Anthony Mato, MD, MSCE

CLL Updates From the 2019 ASH Annual Meeting

Question

What data in chronic lymphocytic leukemia (CLL) that came out of the American Society of Hematology (ASH) 2019 meeting were considered practice changing?

Answer

The most practice changing presentation at the meeting was by Jeff Sharman, MD, who presented the results of the ELEVATE TN trial.¹ This trial was in treatment-naive patients with CLL and looked at the role of acalabrutinib alone or combined with obinutuzumab compared with obinutuzumab plus chlorambucil.

The reason this trial was exciting is that it brings [US Food and Drug Administration] approval for acalabrutinib in the frontline setting. The trial was overall very positive, demonstrating an improvement in progression-free survival with acalabrutinib with or without obinutuzumab as compared to the control arm. This is now a brand new first-line option for patients with CLL.

Question

What novel treatments for CLL that were highlighted during the meeting seem most promising?

Answer

There were several presentations of promising new treatments for CLL. The presentation I gave was on LOXO-305.² [They were] very early data, but LOXO-305 is a new, noncovalent-binding BTK inhibitor studied in patients who had relapsed or refractory CLL.

With all of the caveats of follow-up being incredibly short, we did see responses of about 77% in patients with CLL and an adverse events profile that looked quite favorable. These results are not practice changing yet, but are exciting because this is potentially another line of therapy in the sequence of agents for patients being treated for CLL.

Other exciting data looked at zanubrutinib, another BTK inhibitor.³ Zanubrutinib is not yet approved in CLL, but is approved for treating patients with certain lymphomas. These data suggested that zanubrutinib was active and well tolerated in patients with CLL in the frontline setting. We expect more data in the near future.

Question

It was shown in a retrospective analysis that ibrutinib was the top-prescribed drug among said study population, but 24-month overall survival was highest for those who received bendamustine-rituximab.⁴ What do you make of these findings, and how should it guide future treatment decisions, if at all?

Answer

I think whenever you look at claims data it is very hard to draw any conclusions particularly because of the fact you don’t have a lot of patient information such as prognostic profiles or medical comorbidities, etc. That makes it hard to judge or make comparisons between groups of patients. The major concern here would be treatment selection bias based on study design. It would be like conducting a clinical trial but not knowing about the patients enrolled in either arm. These types of studies are informative in terms of practice patterns, selection of therapy, or what drug is used more commonly, but to draw survival comparisons from medical claims data is incredibly difficult to do. It can only be seen as hypothesis-generating.

Question

Combination ibrutinib plus venetoclax: Is undetectable minimal residual disease (MRD) a good surrogate endpoint for survival? Why or why not?

Answer

Undetectable MRD is a helpful endpoint and we will see this more in future studies. Probably the best use of MRD, at this time, is for designing therapies and trials that are focused on discontinuation of therapy. There are a lot of trials that have looked MRD as a prognostic marker, which is interesting, but the goal is to really have it drive treatment decision making.

For example, the combination of ibrutinib plus venetoclax seems to induce a high proportion of patients having undetectable MRD. Maybe those are the patients for whom it is best to discontinue the combination. For those who have persistent disease, maybe those patients need to switch therapy, need to have continuous therapy, or need to have something added to their therapy to help overcome that resistant clone. I think that is the best use. I also think that it is a surrogate endpoint for survival outcomes like progression-free survival, for example.

Question

Given the fact that many patients with CLL discontinue treatment or undergo dose reductions⁵ is time-limited treatment in CLL⁶ ultimately the best approach to drug therapy in your opinion? Why or why not?

Answer

It is going to vary patient by patient. Certainly double or triple novel-novel combination therapy or time-limited therapy is a wonderful option for many patients, but it does often expose patients for a fixed duration to multiple drugs at once, which potentially exposes them to more adverse events. Those therapies are most appropriate for patients with poor-risk features who would not do as well with single targeted agents or targeted agents paired with anti-CD20 monoclonal antibodies. It is not going to be the answer for everybody, unless one can prove that the intent of a particular combination is [of] curative intent as opposed to an aim of disease control.

There are many patients who can do really well with single targeted agents who may not require multiple novel agents at the same time. Right now, combination therapies are successful at inducing deep remissions, but we are not yet able to identify patients who need those combinations.

Question

Chimeric antigen receptor T-cell (CAR-T) therapies in CLL: What were some of the most interesting insights from the data presented on adoptive cell therapies in CLL?

Answer

There were limited data about CAR-T in CLL presented at ASH this year. The one that comes to mind was given by Tanya Siddiqi during the oral sessions.⁷ In a population of heavily pretreated patients with CLL who had progressed on ibrutinib, more than 80% responded to CD-19 directed CAR-T therapy. There were also some durable remissions in a minority of patients with CLL. Immunotherapy, in the form of cellular therapy — whether it’s transplant or CAR-T — is still very much experimental. They are not currently approved for CLL and are not yet the standard of care. Right now, we are existing in a space with so many effective targeted agents for CLL. CAR-T will play a role, but it is hard to know where in the sequence of therapies it will fit.