Top ▲

B-cell chronic lymphocytic leukemia

GtoPdb Disease Summaries

This section gives an overview of the disease, and where available shows the following:

  • Synonyms: Shows known synonyms for the disease.
  • Description: Gives a basic description/definition of the disease.
  • Database Link: External links to the same disease at the Disease Ontology, OMIM or Orphanet sites.
  • Immunopharmacology comments: General comments about the target's role in immunopharmacology, provided by GtoImmuPdb curators.
  • Associated with: Counts are displayed for the total targets the disease is associated with in GtoPdb. The counts of targets and ligands of immunological relevance associated to the disease are also shown.

More information can be found in the help pages.

✖
Disease ID:1134
Name:B-cell chronic lymphocytic leukemia
Associated with:2 targets
5 immuno-relevant ligands
Synonyms
B-CLL | lymphoplasmacytic leukemia | small lymphocytic lymphoma
Description
B-cell chronic lymphocytic leukemia (B-CLL) is a type of B-cell non-Hodgkin lymphoma.
Database Links
OMIM: 151400
Orphanet: ORPHA67038

Targets

GtoPdb Disease Summaries - Targets

Click on the target name to link to its detailed view page

Where available, information is display on the role of the target in the disease; drugs which target the disease and their therapeutic use and side-effects.

If there is mutation data curated in GtoPdb this is indicated, with a link back to the appropriate section on the target detailed view page

Immuno ligand interactions - If available, a table of immuno-relevant ligands is shown. These ligands have been curated as having an association to the disease and possess interaction data with the target in GtoPdb. The approval status of the ligand is shown, along with curator comments and an indication of whether the target is considered the primary target of the ligand.

More information can be found in the help pages.

✖
Key to terms and symbols
CCR7
References:  4
CXCR5
Role:  CXCR5 and its ligand, CXCL13 are over-expressed in B-cell chronic lymphocytic leukemia.
References:  3

Ligands

GtoPdb Disease Summaries - Ligands

Click ligand name to view ligand summary page

  • Approved: If the ligand is an approved drug this is indicated, along with approval bodies.
  • Immuno: Immuno icon indicates the ligand is immuno-relevant

Click the arrow in the final column to expand comments

  • Immuno Disease Comments: Curatorial comments specifically added as part of GtoImmuPdb. They give more information on the association between the ligand and disease in the context of immunopharmacology.
  • Clinical Use: General clinical comments relating to the ligand and may not necessarily be specific to the disease in question. With hyperlink to more details on the ligand summary pages.
  • Bioactivty Comments: Curatorial comments specifically about the compounds biological activity - with hyperlink to more details on the ligand summary pages.

More information can be found in the help pages.

✖
Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
lenzilumab
Immuno Disease Comments: Phase 1 clinical candidate for CLL (see NCT02546284).
Clinical Use: Lenzilumab has completed Phase 2 clinical trial for uncontrolled asthma, whereas a Phase 2 study in patients with inadequately controlled rheumatoid arthritis has been terminated. A Phase 1 trial in patients with previously treated chronic myelomonocytic leukemia (CMML) is ongoing [7].

SARS-CoV-2 and COVID-19:Lenzilumab has been entered into clinical trial to determine if blocking GM-CSF signalling can help to alleviate the immune-mediated cytokine release syndrome in patients with severe or critical COVID-19 pneumonia. The aim would be reduce the time to recovery in hospitalised patients. | View clinical data
acalabrutinib
Immuno Disease Comments: Phase 3 clinical candidate for CLL.
Clinical Use: Having already received FDA Orphan Drug Designation and Breakthrough Therapy Designation for mantle cell lymphoma (MCL: a rare and fast-growing type of non-Hodgkin lymphoma), in August 2017 the FDA granted priority review for acalabrutinib's New Drug Application (NDA), based on results from a Phase 2 study in relapsed/refractory MCL (NCT02213926). This resulted in full FDA approval in October 2017 (link to FDA announcement). This approval is for the treatment of MCL patients who have received at least one prior therapy.

For a list of all registered acalabrutinib trials, link here to ClinicalTrials.gov.

In November 2019, FDA approval was expanded to include treatment of CLL or SLL, following evaluation in trials including NCT02475681 and NCT02970318; clinial trial results in patients with CLL are reported in [9], [2] and [1].

Trials to assess acalabrutinib's efficacy in a variety of solid tumours (such as bladder, prostate and non-small cell lung cancers) are ongoing.

In the European Union, the EMA has granted acalabrutinib orphan designation for three rare diseases (as of 2016): CLL/SLL, lymphoplasmacytic lymphoma and MCL.

SARS-CoV-2 and COVID-19: In response to the SARS-CoV-2 pandemic acalabrutinib was evaluated in COVID-19 patients, as part of the UK's Accelerating COVID-19 Research and Development (ACCORD) initiative (June 2020). ACCORD is designed to fast-track potential treatments for COVID-19 through early-stage clinical trials [10]. In this setting researchers would aimed to determine if the anti-inflammatory action of BTK-inhibition has efficacy to reduce mortality in patients with severe COVID-19. In November 2020, AstraZeneca announced that acalabrutinib missed its primary endpoint in Phase 2, and failed to "increase the proportion of patients who remained alive and free of respiratory failure". | View clinical data
Bioactivity Comments: Acalabrutinib has improved selectivity, pharmacologic features (rapid oral absorption, favourable plasma exposure and a short half-life for example) and in vivo target coverage compared to the first generation BTK inhibitor, [2,11]. The IC50 values in the table below are for kinases that contain a cysteine residue aligning with Cysteine-481 in BTK (with exception of LYN). Unlike ibrutinib, acalabrutinib is devoid of activity across the SRC family kinases (IC50s > 1000 nM) [2]. | View biological activity
spebrutinib
Immuno Disease Comments: Phase 1 clinical candidate for B cell malignancies (see NCT01732861).
Clinical Use: Spebrutinib has been granted orphan drug designation by the EMA (using the chemical name n-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide benzenesulfonic acid salt) for the treatment of B-cell chronic lymphocytic leukemia (CLL). Spebrutinib (as research code CC-292) has been compared with placebo as a co-therapy with for active rheumatoid arthritis, in completed clinical trial NCT01975610. In addition it is in various Phase 1 trials for B-cell lymphomas. Click here to view these trials at ClinicalTrials.gov. | View clinical data
bafetinib
Immuno Disease Comments: FDA and EMA orphan drug for Philadelphia chromosome-positive CML. Phase 2 clinical trial in B cell CLL has been completed (see NCT01144260).
Clinical Use: Bafetinib has been assessed in two completed Phase 2 clinical trials for hormone-refractory prostate cancer (NCT01215799) and relapsed or refractory B-cell chronic lymphocytic leukemia (CLL; NCT01144260).
Both the US FDA and EMA have granted bafetinib orphan drug status for the treatment of Philadelphia chromosome-positive CML. | View clinical data
Bioactivity Comments: In vitro, of 13 of most frequent imatinib-resistant Bcr-Abl point mutations, bafetinib inhibits all but one, Thr315Ile, and in preclinical studies it proved to be ≥10-fold more potent than in vivo [8] | View biological activity
fenebrutinib
Immuno Disease Comments: Phase 2 clinical candidate for CLL (see NCT01991184).
Clinical Use: GDC-0853 was reported to be well tolerated with no dose-limiting adverse events in phase 1 studies in healthy volunteers [5]. It was advanced to clinical evaluations is patients with B-cell malignancies, and to determine efficacy against difficult-to-treat autoimmune or inflammatory conditions. GDC-0853 has demonstrated efficacy to reduce brain lesions in multiple sclerosis in phase 2 clinical study (NCT05119569) [6] (unpublished findings). | View clinical data

References

Show »

1. Awan FT, Schuh A, Brown JR, Furman RR, Pagel JM, Hillmen P, Stephens DM, Woyach J, Bibikova E, Charuworn P et al.. (2019) Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv, 3 (9): 1553-1562. [PMID:31088809]

2. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 374 (4): 323-32. [PMID:26641137]

3. Bürkle A, Niedermeier M, Schmitt-Gräff A, Wierda WG, Keating MJ, Burger JA. (2007) Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia. Blood, 110 (9): 3316-25. [PMID:17652619]

4. Ghobrial IM, Bone ND, Stenson MJ, Novak A, Hedin KE, Kay NE, Ansell SM. (2004) Expression of the chemokine receptors CXCR4 and CCR7 and disease progression in B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma. Mayo Clin Proc, 79 (3): 318-25. [PMID:15008605]

5. Herman AE, Chinn LW, Kotwal SG, Murray ER, Zhao R, Florero M, Lin A, Moein A, Wang R, Bremer M et al.. (2018) Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor. Clin Pharmacol Ther, 103 (6): 1020-1028. [PMID:29484638]

6. Meglio M. Phase 2 Data Highlight Fenebrutinib’s Impact on Brain Lesions in Relapsing Multiple Sclerosis. Accessed on 25/07/2023. Modified on 25/07/2023. NeurologyLive, https://www.neurologylive.com/view/phase-2-data-highlight-fenebrutinib-impact-brain-lesions-in-relapsing-multiple-sclerosis

7. Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, Kim E, Bebbington C, Baer M, Yarranton G et al.. (2013) GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood, 121 (25): 5068-77. [PMID:23632888]

8. Santos FP, Kantarjian H, Cortes J, Quintas-Cardama A. (2010) Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Curr Opin Investig Drugs, 11 (12): 1450-65. [PMID:21154127]

9. Sharman JP, Banerji V, Fogliatto LM, Herishanu Y, Munir T, Walewska R, Follows G, Karlsson K, Ghia P, Corbett G et al.. (2019) ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Blood, 134 (Supplement_1): 31. [PMID:31724010]

10. UK Department of Health and Social Care. COVID-19 treatments could be fast-tracked through new national clinical trial initiative. Accessed on 01/06/2020. Modified on 01/06/2020. gov.uk, https://www.gov.uk/government/news/covid-19-treatments-could-be-fast-tracked-through-new-national-clinical-trial-initiative

11. Wu J, Zhang M, Liu D. (2016) Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol, 9: 21. [PMID:26957112]