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Chronic lymphocytic leukemia

Disease ID:218
Name:Chronic lymphocytic leukemia
Associated with:4 targets
1 immuno-relevant target
10 immuno-relevant ligands
Synonyms
B-cell chronic lymphocytic leukemia | Chronic lymphatic leukemia | Chronic lymphoid leukemia
Database Links
Disease Ontology: DOID:1040
OMIM: 151400
Orphanet: ORPHA67038

Targets

GPR17
Comments:  GPR17 expression associated with unfavorable 11q23 deletion and Binet stages B and C in chronic lymphoid leukemia.
References:  1
FZD3
References:  9-10
ATM serine/threonine kinase
CD20 (membrane-spanning 4-domains, subfamily A, member 1)
Comments:  CD20 is the molecular target of the CLL therapeutics ofatumumab and obinutuzumab.
Ligand interactions: 
Ligand Comments
ofatumumab
Approved drug for some CLL patients.
veltuzumab
FDA and EMA orphan drug for CLL.
rituximab
An anti-CD20 therapy approved for CLL and non-Hodgkins lymphoma.
obinutuzumab
Approved for use in combination with chemotherapy in patients who have received no prior therapy.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
ofatumumab
Immuno Disease Comments: Approved drug for some CLL patients.
Clinical Use: Approved to treat chronic lymphocytic leukemia that is refractory to and , or which is previously untreated. May also be beneficial in the treatment of follicular non-Hodgkin's lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. The effectiveness of ofatumumab against additional hematological malignancies is being investigated in Phase III clinical trial.
In January 2015, the FDA expanded approval to include extended treatment for CLL patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive disease.
In August 2016, the FDA expanded approval again to include use of ofatumumab in combination with and for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL). | View clinical data
veltuzumab
Immuno Disease Comments: FDA and EMA orphan drug for CLL.
Clinical Use: The EMA and FDA have granted veltuzumab orphan designation for the treatment of the rare disease chronic lymphocytic leukemia (CLL). The FDA also includes treatment of pemphigus (a group of autoimmune diseases causing severe blistering of the skin and mucous membranes) in its orphan drug designation. Phase II clinical trials for non-Hodgkin's lymphoma, CLL and autoimmune thrombocytopenic purpura are ongoing. | View clinical data
idelalisib
Immuno Disease Comments: Approved in combination with rituximab for CLL. Also used to treat relapsed small lymphocytic leukemia (SLL).
Clinical Use: Idelalisib is a treatmet for difficult to treat leukemia and lymphomas. The potential of this drug was highlighted by the early termination of a phase 3 clinical trial, so that all participants could be given the drug [7]. Idelalisib was approved in July 2014, for patients with relapsed chronic lymphocytic leukemia (CLL), in combination with . The FDA also granted the drug accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), particularly indicated for patients who have received at least two prior systemic therapies.

To view a full list of trials registered with ClinicalTrials.gov assessing idelalisib, click here. | View clinical data
rituximab
Immuno Disease Comments: An anti-CD20 therapy approved for CLL and non-Hodgkins lymphoma.
Clinical Use: Used to treat CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Rituximab is also used to suppress antibody-mediated rejection in living-donor kidney recipients prior to an ABO-incompatible transplant [6,11]. A modified formulation containing rituximab + human hyaluronidase (Rituxan Hycela) that can be delivered subcutaneously (the original rituximab only formulation was administered intravenously) was FDA approved in June 2017 for the treatment of previously untreated and relapsed or refractory follicular lymphoma, previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL). In June 2018, the FDA approved the use of rituximab as a much needed treatment for the potentially life-threatening skin disease pemphigus vulgaris that can be used for adults patients with moderate to severe disease. | View clinical data
Bioactivity Comments: The patents covering rituximab do not contain any data regarding antibody-antigen affinity [2-3], but a dissociation constant is provided by Stein et al (2004) [16]. | View biological activity
ibrutinib
Immuno Disease Comments: Approved drug for CLL.
Clinical Use: Ibrutinib is approved to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of leukemia, especially patients with MCL who have received at least one prior therapy. In Feb 2014 ibrutinib was granted US FDA approval for treating chronic lymphocytic leukemia (CLL), as with MCL, this is only indicated for patients who have received at least one prior therapy. In February 2015, the US FDA expanded approval to include the treatment of Waldenström's macroglobulinemia (WM), which is a form of type of non-Hodgkin's lymphoma. Approval was granted based on the outcome of clinical trial NCT01614821 which indicated that the drug can offer a substantial improvement over contemporary therapies.
In August 2017, the FDA expanded approval to include treatment of chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (e.g. first-line corticosteroid therapy). This approval followed results from clinical trial NCT02195869. The recommended dose of ibrutinib for cGVHD is 420 mg, orally once daily. | View clinical data
obinutuzumab
Immuno Disease Comments: Approved for use in combination with chemotherapy in patients who have received no prior therapy.
Clinical Use: Initially approved to treat chronic lymphocytic leukemia (CLL) in combination with chemotherapy in patients who have received no prior therapy. In November 2012, this antibody was authorised as an orphan drug by the EMA for the treatment of CLL. Full EMA approval for CLL was granted in July 2014.
In February 2016, the US FDA expanded approval to include treatment of patients with follicular lymphoma (FL) who have relapsed after, or are refractory to, a -containing regimen. This new approval is for a combination therapy of obinutuzumab with , followed by obinutuzumab monotherapy. | View clinical data
Bioactivity Comments: In vitro, obinutuzumab induces cell death and antibody-dependent cell-mediated cytotoxicity (ADCC) more effectively than the original type I anti-CD20 antibodies and [8]. In vivo, obinutuzumab induces a strong antitumour effect [8].
However, we have been unable to find affinity data for this antibody from any open access source. | View biological activity
milatuzumab
Immuno Disease Comments: FDA and EMA orphan drug for CLL and multiple myeloma; in Phase 2 trial.
Clinical Use: Both the FDA and EMA have granted milatuzumab orphan designation for the treatment of the rare diseases multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Phase II clinical trials of milatuzumab for MM and CLL have been completed. A Phase I/II study of hLL1-DOX for relapsed non-Hodgkin's lymphoma and CLL is ongoing (NCT01585688). | View clinical data
zanubrutinib
Immuno Disease Comments: Phase 3 clinical candidate for CLL and SLL- NCT03336333 will compare BGB-3111 with bendamustine + rituximab.
Clinical Use: ClinicalTrials.gov list 14 registered BGB-3111 studies from Phase 1 to Phase 3. The Phase 3 trials are in patients with CLL or SLL (NCT03336333) and Waldenström's macroglobulinemia (NCT03053440). | View clinical data
Bioactivity Comments: In a cellular assay, zanubrutinib inhibits BTK with an IC50 of 20nM [17]. | View biological activity
otlertuzumab 4
Immuno Disease Comments: Phase 1 clinical candidate for CLL- see NCT01644253.
Clinical Use: Preliminary evidence of clinical efficacy in a small number of patients with highly refractory, heavily pretreated B-cell non-Hodgkin lymphoma has been reported [12]- see NCT00614042. A Phase 1b study of TRU-016 plus other biological or small molecule chemotherapeutic drugs (NCT01644253) is under way (May 2018). | View clinical data
Bioactivity Comments: Rafiq et al. (2013) [13] show a dose-respnse curve of TRU-016 binding to CD37 on Daudi cells (with the x axis labeled as 'ng/well' rather than as a defined molarity), but do not present a calculated affinity constant. | View biological activity
venetoclax 5
Immuno Disease Comments: Approved drug for CLL with or without 17p deletion.
Clinical Use: Venetoclax (in combination with and in comparison with currently approved anti-neoplastics) was assessed in Phase III clinical trials as a potential treatment for chronic lymphocytic leukemia (CLL). See NCT02005471 and NCT02242942 for full details.
In January 2016, the US FDA granted venetoclax (in combination with hypomethylating agents) breakthrough designation as a first-line treatment for patients with acute myeloid leukemia (AML) who are ineligible to receive high-dose chemotherapy.

Full marketing authorisation: In April 2016, the US FDA granted full approval for venetoclax as an oral treatment regimen for patients with chronic lymphocytic leukemia (CLL) with 17p deletion (or TP53 mutation) (detected by an FDA-approved test), who have received at least one prior therapy. EMA approval followed in December 2016. In June 2018, the FDA expanded approval to include treatment of both CLL and small lymphocytic lymphoma (SLL), with or without 17p deletion in patients who have received at least one prior therapy. This approval is for a combined regimen using venetoclax plus the anti-CD20 monoclonal [14], and offers a chemotherapy-free option for CLL patients. | View clinical data
Bioactivity Comments: Venetoclax is reported to be >4800-fold more selective for Bcl-2 compared to other protein family members Bcl-xL and Bcl-w [15]. | View biological activity

References

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1. Aalto Y, El-Rifa W, Vilpo L, Ollila J, Nagy B, Vihinen M, Vilpo J, Knuutila S. (2001) Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion. Leukemia, 15 (11): 1721-8. [PMID:11681413]

2. Anderson DR, Nabil H, Leonard JE, Newman RA, Reff ME, Rastetter WH. (1998) Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma. Patent number: US5843439. Assignee: Anderson DR, Nabil H, Leonard JE, Newman RA, Reff ME, Rastetter WH. Priority date: 13/11/1992. Publication date: 01/12/1998.

3. Anderson DR, Rastetter WH, Hanna N, Leonard JE, Newman RA, Reff ME. (1994) Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma. Patent number: WO1994011026. Assignee: Idec Pharma Corp. Priority date: 26/02/2015. Publication date: 26/05/1994.

4. Byrd JC, Pagel JM, Awan FT, Forero A, Flinn IW, Deauna-Limayo DP, Spurgeon SE, Andritsos LA, Gopal AK, Leonard JP et al.. (2014) A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia. Blood, 123 (9): 1302-8. [PMID:24381226]

5. FDA. FDA approves venetoclax for CLL or SLL, with or without 17 p deletion, after one prior therapy. Accessed on 18/06/2018. Modified on 18/06/2018. FDA.gov, https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610308.htm?utm_campaign=Oncology%206%2F8%2F18%20&utm_medium=email&utm_source=Eloqua&elqTrackId=3413c3557cf04e12aaa41ce1a31ef707&elq=4d3e9515bb1e4f708c454b998d0707f7&elqaid=3844&elqat=1&elqCampaignId=2978

6. Fehr T, Stussi G. (2012) ABO-incompatible kidney transplantation. Curr Opin Organ Transplant, 17 (4): 376-85. [PMID:22790072]

7. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I et al.. (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med., 370 (11): 997-1007. [PMID:24450857]

8. Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, Fauti T, Muth G, Ziegler-Landesberger D, Van Puijenbroek E, Lang S et al.. (2013) Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol. Cancer Ther., 12 (10): 2031-42. [PMID:23873847]

9. Kaucká M, Plevová K, Pavlová S, Janovská P, Mishra A, Verner J, Procházková J, Krejcí P, Kotasková J, Ovesná P et al.. (2013) The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration. Cancer Res., 73 (5): 1491-501. [PMID:23338609]

10. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA. (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A, 101: 3118-3123. [PMID:14973184]

11. Macklin PS, Morris PJ, Knight SR. (2015) A systematic review of the use of rituximab as induction therapy in renal transplantation. Transplant Rev (Orlando), 29 (2): 103-8. [PMID:25555541]

12. Pagel JM, Spurgeon SE, Byrd JC, Awan FT, Flinn IW, Lanasa MC, Eisenfeld AJ, Stromatt SC, Gopal AK. (2015) Otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR(™) therapeutic protein, for relapsed or refractory NHL patients. Br. J. Haematol., 168 (1): 38-45. [PMID:25146490]

13. Rafiq S, Siadak A, Butchar JP, Cheney C, Lozanski G, Jacob NK, Lapalombella R, McGourty J, Moledor M, Lowe R et al.. (2013) Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies. MAbs, 5 (5): 723-35. [PMID:23883821]

14. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J et al.. (2018) Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N. Engl. J. Med., 378 (12): 1107-1120. [PMID:29562156]

15. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ et al.. (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 19 (2): 202-8. [PMID:23291630]

16. Stein R, Qu Z, Chen S, Rosario A, Shi V, Hayes M, Horak ID, Hansen HJ, Goldenberg DM. (2004) Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin. Cancer Res., 10 (8): 2868-78. [PMID:15102696]

17. Wang Z, Guo Y. (2016) Substituted pyrazolo[1,5-a]pyrimidines as bruton's tyrosine kinase modulators. Patent number: US9447106B2. Assignee: Beigene Ltd.. Priority date: 25/04/2013. Publication date: 20/09/2016.