Concise summary of the treatment history of CLL from the 1950s to the present, by Dr Bruce Cheson, contributor to the iwCLL and much more

[AussieNeil]

I knew Chlorambucil use for CLL dated back to the 1950's but I hadn't appreciated that was also the case for cyclophosphamide, (the 'C' in FCR). It took until the early 90's before Fludarabine, the 'F' in FCR joined, then Rituximab (the 'R') just over 20 years ago, started the long reign of FCR as the gold standard, a title it still holds in far too many countries. Against that backdrop, you begin to appreciate the explosion of treatment options that have become available to us in the last 5 to 10 years. I've tried to document them in this post healthunlocked.com/cllsuppo... and a couple of replies, but the 7,000 character limit on posts and replies means I can no longer edit them, so I've had to reply to my replies! Such is the rate of progress in CLL treatments of late .

The referenced article by Dr Bruce Cheson, was commissioned by Chinese Clinical Oncology and who better to tell it! In addition to being the author of the 1988 publication that evolved into the iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL to which Dr Cheson has also contributed since its inception, per ccbdmd.com/about-us/your-ph... "From 2002-2020 Dr. Cheson was Head of Hematology at Medstar Georgetown University Hospital, Lombardi Comprehensive Cancer Center. Additionally, he has more than 40 years’ experience in academics focusing primarily on lymphoid malignancies and is a Scientific Advisor to the Lymphoma Research Foundation."

Slaying the real giants in the war on chronic lymphocytic leukemia

Bruce D. Cheson

Lymphoma Research Foundation, New York, NY, USA

cco.amegroups.com/article/v...

Per the title of his article, Dr Cheson asks many questions still needing to be researched, so there's no shortage of breakthrough opportunities to uncover, which we can volunteer to support through our participation in clinical trials. With regard to his statement "A recent decision by the US Food and Drug Administration virtually obliterated the entire class of PI3Ki in lymphoma and CLL (28), leaving a vacuum beyond BTKi and BCL-2 inhibition. Based on the demise of the U2 regimen (umbralisib-ublituximab) (29), a highly effective, but indefinite treatment brought about by deaths from COVID-19, and even the increase in COVID-19 related events in the present study, new time limited strategies need to be developed with retreatment upon progression. Intermittent dosing schedules should be considered. The risk-benefit ratio of adding multiple cycles of anti-CD20 antibodies also needs to be taken into account."

CLL research specialists are well aware of this "vacuum beyond BTKi and BCL-2 inhibition" and research is continuing into how modified use of PI3Ki drugs, such as intermittent dosing, can again gain the approval of the FDA for the use of later generation PI3Ki drugs such as duvelisib, umbralisib and zandelisib, now that idelalisib use is no longer approved. There are currently 316 trials for CLL registered on ClinicalTrials in the recruiting and not yet recruiting phases: clinicaltrials.gov/ct2/resu...

There may be a trial available to you not registered with the US based Clinical Trials website, though this site is used worldwide.

Thanks to my co-admin  CLLerinOz for sharing Dr Cheson's article with me.

This is an unlocked post, so that those newly diagnosed, those facing further treatment, or struggling with living with their CLL, can find our community.

Addendum: iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL: ashpublications.org/blood/a...

(This is the 2018 update, still current in December 2022)

Neil

[CLLerinOz Administrator]

This morning, I had an opportunity to look at an Australian website/app called ClinTrialRefer, to see what trials were open in Australia and that highlighted just how much is currently under investigation just here, let alone in centres around the world.

We've seen a huge expansion in the provision of CLL treatments in the last ten years, as described in the Cheson article, but CLL researchers and clinicians aren't resting on their laurels, that's for sure.

What struck me today was the long list of new medications being trialled that CLL patients, here, depending on their circumstances, might consider.

This is a list of some of those medications, with their clinicaltrials.gov ID number provided in brackets:

* LOXO-305 (NCT05023980, NCT04965493, NCT04666038)

* Venetoclax + Obinutuzumab retreatment (NCT04895436)

* BG-11417 - new BCL-2 inhibitor (NCT04277637) 

* JNJ-64264681- an irreversible covalent BTK inhibitor being trialled with JNJ-67856633, a new MALT 1 inhibitor (NCT04657224)

* MK-1026 (formerly ARQ-531) - non-covalent inhibitor of both wt and C481- mutated BTK (NCT04728893)

* BTCT4465A (Mosunetuzumab) +/- Atezolizumab - the Go29781 BiTE trial (NCT02500407)

* GB261 - a novel bispecific antibody targeting CD3 and CD20. It is the first T-cell engager (NCT04923048)

* ETH-155008 - a Pim-3 and CDK4/6 dual kinase inhibitor (NCT04840784)

* Navtemadlin (KRT-232), a Small Molecule MDM2 Inhibitor, plus acalabrutinib (NCT04502394)

* Lisaftoclax (APG-2575) - Single Agent and in Combination With Other Therapeutic Agents (NCT04494503)

* JNJ-80948543 - T-cell redirecting tri-specific antibody (NCT05424822)

* Hu5F9-G4 (5F9) - a humanized IgG4 antibody that targets CD47 to enable phagocytosis (NCT02953509)

* NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy (NCT05020678)

* CD20 specific CAR-T (NCT03277729)

Clin Trial Refer was "developed by Haematology clinical researchers in Sydney to solve the problem of clinical trial patient referral and recruitment" and it "allows doctors and patients to independently search for actively recruiting clinical trials and to access trial site locations and contact details in real time."  

clintrialrefer.org.au/

clinicaltrials.gov/ct2/home

For a running list of BTK inhibitors, see this post curated by  AussieNeil :

healthunlocked.com/cllsuppo....

As the field of medications and therapies gets more complex, it's more important than ever to have a trusted CLL expert to help guide patients through their treatment decisions.

[Smakwater in reply to CLLerinOz]

Thank You for all the research study effort Oz!

[Smakwater in reply to Smakwater]

Thank You for the interesting read Neil, I am looking forward to reading this more in depth.

JM

[CycleWonder]

Dr. Cheson is my CLL specialist and a cyclist too!

[DelrayDave]

This is Delray Dave. Unfortunately I am in hospice with high risk myelodisplasia, quite possibly already AML. caused by clinical trial years ago using chlorambucil. Ibrutinib was still in trial and not approved for clinical use. I probablly have a few months.. Ironically the BMB that showed all the blasts showed also uMRD for CLL.

Thank you again for all the helpful information.

David

[CycleWonder in reply to DelrayDave]

I’m sorry David. I hope your remaining days are comfortable and you enjoy the holiday season. Please keep us posted as you feel able.

[Ghounds in reply to DelrayDave]

I'm sorry to hear this Dave. Ironic indeed that you're uMRD for CLL.

[AussieNeil Partner Administrator in reply to DelrayDave]

Hi David,

I'm sorry to hear your news and encourage you to keep posting. We often hear about the 10% risk of eventually developing MDS or AML from FCR, but not from other true chemo treatments.

A good mate of mine who is over a decade older than me, developed AML in his 60s, though it wasn't a result of prior blood cancer treatment. The survival rates are not flash as you know - 30.5% live beyond 5 years, seer.cancer.gov/statfacts/h... but my mate is well into his second decade of living free of blood cancer. He even escaped COVID-19 when all other close family members succumbed.

I've been wondering about posting about hospice living. That can be an appropriate strategy when you need more support than can be provided at home and may improve your chances of returning home. I hope that's the case for you.

Neil

[Newdawn Administrator in reply to DelrayDave]

Sending concerned thoughts and best wishes to you Dave.

Newdawn

[AnneHill in reply to DelrayDave]

I am really sorry you need to be in a hospice but glad you have told people on this site. Hopefully you can get the support people here can give. I hope you can get treatment that helps, Anne uk

[spi3 in reply to DelrayDave]

You will be on my prayers

[PaulaS Volunteer in reply to DelrayDave]

So sorry to hear this, David. Thanks for letting us know, even though it must be very hard to talk about.

Thinking of you - with best wishes and prayers,

Paula

[SofiaDeo in reply to DelrayDave]

I am sorry to hear you are having problems. I hope that this myelodysplasia resolves. FWIW, I have had periods of time where various cells were abnormal shortly after finishing a treatment. Once it was the RBC parameters where the docs thought some kind of hemolytic process was going on, cells sizes and shapes were abnormal in addition to being low. All their tests for various things were negative, it finally resolved after mmm3-4 months? Plus I had a "blast scare", where it appeared I had an acute leukemic process going on. That too resolved but within a month. I hope you are simply going through something like this, didn't you recently finish a Venclexta treatment? Or were in one?

FWIW I am a year into being uMRD on Venclexta, but started feeling ill again a few months ago. My neuts and RBC's are just under normal, after being low normal the entire treatment after induction fluctuations. I have been having some thoughts about folk who are in a deep uMRD getting ill from continuing to take these meds. If healthy people get sick from taking immune suppressing drugs, it seems to me, once we clear our disease out really well, continuing these meds might possibly affect us the same as normals. So I hope the hospice is simply for supportive care while your docs figure out what is going on. I know even though I have a partner, he would be unable to help me if I became really ill and I too would likely be admitted somewhere for care.

Please keep us posted if you are up to it. Mostly, take care of yourself, I hope you come out the other side of whatever this is.

[Ladydi49]

yes did have Rituxin in 2018….First infusion I felt a heaviness in my legs. The nurse stopped the infusion and notified the doctor who gave orders to give additional prednisone. After about 15-20 minutes they restarted the infusion without any issues. Subsequent Rituxin infusion were fine

[napa]

Not sure, but did you ask me a question about my treatment with Rituximab and Bendamustine?

[AussieNeil Partner Administrator in reply to napa]

I see you mentioned your reasonably good experience on BR here: healthunlocked.com/cllsuppo...

but I don't recall asking you about it recently. Wishing you a long remission.

Neil