More Data Needed to Tease Out Optimal Approaches in Non-Hodgkin Lymphoma

Sonali M. Smith, MD, sheds light on some of the recent advances in follicular lymphoma and mantle cell lymphoma, as well as the challenges that remain overall in non-Hodgkin lymphoma.

Sonali M. Smith, MD

The treatment paradigms in non-Hodgkin lymphoma (NHL), which include BTK inhibitors, chemotherapy-free regimens, and chemoimmunotherapy, vary greatly between subtypes, said Sonali M. Smith, MD. Moreover, aggressive relapses in mantle cell lymphoma (MCL) and lack of data regarding sequencing in follicular lymphoma are ongoing challenges that necessitate further research.

While the approvals of 3 BTK inhibitors—–ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa)––have improved the treatment of patients with MCL who have received at least 1 prior line of therapy, patients who relapse on these agents have poor prognosis.

Ongoing clinical trials looking at earlier use of BTK inhibitors, combination regimens, as well as CAR T-cell therapy could be key to improving patient outcomes in this space.

“BTK inhibitors are currently approved in the second-line and beyond settings, but it would be interesting to see what their activity is in the frontline setting,” said Smith. “Perhaps they can improve progression-free survival (PFS) for patients.”

In follicular lymphoma, the addition of rituximab (Rituxan) in combination with lenalidomide (Revlimid; R2) has demonstrated activity in the frontline and relapsed/refractory settings.

Though R2 failed to show superiority versus chemoimmunotherapy in the frontline phase 3 RELEVANCE trial, the combination could still offer patients with follicular lymphoma a chemotherapy-free alternative as frontline therapy.1

In the phase 3 AUGMENT trial, R2 significantly reduced the risk of disease progression or death compared with rituximab alone in patients with relapsed/refractory disease.2 Data from the trial served as the basis for the May 2019 FDA approval of R2 for previously treated patients with follicular lymphoma. In addition to R2, chemoimmunotherapy and rituximab monotherapy can be used upon progression, explained Smith.

In an interview with OncLive, Smith, the Elwood V. Jensen Professor in Medicine, interim chief of the Section of Hematology/Oncology, and director of the Lymphoma Program at the University of Chicago Medicine, shed light on some of the recent advances in follicular lymphoma and MCL, as well as the challenges that remain overall in NHL.

OncLive: What is already known about indolent lymphoma?

Smith: Indolent NHL generally refers to a group of subtypes of B-cell lymphomas. The prototype [is] follicular lymphoma, but other subtypes include marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma, and small lymphocytic lymphoma (SLL).

Many trials group these diseases together. Of course, chronic lymphocytic leukemia (CLL) and SLL get treated separately, but the other indolent lymphomas are often grouped together.

As such, we have very little data in MZL, which is distinct from the other subtypes of indolent lymphoma.

What is the frontline standard of care in MCL?

The standard of care in the frontline setting depends quite a bit on the amount of disease a patient has, their age, and their overall fitness.

We've come a long way in understanding MCL. When it was first described, it was thought of as a very aggressive disease in all patients. Now, we've learned that there is a subset of patients who have a more indolent presentation and disease course. [These patients could have] nodal [disease] with small volume or low tumor burden, or [have] leukemic [disease], similar to CLL.

It is important to pull those patients aside when we talk about frontline therapy because they can be safely observed for a period of time.

We typically dichotomize patients with classic MCL. In individuals who are young, we tend to use aggressive induction therapy followed by autologous stem cell transplant (ASCT) and maintenance rituximab (Rituxan). In patients who are older or unfit [for intensive therapy], we tend to give chemoimmunotherapy with maintenance rituximab.

[We still don’t know whether] all patients should undergo ASCT. There is currently a large intergroup trial looking at minimal residual disease (MRD) after induction. Patients who have MRD-negative disease are randomized to receive standard ASCT and maintenance rituximab versus maintenance rituximab alone. We will get some answers from that trial as to whether the BTK inhibitors fit into the treatment landscape of MCL.

Where are BTK inhibitors currently used in the MCL paradigm?

There are a number of international trials that are evaluating BTK inhibitors in the frontline setting, as well as looking at BTK inhibitors plus rituximab in patients with low tumor burden.

How do the available BTK inhibitors compare with one another?

We currently have several different BTK inhibitors that are available for use, ibrutinib being the prototype. Ibrutinib made a significant impact in MCL because it showed a response rate of about 70% and a median duration of response of about 1.5 years. We know that ibrutinib has several off-target [toxicities], including myalgias, atrial fibrillation, increased risk of bleeding, and fatigue.

Some of the newer-generation BTK inhibitors have less off-target effects and therefore seem to be better tolerated without compromised efficacy. Though, the follow-up is much shorter for those agents.

How do you determine which BTK inhibitor is most appropriate for a patient?

Selecting a BTK inhibitor for a patient with relapsed MCL is increasingly driven by insurance companies and some of the logistics that are associated with the patient’s pharmacy.

On a medical basis, acalabrutinib and zanubrutinib have a more favorable toxicity profile compared with ibrutinib. I have started to switch my patients over to those 2 agents.

Is there any ongoing research in MCL that you’re excited about?

Patients with relapsed/refractory MCL often have poor survival. Although BTK inhibitors can provide disease reduction, the disease remains incurable. Most patients who relapse will not survive their disease.

One of the more exciting areas of development is CAR T-cell therapy, which appears quite promising. The numbers are still quite small, but this is a unique pathway that is different from standard chemotherapy. Hopefully [CAR T-cell therapy] will lead to better disease control.

Other combinations that are being looked at include adding a BCL-2 inhibitor to a BTK inhibitor in the relapsed/refractory setting.

What advice would you give to a community oncologist treating a patient with relapsed MCL?

[We don’t have great solutions for patients with] relapsed MCL right now. Referral to a tertiary care center, if available, would be the best option. There are some good clinical trials that are available. Patients who are young enough can receive an allogeneic stem cell transplant.

There is much work left to be done.

What frontline treatment options are available to patients with indolent follicular lymphoma?

Indolent lymphomas are essentially chronic malignancies. When you have a patient with a long-expected survival, it is important to think about short- and long-term toxicities of therapy. Treating a patient before they require therapy does not help them live longer or [improve their quality of life] based on the data we have to date.

However, patients may need therapy if they qualify for The Groupe d'Etude des Lymphomes Folliculaires criteria or they have disease progression. If therapy is needed, we have a number of different frontline treatment options.

For patients with low tumor burden, we often use monoclonal antibodies, such as rituximab, alone. However, many patients who have high tumor burden require treatment. We have several options [for those patients], including chemoimmunotherapy or R2.

How are these regimens tolerated? Are there any challenges that accompany their use in the clinic?

The phase 3 RELEVANCE clinical trial compared R2 with chemoimmunotherapy in patients with follicular lymphoma. These were all patients with high tumor burden who required some type of therapy.

The [phase 3 trial] is based on several phase 2 trials that showed synergy, significant efficacy, and a reasonable toxicity profile [with the combination].

The [phase 3] trial enrolled over 500 patients who were randomized 1:1 to R2 or chemoimmunotherapy. The chemotherapy backbone was investigator's choice. Surprisingly, two-thirds of providers chose R-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] as the chemotherapy backbone, whereas only one-quarter chose bendamustine. A few selected CVP [cyclophosphamide, vincristine, and prednisone]. The primary goal was to show the superiority of R2 versus chemoimmunotherapy. Ultimately, the study was negative; there was no difference [between arms].

The results of the RELEVANCE trial have been looked at in different ways. On one hand, it was a negative trial that did not meet its primary end point. On the other hand, the efficacy of R2 in terms of CR rate, PFS, and overall survival (OS) are equivalent. These results allow us to have a discussion with our patients [and allow them to determine] whether they receive chemoimmunotherapy or R2, which is technically a chemotherapy-free regimen. The [regimens] have slightly different toxicity profiles and slightly different lengths of therapy, but equivalent outcomes.

What treatments are available to patients with relapsed follicular lymphoma?

At the time of relapse, there are a number of different options. However, we do not have great data with regard to sequencing.

In terms of early progressors, we know that these patients progress within 24 months of receiving frontline chemoimmunotherapy and have poor survival. Those patients have a 5-year OS of only 50%. This is a pool of patients who require extra attention.

Several clinical trials are attempting to address this [area of unmet need]. Some people will offer ASCT, but early progressors are in need of better options.

For other patients, we can return to chemoimmunotherapy, give rituximab alone, or give R2. This is based on the phase 3 AUGMENT trial. The study randomized patients with relapsed/refractory follicular lymphoma to 1 year of R2 or 1 year of rituximab monotherapy. Interestingly, there was an improvement in the CR rate and PFS as well as a small but [clinically relevant] OS advantage. R2 was approved by the FDA in the relapsed setting, according to these data.

What are some of the unmet clinical needs in indolent lymphoma?

There are a number of unmet needs and challenges for patients with indolent lymphomas, including prognostication at diagnosis. For example, we have a number of prognostic indices including the Follicular Lymphoma International Prognostic Index (FLIPI), the M7-FLIPI, and the FLIPI-2. While none of these indices have been validated or are applicable to an individual patient, they are helpful for groups of patients. Another [need] is to establish time-limited therapy that is well tolerated.


  1. Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36 (suppl; abstr 7500). doi:10.1200/JCO.2018.36.15_suppl.7500.
  2. Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory Indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010.