Emerging Treatments for Myelodysplastic Syndromes: Biological Rationales and Clinical Translation

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients\u27 only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS pathogenesis has enabled the development of new agents that target molecular alterations, cell death regulators, signaling pathways, and immune regulatory proteins in MDS. Here, we review novel therapies for patients with MDS in whom HMA therapy has failed, with an emphasis on the biological rationale for these therapies\u27 development

Targeting TP53-Mutated Acute Myeloid Leukemia: Research and Clinical Developments

TP53 is a key tumor suppressor gene that plays an important role in regulating apoptosis, senescence, and DNA damage repair in response to cellular stress. Although somewhat rare, TP53-mutated AML has been identified as an important molecular subgroup with a prognosis that is arguably the worst of any. Survival beyond one year is rare after induction chemotherapy with or without consolidative allogeneic stem cell transplant. Although response rates have been improved with hypomethylating agents, outcomes remain particularly poor due to short response duration. Improvements in our understanding of AML genetics and biology have led to a surge in novel treatment options, though the clinical applicability of these agents in TP53-mutated disease remains largely unknown. This review will focus on the epidemiology, molecular characteristics, and clinical significance of TP53 mutations in AML as well as emerging treatment options that are currently being studied

Maintenance treatment for recurrent ovarian carcinoma – Evidence supporting the efficacy and safety of PARP inhibitors

While recent advances in treatment mean that women with ovarian cancer are living longer, many eventually experience disease relapse highlighting the need for new treatments that can extend progression-free survival (PFS). The PARP inhibitors olaparib, niraparib and rucaparib have been approved by the US Food and Drug Administration and the European Commission and are currently available for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Here, we review the efficacy and safety data from the key clinical trials supporting the approvals for these treatments as second-line maintenance therapies, including Study 19, SOLO2/ ENGOT-OV21 (olaparib), NOVA/ENGOT-OV16 (niraparib) and ARIEL3 (rucaparib). Across trials, PFS was improved with PARP inhibitor maintenance treatment versus placebo in patients with a BRCA mutation. However, evidence from some of the trials shows that a wider group of patients can benefit from PARP inhibitor maintenance treatment including those with or without homologous recombination deficient tumours. The safety profile for olaparib, niraparib and rucaparib was generally similar across trials with haematological and gastrointestinal adverse events and fatigue/asthenia being the most common. As evidenced by the significant improvements in PFS and manageable safety profiles in these trials, PARP inhibitors represent a new standard of care for recurrent ovarian cancer following platinum-based chemotherapy and delay the need for further chemotherapy

Novel insights and therapeutic approaches in secondary AML

Secondary acute myeloid leukemia (sAML) presents as a complex and multifaceted ensemble of disorders, positioning itself as both a challenge and an intriguing frontier within hematologic oncology. Its origins are diverse, stemming from antecedent hematologic conditions, germline predisposing mutations, or the sequelae of cytotoxic therapies, and its development is driven by intricate genetic and epigenetic modifications. This complexity necessitates a diverse array of therapeutic strategies, each meticulously tailored to address the distinctive challenges sAML introduces. Such strategies require a personalized approach, considering the variegated clinical backgrounds of patients and the inherent intricacies of the disease. Allogeneic stem cell transplantation stands as a cornerstone, offering the potential for curative outcomes. This is complemented by the emergence of innovative treatments such as CPX-351, venetoclax, and glasdegib, which have demonstrated promising results in enhancing prognosis. The evolving landscape of sAML treatment underscores the importance of continued research and innovation in the field, aiming not only to improve patient outcomes but also to deepen our understanding of the disease’s biological underpinnings, thereby illuminating pathways toward more effective and individualized therapies

DNMT3A mutations in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, predominately occurring in elderly people and characterized by the reciprocal translocation between the chromosomes 9 and 22 (t(9;22)(q34.1;q11.2)). Despite the high efficiency of tyrosine kinase inhibitor (TKI) therapy, the disease persists in most CML patients. Epigenetic alterations, such as mutation of DNA methyltransferase-3-alpha (DNMT3A), may contribute to CML stem cell survival during a long term TKI therapy and thus play a critical role in its pathogenesis, therapeutic responsiveness, and treatment-free remission (TFR). In patients with additional mutations outside BCR::ABL1, combination of TKI and epigenetic therapy may improve CML treatment to achieve deep and long-term molecular responses. This study investigated the relative expression changes of CML patients’ samples containing DNMT3A mutations (n = 5 DNMT3Amut at diagnosis, n = 5 DNMT3Amut at follow-up) compared with wild type DNMT3A CML patients’ samples (DNMT3Awt, n = 20). Another aim was to establish a DNMT3Aknock-down cell model for further experimental analysis. For this purpose, a double-nickase transfection was performed on the mouse Ba/F3p210 CML cell line. In vitro incubation experiments were performed on established DNMT3Aknock-down cell lines +/- nilotinib and/or 5-azacitidine (5-AZA). Furthermore, global methylation changes in patients and cell line models were analyzed as well as the clinical effect of DNMT3A mutations on treatment response of affected patients. The presence of DNMT3A mutations in patients was associated with a trend of decreased expression rate. The methylation level showed a statistically significant increase in follow-up samples of patients with DNMT3Amut at diagnosis whereas a trend of decreased level of global methylation was detected in patients with emerging DNMT3Amut in the follow-up samples, corelating with expression analysis

CRISPR Screens Identify Candidate Therapeutic Targets in Leukemia

Acute myeloid leukemia (AML) is a complex hematological malignancy marked by proliferation of immature myeloid cells with a dismal 5-year survival. A major challenge is the persistence of leukemia stem cells (LSCs) after standard treatment, leading to relapse. This thesis employs in vivo CRISPR/Cas9 screening to investigate critical AML and LSC molecular mechanisms, interrogating the dependancies on cell surface receptors for use as potential therapies. In our initial study (Article I), we identify the chemokine receptor CXCR4 as a crucial dependency of AML cell growth and survival. Using a murine model of AML driven by MLL::AF9, we find that CXCR4 loss triggers oxidative stress and differentiation in vivo, with CXCL12 ligand signaling being non-essential for leukemia development.Expanding our study to interrogate nearly one thousand cell surface receptors, we identify three additional AML dependencies. Among these, GLUT1, a primary cellular glucose transporter, emerges as a key regulator of energy metabolism, driving MLL::AF9 LSC survival (Article II). Inhibition of GLUT1 suppresses cellular bioenergetics, prompting autophagy as a metabolic adaptation. Notably, dual inhibition of GLUT1 and oxidative phosphorylation effectively eliminates human AML cells, especially for the RUNX1-mutated AML subtype.Furthermore, our research also reveals iron metabolism as another critical AML dependency (Article III). We found that disrupting iron uptake through genetic knockdown of Tfrc, encoding the transferrin receptor (TFR1), suppresses leukemia development in a p53-dependent manner, leading to transcriptional repression of antioxidant defense and mitochondrial respiration pathways. Patient-derived AML cells were selectively targeted upon iron chelation treatment. Additionally, our work uncovers the role of H2K1 in evading NK cell-mediated immune surveillance in vivo through disruption of NK cell maturation and activation (Article IV). Consistent with this finding, H2k1 disruption alone suffices to reverse this immune evasion, restoring NK cell-mediated anti-leukemic effects.In conclusion, this thesis highlights the value of CRISPR/Cas9 screens in identifying physiologically relevant AML dependencies. It offers insights into targetable LSC vulnerabilities, emphasizing the potential of metabolic targeting and combined treatments for improved AML therapies

Immunotherapy as a turning point in the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly patients. To date, standard chemotherapy protocols are only effective in patients at low risk of relapse and therapy-related mortality. The average 5-year overall survival (OS) is approximately 28%. Allogeneic hematopoietic stem cell transplantation (HSCT) improves prognosis but is limited by donor availability, a relatively young age of patients, and absence of significant comorbidities. Moreover, it is associated with significant morbidity and mortality. However, increasing understanding of AML immunobiology is leading to the development of innovative therapeutic strategies. Immunotherapy is considered an attractive strategy for controlling and eliminating the disease. It can be a real breakthrough in the treatment of leukemia, especially in patients who are not eligible forintensive chemotherapy. In this review, we focused on the progress of immunotherapy in the field of AML by discussing monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor T cells (CAR-T cells), and vaccine therapeutic choices

Case report: VEXAS syndrome: an atypical indolent presentation as sacroiliitis with molecular response to azacitidine

VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine’s anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients

Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives

Since its initial report in 2015, CD47 has garnered significant attention as an innate immune checkpoint, raising expectations to become the next “PD-1.” The optimistic early stages of clinical development spurred a flurry of licensing deals for CD47-targeted molecules and company mergers or acquisitions for related assets. However, a series of setbacks unfolded recently, starting with the July 2023 announcement of discontinuing the phase 3 ENHANCE study on Magrolimab plus Azacitidine for higher-risk myelodysplastic syndromes (MDS). Subsequently, in August 2023, the termination of the ASPEN-02 program, assessing Evorpacept in combination with Azacitidine in MDS patients, was disclosed due to insufficient improvement compared to Azacitidine alone. These setbacks have cast doubt on the feasibility of targeting CD47 in the industry. In this review, we delve into the challenges of developing CD47-SIRPα-targeted drugs, analyze factors contributing to the mentioned setbacks, discuss future perspectives, and explore potential solutions for enhancing CD47-SIRPα-targeted drug development