RARE DISEASE
Myelodysplastic neoplasm with increased blasts
Myelodysplastic neoplasm with increased blasts
Myelodysplastic neoplasm with increased blasts
Synonyms: MDS with excess blasts, MDS-IB, RAEB, Refractory anemia with excess blasts
Synonyms: MDS with excess blasts, MDS-IB, RAEB, Refractory anemia with excess blasts
Synonyms: MDS with excess blasts, MDS-IB, RAEB, Refractory anemia with excess blasts
Drug discovery
0
drugs
With orphan designations
Overview
Myelodysplastic neoplasm with increased blasts (MDS-IB), formerly classified as refractory anemia with excess blasts (RAEB), is a high-risk subtype of MDS characterized by cytopenias, dysplasia, and 5–19% bone marrow/blood blasts. Subtypes RAEB-1 (5–9% blasts) and RAEB-2 (10–19%) carry increased risks of acute myeloid leukemia (AML) transformation. Prognosis is poor due to progressive cytopenias, frequent infections, and treatment-resistant anemia. Molecular abnormalities, including TP53 mutations, further stratify risk [1][6][10][15].
Burden
AML progression: 5–29% overall, rising to 33% in RAEB-2 [6][15].
Survival: Median <2 years (RAEB-1: ~16 months; RAEB-2: 3–12 months) [6][15].
Morbidity/mortality: Driven by infections (neutropenia), bleeding (thrombocytopenia), transfusion dependence, and treatment-related complications [1][12][15].
Therapies
First-line: Hypomethylating agents (azacitidine, decitabine) to delay AML progression [3][7][11].
Curative intent: Allogeneic stem cell transplant for eligible patients; AML-like chemotherapy (e.g., cytarabine) used pre-transplant [3][7][15].
Emerging options: Targeted therapies (e.g., ivosidenib for IDH1 mutations) and clinical trials testing novel combinations [7][11][14].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,995 drug discovery papers about Myelodysplastic neoplasm with increased blasts, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,995 drug discovery papers about Myelodysplastic neoplasm with increased blasts, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology
In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
2026-08-14 | Data from Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine
<div>Abstract Purpose:<p>The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate antiapoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a phase I study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with advanced myeloid malignancies.</p> Patients and Methods:<p>Eligible patients had a diagnosis of (i) secondary or therapy-related AML, (ii) accelerated- or blast-phase myelofibrosis (AP/BP-MF), (iii) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or (iv) relapsed/refractory (R/R) MDS with excess blasts. In 28-day cycles, subjects received navitoclax doses of 25 or 50 mg/day given for days 3 to 14 during cycle 1 and days 1 to 14 in subsequent cycles, target venetoclax doses of 400 mg/day given for days 1 to 14 or days 1 to 21 depending on the myeloid malignancy subtype, and decitabine doses of 20 mg/m<sup>2</sup>/day given for days 1 to 5.</p> Results:<p>Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase II dose was decitabine 20 mg/m<sup>2</sup> days 1 to 5, venetoclax 400 mg/day days 1 to 14, and navitoclax 50 mg/day days 1 to 14 for AP-MF, MDS/MPN, and R/R MDS, respectively. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects.</p> Conclusions:<p>Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.</p></div>
2026-07-29 | Venetoclax combined with azacitidine in the treatment of secondary myelodysplastic syndrome following multiple myeloma: a case report and literature review.
We conducted a retrospective analysis of the clinical data of a patient with myelodysplastic syndrome (MDS) secondary to stable multiple myeloma (MM), who was treated with a combination of venetoclax and azacitidine at the Fifth People's Hospital of Chengdu. Additionally, we reviewed the relevant literature. The patient, a 74-year-old male, was initially diagnosed with multiple myeloma (IgA-γ, DS IIIA, ISS III, R-ISS II) and achieved a very good partial response (VGPR) following sequential treatments with BCTD, RVD, and PVD regimens, subsequently receiving maintenance therapy with pomalidomide. Despite being in continuous remission, the patient developed secondary myelodysplastic syndrome characterized by refractory anemia with excess blasts-2 (MDS-RAEB-II) 51 months post-initial MM diagnosis. He was then treated with venetoclax in combination with azacitidine. After the first treatment course, the patient achieved morphological partial remission of MDS. However, due to non-adherence to continuous treatment, he ultimately succumbed to a secondary infection.
2026-06-30 | A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML
Pre-mRNA splicing gene mutations are common in MDS and CMML and induce R-loops which trigger ATR activation. We studied ceralasertib, an orally bioavailable ATR inhibitor, in adult patients with R/R MDS or CMML in a phase Ib/II study including a safety run-in and expansion of 160mg BID during a 28-day cycle on two schedules: days 1-14 (14on/14off) or days 1-7 and 15- 21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade 3 or higher all-cause adverse events in 10% or more patients included thrombocytopenia (n=13), anemia (n=12), neutropenia (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared to 8 of 16 patients on 14on/14off among patients with a baseline platelet count >50k (p=0.087). ORR was 29.5% (13 of 44 patients) and included one CR, 5 marrow CR (2 with HI-N), and 7 with HI (HI-E=4, HI-N=2, HI-P=1). Median PFS was 4.8mo and OS was 12 months (95%CI 11, 24). ORR (p=0.72), PFS (p=0.9) and OS (p=0.65) did not differ between schedules. While splicing factor mutation VAFs were stable, RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels including TNFRSF8 (CD30) and other TNF family members decreased during ceralasertib exposure; this effect was blunted in RUNX1 mutant samples. In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.
2026-05-26 | Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts. Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects. Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.
2026-08-14 | EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology
In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
2026-08-14 | Data from Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine
<div>Abstract Purpose:<p>The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate antiapoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a phase I study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with advanced myeloid malignancies.</p> Patients and Methods:<p>Eligible patients had a diagnosis of (i) secondary or therapy-related AML, (ii) accelerated- or blast-phase myelofibrosis (AP/BP-MF), (iii) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or (iv) relapsed/refractory (R/R) MDS with excess blasts. In 28-day cycles, subjects received navitoclax doses of 25 or 50 mg/day given for days 3 to 14 during cycle 1 and days 1 to 14 in subsequent cycles, target venetoclax doses of 400 mg/day given for days 1 to 14 or days 1 to 21 depending on the myeloid malignancy subtype, and decitabine doses of 20 mg/m<sup>2</sup>/day given for days 1 to 5.</p> Results:<p>Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase II dose was decitabine 20 mg/m<sup>2</sup> days 1 to 5, venetoclax 400 mg/day days 1 to 14, and navitoclax 50 mg/day days 1 to 14 for AP-MF, MDS/MPN, and R/R MDS, respectively. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects.</p> Conclusions:<p>Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.</p></div>
2026-07-29 | Venetoclax combined with azacitidine in the treatment of secondary myelodysplastic syndrome following multiple myeloma: a case report and literature review.
We conducted a retrospective analysis of the clinical data of a patient with myelodysplastic syndrome (MDS) secondary to stable multiple myeloma (MM), who was treated with a combination of venetoclax and azacitidine at the Fifth People's Hospital of Chengdu. Additionally, we reviewed the relevant literature. The patient, a 74-year-old male, was initially diagnosed with multiple myeloma (IgA-γ, DS IIIA, ISS III, R-ISS II) and achieved a very good partial response (VGPR) following sequential treatments with BCTD, RVD, and PVD regimens, subsequently receiving maintenance therapy with pomalidomide. Despite being in continuous remission, the patient developed secondary myelodysplastic syndrome characterized by refractory anemia with excess blasts-2 (MDS-RAEB-II) 51 months post-initial MM diagnosis. He was then treated with venetoclax in combination with azacitidine. After the first treatment course, the patient achieved morphological partial remission of MDS. However, due to non-adherence to continuous treatment, he ultimately succumbed to a secondary infection.
2026-06-30 | A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML
Pre-mRNA splicing gene mutations are common in MDS and CMML and induce R-loops which trigger ATR activation. We studied ceralasertib, an orally bioavailable ATR inhibitor, in adult patients with R/R MDS or CMML in a phase Ib/II study including a safety run-in and expansion of 160mg BID during a 28-day cycle on two schedules: days 1-14 (14on/14off) or days 1-7 and 15- 21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade 3 or higher all-cause adverse events in 10% or more patients included thrombocytopenia (n=13), anemia (n=12), neutropenia (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared to 8 of 16 patients on 14on/14off among patients with a baseline platelet count >50k (p=0.087). ORR was 29.5% (13 of 44 patients) and included one CR, 5 marrow CR (2 with HI-N), and 7 with HI (HI-E=4, HI-N=2, HI-P=1). Median PFS was 4.8mo and OS was 12 months (95%CI 11, 24). ORR (p=0.72), PFS (p=0.9) and OS (p=0.65) did not differ between schedules. While splicing factor mutation VAFs were stable, RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels including TNFRSF8 (CD30) and other TNF family members decreased during ceralasertib exposure; this effect was blunted in RUNX1 mutant samples. In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.
2026-05-26 | Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts. Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects. Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.
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