Targeting ineffective hematopoiesis in myelodysplastic syndromes
Authors: Mrinal M. Patnaik, Valeria Santini
Journal: American Journal of Hematology (2021)

Myelodysplastic syndromes (MDS) are clonal hematological neoplasms commonly occurring in the elderly (median age at diagnosis 74 years), often in the background of clonal hematopoiesis, with an inherent but variable risk of progression of acute myeloid leukemia (AML).1 Regardless of the MDS morphologic subtype, anemia remains a major clinical manifestation (> 80% of patients) and is a significant contributor to morbidity and mortality.2 While the mechanisms of anemia in MDS are diverse, common abnormalities involve defective erythropoietin (EPO) signaling, including abnormal phosphorylation of critical EPO substrates such as STAT5 and ERK1/2 and faulty formation of lipid raft microdomains that might impair assembly of EPO receptors, JAK2, STAT5, and Lyn kinases.3-5 In MDS with del5q, haploinsufficiency of critical genes such as RPS14 and CSKN1A1, located in the commonly deleted chromosome 5q regions (CDR- 5q31 and 5q32-33) result in TP53 mediated apoptosis of red cell precursors, secondary to sequestration of MDM2.6, 7 Regardless of the mechanism, chronic anemia in MDS adversely affects quality of life and results in ongoing organ damage secondary to demand ischemia, persistent tachycardia, increased cardiac output, left ventricular remodeling, and specific adverse effects related to red blood cell transfusion dependency (RBC-TD) and iron overload.2 The management of anemia in MDS largely centers around the use of supportive care measures such as RBC transfusions and the use of erythropoiesis stimulating agents (ESA). ESA are more likely to be effective in lower-risk MDS patients, especially those with endogenous EPO levels < 200 U/L and those with low or no RBC transfusion dependance (40%–70% response rates).2, 8, 9 In a recent phase 3, randomized, double-blinded placebo controlled trial, assessing the efficacy of weight adjusted dose of epoetin-alfa (ESA) in lower-risk MDS, both in transfusion dependent and independent cases, the erythroid response rate was 45.9% versus 4.4% for the ESA treated versus placebo groups (p < .001), respectively, with ESA significantly increasing hemoglobin levels, reducing the need for RBC transfusions and the time to first RBC transfusion in responding patients.8 While ESA remain the mainstay for management of anemia in MDS, there are several patients who are ESA-ineligible, or less likely to respond, due to high baseline levels of EPO and long-standing RBC transfusion dependency. In addition, while ESA responses can be sustained, the median duration of response is often 12–18 months, with very limited options for those with eventual loss of response, or refractoriness.9 Additional therapies that have been assessed include lenalidomide, an immunomodulatory enantiomer of thalidomide that is very effective in alleviating anemia in patients with MDS-del5q (67% RBC transfusion independence rate).10 Lenalidomide induces the ubiquitination of CSKN1A1 by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN, resulting in casein kinase1α degradation and restoration of erythropoiesis.11 Lenalidomide also has activity in lower-risk, non-del5q MDS (26%–30% response rates) patients,12 with a recent randomized phase 3 trial demonstrating synergy with ESA, regardless of prior exposure, or high endogenous EPO levels (major erythroid response 28.3% vs. 11.5%).13, 14 SMAD2–SMAD3 signaling is constitutively increased in patients with lower-risk MDS and impacts erythroid maturation. Luspatercept is a recombinant fusion protein that traps GDF11 and activin ligands belonging to the TGF-beta superfamily, thereby decreasing SMAD2 and SMAD3 signaling, enabling late-stage erythroid maturation.15 In 2020, luspatercept was US FDA and EMA approved for the management of anemia in transfusion dependent patients with MDS with ring sideroblasts (MDS-RS), based on a phase 3 randomized, placebo controlled clinical trial that demonstrated an RBC transfusion independence rate (> 8 weeks) of 38% versus 13% in the placebo arm (p < .001).16 This drug is now being assessed for the management of anemia in other MDS subtypes and as a frontline agent compared to ESA in lower-risk MDS patients. The small activin receptor-like kinase 5 (ALK5 kinase) inhibitor galunisertib is an oral agent that blocks TGF-β/SMAD2 activation and is effective in ESA-resistant/relapsed lower-risk MDS patients.17 Imetelstat, a novel telomerase inhibitor, in a recent phase 2 clinical trial (with 38 patients having received only prior ESA therapy) has demonstrated 8- and 24-week RBC transfusion independence rates of 42% and 29%, respectively, with a median duration of transfusion independence of 86 weeks (lower-risk, RBC-TD and ESA relapsed/refractory, non-del5q MDS patients).18 Interestingly, this agent seems to have a disease specific effect decreasing the variant allele fractions of dysplastic clones carrying somatic mutations. DNA methyltransferase inhibitors (DNMTi) such as 5-azacitidine, decitabine, and oral decitabine combined with cedazuridine (cytidine deaminase inhibitor), given in either conventional doses, or in attenuated dose schedules for lower-risk MDS patients have also shown ability to alleviate RBC transfusion dependence.19 While studying the regulation of hypoxia inducible mRNA such as EPO and VEGF, the hypoxia inducible factor (HIF) axis was discovered and consists of an unstable α-subunit (HIFα) and a stable β-subunit (HIFβ), with the Von Hippel Lindau (VHL) protein being a substrate-recognition subunit of an E3 ubiquitin ligase that targets HIFα subunits for proteasomal degradation under normoxia.20, 21 In the context of hypoxia, HIFα escapes recognition by pVHL, dimerizes with HIFβ and transcriptionally activates HIF target genes (EPO and VEGF) (Figure 1).20, 21 This interaction of pVHL with HIFα is oxygen dependent and requires HIFα to be prolyl-hydroxylated on one of two conserved prolyl residues by members of the EglN (Egl-9 family hypoxia inducible facto /PHD—prolyl hydroxylase) family to bind to pVHL. Roxadustat, is a first-in-class, oral, HIF–PHD inhibitor that mimics the body's response to hypoxia by inhibiting the HIF–PHD axis, preventing hydroxylation of HIFα, thus allowing for the transcription of EPO and VEGF, along with other hypoxia responsive genes. In phase 2 studies involving patients with chronic kidney disease (CKD), roxadustat increased endogenous EPO levels, improving anemia and iron homeostasis.22, 23 In a subsequent pivotal, randomized, double-blinded, phase 3, placebo controlled clinical trial in CKD patients not receiving hemodialysis, roxadustat was associated with a mean increase in hemoglobin levels of 1.9 ± 1.2 g/dl versus placebo (p < .001), along with a mean reduction in hepcidin levels of 56.14 ± 63.4 ng/ml versus placebo, with hyperkalemia (12% vs. 2%) and metabolic acidosis (16% vs. 8%) being common side effects of the drug.24 In a separate randomized, open-label, active-controlled, phase 3 trial in patients with CKD undergoing hemodialysis, roxadustat was found to be noninferior to ESA with regards to anemia management, but demonstrated a positive impact on iron homeostasis, lowering hepcidin levels and improving lipid profiles.25 Despite the putative thrombotic risk associated with increased EPO and VEGF levels, vascular access site thromboses were reported in only 2/204 (1%) patients treated with roxadustat versus none in the ESA arm.25 These studies among others, have led to the regulatory approval for the use of roxadustat in CKD patients in China, Japan, South Korea, Chile, and the European Union. The US FDA has not yet approved the drug for CKD citing emerging safety concerns with regards to an increased incidence of vascular access site thrombotic events and has asked the sponsors to carry out additional trials potentially using lower doses of the drug. In the current issue of the journal, David Henry et al., report on an open-label, dose selection, lead into the MATTERHORN clinical trial. This phase 3, randomized, double-blind, placebo-controlled study was designed to assess the efficacy and safety of roxadustat in lower-risk MDS patients with anemia (endogenous EPO ≤ 400 mIU/ml and low RBC-TD). Patients were assigned to 1 of 3 thrice weekly starting roxadustat doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg, with the primary endpoint being the proportion of patients achieving RBC transfusion independence for ≥8 consecutive weeks in the first 28 weeks of therapy, according to International Working Group MDS response criteria. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over any 8-week period. Of the 24 enrolled patients, RBC transfusion independence was achieved in nine patients (37.5%) at 28 and 52 weeks (7 at the 2.5 mg/kg dose), while a ≥ 50% reduction in RBC-TD was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat was well-tolerated, with no fatalities, thrombotic events, or AML progressions documented. Based on these outcomes, 2.5 mg/kg was chosen as the starting roxadustat dose for the ongoing double-blind phase 3 study phase. As long as long-term safety and efficacy data continue to remain promising, roxadustat intuitively remains an exciting prospect for MDS, given that it is an oral formulation, and unlike ESAs, roxadustat increases EPO receptors on bone marrow progenitors, positively impacts iron metabolism by downregulating hepcidin levels and stimulates effective erythropoiesis at physiologic EPO levels, with its impact being independent of baseline inflammation that is very common in MDS.22, 23 While the current trial only includes lower-risk MDS patients with an endogenous EPO level of < 400 U/L, based on the mechanism of action of the inhibitor, it remains unclear as to whether patients with higher endogenous EPO levels will respond to this class of drugs. Additional HIF–PHD inhibitors in development for anemia management in CKD include GSK1278863 (Daprodustat), Bay85-3934 (Molidustat), and AKB-6548 (Vadadustat).26 Cell-based results reveal that these inhibitors have similar effects on the upregulation of HIF target genes but differ in the kinetics of their effects and in the extent of inhibition of hydroxylation of the N- and C-terminal oxygen dependant degradation domains.26 The role that these drugs might play and additional safety data with regards to thrombotic events in the management of anemia related to CKD and MDS is eagerly awaited. Mrinal M. Patnaik has served on advisory boards for Stemline Pharmaceuticals and Kura Oncology. Valeria Santini has participated in advisory boards of Geron, BMS/Celgene, Novartis, Gilead. Data sharing not applicable - no new data generated, or the article describes entirely theoretical research.