Kahl Weighs the Complexities of Treatment Selection in Indolent Lymphoma

Brad S. Kahl, MD

Optimizing treatment for patients with indolent non-Hodgkin lymphoma (iNHL) has become a challenge as the frontline and recurrent treatment settings continue to evolve, said Brad S. Kahl, MD.

"The management of [recurrent] indolent lymphoma is complicated because there are so many variables," said Khal. "There are lot of treatment options and factors to consider, including a patient's age and fitness, their prior lines of therapy, and how well those previous therapies worked for them. It is hard to have a blueprint of how to manage these patients."

Additionally, treatments can have varying utility between lymphoma types, explained Kahl.

For example, PI3K inhibitors have demonstrated impressive efficacy in follicular lymphoma but have been less promising in marginal zone lymphoma (MZL). Conversely, treatment with ibrutinib (Imbruvica) has elicited responses in up to half of patients with MZL, but it has not had the same success in follicular lymphoma.

In an interview with OncLive, Kahl, a professor in the Department of Medicine, Division of Hematology and Oncology at the Washington University School of Medicine in St. Louis, Siteman Cancer Center, outlined the available treatment options in iNHL, factors that may influence treatment selection, and promising agents on the horizon.

OncLive: What are the current frontline treatment options for patients with iNHL, and how are you selecting treatment in the clinic?

Kahl: When you are treating patients with iNHL in the frontline setting, the first question is “Does the patient require treatment at this time?” Some patients [with iNHL] are asymptomatic and present with low tumor burden. These patients can be observed until they develop symptoms or high tumor burden.

If patients are symptomatic or have high tumor burden, the most commonly used regimen in the United States is bendamustine in combination with rituximab (Rituxan; BR). That regimen is fairly well tolerated and is very effective.

Some older patients may struggle with BR and may be better served with a gentler treatment, such as single-agent rituximab. Conversely, some younger patients who have particularly aggressive disease may be better suited for rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

What options are available as maintenance therapy?

Once a patient completes treatment, the big decision becomes whether to offer them maintenance therapy or not.

Some physicians routinely administer maintenance therapy, others never do, and some make it optional. I tend to make it optional. I'll prescribe maintenance therapy to a patient, explain what it can do for them, and then [let the patient decide]. Maintenance therapy can extend a patient’s first remission, but it does not appear to impact overall survival (OS). If it did improve OS, all patients would receive maintenance therapy.

Maintenance therapy has some weakening effects on the immune system. For some patients, this can become a [problem]. Patients may develop problems with hypogammaglobulinemia that can lead to recurrent infections.

If I do have a patient on maintenance therapy and they begin to have these problems, I have a low threshold for discontinuing maintenance. Most of my patients receive maintenance rituximab, but I will stop it if patients are having problems with it.

What does the treatment landscape look like for patients with relapsed indolent lymphoma?

The management of patients with iNHL in the relapsed setting is complicated because there are so many factors that weigh into the decision-making process.

First, there are a ton of treatment options to begin with. Then, patient-specific factors, such as age, the patient's underlying health, and their goals of treatment need to be considered.

One also needs to factor in the patient's previous treatments and how well those treatments worked. For example, if a patient receives something in the frontline setting and it worked well with minimal toxicity, you could offer that again. However, that doesn't happen terribly often because there are so many options.

Let's take the most common scenario. You give a patient BR and maintenance rituximab, and they achieved a nice remission. Then, 5 or 6 years later, their disease returns, and it proves to be iNHL as determined by biopsy. Now, you are having a conversation with your patient about options, the most common being rituximab and lenalidomide (Revlimid; R²).

That regimen received FDA approval based on data from the AUGMENT study. Lenalidomide is given for 21 out of 28 days at 20 mg/day for 1 year in conjunction with rituximab which is administered for the first 6 months of that year. That regimen was compared head-to-head with rituximab/placebo, and R² performed far better. That is going to be the go-to regimen for many people now that it is approved.

Other targeted strategy options could be administered. We have 3 PI3K inhibitors idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra). The efficacy with these agents is comparable with response rates around 60%; however, complete response rates are quite low.

Idelalisib and duvelisib are both oral agents. There is some risk for pneumonitis, colitis, and infections with these agents. The pneumonitis and colitis tend to be severe and potentially fatal. As such, people need to be aware of these potential toxicities and have a low threshold [for stopping treatment] if their patients begin to develop symptoms consistent with these toxicities.

Copanlisib, on the other hand, is given intravenously for 3 consecutive weeks followed by 1 week off in repetitive cycles. It is a prolonged intravenous treatment that is given indefinitely. As such, some patients may find it burdensome to come into the clinic to receive an intravenous treatment nearly every week for the foreseeable future. However, copanlisib does not seem to cause pneumonitis or colitis. The unique toxicities of copanlisib are transient hypertension and transient hyperglycemia, both of which typically last 1 or 2 days and are manageable.

Most physicians are saving PI3K inhibitors for later-line settings due to the toxicity profiles. Additionally, their efficacy is not quite as strong as something like R².

Do these agents have similar efficacy across indolent lymphoma subtypes?

There are differences between follicular lymphoma and MZL in terms of efficacy. PI3K inhibitors are approved in follicular lymphoma, but their efficacy in MZL is less clear.

On the other hand, the BTK inhibitor ibrutinib is approved in the relapsed setting in MZL at 560 mg daily, which is the same dosing regimen used in mantle cell lymphoma (MCL). Ibrutinib elicits response rates of around 50% and a median progression-free survival (PFS) of around 14 months [in MZL].

Therefore, if you have a patient with recurrent MZL, ibrutinib is a good option to consider. It is interesting that ibrutinib is very active in chronic lymphocytic leukemia and small lymphocytic lymphoma, MCL, and MZL, but has very little activity in follicular lymphoma. Not all indolent lymphomas are the same.

What challenges remaining in managing patients with recurrent indolent lymphoma?

There is still a lot of room for improvement in terms of efficacy. With the PI3K inhibitors or ibrutinib, the median PFS is right around 1 year. If a patient gets an average result [with these agents], they will need another option in just about 1 year. As such, it is easy to burn through these options rather quickly.

The challenge is to find better agents that have more durable responses. There are some drugs in development that work through the immune system that will hopefully pan out in this regard.

What agents or treatment modalities on the horizon look promising in this space?

I am keeping my eye on the bispecific monoclonal antibodies that target CD3 on T cells and CD20 on B cells. They bring the T cells and B cells into proximity so that the T cells can effectively function inside toxic T cells to kill the neoplastic B cells. For example, mosunetuzumab is showing response rates at more than 60% in indolent lymphoma. We don't know the durability of these responses because this is a relatively new treatment.

Another immunotherapeutic class of agents that appear interesting are the CD47-targeted monoclonal antibodies. One was tested with rituximab and showed responses in the 50% to 60% range. Again, we don't yet know about durability, but these agents are well tolerated.

Also, we will see CAR T-cell strategies being explored more in indolent lymphomas. While CAR T-cell therapy can cause a lot of toxicity, it could have utility for the right patient with follicular lymphoma or MZL.

For example, if you have a young patient who has already been through a couple lines of therapy, and it is clear they are not having durable responses, they should be considered for CAR T-cell therapy trials. These could turn out to be fantastic treatments in this space.

What is your take home message regarding the current treatment landscape of iNHL?

We have a lot of options, which is a good problem to have. It does make the decision-making process more complicated, but I am grateful to have these options to manage patients with recurrent indolent lymphoma. One needs to take a thoughtful long-term strategy when making these decisions for their patients.