What value do cell cycle inhibitors have in the treatment of myelodysplastic syndrome?

KEYWORDS:

• Myelodysplastic syndrome
• cell cycle inhibitors
• hypomethylating agents
• lenalidomide
• intensive chemotherapy

1. Introduction

Myelodysplastic syndromes (MDS) are a heterogenous disease arising in clonal hematopoietic stem cells (HSCs) that cause dysregulated hematopoiesis with resultant cytopenias [1]. Normal hematopoiesis entails strictly regulated cellular replication via the cell cycle a sequence of events starting from Gap 1 (G1) progressing to Synthesis (S), Gap 2 (G2), and mitosis (M) phase. Disrupting this process can cause cellular arrest or confer limitless replicative potential. In the case of early MDS, this can result in maturation arrest/inappropriate cell death resulting in cytopenias, while in later stage, MDS can result in a proliferative phenotype.

This review focuses on the drugs used in low and high risk MDS (LR-MDS/HR-MDS) that target the cell cycle, cell cycle regulators controlling cellular proliferation/differentiation.

2. Cell cycle inhibitors

2.1. DNA methyltransferases inhibitors (DNMT3i)

Epigenetic regulation plays a key role in pathogenesis of MDS by causing altered DNA methylation patterns contributing to disease [2,3]. Inhibitors of DNA methyltransferases (DNMT3i)/hypomethylating agents (HMAs), azacitdine and decitabine, exert antileukemic activity by integrating into the S phase of the cell cycle and cause inhibition of DNA methyltransferases, enzymes that maintain DNA methylation [4]. Demethylation by DNMT3i results in re-expression of previously silenced genes involved in cellular pathways of DNA repair, apoptosis, tumor suppression, and immune modulation [4,5]. Early clinical developments of these drugs were as alternatives to nucleoside analogs like cytarabine, till their potential as DNMT3i was realized at doses substantially lower than initially investigated.

Azacitidine initially received FDA approval for HR-MDS in 2004. In the CALGB-2 study, patients were randomized to azacitidine or best supportive care. Silverman et al. reported an overall response rate (ORR) of 23% in the azacitidine group and 0% in the supportive care group (p < 0.001). The overall survival (OS) of azacitidine vs supportive care was 20 months vs 14 months (p < 0.1) with a landmark analysis later reporting an OS benefit (p = 0.03) [6]. Fenaux et al. conducted a phase III randomized study in HR-MDS with conventional therapy as comparator (including high dose chemotherapy, low dose cytarabine, and supportive care) and reported an OS of 24.5 months in the azacitdine group vs 15 months in the conventional group (p = 0.001) [7].

Decitabine was studied in International Prognostic Scoring System [IPSS] intermediate-1, intermediate-2 and high risk MDS and CMML in a phase III randomized controlled trial. In the study by Kantarjian et al,170 MDS patients received decitabine versus supportive care. The trial did not report an OS benefit but showed an increased progression free survival (PFS) for acute myeloid leukemia (AML) transformation leading to FDA approval in 2006 [8]. Optimal dosing and route of administration have led to successful development of oral HMA formulations. Garcia-Manero et al. led a phase II study of oral decitabine-cedazuridine formulation (ASTX-727) in a fixed dose combination (35-100 mg) compared to intravenous decitabine (20 mg/m2 daily for 5 days at 28 day cycles) in patients with IPSS intermediate-1, intermediate-2, and high risk MDS and CMML. Cedazuridine inhibits cytidine deaminase that can inactivate decitabine in the gut and liver, thereby ensuring achievement of optimal decitabine PK with oral dosing. The study showed similar safety, demethylation activity and pharmacological equivalency for oral decitabine-cedazuridine compared with intravenous decitabine leading to its approval by the FDA in 2020 [9]. Oral azacitidine (CC-486) currently approved for maintenance therapy in AML, is also being studied in HR-MDS, with preliminary studies showing encouraging results [10].

Studies with mitigated dosing schedules for both intravenous azacitidine and decitabine have demonstrated efficacy in patients with low risk MDS (LR-MDS) [11,12]. Lower doses of oral DNMT3is are being explored for patients with LR-MDS. A phase I/II study investigated the use of ASTX-727 with a lower decitabine dose and showed decitabine-cedazuridine 10/100 mg for 5 days was clinically efficacious with manageable toxicity profile, and a phase II trial comparing it to standard decitabine-cedazuridine 35/100 mg for 3 days for 28 day cycles is currently ongoing [13]. A phase III randomized, placebo controlled trial of CC-486 (oral azacitidine) in LR-MDS with transfusion dependent anemia and thrombocytopenia showed improved transfusion independence in the azacitdine arm (31% vs. 11%; p = 0.0002) compared to placebo [14].

2.2. Low MDS; Immunomodulatory agents

In LR-MDS, MDS with 5q- holds a key distinction as the first-line agent for treatment is lenalidomide, an angiogenic inhibitor and immunomodulatory agent, that reduces transfusion dependence by restoring erythropoiesis [15]. Lenalidomide has multiple mechanisms of actions working both directly and indirectly against leukemic cells [16]. Directly, lenalidomide causes cell cycle arrest by inhibition of phosphorylation with the end result of deactivation of CDK-1, an essential regulator at G2/M entry and cell cycle progression [17]. Lenalidomide mediates apoptosis by causing ubiquination of proteins that regulate p53 activity and through reactivation of G-protein coupled receptors involved in calcium metabolism raising intracellular calcium levels with resultant apoptotis [18]. In the phase II clinical trial MDS-003, List et al. reported the use of lenalidomide at varying dosing in patients with MDS with and without 5q- which showed erythroid responses (decreased transfusion needs/transfusion independence) in 76% and cytogenetic response in 73% of patients. In patients with predominantly isolated del 5q mutated MDS (76% of participants), 83% had a cytogenetic response with median time to response of 8 weeks [19].

2.3. High risk MDS; Intensive chemotherapy

Antimetabolite agents including purine, pyrimidine, and cytidine analogs have been the backbone for treatment of AML. These agents are usually reserved in HR-MDS for patients with disease relapsed/refractory to HMAs, as there are limited options with an overall survival of 4–6 months. A retrospective study evaluated the use of purine analog regimens, intermediate and high dose cytarabine (IDAC/HDAC) and combination of cytarabine and anthracyclines (7 + 3) in patients with MDS after HMA failure. The ORR was 41% with a median survival of 10.8 months, with 47% patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT), demonstrating rationale for their use in this population [20]. Other studies have evaluated clofarabine in HR-MDS with limited success. A phase II trial with low dose clofarabine and cytrabine in patients with relapsed/refractory MDS for better tolerability. The study showed an ORR of 44% and a median survival of 10 months with complex karyotype heralding a poor prognosis [21]. CPX- 351, a dual dose liposomal combination of cytarabine and anthracycline, has been used in a phase I/II trial in patients with relapsed/refractory HR-MDS with an ORR of 71% (marrow CR 59%) with median OS of 12.6 months. The study used attenuated dosing compared to that in AML with 24% of the patients proceeding to allo-HSCT [22].

CPX-351 has also been evaluated in the frontline setting in patients with HR-MDS. The phase II study with 31 patients reported a 52% CR rate and 22 patients were bridged to allo-HSCT [23]. Other frontline regimens include the use of cladribine, idarubicin, and cytarabine (CLIA) in combination with the BCL-2 inhibitor, venetoclax. The phase II trial (NCT02115295) evaluated CLIA and venetoclax in the frontline setting in patients with AML and HR-MDS with impressive results. The study showed a CR rate of 85% with 62% patients bridged to allo-HSCT. Median OS was not reached [24].

3. Conclusion

Hypomethylating agents form the backbone of treatment especially in HR-MDS with oral formulations transforming the treatment paradigm. Intensive chemotherapy with nucleoside analogues is reserved for relapsed/refractory settings.

4. Expert opinion

Several clinical trials are employing cell cycle inhibitor backbones as novel treatment options in MDS. Y-The phase II SY-1425-201 trial evaluated azacitidine with tamibarotene, a retinoic acid receptor alpha (RARA) agonist, which showed an ORR of 67% vs 39% in patients with RARA-positive AML compared to RARA-negative AML [25]. The regimen is now being studied in the phase III double-blind, placebo-controlled SELECT MDS-1 trial (NCT04797780) evaluating response in newly diagnosed RARA-positive HR-MDS [26]. Agrawal et al. demonstrated activity with decitabine and pembrolizumab, a PDL-1 inhibitor, in relapsed/refractory AML, and the study is currently enrolling patients with HR-MDS post HMA failure [27]. T-cell immunoglobulin and mucin domain-3 (TIM-3) is an immune-myeloid regulator present on leukemic stem cells but absent on hematopoietic stem cells. Overexpression in MDS has led to development of sabatolimab (MBG-453), a monoclonal antibody targeting TIM-3. A phase II trial of sabatolimab in combination with HMA in HR-MDS patients demonstrated ORR of 49.3% with CR improvement in treated vs placebo group (49% vs 37%) but was not statistically significant. A phase III trial (NCT04266301) is currently exploring the combination with OS as primary endpoint [28].

Oral hypomethylating agents, as monotherapy or combination regimens, have reinvigorated the therapeutic landscape. The ASCERTAIN trial reported a survival of 13 months in patients with biallelic TP53 MDS treated with oral decitabine-cedazuridine, a category with non-durable response to HMAs with a remarkably poor prognosis [29]. Similarly, combination treatment of oral decitabine-cedazuridine with magrolimab, an anti CD47 antibody is being studied in patients with high risk MDS based on phase III ENHANCE study (NCT04313881) [30]. Among other cell cycle agents, Polo-like kinase 4 (PLK4) inhibitor CFI-400945 has demonstrated early activity in high-risk AML. PLK4 over-expression is involved in centrosome amplification causing DNA instability. CFI-400945 is being studied as both monotherapy and in combination with HMAs [31]. Preclinical data show potential activity of azacitidine with cyclin-dependent kinase 9 (CDK-9) inhibitor, Alvocidib, in high-risk MDS with presence of ASXL1 mutations predicting response [32]. ATM-Rad3-related (ATR) inhibition sensitizes TP53 mutated MDS cells to decitabine providing a potential avenue for more durable responses in this group [33]. These novel agents offer the hope that MDS in the future could be treated entirely with an all oral regimen, which is an exciting prospect.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.