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
1,991 drug discovery papers related to Myelodysplastic neoplasm with increased blasts, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
1,991 drug discovery papers related to Myelodysplastic neoplasm with increased blasts, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-05-21 | Venetoclax and azacytidine in childhood primary advanced myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia and therapy-related myeloid neoplasms.
Pediatric refractory/relapsed acute myeloid leukemia (r/r-AML), myelodysplastic syndromes with excess blasts (MDSEB), and therapy-related MDS/AML (t-MDS/AML) remain a clinical challenge due to high rate of treatment failure. Venetoclax plus azacytidine (ven/aza) has transformed adult myeloid neoplasm treatment, but pediatric data are limited and heterogeneous. This AIEOP retrospective, multicenter study analyzed 50 patients (M/F=1.8/1; median age 11 years) with r/r-AML (n=32), MDS-EB (n=10), or t-MDS/AML (n=8) treated with ven/aza. Responses were defined as complete (CR), partial (PR), or non-response (NR) based on bone marrow (BM) blast evaluation. Adverse events (AEs) were graded per CTCAE v5.0; outcomes were evaluated with Kaplan-Meier and Cox-regression analysis. Patients received a median of 2 cycles (range, 1-7). Grade ≥3 AEs occurred in 34% of patients. Overall, 30 patients (60%) achieved CR (24 MRD-negative), 9 (18%) PR, and 11 (22%) NR. CR were 58%, 57% and 100% in KMT2A-AML, FLT3-ITD-AML (ven/aza+FLT3-inhibitors) and UBTF-TD myeloid neoplasms, respectively. In 10 MDS-EB, 7 CR and 2 PR were recorded. In 8 t-MDS/AML, we observed 5 CR and 2 PR. Thirty-three patients (66%) underwent hematopoietic cell transplantation (HCT), after a median of 97 days (range: 33-933) from ven/aza start. Median follow-up was 389 days (range 36-1405). Two-year event-free survival (EFS) was 54.5% (CI:46.7-62.3), being 75.8% in transplanted patients, and 77.2% in those achieving CR. CR and HCT were associated with better EFS. Ven/aza shows substantial activity and manageable toxicity in pediatric high-risk myeloid diseases, especially as a bridge to HCT and in specific molecular subgroups, supporting future, prospective, genetically-guided studies.
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.
2026-05-21 | Venetoclax and azacytidine in childhood primary advanced myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia and therapy-related myeloid neoplasms.
Pediatric refractory/relapsed acute myeloid leukemia (r/r-AML), myelodysplastic syndromes with excess blasts (MDSEB), and therapy-related MDS/AML (t-MDS/AML) remain a clinical challenge due to high rate of treatment failure. Venetoclax plus azacytidine (ven/aza) has transformed adult myeloid neoplasm treatment, but pediatric data are limited and heterogeneous. This AIEOP retrospective, multicenter study analyzed 50 patients (M/F=1.8/1; median age 11 years) with r/r-AML (n=32), MDS-EB (n=10), or t-MDS/AML (n=8) treated with ven/aza. Responses were defined as complete (CR), partial (PR), or non-response (NR) based on bone marrow (BM) blast evaluation. Adverse events (AEs) were graded per CTCAE v5.0; outcomes were evaluated with Kaplan-Meier and Cox-regression analysis. Patients received a median of 2 cycles (range, 1-7). Grade ≥3 AEs occurred in 34% of patients. Overall, 30 patients (60%) achieved CR (24 MRD-negative), 9 (18%) PR, and 11 (22%) NR. CR were 58%, 57% and 100% in KMT2A-AML, FLT3-ITD-AML (ven/aza+FLT3-inhibitors) and UBTF-TD myeloid neoplasms, respectively. In 10 MDS-EB, 7 CR and 2 PR were recorded. In 8 t-MDS/AML, we observed 5 CR and 2 PR. Thirty-three patients (66%) underwent hematopoietic cell transplantation (HCT), after a median of 97 days (range: 33-933) from ven/aza start. Median follow-up was 389 days (range 36-1405). Two-year event-free survival (EFS) was 54.5% (CI:46.7-62.3), being 75.8% in transplanted patients, and 77.2% in those achieving CR. CR and HCT were associated with better EFS. Ven/aza shows substantial activity and manageable toxicity in pediatric high-risk myeloid diseases, especially as a bridge to HCT and in specific molecular subgroups, supporting future, prospective, genetically-guided studies.
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