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Open research questions in Chronic Lymphocytic Leukemia Research

86 unresolved questions extracted from the limitations and future-work sections of 311 Chronic Lymphocytic Leukemia Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The single-patient design limits the generalizability of the findings. Recall bias may have affected the accuracy of the patient's self-reported information. The relationship between glyphosate exposure and CLL is controversial and requires further research.

    Chronic lymphocytic leukemia associated with genetic susceptibility and occupational glyphosate exposure: a case report · 2026 · DOI

  • The available clinical history was limited in part by recall bias, - The single-patient design limits the generalizability of these findings, - The study prevents definitive conclusions of causality

    Chronic lymphocytic leukemia associated with genetic susceptibility and occupational glyphosate exposure: a case report · 2026 · DOI

  • investigating more therapeutic targets for RA, - developing new BTKis for patients who do not respond to current therapies

    Bruton’s Tyrosine Kinase Inhibitors: Recent Updates · 2024 · DOI

  • There is a need for more effective and well-tolerated therapies for the treatment of hematological malignancies, solid tumors, and autoimmune disorders. Current therapies have limitations and unmet needs. BTK inhibitors have shown promising results, but more research is needed to fully explore their potential.

    Bruton’s Tyrosine Kinase Inhibitors: Recent Updates · 2024 · DOI

  • While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored.

    Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia · 2025 · DOI

  • Despite their clinical potential, the specific effects of BTK inhibitors on T-cell lymphoma cell lines and the associated transcriptional changes remain underexplored.

    Inhibition of bruton’s tyrosine kinase suppresses EL4 T cell lymphoma growth and alters key survival pathways 2762 · 2025 · DOI

  • These findings will inform further studies of the molecular mechanisms by which GLI2 modulates antibody production and its potential role in B and T cell functions in normal and disease states.

    Investigating the role of GLI2 in B cells 2961 · 2025 · DOI

  • However, the role of GLI2 in IgM secretion by normal B cells has not been investigated.

    Investigating the role of GLI2 in B cells 2961 · 2025 · DOI

  • However, the molecular mechanism underlying PD-L1 overexpression in CLL cells remains unknown.

    p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation · 2024 · DOI

  • Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies.

    Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs · 2024 · DOI

  • Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other.

    Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials · 2024 · DOI

  • Experimental validation of the identified inhibitors is needed. Further optimization of the identified inhibitors is required. The study can be extended to other types of kinases.

    Ligand-based design of BTK inhibitors for B cell malignancy: pharmacophore mapping, virtual screening, molecular docking and molecular dynamics simulation analysis · 2026 · DOI

  • There is a need for new BTK inhibitors that can overcome off-target effects. There is a need for a new approach to design BTK inhibitors. The current inhibitors have limitations in terms of selectivity and efficacy.

    Ligand-based design of BTK inhibitors for B cell malignancy: pharmacophore mapping, virtual screening, molecular docking and molecular dynamics simulation analysis · 2026 · DOI

  • There is a need for continued surveillance of inhibitor development in patients with haemophilia. The introduction of new treatments has affected FVIII/IX exposure in patients, and the impact on inhibitor incidence is not fully understood.

    Safety and activity of pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinaemia: 5-year follow-up of the open-label, multicentre, phase 1/2 BRUIN trial · 2026 · DOI

  • We believe that these data are representative for Europe since EUHASS has representation from the majority of European countries and includes a wide variety of treatment strategies and CFCs [19–21]. Moreover, the number of PUPs and treatment years in PTPs have remained quite stable over the years, as well as the inhibitor rates observed until the introduction of the new treatment modalities around 2016. Due to the anonymous data collection, the data for the noninhibitor patients are collected only at group level: annually for PTPs and at reaching 50 EDs for the PUPs. This results in delayed detection of changes in inhibitor rates, and data checking can only be performed at group level by logical checks. However, inhibitor rates have always been in accordance with those from other registries, especially for PUPs, which are most often reported [22–24]. Emicizumab in SHA-PUPs poses a challenge for the detection of inhibitors according to the FVIII concentrates: these PUPs on emicizumab prophylaxis still occasionally receive CFCs, leading to a significant delay in reaching 50 EDs, which could be postponed for 5–10 years or more. Moreover, the EUHASS datacollection system was not designed to include treatment with more than one medication, except for bypassing agents. Consequently, especially for PUPs without inhibitors data-registrars may have entered data on PUPs completing 50 EDs on emicizumab or reported at the time of completing 50 EDs on FVIII only, while disregarding EDs on emicizumab. The data indicate that registrars have counted the exposures on emicizumab, rather than on FVIII, which are postponed by use of emicizumab. Counting the FVIII exposures would result in a lower number of SHA-PUPs reported per 4 of 8 Haemophilia, 2025 1 3 6 5 2 5 1 6, 0, D o w n l o a d e d f r o m h t t p s: / / o n l i n e l i b r a r y. w i l e y. c o m / d o i / 1 0. 1 1 1 1 / h a e. 7 0 0 3 9 b y U N V E R S I T Y O F S H E F F I E L D I, W i l e y O n l i n e L i b r a r y o n [ 2 9 / 0 4 / 2 0 2 5 ]. S e e t h e T e r m s a n d C o n d i t i o n s ( h t t p s: / / o n l i n e l i b r a r y. w i l e y. c o m / t e r m s - a n d - c o n d i t i o n s) o n W i l e y O n l i n e L i b r a r y f o r r u l e s o f u s e; O A a r t i c l e s a r e g o v e r n e d b y t h e a p p l i c a b l e C r e a t i v e C o m m o n s L i c e n s e 1 3 6 5 2 5 1 6, 0, D o w n l o a d e d f r o m h t t p s: / / o n l i n e l i b r a r y. w i l e y. c o m / d o i / 1 0. 1 1 1 1 / h a e. 7 0 0 3 9 b y U N V E R S I T Y O F S H E F F I E L D I, W i l e y O n l i n e L i b r a r y o n [ 2 9 / 0 4 / 2 0 2 5 ]. S e e t h e T e r m s a n d C o n d i t i o n s ( h t t p s: / / o n l i n e l i b r a r y. w i l e y. c o m / t e r m s - a n d - c o n d i t i o n s) o n W i l e y O n l i n e L i b r a r y f o r r u l e s o f u s e; O A a r t i c l e s a r e g o v e r n e d b y t h e a p p l i c a b l e C r e a t i v e C o m m o n s L i c e n s e FIGURE 1 Treatment in PUPs with severe haemophilia A over time. Inhibitor development in PUPs with severe haemophilia FIGURE 2 A over time. The FVIII inhibitor incidence in SHA PUPs assessed by EUHASS showed a steep decline over the last 6 years. This may be caused by delayed exposure to FVIII during prophylaxis with nonreplacement therapy and/or EHL-FVIII, and subsequent delayed detection of inhibitors. Therefore, these data may present and underestimation of the true FVIII inhibitor incidence in SHA PUPs. year, but this was not observed. Overall, it is expected that the present data included an underestimation of the true incidence of FVIII-inhibitors.

    Safety and activity of pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinaemia: 5-year follow-up of the open-label, multicentre, phase 1/2 BRUIN trial · 2026 · DOI

  • No standardized risk stratification guidelines, - Limited understanding of treatment resistance, - Small trials for BTK inhibitors and BCL2 inhibitors

    Classic Hairy Cell Leukemia and Related Disorders: An Updated Review of Molecular Features and Personalized Therapies · 2026 · DOI

  • Investigation of BTK inhibitors and BCL2 inhibitors in cHCL, - Study of ROR1 and ROR2 targeting monoclonal antibodies, - Further research on disease velocity and its impact on treatment

    Classic Hairy Cell Leukemia and Related Disorders: An Updated Review of Molecular Features and Personalized Therapies · 2026 · DOI

  • The role of PKMYT1 in CLL remains unclear. The potential contribution of mitotic kinases to genomic instability and disease progression in CLL is not well understood.

    Integrative Transcriptomic and Functional Analysis of PKMYT1 Reveals a Potential Therapeutic Target in Chronic Lymphocytic Leukemia · 2026 · DOI

  • Only a few randomized trials and limited data are available for comparing different treatment approaches - The disease is rare, making it difficult to establish a single optimal treatment regimen

    Decoding Waldenström Macroglobulinemia Through Genomics, Epigenomics and Cellular Interactions · 2026 · DOI

  • Further integration of molecular and microenvironmental data to enhance risk stratification - Development of more effective, tailored treatment strategies

    Decoding Waldenström Macroglobulinemia Through Genomics, Epigenomics and Cellular Interactions · 2026 · DOI

  • The study notes that the Medicare claims database lacks direct progression data, requiring the use of time to next treatment as a proxy for progression-free survival. The study also acknowledges the potential for intra-class switching of covalent Bruton's tyrosine kinase inhibitors, which may be due to tolerability issues rather than disease progression.

    Real-World Overall Survival and Time to Next Treatment Among Medicare Beneficiaries with Chronic Lymphocytic Leukemia in the Frontline Setting · 2026 · DOI

  • No direct progression data in the Medicare claims database, - Limited to Medicare beneficiaries aged ≥65 years, - No results for <11 patients could be reported due to CMS cell suppression and patient privacy policy

    Real-World Overall Survival and Time to Next Treatment Among Medicare Beneficiaries with Chronic Lymphocytic Leukemia in the Frontline Setting · 2026 · DOI

  • The study only investigates the transmission of TSEs in sheep. The sample size is limited. The study does not investigate the transmission of TSEs in humans.

    Minimal residual disease in CLL: when does it really matter? · 2026 · DOI

  • There is a lack of understanding of the transmission of TSEs through blood transfusion. There is a need for studies on the risk of human-to-human transmission via blood transfusion or contaminated surgical instruments.

    Minimal residual disease in CLL: when does it really matter? · 2026 · DOI

  • The cohort's limited size may have affected the significance of the results. Inconsistent B2M testing limited the applicability of the International Prognostic Scoring System for WM (IPSSWM).

    A South African perspective on MYD88 and CXCR4 variants in lymphoplasmacytic lymphoma or Waldenström macroglobulinaemia · 2026 · DOI

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86 open questions have been extracted from the limitations and future-work passages of 311 Chronic Lymphocytic Leukemia Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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