DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Waldenstrom macroglobulinemia — screening already-approved drugs against its 46-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleWaldenstrom macroglobulinemia maps to a 46-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
Structures already discussed alongside waldenstrom macroglobulinemia in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Co-crystal structure of BTK kinase domain — Zanubrutinib has a real, experimentally solved structure in complex with this target (PDB 6J6M, 1.25 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.
Loading structure…
helix sheet ba0drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6J6M · 1.25 Å · ligand Zanubrutinib (BA0). Experimental structure, not a prediction.
What the evidence adds up to
Waldenström macroglobulinemia remains incurable. Treatment is initiated only when symptoms appear, not based on IgM level alone. Current guidelines recommend either chemoimmunotherapy or BTK inhibitors as first-line options, chosen according to the need for rapid disease control, specific complications, and patient age. Patients are stratified by MYD88 and CXCR4 mutational status into three groups: MYD88MUT/CXCR4WT, MYD88MUT/CXCR4MUT, and MYD88WT/CXCR4WT. For relapsed or refractory disease after both chemotherapy and covalent BTK inhibitors, options include non-covalent BTK inhibitors, novel anti-CD20 antibodies, BCL-2 inhibitors, or more intensive chemotherapy. Younger, fitter patients who have failed both chemoimmunotherapy and BTK inhibitors may be candidates for autologous stem cell transplant. Second-generation anti-CD19 CAR T cells have shown activity in vitro and in vivo. Between 2.4% and 11% of patients undergo histological transformation, most often to diffuse large B-cell lymphoma, with a median time to transformation of 4.6 years. WM patients also have a higher risk of secondary cancers.
Ibrutinib was the first BTK inhibitor approved for WM. In a retrospective review of 189 WM patients treated with ibrutinib, 51 (27%) discontinued therapy. Reasons included disease progression (14%), toxicity (8%), nonresponse (3%), and unrelated causes (2%). The cumulative incidence of discontinuation at 12, 24, 36, and 48 months was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and the presence of tumour CXCR4 mutations were independently associated with a fourfold increased odds of discontinuation. After stopping ibrutinib, an IgM rebound of at least 25% occurred in 37 patients (73%), with nearly half experiencing it within four weeks. The response rate to salvage therapy was 71%; responses were higher when salvage therapy began within two weeks of stopping ibrutinib and in patients without an IgM rebound. Patients who discontinued due to disease progression had significantly shorter overall survival than those who stopped for nonprogression reasons (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death after discontinuation.
Dose reduction of ibrutinib is common due to adverse events. A large retrospective study found that reducing the dose managed adverse events effectively in most patients and was associated with equivalent or better outcomes compared with patients who did not require dose reduction. Other BTK inhibitors now approved or with published prospective data include zanubrutinib, acalabrutinib, and tirabrutinib, each with a different adverse event profile. Expert panel recommendations from Italy address real-world questions about positioning BTK inhibitors in the therapeutic algorithm, including for specific clinical situations.
What remains missing are prospective trials that directly compare BTK inhibitors head-to-head for long-term survival and quality of life, particularly in patients with CXCR4 mutations who are at higher risk of discontinuation. The optimal sequencing of BTK inhibitors after failure of a first covalent BTK inhibitor is not established by randomised data. No trial has yet defined whether dose reduction strategies should be pre-emptive or reactive, and the role of non-covalent BTK inhibitors after covalent BTK inhibitor failure is based on limited evidence. Patient stratification by MYD88 and CXCR4 status is not yet universally applied in treatment decisions outside expert centres.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2019 · 101 citations · open access
How I treat Waldenström macroglobulinemia
AbstractWaldenström macroglobulinemia (WM) is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM). The disease may have an asymptomatic phase, or patients may present with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM. Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions. Specific criteria that define symptomatic disease that needs treatment offer clinical guidance. The treatment of WM has evolved rapidly, with treatment options that include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient's age. With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy. In this review, we focus on different clinical scenarios and discuss treatment options, based on the available data.
American Journal of Hematology · 2017 · 74 citations · open access
Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound
AbstractIbrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.
Use of BTK inhibitors with special focus on ibrutinib in Waldenström macroglobulinemia: An expert panel opinion statement
AbstractThe pivotal role that ibrutinib plays in the management of Waldenström macroglobulinemia (WM) is undisputed but there are ongoing questions regarding its positioning in the therapeutic algorithm of WM as well as in some peculiar clinical situations. A panel of experts from Italy was convened to provide real world recommendations on the use of BTK inhibitors in lymphoproliferative diseases in general, and in patients with WM in particular. This position paper represents the panel's collective analysis, evaluation, and opinions and is made up of a series of questions frequently asked by practicing clinicians and answers based on currently available evidence.
Journal of Personalized Medicine · 2022 · 2 citations · open access
The Use of Bruton Tyrosine Kinase Inhibitors in Waldenström’s Macroglobulinemia
AbstractWaldenström's macroglobulinemia (WM) remains an incurable malignancy. However, a number of treatment options exist for patients with WM, including alkylating agents, anti-CD20 monoclonal antibodies, and small molecule inhibitors such as proteasome inhibitors and Bruton tyrosine kinase inhibitors (BTKi). The focus of this review is to highlight the role of BTKi in the management of WM. The first BTKi to receive US Food and Drug Administration approval for WM was ibrutinib. Ibrutinib has been extensively studied in both treatment-naïve WM patients and in those with relapsed/refractory disease. The next BTKi approved for use was zanubrutinib, and prospective data for acalabrutinib and tirabrutinib have also recently been published. Efficacy data for BTKi will be discussed, as well as the differences in their adverse event profiles.
Mediterranean Journal of Hematology and Infectious Diseases · 2025 · 1 citations · open access
WALDENSTRÖM MACROGLOBULINEMIA - A STATE-OF-THE-ART REVIEW: PART 2- FOCUS ON THERAPY
AbstractThe diagnosis and treatment of Waldenstrom macroglobulinemia (WM) are the subjects of this two-part review, which aims to provide current and thorough knowledge of these topics. The first portion of the study, previously published, investigated the epidemiology, etiology, clinicopathological aspects, differential diagnosis, prognostic factors, and impact on WM-specific groups. Specifically, this second section examines both the standard consolidated method and the new therapeutic strategy to handle the complex topic of the treatment of WM. Key Points: WM has no cure, but therapies can improve survival. Treatment for WM/LPL patients should be initiated when they exhibit symptoms, and the IgM level should not determine WM treatment.Current guidelines suggest various initial personalized therapy treatments, typically chemoimmunotherapy (CIT) or BTK inhibitors (BTKi).Patients with WM can be put into three groups based on their MYD88 and CXCR4 mutational status: those with MYD88 mutations but no CXCR4 mutations (MYD88MUT/CXCR4WT), those with both MYD88 and CXCR4 mutations (MYD88MUT/CXCR4MUT) and those who do not have both MYD88 and CXCR4 mutations (MYD88WT/CXCR4WT).The objective of treatment is to alleviate symptoms and mitigate the risk of organ impairment.The timing of response evaluations, including BM, should be established on a case-by-case basis, informed by clinical and laboratory assessments.Patients with relapsed/refractory WM following chemotherapy and covalent Bruton tyrosine kinase inhibitors may choose non-covalent Bruton tyrosine kinase inhibitors, novel anti-CD20 monoclonal antibodies, BCL-2 inhibitors, or more intensive chemotherapy regimens.Patients who are younger and healthier and have not responded to both CIT and BTKi may be good candidates for an autologous stem cell transplant (ASCT).Second-generation anti-CD19 CAR T cells exhibit anti-WM activity in both in vitro and in vivo settings.From 2.4% to 11% of patients with WM undergo histological transformation, predominantly to diffuse large B-cell lymphoma (DLBCL). The median duration between diagnosis and transformation is 4.6 years.WM patients have a higher risk of secondary cancers.HSV and HZV prophylaxis may be beneficial for patients needing extensive treatment. Screening for Hepatitis B is necessary. Pneumocystis jiroveci prophylaxis is highly recommended. SARS-CoV- 2 and seasonal flu vaccines should be available to all WM patients.
British Journal of Haematology · 2023 · 1 citations · open access
Dose of ibrutinib in Waldenström macroglobulinaemia: Less can be more
AbstractIbrutinib changed the landscape of treatment in Waldenström macroglobulinaemia (WM) with excellent responses; however, there are high rates of dose reduction due to adverse events. The impact of this reduced dosing is unclear with regards to outcomes. Sarosiek and colleagues provide valuable data in a very large retrospective study demonstrating that dose reduction is effective in managing adverse events in the majority, with equivalent, if not better, outcomes than those without dose reductions.
Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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