AS PART of The ASCO Post’s continued coverage of the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, here is an update on seven different studies on new therapeutics in myelodysplastic syndromes (MDS). Among the treatments highlighted here are the erythroid maturation agent luspatercept, the Toll-like receptor 2 antibody tomaralimab, the XPO1 inhibitor selinexor, and the DNA methyltransferase inhibitor guadecitabine.
Syed Ali Abutalib, MD
Alan F. List, MD
ABSTRACT 1: Results of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk (Revised International Prognostic Scoring System [R-IPSS]) MDS with ring sideroblasts who require red blood cell (RBC) transfusions: The phase III MEDALIST trial1
Mechanism of Action: Luspatercept is a first-in-class erythroid maturation agent that binds to the select transforming growth factor-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis.
Key Findings: Overall, 90% of patients had an SF3B1 mutation. Of the 153 patients who received luspatercept, 58 achieved RBC-transfusion independence for at least 8 weeks, compared with 10 of the 76 patients who received placebo (odds ratio = 5.1, P < .0001). Of those receiving luspatercept, 43 (28%) achieved RBC-transfusion independence for at least 12 weeks, compared with 6 of the 76 patients who received placebo (odds ratio = 5.1, P = .0002), and approximately 40% of responders remained transfusion-free at 1 year. Responses were higher in patients with lower baseline RBC-transfusion burden and a higher platelet count. Overall 53% of luspatercept-treated patients achieved a 4 unit or greater reduction in transfusion over 8 weeks or a mean rise of 1.5 g/dL in hemoglobin over 8 weeks without transfusions compared with 12% who received placebo (P < .0001). The safety profile of luspatercept was consistent with that reported in the phase II PACE-MDS study.2
Clinical Implications: Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo and was generally well tolerated.
ABSTRACT 463: Imetelstat in RBC transfusion–dependent, non-del(5q) lower-risk MDS relapsed or refractory patients to erythropoiesis-stimulating agent who are lenalidomide- and hypomethylation-naive3
Mechanism of Action: Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some patients with MDS.
Key Findings: IMerge is a phase II/III trial that includes patients with low-risk MDS who have a high transfusion burden (≥ 4 units/8 wk) and are relapsed or refractory to erythropoiesis-stimulating agent or have a serum erythropoietin > 500 mU/ mL. As of July 2018, the median follow-up is 25.8 months for the initial 13 patients and 5.2 months for the 25 recently included patients. The 8-week RBC transfusion–independence rate was 37%. The durability of 24-week transfusion independence responses was demonstrated, with a median duration of 10 months and the longest ongoing response now more than 2 years. Among the patients achieving durable transfusion independence, all showed a hemoglobin rise of at least 3 g/dL compared with baseline during the transfusion-free interval.
Response rates were similar in patients with refractory anemia who had ring sideroblasts/refractory cytopenia with multilineage dysplasia-ring sideroblasts (33%) and other patients (27%) as well as those with baseline serum erythropoietin levels higher than 500 mU/mL (33%) and up to 500 mU/mL (32%). Reversible grade ≥ 3 neutropenia and thrombocytopenia were reported in 58% of the patients. Reversible grade 3 liver function test elevations were observed in 3 study patients. An independent hepatic review committee deemed the observed liver function test elevations not related to imetelstat.
Clinical Implications: Single-agent imetelstat yielded a transfusion independence rate of 37%, with a median duration of 10 months and limited side effects.
ABSTRACT 798: Tomaralimab (OPN-305) in heavily pretreated, transfusion-dependent patients with lower-risk MDS who failed to respond to a prior hypomethylating agent4
Mechanism of Action: Innate immune sensors such as the Toll-like receptor 2 are consistently overexpressed in bone marrow CD34-positive cells from patients with low-risk MDS, and a gain of function mutation in Toll-like receptor 2 correlates with disease progression. Ex vivo inhibition of Toll-like receptor 2 in cultures of CD34-positive cells using tomaralimab, a fully humanized antagonistic immunoglobulin 4 monoclonal antibody, led to an increase in differentiation of erythroid cultures.
Primary Endpoint: Transfusion independence for two consecutive cycles, as defined in International Working Group criteria.
Key Findings: A total of 22 patients were fully evaluable. Before the study, the average transfusion was 10 units (median = 3.5 units) on study, the average transfusion was 2 units (median = 1.5 units). Six patients met the primary endpoint (27%) across multiple centers, 5 of whom were on tomaralimab monotherapy at the time of response. Furthermore, there were 5 minor responders (at least a 50% reduction in the need for transfusions), yielding an overall response rate of 50%. Additionally, 10 patients remained stable throughout the therapy window. There were no dose-limiting toxicities or development of anti-drug antibodies.
Clinical Implications: Tomaralimab therapy presents a potential therapeutic option for heavily pretreated, low-risk patients with MDS who have failed to respond to hypomethylating therapy.
ABSTRACT 233: Selinexor in patients with MDS who are refractory to hypomethylating agents5
Mechanism of Action: Selinexor, an oral, first-in-class, selective inhibitor of nuclear export compound that inhibits XPO1. The XPO1 is the major nuclear export protein responsible for shuttling many key cellular regulators out of the nucleus and is overexpressed in many cancers.
Key Findings: A total of 25 patients were evaluable for safety, and 19 were evaluable for response. The overall response rate (complete response + marrow complete response + partial response + hematologic improvement) was 32% (all complete marrow response), with an average response duration of 6.8 months. An additional 42% of patients achieved stable disease, for an average response duration of 6.4 months for all patients receiving a clinical benefit. The median overall survival was 9.7 months, with a median follow-up of 2.1 years. The most frequently occurring adverse events thereafter was grade 2 or 3 fatigue. All other adverse events were manageable with routine supportive care. The presence of an SF3B1 hotspot mutation was significantly associated with response to selinexor (P = .01). The levels of XPO1 mRNA increased with treatment within 4 hours of the first dose, indicative of XPO1 target engagement with selinexor.
Clinical Implications: These data indicate that selinexor is safe and tolerable in MDS when given at 60 mg twice weekly for 2 weeks with 1 week off, with a 32% response rate in patients with poor expected survival after azanucleoside treatment failure. Detailed correlative and preclinical analyses are ongoing and should provide further illumination of the biologic relevance of these markers, which will be tested prospectively in future clinical trials. Further studies of selinexor combined with targeted agents that disrupt similar or complementary oncogenic pathways in MDS may further improve responses.
“Further studies of selinexor combined with targeted agents that disrupt similar or complementary oncogenic pathways in MDS may further improve responses.”— Syed Ali Abutalib, MD, and Alan F. List, MD
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ABSTRACT 230: Phase II expansion study of oral rigosertib combined with azacitidine in patients with higher-risk MDS: Efficacy and safety results in hypomethylating treatment-naive and relapsed or refractory patients6
Mechanism of Action: Rigosertib interferes with the RAS-binding domains of RAF kinases and inhibits the RAS-RAF-MEK and the PI3K pathways.
Key Findings: Of the 31 patients evaluable for response, 14 and 17 patients were hypomethylation–naive and had relapsed or refractory MDS, respectively. In patients with relapsed or refractory disease, the number of prior hypomethylating cycles ranged from 2 to 15; 13 failed to respond to azacitidine. At this time point, the median duration of treatment for the overall population is 5 months. For all patients, the overall response rate was 68%; for the hypomethylation-naive cohort, it was 79%; and for relapsed or refractory patients, it was 59%. Both rigosertib and azacitidine may be associated with hematuria. In 43 patients treated with rigosertib (1,120 mg) and azacitidine, grade 1 and 2 hematuria was 16% (5% ≥ 3 grade). The incidence of hematuria of any grade with single-agent azacitidine was 6.3% (2.3% grade ≥ 3).
Clinical Implications: The combination of oral rigosertib and azacitidine in hypomethylation-naive patients with high-risk MDS displays encouraging tolerance and response at least comparable to single-agent azacitidine. The combination also has activity and reverses the hypomethylating clinical resistance in many patients after failure to prior therapy. Dose exploration with a higher dose of oral rigosertib (1,120 mg) administered in different dosing schemes in combination with standard-dose azacitidine continues to be studied to optimize safety and efficacy. By employing risk-mitigation strategies, the incidence of genitourinary adverse events, including hematuria, was substantially reduced.
ABSTRACT 232: Final report of a phase II study of guadecitabine in 94 patients with previously untreated MDS7
Mechanism of Action: Guadecitabine (SGI-110) is a second-generation hypomethylating agent that is a guanosine dinucleotide derivative of decitabine and therefore resistant to deamination. Thus, it may be a more potent inhibitor of DNA methyltransferase activity.
Key Findings: The median number of cycles received was five, and all patients were evaluable for toxicity. Early mortality was 0%. Common toxicities were fatigue, infection, nausea, pain, constipation, mucositis, dyspnea, and diarrhea. A total of 87 patients (93%) were evaluable for response. The median number of cycles to response was three. Overall response was seen in 53 patients (61%), with 19 complete responses, 3 complete responses with incomplete platelet recovery, 36% hematologic improvement, 5 stable disease; 27 patients did not respond. With a median follow-up of 15 months, the median overall survival was 15 months, and the median event-free survival was 14 months.
Clinical Implications: Guadecitabine was well tolerated in previously untreated MDS. The overall response rate appears comparable to that expected compared with azacitidine or decitabine. Longer follow-up and randomized trials are needed to understand the effect on survival. (Also see Abstracts 2318 and 1811.9)
“These results support the use of deferasirox in patients with low- and intermediate-1–risk MDS who have iron overload.”— Syed Ali Abutalib, MD, and Alan F. List, MD
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ABSTRACT 234: Safety and efficacy, including event-free survival, of deferasirox (n = 149) vs placebo (n = 76) in iron-overloaded patients with low- and intermediate-1–risk MDS: Outcomes from the randomized, double-blind, TELESTO study10
Key Findings: All study patients received a mean of 20.28 and 20.27 international units of RBC transfusions 6 months prior to randomization. The median event-free-survival was prolonged by 349 days with deferasirox (1,440 days) vs placebo (1,091 days); risk reduction of 36% in event-free-survival was reported with deferasirox (P = .015). Estimated event-free-survival at 3 years was 61.5% with deferasirox and 47.3% with placebo. Events that occurred first with deferasirox (41.6%) and placebo (48.7%) included worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, progression to acute myeloid leukemia (AML), and death. The median overall survival was 1,907 days with deferasirox and 1,509 days with placebo, with a hazard ratio of 0.832. Iron chelation treatment after study treatment discontinuation may have diluted any potential overall survival difference. The most frequently reported adverse events (≥ 20% in either arm) were diarrhea, pyrexia, upper respiratory tract infection, cough, and increased blood creatinine.
Clinical Implications: The TELESTO trial is the first prospective, randomized study in patients with low- and intermediate-1–risk MDS who have iron overload (serum ferritin > 1,000 ng/mL, transfusion history of 15 to 75 RBC units, without cardiac, liver, and renal abnormalities) to show iron chelation therapy with deferasirox provides a clinical benefit across multiple tissues, leading to longer event-free-survival (including cardiac and liver events as well as transformation to AML) vs placebo. These results support the use of deferasirox in patients with low- and intermediate-1–risk MDS who have iron overload and may establish a new standard of care for transfusion-dependent patients with lower-risk MDS and iron loading. ■
Dr. Abutalib is Associate Director, Hematology and BMT Program; Director, Clinical Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; as well as Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. List is Professor of Medicine; President and Chief Executive Officer, Moffitt Cancer Center, Tampa, Florida.
DISCLOSURE: Dr. Abutalib is on the advisory board of AstraZeneca. Dr. List is a consultant/advisor for, has received honoraria and research funding from, has patent or intellectual property interest in, and has received travel/accommodations/expenses from Celgene.
1. Fenaux P, Platzbecker U, Mufti GJ, et al: The MEDALIST trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red blood cell transfusions. 2018 ASH Annual Meeting & Exposition. Abstract 1. Presented December 2, 2018.
2. Platzbecker U, Germing U, Götze KS, et al: Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): A multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol 18:1338-1347, 2017.
3. Steensma DP, Platzbecker U, Van Eygen K, et al: Imetelstat treatment leads to durable transfusion independence in RBC transfusion-dependent, non-del(5q) lower risk MDS relapsed/refractory to erythropoiesis-stimulating agent who are lenalidomide and HMA naive. 2018 ASH Annual Meeting & Exposition. Abstract 463. Presented December 2, 2018.
4. Garcia-Manero G, Jabbour EJ, Konopleva MY, et al: A clinical study of tomaralimab (OPN-305), a Toll-like receptor 2 antibody, in heavily pre-treated transfusion dependent patients with lower risk myelodysplastic syndromes that have received and failed on prior hypomethylating agent therapy. 2018 ASH Annual Meeting & Exposition. Abstract 798. Presented December 3, 2018.
5. Taylor J, Coleman M, Alvarez K, et al: Selinexor, a first-in-class XPO1 inhibitor, is efficacious and tolerable in patients with myelodysplastic syndromes refractory to hypomethylating agents. 2018 ASH Annual Meeting & Exposition. Abstract 233. Presented December 1, 2018.
6. Navada SC, Garcia-Manero G, Atallah EL, et al: Phase 2 expansion study of oral rigosertib combined with azacitidine in patients with higher-risk myelodysplastic syndromes: Efficacy and safety results in HMA treatment naive & relapsed/refractory patients. 2018 ASH Annual Meeting & Exposition. Abstract 230. Presented December 1, 2018.
7. Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al: Final report of a phase II study of guadecitabine (SGI-110) in patients with previously untreated myelodysplastic syndrome. 2018 ASH Annual Meeting & Exposition. Abstract 232. Presented December 1, 2018.
8. Garcia-Manero G, Ritchie EK, Walsh KJ, et al: Long term results of a randomized phase 2 dose-response study of guadecitabine, a novel subcutaneous hypomethylating agent, in 102 patients with intermediate or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. 2018 ASH Annual Meeting & Exposition. Abstract 231. Presented December 1, 2018.
9. O’Connell CL, Kropf PL, Punwani N, et al: Phase I results of a multicenter clinical trial combining guadecitabine, a DNA methyltransferase inhibitor, with atezolizumab, an immune checkpoint inhibitor, in patients with relapsed or refractory myelodysplastic syndrome or chronic myelomonocytic leukemia. 2018 ASH Annual Meeting & Exposition. Abstract 1811. Presented December 1, 2018.
10. Angelucci E, Li J, Greenberg PL, et al: Safety and efficacy, including event-free survival, of deferasirox versus placebo in iron-overloaded patients with low- and int-1-risk myelodysplastic syndromes: Outcomes from the randomized, double-blind TELESTO study. 2018 ASH Annual Meeting & Exposition. Abstract 234. Presented December 1, 2018.