TREATMENT OF FOLLICULAR LYMPHOMA: Focus on Relapsed Disease and Subsequent Treatment Options

Overview of Follicular Lymphoma

Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma (NHL), accounting for 20 percent to 30 percent of cases and representing 12 percent of all B-cell NHLs. FL is usually not considered to    be curable, but more of a chronic disease.1,2 Though initial response to therapy can be high, the disease is likely to relapse, and with each relapse, the response rate and duration of response (DOR) decreases. Treatment options for the relapsed/ refractory population are limited.

Treatment Options for FL

Treatment for FL depends on the patient’s symptoms, the aggressiveness of the tumor, age, and general health.7 First- line treatment often includes an anti-CD20 antibody, such as rituximab and obinutuzumab, plus chemotherapy, including CVP (cyclophosphamide, vincristine, prednisolone) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), or bendamustine.2,5,8

Once disease relapses, patients may receive another combination of anti-CD20 antibody plus chemotherapy or undergo hematopoietic cell transplantation (HCT).9 Relapsed disease may also be indicated for a more targeted approach with a newer class of agents—phosphoinositide 3-kinase (PI3K) inhibitors. The three currently U.S. Food and Drug Administration (FDA)-approved PI3K inhibitors are idelalisib, duvelisib, and copanlisib.10-12 The National Comprehensive Cancer Network (NCCN) guidelines on NHL recommend PI3K inhibitors as treatment options for FL that is in the secondline and subsequent setting.

Spotlight on Copanlisib as a Thirdline Treatment Option

In 2017, the FDA approved copanlisib for the treatment of adults with relapsed FL who have received at least two prior systemic therapies. It is the first FDA-approved PI3K inhibitor with predominant activity against α and δ isoforms. Copanlisib is administered via a one-hour intravenous (IV) infusion on days one, eight, and 15 of a 28-day cycle.

The drug’s approval was based on results of the single-arm, open-label, multicenter, phase II CHRONOS-1 clinical trial, which included 142 patients, of whom 104 had follicular B-cell NHL and relapsed following at least two prior therapies. Copanlisib result- ed in an objective response rate (ORR) of 58.7% (n = 61; 95% CI 48.6-68.2), including a 14.4% complete response (CR; n = 15) and 44.2% partial response (PR; n = 46). The median DOR among patients with relapsed FL was 12.2 months (range = 0+-22.6 months), and the median time to response was 1.7 months (range = 1.3-9.7 months), indicating a rapid onset of response.

Treatment for follicular lymphoma depends on the patient’s symptoms, the aggressiveness of the tumor, age, and general health.

The most common adverse events (AEs) associated with copanlisib were hyperglycemia (n = 90; 54%), leukopenia (n = 61; 36%), decreased general strength and energy (n = 61; 36%), diarrhea (n= 60; 36%), hypertension (n = 59; 35%), and neutropenia (n = 53; 32%). Forty-four patients (26%) reported serious AEs, the most common of which were pneumonia (8%), pneumonitis (5%), and hyperglycemia (5%).

Copanlisib does not have a boxed warning,14  and because it  is an IV agent, there is low gastrointestinal (GI) toxicity. A study indicated no reported cases of colitis or intestinal perforation  in patients receiving copanlisib, which is common with other PI3K inhibitors. In addition, all hypoglycemia and hyperglycemia events were grade ≤ 3 and transitory.

A number of studies presented at the recent American Society of Hematology (ASH) 2018 Annual Meeting provided updates on the use of copanlisib in the thirdline FL setting. In a longer-term follow-up of the CHRONOS-1 study, re- searchers found that after two years of follow-up, patients with FL receiving copanlisib had an ORR of 58.7% (n = 61), including a 20.2% CR rate (n = 21) and 38.5% PR rate (n = 40). The researchers noted that the findings “demonstrated a deepen- ing of the responses with a conversion of seven patients from PR to CR.” The median duration of treatment was 6.0 months (range = 0.2-44 months), the median DOR was 14.1 months (95% CI, 8.3-22.3), the median progression-free survival (PFS) was 12.5 months (95% CI, 9.0-18.4), and the median overall survival (OS) was 42.6 months (95% CI, 36.5 to not reached). The most common treatment-related AEs were transient hy- perglycemia and transient hypertension. Other AEs of interest were neutropenia, diarrhea, pneumonitis, and colitis.

Another sub-analysis of the CHRONOS-1 study found that patients who relapsed within less than 24 months of firstline chemoimmunotherapy had a similar level of response to copanlisib as those who had a longer DOR with firstline treatment. In a cohort of 140 patients (102 with FL, 85% of whom received some form of R-chemotherapy as firstline treatment), 93 patients’ (66.4%) disease progressed in less than 24 months (POD < 24), while the remaining 47 patients’ (33.6%) disease progressed after 24 months (POD > 24). The median duration of copanlisib treatment was similar: 6.0 months (range = 0.2-44.2 months) for the POD < 24 cohort versus 5.0 months (range = 0.4-32.2 months) for the POD > 24 cohort. The ORR was 58.1% and 68.1%, respectively. The overall median DOR was 14.9 months in the POD < 24 group and 14.1 months in the POD > 24 cohort. The median PFS was 11.3 months and 17.6 months, respectively, and the median OS was 42.6 months and not reached, respectively. “These results suggest that copanlisib should be explored as treatment for patients failing to achieve durable responses in the firstline setting,” the researchers concluded.

Because copanlisib is associated with hypoglycemia and hyperglycemia, patients with diabetes  and  hypertension were thought to be at risk with this treatment. However, another sub-analysis of the CHRONOS-1 study found that patients with well-controlled diabetes or hypertension can safely and effectively receive copanlisib. The study included  28 patients with diabetes and 41 with hypertension. The median duration of treatment did not differ much between patients with and without diabetes (5.0 vs. 6.0 months, respectively) nor those with and without hypertension (6.0 vs. 5.9 months, respectively). Patients  with  diabetes had a lower ORR compared to the overall cohort, at 40%. However, patients with hypertension had the highest rate    of CR (26.8%). The median PFS was 7.2 months for patients with diabetes compared to 13.8 month for patients without, while the median PFS for patients with hypertension was 19.0 months compared to 11.3 months for those without. The median OS had not been reached in these sub-cohorts. “Patients with these preexisting conditions should not be precluded treatment a priori,” the researchers concluded.

Martin Dreyling, MD, PhD

Clinical Discussion with:

Martin Dreyling, MD, PhD
Department of Medicine III at the Klinikum der
Universität München-Grosshadern in Munich, Germany


Q: What are treatment goals for a patient with FL?

A: It’s important to acknowledge that FL is an indolent lymphoma, which means that despite the non-curative, palliative approach to treatment, we can extend survival. On average, median OS can reach two decades. So, we must consider a reasonable, therapeutic algorithm from the beginning to achieve long remissions with as little toxicity as possible.

Q: Can you describe the different rituximab-chemotherapy (R-chemotherapy) treatment options in the firstline setting? How do you position these options?

A: Treatment depends on the patient’s goals. It’s clear why we don’t have a standard, “fits-all” approach, because patient demographics make a difference. For example, a 50-year- old who wants to be fit for the next 10 to 15 years versus an 85-year-old who wants to see his doctor as little as possible will have different treatment goals.

Given that, our standard of care is a combination of an anti-CD20 antibody plus chemotherapy. With chemotherapy, we really tailor treatment according to the distinct patient characteristics and preferences. For example, bendamustine is one of the most frequently prescribed standards of care,   as it does not result in hair loss, which is preferred by many patients. However, bendamustine has long-term hematotoxicity effects, so we must be aware of these toxicities and protect our patients. On the other hand, a CHOP-like regimen has more acute toxicities but less ongoing AEs.

We  have two antibody regimens: The standard of care still   is rituximab, which is well tolerated and very efficient, specifically in combination with chemotherapy. The other is the third-generation anti-CD20 antibody obinutuzumab, which has led to a significant improvement in PFS.

Q: What are particular considerations for patients who require secondline or subsequent treatment?

A: Secondline treatment decision will depend on the firstline treatment, as well as DOR and tolerability of that treatment. For example, if a patient started with bendamustine and relapsed rather quickly—if secondary transformation to aggressive lymphoma is excluded—G/R-CHOP is the standard  of care.  However,  if disease is still indolent but chemotherapy-resistant, it is fair to consider a non-cytostatic approach like R2 (rituximab plus lenalidomide).

Q: Speaking of R2, how does this option compare to R-chemotherapy? How did this combination change the landscape of secondline treatment for FL?

A: About a year ago, the randomized RELEVANCE trial compared R2 versus standard of care, which is antibody plus chemotherapy. The study found that R2 is as efficient as R-chemotherapy; how- ever, this study was designed to detect superiority of R2, but only observed non-inferiority.

At the 2018 ASH Annual Meeting, there was a very important presentation of the randomized AUGMENT trial, which compared R2 with rituximab monotherapy and found R2 was superior to rituximab in terms of response rate and PFS.

Based on this, I think R2 is a definite alternative treatment, specifically in patients who did not respond appropriately to firstline treatment and who are not qualifying for intensifica- tion like autologous HCT (AHCT). This will be an important treatment option for patients with short-term remissions to firstline therapy and those who have contraindications for chemotherapeutic regimens. This trial will very likely lead to the registration of R2 in relapsed FL in the United States.

Q: In the thirdline setting, is R-chemotherapy still a consideration?

A: Potentially, yes; for some patients, it’s appropriate. Based on registry data, this has been standard of care in the past. But in the thirdline setting, patient priorities become even more important, and we may lean toward a treatment with a more favorable toxicity profile. We are moving toward a more palliative approach.

In this setting, we should really discuss a non-cytostatic, more targeted approach. According to the NCCN guidelines, a lenalidomide combination with an antibody and PI3K inhibitors is recommended.

Q: Can you talk more about PI3K inhibitors? How does their safety differ from other options?

A: In the last 5 years, we have learned that the B-cell re-   ceptor and PI3K pathway is crucial in malignant lymphoma, which means that targeting or blocking  this  pathway  can really have an impact, even in patients with double-refractory malignant lymphoma that are resistant to or quickly relapsing after alkylating drugs and anti-CD20 antibodies. In these cases, we tend to run out of ideas on how best to treat these patients. In this setting, PI3K inhibitors are the most efficient approach and definitely superior to Bruton’s tyrosine kinase (BTK) inhibitors.

In United States, three different PI3K inhibitors have been ap- proved by the FDA: idelalisib, a primarily delta inhibitor; duvelisib, a gamma-delta inhibitor; and copanlisib, an alpha-delta inhibitor.

The first two compounds (idelalisib and duvelisib) are oral agents, while copanlisib is an IV treatment. The two oral drugs have a black box warning from the FDA noting auto-immune- trigger toxicities—pneumonitis and delayed colitis—which could be life-threatening. These autoimmune toxicities usually occur after a couple of months of treatment. They have not been observed with copanlisib: Our study showed that just one in  142 patients developed such serious colitis with copanlisib.

Hypertension and hyperglycemia, however, can occur with co- panlisib. But these AEs are typically short-term and transient. If the patient can tolerate the first dose of copanlisib, the side effects are less pronounced after subsequent doses. Chemotherapy is con- sidered well-tolerated from the physician’s perspective, but that may not be the case from the patient’s point of view. Hematologic toxicity and classical impaired general performance are observed one to two weeks after chemotherapy, but these have not been observed with such targeted approaches, like PI3K inhibitors.

Thirdline treatment is really individualized and should depend on the patient’s perspective, priorities, and goal of therapy. Anti-CD20 monotherapy is one option in more vulner- able patients.

Q: Can you discuss the use of copanlisib in the thirdline setting? What makes this different from other treatment options?

A: With an IV treatment, there are pros and cons. Because it is administered by a healthcare provider, we know that the patient is getting the correct dose, but its administration is labor-some (the patient has to come every week to the doctor’s office or hospital for the infusion).

On the other hand, IV treatments do not pass the GI tract, which may explain the improved GI tolerability with copanlisib. Secondly, due to the intermittent dosing, PI3K inhibition is also intermittent, and that might be another reason why we don’t see the frequently-feared autoimmune toxicities associated with oral PI3K inhibitors, which may lead to a dose reduction or delay in about a third of patients.

With copanlisib, hyperglycemia and hypertension are most common but only short-term.

Q: Can you talk about the updated 2-year efficacy and safety data from the CHRONOS-1 study?

A: There’s a very clear and short message: The observed toxicity profile has not changed after 2 years, making the point that auto- immune toxicities did not occur even after delayed observation. These patients will not be cured by PI3K inhibitors, and we have seen a number of relapses, but what is somewhat really calming is that these relapses are not that aggressive as what has been observed with BTK inhibitors, which can have a high cell proliferation and a very aggressive clinical course. So far, this has not been observed for the PI3K inhibitors, at least not in FL.

Q: Can you talk a bit more about outcomes in patients with dia- betes receiving copanlisib in the updated CHRONOS-1 study?

A: These patients are used to measuring their blood glucose, so they may easily slightly increase the insulin dose.

In the study, the overall response rate was slightly lower in patients with diabetes compared to the overall group. However, that might be based on the small patient cohort, which was slightly varying in risk factors. Anyway, when it came to the toxicity profile, these AEs were transient, and no prolonged hyperglycemic events were observed in these patients.

“In the thirdline setting, I think PI3K inhibition is one of the standards of care, specifically in those who had early first relapse or patients who cannot undergo … transplantation. From my point of view, PI3K inhibition is one of the most efficient targeted therapies in follicular lymphoma.”
—Martin Dreyling, MD, PhD

Q: And what about patients with hypertension?

A: We observed a peak in hypertension after a day or so, but, again, it was transient. This was clearly a manageable AE. Patients with either diabetes or hypertension should not be precluded from copanlisib therapy if the disease is well controlled.

Q: So, you would consider copanlisib for these more high-risk patients?

A: Yes, there is no reason to preclude these patients from PI3K inhibitors.

Q: Can you share the results of copanlisib in patients who progress within 24 months of initial chemoimmunotherapy?

A: This is probably the most important finding, because we know that patients relapsing within 2 years of chemotherapy have a more aggressive course and their median survival is only in the range of 5 years.

We found that early and late relapses had similar response rates to copanlisib. In addition, PFS was similar in both groups. We  also found that about 69% of the early relapses have a  high expression of the PI3K pathway, which really confirms  that this is a driving molecular pathway of FL.

I think it’s fair to say that copanlisib demonstrated durable efficacy, specifically in patients with early relapses (within 24 months). That really supports the hypothesis that, specifically in patients less sensitive to chemotherapy, these targeted approaches are very much worthwhile.

I was somewhat surprised by the similar response in early and late relapse cohorts, because PI3K inhibitors target a different pathway, so it makes sense that they are efficacious even in the patients who do not achieve ongoing remission after chemo- therapy. When considering the current treatment algorithm, PI3K monotherapy represents a thirdline option.

Ongoing studies are assessing copanlisib in combination with either antibody-only rituximab or combined immuno-chemotherapy with rituximab plus CHOP or bendamustine. Depending on the results, these studies will pave the way for an introduction of PI3K inhibition into earlier treatment lines.

Q: Can you provide some practical guidance for initiating copanlisib in the thirdline FL setting? Why should physicians consider this treatment option?

A: You have to pay attention to the overall patient. Patients with FL are a largely elderly population. Thus, many of these patients have diabetes or hypertension, so these comorbidities should be properly controlled before PI3K inhibitors are started.

If there are no major AEs after the first dose of copanlisib, you don’t have to fear delayed or cumulative hyperglycemia or hypertension, which we have not observed so far.

The thirdline setting should always incorporate an individualized treatment decision, and PI3K inhibition definitely has some advantages in patients with double-refractory disease.

To conclude, the treatment algorithm is chemotherapy plus antibody for firstline treatment. Secondline treatment remains debatable based on the first DOR. In the thirdline setting, I think PI3K inhibition is one of the standards of care, specifically in those who had early first relapse or patients who cannot undergo dose intensification by AHCT.

Because of these encouraging results, our national study group, the German Lymphoma Alliance, embarked on a phase II trial to assess copanlisib in firstline FL. The study is assessing combination with obinutuzumab, and, based on a pick- the-winner design, subsequently, the most efficient and best tolerated regimen will be compared to the current firstline standard of care antibody plus chemotherapy.


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Martin Dreyling, MD, PhD, was compensated for the creation of this content, which was coordinated by American Medical Communications, independently of Bayer. Funding for the development of this content was provided by Bayer. The content was created by Martin Dreyling, MD, PhD, and American Medical Communications, independently of Bayer.