Has anyone found a clear answer as to what exactly is the necessity and / or contribution of Rituximab when used together with Venetoclax in our CLL treatment? As far as I am aware there is no clinical study comparing results of V+R treatment as opposed to V monotherapy. For reference please see also the link below, although I suppose that most of us must have seen it already.
I suggest you edit your original post, via the "More v"..."Edit" option. The reference link has been broken in your copy too, so you can then delete your corrected reply via the "More v"..."Delete" option.
More generally, your post raises the question of whether adding any anti-CD20 monoclonal antibody to venetoclax contributes to a better outcome. Obinutuzumab/Gazyva is considered superior to rituximab/Mabthera and there are other anti-CD20 monoclonal antibody such as Arzerra/ofatumumab in clinical trials.
The linked reference to the interview with Dr Rick Furman is still a good summary. One reason to add an anti-CD20 monoclonal antibody not mentioned, is that adding rituximab to FC was a game changer over a decade ago, resulting in FCR becoming the gold standard treatment (if you were young enough, i.e. under 65 years of age). FCR is also the only CLL treatment we have to date that is considered to provide an indefinite remission. The ~55% of those who are IGHV mutated and who make it to 7 years without relapsing, are seeing very low relapse rates after 7 years. Early FCR trial participants are now entering their third decade in remission! We haven't run combination trials long enough to learn if we can get indefinite remissions (dare I say a cure?) by including an anti-CD20 monoclonal antibody in combination with venetoclax, but researchers are hopeful.
On a personal anecdotal note, I suspect obinutuzumab made it possible for me to get through the venetoclax ramp up process on my acalabrutinib + venetoclax + obinutuzumab trial, whereas another severely neutropenic patient on the the same trial in the arm without obinutuzumab struggled.
As Dr Furman notes, the down side of treatments including an anti-CD20 monoclonal antibody, in addition to slightly higher adverse event risk, is that you are highly unlikely to make antibodies to illnesses or vaccinations for up to a year after your last infusion.
Wow NeilI'd never heard of an acalabrutinib + venetoclax + obinutuzumab trial, I'm glad that worked. There are so any options!
Just inspired by the comment.
To add to discussion, my Dr says ritux at this time is my last resort because it wipes your antibodies out. Currently I'm on Venetoclax alone at 200 mg and it's working well at month 3.
Dana Farber have done one AVO trial and AstraZeneca another, very similar AVO trial, with one less cycle.
You've either misquoted your doctor or your doctor hasn't explained well how anti-CD20 monoclonal antibodies work. They don't wipe out antipodies or the plasma cells making them. What they do, is very effectively eliminate CLL cells along with any new B cells, so there are negligible B cells around to mature into new antibody factory plasma cells. After your last infusion, the anti-CD20 monoclonal antibody drug keeps circulating in your blood, eliminating further CLL cells along with any new B cells until all of the anti-CD20 monoclonal antibodies are used up. That can take up to a year after your last infusion.
Isn't it "at least a year" after last infusion? I am unaware there is any info as to just how long after anti CD 20 treatment, our antibody production is affected. I know there was an ASH publication that said they were affected out to 12 months. But not that further testing indicated that 18, or 24, or another number of months had been tested and antibody production resumed. Just, "at least 12 months".
In my case, it was 15 months after my last day of acalabrutinib and venetoclax tablets and 21 months after my last obinutuzumab infusion before any B cells appeared in my peripheral blood. So yes, it's probably at least a year .
At times I wonder if FCR might be the way to go? I fully understand the possible secondary effects (e.g., secondary cancers), but a couple of decades of remission would be tempting. Plus I recently watched some CLL KOLs say there are some indications that immunity returns after FCR.
If Obinutuzumab works better than Rituximab, could FCO replace FCR at some point, or doesn't it work that way?
Makes sense to me, but interestingly the closest researchers have come is a multi centre phase 2 clinical of FCR + ibrutinib with an enrollment of 85 treatment naive patients: clinicaltrials.gov/ct2/show...
In this Dana Farber initiated study, the ibrutinib is given in the first cycle, during the regular 6 FCR cycles and then as a monotherapy for 2 years in an effort to increase the percentage of patients reaching uMRD and hence hopefully a cure.
Neil's reply is about the best advice you will get. I went through the same issue last year, I dropped Rituximab after one infusion because both my consultant and I thought it was making me feel unwell and worsening my bloods (at least in the short term), plus it stops any anti covid vaccine working, which was then, and still is, pretty important.The decision we made was to wait and see, ramp up the Venetoclax slowly without any anti-CD20 monoclonal antibody, and test regularly. Ten months later I am still on a low dose V, (100 mg a day), I've not had any more R, but feel fine and my bloods are good (normal). Downside is that the 1 R infusion has meant that despite 5 anti covid vacs I still have no antibodies.
Unfortunately there are no trials comparing V alone versus V with R or O. Unless there are (unlikely I guess), we will have to wait for real world data, ie we are all to some extent guinea pigs,albeit very lucky ones to get the choice.
I am planning/hoping of doing 2 years of V monotherapy, to minimize the possibility of resistance. It will depend on the December uMRD test; I came back at 12 cells in a million in January. Hoping the Dec one is at least lower, if not zero. There's initial data indicating that the resistance develops but isn't reflected in bloodwork for a few months. Old non resistant cells continue to die, blood counts drop or remain steady, but resistant cells start growing. Testing for this resistance is not available outside a research lab right now.
P.S. Someone asked a while ago, why another agent might be urgently started *as soon* as resistance is seen. The above is why. The new agent will hopefully kill the newly emerging cell line, with older one continuing to kill sensitive ones. With 2 drugs, less likely for a resistance to continue to emerge. As opposed to stopping one drug, then starting another.
We are now seeing 3 combo clinical trials, to address this resistance issue. The deeper one can get into remission, the more likely one can stay there/the longer it can take cells to grow back. My BMB and bloodwork after my initial alemtuzumab treatment showed zero CLL cells, and gave me a nice long almost 5 year remission. Not bad for someone initially expected to die within 3-5 years of diagnosis. And I *was* dying just before starting that treatment, I was highly symptomatic, getting weaker and weaker, virtually bedridden, treatment was delayed a few extra weeks "because the non CLL onc wanted to verify something with the CLL researcher across the country" even though I was pleading to start. It was an experimental protocol, only researchers had done it, and no one there had even heard of it, so I understand their caution. Lucky for me, the treatment worked.
With the various drugs sometimes showing resistance during indefinite therapy, there is discussion around if and when to continue this. I have an aggressive variant, and so far haven't tolerated a BTK inhibitor well. So there is a plan to stop, and see just how long I can go before my critter needs treatment again, and I hope to do a repeat of V monotherapy. I am tolerating it well with very few side effects. Plus, newer agents may be available in another 5 years!
You are right patagozon. According to the Abbvie protocol V monotherapy is offered as indefinite, while V+O is a defined duration treatment (typically one year) and so is V + R (typically two years). But then again the question remains, what exactly is the contribution of these anti-CD20 monoclonal antibodies, which makes them necessary or just useful and allows Venetoclax to be taken as defined duration treatment?I think Aussie Neil's and Roger Pinner's replies and experience clarify the situation.
My neighbor with CLL developed acute thrombocytopenia, and his oncologist started him on rituximab infusions which has had the added benefit of decreasing his CLL cells. He really hasn't wanted to treat, and has up until recently had an indolent course these past mmm 7? years. But yesterday he also told me, his Hct had dropped to 12 point something. No splenomegaly or other abnormalities. He refused the bone marrow biopsy, so it's not known his level of infiltration. He also rejected doing the SC rituximab after his initial infusion, saying "his doctor prefers the infusion." So he is sitting in a clinic for hours in a raging Covid area, instead of in-n-out. Of course she wants the infusion, she's a new VP of this for-profit cancer center, they can bill more $ for infusions than injections. Our insurance (we have the same) pays for both. He also is rejecting the free second opinion from CLL Society, and he's not seeing a CLL specialist. Sigh. At least he went for an urgent blood draw when I insisted/badgered him, when he developed extensive petechiae overnight, so he's still alive & getting some treatment.
Combo therapies are to prevent resistance emerging. The quicker one can stamp down the cells, the less likely resistance can emerge. Plus it was noted decades ago, in other disease states, that lower doses of multiple drugs tended to cause fewer side effects than a higher dose of a single agent, in many patients. The quicker one can get into remission, the better IMO.
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Cll treatment 
Optimal Treatment Combinations in the Management of CLL/SLL Jeff Sharman, MD Provided by Clinical Care Options, LLC 
Month 21 of 24 Rituximab and Venetoclax 
