B-cell chronic lymphocytic leukemia

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

CCR7
References:  3
CXCR5
Role:  CXCR5 and its ligand, CXCL13 are over-expressed in B-cell chronic lymphocytic leukemia.
References:  2

Ligands

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 II clinical trial for uncontrolled asthma, whereas a Phase II study in patients with inadequately controlled rheumatoid arthritis has been terminated. A Phase I trial in patients with previously treated chronic myelomonocytic leukemia (CMML) is ongoing [4]. | 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.

Additional trials are evaluating acalabrutinib in other cancers. For example: Phase 3 trial in patients with chronic lymphocytic leukemia (CLL)- see NCT02475681 and NCT02477696; Phase 2 clinical trials to assess acalabrutinib's efficacy against other B cell malignancies and a variety of solid tumours (such as bladder, prostate and non-small cell lung cancers). In total, more than 25 acalabrutinib clinical trials are underway or have completed. For a list of all registered trials, link here to ClinicalTrials.gov. Phase 1/2 trial results in patients with CLL are reported by Byrd et al. (2015) [1].

In the European Union, the EMA has granted acalabrutinib orphan designation for three rare diseases (as of 2016): chronic lymphocytic leukaemia / small lymphocytic lymphoma, lymphoplasmacytic lymphoma and mantle cell lymphoma. | 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, [1,6]. 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) [1]. | 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 I 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 II 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 [5] | View biological activity
fenebrutinib
Immuno Disease Comments: Phase 2 clinical candidate for CLL (see NCT01991184).
Clinical Use: GDC-0853 has reached Phase 2 clinical trial in patients with rheumatoid arthritis (RA: see NCT02833350), and Phase 1 in patients with resistant B-cell lymphoma or chronic lymphocytic leukemia (CLL). | View clinical data

References

Show »

1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

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