Recent and Emerging Treatments for CLL

I am on a trial of Imbruvica and Venetoclax and doing well so far. I got to MRD negative (minimal residual disease) in my bone marrow after 15 months. This is very good since I am 17P deleted, Trisomy 12 and unmutated. As a result I am always looking at future options- if needed. Fortunately there are a lot of new emerging treatments. Note: I am not an expert and this is just my opinion and my research.

Some terminology to start. Technically, all drugs are chemotherapy, which is derived from the term “chemical” therapy. However, the term that chemotherapy has become most associated with is cytotoxic (cell-killing) chemotherapy (i.e., fludarabine/ cyclophosphamide taken with the immunotherapy antibody rituximab (FCR), bendamustine/rituximab (BR), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)). The problem with the cytotoxic chemotherapy is it can damage one’s bone marrow and immune system while simultaneously killing the cancer. This has short-term and possible long-term effects. 

In my opinion, with so many new options available, it is best to use at least one, or a combination of the drug types below, especially with the promise of combinations, such as the one that I am on which can bring people to MRD negative in the bone marrow after 15 months. The goal of the combination treatments is to get to MRD negative and to be able to discontinue treatment for an extended period of time. The argument that ongoing treatment with the targeted drug ibrutinib may not be true anymore when you add in Venetoclax. As Bob Dylan once wrote: “The times they are a changing…”

Below are some of the new CLL treatments I have discovered:

Targeted therapy works mostly by blocking key pathways that the CLL cells depend on to survive. CLL cells rely on the host body to provide support and send signals to stay alive. Outside of the body, CLL cells die in a day or two in the lab.

Immunotherapy works by enhancing the immune system. Combining non-cytotoxic drugs that have synergies in killing CLL cells without increasing toxicity is another active area of research.

It is great how many new drugs are being developed!!! This is partial list of what I, as a motivated patient, was able to discover with my own research. This is not meant as a comprehensive list of approved CLL drugs or those in the pipeline to treat chronic lymphocytic leukemia.

Targeted Therapy

BTK Inhibitors

Ibrutinib (Imbruvica, PCI-32765) – the first BTK inhibitor. Brian Koffman was on one of the earliest trials with ibrutinib.

Vecabrutinib (SNS-062) – inhibits cysteine-481 (C481S) mutated Bruton’s tyrosine kinase. Works for those who become resistance due to ibrutinib due to a mutation at its binding site – C481S. https://clinicaltrials.gov/ct2/show/NCT03037645

Acalabrutinib (Calquence, ACP-196) – still in trials. 2nd Generation BTK inhibitor that may have a different side effect profile than ibrutinib. See https://cllsociety.org/2017/10/acalabrutinib-fda-accelerated-approval/

LOXO-305 – Potent selective, and reversible Bruton’s tyrosine kinase (BTK) inhibitor with equivalent potency against wild-type and cysteine-481 (C481) mutated BTK. This too should work for those who become resistance due to ibrutinib due to a mutation at its binding site – C481S

SNX-5422 – a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). In a trial with ibrutinib https://clinicaltrials.gov/ct2/show/NCT02914327

BGB-3111 – See: https://cllsociety.org/2018/03/ash-2017-tam-bgb-3111-zanubrutinib-cll/

ARQ-531– It is like other BTK inhibitors that do not require the intact C481S to work. https://www.arqule.com/pipeline/btk-inhibitor-arq-531-2/

PI3 Kinase inhibitors

Idelalisib (Zydelig) -more specifically, it blocks P110δ, See https://cllsociety.org/2018/03/things-to-know-about-idelalisib/

Umbralisib (TGR-1202) – in trial with Ublituximab. See https://cllsociety.org/2018/05/ash-2017-dr-matthew-davids-on-umbralisib-cll/

Duvelisib (IPI-145) (In trial) Dual inhibitor of PI3Kδ and PI3KƔ. See https://cllsociety.org/2018/04/fda-priority-review-duvelisib/

BCL-2 Blocker

Venetoclax (Venclexta, ABT199) – Approved for CLL patients that have received one prior therapy (as of 6/8/18).Many combination trial with other agents. I am on a trial of Venetoclax and Ibrutinib. It is call the CAPTIVATE trial. https://clinicaltrials.gov/ct2/show/NCT02910583

CDK Inhibitor

CYC065 – CDK 2/9 Inhibitor that target the various phases of cell cycle control, being studied with Venetoclax to target anti-apoptotic proteins. See https://globenewswire.com/news-release/2018/03/15/1437835/0/en/Phase-1-Clinical-Data-With-Cyclacel-s-CYC065-CDK-Inhibitor-Have-Been-Selected-for-Oral-Presentation-at-AACR-2018-Annual-Meeting.html

MCL1 Inhibitors

MCL1 up-regulation could be an escape pathway around Venetoclax as a way to stop cell death (apoptosis) so blocking it makes good sense. It seems like it would work well with Venetoclax and Imbruvica possibly a triple combo. I don’t know if this type of trial is coming.

ME-522 – See http://investor.meipharma.com/2018-01-08-MEI-Pharma-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-CDK-Inhibitor-Voruciclib

AZD5991 – See https://clinicaltrials.gov/ct2/show/NCT03218683

MicroRNA155 inhibitor

MicroRNA 155 is found in high quantity in aggressive CLL

MRG-106 by Miragen – See miragen.com/clinical-trials/

Antibodies

Cirmtuzumab (UC-961) – ROR1 Antibody. See https://cllsociety.org/2017/09/cirmtuzumab-whats-ror-ing/

Daratumumab– CD38 target. In Trials with Daratumumab and Imbruvica. See https://clinicaltrials.gov/ct2/show/NCT03447808

Ublituximab – CD20 Antibody. See https://cllsociety.org/2017/02/news-on-ublituximab/

Bi-clonal Antibodies – Sticks to more than one marker.

REGN1979 – A Phase 1 Study to Investigate the Safety and Tolerability of REGN1979 in Patients with CD20+ B-Cell Malignancies – Full Text View see https://clinicaltrials.gov/ct2/show/NCT02290951 Here is some very early data: http://www.bloodjournal.org/content/128/22/621?sso-checked=true

Cellular Therapies

CAR (chimeric antigen receptor)

CAR-T with CD19 as a target – See https://cllsociety.org/car-t-and-other-cellular-therapies/

CAR-T with ROR1 as a target. See https://clinicaltrials.gov/ct2/show/NCT02706392

CAR-NK. See https://cllsociety.org/2017/07/car-nk-cellular-therapy-cll/

Others

CC-122 – CC-122 is a next generation Revlimid (lenalidomide). It has anti-proliferative activity, anti-angiogenic (blocks the formation of new blood vessels) activity, and immunomodulatory effects. See: https://cllsociety.org/2016/05/cc-122-chronic-lymphocytic-leukemia/

The ENHANCE trial is evaluating CC-122 in Combination with Ibrutinib and Obinutuzumab. See https://clinicaltrials.gov/ct2/show/NCT02406742

BNC105P – This agent is a Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis (death from lack of blood supply). It is being studied in combination with Ibrutinib. See https://clinicaltrials.gov/ct2/show/NCT03454165

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Mark is 53 yrs. and lives in San Diego with his wife and 3 children. He was diagnosed with CLL is December of 2015. He enjoys biking, back packing and other outdoor activities.

Originally published in The CLL Tribune Q2 2018.