Cancer Lab · DeCure for X
DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for chronic lymphocytic 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.
Structures already discussed alongside chronic lymphocytic leukemia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
SAMHD1 — Cladribine has a real, experimentally solved structure in complex with this target (PDB 6DW4, 1.99 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
RCSB Protein Data Bank · entry 6DW4 · 1.99 Å · ligand Cladribine (HF7). Experimental structure, not a prediction.
Two review papers from 2005 and 2003 describe changes in the understanding of chronic lymphocytic leukaemia, noting that the disease arises from a subset of CD5-B cells and that its pathogenesis is likely a multistep process. A 1990 review identified trisomy 12 as the most common chromosomal abnormality, followed by 14q+, 13q, and 11q, and stated that these abnormalities portend a poor prognosis. The same review reported that therapy with intravenous immunoglobulin can prevent or delay moderate bacterial infections in persons with the disease.
A 1996 phase II study gave 63 previously untreated patients oral cladribine at 10 mg/m2 daily for five consecutive days each month. Complete remission was achieved in 24 patients (38%), and 23 patients (37%) had a partial response. The median response duration was not reached at two years. The overall survival rate at two years was 82%. Grade III to IV infectious toxicity occurred in one third of patients. A 2002 phase II study tested a different schedule of oral cladribine (10 mg/m2 daily for three days every three weeks) in 107 patients, including 63 previously untreated patients. In the combined analysis of 126 previously untreated patients from both studies, the complete response rate was 15%, nodular partial response 21%, and partial response 41%. Quality of response had no impact on survival. The three- and five-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Major infections occurred in 21% of patients on the three-day schedule compared with 35% on the five-day schedule. In 40 previously treated patients, the overall response rate was 34% and complete response rate 5%; median overall survival was 24 months.
A 1972 paper reported that hydroxyurea lowered white blood cell counts to normal in all 20 patients with chronic myelogenous leukaemia, but it did not prevent the development of the acute phase of that disease. A 1977 paper described hydroxyurea given orally to prevent leukostasis in adults with acute leukaemia who had peripheral blast counts above 100,000/cu mm; a single dose lowered the blast count by an average of 50% in each of ten episodes, and no patient developed symptoms of leukostasis. Neither paper concerns chronic lymphocytic leukaemia. A 2020 German-language paper notes that new drugs have improved outcomes and that an increasing proportion of patients are able to return to work, but it provides no new trial data.
What is still missing are prospective trials that directly compare oral cladribine schedules against each other or against newer agents, long-term quality-of-life data from the cladribine studies, and any evidence that the chromosomal or gene-expression subsets identified in the reviews can be used to select therapy in a way that improves survival.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractOur concept of the pathogenesis of chronic lymphocytic leukemia has undergone remarkable changes during the past decade. This review addresses the latest ideas concerning the origin of this common form of leukemia and discusses how molecular investigations are beginning to change the management of the disease.
https://doi.org/10.1056/nejmra041720AbstractPURPOSE: To review the recent advances in the biologic and clinical research of chronic lymphocytic leukemia. DATA IDENTIFICATION: English-language literature search using MEDLINE (1980 to 1990) and CANCERLIT (1980 to 1990), review of meeting abstracts and reports, and an extensive manual search of bibliographies of identified articles. STUDY SELECTION: Approximately 800 articles, abstracts, and book chapters were selected for analysis. DATA EXTRACTION: The literature was reviewed and 227 articles were selected as representative of the important advances in chronic lymphocytic leukemia. RESULTS OF DATA SYNTHESIS: Chronic lymphocytic leukemia is a disease of lymphocytes that appear to be mature but are biologically immature. These B lymphocytes arise from a subset of CD5-B cells that appear to have a role in autoimmunity. The pathogenesis of chronic lymphocytic leukemia is likely a multistep process, initially involving a polyclonal expansion of CD5-B cells followed by transformation of a single cell. Chromosome studies indicate that trisomy 12 is the most common abnormality, followed by 14q+, 13q, and 11q. These abnormalities portend a poor prognosis. Recent progress in the treatment of chronic lymphocytic leukemia involves three new drugs: fludarabine, pentostatin, and 2-chlorodeoxyadenosine. Recent preliminary results of allogeneic bone marrow transplantation present insights into the potential curability of chronic lymphocytic leukemia. Therapy with intravenous immunoglobulin can prevent or delay moderate bacterial infections in persons with chronic lymphocytic leukemia. CONCLUSION: Major advances in the biologic research of chronic lymphocytic leukemia have resulted in new understanding of this complex disease. New therapies, such as those with intravenous immunoglobulin and fludarabine, may lead to improved outcome.
https://doi.org/10.7326/0003-4819-113-7-525AbstractHydroxyurea was administered to 20 patients with chronic myelogenous leukemia. The white blood cell counts decreased to normal in all the patients, anemia improved, splenomegaly decreased or disappeared, thrombocytosis was corrected, and bone marrow improvement occurred in all the patients. Megaloblastosis was noted consistently. Hydroxyurea was effective in treating chronic meylogenous leukemia refractory to busulfan. Hydroxyurea did not prevent the development of the acute phase of chronic myelogenous leukemia, hemolysis, or myelofibrosis. The chief systemic reaction was reversible myelo-suppression and an unusual dermatologic alteration. Hydroxyurea is as effective as busulfan and may be utilized as a primary therapy of chronic myelogenous leukemia.
https://doi.org/10.1002/1097-0142(197204)29:4<1052::aid-cncr2820290454>3.0.co;2-7AbstractPURPOSE: Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS: Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION: Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.
https://doi.org/10.1200/jco.1996.14.7.2160AbstractB-cell chronic lymphocytic leukemia increasingly is being recognized as a useful model disease with which to study more general processes involved in the evolution of neoplastic disease. The accessibility of the tumor cells and the capacity to confirm their clonal relatedness allow for evaluation of the processes associated with neoplastic transformation and/or disease progression. Recent studies have provided fascinating insight into the potential pathogenesis and pathophysiology of this disease. In addition, features of leukemia cells have been identified that can distinguish subsets of patients that have different tendencies for disease progression. Gene expression studies have identified a relatively small number of genes that are differentially expressed between these subsets, allowing for focused attention on proteins that might contribute to the noted differences in clinical behavior. Finally, recognition that chronic lymphocytic leukemia cells depend upon specific microenvironmental growth and survival factors identifies novel targets for disease intervention. This article focuses on the reports of the past year that have contributed to these areas of active research on chronic lymphocytic leukemia, the most common adult leukemia in Western societies.
https://doi.org/10.1097/00062752-200307000-00010AbstractA phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin <11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.
https://doi.org/10.1046/j.0007-1048.2001.03296.xAbstractHydroxyurea was administered orally to prevent the effects of leukostasis in adults with acute leukemia who had peripheral blast cell counts greater than 100,000/cu mm. A single oral dose of 50 to 100 mg/kg was given daily until the absolute blast cell count decreased to less than 100,000/cu mm. Hydroxyurea was effective in rapidly lowering the blast cell count by an average of 50% after one dose in each of ten episodes. No patient developed symptoms or signs of the leukostasis syndrome, and no side effects directly attributable to hydroxyurea were observed. The leukostasis syndrome associated with very high blast cell counts in adults with acute leukemia can be avoided by the use of hydroxyurea in the manner described. This treatment can be particularly useful in the interval before consultation or referral and prior to the cytotoxic effect of definitive induction chemotherapy. (<i>Arch Intern Med</i>137:1246-1247, 1977)
https://doi.org/10.1001/archinte.137.9.1246AbstractTherapy of chronic lymphocytic leukemia and patient outcome have been improved significantly in recent years with the introduction of new drugs. Therefore, an increasing proportion of patients is able to return to work. This paper deals with the functional disorders to be expected during and after the treatment of chronic lymphocytic leukemia and the resulting socio-medical assessment of performance.
https://doi.org/10.3205/ors000039Disease 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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