Novel Insights in Myelodysplastic Syndromes: Highlights From 2020 ASH Meeting

Get Permission

To complement The ASCO Post’s comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel clinical trial findings in myelodysplastic syndromes (MDS). For full details of these study abstracts, visit

Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Peter Greenberg, MD

Peter Greenberg, MD

Molecular Genetic Markers in MDS

ABSTRACT 538: Molecular genetic analysis for diagnostic and prognostic decision-making in clonal cytopenia of undetermined significance (CCUS) and MDS1

Background: The term CCUS defines individuals with myeloid mutations and some degree of cytopenia but without fulfilling criteria for MDS or other hematologic diagnoses.2 The availability of routine next-generation sequencing allowed the investigators of this study to (1) identify the frequency and type of clonality in MDS and CCUS cohorts; (2) further subcategorize patients with CCUS as at low or high risk of developing MDS; and (3) to identify subsets of patients with CCUS and MDS with possible targetable mutations. In a study by Malcovati and colleagues,3 SF3B1 mutation was almost invariably associated with subsequent development of overt MDS with ring sideroblasts in patients with CCUS; their findings suggested this mutation might be included among the genetic lesions that provide presumptive evidence of MDS, even in the absence of definitive morphologic features of MDS.

Methods: This study analyzed morphologic and cytogenetic data according to the 2016 revision of the World Health Organization (WHO) classification2 standard algorithms in 576 patients (median age, 72 years [17–94 years]) with cytopenia and clinical conditions requiring bone marrow biopsy and aspirate to exclude or diagnose MDS (Table 1). Individuals with other possible explanations (eg, lymphoma, paroxysmal nocturnal hemoglobinuria) were excluded upfront by combining morphology and flow cytometry.

Results: A total of 499 mutations were detected in 85% of patients (181 of 213) with a diagnosis of MDS, and 259 mutations were detected in 36% (132 of 363) of other patients with non-MDS cytopenia (idiopathic cytopenia of undetermined significance [ICUS] or CCUS; P < .01). The typical aging pattern mutations (DNMT3A, TET2, and ASXL1) as the sole molecular genetic aberration (variant allele frequency < 10%) were significantly more frequent in the CCUS cohort than in the MDS cohort—25% vs 4%, respectively (P < .01).

In the CCUS cohort, 5% of individuals (7 of 132, P = .03) had an SF3B1 mutation. About 55% of patients (72 of 132) in the CCUS cohort, which corresponds to 20% of patients with cytopenia without a definitive diagnosis of MDS (72 of 363), had a highly specific clinical pattern (20% risk of developing a WHO-defined myeloid malignancy/year).3,4

A potential for targeted therapies (mutations in CSNK1A1, FLT3 [ITD, TKD], IDH1, IDH2, KRAS, NRAS) was found in 6% (12 of 213) of the remaining patients with MDS and 3% (4 of 132) of the patients with CCUS.

Clinical Implications: MDS with isolated del(5q) remains the only MDS subtype defined by a genetic abnormality.2 Evidence supports recognition of SF3B1-mutant cytopenia of undetermined significance as a distinct nosologic entity. Proposed diagnostic criteria for MDS with mutated SF3B1 have been suggested on behalf of the International Working Group for the Prognosis of MDS.5 However, prospective studies are warranted to validate these observations and establish the value of SF3B1-mutated (and other molecular) clones in the context of ICUS/CCUS. 

Patients diagnosed with ICUS or CCUS should be regularly monitored to avoid neglect of progression to MDS/acute myeloid leukemia (AML). The study also showed that two-thirds of patients with MDS and one-third of patients with CCUS had targetable mutation(s); these patients might benefit from personalized treatment approaches (eg, luspatercept in SF3B1-mutated CCUS or enasidenib in IDH2-mutated MDS).

Lenalidomide in Lower-Risk MDS

ABSTRACT 536: Interim analysis after completion of fixed-duration treatment from the Sintra-REV trial of lenalidomide (5 mg daily) vs placebo in patients with nontransfusion-dependent lower-risk del(5q) MDS ( identifier NCT01243476)6

Background: Lenalidomide therapy is recommended in patients with lower-risk, isolated del(5q) MDS with symptomatic anemia. The usual dose in this setting is 10 mg once daily continuously until disease progression or unacceptable toxicity. Patients with lower-risk del(5q) MDS with anemia who are transfusion independent develop transfusion dependence or need treatment for symptomatic anemia after diagnosis (median time to transfusion/treatment, 20 months).7 Retrospective data suggest a role for lenalidomide in nontransfusion-dependent patients with del(5q) MDS.8 The Sintra-REV clinical trial6 is a phase III European multicenter randomized study in patients with low-risk del(5q) MDS with anemia (hemoglobin < 12 g/dL; median hemoglobin at inclusion, 9.8 g/dL) who are asymptomatic and do not require red blood cell transfusion.

Methods: The primary endpoint was the time to transfusion dependence. Patients were randomly assigned in a double-blind fashion to receive lenalidomide (n = 40; 5 mg once daily continuously) vs placebo (n = 21; 2:1 randomization) for 2 years of treatment and 2 years of follow-up. Overall, 57 patients were included in the intent-to-treat evaluable population for efficacy and 59, for safety (2 patients did not receive any drug). The median age was 72 years (range, 37–89 years), the median time since diagnosis was 3.6 months, and the median hemoglobin level at inclusion was 9.8 g/dL (7.1–11.7 g/dL); 93% of patients had isolated del(5q).

Results: About 47% of patients in the lenalidomide arm successfully completed the study, compared with 33% in the placebo arm.The median time to transfusion dependence was 75.7 months with lenalidomide and 25.9 months with placebo (hazard ratio [HR] = 2.703, 95% confidence interval [CI] = 1.162–6.286, P = .021). About 80% of patients treated with lenalidomide achieved a cytogenetic response, compared with 4.8% of patients given placebo (P < .001, complete cytogenetic response of 70% in the experimental arm).

After a median follow-up of 25.6 months, the overall survival was similar in both arms (not reached), whereas the event-free survival was superior with lenalidomide (HR = 2.274, 95% CI = 1.034–5.001, P = .041). AML evolution was similar in both arms (5%).

Hematologic toxicity occurred in 40 patients in the lenalidomide arm (50% grades 3 and 4) and 4 patients in the placebo arm (25% grade 3 and 4). At least one serious adverse event was seen in 31.6% of those given lenalidomide, compared with 4.8% of those given placebo (P = .022), and it was not considered to be related to the drug. A total of 19 serious adverse events were reported in 13 patients, 4 of them (second neoplasia, pulmonary embolism, febrile neutropenia, and blurred vision) were potentially related to lenalidomide, with no related deaths.

MDS with isolated del(5q) remains the only MDS subtype defined by a genetic abnormality.
— Syed Ali Abutalib, MD, and Peter Greenberg, MD

Tweet this quote

Clinical Implications: The interim analysis of the European Sintra-REV study confirmed that low doses of lenalidomide in patients with anemic (nontransfusion-dependent) low-risk del(5q) MDS prolonged the time to transfusion dependence, improved hemoglobin levels (72.5% of erythroid response; P < .001), and induced clonal responses (70% complete cytogenetic response). As no survival benefit was reported and a higher toxicity profile was noted in the experimental arm, longer follow-up is needed before this treatment approach can be recommended.

MDS and CMML With Genetic Mutation

ABSTRACT 539: MDS and chronic myelomonocytic leukemia (CMML) with TET2 or IDH mutation: Association with systemic inflammatory and autoimmune diseases and T-cell dysregulation9

Background: Approximately 20% of cases of MDS and CMML are associated with systemic inflammatory and autoimmune diseases, but pathophysiologic mechanisms underlying this association remain largely unknown, and data on somatic mutations are scarce. Autoreactive T lymphocytes play a major role in the development of systemic inflammatory and autoimmune diseases. The main objective of this study was to investigate the mutational landscape of MDS and CMML associated with systemic inflammatory and autoimmune diseases and its impact on the immunologic phenotype of T lymphocytes.

Methods: Investigators used next-generation sequencing (80 genes) to analyze patients with MDS and CMML who had associated systemic inflammatory and autoimmune diseases (n = 85 of 404; 21%) compared with patients with MDS and CMML without such diseases (n = 319 of 404), who constituted the control cohort. The median number of mutations was two in both cohorts. Flow cytometry was performed on peripheral blood samples from 28 patients with MDS and CMML (of whom 12 of 28 had systemic inflammatory and autoimmune diseases) and 18 healthy controls, to study CD8-positive T-lymphocyte subsets and the expression of immune checkpoints.

Results: TET2 mutations were found in 46% of patients (39 of 85) and 34% of patients (108 of 319) in the systemic inflammatory and autoimmune diseases and control cohorts, respectively (P = .04). IDH1 or IDH2 mutation was noted in 14% of patients (12 of 85) in the systemic inflammatory and autoimmune diseases cohort vs 4% (14 of 319) in the control group (P < .01).

When considering both patients with TET2 and IDH mutations, the study authors found that their mutations were more frequent in the systemic inflammatory and autoimmune diseases cohort than in the control cohort: 60% (51 of 85) vs 38% (122 of 319), respectively (P < .01). SRSF2 mutations were also more frequent in the systemic inflammatory and autoimmune diseases cohort: 31% (26 of 85) vs 15% (47 of 319; P < .01), but they were correlated with the presence of TET2 or IDH mutations in both cohorts (P < .01). There was no difference in the rate of mutations in other genes.

The proportion of CD8+CD96+ T cells was significantly reduced in patients with TET2/IDH mutations compared with those who had TET2/IDH wild-type disease (48.8% vs 71.1%, respectively, P < .05).

Clinical Implications: This retrospective analysis suggests common mechanisms may underlie both systemic inflammatory and autoimmune diseases and MDS and CMML. A retrospective study10 has shown that azacitidine was frequently effective (n = 16 of 22; 73%) in controlling steroid-dependent systemic inflammatory and autoimmune diseases associated with MDS and CMML, but prospective studies are necessary to confirm these findings. CD96 is an immune checkpoint that regulates CD8-positive T-cell functions, activation, and effector responses. The findings of this study suggest reduced control against autoimmune reactivity in patients with MDS and CMML harboring TET2 and IDH2 mutations.

Imetelstat in Lower-Risk MDS

ABSTRACT 658: IMerge (MDS3001) Study—Treatment with imetelstat provides durable transfusion independence in heavily transfused non-del(5q) lower-risk MDS relapsed and refractory to erythropoiesis-stimulating agents (ESAs) in patients who are naive to lenalidomide and hypomethylating treatment—Long-term efficacy, safety, and biomarker updates from the open-label, single-arm phase II portion of the study (NCT02598661)11

Background: Patients with lower-risk MDS who are red blood cell transfusion dependent and have ESA-refractory or -resistant disease have limited treatment options of lenalidomide or hypomethylating agents. 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.

Methods: Patients received imetelstat at 7.5 mg/kg intravenously every 4 weeks.

Results: For 38 patients followed for a median of 24 months, imetelstat achieved an 8-week transfusion independence rate of 42%, for a median duration of 20 months, and 29% of patients achieved transfusion independence for at least 1 year. A total of 12 patients showed a hemoglobin rise of at least 3 g/dL during the transfusion-free interval compared with the pretreatment level. Furthermore, a high and durable erythroid response rate (68%, for a median of 21 months) was also achieved in heavily red blood cell transfusion dependent, ESA-refractory or -resistant lower-risk-MDS. Most frequently reported adverse events were manageable and reversible grade ≥ 3 cytopenias. Of note, five of six patients with IPSS-R (Revised International Prognostic Scoring System) intermediate or poor cytogenetic risk achieved at least 8 weeks of transfusion independence, all with ring sideroblastic WHO subtypes; three patients had at least 1 year of transfusion independence.

Clinical Implications: Single-agent imetelstat yielded a transfusion independence rate of 42%, with a median duration of 20 months and limited side effects. Enrollment is ongoing in the phase III portion of the IMerge study, a placebo-controlled trial of the efficacy and safety of imetelstat, including potential predictive biomarkers of response.

Single-agent imetelstat yielded a transfusion independence rate of 42%, with a median duration of 20 months and limited side effects.
— Syed Ali Abutalib, MD, and Peter Greenberg, MD

Tweet this quote

Venetoclax/Azacitidine in Higher-Risk MDS

ABSTRACT 656: Safety, efficacy, and patient-reported outcomes of venetoclax/azacitidine for treatment-naive patients with higher-risk MDS: A phase Ib study (NCT02942290)12

Background: Hypomethylating agents form the current standard treatment for patients with higher-risk MDS who are not prepared (pending selection for an allogeneic donor) or ineligible for allogeneic hematopoietic cell transplantation. The overall response rates remain low, at 38%, in patients receiving azacitidine, and the median overall survival is reported as approximately 15 months.13 Venetoclax is a selective, potent, orally bioavailable BCL2 inhibitor, which has demonstrated synergy with azacitidine in preclinical studies of higher-risk-MDS. On October 16, 2020, the U.S. Food and Drug Administration approved venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults aged 75 or older precluding intensive induction chemotherapy.14,15

Methods: To test the safety and efficacy of venetoclax (400 mg once daily for 14 days in a 28-day cycle) with azacitidine (75 mg/m2 given subcutaneously or intravenously on days 1–7 of each 28-day cycle), investigators administered these drugs to 57 patients with higher-risk MDS who had not previously been treated. The patients ranged in age from 26 to 85 years, with a median age of 71 years. Patients with MDS commonly report fatigue and poor quality of life due to underlying disease, so the study also evaluated patient-reported outcomes while the population was on treatment. The median follow-up of the study was 13.0 months (95% CI = 11.3–15.6 months) at data cutoff.

Results: The overall response rate was 77%, including a complete remission rate of 42% and a marrow complete response rate of 42%. The median overall survival was not reached; the median duration of response was 14.8 months (95% CI = 12.9 months to not estimable). The median progression-free survival was 17.5 months (95% CI = 14.5 months to not estimable).

The most commonly reported adverse events were constipation, neutropenia, and nausea. The most common serious adverse events were caused by myelosuppression (neutropenia 51%, febrile neutropenia 46%, and thrombocytopenia 30%). The 30-day mortality rate was 2%. Clinically meaningful improvement in fatigue and shortness of breath was achieved by the beginning of cycle 5 and was maintained through week 48.

Clinical Implications: The combination of venetoclax/azacitidine demonstrates promising efficacy, including response durability, and an acceptable safety profile for treatment-naive patients with higher-risk MDS. Based on these data, a phase III clinical trial (VERONA) was launched comparing azacitidine plus venetoclax with azacitidine plus placebo for the treatment of higher-risk MDS. Also, for consideration, review Abstract 190,16 which highlights a phase I study testing the safety and efficacy of adding venetoclax (400 mg on days –8 to –2) to fludarabine and busulfan reduced-intensity conditioning prior to allogeneic hematopoietic cell transplantation in patients with high-risk myeloid malignancies. 

Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at the Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Greenberg is Professor Emeritus and Director of the Stanford MDS Center at the Stanford Cancer Institute, Division of Hematology, Stanford University School of Medicine, Stanford, California.

DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Greenberg has received research funds from Celgene, Gilead Sciences, Aprea Therapeutics, and Notable Labs.


1. Baer C, Stengel A, Kern W, et al: The potential of molecular genetic analysis for diagnostic and prognostic decision making in clonal cytopenia of undetermined significance and MDS: A study on 576 patients. 2020 ASH Annual Meeting & Exposition. Abstract 538. Presented December 7, 2020.

2. Swerdlow SH, Campo E, Harris NL, et al, eds: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon, France, International Agency for Research in Cancer, 2017.

3. Malcovati L, Gallì A, Travaglino E, et al: Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129:3371-3378, 2017.

4. Kwok B, Hall JM, Witte JS, et al: MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 126:2355-2361, 2015.

5. Malcovati L, Stevenson K, Papaemmanuil E, et al: SF3B1-mutant MDS as a distinct disease subtype: A proposal from the International Working Group for the Prognosis of MDS. Blood 136:157-170, 2020.

6. López Cadenas F, Lumbreras E, Xicoy B, et al: Phase 3 study of lenalidomide vs placebo in non-transfusion dependent low risk del(5q) MDS patients: Interim analysis of the European Sintra-REV trial. 2020 ASH Annual Meeting & Exposition. Abstract 536. Presented December 7, 2020.

7. Rojas SM, Díez-Campelo M, Luño E, et al: Transfusion dependence development and disease evolution in patients with MDS and del(5q) and without transfusion needs at diagnosis. Leuk Res 38:304-309, 2014.

8. Oliva EN, Lauseker M, Aloe Spiriti MA, et al: Early lenalidomide treatment for low and intermediate-1 International Prognostic Scoring System risk myelodysplastic syndromes with del(5q) before transfusion dependence. Cancer Med 4:1789-1797, 2015.

9. Zhao LP, Boy M, Azoulay C, et al: MDS/CMML with TET2 or IDH mutation are associated with systemic inflammatory and autoimmune diseases and T cell dysregulation. 2020 ASH Annual Meeting & Exposition. Abstract 539. Presented December 7, 2020.

10. Fraison JB, Mekinian A, Grignano E, et al: Efficacy of azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res 43:13-17, 2016.

11. Platzbecker U, Fenaux P, Steensma DP, et al: Treatment with imetelstat provides durable transfusion independence in heavily transfused non-del(5q) lower risk MDS relapsed/refractory to erythropoiesis stimulating agents. 2020 ASH Annual Meeting & Exposition. Abstract 658. Presented December 7, 2020.

12. Garcia JS, Wei AH, Borate U, et al: Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: A phase 1b study. 2020 ASH Annual Meeting & Exposition. Abstract 656. Presented December 7, 2020.

13. Sekeres MA, Othus M, List AF, et al: Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753, 2017. 

14. DiNardo CN, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.

15. Wei AH, Montesinos P, Ivanov V, et al: Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: A phase 3 randomized placebo-controlled trial. Blood 135:2137-2145, 2020.

16. Garcia JS, Kim H, Cutler C, et al: Safety and efficacy of adding venetoclax to reduced intensity conditioning chemotherapy prior to allogeneic hematopoietic cell transplantation in patients with high risk myeloid malignancies. 2020 ASH Annual Meeting & Exposition. Abstract 190. Presented December 5, 2020.