Evolution Anticipated in First-Line Treatment for CLL, Indolent Lymphomas

Andrew D. Zelenetz, MD, PhD

Novel therapies are being investigated in 2 areas of hematologic malignancies, but the first-line setting is where the brunt of research needs to be conducted, explains Andrew D. Zelenetz, MD, PhD.

For patients with indolent lymphoma or chronic lymphocytic leukemia (CLL), the optimal frontline choice does not exactly exist, he says. While treatment options have evolved and improved over time, researchers are still debating between bendamustine- or CHOP-based regimens for follicular lymphoma, for example. And while chemoimmunotherapy remains a standard frontline approach for younger, fit patients with CLL, it’s not as clear as to what is best for the older patient population.

OncLive: Can you provide an overview of your presentation?

Zelenetz, the medical director of Quality Informatics at Memorial Sloan Kettering Cancer Center, spoke on indolent lymphoma and CLL treatment during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies. In an interview during the meeting, he discussed how the field has evolved over the last several years to include more effective treatments, and the work being done to determine optimal first-line therapies in both spaces.Zelenetz: When you are diagnosed with follicular lymphoma, your expected survival is inferior to the age match general population, but not by very much. The median survivals in this disease have changed from 8 to 10 years 25 years ago, to 16 to 20 years as a median survival today.

We know that first-line therapy is important. First-line therapy can result in long progression-free survival (PFS). We’re still struggling to find the optimal first-line therapy, whether it’s bendamustine-based, or CHOP or CVP; the answer is not crystal clear.

One of the interesting things we saw from the 2016 ASH Annual Meeting is what’s called the GALLIUM trial, which is bendamustine plus CHOP or CVP combined with rituximab (Rituxan) or obinutuzumab (Gazyva). This was a head-to-head comparison of rituximab versus obinutuzumab in indolent lymphoma. The follicular lymphoma cohort was spoken about at the presentation, while the non-follicular indolent cohort wasn’t. It actually met its endpoint. The statistical plan was looking for an improvement (with obinutuzumab)—a hazard ratio of 0.74. The hazard ratio is 0.66. That corresponds to a 50% increase in the PFS.

What about the CLL landscape?

People think that not much has been accomplished because the curves don’t look that different, but the curves can’t look that different. A 50% increase in PFS is going to correlate to about a 10-year survival after first-line therapy. That’s pretty impressive, and it’s going to be hard to beat. We have a large, randomized study comparing rituximab and lenalidomide (Revlimid) with rituximab chemotherapy, but it’s going to be hard to beat a median PFS of 10 years with chemoimmunotherapy.In the CLL world, we are still struggling with first-line therapy. There’s a group of patients, particularly young, fit patients with mutated immunoglobulin genes, who have a 10-year PFS in the range of 70%. They’re probably cured. There are very few events in that group of patients. From that group, which is a very small group, we can define a standard of care, which is FCR (fludarabine, cyclophosphamide, and rituximab).

However, for the older patient or the fit patient who does not have a mutated immunoglobulin gene, chemoimmunotherapy works, but will fail. Findings from the RESONATE-2 trial suggest that you can give ibrutinib (Imbruvica). However, the problem with ibrutinib is it’s going to be far too expensive in the United States, let alone the rest of the world. This is the economic challenge of introducing new drugs early in the treatment paradigm. We know ibrutinib works really well after chemoimmunotherapy. In the selected patient, ibrutinib should be used. We now have idelalisib (Zydelig) and venetoclax (Venclexta), so we have other options in the relapsed refractory setting.

There are a couple of the emerging things from the 2016 ASH Annual Meeting in the relapse setting for indolent lymphoma. Ibrutinib looks okay in marginal zone lymphoma, but positively awful in follicular lymphoma. Again, this is pointing out that all indolent lymphomas are not created equal; these are different diseases.

Going back to indolent lymphoma, you mentioned there’s no optimal first-line choice. What are the factors you consider when looking at a patient to determine which therapy you are going to give them first?

In upfront CLL, following chemoimmunotherapy, there seems to be a role for lenalidomide maintenance. Here’s yet another treatment we have that can [improve] PFS—not in itself a very cheap one either—but at least this was demonstrated in a particularly high-risk population that did not achieve an minimal residual disease (MRD)-negative status. These are patients who had greater than 10^-2 residual disease or between 10^-2 and 10^-4 but another adverse feature, such as an unmutated immunoglobulin gene, p53 mutation, or deletion 17p. This group of patients, when selected, had a clear benefit in PFS. It is too early to see any survival difference, and there may not be an overall survival (OS) difference given the ability to treat patients in the relapsed setting.It’s interesting because the GALLIUM study is actually the first large-scale, well-done study of a bendamustine-containing treatment. People may argue we already have the StiL trial and the BRIGHT trial, but the StiL trial was a community-based study. The toxicity was dramatically underreported, as well as the long-term consequences because the follow-up wasn’t very good.

Given the data we saw at this year’s ASH Annual Meeting, where do you see the future for indolent lymphomas going?

In CLL, what is your go-to approach for when patients fail on either ibrutinib or idelalisib?

The BRIGHT study was an overall response rate study, so follow-up essentially ended at response. One of the things we’ve seen in the GALLIUM study is there is an excess early-death rate in bendamustine-treated patients. When I first saw that data number months ago, I was concerned. That will have a bearing on what I do in the upfront setting. I will probably give a little more old-fashioned CVP and stick to CHOP-based treatments. Based on the data, integration of obinutuzumab in chemoimmunotherapy and follicular lymphoma really is the right way to go.The challenge is going to be in identifying high-risk patients. If the median time to progression is going to be around 10 years, what we really need to do is identify those 20% or so patients who fail within the first 12 months or the first 24 months. Those patients have a very poor survival, but the challenge has been to identify them when we first treat them. Those are the patients who need to be targeted for novel treatment strategies because chemoimmunotherapy is a very effective treatment for the standard-risk patient.There are 2 ways to fail a kinase inhibitor. One is to progress. If you progress on ibrutinib, then going to the other kinase inhibitor apparently doesn’t work very well. We know that from a retrospective study presented at the 2015 ASH Annual Meeting by Anthony Mato, MD.

Secondly, you can fail if you’re intolerant of the drug. You come off of ibrutinib because you have severe muscle cramping and you just can’t tolerate any more. You have copious diarrhea on idelalisib but you’re responding, then switching to the alternative kinase inhibitor is a viable treatment strategy.

What are your thoughts on acalabrutinib?

However, for patients who are progressing on ibrutinib and idelalisib, we saw preliminary data from Jeffrey Jones, MD demonstrating that single-agent venetoclax is very effective in this group of patients with very high response rates. A number of patients were actually able to achieve an MRD state. We do have treatment options for patients who are progressing on the kinase inhibitors.Acalabrutinib and BGB-3111 are pseudo next-generation [drugs]. The reason they are pseudo-next generation is they’re really not “next-generation” drugs. They have exactly the same mechanisms of action. They bind to the active site cysteine and they covalently modify the drug.

We know that acalabrutinib and BGB-3111 don’t interfere with antibody-dependent cell-mediated cytotoxicity in culture, so they should play better in vivo with monoclonal antibodies. That has to be proven. There should be fewer T-cell effects with acalabrutinib and BGB-3111. We know they can achieve very high levels of occupancy of BTK and are highly active in CLL.

What are your thoughts on the ongoing research exploring nivolumab (Opdivo) in CLL?

What are the important takeaways oncologists should have?

If you had the 2 drugs at the same time in the laboratory and had to pick 1, you might have picked 1 of the others, but once ibrutinib is there it becomes pretty hard to displace—unless there’s a clear differentiating factor. That might be in combination with drugs. Limited duration of therapy in combination might be more effective with 1 or the other of the BTK inhibitors.There was a trial of nivolumab combined with ibrutinib with Richter’s transformation. All of the activity observed with nivolumab was in patients who had Richter’s transformation, which is the activity you would expect ibrutinib to have in patients with CLL. Nivolumab really added something to patients with Richter’s transformation, but not very much to patients with CLL.We are in an evolving era of management of indolent lymphoma. Initial therapy is providing very long and durable benefits. The benefits we are seeing now are better than the OS from 2 decades ago. Chemoimmunotherapy remains the standard of care. Personally, I’m going to use less bendamustine.

With CLL, the major challenge is figuring out how to use the novel agents in a much more effective way rather than giving them continuously. What I hope community oncologists will do is try to get involved in novel clinical trials, get their patients enrolled or refer them to these trials because we need to learn how to optimally use these new agents.