (66% vs. 24%, p = 0.034). Molecular CR was a significant predictor of second relapse in both univariate (p = 0.035) and multivariate analyses (p = 0.036). CONCLUSIONS: Our findings support the efficacy of ATO-based therapies in first relapse of APL and confirm the achievement of molecular remission as an independent outcome predictor in both first and second APL relapse.

Autologous Cryopreserved Adipose Tissue Using an Innovative Technique: An In Vitro Biological Characterization.

BACKGROUND: The use of autologous adipose tissue transplantation in plastic and orthopedic surgery such as breast, reconstructions and intra-articular injection, has become an attractive surgical treatment with satisfactory clinical outcomes. Nevertheless, repeated liposuctions necessary to harvest fatty tissue normally performed with sedation or general anesthesia, may represent a noteworthy concern. OBJECTIVES: To demonstrate through an in vivo characterization, the validity of the surgical option to use cryopreserved autologous adipose tissue harvested in a single shot for repeated graft transfer, in breast reconstruction, without impairment of cell viability and sterility. METHODS: Adipose tissue is collected as a standard liposuction from patients who need numerous fat grafting procedures for breast reconstruction. According to an innovative and patented cryopreservation method, autologous adipose tissue is subsequently fractioned in a sterile bag system and frozen at RER Tissue Bank of the Emilia Romagna Region. Each graft is evaluated for sterility and cell viability immediately after harvesting and 1, 3, 6, 12 and preliminarily 18 months after cryopreservation and thawing. RESULTS: In vitro results showed that after processing, middle, and long-term cryopreservation and subsequent thawing, autologous cryopreserved adipose tissue, retains absence of bacterial contamination, high cellular viability and unmodified histomorphological properties, thereby ensuring the maintenance of the stromal vascular niche and the filling properties in multi-step different surgical procedures. CONCLUSIONS: In vitro study and sterility assessment, showed that autologous cryopreserved adipose tissue grafting is a safe procedure able to avoid multiple liposuction surgery. No impairment of either sterility, cell viability, and morphology were observed over time.

CD146 Molecule Expression in B Cells Acute Lymphoblastic Leukemia (B-ALLs): A Flow-Cytometric Marker for an Accurate Diagnostic Workup.

Background: B-lineage acute lymphoblastic leukemias (B-ALL) harboring the t(9;22)(q34;q11)/BCR::ABL1 rearrangement represent a category with previously dismal prognosis whose management and outcome dramatically changed thanks to the use of tyrosine kinase inhibitors (TKIs) usage and more recently full chemo-free approaches. The prompt identification of these cases represents an important clinical need. Objectives: We sought to identify an optimized cytofluorimetric diagnostic panel to predict the presence of Philadelphia chromosome (Ph) in B-ALL cases by the introduction of CD146 in our multiparametric flow cytometry (MFC) panels. Methods: We prospectively evaluated a total of 245 cases of newly diagnosed B-ALLs with a CD146 positivity threshold >10% referred to the Division of Hematology of 'Sapienza' University of Rome. We compared the results of CD146 expression percentage and its mean fluorescence intensity (MFI) between Ph+ ALLs, Ph-like ALLs, and molecularly negative ALLs. Results: Seventy-nine of the 245 B-ALL cases (32%) did not present mutations at molecular testing, with 144/245 (59%) resulting in Ph+ ALL and 19/245 (8%) Ph-like ALLs. Comparing the 3 groups, we found that Ph+ B-ALLs were characterized by higher expression percentage of myeloid markers such as CD13, CD33, and CD66c and low expression of CD38; Ph+ B-ALL showed a higher CD146 expression percentage and MFI when compared with both molecular negative B-ALL and Ph-like ALLs; neither the mean percentage of CD146 expression neither CD146 MFI were statically different between molecular negative B-ALL and Ph-like ALLs. Conclusions: Our data demonstrate the association between CD146 expression and Ph+ ALLs. CD146, along with myeloid markers, may help to identify a distinctive immunophenotypic pattern, useful for rapid identification in the diagnostic routine of this subtype of B-ALLs that benefits from a specific therapeutic approach.

Protocol for the purification of replisomes from the Xenopus laevis egg extract system for single-particle cryo-EM analysis.

Here, we present a large-scale FLAG immunoprecipitation protocol to isolate large protein complexes driving DNA replication at replicating chromatin assembled in Xenopus laevis egg extract. We describe how to prepare demembranated sperm nuclei (DNA) and low-speed supernatant egg extract (LSS) and present detailed procedures for sample preparation and application onto grids for negative stain electron microscopy (NS-EM) and cryoelectron microscopy (cryo-EM). For complete details on the use and execution of this protocol, please refer to Cvetkovic et al.1.

A Green Lantern for the Surgeon: A Review on the Use of Indocyanine Green (ICG) in Minimally Invasive Surgery.

Indocyanine green (ICG) fluorescence imaging has revolutionized surgical practice across various medical and surgical specialties. This article reviews the clinical applications of ICG in abdominal, urological, thoracic, and gynecological surgery. ICG fluorescence imaging has been widely adopted in general surgery for various applications, including perfusion assessment, intraoperative visualization of the ureter, and tumor localization. It is particularly valuable in evaluating anastomotic leaks and aiding in precise tumor resection during minimally invasive surgeries. Studies have shown mixed results on its effectiveness in reducing anastomotic leak rates, highlighting the need for further research. In thoracic surgery, ICG facilitates the identification and resection of pulmonary bullae, as well as the precise localization of pulmonary nodules during video-assisted surgery. In urology, ICG aids in localizing renal tumors and guiding selective arterial occlusion during partial nephrectomy. Its role in identifying the lymphatic pathway in prostate cancer and sentinel lymph node biopsy in gynecological cancer is also discussed. Despite its benefits, the use of ICG fluorescence faces challenges such as limited tissue penetration, the potential for false results, a lack of standardized protocols, and high equipment costs. Nonetheless, it remains a powerful tool that could improve surgical outcomes.

The new neural pressure support (NPS) mode and the helmet: did we find the dynamic duo?

BACKGROUND: Noninvasive ventilation (NIV) is commonly used in clinical practice to reduce intubation times and enhance patient comfort. However, patient-ventilator interaction (PVI) during NIV, particularly with helmet interfaces, can be challenging due to factors such as dead space and compliance. Neurally adjusted ventilatory assist (NAVA) has shown promise in improving PVI during helmet NIV, but limitations remain. A new mode, neural pressure support (NPS), aims to address these limitations by providing synchronized and steep pressurization. This study aims to assess whether NPS per se improves PVI during helmet NIV compared to standard pressure support ventilation (PSV). METHODS: The study included adult patients requiring NIV with a helmet. Patients were randomized into two arms: one starting with NPS and the other with PSV; the initial ventilatory parameters were always set as established by the clinician on duty. Physiological parameters and arterial blood gas analysis were collected during ventilation trials. Expert adjustments to initial ventilator settings were recorded to investigate the impact of the expertise of the clinician as confounding variable. Primary aim was the synchrony time (Timesync), i.e., the time during which both the ventilator and the patient (based on the neural signal) are on the inspiratory phase. As secondary aim neural-ventilatory time index (NVTI) was also calculated as Timesync divided to the total neural inspiratory time, i.e., the ratio of the neural inspiratory time occupied by Timesync. RESULTS: Twenty-four patients were enrolled, with no study interruptions due to safety concerns. NPS demonstrated significantly longer Timesync (0.64 ± 0.03 s vs. 0.37 ± 0.03 s, p < 0.001) and shorter inspiratory delay (0.15 ± 0.01 s vs. 0.35 ± 0.01 s, p < 0.001) compared to PSV. NPS also showed better NVTI (78 ± 2% vs. 45 ± 2%, p < 0.001). Ventilator parameters were not significantly different between NPS and PSV, except for minor adjustments by the expert clinician. CONCLUSIONS: NPS improves PVI during helmet NIV, as evidenced by longer Timesync and better coupling compared to PSV. Expert adjustments to ventilator settings had minimal impact on PVI. These findings support the use of NPS in enhancing patient-ventilator synchronization and warrant further investigation into its clinical outcomes and applicability across different patient populations and interfaces. TRIAL REGISTRATION: This study was registered on www. CLINICALTRIALS: gov NCT06004206 Registry URL: https://clinicaltrials.gov/study/NCT06004206 on September 08, 2023.

Treatment free remission (TFR) after second-generation tyrosine kinase inhibitors (2G-TKIs) treatment in chronic myeloid leukemia (CML): from feasibility to safety.

INTRODUCTION: Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. AREAS COVERED: In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase, and archives from EHA and ASH congresses. EXPERT OPINION: Overall, TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication, and optimal strategies need to be better clarified to improve successful TFR rate.

Physical Exercise in Kidney Renal Recipients: Where Have We Come?

BACKGROUND: Kidney transplantation constitutes the most effective therapeutic option for patients suffering from end-stage renal disease but remains burdened by a high incidence of cardiovascular disease. To date, exercise is an important preventive strategy that has been underestimated; in kidney transplant patients, exercise programs lead to an improvement in cardiorespiratory performance, muscle strength, arterial stiffness, and patients' quality of life perception. SUMMARY: The nephrology and transplant community have moved from generic suggestions to specific indications regarding frequency, intensity, time, type, volume, and progression of physical exercise both in the pre- and posttransplant phase. The latest guidelines from the World Health Organization for patients with chronic conditions propose a combination of aerobic, muscle-strengthening, and multicomponent exercises (e.g., balance) to improve health. Based on recent evidence, a combined exercise program (aerobic and strength exercise) is largely proposed to kidney transplant recipients. Aerobic exercise should be performed at an intensity >60% of theoretical maximum heart rate or maximum oxygen uptake possibly every day, and strength training should be performed at a >60% the estimate single maximum repetition, at least 2 times per week. KEY MESSAGES: Physical exercise should be personalized in relation to the patient's baseline performance; increases must be progressive and gradual. Regular physical activity should also be recommended to patients awaiting for a transplant. Eventually, organizational models based on a network of nephrology units, transplant centers, sports medicine centers, and fitness center or outdoor gym are essential elements for overcoming the logistical barriers for prescribing and carrying out regular physical activity.

Unwinding of a eukaryotic origin of replication visualized by cryo-EM.

To prevent detrimental chromosome re-replication, DNA loading of a double hexamer of the minichromosome maintenance (MCM) replicative helicase is temporally separated from DNA unwinding. Upon S-phase transition in yeast, DNA unwinding is achieved in two steps: limited opening of the double helix and topological separation of the two DNA strands. First, Cdc45, GINS and Polε engage MCM to assemble a double CMGE with two partially separated hexamers that nucleate DNA melting. In the second step, triggered by Mcm10, two CMGEs separate completely, eject the lagging-strand template and cross paths. To understand Mcm10 during helicase activation, we used biochemical reconstitution with cryogenic electron microscopy. We found that Mcm10 splits the double CMGE by engaging the N-terminal homo-dimerization face of MCM. To eject the lagging strand, DNA unwinding is started from the N-terminal side of MCM while the hexamer channel becomes too narrow to harbor duplex DNA.

Long-term health-related quality of life and mental health in patients with immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially life-threatening disorder. Treatment advances have lowered morbidity rates, but past acute events can still cause long-term consequences, reducing health-related quality of life (HRQoL) and determining cognitive impairment, anxiety, and depression. We aimed to investigate these aspects and the role of caplacizumab and rituximab: 39 patients were evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the FACIT-Fatigue, the Hospital Anxiety and Depression Scale, and the Functional Assessment in Cancer Therapy-Cognitive Function questionnaires. The median age at study inclusion was 50 years (IQR 38-60), and the median follow-up from diagnosis was 97 months (IQR 14-182); 82% of patients were female, and 36% had one or more recurrences. Caplacizumab was administered in 16 patients (41%), as well as rituximab. ITTP patients reported lower physical and mental HRQoL scores than the general population. No differences in physical or mental domains were observed between patients treated or not with caplacizumab, while those who received rituximab reported lower scores in mental health. Neurological impairment at diagnosis correlated with worse fatigue. The majority of patients (72%) reported anxiety or depression (82%). ITTP had a significant impact on the long-term cognitive function, fatigue, depression, and anxiety levels of patients, with a negative effect on their HRQoL. Our findings underscore the need to pay special attention to patients' long-term physical and mental health, regardless of the medical treatments received.

Cascade reactions with two non-physiological partners for NAD(P)H regeneration via renewable hydrogen.

An attractive application of hydrogenases, combined with the availability of cheap and renewable hydrogen (i.e., from solar and wind powered electrolysis or from recycled wastes), is the production of high-value electron-rich intermediates such as reduced nicotinamide adenine dinucleotides. Here, the capability of a very robust and oxygen-resilient [FeFe]-hydrogenase (CbA5H) from Clostridium beijerinckii SM10, previously identified in our group, combined with a reductase (BMR) from Bacillus megaterium (now reclassified as Priestia megaterium) was tested. The system shows a good stability and it was demonstrated to reach up to 28 ± 2 nmol NADPH regenerated s-1 mg of hydrogenase-1 (i.e., 1.68 ± 0.12 U mg-1, TOF: 126 ± 9 min-1) and 0.46 ± 0.04 nmol NADH regenerated s-1 mg of hydrogenase-1 (i.e., 0.028 ± 0.002 U mg-1, TOF: 2.1 ± 0.2 min-1), meaning up to 74 mg of NADPH and 1.23 mg of NADH produced per hour by a system involving 1 mg of CbA5H. The TOF is comparable with similar systems based on hydrogen as regenerating molecule for NADPH, but the system is first of its kind as for the [FeFe]-hydrogenase and the non-physiological partners used. As a proof of concept a cascade reaction involving CbA5H, BMR and a mutant BVMO from Acinetobacter radioresistens able to oxidize indole is presented. The data show how the cascade can be exploited for indigo production and multiple reaction cycles can be sustained using the regenerated NADPH.

Laparoscopic Treatment of Perforated Peptic Ulcer: A Propensity Score-Matched Comparison of Interrupted Stitches Repair versus Knotless Barbed Suture.

Background: Peptic ulcers result from imbalanced acid production, and in recent decades, proton pump inhibitors have proven effective in treating them. However, perforated peptic ulcers (PPU) continue to occur with a persistent high mortality rate when not managed properly. The advantages of the laparoscopic approach have been widely acknowledged. Nevertheless, concerning certain technical aspects of this method, such as the best gastrorrhaphy technique, the consensus remains elusive. Consequently, the choice tends to rely on individual surgical experiences. Our study aimed to compare interrupted stitches versus running barbed suture for laparoscopic PPU repair. Methods: We conducted a retrospective study utilizing propensity score matching analysis on patients who underwent laparoscopic PPU repair. Patients were categorised into two groups: Interrupted Stitches Suture (IStiS) and Knotless Suture (KnotS). We then compared the clinical and pathological characteristics of patients in both groups. Results: A total of 265 patients underwent laparoscopic PPU repair: 198 patients with interrupted stitches technique and 67 with barbed knotless suture. Following propensity score matching, each group (IStiS and KnotS) comprised 56 patients. The analysis revealed that operative time did not differ between groups: 87.9 ± 39.7 vs. 92.8 ± 42.6 min (p = 0.537). Postoperative morbidity (24.0% vs. 32.7%, p = 0.331) and Clavien-Dindo III (10.7% vs. 5.4%, p = 0.489) were more frequently observed in the KnotS group, without any significant difference. In contrast, we found a slightly higher mortality rate in the IStiS group (10.7% vs. 7.1%, p = 0.742). Concerning leaks, no differences emerged between groups (3.6% vs. 5.4%, p = 1.000). Conclusions: Laparoscopic PPU repair with knotless barbed sutures is a non-inferior alternative to interrupted stitches repair. Nevertheless, further research such as randomised trials, with a standardised treatment protocol according to ulcer size, are required to identify the best gastrorraphy technique.

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.