Emerging Treatments and Trends in Hematologic Malignancies: A Q&A With Anas Younes, MD

Anas Younes, MD

The FDA is currently reviewing New Drug Applications for idelalisib in chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). What has the data shown in support of the drug’s efficacy?

Ibrutinib is now approved for mantle cell lymphoma and CLL. What are your thoughts on the potential for sequencing ibrutinib and idelalisib?

At the 18th Annual International Congress on Hematologic Malignancies, Anas Younes, MD, sat down with Oncology & Biotech News to discuss trends in the management of hematologic malignances. Younes, who is chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, discussed a wide range of topics, including novel targeted agents, chimeric antigen receptor (CAR)-modified T-cell therapy, and the appropriate role for oncologists on social mediaThe PI3K delta specific inhibitor idelalisib has demonstrated significant activity in both relapsed CLL and relapsed follicular lymphoma. The CLL results came from randomized trials, so it was easy to compare treatments and get the data. The relapsed follicular lymphoma data was in patients who were refractory to both alkylating agents and rituximab, which is an area of unmet medical need. About 57% of these patients responded to single-agent oral therapy, which is remarkable.Right now, there is no guidance as to which one you should start with. It is going to be based on what is available, what sort of indication, what is the fine print on the indication, what are the future guidelines from the NCCN, and so forth. You will likely have a group of patients who could be eligible for both, and it is difficult to pick one over the other.

There are some groups, however, that have clear contraindications. For example, ibrutinib should not be given to patients on an anticoagulant, such as Coumadin. That set should receive idelalisib.

Other agents being developed in this space include IPI-145 and ABT-199. What are your thoughts on these therapies?

This is not the first time where we have multiple options, and, in the end, the treating oncologist and the patient discuss the pros and cons of each one and decide to go with one over the other. It is good to have more than one option.IPI-145 is a gamma and delta pathway kinase inhibitor, so it has a wider range of activity than idelalisib. It seems to have good activity across different lymphoma malignancies, including indolent lymphoma, MCL, CLL, and T-cell lymphoma. It will be interesting to see where this will go moving forward.

What about the anti-CD20 agent obinutuzumab?

Please discuss your research on brentuximab vedotin that was recently published in The Lancet Oncology.

ABT-199 is a selective Bcl-2 inhibitor that induces cell death. In phase I trials the data were impressive in CLL and MCL, and there is even a good signal in there for it in larger lymphomas. Although it is too early to call, I think it is going to be an active agent that we should watch very closely.Obinutuzumab was recently approved for the treatment of CLL, and it seems to be more effective than rituximab in some subsets of B-cell lymphomas. Now we have to go through multiple randomized trials to determine, in a more scientific way, whether substituting rituximab with obinutuzumab would be more beneficial in these diseases that have an indication for rituximab. There is a good chance to build up on the success in CLL and potentially change the treatment paradigm for other B-cell lymphomas by replacing rituximab with obinutuzumab.The antibody-drug conjugate brentuximab vedotin targets CD-30. It is approved by the FDA for patients with relapsed classical Hodgkin lymphoma and anaplastic large cell lymphoma. In the relapse setting, single-agent activity for brentuximab vedotin exceeds 75% in Hodgkin lymphoma and 86% in anaplastic large cell lymphoma. This is remarkable single-agent activity, so it makes a lot of sense to take a highly effective agent in a relapse setting and move it upfront and combine it with effective regimens.

At the ASH Annual Meeting in December, there was a lot of excitement surrounding CAR-modified T-cell therapy. Can you discuss this treatment strategy and potential implications for clinical practice?

And that is what we did in Hodgkin lymphoma. The most widely used regimen for a newly diagnosed patient with Hodgkin lymphoma is ABVD. We added brentuximab to ABVD in this setting to determine if outcomes could be improved. When we administered ABVD plus brentuximab, there was an unexpected pulmonary toxicity, so the bleomycin had to be dropped from the ABVD. So right now, the experimental arm is AVD plus brentuximab, which is being randomized against ABVD. If the AVD plus brentuximab is better than ABVD, hopefully the treatment paradigm for Hodgkin lymphoma will change.CAR-modified T-cell therapy is a technology that allows you to target different antigens based on what you plan in advance. The one that is most widely used is the CAR CD-19, which binds to the binding site of an antibody that targets CD-19 with a T-cell receptor machinery. There are different technologies for this, but the bottom line is you’re binding a T-cell receptor machinery to a portion of antibody that targets a target and this example is an antibody that targets CD-19. So you have an antibody on T cells that is artificially expressed. B cells express antibodies and T cells don’t express antibodies. Now you have a T cell that is armed with an antibody to CD-19. So you go find CD-19, you stick to it and then activate T cells and the T cells then kill the CD-19-positive cells.

One final nonclinical question. You are active on social media. How can this platform be effectively used in the field of oncology?

The technology is very fascinating. The advantage of it is that this is a patient’s own autologous T cells—you don’t need allogeneic. So this is a T-cell therapy, an immune therapy, that is from your own cells, making it more effective. So, if the therapy is proven to be effective, you don’t need to worry about finding a donor and you don’t need to worry about GVHD and toxicity of allogeneic transplant. You can potentially widen the pool of patients who are eligible for immune therapy (T-cell therapy) as a potential replacement of allogeneic transplant, maybe a potential replacement for autologous transplant in the future. So it’s not only widening the pool of patients who may be eligible, but it also may be a replacement therapy for patients who would have been eligible for more toxic allogeneic transplant. This opens the door mainly for elderly patients with lymphoma, where most of them would not be eligible for transplant. Patients with large cell lymphoma or MCL who fail frontline therapy are not candidates for transplant because they can’t tolerate it, whereas potentially they can tolerate their own T cells going in without the need for toxic conditioning regimens.Social media is where everybody has a presence: patients, foundations, caregivers, doctors, hospitals— everybody is on social media. But the name social media is sort of a misnomer. People think that it is just following the pattern of Facebook: friendship, sharing what you ate, what party you went to, and so forth. It is more like a grass-root communication tool where you can communicate with anyone at anytime, anywhere, with ease and accessibility.

There are two major advantages of having an oncologist like myself—as well as my colleagues from institutions across the world—on social media platforms: You are providing reliable information that corrects a lot of misinformation on the Web, and you are providing a public service for people who need credible information who can now reach out to you and ask for guidance.

This is not for one-on-one consultation. It is not for someone to reach out to you and say, “My son has this diagnosis, his doctor told him this, and what do you think?” This is not for consultation. This is for general guidance—to refer patients to clinical trials or point out that there is something there that you should explore. That is where I see my role on social media: providing a presence that people can trust and offering general guidance as a public service.