Chronic Lymphocytic Leukemia: RESONATE-2 Trial

EP: 1.Case Presentation: A 67-Year-Old Man with Chronic Lymphocytic Leukemia

EP: 2.Testing and Risk Stratification in CLL

EP: 3.First-Line Therapy Options in CLL

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EP: 4.Chronic Lymphocytic Leukemia: RESONATE-2 Trial

EP: 5.Comparing BTK Inhibitors in CLL Treatment

EP: 6.Treatment Approaches for High-Risk Chronic Lymphocytic Leukemia

EP: 7.The Future of Chronic Lymphocytic Leukemia Treatment

John Allan, MD: In this case, ibrutinib was chosen as the frontline therapy, I do think it was appropriate for this patient. They needed treatment and had high-risk features of deletion 11q as well as an IgVH-unmutated status. Their age was a little bit older, approaching 70 years, and presumably they had this informed discussion and felt that that was an appropriate approach. I do think it's a good approach, and an approach I probably would have taken with this patient myself, honestly. There was some data in the Resonate-2 updated data as well that early on the 11q patients actually seemed like they were performing even better than those patients without an 11q when they are treated with ibrutinib and thus, flipping this whole concept of what is considered high-risk on its head. While 11q is high-risk in terms of aggressiveness of the disease before you get treatment, what Resonate-2 has shown us, which is a frontline study of ibrutinib, is that once you start treatment that high-risk feature has been overcome.

At the seven-year update now we've seen that 11q does not predict for inferior progression-free survival like it does when you use chemoimmunotherapy. While the curves have somewhat come back together, it does not seem to identify someone who's going to do better with ibrutinib. It does identify someone who's going to have the same long-term outcome as everyone else without this high-risk feature. For that reason alone, I do think ibrutinib was a good choice for this patient as well. CLL14 has not identified a certain side of genetic abnormality aside from del17p to have inferior progression-free survivals, etcetera. Ibrutinib is a great option here, it's easy to start, easy to get going and overall, a well-tolerated drug.

John Allan, MD:Resonate-2 was a large phase 3 clinical trial that was a frontline study looking at ibrutinib versus chlorambucil in patients greater than 65 years of age and/or those with comorbidities and not eligible for intensive chemoimmunotherapy. This study has put ibrutinib on the map in the frontline setting. It was a monotherapy study. It's been updated for several times and with publications behind it and has really kind of set the stage for what we expect out of our targeted agents and has been a very important landmark study. We understand the long-term toxicities of ibrutinib and BTK inhibitors in general.

We understand the long-term outcomes based on this study alone. Last year's ASH [American Society of Hematology] or ASCO [American Society of Clinical Ontology] and several other updates over the summers that we've seen now, close to six and a half years of median follow-up, with patients followed out to seven years plus. We’ve also identified, as the new standard bearer for targeted agents, what people need to meet in order to think that a newer therapy is going to have relevance. What we see here is that the response rate has deepened over time.

At the seven-year mark, 34% of patients have achieved a complete remission. This is something that's been a phenomenon across BTK inhibitors that we see deepening of response over time. At any certain time point that you look doesn't necessarily predict that a patient who hasn't gotten much of CR [complete remission] at that point is not going to achieve it. This decreases the relevance of response rate in CLL because it continuously changes over time as you stay on these drugs. What we've also noted from this study in the long-term follow up is that the progression free survival with median progression free survival has not been met yet at close to the six and a half years of follow up with a 61% of patients still progression-free at that six-and-a-half-year mark.

What's interesting half of the patients had six years or longer of drug and at that last data cut off 47% of patients remain on continuous agent ibrutinib doing very, very well. The overall survival, is around the mid-70s to highest 70% range which is a remarkable feat especially in this older patient population. Most are living normal life expectancies with this agent in this study. What we've found was that toxicities in general decreased over time. There are a few that kind of is persistent such as hypertension.

Atrial fibrillation is an issue, arthralgias, etcetera. From the five-year follow-up, we know that close to 25% of patients are developing hypertension, atrial fibrillation, arthralgias, etcetera, which results in dose reductions. From this study, we found that 23% of patients discontinued ibrutinib due to an adverse event, whereas only 12% of these patients discontinued due to progression of disease. It shows you how powerful these drugs are and if you can stay on them, that it's very unlikely that the disease will become resistant potentially with very few true progressions on drug as a cause of discontinuation. If anything, is very encouraging. I do think the side effects can be managed appropriately with those reductions and education to the patient and expectations and some familiarity with the drug. Overall, this has basically set the landmark for what we expect out of targeted agents from this study.

John Allan, MD: One other specific finding from this long-term update was looking at the prespecified subgroups of IgHV mutational status and 11q. What we found, was that the IgHV unmutated status, which predicted four responses to chemoimmunotherapy in fear of progression-free survival year after year.

As the six and a half, seven-year mark has shown, there is no predictive capability by mutated status identifying a patient subgroup that's going to fail ibrutinib at a higher rate, or have an inferior progression-free survival. The curves overlap, and therefore this is not a real differentiating factor for the drug. It brings up this argument: if I'm going to use ibrutinib, do I have to check any of these things? While it's possibly true, you don't have to check a lot of these things. If you're going to use a drug like ibrutinib, I still find a lot of value.

I definitely recommend doing this based on who your patient is. You can talk to them about what the future may hold. Just like the findings with the unmutated status, this was also found in deletion 11q. These patients did just as well as patients without an 11q, and this was one of the first times that we're seeing this phenomenon with these targeted agents.

There used to be, seemingly, a benefit for 11q patients, but this has come back together a little bit and now these curves overlap. It completely eliminated, quote-unquote, this high-risk feature of deletion 11q, and you overcome it essentially, once you start on treatment. These patients can still present very aggressively and need treatment soon after their diagnosis, much like our patient here.

All of this identifies high-risk biology. Once you start on treatment with these targeted agents, it can be overcome and contained. One subgroup that you may be wondering about the del17p patients, it should just be noted that they were excluded from this clinical trial and therefore, we can't really analyze that patient subgroup. Patients with P53 mutations were enrolled and found to have a mutation afterwards in very small numbers in any specific group. There have been further studies looking with pooling these analyses of frontline ibrutinib studies looking at these patients, so I encourage you to look at some of that data as well that's out there.

Transcript Edited for Clarity

Initial Presentation

• A 67-year-old man presented to PCP with complaints of fatigue and night sweats
• PMH: patient takes OTC antiacid tablets a few times a week for a “sensitive” stomach
• PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver
• Laboratory findings:
• WBC; 102 X 109/L
• Lymphocytes; 79 X 109/L
• Hb; 11.4 g/dL
• Platelets; 180 X 109/L
• ANC; 1,900/mm3
• LDH 1470 U/L
• Cytogenetics; del(11q), IgVH-unmutated
• beta2M, 3.0 mg/L
• Rai Stage I

Treatment Plan

• Patient was started on ibrutinib