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Open research questions in Chronic Lymphocytic Leukemia Research

26 unresolved questions extracted from the limitations and future-work sections of 225 Chronic Lymphocytic Leukemia Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although the BCL-2 inhibitor venetoclax has demonstrated significant clinical efficacy, microenvironment-induced resistance, particularly by MCL-1 upregulation, remains a major limitation.

    Dual action of pimozide through lysosome disruption and inhibition of STATs induces apoptosis in chronic lymphocytic leukemia (CLL) · 2026 · DOI

  • Increased Awareness and Early Diagnosis: there is a need for increased awareness of chronic Okoli R O, Osunde I, Omenka L lymphocytic leukaemia among healthcare providers and the general population in order to promote early diagnosis and prompt referral, to reduce the incidence of patients presenting with advanced disease. 2. Healthcare Policy and Funding Support: Governments and healthcare agencies should provide increased funding for cancer care, expansion of diagnostic laboratory services (such as flow cytometry, immunophenotyping, fluorescence in-situ hybridisation (FISH), and molecular testing), as well as improving the availability and affordability of targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based regimens in developing countries and access to novel therapies in order to improve outcomes in patients with CLL. 3. Development of Local Treatment Guidelines: there is a need to develop local treatment guidelines useful for the diagnosis and management of CLL in African populations, taking into account the peculiar issues such as the sub-par healthcare realities and resource limitations. 4. Strengthening Research in African Populations: more multi-centre studies are needed in Africa to better understand the epidemiology, genetic profile, treatment outcomes, and survival patterns of CLL among African patients. 5. Increased Participation in Clinical Trials: efforts should be made to improve the inclusion of African populations in international clinical trials to enhance the applicability of emerging treatment data. REFERENCES 1. Kipps TJ. Chronic lymphocytic leukemia and related diseases. In: Kaushansky K, Lichtman MA, Kipps TJ, Seligsohn U, Prchal JT, editors. Williams Hematology. 8th ed. New York: McGraw-Hill; 2010. p. 1431-1481. 2. Johnston JB, Seftel MD, Gibson SB. Chronic lymphocytic leukemia. In: Greer JP, Arber DA, Glader B, List AF, Means RT, Paraskevas F, et al., editors. Wintrobe's Clinical Hematology. 13th ed. Philadelphia: Lippincott Williams & Wilkins; 2014. p. 1916-1956. 3. Davids MS, Stilgenbauer S, Tam CS. First-line treatment for CLL in the era of targeted therapy. Blood Cancer J. 2026;16(1):19. doi:10.1038/s41408-025- 01434-2. 4. Nwannadi IA, Alao OO, Bazuaye GN, Halim NKD, Omoti CE. The epidemiology of haematological malignancies at the University of Benin Teaching Hospital: a ten-year retrospective study. Int J Epidemiol. 2010;9(2). doi:10.5580/1fbb. 5. Lenartova A, Johannesen TB, Tjønnfjord GE. National trends in incidence and survival of chronic lymphocytic leukemia in Norway for 1953-2012: a systematic analysis of population-based data. Cancer Med. 2016;5(12):3588-3595. 6. Mukkamalla SKR, Taneja A, Malipeddi D, Master RSl. Chronic Lymphocytic Leukemia.

    Epidemiology, Pathogenesis And Treatment Of Chronic Lymphocytic Leukaemia: An Update · 2026 · DOI

  • ABSTRACT Background Optimal patient selection for the most effective BTK inhibitor (BTKi) partner of venetoclax in fixed‐duration (FD) BTKi–venetoclax regimens for chronic lymphocytic leukemia (CLL) remains uncertain.

    Bridging Trials and Real Life in Fixed‐Duration <scp>BTKi</scp> –Venetoclax for <scp>CLL</scp> : A Delphi‐Enhanced Synthesis Incorporating Artificial Intelligence ( <scp>AI</scp> ) Benchmarks · 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

  • The choice of any CFC depends on efficacy and side effects, especially inhibitor development, and continuous monitoring of inhibitor development remains mandatory. As the method of data collection of the denominator of the inhibitor development for PUPs in EUHASS depends on reporting the number of PUPs completing 50 EDs per CFC, this will be delayed and difficult to register for the centres. Therefore, it was decided to abandon this data collection from 2023 onwards. Consequently, monitoring of inhibitor development will have to continue in other (inter)national registries and can only be done by the collection of details of the exposure to both nonreplacement therapy and CFC. This effort requires detailed data collection and informed consent at patient level, as is obtained in most national registries [26–28]. In conclusion, EUHASS showed progressive uptake of new treatments since 2015. A large proportion of SHA switched to emi- cizumab, and this coincided with a steep reduction in the number of inhibitors reported in SHA-PUPs. However, this downward trend in inhibitor incidence may be caused by delayed exposure to FVIII and, therefore, represents a temporary phenomenon. For SHB, vast majority of PUPs and PTPs had switched to EHL-rFIX, 5 of 8 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.70039 by UNIVERSITY OF SHEFFIELD, Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 5 2 0 2 , a i l i h p o m e a H . e m i t . e m i t . e m i t r e v o B a i l i h p o m e a h e r e v e s h t i w s P U P n i r e v o A a i l i h p o m e a h e r e v e s h t i w s P T P n i r e v o B a i l i h p o m e a h e r e v e s h t i w s P T P n i t n e m t a e r T 3 E R U G I F t n e m t a e r T 4 E R U G I F t n e m t a e r T 5 E R U G I F 8 f o 6 and a potential trend towards lower inhibitor development in SHB-PUPs was observed. Although the full impact of new treatments on inhibitor devel- opment still needs to be established, it is evident that monitoring of the inhibitor development for novel and recently introduced CFCs will be more difficult but continues to be important.

    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

  • Limitations of this study include its ret- rospective design, limited molecular character- ization, heterogeneous treatment regimens, and relatively short follow-up.

    Response Rate in CLL Patients Treated with Obinutuzumab - Single Centre Experience from University Clinic of Hematology, Skopje · 2026 · DOI

  • The results of current studies analyzing the influence of atypical CLL on prognosis are inconclusive.

    Atypical immunophenotype of chronic lymphocytic leukemia · 2022 · DOI

  • So far, questions regarding patient management after venetoclax and venetoclax-based regimen failure have yet to be answered, and only a few studies have addressed this problem.

    Chronic lymphocytic leukemia following venetoclax treatment failure · 2022 · DOI

  • These inconsistent results can be explained by the fact that the immune system develops differently in each individual due to environmental factors, past infections, intestinal flora, vaccines, ethnicity, and even gender.

    IL-17 and IL-23 levels in patients with early-stage chronic lymphocytic leukemia · 2020 · DOI

  • Pathogenesis of chronic lymphocytic leukemia is not fully understood; however, aberrant antigenic stimulation, apoptosis deregulation and microenvironmental interactions play a crucial role in disease development.

    Molecular Prognostic Markers and Their Clinical Relevance in Chronic Lymphocytic Leukemia · 2015 · DOI

  • A potent antiangiogenic factor, bevacizumab (Avastin, AVA), has been poorly explored in CLL so far.

    Mechanisms of action of the anti-VEGF monoclonal antibody bevacizumab on chronic lymphocytic leukemia cells · 2013 · DOI

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26 open questions have been extracted from the limitations and future-work passages of 225 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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