Bruno António Cardoso ^1,2* Natalia Neparidze ³

• ¹ Universidade Católica Portuguesa, Centro de Investigação Interdisciplinar em Saúde, Sintra, Portugal
• ² Universidade Católica Portuguesa, Faculdade de Medicina, Sintra, Portugal
• ³ Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States

expanded this initial objective into other crucial areas covering disease biology and precursor conditions. Taborda et al wrote a review manuscript describing the importance of discriminating CCUS as an independent hematological entity from Clonal hematopoiesis of Indetermined Potential (CHIP) (1). As the authors discuss in the article, CHIP is defined as a condition characterized by the acquisition of somatic mutations commonly found in myeloid malignancies with a variant allele fraction (VAF) of ≥2% in the absence of hematologic malignancy or unexplained cytopenia when such cytopenia is persistent is it classified as CCUS. The incidence of CCUS is around 30% in patients who do not meet the criteria for Myelodisplastic syndromes (MDS) (2). The CCUS mutational landscape overlaps CHIP and MDS and includes genes commonly mutated in myeloid neoplasms (TET2, DNMT3A, ASXL1, and others). Increased understanding of clonality (through genome-wide association studies) led to the development of risk stratification tools to assess the likelihood of progression to myeloid neoplasms.Finally, the authors also discuss potential therapeutic targets that are currently being tested in the context of CCUS; these include epigenetic regulators (TET2 and IDH1/2) and deregulated inflammation signaling. Hematopoiesis is the complex process that gives rise to all the blood cellular lineages cells (3). This complex process occurs in a particular microenvironment and, when disrupted, allows for leukemic transformation and proliferation. The bone marrow comprises different cellular components that modulate and regulate hematopoiesis, and understanding these interactions is essential for developing effective therapies. In the review by Semedo and Caroço, the authors suggest that successful treatment of leukemia may require strategies that simultaneously target leukemic cells and the supportive microenvironmentthe dual targeting approach. This targeting approach could improve patient outcomes and reduce the likelihood of resistance to therapies. To illustrate their claims, the authors provide a comprehensive and detailed overview of all the clinical studies using therapeutic strategies targeting leukemic cells and the bone marrow microenvironment. Wei and Konopleva provided a comprehensive overview of the role of Bcl-2 inhibitors in hematologic malignancies, highlighting their potential, challenges, and the need for personalized treatment approaches in blood cancers. The Bcl-2 protein is a crucial regulator of apoptosis and is often upregulated in blood cancers, which makes them an attractive target in cancer research (4)(5).Venetoclax is the first FDA-approved Bcl-2 inhibitor to treat malignancies where this antiapoptotic protein is aberrantly overexpressed (6). The authors discuss the clinical applications of Venetoclax in several conditions, particularly in Chronic Lymphocytic Leukemia (CLL) and Acute Myeloid Leukemia (AML), and cast the outcomes of clinical trials that demonstrate its efficacy and safety profile. Furthermore, the article also discusses the future directions in developing Bcl-2 inhibitors and combination therapies, resistance mechanisms, and the need for personalized treatment approaches. Phillips et al conducted a retrospective review of 31 B-cell Acute Lymphoblastic Leukemia (B-ALL) patients who received Anti-CD19 CAR-T cell therapy (Tisagenlecleucel) (7)(8). The authors analyzed clinical data (response, survival rates, and remission duration) from relapsed or refractory B-ALL patients treated with Anti-CD19 CAR-T cell therapy without prior hematopoietic stem cell transplantation (HSCT). Notably, the results suggest that in a significant proportion (12/31) of relapsed/refractory B-ALL patients, Anti-CD19 CAR-T cell therapy is sufficient to induce long-term remissions without the need for further therapy but also to delay the HSCT procedure in this difficultto-treat group of patients. The authors discuss the importance of careful assessment and clinical judgment to determine the best clinical protocol for each patient since not all patients will benefit from a high-risk procedure like HSCT. Abdallah and colleagues presented the results of the CheckMate 039 clinical trial. This is a multicentric (seven centers involved), randomized phase I/II clinical trial that tested the combination of Nivolumab (Checkpoint inhibitor) and Daratumumab (Anti-CD38) in patients with relapsed/refractory Multiple Myeloma (RRMM). The MM outcomes have improved over the years with the introduction of immunomodulatory agents, proteasome inhibitors (PIs), and monoclonal antibodies (mAbs) (9). This study evaluated Nivolumab-Daratumumab combination MM patients' safety, tolerability, and efficacy.Despite the small patient sample, this combination was safe and demonstrated encouraging efficacy signals, particularly in achieving high response rates. The findings are notable and challenge the hematology community to re-examine and re-consider the significance of a PD-1 checkpoint pathway in myeloma. These encouraging results suggest that combining immune checkpoint inhibitors with monoclonal antibodies may represent a promising strategy to improve outcomes for patients with RRMM, addressing a critical need in this patient population where a clinical unmet need still exists. In conclusion, even though the articles that compose this research topic extend beyond the intended original scope, they provide not only original data on therapeutic targeting of hematological malignancies but also essential reflections on the targets and strategies that the scientific research community should take into consideration to develop effective therapies for such patients. Notably, the introduction of cutting-edge diagnostic tools like next-generation sequencing and single-cell sequencing, a conscious effort should be put in place to provide personalized and effective treatment for patients with hematological malignancies. BAC: Writingoriginal draft, Writingreview & editing. NN: Writingreview & editing All claims and points of view expressed in this article solely represent the opinions of the authors and do not necessarily reflect those of their affiliated organizations, the publisher, the editorial team, or the reviewers.