Chronic lymphocytic leukemia

Disease ID:218
Name:Chronic lymphocytic leukemia
Associated with:4 targets
1 immuno-relevant targets
8 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:  4-5
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 Name Disease Association Comments Approved Primary Target Immuno
ofatumumab
Approved drug for some CLL patients.
 [  (Drugs.com) ]
veltuzumab
FDA and EMA orphan drug for CLL.
rituximab
An anti-CD20 therapy approved for CLL and non-Hodgkins lymphoma.
 [  (Drugs.com) ]
obinutuzumab
Approved for use in combination with chemotherapy in patients who have received no prior therapy.
 [  (Drugs.com) ]

Ligands

Ligand Approved Immuno References Clinical comments
ofatumumab  [  (Drugs.com) ]
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).
Immuno Disease Comments: Approved drug for some CLL patients.
veltuzumab
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.
Immuno Disease Comments: FDA and EMA orphan drug for CLL.
idelalisib  [  (Drugs.com) ]
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 [3]. 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.
Immuno Disease Comments: Approved in combination with rituximab for CLL. Also used to treat relapsed small lymphocytic leukemia (SLL).
rituximab  [  (Drugs.com) ]
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 [2,6]. 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).
Immuno Disease Comments: An anti-CD20 therapy approved for CLL and non-Hodgkins lymphoma.
ibrutinib  [  (Drugs.com) ]
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.
Immuno Disease Comments: Approved drug for CLL.
obinutuzumab  [  (Drugs.com) ]
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.
Immuno Disease Comments: Approved for use in combination with chemotherapy in patients who have received no prior therapy.
milatuzumab
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).
Immuno Disease Comments: FDA and EMA orphan drug for CLL and multiple myeloma; in Phase 2 trial.
zanubrutinib
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).
Immuno Disease Comments: Phase 3 clinical candidate for CLL and SLL- NCT03336333 will compare BGB-3111 with bendamustine + rituximab.

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

3. 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]

4. 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]

5. 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]

6. 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]