Dr Furman says that genetically unstable CLL patients need a combination therapy approach to treatment irrespective of MRD assessment results.
This is only a short read and Dr Furman's opinion is always worth taking note of.
In case it’s behind a paywall, here is the article in full. Credit to Medscape
NEW YORK – Most patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with a single agent Bruton's tyrosine kinase (BTK) inhibitor have one of several high-risk characteristics, including complex karyotype, 17p-chromosome deletion, or a TP53 mutation. In contrast, genomically stable patients have a 4-year progression-free survival (PFS) rate of about 98% on single agent Bruton's tyrosine kinase inhibitor therapy.
In people who are genomically unstable, almost half will have their CLL progress on single agent BTK inhibitor therapy. These patients, I'd like to treat with combination of a Bruton's tyrosine kinase inhibitor plus venetoclax," said Richard R. Furman, MD, Morton Coleman MD Distinguished Professor of medicine at Weill Cornell Medicine/New York Presbyterian Hospital. He presented on treating relapsed CLL at the Great Debates and Updates Hematologic Malignancies Conference in New York, April 13-15.
The efficacy of venetoclax (VX) in treating high risk CLL patients was demonstrated in the 2019 CLL14 trial (NCT02242942) in which the main entry criteria were being treatment-naive and being considered "unfit" for treatment, meaning that a patient's Cumulative Illness Rating Scale score was >6, or they presented with decreased kidney function. Study participants were treated with six cycles of either venetoclax-obinutuzumab (VO) or chlorambucil-obinutuzumab (CO); the 4-year PFS was 74% vs. 35.4% (P < .0001) respectively. After 12 cycles of treatment, the 74% of patients in the VO group achieved undetectable minimal residual disease rate (MRD) vs. 32% in the CO group.Achievement of MRD did predict for outcome, but Dr. Furman concluded that while MRD is a powerful prognostic tool, it is not clinically useful given the inability of its results to guide therapy. He went on to emphasize that "of those patients who achieved MRD levels of 10-4 after 12 cycles of venetoclax, 50% had worsening and 50% had improvement of the residual disease, suggesting that we do not know the optimal duration of venetoclax treatment, as half of the patients still continue to derive benefit."
Dr. Furman noted that ibrutinib (IB) and the second-generation drugs zanubrutinib (ZB) and acalabrutinib (AL) are all effective, but that the second-generation Bruton's tyrosine kinase inhibitors enable patients to derive the benefit of remaining on treatment longer, because the rate of concerning cardiac complications is lower than with IB.
The ALPINE trial (NCT03734016) confirmed ZB's significantly improved overall response rate at 78.3% vs. IB's 62.5%, as well as a lower rate of atrial fibrillation (2.5%) vs. IB (10.1%).Noninferiority of AL vs. IB in high-risk relapsed CLL patients was demonstrated in the ELEVATE-RR trial (NCT02477696) with both drugs having a median PFS of 38.4 months. With a median follow up of 41 months, AL demonstrated less atrial fibrillation/atrial flutter, compared with IB (9.4% vs. 16.0%) with no difference in grade > 3 infections. Furthermore, AL's half-life being shorter than that of IB means that side effects are shorter lived."That's the advantage of the second generation of Bruton's tyrosine kinase inhibitors," said Stefan Glück, MD, PhD, a hematologic oncologist and independent consultant who was formerly affiliated with the Sylvester Comprehensive Cancer Center and taught at the Miller School of Medicine at the University of Miami.Dr. Glück added that "acalabrutinib and zanubrutinib have demonstrated strong efficacy and safety. When patients no longer respond to these drugs, the addition of VX is crucial. It has a completely different mechanism of action and can reverse resistance to Bruton's tyrosine kinase inhibitors, allowing them to start working again."
Dr. Furman also discussed proteolysis-targeting chimeras (PROTACs), one area that he expects to make a significant impact as a future therapy for CLL and many other malignancies. Despite the fact these agents are in phase I studies, he commented that "they appear, thus far, to have tremendous potential."
Dr. Furman disclosed relationships with Abbvie, Acerta/AstraZeneca, Beigene, Jansen, TG Therapeutics, Genentech-Roche, Incyte Corporation, Loxo Oncology, MEI Pharma, Morphosys, Pharmacyclics, Sanofi/Genzyme, and X4 Pharmaceuticals. Dr. Glück reported no conflicts of interest.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
Thank you, Jackie. I’m happy to see the suggestions of combinations with old, new, & current - ibrutinib, zanabrutinib and venetoclax or alcalabrutinib - I would like to see more information on BMB and NGS and how they are interpreted with AE of drugs and or the optimum outcomes of PFS.
Secondary primary neoplasms are an issue hanging in limbo. Focus is always on cardio issues but no one seems to take the leap and acknowledge the possibility - of secondary primary cancers developing with the single novel agents and now the cocktails using 2 or 3.
ATM mutations are where the CLL 11q resides - correct? Several secondary primary neoplasms are associated with this issue. Yet - it is difficult to get a hem/onc physician to commit to this as being the source of additional cancers.
It does a diserverto the patient By not having the best risk management for the issue. It is not a simple algorithm when combined with novel agents.
Clearing up some questions for me was reading - Theodora Ross MD PhD ’ A Cancer in the Family.
For us- as a family w the ATM hereditary mutation - it has been an ongoing game of
*cancer- Whac -a - mole*
Ibrutinib has been my savior and my fertilizer.
Thanks again, Jackie. I hope this has found you well - resourcefully PFS and enjoying the company of your long treks with your beloved dogs.
Hi Diana,From your mention of a family ATM hereditary mutation, I take it that all your body cells share this mutation, so it's in your germline rather than being somatically acquired due to an 11q deletion occuring in the B cell stem line or later, resulting in a sub-clone during CLL cell division. Per ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution "Approximately 9–18% of CLL harbor del(11q) which occurs in younger patients with bulky disease and poor survival. These deletions are frequently associated with germline and acquired mutations of ATM [6]. Patients with the inherited disorder ataxia telangiectasia have biallelic alterations of the ATM gene and increased susceptibility to lymphoid malignancies [7]. Rare, protein-coding germline ATM variants are associated with CLL in adults [8]. However, ATM mutations are uncommon in familial CLL [9].
The same paper notes that "0.85–3.7% of patients with CLL are diagnosed in adolescent and young adults."
Prior to targeted therapies becoming available, ATM deletion/mutation was associated with poor survival. That was because the older chemotherapy treatments worked by disrupting the CLL DNA duplication during cell division and then relying on intact ATM and TP53 genes to discover unrepairable double DNA strand breaks and trigger cell apoptosis.
It's important to distinguish the risk of secondary primary neoplasms arising from germline ATM mutations and those that might be caused CLL treatment drugs. There have been studies into Second cancer incidence in CLL patients receiving BTK inhibitorspubmed.ncbi.nlm.nih.gov/327...
That study notes that "CLL patients treated with BTKi remain at increased risk for SPM, and secondary cancer detection is an important consideration in this population.", but the mechanism for the development of those cancers is probably reduced effectiveness of T cell surveillance, due to the way CLL drives T cells into exhaustion. With a germline ATM mutation, ibrutinib might actually reduce your risk of an SPM, due to how it improves T cell function, a property not shared by acalabrutinib and presumably other BTKi drugs, but then you have the trade-off of a lower risk of adverse events from less off target activity.
Thank you, AussieNeil! Over the years, I’ve been in several systems - NIH, FCCC, Penn, MSKCC - sitting across from Professors of Genetics and Hem Onc disorders and no one has addressed the complexity of ATM, 11q, - and SPM - as well as you have laid out the current knowledge. I realize it is always changing - but in reviewing past genetic sequences- I saw things I didn’t understand.
I need to take the links and digest the information- and welcomed comments from the HU threads. I did notice - some of my sequences started out with the ATM being described as ATM monoalleic (sp?) , it has now become ATM heterozygous (?) - - need to check but I think you know what I mean.. to me it says - from both parents?
Was the first sequence incorrectly stated? How can the ATM now reflect a *double dose?*? - I’m sure my limited genetic knowledge is evident.
About the time ibrutinib (2014- present) was reduced again - AE - 140 mg 2019 now 70 mg - the SPM began.
Every 2 years - kidney, 2019, Breast DCIS, 2021, Liver, 2023, thyroid, 2023, possibly breast scar from lumpectomy, 2023 (last 3 are Christmas Lights in the PET/Ct of 4/7/2023. Liver ablation done 4/18 - 2 more issues to address.
To date- no one has addressed the 3 month holiday from BTKi ibrutinib (short stint on zanabrutinib 1 month 2022 - could not adjust to it AE - ) - headed back to MSKCC new provider - Thompkins- (Anthony R Mato where did you go)?!?
***One very important question- is BMB, FLOW and NGS of the BLB sample - the best surveillance for T cells and *vus* genetic variance of unknown significance - BRIP1 emerged - occurring in the changing genetic profile? ***
Thank you, to everyone contributing to this thread. My mnemonic for my SPM is now up to 7 words (futbol theme - Ted Lasso influence) - I’d like to put a *period* at the end of that sentence.
I'm not that well read up on genetics, but my take is that heterozygous means different genes from each parent and monoalleic means only one of the genes is working. Perhaps part of the confusion is different tests or an improvement in testing capability?
Thats a good article. In the “you learn something new every day” category, I did not know that venetoclax can reverse resistance to btk drugs. Wow, that seems like kind of big news to bury in an article. Also, the PROTAC drugs are new to me. A bit of quick research confirms that there is exciting potential in this new class of drugs. Maybe I’ll live to be a hundred after all. 😎
I saw something, I am not sure it was "technically reversing resistance" so much as, if you started the second drug as resistance was emerging, the CLL overall got driven back down. The second drug started affecting the newer BTK resistant clones while the BTK was still attacking the older cells not yet carrying a resistence mechanism. I didn't read where this combo technically "reversed" the mechanism in the resistant clones.
Thx for the article. It makes me wonder if I’ve made the right choice in treatment for my relapsed CLL after FCR in 2018. I have all excellent genetic markers. However my doc seemed to push me hard to combo Tx as opposed to Acal or ZANU
I’m on week 5 of V + O and the side effects are not only worse than FCR chemo, they are almost non-stop. With FCR I’d have 3 horrible days per month and 15-18 great days.
Wondering if the slightly longer PFS is worth feeling like this possibly for the 2 years of Venetoclax.
Are you still pushing yourself physically, or have you started "hospitalizing at home?" I do wonder to what extent not resting, and pushing yourself physically, may be contributing to your side effects. Some people seem to have zero effects, others of us need to rest more to mitigate side effects.
I recall, pushing myself post knee replacement, physiotherapist told me to ease up. I did, felt better and made faster progress. I know its not the same process, I too had FCR and got well practiced at physical exertion through out. My fitness actually improved during FCR, not a lot, but enough.
I did a bunch of "targeted meditation", envisioning my defective CLL cells rupturing, and also envisioned the drugs affecting my stem cells such that DNA repair enzymes were now suddenly super active and going about repairing the problems causing new cells to have various deletions and mutations. I did this several hours a day instead of hitting the gym, initially.
If you broke your leg, what would you do? Would you be out trying to snowshoe, even in a walking cast? You broke your DNA/bone marrow. The CLL repair process isn't a 2 hour surgery or a cast placement, it's a lengthier one. Please consider letting internal organs and bone marrow preferentially have nutrition sources/energy for a month or so, instead of having skeletal muscle pull most of it. If you had 250 internal stitches, you would need time for the sutures to heal before once again doing heavy exercise. When the docs tell us "you can go about your normal life" they are likely assuming we are average somewhat sedentary people. Do yoga, stretching, floor exercises if you must. Walk. Eat extra nutrition for energy sources re:kidney, liver function as well as building blocks of healthy new cells.
I haven't kept a large amount of data so I have nothing statistically significant, but I've noted 3 people here who have reported problems during induction all have said they are doing lots of physical exercise. Enough to be considered more than the "standard recommended minimum" amount. Try it for 2 weeks, please? It's induction only I think we are best served letting our internal organs have most all our energy, by not using our skeletal muscle a lot. So just take it easy, pull back a bit, until you are through the Venclexta ramp up?
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