DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for chronic myelomonocytic leukemia — screening already-approved drugs against its 47-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleChronic myelomonocytic leukemia maps to a 47-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for chronic myelomonocytic leukemia is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
Cbl proto-oncogene B (CBLB) — CBLB is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4-methyl-1,2,4-triazol-3-yldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QTG · 1.419 Å · ligand 3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1~{H}-pyridin-2-one (WUQ). Experimental structure, not a prediction.
What the evidence adds up to
In a Spanish registry study of 414 patients with chronic myelomonocytic leukemia, abnormal karyotype was found in 110 patients (27%) and was associated with poorer overall survival (P=0.001) and higher risk of acute myeloid leukaemia evolution (P=0.010). Three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), intermediate risk (all other abnormalities), and high risk (trisomy 8, abnormalities of chromosome 7, or complex karyotype). Five-year overall survival for low, intermediate, and high risk categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed cytogenetic risk as an independent prognostic variable for overall survival (P=0.001). High-risk cytogenetic category also predicted acute myeloid leukaemia evolution on univariate (P=0.001) but not multivariate analysis.
Consensus recommendations from Italian haematology societies, produced through a Delphi process, advise that first-line therapy should be stratified by disease subtype and bone marrow blast percentage. For myelodysplastic-type CMML with less than 10% blasts, supportive therapy to correct cytopenias is recommended. For myelodysplastic-type with 10% or more blasts, supportive therapy should be integrated with 5-azacytidine. For myeloproliferative-type CMML with low blasts (<10%), cytoreductive therapy with hydroxyurea is the drug of choice. For myeloproliferative-type with high blasts, polychemotherapy is recommended. Allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
Chronic myelomonocytic leukaemia remains a virtually incurable disease, most often seen in the elderly. At least one gene mutation can now be identified in almost all patients; the most frequently mutated genes are TET2, SRSF2, and ASXL1, with ASXL1 mutations defining a poor prognostic subgroup. Mutations in RUNX1 induce thrombocytopenia, those in SF3B1 can be associated with anaemia, and mutations in signalling molecules including NRAS, KRAS, CBL, JAK2, and FLT3 characterise proliferative forms of the disease. The malignant clone generates myeloid-derived suppressive cells that may contribute to disease expansion, and progenitor hypersensitivity to granulomonocyte colony-stimulating factor probably defines two distinct subgroups.
What is still missing are prospective trials that validate the cytogenetic risk stratification and the molecular subgroups as guides to therapy, and randomised comparisons of the recommended treatments — particularly 5-azacytidine versus hydroxyurea versus polychemotherapy — in defined molecular and cytogenetic strata. The rarity of the disease and the advanced age of most patients limit recruitment and funding for such trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2010 · 264 citations · open access
Cytogenetic risk stratification in chronic myelomonocytic leukemia
AbstractBACKGROUND: The prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes. DESIGN AND METHODS: We studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia. RESULTS: Patients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMML-specific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis. CONCLUSIONS: Cytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.
Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial
AbstractAbstract Background: Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of acute myeloid leukemia (AML). In-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. We present the results of the randomized placebo-controlled SORAML trial testing sorafenib versus placebo as add-on to standard induction and consolidation treatment in AML patients ≤60 years. Patients and Methods: Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1-3 plus mitoxantrone 10 mg/m2 days 3-5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a sibling donor and for all high-risk patients with a matched related or unrelated donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial was event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were relapse-free survival (RFS), overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the final analysis of the primary endpoint EFS (intent to treat) after the occurrence of 134 events. Results: Out of 276 enrolled patients, 267 received study treatment, 134 in the sorafenib arm and 133 in the placebo arm. Demographic and disease characteristics were equally distributed between the two arms; the incidence of FLT3-ITD was 17%. The median cumulative dose of administered study medication was similar in both arms. The CR rates were 59% versus 60% in the placebo versus sorafenib arm (p=0.764). After a median observation time of 36 months, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm, corresponding to a 3-year EFS of 22% versus 40% (p=0.013). Median RFS after standard treatment plus placebo was 23 months and not yet reached after sorafenib treatment, corresponding to a 3-year RFS of 38% and 56%, respectively (p=0.017). The median OS had not been reached in either arm; the 3-year OS was 56% with placebo versus 63% with sorafenib (p=0.382). In 46 FLT3-ITD positive patients, no difference in EFS, but a trend for prolonged RFS and OS in favor of sorafenib was observed. The most common reported AEs Grade ≥3 were fever (40%), infections (22%) and bleeding events (2%). The risk for fever, bleeding events and hand-foot syndrome was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences. Conclusions: In younger AML patients, the addition of sorafenib to standard chemotherapy in a sequential manner is feasible and associated with antileukemic efficacy. We observed a higher incidence of infections and bleeding events under sorafenib. Whereas OS in both treatment arms was similar, sorafenib treatment resulted in a significantly prolonged EFS and RFS. Figure 1: Event-free survival Figure 1:. Event-free survival Disclosures Off Label Use: sorafenib for treatment of aml. Serve:Bayer HealthCare: Research Funding. Ehninger:Bayer HealthCare: Research Funding.
Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups
AbstractWith the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥ 10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.
Sorafenib plus intensive chemotherapy in newly diagnosed <i>FLT3</i>-ITD AML: a randomized, placebo-controlled study by the ALLG
AbstractSorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.
International Journal of Hematologic Oncology · 2012 · 1 citations
Current Insights in the Cellular and Molecular Biology of Chronic Myelomonocytic Leukemia
AbstractSUMMARY Chronic myelomonocytic leukemia is a rare clonal myeloid disorder most often seen in the elderly that remains a virtually incurable disease. Chronic myelomonocytic leukemia has long been considered as a myelodysplastic syndrome by diagnostic classifications, but recent insights in the cellular and molecular biology of the disease has refined its identity. The malignant clone was shown to generate myeloid-derived suppressive cells that may contribute to disease expansion, whereas the role of progenitor hypersensitivity to granulomonocyte colony-stimulating factor probably defines two distinct subgroups. At least one gene mutation can now be identified in almost all the patients. The most frequently mutated genes are TET2, SRSF2 and ASXL1, with a frequent combination of mutations in the first two genes, whereas ASXL1 mutations define a poor prognostic subgroup of patients. A number of additional mutations have been identified that confer to the disease its phenotype specificity; for example, mutations in RUNX1 induce thrombocytopenia, those in SF3B1 can be associated with anemia, and those in signaling molecules including NRAS, KRAS, CBL, JAK2 and FLT3, characterize the proliferative forms of the disease. Based on these recent observations, new working models on disease pathogenesis are proposed and may serve as a basis for the search for alternative and more efficient therapeutic approaches.
American Journal of Clinical Pathology · 1979 · 0 citations
Chronic Myelomonocytic Leukemia
AbstractJournal Article Chronic Myelomonocytic Leukemia Get access Carl R. Kjeldsberg, M.D. Carl R. Kjeldsberg, M.D. Department of Pathology University of Utah College of Medicine Veterans Administration Hospital Salt Lake City, Utah Search for other works by this author on: Oxford Academic Google Scholar American Journal of Clinical Pathology, Volume 71, Issue 3, 1 March 1979, Page 357, https://doi.org/10.1093/ajcp/71.3.357 Published: 01 March 1979 Article history Received: 21 August 1978 Accepted: 21 August 1978 Published: 01 March 1979
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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