I have been on IB for 3 years and am very happy with my doctors approach is that once I progress on IB then we will switch to Venetoclax.
I want to appeal to any Canadians who have managed to take these drugs together as Health Canada doesn’t allow it and won’t fund them.
Thank you
Steve
Steve, I am not in Canada but I just this past month added venetoclax to my acalabrutinib in the US. That combination is not really approved yet, so it was unclear if social security would for pay for both. I suspect, but do not know, that having the venetoclax prescription come from a Dr at Md Anderson helped get it approved.
Had venetoclax not been approved, my argument to social security would have been, since the hope is for me to get mrd negative and get off both drugs in a year, that it’s way cheaper to have me on two expensive drugs for a year than one indefinitely. I never had to argue for venetoclax approval, Medicare approved it with no questions
There is no doubt adding venetoclax to acalabrutinib will dramatically increase my chances of getting a deep mrd negative remission. So adding venetoclax is a no brainer, right?
Maybe not. The long game with Cll is who lives the longest, not who gets into a remission first. If I get a deep remission on acalabrutinib and venetoclax, there is no guarantee how long it lasts and if I would have a better chance of overall survival by staying on acalabrutinib alone and then sequencing to venetoclax if and when acalabrutinib ever stopped working. Shooting both of my big guns at once might not leave me with a good back up plan.
I, with the advice of my doc, decided to take the chance and go for it. I just wanted to point out that your doctors plan to wait to add venetoclax might be the best plan, no one knows for sure. Further complicating matters is that the right plan for me might not be the right plan for someone else. Cll treatments are becoming very individualized.
It’s certainly a good question you are looking into. I don’t know if there is a way in Canada, outside of a clinical trial, to add venetoclax. I would hope that option is available for those wanting to pursue a more aggressive treatment plan. Aggressive doesn’t always mean better, I know adding venetoclax adds additional risk, and possible benefit, for me. Good luck.
This is the million dollar question. Am I better off firing all the big guns at once or using them in sequence one after the other? Did your doctor give you an estimate of when he thought the research would have an answer to this question? Jeff, I’m curious are you mutated or unmutated? Do you think there are different answers for each of these prognostic markers? I’m unmutated and wonder when it is time to make my decision this will factor into the decision making.
Thanks
Mark
Mark I have mutated IGHV Cll but it acts aggressively.
I am not qualified to answer your question. My guess is that doctors might be more inclined to be more aggressive with unmutated Cll and add novel drugs to see if the Cll can be stopped before evolving into a more serious type of cll.
That strategy arguably didn’t work well with fcr (chemo) where fcr might have accelerated clonal evolution.
I did read one well known Cll doctor write that he is more likely to use combination therapy with aggressive Cll and more likely to use just a single agent btk drug with more indolent cll.
I can’t recall who wrote that or where I read it.
Jeff, out of interest what second line treatments might be suitable now for a CLL patient who relapsed after first line with I or A plus V?
For what it's worth (diddly squat!) my hunch is that first line A plus V will give most patients a long remission, time enough for new treatments to establish.
I’m hope I don’t have to test it out but having received I&V first line treatment, my haematologist told me it would be Venetoclax (possibly with Obinutuzumab) should I relapse but of course the choice is more difficult if the issue is resistance.
Newdawn
Resistance to both I and V you mean? That would be tough luck.
Could bispecific antibodies be the answer in years to come?
It was recently reported that a CD3×CD19 bispecific antibody can mediate effective killing of CLL cells regardless of IGVH and TP53 mutational status, and irrespective of sensitivity to ibrutinib or venetoclax.76 Another study showed that a CD3×CD19 bispecific antibody more rapidly killed CLL cells from patients previously treated with ibrutinib, and that the antibody was active also against ibrutinib resistant CLL cells.77 These studies suggest that bispecific antibodies may overcome resistance to ibrutinib and venetoclax (Figure 1D).
ashpublications.org/bloodad...
When I was diagnosed nearly 10 years ago, I&V were a pipe dream so who knows what the treatment landscape holds?W&W the sequel is quite scary however especially when you start with the ‘big guns’ first.
Newdawn
If a person relapsed after getting off ibrutinib and venetoclax for a period of time, their Cll could be rechallenged with ibrutinib, venetoclax or both.
It gets trickier if they are resistant to ibrutinib and venetoclax. I think the first choice might be a trial with a non covalent binding btk drug.
The next category of inhibitor drugs includes duvelisib. The problem with duvelisib is that there are more side effects than with btk and bcl inhibitor drugs and it usually just buys a person a couple years.
After that you start talking about CarT type therapies which are involved and have mixed results.
Not many people sequence from a novel drug to chemo drug, but I suppose if someone is young enough they might try Bendustamine or fcr.
There are all sorts of trials someone might try. We need more options after ibrutinib and venetoclax for sure.
Thanks. Those options will surely come over the next few years.
Jeff, a few points that I've heard that made the I/V trial I was on more attractive that single agent treatment. First, the I and V are complimentary. I works better in the nodes and V works better in the blood and marrow. Second, It's harder for either drug to become resistant when both are used at the same time, because if CLL clone starts to become resistant to one it will be killed by the other. Lastly the time off drug will also help prevent developing resistance.
john
John, these are all the reasons I have added venetoclax to my acalabrutinib. I think that might be the standard treatment combination of the future.
But there’s a reason I plus V is used in trials and not as an approved combination. One is that venetoclax adds toxicity, some of it which might be unknown, as it is a new drug with little data beyond ten yrs. Some people do so well on ibrutinib or acalabrutinib, they might never need another drug and don’t need the added toxicity.
The other question being studied is what sequence creates the longest survival. Ibrutinib and venetoclax taken together will almost always outperform either drug taken individually in the short term due to the synergy you describe.
What is not known is if someone relapses after I plus V, would they have lived longer just using ibrutinib and then adding venetoclax when the ibrutinib stops working.
My guess is that when the trials are done, some version of I plus V will be approved and will be gold standard combination. That’s why I chose to add venetoclax. I was just pointing out for those considering the same path you and I took, that there are risks still being studied. Indeed outside of a trial, I don’t think most top Cll doctors use ibrutinib in combination with venetoclax as a frontline treatment.
Yes ,there is a way in Canada. For the first six months on Venetoclax and Rituximub ,you could still use your RX at the pharmacy for Ibrutinib until Rituxan infusions are completed (6months) since patients on this regime are getting Venetoclax and Rituximub from the hospital’s pharmacy. I really don’t know how it worked and who was paying for what.The reason I was started on V + R was ,that Ibrutinib slowly was refusing to work on my mixture of MZL and CLL cells. So, for the first month of V+R therapy I was also taking Ibrutinib. Well,after a month I couldn’t take it anymore. I had edema all over my body ,my face , my hand ,I had pains all over and in general I was not well . I decided to stop Ibrutinib on my own since my dr. was on vacation.I felt ,I am doing myself more harm that good, by taking them together .After I stoped Ibrutinib ( I was on it for 2.5 years) ,swelling gradually subsided ,and I started to feel better. It would be good to know if someone else had a similar reaction to those two drugs .
Hi steve_canada,
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cajunjeff has given an excellent answer. And I just started the opposite sequence to his and your order of treatment. I have been on Venetoclax for 5.5 years and started Calquence 2 weeks ago. We (Dr. Furman and I) have no idea whether that will yield as good a response as taking Ibrutinib for one or more years and then adding Venetoclax.
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There is some early indication that Ibrutinib causes a small improvement in "exhausted" T-cells, and that more CLL patients get to MRD-U if the Ibrutinib was taken for one year or more before starting Venetoclax.
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What is not yet known is whether Alcalabrutinib / Calquence causes the same benefit or whether the BTK inhibitor can be stopped when the Venetoclax is started and get the same benefit.
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So may be we should start a clinical trial among the 3 of us and see which sequence of Venetoclax and Calquence gives the best results, especially in OS (Overall Survival). Of course we will all 3 need to survive at least 10 years to prove it. So if both of you agree, let's all plan to live at least 10 more years, and then publish the results.
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Len
While the combination of Ibrutinib and venetoclax may not be approved in Canada, venetoclax on its own is available. My cll specialist (Ontario), like yours, has recommended that if and when my cll progresses, we switch to Venetoclax but not before. I suspect, however, that combination therapies like you suggest, will soon be on the table in Canada especially if clinical trials show the advantages of such treatment. I’m hoping these approvals occur before acalabrutinib looses its effectiveness for me.
I became uMRD after 5.5 years of Ibrutinib and 1.25 years of Venetoclax, taken in sequence with one month overlap. From what i've read and heard from leading hemocs taking the two in combination will yield the fastest trip to uMRD land and also provide the longest OS. Typically CLL patients stop taking V after hitting uMRD (I've been in my second W&W mode for 1.5 years) and i'm told that when CLL returns, i can resume V and expect good results. For those who develop resistance, or are worried about it, an even more amazing drug is in clinical trials. Check out LOXO-305 if you're worried about having CLL problems after using I and V. LOXO, in combination with one of the CD-20 agents like Obinituximab or alone, has shown great results in CLL patients who failed I and/or V.
I’ve been on IB only for 3 years and doing well but I really want to be done with taking pills every day.
I want to see how I can add Venetoclax now in junction with IB and hopefully knock this on its butt.
Are you fully covered for both drugs?
i have medicare plus a Part d supplement, which covered both drugs up to certain limits. So i had a serious copay. for awhile i had some help from the various u.s. foundations, though. you're absolutely right to try to get rid of CLL, at least for some unknown period of time, via going the I+V route, either together or in succession. The clinical trials testing the two combined are showing great success, so it will be matter of time before I+V is the gold standard.
Ibrutinib and funding in Ontario 
Ibrutinib and Shingrix issues
First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia.
Ibrutinib and Venetoclax 
