A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia

Navada, Shyamala C.; Fruchtman, Steven; Odchimar-Reissig, Rosalie; Demakos, Erin P.; Petrone, Michael E.; Zbyszewski, Patrick S.; Holland, James F.

doi:10.1016/j.leukres.2017.11.006

Cited by 37 publications

(25 citation statements)

References 18 publications

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“…Preclinical and early phase clinical trials showed encouraging activity of this drug in patients with MDS that failed hypomethylating agents. Some of these patients achieved partial/complete marrow responses with acceptable hematologic toxicity (cytopenias) and no other significant adverse events (Navada et al, 2018). Thus, this therapeutic approach is now tested in a phase III clinical trial.…”

Section: Emerging Therapies In Mds Rigosertibmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

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Section: Emerging Therapies In Mds Rigosertibmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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“…Through these interactions, these proteins result in inactivation, leading to mitotic arrest and apoptosis of tumor cells. 73 In a phase III trial, 74 patients with high-risk MDS after failure to respond to HMAs were randomized to rigosertib plus best supportive care (BSC) versus BSC. No patients had an overall CR or PR, but 27% patients in the rigosertib group and 17% in the BSC group achieved a confirmed best bone-marrow blast response of either bone-marrow CR or bone-marrow PR.…”

Section: Novel Therapies To Overcome Failure Of Response To Hypomethymentioning

confidence: 99%

Management of myelodysplastic syndromes after failure of response to hypomethylating agents

Gil-Perez

Montalban‐Bravo

2019

Therapeutic Advances in Hematology

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Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.

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“…Newer RAS-inhibitors like the RAS-mimetic Rigosertib, which blocks the RBD in RAS-effectors, as seen for bRAF and p110αPI3K in our PLA analysis on MUTZ-5 cells, could also allow blocking of both wt and mutant RAS and Rigosertib is currently being evaluated in a Phase III study for MDS/AML (40). Our data reveal that reducing RAS activity via inhibition of PTPN11 catalytical action may provide a functional alternative for ALL cells, while blocking the phosphorylation of PTPN11 via JAK inhibitors was not sufficient to prevent RAS activity, and concordantly with our mechanistic insight was also unable to block the direct interaction between PTPN11 and RAS.…”

Section: Discussionmentioning

confidence: 97%

RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

Koschut

Ray

et al. 2020

Preprint

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Background: Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by the high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices.Results: Here we show that in primary leukemic cells from DS-ALL, in the absence of RAS-mutations, wild-type (wt)RAS is active, and/or can be induced by the physiological ligand TSLP of the transmembrane-receptor CRLF2. We show active/inducible RAS in 14/20 (70%) of primary DS-ALL samples analyzed, 8 of which had no RAS-mutations, but 75% of those had either mutated or hyperphosphorylated JAK2. No wtRAS cases with mutated/hyperphosphorylated JAK2 were observed that lacked activated RAS protein. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. We show that TSLP boosts the direct binding of active PTPN11 to wtRAS. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK signaling, prevented TSLP-induced RAS-GTP boost.Using multivariate-clustering based on RAS-activity/inducibility we show significant separation between standard-risk and high-risk DS-ALL groups. Cox proportional-hazards model showed proteinactivity (but not mutation status) as independently predictive of outcome. Conclusions:Our data indicate that RAS protein activity levels (and not JAK2/RAS mutation profiles), are predictive of outcome. Importantly, our data suggest that inhibition of RAS and direct RASpathway components should be combined with PI3K/mTOR and/or JAK2 inhibitors for high-risk cases.Therapeutically this is relevant for >75% of DS-ALL and our additional data suggest that it warrants further investigation in high-risk non-DS-ALL.wtRAS activation is frequent in DS-ALL

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A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia

Cited by 37 publications

References 18 publications

Targeting the Microenvironment in MDS: The Final Frontier

Targeting the Microenvironment in MDS: The Final Frontier

Management of myelodysplastic syndromes after failure of response to hypomethylating agents

RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

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