Medicine and Pharmacology

Abstract: Sickle cell disease (SCD) is one of the most common inherited blood disorders worldwide. Clinical manifestations are variable, but include hyposplenism, renal impairment, cardiovascular disease, respiratory complications, and cerebrovascular disease. Frequent painful vaso-occlusive crises, hospitalisations, and other physical and psychological ramifications can have profound effects, including children missing school time resulting in impaired academic performance and adults missing work leading to employment loss. This review examines the possible risks and benefits of exercise in the SCD population. Regular exercise plays an important role in improving physical and mental health, but fears around the potential consequences of exercise for the SCD population are present in children, their families, schools, and other organisations. This can result in children not taking part in as much regular exercise as their peers and being excluded from group activities. Studies have suggested that healthcare professionals are often not discussing possible benefits of physical exercise with patients, likely as there are no guidelines regarding a safe level of activity. An acute increase in inflammation secondary to exercise could increase the risk of vaso-occlusive crises, but regular physical activity is known to play an important role in disrupting chronic inflammation across a wide range of pro-inflammatory diseases. Indeed, studies have demonstrated positive responses to exercise in the SCD population, from improvements in skeletal muscle microvasculature to performance in cardiovascular tests. It is important that recommendations are developed regarding types of exercise and the ideal amount of exercise for maximum benefit with minimum risk in SCD individuals.

Abstract: Objectives: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, and consolidation with autologous hematopoietic stem cell transplantation (HSCT) in AML patients represents an alternative therapeutic option in the absence of related or unrelated donors, in the elderly or in patients with good or standard risk. In this retrospective analysis, the data were evaluated from a total of 47 AML patients who underwent autologous hematopoietic stem cell transplantation between November 2012 and March 2023 at the Bone Marrow Transplantation Unit of Medicalpark Izmir Hospital. The present study also investigates the factors affecting overall survival (OS) and pro-gression-free survival (PFS). Methods: This study is a retrospective evaluation of the data obtained from 47 patients with AML who underwent an autologous HSCT. Results: 24 patients were female, and 23 patients were male. The median age at diagnosis was 39 years (range: 18-68 y). The mean OS from diagnosis to the last follow-up or death was 26 months (4-116 months), and the PFS was 20 months (3-69 months). An assessment of the factors that influenced OS and PFS showed no significant association of NPM positivity, gender, risk group, response to first-line chemotherapy, transplantation at CR (Complete remission) 1 or CR2, LDH (lactade dehidrogenase) , CD34 count, and the day of neutrophil engraftment with OS or PFS. In patients with FLT3(fms benzeri tirozin kinaz 3) positivity, OS was significantly shorter (p < 0.05), while PFS was not significantly different (p=0.21). Conclusions: Consolidation with auto-HSCT in AML patients can be preferred in subjects with good or intermediate 1 risk category according to ELN (European leukemia net )criteria, or in subjects with intermediate 2 or poor-risk category who have no related or unrelated donor.

Abstract: Physiotherapy is an evidence-based healthcare occupation aiming to collaborate in the diagnosis, prevention and treatment of myriad of diseases and clinical scenarios throughout all stages of human life. Its development has been accelerated over the last two decades. The scope of physiotherapy is continuously evolving. However, the accumulated evidence in the context of rare diseases is scarce. Remarkably, the opportunity for improvement and potential benefit for complex diseases with low prevalence is also very high, both as an isolated approach or within multidisciplinary specialized units. Systemic light-chain (AL) amyloidosis is a rare, chronic, complex, heterogeneous, incurable, and challenging disease, which may involve different organs and systems, including the heart, kidney, liver, peripheral nerves, lung, muscle, skin, and others. Heart is the most frequently involved organ leading to failure and arrhythmias. Peripheral neuropathy is a relatively frequent symptom. Renal, respiratory, and hepatic failure may also occur. The aim of this narrative review is summarizing, updating, and critically underlining potential new avenues of development on the role of physiotherapy in systemic light-chain (AL) amyloidosis, compared with its application on multiple myeloma, a closely related but not so rare entity.

Abstract: Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically with the introduction of targeted agents, particularly Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is). This review summarizes contemporary frontline and relapsed/refractory treatment strategies, with an emphasis on molecular risk stratification, combination and triplet regimens, measurable residual disease (MRD)–guided therapy, and time-limited approaches. We further examine how genomic complexity, prior therapies, and sociodemographic factors influence disease progression, treatment resistance, and clinical outcomes.

Abstract: This review aims to provide comprehensive and practical information on the once-nearly-forgotten but now resurgent roles and trends of autologous transplantation in leukemias. We seek to categorize when it is necessary as a first-line treatment (plasma cell leukemia) and to identify well-defined patient subgroups (such as certain types with intermediate prognosis in AML, APL second remission, etc.) in which autologous transplantation might be comparably or even slightly more effective than allogeneic transplantation, not only in frail patients. In some leukemias, such as CLL, autologous transplantation still does not play a role. Attempts to achieve anti-leukaemic effects in autologous settings have proven largely ineffective, but new approaches might be promising. Newer cell therapies (such as CAR-T) are significantly more effective, and the same applies to in vitro graft purging. However, this area has been investigated relatively recently in an innovative manner, using specific graft pretreatments that may also stimulate anti-leukemic immune responses in autologous cases.

Abstract: Despite transformative therapeutic advances, multiple myeloma (MM) remains an incurable malignancy characterized by sequential relapses and progressive treatment resistance. Patients with heavily pretreated relapsed or refractory MM continue to face limited therapeutic options and poor outcomes. Melflufen (melphalan flufenamide) is a peptide–drug conjugate that enhances intracellular delivery of alkylating agents via aminopeptidase-mediated activation. Early clinical studies demonstrated encouraging activity in advanced MM, leading to accelerated approval by the U.S. Food and Drug Administration in 2021. However, results from the phase III OCEAN trial raised concerns re-garding overall survival, ultimately resulting in withdrawal of the drug from the U.S. market. In this review, we examine the biological rationale, clinical development, and regulatory trajectory of melflufen, and critically reassess its role within the evolving therapeutic landscape of MM. The negative survival signal observed in OCEAN challenges the clinical viability of melflufen, yet also provides key insights into patient selection and mechanism-based drug delivery strategies. These observations support a selective, mechanism-based positioning of melflufen and argue for a broader shift from drug-centered evaluation to biology-driven therapeutic strategies.

Abstract: Background: Cold agglutinin-associated hemolysis (CAH) occurs in diverse clinical con-texts, including primary cold agglutinin disease (pCAD) and Waldenström macroglobu-linemia-associated cold agglutinin syndrome (WM-CAS). The differentiation of these enti-ties is often challenging, particularly in MYD88 L265P-negative cases. Since studies that examined the effects of chemoimmunotherapy (CIT) frequently predated routine molecular testing, it remains unclear whether the disease classification has an impact on treatment responses and durability. Methods: We retrospectively analyzed patients with pCAD, WM-CAS, and WM without CAS (WM-only) treated at a single center between April 2010 and November 2025. Diagnoses followed the revised fifth edition of the WHO Classifica-tion of Haematolymphoid Tumours. Clinicopathological features and outcomes were compared. Treatment responses were assessed using CAD-specific criteria based on he-moglobin and hemolysis markers. Time to next treatment (TTNT) and overall survival (OS) were analyzed using Kaplan-Meier methods. Results: Ten patients had CAH (5 pCAD, 5 WM-CAS) and 29 had WM-only. CAH cases showed higher lactate dehydrogenase and total bilirubin levels, whereas WM-only cases had higher serum IgM levels and greater bone marrow involvement. Rituximab-based CIT predominated as the first-line therapy for both pCAD and WM-CAS. Overall response rates were 100% in pCAD and 80% in WM-CAS, with similar kinetics. TTNT did not significantly differ between pCAD and WM-CAS. Elevated FDP was more frequent in CAH, while no overt thrombotic events or grade ≥3 infections were observed. Conclusions: Rituximab-based CIT effectively con-trolled CAH in both pCAD and WM-CAS, with similar durability. When hemolysis is the dominant clinical issue and the disease classification is unclear, tumor-directed therapy represents a treatment strategy.

Abstract: ADAM17 (a disintegrin and metalloproteinase 17) is increasingly recognized as a central regulator of multiple myeloma (MM) biology beyond its canonical role in TNF-α shedding. Rather than acting as a classical oncogenic driver, ADAM17 functions as a master regulator of ectodomain shedding, controlling the balance between membrane-bound and soluble mediators that shape signaling across the bone marrow microenvironment. Through coordinated processing of cytokines, cytokine receptors, growth factor ligands, and adhesion molecules, ADAM17 amplifies inflammatory signaling, endothelial activation, immune dysfunction, and tumor dissemination.In MM, ADAM17 contributes to key pathogenic processes by modulating the spatial and temporal dynamics of extracellular communication. Shedding of CX3CL1 and adhesion molecules such as JAM-A promotes angiogenesis and vascular niche remodeling, while IL-6R cleavage enables trans-signaling that sustains stromal activation, chronic inflammation, and malignant plasma cell survival. In parallel, ADAM17-dependent processing of immune receptors, including CD62L, alters lymphocyte trafficking and immune surveillance, contributing to an immunologically permissive niche. Proteolytic remodeling of adhesion systems may also facilitate niche escape and extramedullary dissemination.These coordinated shedding events define a dynamic myeloma “sheddome,” in which ADAM17 acts as a systems-level node integrating tumor, stromal, endothelial, and immune signals. This framework helps explain the context-dependent and pleiotropic effects of ADAM17 throughout disease evolution. Clinically, circulating ADAM17 shows promise as a dynamic biomarker reflecting tumor burden, microenvironmental activation, and immune dysfunction. However, therapeutic targeting remains challenging because of substrate redundancy, systemic functions, and the risk of disrupting physiological immune regulation. Future strategies will require selective and context-aware modulation of ADAM17-driven shedding networks to effectively reprogram the myeloma microenvironment.

Abstract: Background: Chronic myeloid leukemia (CML) is a paradigm of targeted therapy, driven by the BCR::ABL1 fusion kinase. Over the past four decades, therapeutic strategies have evolved from early molecular targeting approaches and interferon-α to tyrosine kinase inhibitors (TKIs), dramatically improving survival and transforming CML into a largely controllable disease. Methods: We performed a narrative review of the literature, focusing on key milestones in CML therapy, including antisense strategies, interferon-based treatment, first-, second-, and third-generation TKIs, and the development of allosteric inhibitors. Current management strategies, treatment-free remission (TFR), and emerging therapies were also analyzed. Results: The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements. Second- and third-generation TKIs further enhanced response depth and addressed resistance, including the T315I mutation. The development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients. Deep molecular responses have enabled TFR in approximately 40–60% of selected patients, redefining treatment goals toward functional cure. Emerging agents, including next-generation ATP-competitive and allosteric inhibitors, are showing promising activity in resistant disease and may further improve outcomes. Conclusions: CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.

Abstract: Background/Objectives: Iron deficiency remains a prevalent condition, needing specific laboratory tests for diagnosis. This study aimed to evaluate whether routine complete blood cell count (CBC) parameters can be used within a machine learning framework to predict iron deficiency, potentially optimizing laboratory test utilization. Methods: A ret-rospective dataset of outpatients (2023–2026) undergoing both CBC and iron testing was analyzed. Iron deficiency was defined using sex-specific thresholds for ferritin and trans-ferrin saturation. After cleaning data and excluding incomplete records, demographic variables and CBC indices were tested as potential predictors. The dataset was split into training and test sets with stratified sampling. Multiple supervised machine learning models, including logistic regression, decision tree, random forest, XGBoost, support vec-tor machine, k-nearest neighbors, and Naive Bayes, were trained. Hyperparameter tuning and model selection were performed using repeated stratified 10-fold cross-validation, op-timizing the area under the curve (AUC). Model performance was assessed by AUC, sen-sitivity, and specificity, and validated on an independent test set. Results: All models demonstrated predictive capability using CBC parameters alone. Ensemble methods, es-pecially random forest and XGBoost, reached the best performance (AUC values of 0.80–0.87 for ferritin and 0.85–0.96 for transferrin saturation). Sensitivity and specificity were balanced, supporting clinical screening applicability. Results were maintained across validation and confirmed in the test set. Prediction of transferrin saturation showed slightly higher accuracy than ferritin. Feature importance analysis identified MCV, MCH, and RDW as key predictors. Conclusions: CBC-based machine learning models can relia-bly identify subjects with iron deficiency, supporting subsequent, more targeted analyses.

Abstract: Blastic Plasmocytoid Dendritic Cell Neoplasm (BPDCN) is a rare myeloid malignancy, characterized by the involvement of multiple organs, including skin, bone marrow and blood, lymph nodes and central nervous system. According to tumor location, the disease is classified as skin only, systemic only and skin and systemic. The cutaneous manifestations of disease are typical and are represented by violaceous single tumors or multiple plaques present in sun-exposed cutaneous areas. BPDCN is issued from the malignant transformation of dendritic cell progenitors and is immunophenotypically diagnosed by the classical immunophenotypes CD123, CD4 and CD56 in addition to specific membrane markers of plasmocytoid dendritic cells. BPDCN is an aggressive disease and is associated with a short survival. Upfront therapies involve either chemotherapy regimens in fit patients and CD123-targeted therapies, including interleukin-3 conjugated with diphtheria toxin (Tagraxofusp, SL-401) or Pivekimab sunirine an anti-IL-3R-drug conjugate, for both fit and unfit patients. Targeted treatments limit the toxicities of chemotherapy and allow the bridging of a consistent proportion of patients to hematopoietic stem cell transplantation, the only treatment associated with potential long-term survival.

Abstract: Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly additional sex combs like 1 (ASXL1), have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1,339 records were identified; after duplicate removal and screening, 11 studies met inclusion criteria and were included in qualitative synthesis and meta-analysis. Eligible studies included adult and pediatric patients with chronic and advanced phase (accelerated or blast) CML with ASXL1 mutation status assessed using validated molecular methods. Outcomes included molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the I² statistic. Results: Across included studies, ASXL1 mutations were detected in approximately 16% of patients. At 12 months, ASXL1-mutated patients had significantly lower odds of achieving major molecular response (MMR) compared with ASXL1–wildtype patients (OR 0.29; 95% CI 0.16–0.51; p< 0.0001; I²=30%). No statistically significant difference was observed in complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p=0.41; I²=68%). Compared with patients harbouring other non-ASXL1 somatic mutations, ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p=0.067; I²=0%). Conclusions: ASXL1 mutations are associated with inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies.

Abstract: Background/Objectives: In the recent years there has been a consistent development of clinical studies surrounding the incorporation of the B-cell lymphoma 2 (BCL-2) inhibitor Venetoclax (VEN) into the treatment of acute myeloid leukemia (AML). Methods: A search of literature showed a tremendous development of experimental and clinical studies evaluating the impact of VEN-based regimens in the treatment of AML patients. Results: Recent studies have evaluated VEN-based regimens in newly diagnosed (ND) and refractory/relapsed (R/R) AML patients, showing the efficacy of these treatments. VEN with hypomethylating agents (HMAs) became the standard-of-care for elderly/unfit AML patients. Recent studies strongly support the effectiveness of VEN-based regimens in frontline treatment of adult AML patients eligible for intensive treatments. VEN-based therapies were also used in combination with targeted therapies, thus generating triplet therapeutic regimens that are under evaluation for the treatment of some AML subtypes. However, the response to VEN+HMAs is highly variable and in part depend on tumor genetics; some patients are resistant or relapse following VEN-based treatments and future studies will be required to develop therapeutic strategies able to circumvent resistance and to identify patients at high risk of relapse. Prospective randomized trials are required to establish the real efficacy of VEN in various clinical settings and to refine maintenance and discontinuation strategies, aiming to improve long-term outcomes and to make more safe treatments based on VEN.

Abstract: Chromosomal rearrangements involving the Lysine Methyl Transferase 2 A (KMT2A) define a genetically distinct subset of acute myeloid leukemia (AML) in about 10% of cases in adult patients; the frequency of KMT2A-r is higher in pediatric AML. Translocations involving the KMT2A-locus at chromosome 11q23 result in the formation of a chimeric oncogene partner, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The leukemogenic activity of KMT2A-fusion partners is related to their capacity to hyperactivate the expression of HOX-A and MEIS1 target genes which stimulate the proliferation and expansion of hematopoietic stem cells. The oncogenic activity of KMT2A fusion proteins requires the interaction with Menin and this interaction can be targeted pharmacologically by small molecules acting as potent and selective Menin inhibitors. The presence of KMT2A-r is associated with adverse outcomes in AML patients. In the present review article, we summarize our current understanding about the biology of KMT2A-r in AML development and the recent consistent progresses made in the treatment of KMT2A-r AML through new chemotherapy regimens and targeted therapy using Menin inhibitors. These studies have led to consistent improvements in the outcomes of KMT2A-r AML patients. However, the prognosis of older KMT2A-r AML patients remains poor and could be improved by drug combination studies including Menin inhibitors. Many encouraging observations derived from ongoing clinical trials with Menin inhibitors need to be confirmed through randomized clinical trials.

Abstract:

Acute myeloid leukemia (AML) is a genetically diverse clonal illness marked by the accumulation of somatically acquired genetic abnormalities in hematopoietic progenitors, leading to poor differentiation and unchecked proliferation. Over the last twenty years, the amalgamation of traditional cytogenetics, molecular genetics, and, more recently, next-generation sequencing (NGS) has transformed diagnostic procedures, enhanced risk stratification models, and revealed new therapeutic targets that are altering the treatment landscape. Molecular genetic analysis of CEBPA, NPM1, and FLT3 is currently standard of care in AML patients, and mutations in several other genes are becoming more important, including NPM1, TET2, KIT, DNMT3A, IDH1/2, RUNX1, AXSL1, WT1, and RAS. In this article, the authors review the most relevant literature concerning AML genetics and discuss, based on their own experience and expertise, the perspectives on precision medicine in AML, and addresses practical issues faced in low-resource nations like Albania and Kosovo.

Abstract: The treatment of chronic lymphocytic leukemia (CLL) has significantly shifted from chemoimmunotherapy to targeted therapies like Bruton’s tyrosine kinase and BCL2 inhibitors. Despite these advancements, CLL remains an incurable disease characterized by immune dysregulation, therapeutic resistance, and cumulative toxicities. To overcome these challenges, novel immunotherapeutic strategies are emerging as fundamentally different approaches that target the immune-tumor interactions. These innovations include novel monoclonal antibodies, bispecific antibodies that redirect T-cell cytotoxicity, chimeric antigen receptor (CAR)-T cell therapies, and natural killer (NK) cell-based platforms. By actively engaging cellular cytotoxicity, these approaches show promise in high-risk and treatment-resistant scenarios where standard pathway inhibition is inadequate. Establishing the optimal use, toxicity management, and combination strategies of these cellularly engaged immunotherapies is now a critical priority in contemporary CLL research.

Abstract: Objective: Neurological complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) are rare but serious events that significantly impact morbidity and mortality. This study aims to evaluate the incidence, clinical spectrum, and associated risk factors of neurological complications in patients who underwent allo-HSCT at a single center. Methods: We retrospective analyzed 108 patients who underwent allo-HSCT between January 2022 and December 2024. Patients were categorized by transplant type: myeloablative related donor (n=48), myeloablative unrelated donor (n=36), and haploidentical transplant (n=24). Neurological complications were observed in 18 patients (16.7%) and analyzed in terms of demographics, transplant type, hematologic diagnosis, conditioning regimen, infections, GVHD status, and outcomes. Results: The mean age of affected patients was 52.56 years (range 20–71), with equal gender distribution. Neurological complications developed between day 15 and day 395 post-transplant (mean: day 200). CMV positivity was detected in 14 of 17 patients with neurological complications. Acute GVHD was present in 11 patients and chronic GVHD in 5 patients. Statistical analysis revealed a significant association between neurological complications and CMV positivity (p=0.000), acute GVHD (p=0.014), and chronic GVHD (p=0.009). Ten patients died, with causes including disease progression, severe GVHD, CMV encephalitis, and hemophagocytic syndrome. Conclusion: Neurological complications post-allo-HSCT are diverse and often fatal. CMV infection, acute and chronic GVHD are significant risk factors. Early diagnosis and multidisciplinary management are essential to improve outcomes.

Abstract: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous; genotype-directed first-line therapy may improve outcomes. We conducted a single-center, prospective, non-randomized interventional study evaluating a molecularly adapted R-CHOP-X strategy with two-year follow-up. Between February 2023 and the data cut-off (September 16, 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using LymphGen after targeted sequencing: an initial cohort had Sanger sequencing of a 19-gene panel (n = 35) and a second cohort an expanded 60-gene panel (n = 8). All patients received one cycle of R-CHOP followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response assessment followed Lugano criteria; adverse events were recorded per NCI CTCAE v5.0. The overall response rate was 100% (n = 43); complete response among patients completing therapy (n = 35) was 100%. At two years, overall survival was 92% (95% CI 83%–100%) and progression-free survival was 94% (95% CI 86%–100%); two early relapses occurred. These findings indicate that molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival and warrant validation in larger randomized clinical trials.

Abstract:

Myeloid/lymphoid neoplasms with tyrosine kinase rearrangements (MLN-TK) are rare clonal eosinophilias driven by PDGFRA, PDGFRB and other kinase fusions, highly sensitive to tyrosine kinase inhibitors. Their detection remains challenging, particularly for cryptic PDGFRA rearrangements. We performed a large multicenter real-world validation of the generic quantitative RT-PCR assay (gPDGFR), which detects 3′ PDGFRA/PDGFRB overexpression independently of fusion partner. A total of 231 consecutive patients with hypereosinophilia from 12 French centers were analyzed, and assay robustness was further assessed in an independent heterogeneous cohort of 102 TKI-treated patients. Twenty-two PDGFR-rearranged cases (14 PDGFRA-r, 8 PDGFRB-r) were identified. The assay demonstrated 100% sensitivity and 100% negative predictive value. For PDGFRA, positive predictive value and specificity reached 100%. In contrast, PDGFRB overexpression showed lower specificity due to borderline false-positive cases, underscoring the need for confirmatory testing. In selected patients, longitudinal gPDGFR kinetics paralleled fusion-specific RT-qPCR, supporting its use for molecular follow-up when dedicated assays are unavailable, although it does not provide quantitative measurable residual disease assessment. Overall, gPDGFR represents a robust, partner-independent first-line screening strategy that can be readily integrated into routine diagnostic workflows to enable timely identification of patients eligible for targeted therapy.

Abstract: Core-binding factor acute myeloid leukemia (CBF-AML), defined by the chromosomal rearrangements t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16), has traditionally been classified as a favorable-risk subtype of AML. Nevertheless, relapse occurs in approximately 30–40% of patients, highlighting substantial biological and clinical heterogeneity within this entity. In this review, we synthesize emerging evidence delineating the distinct molecular architecture and prognostic divergence between RUNX1::RUNX1T1 and CBFB::MYH11 AML. We focus on the clinical implications of measurable residual disease (MRD) dynamics and recurrent cooperating lesions, including KIT, FLT3, RAS pathway genes, cohesin-complex alterations, and ZBTB7A, and critically evaluate their impact on relapse risk and therapeutic decision-making. Current treatment paradigms, centered on intensive chemotherapy and high-dose cytarabine consolidation, are reviewed alongside evolving targeted, epigenetic, and immunotherapeutic strategies, with emphasis on distinguishing practice-changing interventions from investigational approaches. Collectively, the available data challenge a uniform “favorable-risk” designation for CBF-AML and support a shift toward fusion-specific, MRD-guided, and molecularly integrated management strategies. We propose a contemporary framework in which dynamic MRD assessment and biological risk modifiers inform treatment intensification, including selective use of targeted agents and allogeneic transplantation, with the goal of achieving durable remissions and reducing relapse in this heterogeneous leukemia subtype.