CLL Medications List: Kinase Inhibitors, MABs, and Others

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Chlorambucil (Leukran) 

Trade name: ​​Leukeran

Company name: Excella GmbH & Co. KG

Date of approval: April 17, 2014 [ref]

MOA:

It acts vis 3 different mechanisms to inhibit DNA synthesis and RNA transcription from the compromised DNA:

1. attaching alkyl groups to DNA bases, resulting in DNA fragmentation as the enzymes try to repair and replace the alkylated bases;
2. Damaging the DNA by forming cross-links between the DNA and
3. inducing nucleotide mispairing.

Uses:

It is used to treat chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphomas, giant follicular lymphoma, Waldenström’s Macroglobulinemia, Hodgkin’s disease, and others.

Major contraindications:

Hypersensitivity or any signs or resistance towards Chlorambucil recorded previously.

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Fludarabine

Trade name: Fludara

Company name: Bayer HealthCare Pharmaceuticals

Date of approval: December 18, 2008 [ref]

MOA:

Fludarabine phosphate is activated to triphosphate, 2-fluoro-ara-ATP which prevents DNA synthesis by impeding DNA primase, ribonucleotide reductase, and DNA polymerase alpha. The exact mechanism is, however, not known.

Uses:

It is indicated in the treatment of CLL, Acute myeloid leukemia (AML), hairy cell leukemia, low-grade non-Hodgkin lymphoma (NHL), and mycosis fungoides, a skin-related malignancy.

Major contraindications:

• ​​Hypersensitivity
• Concurrent use of pentostatin: chances of deadly pulmonary toxicity.

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Bendamustine

Trade name: Belrapzo, Bendeka, Treanda, Vivimusta

Company name: Cephalon, Inc

Date of approval: March 2008 [ref]

MOA:

A bifunctional derivative of mechlorethamine known as bendamustine can create electrophilic alkyl groups that can covalently link to other compounds.

Bendamustine kills cells by creating intra- and inter-strand crosslinks between DNA bases as a result of its role as an alkylating agent. It is effective against both active and quiescent cells.

Uses:

It is indicated in patients with indolent B-cell non-hodgkin’s lymphoma and CLL who have already undergone prior therapies.

Major contraindications:

• Congestive heart failure
• Myocardial infarction
• Hypersensitivity to mannitol or Bendamustine.

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Duvelisib

Trade name: Copiktra

Company name: Verastem Oncology

Date of approval: September 24, 2018 [ref]

MOA:

The PI3K isoforms gamma, which is crucial for cytokine signaling and the pro-inflammatory response, and delta, which is required for cell proliferation and survival, are both inhibited by Duvelisib.

Uses:

Relapsed or refractory Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (to at least two prior therapies)

Major contraindications:

None

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Idelalisib

Trade name: Zydelig

Company name: Gilead Sciences

Date of approval: July 23, 2014 [ref]

MOA:

Zydelig blocks phosphoinositide 3-kinase (PI3K) delta, a crucial protein that is required for the activation, proliferation, migration, and viability of B-cells. The medication functions by obstructing the processes that lead to B-cell viability.

Uses:

Relapsed follicular B-cell non-Hodgkin lymphoma, relapsed Chronic Lymphocytic Leukemia (CLL), and relapsed small lymphocytic lymphoma.

Major contraindications:

• Anaphylaxis and other severe allergic responses in the past
• Toxic epidermal necrolysis.

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Ofatumumab

Trade name: Arzerra, Kesimpta

Company name: GlaxoSmithKline, Genmab

Date of approval: ​​August 31, 2016 [ref]

MOA:

It is a human anti-CD20 monoclonal antibody that prevents early B-cell activation

Uses:

Chronic lymphocytic leukemia (CLL)

Major contraindications:

Hypersensitivity

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Alemtuzumab

Trade name: Lemtrada, MabCampath, Campath

Company name: Sanofi-Aventis

Date of approval:  September 19, 2007 [ref]

MOA:

Lymphocyte antigen CD52 recombinant monoclonal antibody that promotes antibody-dependent lysis​​

Uses:

Chronic lymphocytic leukemia

Major contraindications:

None for Campath

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Rituximab

Trade name: Riabni, Rituxan Hycela, Ruxience, MabThera, Rituxan, Truxima

Company name: Biogen Idec

Date of approval:  April 21, 2020 [ref]

MOA:

The humanized monoclonal antibody attaches to the CD20 antigen and causes complement- or antibody-mediated cytolysis.

Uses:

It is indicated for the treatment of CLL or SLL in conjunction with Ibrutinib.

Major contraindications:

None

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Pentostatin

Trade name: Nipent

Company name: SuperGen

Date of approval:

MOA:

This adenosine analog effectively inhibits the enzyme adenosine deaminase, which produces purines (ADA). Through enhanced nucleoside diffusion, it is moved across cell membranes where it binds firmly to ADA.

Uses:

CLL, cutaneous T-cell lymphoma, and hairy-cell leukemia.

Major contraindications:

• Active infections
• Concurrent use of fludarabine: risk of fatal pulmonary toxicity
• Hypersensitivity

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Acalabrutinib

Trade name: Calquence

Company name: AstraZeneca Pharmaceuticals

Date of approval: November 21, 2019 [ref]

MOA:

The drug CALQUENCE inhibits tyrosine kinases, which are enzymes that are involved in different cell processes, including cell signaling, growth, and division. These medications operate by inhibiting the activity of these enzymes.

Uses:

CLL, MCL, and SLL.

Major contraindications:

None

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Venetoclax

Trade name: Venclexta

Company name: AbbVie Inc.

Date of approval: May 15, 2019 [ref]

MOA:

Bcl-2 has been shown to be overexpressed in CLL cells, where it promotes malignant cell survival and has been linked to chemotherapeutic drug resistance.

This medication is a selective inhibitor of the anti-apoptotic protein, which regulates B-cell lymphoma 2 (Bcl-2).

By directly binding to the Bcl-2 protein, displacing proapoptotic proteins such as BIM (a new member of the Bcl-2 family), causing mitochondrial outer membrane permeabilization, and activating caspases, Venetoclax aids in the restoration of the apoptotic process.

Uses:

SLL and CLL

Major contraindications:

During the ramp-up phase particularly in the beginning, strong CYP3A inhibitors

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Ibrutinib

Trade name: Imbruvica

Company name: Pharmacyclics LLC

Date of approval: February 12, 2014 [ref]

MOA:

Ibrutinib blocks Bruton’s tyrosine kinase (BTK) resulting in the inhibition of the BCR pathway from being activated, preventing malignant B cells from growing, proliferating, and surviving.

Uses:

CLL, MCL, and SLL.

Major contraindications:

None

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Zanubrutinib

Trade name: Brukinsa

Company name: BeiGene

Date of approval: January 19, 2023 [ref]

MOA:

It is a kinase inhibitor that blocks the activity of BTK by forming a covalent link with a cysteine residue in the active site. B-cell antigen receptor (BCR) and cytokine receptor pathways both use BTK as a signaling molecule.

Uses:

SLL and CLL.

Major contraindications:

None

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Obinutuzumab

Trade name: Gazyva

Company name: Genentech Inc.

Date of approval: November 2013 [ref]

MOA:

This medicine works as a cytolytic antibody against CD20 (Pre- and mature B-lymphocytes express the CD20 antigen). Obinutuzumab causes B-cell lysis after binding to CD20 by

1. activating immune effector cells
2. activating the intracellular death signaling pathways directly
3. activating the complement cascade

Uses:

Follicular non-Hodgkin’s lymphoma, and CLL.

Major contraindications:

None

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Rituximab-hyaluronidase

Trade name: Rituxan Hycela

Company name: Genentech

Date of approval: June 22, 2017 [ref]

MOA:

It is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B cells.

When it binds to CD20, it causes B-cell lysis.

By momentarily depolymerizing hyaluronan, hyaluronidase human enhances the permeability of SC tissue.

Uses:

It is used in the therapy of Follicular lymphoma, Diffuse large B-cell lymphoma, and Chronic Lymphocytic Leukemia (CLL).

Major contraindications:

None

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