Follicular Lymphoma Moves Toward Chemo-Free Regimens

Michael L. Grossbard, MD

Treatment for patients with follicular lymphoma is moving toward more nonchemotherapy-based approaches, including PI3K inhibitors and a more widespread use of allogeneic stem cell transplant, explained Michael L. Grossbard, MD, adding that CAR T-cell therapy is also being investigated.

“As time has gone by, we have tried to move more toward nonchemotherapy brute force approaches to managing follicular lymphoma,” said Grossbard, a professor in the Department of Medicine, chief of the Hematology and Medical Oncology Inpatient Service at Tisch Hospital, NYU Langone Health’s Perlmutter Cancer Center.

In September 2018, the FDA approved the PI3K inhibitor duvelisib (Copiktra) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed/refractory follicular lymphoma. The follicular lymphoma indication was based on findings from the phase III DYNAMO trial, in which duvelisib demonstrated an overall response rate (ORR) of 42.2% in this patient population.

Moreover, minimal residual disease (MRD) may help measure the length of remission for a patient, added Grossbard.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Grossbard, who is also section chief of Hematology at NYU Langone Health’s Perlmutter Cancer Center, discussed recent changes to the follicular lymphoma paradigm and therapeutic approaches on the horizon.

OncLive: What is the current state of maintenance therapy in follicular lymphoma?

Grossbard: Follicular lymphoma is easy to get into remission with a lot of the new therapies we have, but there is a continuous period of relapse. Patients are not cured with their initial therapy. Maintenance rituximab (Rituxan) is very helpful because you can use a targeted monoclonal antibody to prolong remissions, which may not have an impact on long-term survival, but prolonging remissions for patients is really important. For a patient, not having disease means a lot—emotionally and psychologically—in terms of quality of life.

The PRIMA trial looked at maintenance therapy with rituximab. Could you highlight those data?

The PRIMA trial was designed to look at maintenance rituximab following one of several induction chemotherapy regimens or chemotherapy and rituximab regimens. Patients were treated until remission and then were randomized to receive no additional therapy or maintenance rituximab. Patients who had maintenance rituximab had longer remissions than those who did not receive maintenance therapy.

How is MRD status assessed used in follicular lymphoma?

MRD can be used monitor how deep of a remission a patient can get. In some diseases, such as multiple myeloma, MRD may have a clinical outcome and impact [on treatment]; however, in follicular lymphoma, there are no studies right now that show that achievement of MRD is critical. On the other hand, the lower the tumor burden, the longer the potential remission.

Is there any ongoing research focusing on MRD in follicular lymphoma?

There are a lot of studies that have looked at MRD in follicular lymphoma. Some of those studies go back more than 20 years, which originally showed that the only modality we had to get patients to a MRD-negative state was transplant. Now, with rituximab and other targeted therapies, we can actually achieve that MRD-negative state with more minimalist approaches.

Moving into the frontline setting, could you give an overview of the GALLIUM study?

The GALLIUM study looked at obinutuzumab (Gazyva), which is a second-generation anti-CD20 agent. It still targets the same antigen or protein as rituximab, but it has some advantages in terms of its efficacy and its ability to offer cytotoxicity and antibody-dependent cellular cytotoxicity. That study randomized patients with follicular lymphoma to receive either a rituximab-based or an obinutuzumab-based induction regimen. We saw improved progression-free survival and responses with the obinutuzumab regimen. It's a next-generation program to treat patients with follicular lymphoma and get them into remission.

How are PI3K inhibitors used in follicular lymphoma?

PI3K inhibitors are yet another kind of targeted therapy that can be used to target follicular lymphomas. We understand more about B cells gone awry, which are the essence of what lymphoma is. The B-cell receptor pathway is triggered by the number of enzymes in a cascade. One of those [enzymes] is PI3K, and by blocking that particular enzyme, we can block the growth and proliferation of B cells and cause the killing of lymphoma cells.

The DYNAMO study was a pivotal trial in follicular lymphoma. What do these data show about duvelisib?

The DYNAMO study looked at the next-generation PI3K inhibitor duvelisib, which has some advantages in that it's a dual inhibitor of PI3K, so it works on 2 different isoforms of the enzyme. Therefore, it has a chance to be more effective, targeted, and cytotoxic than the earlier-generation PI3K inhibitors.

That study showed very high response rates with duvelisib in patients with previously treated follicular lymphomas; the median duration of response was around 1 year. It allows you to use an oral therapy, even for patients who have failed chemotherapy or rituximab-based therapy and buy them additional time.

How do you determine which type of PI3K inhibitor a patient should receive?

That is a very difficult decision to make and there are no clear guidelines that one can follow, as some of it depends on personal experience and comfort with the drugs. There are some suggestions that duvelisib may have a better toxicity profile than the earlier-generation drugs. In either case, once you've chosen a class of drugs, my recommendation would be to get familiar with 1 or more of them and see where they fit into your patient’s treatment course.

What are some emerging treatment options in follicular lymphoma?

We have moved toward nonchemotherapy approaches—even for induction regimens, including the use of lenalidomide (Revlimid)—as part of a [more modern] frontline regimens.

There are investigational therapies [being evaluated, such as] CAR T-cell therapies. We have been able to do a lot better with allogeneic transplant because we can do nonmyeloablative transplants. For patients with heavily pretreated follicular lymphomas, [allogeneic transplant] opens an option for potential cure, even in later stages and in those with more advanced and refractory disease.

What is the eligibility criteria for transplant?

Typically, we don't recommend allogeneic transplant to patients unless they have been extensively pretreated. Still, even though we do a lot better with managing toxicities than we used to, there are significant potential adverse events of graft-versus-host disease and other complications of allogeneic transplant. Patients who have been through multiple chemotherapy regimens, multiple biological therapy regimens, and still have a good performance status and a tolerable amount of comorbid disease would fall into that sweet spot of considering allogeneic stem cell transplant.

What is the status of venetoclax (Venclexta) in follicular lymphoma?

Venetoclax has been a revolution in chronic lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndromes. Venetoclax is a BCL2 inhibitor, and the particular chromosomal alteration that you see in follicular lymphoma is t(14;18), which results in an overexpression of BCL-2. In theory, venetoclax should be a marvelous drug for follicular lymphoma, but the response rates in follicular lymphoma with single-agent venetoclax have been a little more disappointing than we would have anticipated. Venetoclax’s place in follicular lymphoma still remains to be defined.

Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi: 10.1200/JCO.18.00915