New Standards Are Emerging for Follicular Lymphoma and CLL

Krishna V. Komanduri, MD

Non-Hodgkin lymphoma (NHL) encompasses several hematological malignancies, which are broadly categorized as indolent or aggressive. Low-grade lymphomas, which typically progress slowly, include follicular lymphoma (FL), mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and marginal zone lymphoma. Indolent NHL has the potential to transform to aggressive or high-grade lymphoma, which is one reason controlling indolent disease remains such a priority.

Follicular Lymphoma

In an OncLive Peer Exchange® discussion led by Krishna V. Komanduri, MD, experts in hematological malignancies reviewed the evolving paradigm for managing indolent NHL. “The past few years have been incredibly exciting in terms of improving our understanding of lymphoma biology and developing novel approaches for treatment,” Komanduri said.Patients with FL are often asymptomatic and their condition is discovered incidentally during a routine examination or workup for another health problem. Leo I. Gordon, MD, explained that most patients whose disease presents this way do not require treatment until the lymphoma progresses. “There are no data that suggest earlier treatment offers a survival advantage,” he said.

First-Line Options

When treatment is required, physicians must decide whether to use a regimen that includes chemotherapy. Gordon said data increasingly show patients with less aggressive FL derive similar benefits from less toxic, chemotherapy-free regimens. Historically, the most common choice is single- agent rituximab (Rituxan). He said data presented at the 2016 American Society of Hematology Annual Meeting suggest that “the addition of lenalidomide [Revlimid]... might offer a response and complete response [CR] advantage.” An immuno- modulatory agent, lenalidomide is approved for various types of lymphoma but not for FL. The randomized phase II SAKK 35/10 trial (Table 1) compared rituximab monotherapy versus rituximab plus lenalidomide.¹ The combination was associated with higher rates of CR/unconfirmed CR, CR at 30 months, and longer time to next treatment.

Table 1. Outcomes in the Phase II SAKK 35/10 Trial

CR indicates complete response; CRu, complete response unconfirmed; n/a, not applicable; NR, not reached; OS, overall survival; PFS, progression-free survival.

Gordon said several options are available for patients who need more intensive therapy. Typical regimens are R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and BR (rituximab plus bendamustine [Treanda]). Although studies show BR is less toxic than R-CHOP, Gordon expressed unease about the lack of long-term data for BR. “My concern is that we may begin to see certain malignancies occurring in patients treated with BR,” he said.

Komanduri asked panelists about the role for consolidation and maintenance in FL. John P. Leonard, MD, said that, while studies have found rituximab or obinutuzumab (Gazyva) maintenance therapy prolongs progression-free survival (PFS), they have not shown improvement in overall survival. He noted that the RESORT study reported similar outcomes for patients who received maintenance rituximab and patients retreated with rituximab after progression.

Leonard said maintenance was essentially prolonging 4 to 6 months of treatment into 2.5 years of treatment, with no survival benefit and greater toxicity. He stressed the importance of ensuring that patients understand maintenance therapy’s risks and limited benefits.

Relapsed or Refractory Follicular Lymphoma

“The nature of this disease is that we don’t cure patients and they have multiple relapses,” Komanduri said. Several options are available for relapsed or refractory FL, leaving hematologists to wrestle with how best to sequence therapy. Gordon said Follicular Lymphoma International Prognostic Index scores, molecular analysis, or time to recurrence can help identify patients who are apt to respond poorly to second-line options. Recurrence within 12 to 24 months of first-line therapy is an especially strong predictor of poor response to subsequent therapy. Gordon recommended considering a clinical trial of a novel therapy or a transplant, when feasible, for high-risk patients.

Patients whose FL recurs after 24 months of remission are considered treatment sensitive. Leonard said, “you can do whatever you want” for such patients. Options for relapsed or refractory FL include bendamustine monotherapy, BR, a fludarabine-based regimen, radioimmunotherapy, single-agent rituximab, or bendamustine plus obinutuzumab.

Rituximab plus lenalidomide could become another option based on positive results from a trial Leonard helped lead that compared rituximab alone or with lenalidomide in relapsed—but not refractory—FL. “In these rituximab-relapsed patients or chemo-rituximab—relapsed patients, lenalidomide had about a 50% response rate lasting over a year. When you look at the combination of lenalidomide/rituximab, the response rate went up to about 75%, with the PFS being about 2 years—so, clearly, a big difference,” Leonard said. He mentioned that AUGMENT is another phase III trial evaluating the rituximab/lenalidomide combination in relapsed FL.

Idelalisib (Zydelig), a PI3K-delta inhibitor, is approved for patients with FL whose disease progresses after 2 regimens. Gordon said several phase III studies that investigated combining idelalisib with BR for patients with relapsed indolent B-cell lymphoma were discontinued after several patients died or developed serious adverse events (primarily due to Pneumocystis jiroveci infection or reactivated cytomegalovirus). He advised caution when giving idelalisib to patients with suppressed T-cell function.

Leonard said he still uses idelalisib for select patients. He said toxicities were manageable if patients were watched carefully, fevers were investigated promptly, and pneumocystis prophylaxis was administered. “I have a number of patients doing well on it, so I wouldn’t throw it out at this point,” he said.

“I echo your sentiment that some patients can do very well on [idelalisib] for a long period of time,” John Byrd, MD, told Leonard. He said he finds idelalisib more appealing than either certain chemotherapy regimens or than lenalidomide for heavily treated patients partly because idelalisib does not cause cytopenias.

Chronic Lymphocytic Leukemia

The panel next discussed emerging targeted therapies for FL (Table 2), including ibrutinib (Imbruvica), venetoclax (Venclexta), pidilizumab, and TAK-659. Komanduri said investigators are also looking at compounds that inhibit MEK or JAK. Gordon said clinical trials of venetoclax and pidilizumab in relapsed FL had disappointing response rates, whereas a trial of the novel drug TAK-659 for relapsed FL had a “very impressive” response rate. Gordon said he believes greater progress will require “investigating different parts of the B-cell receptor pathway in FL.”Like patients with FL, patients with newly diagnosed CLL frequently do not require treatment immediately. However, Michael J. Keating, MBBS, advised against telling patients you plan to “watch and wait.” He said, “they hate the term,” noting that some of his patients call it “watch and worry.” Keating said he prefers “watch and investigate.” He said that despite newer, more sophisticated biomarker tests that can identify high-risk patients, guidelines for initiating treatment have changed little in 10 years.

Table 2. New and Emerging Targeted Agents in Follicular Lymphoma

Keating said treatment decisions should be based on whether the patient has bulky disease, marrow failure, or rapidly progressive disease during observation. He added that the guidelines are useful but not absolute and said treatment decisions require common sense. “If you have a lymph node in a particular area, you’re going to make different decisions based on that,” Keating said.

First-Line Treatment

Keating said US and European experts agree that FCR (fludarabine/cyclophosphamide/rituximab) should be the standard first-line therapy for young, fit adults but the outstanding question is whether the age cut-off should be 65 or 70 years. He expressed dismay that even though 72 years is the average age of CLL diagnosis, no standard regimen exists for patients older than 70 years, and no treatment is approved for this population.

Ibrutinib is a newer option approved for all stages of CLL. It is given continuously until progression or intolerance. Although ibrutinib is well tolerated, Keating said some of his patients with good prognostic features, such as an IGHV mutation, prefer FCR, which is discontinued after 6 months. As Keating and colleagues at The University of Texas MD Anderson Cancer Center observed in a recent study, two-thirds of patients with CLL harboring an IGHV mutation initially treated with FCR sustained remission for 12 to 18 years with no additional treatment.

Byrd called the study practice changing but said the decision between FCR and ibrutinib for older patients with an IGHV mutation is less clear. “[FCR] is a harder therapy over 6 months than ibrutinib,” he said. In addition, 3% to 5% of patients treated with FCR develop treatment-related myeloid neoplasia, which Byrd said is usually fatal. Keating said he would like more data on whether ibrutinib doses can be decreased for patients who have a strong response and on how CLL cells change with prolonged ibrutinib exposure.

For the many patients whose advanced age or disease characteristics make them ineligible for FCR, Byrd said combining obinutuzumab with chlorambucil is highly effective, as is ibrutinib. The RESONATE-2 trial and extension study found patients with CLL older than 65 years treated with ibrutinib had an 88% reduction in risk of progression or death compared with those treated with chlorambucil. The PFS bene t observed with ibrutinib was also observed in patients with unmutated IGHV and deletion 11q, which predict poor response to FCR.

On the maintenance front, Keating said the German CLL Study Group recently showed lenalidomide significantly prolonged PFS for patients with CLL who failed to achieve minimal residual disease after chemotherapy. “Whether it translates into an overall survival outcome is questionable,” he said. Lenalidomide did not increase infection risk, which is something Keating said occurred in maintenance trials of rituximab. Byrd suggested lenalidomide may normalize the immune system in patients with CLL and mentioned individuals in a study he participated in who stopped lenalidomide after disease progression, yet had prolonged stable disease. “It’s going to be interesting to see how [lenalidomide] integrates with some of the targeted therapies,” he said.

Relapsed or Refractory Chronic Lymphocytic Leukemia

Several targeted therapies are approved for relapsed CLL, but good evidence for how to sequence them is scarce. Byrd said his first choice for relapsed patients is ibrutinib. “If you have low-risk features in the setting of relapse...it’s extremely unlikely that you’re going to progress on ibrutinib,” he explained. Ibrutinib is approved for hard-to-treat patients with deletion 17p, but Byrd said the RESONATE-17 trial shows many of them have progression within 5 years (Table 3). Although there have been no head-to-head comparisons of ibrutinib, venetoclax, and idelalisib, Byrd said a retrospective study of registry data found all 3 were highly effective, but associated ibrutinib with slightly more favorable outcomes. The panel briefly mentioned ongoing studies in relapsed CLL that are looking at lenalidomide, combinations of targeted agents, a new immuno-modulatory drug called CC-122, and potentially curative chimeric antigen receptor T-cell therapies. Keating reminded everyone that allogeneic stem cell transplants are also curative and an option, even for very elderly patients. Komanduri, who specializes in stem cell transplants, agreed, but said patients with CLL or FL are rarely referred to him for transplant these days. “I would like people to realize, especially when they have younger patients who failed multiple lines of therapy, that early treatment-related morbidity or mortality is quite low [with allogeneic transplant] and we clearly can cure patients,” he said. Komanduri added that unmatched donor trans- plants now have similar outcomes to transplants with sibling donors.

Table 3. Outcomes in RESONATE-17 Study of Ibrutinib in Patients With Deletion 17p

AE indicates adverse events; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Leonard said treatment decisions are easy when therapy is curative or improves survival but that most current treatments for indolent lymphomas do neither. He said the key focus should then be the patient’s quality of life. Leonard said that for patients to decide what is best for themselves, physicians must present information objectively and not let their biases about what they think is best get in the way.

References

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