Novel Approaches Across Non-Hodgkin Lymphoma Subtypes Demonstrate Continued Benefit

Jean L. Koff, MD, MS

Longer-term data from key clinical trials are providing additional insight into the benefit of maintenance strategies, chemotherapy-free approaches, and chimeric antigen receptor (CAR) T-cell therapies in select subtypes of non-Hodgkin lymphoma, said Jean L. Koff, MD, MS.

For example, the phase III PRIMA trial demonstrated that 2 years of rituximab (Rituxan) maintenance following first-line chemoimmunotherapy led to a significant improvement in progression-free survival (PFS) compared with observation in patients with follicular lymphoma. Nine-year follow-up data showed a median PFS of 10.5 years with rituximab maintenance versus 4.1 years with observation (HR, 0.61; 95% CI, 0.52-0.73; P <.001). Despite the significant improvement in PFS, no difference was observed in terms of overall survival (OS).¹

“There’s no real change in the data, but I believe they provide us with more information for when we’re making that decision with patients about whether to proceed with maintenance therapy or not,” said Koff, an assistant professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University School of Medicine.

Encouraging data have also been reported with the PI3K inhibitors copanlisib (Aliqopa) and duvelisib (Copiktra) in patients with relapsed/refractory follicular lymphoma. Specifically, copanlisib and duvelisib have been shown to induce overall response rates (ORRs) of 59% and 42.2% in the CHRONOS-1² and DYNAMO trials,³ respectively.

In large B-cell lymphoma, updated data from the phase I/II ZUMA-1 trial presented at the 2019 American Society of Hematology Annual Meeting showed that the CAR T-cell therapy product axicabtagene ciloleucel (axi-cel; Yescarta) led to a 3-year OS rate of 47% with about 60% of patients having relapsed or progressed.⁴ A previous 2-year analysis of the study showed that the product resulted in an objective response rate of 83% and a complete remission rate of 58%. The 2-year OS rate was 51% and the 2-year PFS rate was 39%.⁵

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Koff highlighted exciting advances made in follicular lymphoma and the promise of CAR T-cell therapies in other lymphoma subtypes.

OncLive^®: What are some of the available systemic options in follicular lymphoma?

Koff: Many options are available, both in the frontline and relapsed/refractory settings. [Often], your choice of therapy depends on the patient’s burden of disease, patient-related factors, and personal preference. A lot of new, exciting data are coming out in terms of chemotherapy-free strategies, such as R2 with lenalidomide (Revlimid) and rituximab. However, [we need] more clinical trials to figure out what the optimal sequencing of these elements is and which patients benefit most from which therapies. [Those trials] will give us more information on what the ideal therapy for a particular patient might be.

How are you currently approaching treatment decisions in clinical practice?

The first questions that I have for any of my patients with follicular lymphoma are, “Do we need to start treatment? Does this patient meet the criteria to go from observational therapy to initiating treatment?”

Then, the [next] question that I ask is, “Is the patient a candidate for a clinical trial?” Since there is no standard of care, we are constantly looking to improve upon what our ideal therapy is in this disease. I’m always looking to see if we have a patient who fits onto a clinical trial [at Emory University School of Medicine]. The next step is to look at their disease burden to see whether I need to incorporate chemotherapy into my initial approach or if they can be best served by a chemotherapy-free strategy.

Could you discuss the PRIMA trial examining maintenance rituximab in this population?

We have known the initial results of the PRIMA trial for quite some time. [Those data showed] that 2 years of rituximab maintenance following frontline chemoimmunotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in [patients with] higher-burden follicular lymphoma extends PFS, but it doesn’t necessarily extend OS. Recently, the 9-year follow-up data were released, and they showed the same trends. We see a PFS of 10.5 years in those patients who received rituximab maintenance for 2 years compared with just 4 years of PFS in the patients who didn’t receive any maintenance. However, we still see no difference in OS, even with 10 to 12 years of follow-up.

What research is being done with PI3K inhibitors?

There are 2 newer PI3K inhibitors; they target slightly different isoforms of PI3 kinase. One is copanlisib, which is an intravenous medication that is given on days 1, 8, and 15 of a 28-day cycle. Results from the CHRONOS-1 study showed a pretty good ORR of about 60%, with a fairly long DOR of about 23 months in a relapsed/refractory follicular lymphoma setting; that is very encouraging. The adverse events (AEs) associated with this agent are hyperglycemia, hypertension, cytopenia, and pneumonia, which are similar to that of other PI3K inhibitors.

The phase II DYNAMO trial had a similar patient population and looked at duvelisib, which is an oral medication that’s given twice daily. [Results showed a] slightly lower ORR of around 40% and a slightly lower DOR of about 10 months [compared with what we saw with copanlisib]. However, duvelisib is an oral medication, so it’s a bit more convenient [to take]. The safety profile of duvelisib is a little different; we don’t see hyperglycemia and hypertension to the extent that we do [with other PI3K inhibitors]. However, again, we do see some cytopenia, which can be treatment-limiting.

Moving on to other emerging modalities in non-Hodgkin lymphoma, what work with CAR T-cell therapy should be mentioned?

Many, many studies are being done with CAR T therapy. This is a very exciting, new approach for targeting not just diffuse large B-cell lymphoma (DLBCL)—which has FDA approvals for 2 different CAR T-cell therapies—but also many other lymphoma subtypes.

[There was the] 2-year update of the ZUMA-1 trial, which is looking at the anti-CD19 CAR T-cell therapy axi-cel. The patients were recruited and received CAR T-cell therapy in 2015 and 2016, and at about 2 years of follow-up, we see a subset of patients are able to achieve a long-term response. About 39% of patients had achieved a long-term response.

The AEs that were reported were very similar to what we have seen in other studies. About 11% of [patients experienced] cytokine release syndrome, and then about 35% had neurotoxicity that was grade 3 or higher. Cytopenias are fairly high [with this product] and range from about 30% to 40%, depending on the cell line. What we’ve seen in practice, as well as what was reported in the study, is that sometimes these cytopenias are long lasting and can be life threatening, especially febrile neutropenia.

[Despite the AEs, I believe these data are] very encouraging. A few years ago, we did not have anything curative that we could offer to patients with relapsed/refractory DLBCL apart from maybe an allogeneic stem cell transplant. We’re looking forward to even longer-term data to see whether these longterm responses that we’re seeing will turn into even longer-term survival in patients with this really difficult-to-treat disease.

Is there anything else that you would like to add?

We don’t have a curative or standard therapy that will work for every single patient. That’s why I always recommend a call to your academic center that has clinical trials, [as these trials] can provide patients with the opportunity to access these therapies even before they are commercially available. CAR T-cell therapies are especially exciting. Getting patients who may be running out of other options access to trials, or even commercially available CAR T-cell products, is a very important new step in our treatment of [patients with] lymphoma.

References

1. Bachy E, Seymour JF, Feugier P, et al. Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study. J Clin Oncol. 2019;37(31):2815-2824. doi: 10.1200/JCO.19.01073.
2. Leppä S, Santoro A, Demeter J, et al. Long-term follow-up of patients (pts) with relapsed or refractory (r/r) follicular lymphoma (FL) treated with copanlisib. J Clin Oncol. 2019;37(suppl 15; abstr 7553). doi: 10.1200/JCO.2019.37.15_suppl.7553.
3. 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.
4. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7.