Chemo-free treatment with acalabrutinib can benefit CLL/SLL patients never treated before: a plain language summary of the ELEVATE-TN study

[AussieNeil]

The ELEVATE-TN international study commenced in September 2015. The plain language article illustrates how this clinical trial was established and run to determine whether targeted therapy arms using acalabrutinib, a Bruton's Tyrosine Kinase inhibitor ( BTKi), with or without obinutuzumab, would outperform a chemoimmunotherapy arm using chlorambucil and obinutuzumab. The first draft of the plain language summary draft was submitted by Jeff Sharman & Shweta Hakre on 14 May 2024. It was accepted for publication on 16 January 2025.

Chlorambucil (Leukeran) is a very old chemotherapy drug, dating back to the 1950s. Obinutuzumab (Gazyva) is a more recent second generation humanised anti-CD20 monoclonal antibody targeted immunotherapy drug, which was developed in the early 2000s. It has proven slightly superior to the first generation anti-CD20 monoclonal antibody rituximab (Rituxan, Mabthera), which was developed in the 1980s and approved for human use in 1997. Rituximab is chimeric mouse/human antibody that is produced in mammalian cell culture using Chinese hamster ovary cells. Acalabrutinb (Calquence) is a second generation BTKi targeted therapy. It was approved for medical use in the United States in 2017 and in the European Union in November 2020.

Patients were divided into 3 groups:

1) acalabrutinib alone

2) acalabrutinib plus obinutuzumab, a monoclonal antibody

3) the usual chemoimmunotherapy treatment (chlorambucil plus a monoclonal antibody). Chemoimmunotherapy uses two or more treatments that combine chemotherapy and immunotherapy.

What are the key takeaways?

This study looked at how well treatment with acalabrutinib plus obinutuzumab (a monoclonal antibody) worked by measuring the length of time during treatment that a patient lives with the disease without it getting worse.The doctors estimated that 87% of patients who had acalabrutinib plus obinutuzumab would be alive without disease getting worse 4 years after starting treatment compared with only 25% of patients who had the usual chemoimmunotherapy option of obinutuzumab plus chlorambucil. It also showed that 96% of patients in the two groups taking acalabrutinib had their cancer stay the same or decrease compared with 83% of those treated with the usual chemoimmunotherapy.

The doctors found that the most common side effects (an unwanted and sometimes dangerous reaction caused by a medication) for the 2 groups of patients treated with acalabrutinib (with or without obinutuzumab) were diarrhea and headache, which happened more often during the first year of treatment and happened less over time.

What were the main conclusions reported by the researchers?

These results mean that acalabrutinib is a useful chemotherapy-free option and gave better results than chemoimmunotherapy with low side effects for patients with CLL/SLL who are starting their treatment for leukemia.

Full Text (PDF)

tandfonline.com/doi/epdf/10...

The original article, “Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia”, is free to access at:

nature.com/articles/s41375-...

Neil

[Lil0ppie]

I’ve been on A since May. Did 6 cycles on O. My CLL is under control, and it’s a huge relief!

[spi3]

Thank you Neil for this exciting update!

[cajunjeff]

Interesting study. I am on acalabrutinib only. I have mostly mild side effects from it. I am so grateful to have a type of cancer that can be treated with a couple pills a day. It’s a miracle drug in my mind.

It is a pet peeve of mine, though, that when they do these clinical trials, they use chlorambucil as the comparative drug. Chlorambucil is a dinosaur chemo drug that has never been as effective as other chemo options for cll like bendustamine and rituxan or FCR. If you are doing a trial to compare the efficacy of the new cll drugs, make fcr the comparative therapy to make it a fair fight.

Did anyone, anywhere, even back when this trial was started, think chlorambucil would beat acalabrutinib? It feels like the drug companies stacked the deck on this trial to make certain their potential billion dollar baby drug won its first fight. Regardless , I agree with the results. Acalabrutinib is a better option than chemo for most all Cll patients.

[AussieNeil Partner Administrator in reply to cajunjeff]

Totally agree about chlorambucil being a poor choice, even though it was coupled with obinutuzumab. That's why I highlighted when the respective drugs were developed and approved. I remember several CLL research specialists being rather scathing about the choice of chlorambucil at the time the study was announced. The trial sponsors wanted to be absolutely certain that acalabrutinib would prove more effective than an approved treatment in that trial.

Neil

[Jm954 Administrator in reply to cajunjeff]

I agree.

Unfortunately, it's extremely rare to find a trial where two newish drugs go head to head eg Acalabrutinib v Zanubrutinib as the drug companies won't sponsor them and it's impossibly expensive for the NHS/private sector to do. Chlorambucil is approved in this setting and so was used.

[cajunjeff in reply to Jm954]

Yup. The best way to get your drug approved is to pick a weak comparator drug for the other arm. Here is how Dr Sharman described designing a trial years ago with ibrutinib vs chlorambucil, chlorambucil being the volkswagon:

DR SHARMAN: This study was really no surprise whatsoever. It’s putting a Ferrari against a Volkswagen with regards to the clinical efficacy in the front-line CLL. I think this puts the final nail in the coffin for front-line single-agent chlorambucil, at least from a US perspective.

researchtopractice.com/inde...

[Skyshark in reply to cajunjeff]

They didn't pick a weak comparator, they picked an old, weak and frail patient subset that were unsuitable for FCR/BR.

The surprise is that they got drugs approved by FDA for everyone in US and not restricted to the old, weak and frail patient subset, which is exactly what has happened in UK and elsewhere.

UK NHS approval of Acalabrutinib :

1.1 Acalabrutinib as monotherapy is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if: There is a 17p deletion or TP53 mutation, or there is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR) is unsuitable.

1.2 Acalabrutinib as monotherapy is recommended, within its marketing authorisation, as an option for previously treated CLL in adults.

UK NHS approval of V+O :

1.1 Venetoclax plus Obinutuzumab is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if: there is a 17p deletion or TP53 mutation, or there is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR), is unsuitable.

1.2 Venetoclax plus Obinutuzumab is recommended for use within the Cancer Drugs Fund as an option for untreated CLL in adults, only if: There is no 17p deletion or TP53 mutation, and FCR or BR is suitable.

Clause 1:1 is identical for Acalabrutinib and V+O. V+O is not yet routine for the fit that are suitable for FCR/BR. Clause 1.2 for Acalabrutinib is for relapsed CLL. Clause 1.2 of V+O is effectively a local NHS trial to gather data to approve V+O for those that are suitable for FCR/BR. Application for this approval is in development, likely to commence May 2025.

The GLOW trial for V+I excluded TP53 aberrations and had a fit cohort that could have FCR/BR. The CAPTIVATE FD trial was phase II for "high risk" patients, TP53 aberrations or unfit for FCR/BR. As these two trials covered the whole patient population V+I got UK NHS approval for all without any "only if" restrictions. FDA declined US approval.

UK NHS approval of V+I :

1:1 Ibrutinib plus Venetoclax is recommended, within its marketing authorisation, as an option for untreated chronic lymphocytic leukaemia (CLL) in adults.

UK NHS approval of Ibrutinib :

Ibrutinib alone is recommended within its marketing authorisation as an option for treating chronic lymphocytic leukaemia in adults: who have had at least 1 prior therapy or who have a 17p deletion or TP53 mutation, and in whom chemo-immunotherapy is unsuitable

All cBTKi including Zanubrutinib have approval by UK NHS for relapsed CLL but are restricted use for untreated CLL. Both V+O and V+I are only approved for untreated CLL as there weren't any trials for relapsed CLL using these combinations.

None of the NHS high cost drugs Bluteq funding forms ask about IgHV. BSH guidelines 2021 state anyone whose IgHV is not mutated is unsuitable for FCR and use of BR/Clb-Obin is depreciated. BSH guidelines 2022 were updated to state that IgHV should be tested but who reads everything?

[Smakwater in reply to Skyshark]

Your analytics are attentive Skyshark.

Appreciate that.

JM

[Skyshark in reply to cajunjeff]

They couldn't use FCR/BR as they wanted to include the full range of genetics. They already knew that FCR/BR was contraindicated for TP53 aberrations. Everywhere except the US, use of Ibrutinib (and other cBTKi) is restricted to those with TP53 aberrations or unsuitable for FCR/BR. The definition of "unsuitable for FCR/BR" is very variable, it may or may not include unmutated IgHV depending on location.

In making the choice for Clb-Obin they selected aged and unfit patients that couldn't have CIT - FCR/BR. CLL14 for V+O used the same criteria and tested against Clb-Obin.

The alternative is to exclude the unfit for CIT and those with TP53 aberrations. This is what GLOW and FLAIR trials of V+I v's CIT did. It's also what GAIA/CLL13 did for CIT/VenR/V+O/GIV. Then people complain that those with high risk TP53 aberrations have been excluded.

Another alterative used by the later SEQUOIA trial of Zanu and V+Zanu was, arm A Zanu excluding TP53ab, arm B BR excluding TP53ab, arm C Zanu for TP53ab and arm D V+Zanu. This excluded younger patients that were fit for FCR. Arm C is effectively a phase II trial, it was "biased" to success by having 40% mutated IgHV in this selected cohort instead of the natural 20%. As was the CAPTIVATE FD trial which had about 12 mutated IgHV out the 27 with TP53 aberrations. ELEVATE TN and CLL14 had about 5 mutated IgHV out of 23(A)/25(A+O) and 21 with TP53 aberrations.

Anyone designing a trial now the standard of care is either continuous cBTKi or V+O or V+I (except US). Such as the European CLL17 trial of Ibrutinib, V+O and V+I.

[Smakwater in reply to Skyshark]

Again, You have given a lot of consideration to the data observation.👀👍

[Smakwater in reply to cajunjeff]

"Chlorambucil is a dinosaur chemo drug " That makes Chlorambucil a DCD compared to a BTKI.

[Skyshark]

What I don't understand is why 4 year results are being discussed when 6 year results were published over a year ago at ASH 2023.

[AussieNeil Partner Administrator in reply to Skyshark]

The main reason I posted this acknowledged out of date information, was because the presentation was specifically written in plain language, so is much more readily understandable to our members. As I noted, the presentation was only approved for release 7 weeks ago. I don't know why the authors didn't use more recent data when writing the plain language article, or why peer review took so long.

You are welcome to link to a more recent post with updated study results, to round out the post. Thanks for your earlier reply.

Neil

[johnliston]

Neil, I did I/V initial treatment and after 4 years off treatment developed AIHA. I wonder if I had started on a BTK instead would I have developed AIHA. Have you ever heard of someone developing AIHA while on a BTK?

john

[AussieNeil Partner Administrator in reply to johnliston]

I suspect you wouldn't have developed Autoimmune Haemolytic Anaemia (AIHA) on BTKi maintenance. I don't recall mention of this happening. There are 154 community posts on AIHA healthunlocked.com/cllsuppo...

Neil

[tesoro5858 in reply to johnliston]

My expert CLL doctor told me that my AIHA may eventually cause me to start treatment for the underlying CLL. He mentioned that he has not seen AIHA recur after BTKi treatment. Incidentally, he has seen AIHA develop in patients who treated their CLL with venetoclax (who did not have AIHA prior to treatment) though it is rare. It begs the question that I will ask when my time comes, should I consider venetoclax-based CLL treatment considering my history of AIHA?

[johnliston in reply to tesoro5858]

I don't think AIHA develops because of Venetclax, but rather because you take Venetclax for a set time and then you are off treatment and the AIHA can arise. When you're on a BTK inhibitor you're always on treatment so it's always controlling the AIHA.

john

[SofiaDeo in reply to johnliston]

Johnliston, Are you possibly taking ANY medication linked to drug induced AIHA? For decades, my go-to OTC choice for minor pain was ibuprofen, it relieved my monthly menstrual cramping, as well as various aches/sprains I got from my very athletic lifestyle. When the CLL hit, I had severe bone pain, and was taking Vicoprofen at night to help sleep without waking. I wasn't interested in acetaminophen/paracetamol (APAP) containing meds, because I enjoyed wine/beer, was a social drinker, and knew the potential problems of having alcohol mixing with the APAP.

When I had a severe knee injury/multiple torn meniscus with a ruptured Baker's cyst a few years ago, instead of trying the "usual" steroid injection into the knee capsule, I jumped straight to wanting arthroscopic surgery to trim the torn ends. Preop, while waiting for my surgery slot and to arrange all the insurance approvals, I was prescribed OTC ibuprofen, 200mg three times a day, to decrease the inflammation/swelling as well as pain control. Long story short, I developed an AIHA in mmm 3-4 weeks. It definitely was drug induced, as evidenced by my DAT becoming negative some months later. Also, when the preop bloodwork showed severe anemia, my first thought was "the only difference is ibuprofen" and my hemoglobin & hematocrit stopped dropping & started rising within 72 hours. If it was a CLL-thing, the DAT rarely returns to negative, according to my specialist. He was surprised it turned negative, said "once CLL'ers get AIHA, even when that resolves, the DAT stays positive."

So I wonder if you are taking aspirin, or an NSAID, or other drug that you may have suddenly developed an immune reaction to.

[johnliston in reply to SofiaDeo]

No, I haven't taken NSAIDs in years because in my first treatment I was taking Ibrutinib and you not supposed to take NSAIDs with that. When I first got AIHA I had just had the flu and I believe they gave me tamaflu.

john

[SofiaDeo in reply to johnliston]

Acetaminophen is on the list, do you take that? Did you take it recently since you had the flu & were feeling crappy? I think that's how my DI-AIHA started; instead of intermittent use, I started ingesting it daily. Who knows.

Also know, those of us who take Bactrim (sulfamethoxazole/trimethoprim) as a pneumocystiis prevention protocol are at risk, too, it's been linked with a few cases. As has fluconazole, another antifungal.

It's still considered "rare" but IMO those were in the days of older technologies. An author from an earlier publication than the one I linked below, commented he thought the number was under-represented. The one below, talks about how the list of agents involved in a DI-AIHA has increased, and the known mechanisms behind *how* various drugs can induce a persons body to attack its own red blood cells, has also increased.

ashpublications.org/blood/a...

[johnliston in reply to SofiaDeo]

I would occasionally take Tylenol when I first got AIHA, but not very often.

john

[camper2]

I started initial treatment on Acalabrutinib. I didn’t qualify and was reluctantly heading for chemotherapy treatment - then along came Covid and, to stop me having to enter hospital, I was given Acalabrutinib at home.

Covid was an awful time for everyone but every cloud has a silver lining and Covid was that for me. I wonder how many of us avoided the chemo route because of Covid and will live longer with our CLL because of it? How surreal.

[SERVrider in reply to camper2]

My circumstances were the same as Camper2's, I would have had Obin' and Chlorambucil but the likely peak in Covid would coincide with the destruction of my immune system so I was offered Acalabrutinib. Here I am, 4 years later, with pretty much perfect bloodwork, feeling normal, no fatigue, the only side-effect being some spectacular bruising and persistent bleeding after excision of BCCs (which means stopping the Acalabrutinib for some days).

[Jagle]

So interesting and encouraging, AussieNeil! I completed a first round therapy with O+C in 2017, but stopped the C after it proved too toxic for me. My doctor said it was really the insurance companies that insisted on the combination and that he didn’t think C was needed. The O was very effective for me until just now when my doctor suggested A as the best therapy for me. I am a week into it and am dealing with some of the “minor” expected side effects, the worst being headache and some fatigue. I too feel so fortunate that these drugs came along just as I needed them! Thanks for the article, your insight is always so welcome!

[Skyshark in reply to Jagle]

You have done very well for what amounts to Obinutuzumab monotherapy. The median for Obinutuzumab monotherapy is measured in days, about 1000 days - 3 years.

researchgate.net/publicatio...

Coffee is the usual goto for cBTKi headaches.

[Jagle in reply to Skyshark]

Yes, Skyshark, I feel very lucky to have had an 8 year ”remission” on O. My doctor called me Lady Gazayva! I have tried the iced coffee remedy members here have recommended and it does seem to work now and then. I’m prone to headaches anyway, so…Thanks for your suggestion!

[AussieNeil Partner Administrator in reply to Jagle]

You've reminded me that some specialists actually advised their patients prescribed C+O after it was approved, to throw away the chlorambucil pills!

[Jagle in reply to AussieNeil]

Wise advice!

[DoriZett]

Thanks, Neil! That was my clinical trial - Acalabrutinib only arm. Five years on treatment, and now 3.5 years off treatment - partial remission (SLLer) still holding! 👍