Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease

Mohty, Razan; Hamed, Rama Al; Bazarbachi, Ali; Brissot, Éolia; Nagler, Arnon; Zeidan, Amer M.; Mohty, Mohamad

doi:10.1186/s13045-022-01346-9

Cited by 7 publications

(6 citation statements)

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“…The hypomethylating agent decitabine has been approved for the treatment of myelodysplastic syndromes (MDS) and myelomonocytic leukemia [ 222 ]. However, the oral bioavailability of decitabine is compromised by cytidine deaminase in the gastrointestinal tract and liver [ 223 ]. This problem can be overcome by the cytidine deaminase inhibitor cedazuridine.…”

Section: Activation Of Rlr Signaling For Cancer Therapy By Viral Mimicrymentioning

confidence: 99%

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

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Section: Activation Of Rlr Signaling For Cancer Therapy By Viral Mimicrymentioning

confidence: 99%

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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“…70 Numerous clinical trials using newer-generation FLT3 inhibitors as doublet or triplet combinations in both newly diagnosed MDSs and relapsed/refractory settings are ongoing (NCT04027309, NCT04140487, NCT03661307, NCT04493138, NCT01892371). 71 CPX-351 is liposomal combination of cytarabine and daunorubicin at synergistic 5:1 ratio. CPX-351 improved clinical outcomes (OS) in patients diagnosed with secondary AML, including those with history of MDSs or AML with MDS-related changes.…”

Section: Investigational Combinatorial Approachesmentioning

confidence: 99%

“…73 The study included 31 patients with intermediate-or high-risk MDSs. 71 Approximately 90% of the patients with baseline marrow blasts >10% reached <5% blasts after induction treatment, and >70% of the patients underwent alloSCT. 73 The hematological toxicity of this cytotoxic approach has been challenging in MDS patients because of prolonged aplasia and risk of infection.…”

Section: Investigational Combinatorial Approachesmentioning

confidence: 99%

“…A combination of midostaurin and azacitidine was tested in patients with high-risk MDSs, which showed some clinical benefit with an overall response rate of 26% 70 . Numerous clinical trials using newer-generation FLT3 inhibitors as doublet or triplet combinations in both newly diagnosed MDSs and relapsed/refractory settings are ongoing (NCT04027309, NCT04140487, NCT03661307, NCT04493138, NCT01892371) 71 …”

Section: Higher-risk Mdsmentioning

confidence: 99%

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Overview of the Management of Higher-Risk Myelodysplastic Syndromes

Singh

Carraway

2023

Cancer J

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Myelodysplastic syndromes or myelodysplastic neoplasms (both abbreviated MDSs) (Leukemia 2022;36:1703–1719) have historically been challenging diseases to treat owing to their complex biology, molecular diversity, and a patient population that is elderly with comorbidities. As the patients are living longer, incidence of MDSs is rising, and challenges in selecting MDS treatments or lack thereof have been becoming more apparent. Fortunately, with better understanding of molecular underpinnings of this heterogeneous syndrome, numerous clinical trials reflecting the biology of disease and catering to the advanced age of MDS patients are in development to maximize the likelihood of identifying active drugs. Addressing this diverse nature of genetic abnormalities, novel agents, and combinations are in development to formulate personalized treatment approaches for MDS patients. Myelodysplastic syndrome is categorized into subtypes that are associated with lower or higher risk for leukemic evolution, and that knowledge helps with therapy selection. Currently, as it stands, for those with higher-risk MDSs, hypomethylating agents are the first-line therapy. Allogenic stem cell transplantation represents the only potential cure for our patients with MDSs and should be considered for all eligible patients with higher-risk MDSs at the time of diagnosis. This review discusses current MDS treatment landscape, as well as new approaches in development.

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“…While several new drugs targeting specific pathways crucial for MDS are currently investigated, we will focus herein on some agents potentially entering routine clinical practice in the next few years (Fig. 4) [96].…”

Section: A Glimpse Into the Future: Brief Overview Of New Treatments ...mentioning

confidence: 99%

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

2022

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Myelodysplastic neoplasms, formerly known as myelodysplastic syndromes (MDS), represent a group of clonal disorders characterized by a high degree of clinical and molecular heterogeneity, and an invariable tendency to progress to acute myeloid leukemia. MDS typically present in the elderly with cytopenias of different degrees and bone marrow dysplasia, the hallmarks of the disease. Allogeneic hematopoietic stem cell transplant is the sole curative approach to date. Nonetheless, given the disease’s demographics, only a minority of patients can benefit from this procedure. Currently used prognostic schemes such as the Revised International Prognostic Scoring System (R-IPSS), and most recently the molecular IPSS (IPSS-M), guide clinical management by dividing MDS into two big categories: lower- and higher-risk cases, based on a cut-off score of 3.5. The main clinical problem of the lower-risk group is represented by the management of cytopenias, whereas the prevention of secondary leukemia progression is the goal for the latter. Herein, we discuss the non-transplant treatment of MDS, focusing on current practice and available therapeutic options, while also presenting new investigational agents potentially entering the MDS therapeutic arsenal in the near future.

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Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease

Cited by 7 publications

References 100 publications

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

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