There is no doubt to me that Venetoclax is a very exciting development for us in CLL. And yet we don't seem to talk about it quite as much on here as Ibrutinib and FCR. Just this month a very helpful and quite detailed review article has been released.
It is well worth a look whether you are in watch and wait, remission, or coming up for treatment. Venetoclax is available for all patients with CLL in the USA and mostly second line and beyond in the UK and Europe.
One of the many aspects of this review is it lists the studies and as you can see there are quite a few now for Venetoclax in CLL and some of them are beginning to be reasonably long. It may well be that this drug, particularly if used in combination, could turn out to be actually curative for some of us.
If anyone has questions about this study this might be a good place to share them. Note that this is an Unlocked post however, so do not share personal experiences you would prefer didn't find there way into a google search!
It has longer time follow up yes. And what we now know about ibrutinib is it’s great at driving the cells out of the nodes so the nodes shrink, the blood initially tends to have more lymphocytes in but then as they can’t mulitiply any more they gradually reduce in number. BUT almost never get to zero. So if we are aiming for MRDU and then just maybe a cure, we’ll ibrutinib alone just ain’t gonna cut it. But when you hear that venetoclax is great at killing cells in blood and bone marrow but sometimes doesn’t clear the nodes as well.... you can see why the combo is looking so exciting for a time limited period to get to MRDU
Well some people with FCR have essentially been cured with a remission lasting well over twenty years. Since venetoclax gets more people to MRDU than FCR especially if it’s used in combo well the hope is maybe more people will share a similar experience.
Thanks. Very nice summary article and I am sure there with be more at ASH , especially about combinations with G or I.
I am cautious about it being curative. Certainly reaching U-MRD is a signpost we must pass on the way to cure, but cures are a long journey and take years to prove. Some folks relapse who were U-MRD with many treatments including V. Still most who get to a U-MRD response seem to have durable remissions. Data is early, but promising.
I think the future will be non-chemo combinations that include V.
Stay strong, We are all in this together. Brian (CLLSociety.org)
Hi Brian, totally agree about the long time needed. I mean some of those early FCR patients have got to over twenty years remission now...at what point do we declare them cured?? Last time I saw Peter Hillmen he actually used the cure word and said that he foresees a time when after a certain period of time being in MRDU status then a patient would be declared to be essentially cured as it would be highly unlikely they’d still relapse. Of course MRDU would normally be expected to change first before a relapse. Having said that of course CLL does have a tendency to bite us in ways we don’t expect so of course one could get it growing back in nodes when one was still in MRDU I suppose in rare cases perhaps.
We might cures- we just don't know yet. A few caveats. I have seen relapses in MM and CLL after more than a decade. Second, CLL can relapse in the nodes and still be U-MRD in the blood and marrow.
This blasted disease, eh! Just when we think it’s best....but still I’m sure most of us would take a decade pretty happily for a remission. Especially if we can then repeat it either with the same drug or combo or a different one. My working plan at the moment is unless there’s been developments by then I’ll probably go for a venetoclax combo next time round, which I hope is a long time off.
When we are in remission after FCR we dont know how long for. I thought I was told that 5 years was the average time. I was 5 years and 3 years waiting whilst my numbers rose. In that time Ibrutinib was developed and I was lucky because NICE had only just agreed it on the NHS.
I found though that it wasnt my choice of which treatment I was given. The consultant put me on Ibrutinib and had no intention of offering Venetaclax until Ibrutinib failed. He actually said that he thought Venetaclax involved hospital stays. He was pretending to be ignorant as he told me they were doing the Flair trial.
I believe the lack of hospital beds influenced the decision. It is a serious problem. My friend had pneumonia and sepsis and her husband agreed to nurse her at home because there wasnt a bed at that time.
In 8 years treatments have been developed and Im hoping that the Ibrutinib will work for long enough for a cure can be found.
I had to change 1 of my epilepsy drugs and then increase the dose.
My appetite has decreased and Iv started feeling queazy and Im dopey.
Im convinced the co trimoxazole tablets are responsible for diarrhea on some days and the change in meds could cause the side effects and not the Ibrutinib.
BUT my numbers are amazing. They didnt go up initially and in 16 weeks my wbc was 8.5. I dont know what to expect in 2 weeks but my neutrophils were 6.
I would love an end date and hope like you its possible. Hopefully your remission lasts, Anne uk.
I started on a ramp up of Veneteclax in April and when reaching 400mg I was on a monthly course of Rituximab m for 6 months, one more to go in November. Withing 4 months of taking Veneteclax by July- August I was in almost complete remission. Of course we do not know the long term outcomes of Veneteclax as it has not been around that long but so far so good and I think it is less likely to cause side effects, for instance Ibrutinib is well reported as causing some cardiac side effects. I will be on V for 2 years. The side effects are usually related to nausea, GORD but nothing too dramatic. I think it is a great drug and of course I boast that it was developed here in Aus.
Good luck with the V ramp up. Having done it my advice would be drink water and then drink more! Hydration is essential and they don’t always stress how much is needed.
Hope all goes well. Be prepared for lots of sitting around but hopefully you may not require overnight stays. I had 3 overnights out of 5 due to high phosphate levels but I don’t think I’d have had that if issue they’d kept me sufficiently hydrated.
I watched a webinar from a doctor from MD Anderson who stated some doctors (himself included) feel UMRD is a cure if it lasts 10+ years. On the other hand there is 30% of the CLLers never have to have treatment, so depends on how you define cure. Some part of the 30% may well have passed from something else. Just a thought.
I see reaching UMRD as quite different to living without the need for intervention for the CLL. The former demonstrates no detectable cancer cells and the latter means the malignancy is still active but possibly more indolent and liveable with. It doesn’t mean it’s not still causing issues though and I’m always a bit bemused at the expression that people ‘die with and not because’ of CLL. I wonder how many of these people actually had infections induced by or exacerbated by their CLL? I once had a very serious pneumonia and sepsis. I pretty much know that had it finished me off, the cause wouldn’t have been cited as immune deficiency, CLL or hypogammaglobulinemia. It would have said pneumonia and at that time I was untreated.
I very much rely on the views that our late, esteemed member Chris Dwyer used to have on the 30% statistic and because of it I’m wary of telling much younger, newly diagnosed CLL’ers that they may never need treatment because the odds are massively reduced.
I am hoping my BMB yields good news for me in a few weeks having been on I&V for 9 months by then. Somehow though, at the moment I see CLL as being more tamed than cured even for those who reach UMRD status. Sadly too, immune function can already be pretty seriously impaired (which is why I have monthly IVIG).
I’m hugely encouraged by what Venetoclax can achieve but part of me remains respectfully cautious because CLL is an unpredictable foe! 👿
Yes I agree there is little difference between those who do not require treatment versus those who achieve remission or UMRD status due to side effects. I also agree with Chris on 30% not needing treatment, kind of depends on your age. :), but I prefer to give other hope. Blessings.
I agree with your point. My wife (mutated, CD38negative, TP53 intact, normal FISH,<65 Y) will start treatment on October 31.
After consultation with two CLL specialists and much navigation and reading, we were persuaded that the recently approved venetoclax+obinutuzumab combo (12 month fixed duration) was the way to go. A third doctor (hematologist) had strongly recommended FCR (6 months fixed duration), but the the two CLL specialists and a fourth hematologist disagreed with FCR is very strong terms. Doctors #5 (Paris) and #6 (Barcelona) cheered for ibrutinib.
Doctor #3 had argued for FCR on the grounds that it has produced long remissions, even possibly cure, in about 50% of patients with her profile, but was concerned about the unknown long term effects of novel agents; actually, we are beginning to see many issues as experience with ibrutinib (and acalabrutinib to a lesser extent) has accumulated. However, FCR causes myelosupression, produces hematological damage and increases the risk of AML severely.
Venetoclax is not a walk in the park, but the results so far are impressive. There is no evidence as to whether or not obinutuzumab helps, but the design of the trials (e.g., CLL14) leading to FDA approval impeded an unambiguous answer, as no venetoclax monotherapy was examined. I would not be surprised if obinutuzumab does not add much; perhaps a future trial will address the question (perhaps not).
The CLL specialists often say that they are "excited" about venetoclax. Treatment is not a very exciting option, but Venetoclax+obinutuzumab seems to be the less unexciting path among the many "exciting" (as per the doctors that often appear in videos) possibilities that have emerged in recent years. ASH 2019 will hopefully bring new information.
Hi Motoli, Thanks for the info on the venetoclax and the obinutuzumab. I have been given the choice of FCR or V and O......I was going to go for the FCR but the more thought I give it and the more I read I am now leaning towards V and O treatment. My Dr. says a year and a half for the two drugs. I will have to ask him what happens if my numbers drop to normal - what then?
So glad for all of the new drugs, options and choices for us CLL'ers. If I find V and O does not work I guess I could always do FCR. Just happy to have choices! Not sure of the side effects of the venetoclax and the obinutuzumab? Anyone have experience with those two? I'd like to hear what you experienced.
If VO doesn’t work then ibrutinib I is also an option. But look at the data for VO an astonishingly high proportion of patients do get a response and many of them to MRDU. I get the feeling that most doctors would advise you to take at least a year even if you got to MRDU earlier because you want to kill off the last remaining cells (post FCR they found four out of two million of my cells looked suspicious so I’m technically MRDU but may not be cured. The test requires 20 suspicious cells in the sample to them confirm they are CLL and so I am MRDU at the less tuna 1 in 100,000 level (actually I guess you could even say less then 1 /500,000 as that’s two million dividdd by four, but they can’t detect the cells at such a low level.
Remember that we all probably had a single cell give rise to our cancer. So the idea is to kill them all if you can.
But having said that since this is otheewise like a game of wack a mole , some people would stop treatment after that year or two even if they didn’t get a full remission / MRDU to give the body a break and then restart when the cells start to grow back.
Ibrutinib monotherapy doesn’t really have the goal of erradicating the cells more containing them and reversing their growth in numbers. So one approach would be to try and abolish as close to all the CLL cells as possible and if that is no longer working switch to ibrutinib to control what’s left?
Note that this is all quite controversial still at the moment so a consensus will gradually emerge over time and with more data.
As I’m MRDU and should stay without needing treatment for a few years Prof Hillmen told me that by the time I need retreatment hopefully the field will know what to do.
Right now you have to pick a side: eradication attempt or control, and that determines what your treatment will be.
Honestly if possible getting into a study is also a great idea with the AVO study or the FLAIR trial (UK only) both quite attractive for first time treatments.
It is still possible that by going for FCR first and reserving the other treatments for later you might end up doing better in the really long term. The FLAIR trial will he’ll see that as we are putting a huge number of Brits through that so we will know if FCR, I, IR or VI works best both in the first few years but also in time in ten years and twenty years given that we will then all have access to V or I down the line for free on the NHS. So we will be an interesting cohort to watch.
For sure we can’t tell what O contributes. But two things one obinituzimab may help with reducing the risk of tumor lysis and two there are some people on venetoclax monotherapy who have got to MRDU in blood and bone marrow but not nodes. So perhaps O might be helping to clear nodes out. Since we have good evidence that CD20 antibodies in general help save lives in this condition I guess for me I’d be happy for now to assume it was working.
V plus I is another possible option in the future but the data so far just isn’t clear enough. And of course going for A V O may turn out to really knock CLL for six.
The idea of intermittent treatment with a combination of agents for a limited period is not new (think FCR) and may help reduce the risk of resistance (again something O might help with by killing off any cells resistant to V that might otherwise grow)
I do think that after one year if I wasn’t at MRDU I would be hoping to continue to two years like the VR relapse trial did and then maybe you’d have a better chance of a really long remission.
The way I see it at least some people who get to MRDU may be considered cured. Tho you won’t know till they have lived the twenty plus years with no remission. One prof said to me that monitoring for ongoing MRDU would be useful as at a certain point if you were still MRDU given that it takes a while to grow back to a level you’d need treatment for, you’d be able to say you were essentially cured and it would most likely never come back.
It seems to me we are tantilisingly close to a cure at least for some people. Indeed if someone has lived for more than 20 years post FCR why wouldn’t we think they were cured? And since VO data showed a much higher proportion of people getting to MRDU than with FCR well as we follow those people up maybe a hhigher proportion of them could get these super remissions too. We won’t know. But at least it seems one to two years of a Venetoclax combo is typically enough and so we are not exposed to the long term risks of being on a drug for multiple years and presumably long term treatment with one drug must increase the risk of resistance over “take it for a year or two then break and only restart it if the disease grows back”.
A very interesting article and well worth the read. I thought I would just give you so details of my CLL journey so far. I was diagnosed in 2009 (age 47) and was on W&W for a couple of year when I developed ITP. 2012 did 6 x FCR and that but it to bed but not for long. In 2017 I was selected to take part in FUSION opting for the Ibrutinib + Rituximab. That lasted for a month before I ended up with zero platelets with lots of bleeding. At the start of Aug 2017 I started Venetoclax with pretty much immediate results in that my platelets started to rise and I wasn't spending every other day in hospital having transfusions. Since then but more in the early days my LFT went a crazy but that has settled down. Generally my health has got better although I am Neutropenic most of the time and fatigue takes it's toll.
My most recent MRD was Pos 0.0425. I've now been informed that given the length of time I've been on Venetoclax it would appear that it's effect is now starting to slow down and that I'm likely not to achieve MRD Neg whilst on the treatment. This is a little concerning but I will not give up the fight.
For me, the CLL journey has been a long journey but I am of the belief that one day there will be a cure and Venetoclax is just the start.
Thanks for sharing your experience and journey here, It's all very interesting. We're all so different. I too believe that some day soon there will be some kind of long term remission with these new drugs like venetoclax and Obintuzmab. In the mean time I'm going with the newer drugs as well.
Venetoclax ramp-up begins tomorrow, with the first week at 20 mg. How long does it take to see effects on either WBC or lymphocytes? How soon do neutropenia or thrombocytopenia show up when these issues occur?
Prep has been alopurinol for 2 days prior to the beginning, and >2 liters of water per day.
Any suggestions or words of wisdom will be appreciated!
My ALC was almost down to normal levels before the final 400 mg commenced and I could see it dropping in between 8 hr blood tests! Venetoclax can be a hard hitter on the errant lymphocytes.
I didn’t develop issues with reduced neutrophils and platelets until I’d been on V about 2 months. Much depends on the starting level of course and mine had been pretty robust. They did rebound from month to month however and have remained within low normal or just below normal.
The ramp up can be very tedious in terms of sitting around being monitored and waiting between blood tests. My main advice would be keep hydrated. I can honestly say I didn’t have a single side effect from the Venetoclax apart from slight nausea at the final ramp up and curious ear problems! I’ve always taken the V after my evening meal and find it suits me.
Best wishes and hope it goes well without the need for overnight stays. I had 3 out of 5 overnights due to slightly raised phosphate levels.
Thanks, Newdawn! Due to high ALC (105,000) and visibly large nodes and enlarged spleen after almost 6 years of WW, my wife will be hospitalized for 2 days in each of the first 2 weeks of ramp-up. Lots of reading and Netflix phone viewing planned!
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