DeCure for B-lymphoblastic leukemia/lymphoma with hypodiploidy
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for B-lymphoblastic leukemia/lymphoma with hypodiploidy — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleB-lymphoblastic leukemia/lymphoma with hypodiploidy maps to a 1-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 b-lymphoblastic leukemia/lymphoma with hypodiploidy 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.
What the evidence adds up to
Of 457 adults with precursor B-ALL treated at one hospital, 44 (9.6%) had a prior malignancy. Among those, 30 had received cytotoxic therapy and showed a significantly shorter interval to onset of B-ALL (36 versus 144 months). The frequencies of t(4;11)(q21;q23) and hypodiploidy with loss of chromosome 5, 7 or 17 were significantly higher in patients who had received topoisomerase II inhibitors or alkylating agents. These patients were older, had a lower complete remission rate, and showed inferior survival in univariate analysis, though not in multivariate analysis. The authors conclude that therapy-related B-ALL with these cytogenetic abnormalities has a poor prognosis.
Hypodiploid B-ALL with fewer than 40 chromosomes is rare. Five-year overall survival is below 50% in children and below 20% in adults. Half of these cases show chromosome doubling of the hypodiploid clone, producing clones with 50–78 chromosomes that can be mistaken for good-prognosis hyperdiploidy. In a Children’s Oncology Group study of 8091 children, 92 (1.1%) had cytogenetics suggestive of hypodiploidy. Among these, 23 patients (25%) displayed only the doubled clone; in 13 of those 23, DNA index and FISH did not reveal the underlying hypodiploidy, making the hypodiploidy masked. Loss of heterozygosity studies confirmed the doubling in all 13. No statistically significant differences in NCI risk group or induction response were found between masked and visible hypodiploid cases, but numbers were too small for outcome analysis.
In a single-centre Egyptian study of 77 children with lymphoblastic lymphoma treated on St Jude Total Therapy XV, 4-year overall survival was 86.45% and event-free survival 82.18%. All relapsed patients had T-cell disease and advanced stage at presentation; none survived salvage chemotherapy. Common toxicities included cerebral venous thrombosis (20%), bone infarcts (10.6%), and avascular necrosis of the femoral head (9.3%). One patient developed secondary acute myeloid leukaemia. A separate review notes that relapsed and refractory T-lymphoblastic lymphoma remains an active problem, with targeted drugs under investigation but no established standard.
What is still missing are prospective trials that stratify hypodiploid B-ALL by masked versus visible status, sufficient sample sizes to compare outcomes between these subgroups, and validated strategies for relapsed T-lymphoblastic lymphoma. Funding for multi-centre collaboration and for molecular studies to identify druggable targets in hypodiploid clones is lacking.
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 · 2011 · 47 citations · open access
Precursor B-acute lymphoblastic leukemia occurring in patients with a history of prior malignancies: is it therapy-related?
AbstractBACKGROUND: Precursor B-acute lymphoblastic leukemia occurring in patients with a history of malignancies is uncommon, and this condition is not well understood. DESIGN AND METHODS: A retrospective review of 457 adults with precursor B-acute lymphoblastic leukemia treated at our hospital identified 44 (9.6%) patients with prior malignancies. The clinical and genetic characteristics of this group of patients was compared with those of their counterparts with de novo disease and the relationship with prior chemoradiation therapy was assessed. RESULTS: Thirty of 44(6.2%) patients received cytotoxic therapies, whereas 14 patients did not. The former group showed a significantly shorter interval from prior malignancy to onset of precursor B-acute lymphoblastic leukemia (36 versus 144 months; P = 0.002). Compared with 413 de novo cases, the frequencies of t(4;11)(q21;q23) (P<0.001) and hypodiploidy (P = 0.009) with loss of chromosome 5, 7 or 17 were significantly higher in patients who received topoisomerase II inhibitor and/or alkylating agents. By contrast, Philadelphia-positive and normal karyotype were more frequent in patients who either did not receive chemotherapy or received only local radiation or nucleoside analogs. Patients with precursor B-acute lymphoblastic leukemia following prior malignancies and chemoradiation were older, had a lower complete remission rate and showed an inferior survival in univariate, but not multivariate analysis. CONCLUSIONS: The data support the interpretation that therapy-related precursor B-acute lymphoblastic leukemia does occur. In particular, cases associated with t(4;11)(q21;q23) or hypodiploidy with -5, -7, -17 are likely to be therapy-related and have a poor prognosis. The inferior outcome of these patients may be attributable to the high-risk cytogenetic abnormalities that are found in this group of patients.
Pediatric Hematology and Oncology · 2013 · 37 citations
Mature B-Cell Lymphoma and Leukemia in Children and Adolescents—Review of Standard Chemotherapy Regimen and Perspectives
AbstractMature B-cell non-Hodgkin lymphoma (B-NHL) comprises more than 50% of all non-Hodgkin lymphoma (NHL) in children and adolescents. Many B-NHL subtypes frequently observed in adults are rarely diagnosed in children and adolescents. In this age group, Burkitt lymphoma (BL), Burkitt leukemia or FAB L3 leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBL), follicular lymphoma (FL), and aggressive mature B-NHL not further classifiable (B-NHL nfc) are the most common subtypes. Diverse clinical trials demonstrated similar results of current combination chemotherapy regimens succeeding in overall survival rates of more than 80%. However, treatment-related toxicity and the poor prognosis of relapse are serious concerns. Furthermore, specific histological B-NHL subtypes are rare in children and optimal treatment is not established. New treatment modalities are urgently needed for these patient groups. Rituximab, a monoclonal antibody that is already established in the treatment of adults with mature B-NHL, demonstrated promising results in pediatric patients. The definitive role of rituximab in the treatment of children and adolescents with B-NHL needs to be evaluated in prospective controlled clinical trials. This review provides a comprehensive overview of chemotherapy regimens and the perspectives for children and adolescents with mature B-cell lymphoma and leukemia.
Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much
AbstractHypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-cell acute lymphoblastic leukemia (B-ALL). This condition can be classified based on modal chromosome number as low-hypodiploidy (30-39 chromosomes) and near-haploidy (24-29 chromosomes), with unique cytogenetic and mutational landscapes. Hypodiploid B-ALL with <40 chromosomes has an extremely poor outcome, with 5-year overall survival rates below 50% and 20% in childhood and adult B-ALL, respectively. Accordingly, this genetic feature represents an adverse prognostic factor in B-ALL and is associated with early relapse and therapy refractoriness. Notably, half of all patients with hypodiploid B-ALL with <40 chromosomes cases ultimately exhibit chromosome doubling of the hypodiploid clone, resulting in clones with 50-78 chromosomes. Doubled clones are often the major clones at diagnosis, leading to "masked hypodiploidy", which is clinically challenging as patients can be erroneously classified as hyperdiploid B-ALL. Here, we summarize the main cytogenetic and molecular features of hypodiploid B-ALL subtypes, and provide a brief overview of the diagnostic methods, standard-of-care treatments and overall clinical outcome. Finally, we discuss molecular mechanisms that may underlie the origin and leukemogenic impact of hypodiploidy and may open new therapeutic avenues to improve survival rates in these patients.
Masked Hypodiploidy: Hypodiploid Acute Lymphoblastic Leukemia (ALL) in Children Mimicking Hyperdiploid ALL: A Report From the Children's Oncology Group (COG) AALL03B1 Study.
AbstractAbstract Abstract 1580 Poster Board I-606 Hyperdiploidy with greater than 50 chromosomes is usually associated with a good prognosis in childhood acute lymphoblastic leukemia (ALL). By contrast, hypodiploidy with 44 or fewer chromosomes is a recurring abnormality detected in approximately 1% of children with ALL and is associated with an extremely poor prognosis with a projected event-free survival of less than 35% (Nachman et al Blood 110:1112, 2007; Harrison et al Br J Haematol 125:552, 2004; Raimondi et al Cancer 98:2715, 2003). Three distinct subgroups of hypodiploidy are recognized; near-haploidy (24-31 chromosomes), low hypodiploidy (32-39 chromosomes), and high hypodiploidy (40-44 chromosomes). It is common for leukemic cells with near-haploid or low hypodiploid chromosome numbers to undergo an exact or nearly exact doubling of the hypodiploid clone that results in a modal chromosome number in the hyperdiploid range, which might be misconstrued as indicating a good prognosis. In these cases of hypodiploid doubling, most chromosomes will be disomic or tetrasomic, but not trisomic. These cases are usually found to be mosaic with both hypodiploid and hyperdiploid (doubled) clones visible by standard cytogenetics, DNA Index (DI) by flow cytometry, and/or fluorescence in situ hybridization (FISH). We reviewed the cytogenetics and presenting clinical features of children with ALL enrolled on the COG AALL03B1 study between 12/29/03 and 6/30/09. Among 8091 eligible patients, 92 (1.1%) had abnormal cytogenetics that were suggestive of hypodiploidy with fewer than 44 chromosomes. Of the 92 hypodiploid patients with visible chromosome abnormalities 54 were near-haploid, 32 low hypodiploid, and 6 high hypodiploid. Thirty-three patients (36%) had only the hypodiploid clone, 36 (39%) were mosaics with both a hypodiploid and a doubled hypodiploid clone identified, and most importantly, 23 (25%) patients displayed only the doubled hypodiploid clone. While the few previously described cases with only the doubled clone have always been shown to have evidence of hypodiploidy by DI, we found that only 10 of these 23 cases had a DNA index that suggested the presence of a hypodiploid clone. The remaining 13 cases had ploidy and FISH results consistent with the presence of a single, hyperdiploid (doubled) clone, thus effectively masking the underlying hypodiploidy. However, these cases all demonstrated a unique chromosome pattern characterized primarily by tetrasomy rather than trisomy, which distinguished them from a “typical” hyperdiploid case with an equivalent number of chromosomes. Tumor and germline DNA from all 13 masked hypodiploid patients were evaluated for loss of heterozygosity (LOH) using a microsatellite panel that tested 15 distinct loci on 13 different chromosomes. In all 13 patients LOH at multiple loci confirmed that the hyperdiploid cells had arisen by way of a doubling of a hypodiploid clone. Although numbers are too small for outcome analysis, there were no statistically significant differences in NCI Risk group or response to induction therapy (marrow morphology at day 15 or 29, and day 29 minimal residual disease levels) among masked hypodiploid cases and others in which the hypodiploid clone was visible. We conclude that a significant proportion (15-25%) of blast cell hypodiploidy may have been overlooked in children with ALL in previous studies due to the presence of a doubled hypodiploid clone and the absence of hypodiploid interphase/metaphase cells. Heightened awareness among cytogeneticists and clinicians about the unique karyotypic “signature” of a doubled hypodiploid clone coupled with the coordinated use of DI, FISH and LOH studies when indicated are important for the identification of patients with masked hypodiploidy so that they can be assigned to appropriate very high-risk treatment strategies. Disclosures No relevant conflicts of interest to declare.
Journal of the Egyptian National Cancer Institute · 2016 · 5 citations · open access
Results of treatment of lymphoblastic lymphoma at the children cancer hospital Egypt – A single center experience
AbstractIntroduction Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are neoplasms of immature B or T-cell precursors. They are considered as a unique biological entity in the 2008 World Health Organization Classification of Hematologic Neoplasm. Both entities are arbitrarily separated by a cut-off point of 20-25% of blast cells in the bone marrow. Treatment of LBL has evolved over time from conventional high-grade NHL schedules to ALL-derived protocols. The aim of this work is to report the clinical characteristics, overall survival (OS), event free survival (EFS), and common chemotherapy toxicities of lymphoblastic lymphoma (LBL) patients during a 5.5year period. Patients and methods A Retrospective review of patient's charts diagnosed and treated as LBL during the period between July 2007 and end of December 2012 was done. Patients were treated according to St. Jude Children Research Hospital ALL Total Therapy XV protocol, standard risk arm. Results This study included 77 patients. T-cell LBL patients were 67, while 10 were of B-cell origin. The median age at diagnosis was 9years (95% CI: 7-10). The majority were males 54/77. Stage III patients were 51, stage IV 13, stage II 11 and stage I 2 patients. Two patients were excluded from analysis as they died before receiving chemotherapy. Complete remission post induction chemotherapy was seen in 22 patients considered early responders, and partial remission in 55 considered late responders. With a median follow up duration of 47months (95% CI: 38-56), the 4year overall survival and event free survival were 86.45% (95% CI: 73.78-94.09) and 82.18% (95% CI: 69.25-90.61) respectively. Twelve patients died during the study period; 2 early deaths before starting chemotherapy from disease progression, 2 in CR due to chemotherapy related toxicity and 8 from disease progression. All the relapsed patients were T-cell, had advanced disease at presentation (6 with stage III; 2 with stage IV). Two patients (2.6%) had isolated local, BM, and CNS relapse each, while 1 (1.3%) had both local and CNS relapse. Disease recurrence was local in 3 patients (3.9%), and systemic in 5 (6.4%), while it was early in 6 (7.8%), and late in 2 (2.6%) patients. Median time to disease progression was 20months (range 5-39months). All relapsed patients did not survive salvage chemotherapy. The most common chemotherapy toxicities were cerebral venous thrombosis (20%), followed by bone infarcts (10.6%), and avascular necrosis (AVN) of head of femur (9.3%). One patient developed secondary acute myeloid leukemia after 3years of FU with unfavorable cytogenetic abnormalities. Conclusion Results of treatment of LBL on the St Jude's total therapy XV study are comparable to most of the similar reported studies. Outcome of relapsing patients is extremely poor, hence there is a need to identify biologic or clinical prognostic factors including minimal residual tumor to better evaluate chemotherapy response. Steroid induced AVN, and cerebral vascular thrombosis were the main chemotherapeutic adverse events.
Pediatric Hematology/Oncology and Immunopathology · 2020 · 0 citations · open access
Features of relapses and refractory forms of T-lymphoblastic lymphoma in children
AbstractLymphoblastic lymphoma (LBL) is a rapidly progressive, malignant disease from T and B progenitor cells. Lymphomas from T cell precursors (T-LBL) account for up to 80% of all LBLs. Despite the rather rare occurrence of T-LBL, the relapsing and refractory course of this disease is an actual problem. Programs for the treatment of relapses and refractory forms of T-LBL are currently being actively developing. The role and place of targeted drugs in the multimodal T-LBL relapse strategy is determined. Further fundamental research is aimed at overcoming drug resistance, studying the molecular genetic mechanisms, tumor cell signaling pathways, which will improve treatment outcomes and survival. Based on clinical case the authors will be considered clinical features of relapses and refractory form of T-LBL and possible methods of treatment. Parents gave their consent to use information about the child, including fotos, in the article.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
