I was just reading this story and it relates to a patient in the same position as myself who has achieved uMRD status on the Ibrutinib & Venetoclax arm of the Flair trial.
This combination has proven to be highly effective in achieving undetectable status whilst avoiding some of the toxicities associated with FCR. Let’s not forget however that there are categories of patients who have achieved long remissions which are essentially classed as a cure after a 10 yr period.
I&V can be a tough combination to weather for some and as expected with ‘feel good’ stories, it was painted as a simple, no issue type solution leading to total eradication of CLL. Not all participants achieve uMRD status (I’d need to dig out the actual studies for figures). I don’t wish to be a party pooper but I think we need to issue a bit of optimistic caution without losing sight of the efficacy of this fabulous oral combination . The participant says ‘he’s glad it’s all over’ and I totally share his sentiments being in that position but regrettably, it’s not yet a complete cure. Remission can be long and durable on I&V but relapse remains a possibility at some point. I’m now on W&W Part 2 hoping it will be a very long period but I’m a realist.
The very good news is that 30 days ago, ‘UK NICE Approved Ibrutinib +Venetoclax for First Line treatment for ALL Patients’. This is fantastic news for patients like yourself Lellyandme as it opens up treatment opportunities to avoid chemo first line even for younger, fitter patients.
I’m delighted for the subject of this story and his family but read it with perhaps a little more realism. However, I hope both of us don’t have to face realities for a very, very long time! 😊
The primary endpoint was met with a CR rate of 56% (95%) by investigator assessment in patients without del(17p). This rate significantly exceeds the minimum CR rate of 37% (1-sided P < .0001) and 40% rate of the historical FCR comparator.
‘Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively.’
Among the 57% of patients who achieved complete response, 93% had a response lasting 12 months or longer post-treatment.
Thank you for posting Lellyandme, the story in this article will be no surprise to users of this forum, but it is good to see CLL getting a mention in the press, and I am sure new CLLers will have been encouraged.
Hi Lellyandme, Spot on timing for this, my Haematologist has just asked me to start this treatment! I have been on W & W for just 10 years and have been coping reasonably ok, tiredness and fatigue gets worse, I am 75 going on 15😀 but can no longer run without being out of breath!
I have taken a great deal of confidence from this news item although I take onboard the comments from Newdawn.
I had bowel cancer in 2004 and after the big operation, and several smaller ones, I was given 30 weeks of chemotherapy, which was pretty harsh on the body although I did work full time thru the chemo having treatment on my day off, so I am no stranger to how much treatments can take out of the body.
Thank you again for posting this, I am a pretty positive person and this article has reinforced my decision to accept this treatment. Best wishes, Cliff.
wishing you all the best for your trials … I agree with realism for sure but success stories can also help with positivity of the mind as well as remission …
I absolutely agree that hope features highly in the way we cope with our condition Lellyandme and it was a feel good story. What concerned me about this story and stories of this ilk is lack of balance. The word ‘cure’ was mentioned several times and I’ve experienced friends reading accounts like this and telling me they’re so pleased a cure has been found. Oh how I wish!
I’d never underestimate the potential of Ibrutinib & Venetoclax and I’ll be forever grateful that I responded so well. It’s an amazing treatment that offers something I couldn’t have believed possible 11 years ago this month when I was diagnosed. I read this story on the edge of my seat thinking a new, curative treatment had been found if I’m honest and was a bit taken aback to discover it was the I&V arm of the Flair trial they were referring to.
I’d recommend it to any CLL’er (even though I am living with side effects and I still have hypogammaglobulinaemia) but there’s still that concern with every set of bloods that slippage has started. I don’t dwell on it but I have reality.
Best wishes for your treatment clifflee and keep well hydrated during your Venetoclax treatment. It makes an enormous difference.
I can’t argue with that because when my sister sent me the article I thought it was going to be a new groundbreaking cure … the fact it has cured him gives hope and optimism to others, but always have your feet firmly on the ground and pinch of reality.
However, it hasn’t ‘cured’ him, it’s effected a remission which is absolutely brilliant but every week on here, we hear from members who have now relapsed and considering ‘what next?’ That’s the reality of CLL at the present time but for any period that it’s undetectable, it’s a tremendous bonus 😊
I feel I need to add a bit more reality into this good news story regarding the use of the word "cured" by both the patient and the Health minister. The patient achieved uMRD - undetectable Measurable Residual Disease; they couldn't detect his cancer after his treatment with ibrutinib and venetoclax, I&V. Unfortunately, as can be appreciated when you read the results of the study referenced by Newdawn healthunlocked.com/cllsuppo... people on this arm of the trial are not cured, but do have long periods of progression free survival (PFS) and excellent Overall Survival (OS), but as far as we know, CLL always comes back. (The combination of I&V has only been trialled for about 5 years, so we'll need longer term monitoring, to see how many people treated with I&V never need further treatment for their CLL).
The real good news from this story - and it truly is fantastic news, is the breakthrough for UK patients in that they will no longer be treated with the older chemo treatments (BR, FCR), that are harsher and come with a later risk of secondary blood cancer and which don't work as well if you have unmutated IGHV version of CLL (which is perhaps 60 to 70% of us, come treatment time). Also, those with 17p del, mutated or missing ATM or TP53 CLL do far better on I&V than the older treatments, which just temporarily cleared out the CLL, which then typically returned within a year or so - and that's perhaps 15% of those who have been previously treated.
The UK is leading the world in countries which have universal health care when it comes to moving away from the older treatments and that's thanks to the work of charities such as our CLL Support UK charity,
healthunlocked.com/cllsuppo... sometimes with the support of the other UK charities that support those with blood cancers, namely Leukemia Care and Bloodwise. One of our admins, Jackie, Jm954 has done much of the very important work in providing submissions to NICE, giving evidence that treatments such as I&V and other non-chemo treatments provide superior outcomes to those of us needing treatment.
Donations can be made to our charity via this Donate button on our About page cllsupport.org.uk/donate
I like a good news story as much as anyone but I'm a bit concerned with this article. Churchill said that "history is written by the victors" and this is case in point.
The subject was among the 18% of study participants who received what we would know now to be the "better" treatment.
The subject stating:
“You have everything to gain and nothing to lose. And you could save the lives of people living with cancer in the future" shows a lack of understanding to the process of studies or empathy to those who volunteer.
For each person in his arm of the study, four people weren't. As inspiring as it is to hear his heartwarming story, realistically, it should have been mirrored by a participant on an alternative arm.
Studies, by nature, are risky. Sometimes you win, sometimes you don't. And his successful treatment was achieved by standing on the shoulders of thousands who volunteered before him-- win or lose.
The recommendation of this combination for approval by NICE is at final draft with expected release at end of this month (31st May 2023). This should make it available in NHS hospitals within 3 months of the document's actual release (~ end of Aug 2023).
Ibrutinib and venetolclax are far less harsh than chemo but some people suffer major side effects, including secondary (skin) cancer, heart problems and (fatal) kidney failure or show intolerance to the drugs. It is a time limited therapy so should avoid resistance developing, which should permit repeat of the therapy if/when CLL relapses. Both drugs have been in use for sometime, either as mono-therapy or in other combinations. This combination of small molecule targeted drugs is an "odd one out", as nearly all other combinations use a monoclonal antibody (including the R in chemo BR and FCR).
Chemo drugs affect the whole body, every cell. They function by preventing the cells dividing, cancer cells divide very quickly but it affects all cells that are dividing. The fastest dividing non cancer cells are skin, nails, gut lining and hair so they are all badly affected. CLL may not proliferate or divide quickly (low Ki67), it produces B cells that refuse to die and accumulate in the blood and lymph glands. Chemo + monoclonal antibody, FCR has been highly effective for a limited number of people with favourable genetic markers (mutated IGVH-M), some have over 12 years progression free survival and there are thoughts that for this group it may be a "cure". FCR is given over 6 cycles with IV infusions on first day of cycle. FCR requires subjects to receive irradiated blood products for life.
Ibrutinib is a targeted therapy. It targets BTKi (Bruton Tyrosine Kinase inhibitor) to prevent B lymphocyte cells dividing. It also helps clear accumulations from lymph glands so may be good for de-bulking. It is taken as tablets.
Venetoclax is also a targeted therapy that blankets BCL-2 receptors present on CLL B lymphocyte cell mitochondria and "suffocates" them. With the cell's power house mitochondria isolated the cell dies. It is taken as tablets. The initial 5 week ramp-up to full dose requires a large number of blood tests, each of the first 2 weeks having at least 3 in 24 hours. This is at least 3 days attendance at outpatients each week, day 1: blood test, consultation, day 2: tablet(s), blood test 6/8 hours later, day 3: blood test 24 hours after first tablets and before taking next tablet(s). If they can't manage to do a blood test on the day in time for consultation you win a 4th day. Anyone with large lymph nodes or high lymph count is at "high risk" of TLS, this scores an extra 2 blood tests for each of the 5 weeks and 2 stays in hospital for initial and first increment dose.
A third drug Obinutuzumab targets CD20 receptors on B lymphocyte cells (both good and cancer cells). It is a monoclonal antibody that signals the B cell lymphocyte for destruction by Natural Killer cells. It can reduce WBC from 125 to 12 in 2 days and normal levels by end of week with first 1000mg dose (split across 2 days). For some people WBC can go to lower than normal levels resulting in serious suppression of the immune system. This is given as an IV. As with Venetoclax if at risk of TLS the first infusion may be in hospital.
Obinutuzumab and Venetoclax is currently available from NHS (since 2020) for untreated CLL with a 17p deletion or TP53 mutation. It is available for untreated CLL without a 17p deletion or TP53 mutation through the cancer drugs fund (for data collection). This is also time limited 12x 4 week cycles, the first 2 cycles are very intense, more so if "high risk" for TLS with 3 hospital stays. It has been found to be more effective than FCR or Venetoclax+R, especially for previously difficult to treat un-mutated IGVH-UM.
You may note the difference between NICE released guidance of O+V and "indevelopment" of I+V. In a little over a week I+V should/will lose the "indevelopement" and "gid-".
Therapy for CLL moves faster than NICE, I+V was last year. There are a number of trials to find out which combination, duration and order of delivery of these three drugs is most effective. It's a reasonable bet to enter a phase III trial for first treatment if fit, under 65 and mustard gas derived chemo isn't in the random mix of therapy.
Everyone is different. Due to the number of implicated genetic markers, that affect CLL outcomes, there are a huge number of different combinations.
They don't usually find out what your genetic markers are until they are doing the work-up for treatment. It would be a big waste of time and money to do it for people that never progress but remain on watch and wait.
Skyshack, you've been doing some serious studying!
A few additions to your good synopsis;
- I'm not aware that the secondary (usually skin) cancer risk is higher with targeted therapies. It's just not lower as was hoped and we "remain at increased risk". pubmed.ncbi.nlm.nih.gov/327... That's more likely to be due to long term suppression of preemptive detection by cytotoxic and killer T cells due to CLL induced exhaustion, possibly along with DNA damage from previous chemo treatments. Note that this study for patients treated with acalabrutinib and ibrutinib found that the risk of secondary cancers was higher still if you were a smoker.
- Venetoclax + a BTK inhibitor like ibrutinib combinations should work well synergistically; the BTKi blocks the adhesion signalling that keeps the CLL cells in the nodes and marrow, so they slip into the blood stream, where venetoclax makes quick work of them. (With just a BTKi, apoptosis takes much longer to kick in, which is why it's common for the Absolute Lymphocyte Count to initially climb on BTKi treatments.)
- All approved CLL treatments kill healthy maturing B cells as well as CLL cells. So far trials hoping to more selectively target CLL cells haven't worked out, though CLL cells are somewhat killed off more than healthy cells, as there can be a higher expression of BTK, BCL-2 or CD20 in CLL.
- There are people from early FCR trials that have now had remissions lasting longer than 20 years. Unfortunately, you ideally need to be under the age of 65 for FCR treatment and the typical age of first treatment is in the late 70s or older for mutated IGHV folk. We also have some early ibrutinib patients who have been able to maintain control over their CLL for over 10 years (6 years for acalabrutinib as it entered clinical trials accordingly later.)
- It's not just FCR which "requires subjects to receive irradiated blood products for life", but per onlinelibrary.wiley.com/doi... the recommendation is that "All patients treated with purine analogue drugs (fludarabine, cladribine, bendamustine and pentostatin) should receive irradiated blood components indefinitely." So for CLL, that also means BR and PCR (Mayo Clinic's answer to FCR). The recommendation also extends to alemtuzumab (marketed as Campath, Lemtrada, etc) and even CAR-T.
- Obinutuzumab (and rituximab, the first generation anti-CD20 monoclonal antibody, also used in combination treatments) directly kill CLL cell as well as targeting them destruction by our immune system, so there isn't a total reliance on a functioning immune system
- The US NCCN CLL guidelines nccn.org/patientresources/p... are regularly updated with recommended treatments. An early NCCN CLL guideline version evolved into the internationally used iwCLL guidelines document, which is unfortunately less frequently updated ashpublications.org/blood/a...
- Other than IGHV mutation status, prognostic markers for CLL can change during watch and wait
Contrary to a another comment I've made it seems that at least one NHS hospital is up and ready to run with protocol linked below, which refers to the "gid-ta10746" and not TA891. Difficult to delay it when they have both drugs as mono-therapy and it's already stocked on NHS cancer hospital pharmacy shelves.
So, to quote your referenced NICE document Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemiaTechnology appraisal guidance [TA891] Published: 31 May 2023
"Clinical evidence shows that CLL takes longer to get worse, and people live longer, when they have ibrutinib plus venetoclax compared with obinutuzumab plus chlorambucil. An indirect comparison with acalabrutinib, FCR, ibrutinib alone, and venetoclax plus obinutuzumab suggests that CLL takes longer to get worse when treated with ibrutinib plus venetoclax."
With this V+I protocol,you first have 3 cycles of 28 days of ibrutinib to reduce tumour load and hence the risk of Tumour Lysis Syndrome (TLS), before starting the venetoclax ramp up. Per your second referenced document, only high risk patients should be considered for in patient monitoring for TLS.
There is also the additional cost of nurses delivering the obinutuzumab infusions for the V+O protocol, plus the risk of COVID-19 infection while travelling for and receiving the infusions, along with the inability to produce antibodies from infections or vaccinations for at least a year after your last infusion.
Unfortunately the Venetoclax ramp-up is the more difficult part of the V+O protocol for some NHS hospitals to get right, particularly provision of the "meal". 3 cycles of Ibrutinib is a more effective de-bulker than 3 weeks of Obinutuzumab. They expect CT scans to show just 2% to still be high risk at the start of Venetoclax ramp-up.
The photo shows what the plan for V+O looked like around about the 3rd infusion of Obinutuzumab on day 16. Yes they managed to run a day late as admission to ward on day 1 was at 4pm, I didn't get IV of saline until 10pm. But no one can do a "high risk" TLS protocol for first Obinutuzumab infusion in less than 4 days as it needs an eight hour 1L saline IV the day/night before.
Then they played catch-up at first Ventoclax. That didn't go to plan as there was an extra day on each inpatient stay for 2x20mg and 50mg Venetoclax. Again whatever the plan was failed because they failed to get me onto the ward in time. Day 22 it was 4pm and first tablet was 8pm, had to give me 3 doses in 37 hours to move it to breakfast time. Day 1 of cycle 2 it was 11am on ward and tablet was given at 4pm followed by infusion half hour later, so about 40 hours for first 3 tablets. That acceleration also won an extra 2 blood tests for each stay. But each of the 3 outpatient ramp-ups lost a blood test as they used the Monday blood test from 40 hours before the tablet was taken as the prior blood test result. The protocols for other hospitals admit the night before so the patient is on the ward for breakfast and first tablet at 6am (not too sure where they find a breakfast in a hospital at 6am - there may be a hole in their plan). With a plan it still takes 3 days/2 nights but fewer blood tests.
The 2 infusions of Obinutuzumab in the day care unit were the easy part. Although they somehow managed to make a four and a half hour infusion with one hour pre-meds take from 10am to 6:30pm, simply by the pharmacy delivering the IV bag late and delays in changing the pump settings. Also not helped by me mistaking the grade 2 IRR I had on 100mg IV for a grade 3, otherwise the rate calculator sheet would been for a three hour IV.
The 5th infusion on day 1 of cycle 3 was really easy. I got the NHS 90 minute infusion (20% in half hour, remaining 80% in an hour), arrival at 10am and was out by 2pm.
Do you always have to be admitted to hospital for the ventoclax treatment? My husband is moving towards second treatment and has been told it will be Rituximab and Venetoclax for 2 years . Interested to know more to be prepared
No, it's based on tumor burden at the time of starting the venetoclax. High risk patients, the protocol is to recommend a planned admission for 2 nights a week the first 2 weeks of venetoclax ramp up. I ended up being hospitalized 4 nights my first week. Not that I was feeling really sick or in danger, but I had certain lab abnormalities and they wouldn't risk people who aren't at "normal values" getting discharged.
The Venclexta package insert details the ramp up protocol. Pages 4 & 5 outline the protocol for otherwise healthy patients with CLL. Anyone who has a comorbidity where electrolyte changes, or disease/stressors on the kidneys or liver, may also get closer monitoring/hospitalization. I can also imagine that people who don't have easy access to outpatient clinics/labs would be hospitalized.
No, only "high risk" TLS (Tumour Lysis Syndrome) need to be inpatients. The number of cells being destroyed can exceed the ability of the kidneys to excrete the potassium and calcium released from the dead cells. This can lead to kidney failure and death when crystals deposit in the kidneys. NHS death count was 7 out of 24 Yellow card events by 2021, 12 of the Yellow cards were for CLL, there were at least 2 deaths during trials.
"High Risk" is any tumour (swollen lymph nodes, spleen etc) that's bigger than 10cm. Or bigger than 5cm with ALC >= 25 x 10^9/L.
And consider inpatient for medium risk with CLcr <80 mL/min.
This is because they require monitoring by 4 hourly blood tests, 4, 8, 12 and 24 hours after taking first dose of 2x20mg and 50mg tablet(s). The 12 hours after is the kicker, a 2 hour wait to get results means it's 14 hours before a patient can be cleared to go home and return for 24hr blood test the next morning. Outpatients don't open that long, take the tablet at 6am, it will be 8pm. On the 100, 200 and 400mg dose increases, I was taking the tablets at home at 7am, blood test at 2pm and not getting the results until after 5pm.
I was considered low risk in that Ibrutinib had successfully reduced my ALC and reduced lymphadenopathy to low levels. However, I was still hospitalised for 3 out of the 5 ramp up sessions due to raised phosphate levels so a low starting position not considered within the medium or high risk category can still result in an in-patient situation.
I had more hours sat in the day-unit than I ever want to experience again and only knew at the final blood check (usually about 5-6pm) whether I’d be able to go home 😳.
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