Identification of prognostic markers remains ‘holy grail’ in follicular lymphoma research

Approximately 2% of Americans will be diagnosed with non-Hodgkin lymphoma during their lifetimes, according to NCI statistics.

Follicular lymphoma — the most common subtype, often diagnosed in those aged 50 and older — typically is an incurable but indolent disease. Median OS in this patient population is 18 years.

Some patients with a low tumor burden require no treatment; instead, they follow a watch-and-wait approach.

For those with higher tumor burden, rituximab (Rituxan; Genentech, Biogen) — approved for first-line treatment in 2006 — added to standard chemotherapy has considerably prolonged OS. Five-year survival rates exceed 90% for patients who do not experience early progression on rituximab.

However, nearly one in five patients progress within 2 years of standard chemoimmunotherapy, and only half of them survive 5 years, according to Nilanjan Ghosh, MD, PhD, director of the lymphoma division in the department of hematologic oncology at Levine Cancer Institute at Carolinas HealthCare System.

Also, transformation to a much more aggressive lymphoma, which leads to rapid progression, occurs at a rate of 2% to 3% per year.

Because follicular lymphoma outcomes generally are favorable, the disease historically has not been a research priority. Consequently, several key questions remain.

“Our main challenge has been to identify patients who will do poorly, and to find therapy that alters aggressive behavior of their follicular lymphoma,” Stefan K. Barta, MD, MS, MRCP, associate professor in the department of hematology/oncology at Fox Chase Cancer Center, told HemOnc Today. “Initiating treatment early has not been shown to prolong OS, and no therapy has been shown to alter the prognosis of patients with high-risk follicular lymphoma.”

Photo courtesy of Fox Chase Cancer Center.

HemOnc Today spoke with follicular lymphoma specialists about the urgent need for biomarkers to predict prognosis and guide treatment for high-risk patients; the incidence and impact of transformation in the modern treatment era; how therapeutic advances have altered the treatment landscape; and whether precision medicine will considerably change disease management.

Lack of validated markers

Biologic markers would greatly improve clinicians’ abilities to predict which patients will respond poorly to initial treatment and progress to more severe disease.

“These are the patients with a big unmet need,” Nathan H. Fowler, MD, associate professor and director of clinical research in the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center, said in an interview. “We are looking at various biomarkers, including changes in gene expression profiles, alterations in cell signaling, circulating tumor DNA and other methods to try to identify patients who will have an inferior prognosis long term. Once we can reliably identify those patients, the next step will be to identify therapies that will change the natural history of those who have a poor prognosis.”

Follicular Lymphoma International Prognostic Index (FLIPI) is widely used to identify high-risk patients.

“It is the most prevalent prognostic index because it takes into account several patient characteristics — such as age and stage of disease — it provides certain blood test results and notifies when serum lactate dehydrogenase is elevated. The answers to these questions can identify which patients might be at more high risk for early recurrence,” Larry W. Kwak, MD, PhD, vice president and associate director of translational research, and director of the Toni Stephenson Lymphoma Center at City of Hope, said in an interview. “We’re developing our new agents for these patients because, although there are many current treatments, they are not effective for this group.”

However, FLIPI index is most effective when providing an overall risk profile for a group of patients, not individuals, Fowler said.

“Unfortunately, it is not 100% [accurate] and has never been a test we use ‘prime time’ to inform treatment decisions,” he said.

FLIPI was developed based on patient populations treated before the introduction of monoclonal antibodies.

FLIPI2 — derived from FLIPI — is more useful in the rituximab era, Ghosh said.

“FLIPI2 is a predictor in the rituximab era and incorporates elevated beta 2 microglobulin, largest nodal mass greater than 6 cm and bone marrow involvement,” Ghosh said. “FLIPI and FLIPI2 are clinical prognostic indices at diagnosis, but they do not include biological predictors of risk. They are predictors for survival, but not used for selecting therapy.”

Based on FLIPI, 10-year OS rates are 71% for low-risk patients, 52% for intermediate-risk patients and 36% for high-risk patients. FLIPI2 predicts 3-year OS rates of 99% for low-risk patients, 96% for intermediate-risk patients and 84% for high-risk patients.

Research also has focused on identifying molecular and genetic factors that are prognostic for outcomes in follicular lymphoma. Several biomarkers have been discovered, such as MLL2, EZH2, IRF4, CREPPB and EPHA7; however, individually, they do not appear linked to outcomes.

Because the FLIPI score is only beneficial in specific settings, m7-FLIPI score — which combines a patient’s performance status, FLIPI score and expression of seven genes — may be more useful, according to Sonali M. Smith, MD, professor in the section of hematology/oncology and director of the lymphoma program at The University of Chicago.

Pastore and colleagues developed the m7-FLIPI score — published in 2015 in The Lancet Oncology — showing it defined a 5-year failure-free survival rate of 38.29% for the high-risk group vs. 77.21% for the low-risk group (HR = 4.14; 95% CI, 2.47-6.93).

“At the time of diagnosis, we have several tools that may guide prognosis, including histologic grade and FLIPI score,” Smith said. “However, although these are excellent stratification factors in clinical trial settings, they are not as precise at an individual level. The m7-FLIPI seems very robust in all studies to date, but it has not been validated in a clinical trial setting.”

This tool can be most helpful for high-risk patients, Barta said.

“This group can be more clearly defined and narrowed down from 46% to 25% of patients,” he said.

Although m7-FLIPI is more robust than FLIPI in identifying high-risk patients, “50% of patients who relapse early after chemoimmunotherapy were classified as low risk by m7-FLIPI,” Ghosh said.

Predictions based on PET/CT

Researchers also have evaluated whether PET and CT scans can predict outcomes; if so, they may be more appropriate for individual patients than FLIPI scores.

A study by Meignan and colleagues, published last year in Journal of Clinical Oncology, evaluated whether total metabolic tumor volume at baseline could serve as a prognostic indicator for patients with high tumor–burden follicular lymphoma, a subset associated with a high risk for progression and death.

The researchers performed a pooled analysis of three multicenter trials that used 18F–fluorodeoxyglucose PET/CT scans to measure tumor volume prior to immunochemotherapy in 185 patients, 92% of whom had stage III or stage IV disease.

The median total metabolic tumor volume was 297 cm³ (interquartile range, 135-567), and researchers defined an optimal PFS and OS with a cutoff of 510 cm³. Patients with total metabolic tumor volume above that cutoff had significantly poorer rates of 5-year PFS (32.7% vs. 65.1%; P < .001) and OS (84.8% vs. 94.7%; P = .013) than patients with lower tumor volume.

High total metabolic tumor volume remained a significant independent predictor for poorer outcomes after researchers adjusted for induction treatments (PFS, P < .001; OS, P = .0141).

“Because total metabolic tumor volume and metabolic response are both independent predictors of PFS, they may provide a platform for study of PET–adapted approaches and contribute to development of risk-adapted individualized care, avoiding both over- and undertreatment of all patients with follicular lymphoma,” Meignan and colleagues wrote.

However, as a single parameter, total metabolic tumor volume remains far from perfect for prognostication, Heiko Schröder, MD, deputy chief of molecular imaging and therapy at Memorial Sloan Kettering Cancer Center, and Craig H. Moskowitz, MD, Steven A. Greenberg chair of hematology at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, wrote in a related editorial.

“In the [Meignan] study, added prognostic information was derived when total metabolic tumor volume was used in combination with the Follicular Lymphoma International Prognostic Index score,” they wrote.

Further, cutoffs only indicate probability and “may also vary depending on the specific patient population, the range of tumor volumes in this population and, possibly, the drug regimen used,” Shröder and Moskowitz added.

Another study by Trotman and colleagues, published in The Lancet Haematology, suggested PET/CT scanning — as opposed to contrast-enhanced CT scanning — be considered the new standard for measuring response to therapy in clinical practice.

Overall, CT–based response was weak for the prediction of PFS (HR = 1.7; 95% CI, 1.1-2.5), whereas a significantly smaller proportion of patients with positive PET scans than negative PET scans achieved 4-year PFS (23.2% vs. 63.4%; P < .0001).

Despite these efforts, the optimal management strategy for patients remains unclear, and the group of patients at risk for relapse or transformation remains relatively unknown.

“The holy grail for treating follicular lymphoma will be able to identify markers in patients before they start treatment, which will allow us to stratify them into different therapies based on their likelihood of response,” Fowler said.

Management strategies

In the 1990s, median OS for follicular lymphoma was 6.7 years, and only 34% of patients survived 10 years.

However, in the era of novel therapies, median OS now reaches 18.4 years, according to data from Tan and colleagues.

Despite the survival improvement, there is no consensus on the optimal strategy for disease management and treatment. Standard therapeutic options include rituximab alone or in combination with other treatments; however, approaches vary for each patient.

Rituximab plus conventional chemotherapy has improved response rates, PFS, OS and EFS; however, no consensus exists on the best chemotherapy to add to rituximab for first-line treatment.

A study by Federico and colleagues — published in 2013 in Journal of Clinical Oncology — compared three chemotherapy strategies in combination with rituximab for frontline treatment: cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP); cyclophosphamide, vincristine sulfate and prednisone (R-CVP); and fludarabine. Results showed R-CHOP exhibited the best risk–benefit profile, with more activity than R-CVP but less toxicity than rituximab and fludarabine.

Increasingly, bendamustine has been used in combination with rituximab. A study by Rummel and colleagues, published in The Lancet, showed first-line treatment with that combination compared with R-CHOP improved median PFS (not reached vs. 40.9 months; P = .007) and led to less toxicity.

The development of kinase inhibitors raises the potential for new treatment combinations, particularly for relapsed and refractory disease.

“We have several new agents that have been approved for patients with follicular lymphoma,” John P. Leonard, MD, Richard T. Silver distinguished professor of hematology and medical oncology and associate dean for clinical research at Weill Cornell Medicine and NewYork–Presbyterian Hospital, said in an interview. “These include idelalisib (Zydelig, Gilead Sciences) — a PI3 kinase delta inhibitor — and obinutuzumab (Gazyva, Genentech), a new antibody. They both have a role in patients with relapsed disease.”

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology recommend idelalisib as a second-line or subsequent therapy for patients with grade 1 to grade 2 follicular lymphoma, making it one of a few alternative treatments available for patients whose disease is refractory to rituximab or alkylating agents.

Fowler and colleagues investigated the combination of rituximab and lenalidomide (Revlimid, Celgene) in treatment-naive patients, 98% of whom attained a response, including 87% with a complete remission.

Leonard and colleagues of the CALGB 50401 trial further evaluated the addition of rituximab to lenalidomide for recurrent follicular lymphoma.

Patients who received the combination demonstrated a higher overall response rate (76% vs. 53%; P = .029) and longer time to progression (2 years vs. 1.1 year; P = .0023).

“This was a trial in relapsed patients with follicular lymphoma, and it showed both regimens were effective, but the combination regimen had a higher response rate and longer duration of response than lenalidomide alone,” Leonard said.

“We’re doing a lot of work and we are hopeful within the next several years we will make progress,” Leonard added.

Obinutuzumab — a glycoengineered type II anti-CD20 monoclonal antibody with enhanced direct cell killing — received FDA approval in 2016 for use in combination with bendamustine for patients who relapsed on or were refractory to rituximab.

The agent also has been evaluated in the frontline setting in the phase 3 GALLIUM study, results of which were presented during the plenary session of last year’s ASH Annual Meeting and Exposition. Patients in that trial received obinutuzumab or rituximab in combination with CHOP, CVP or bendamustine chemotherapy. Those who responded to induction therapy received maintenance with obinutuzumab or rituximab.

Obinutuzumab improved 3-year PFS (80% vs. 73.3%) and was associated with a 34% reduction in risk for progression (HR = 0.66; 95% CI, 0.51-0.85).

These results might change the standard for some — but not all — patients with follicular lymphoma, Leonard said.

“Using a novel antibody that improved PFS certainly is reasonable on the basis of a positive study,” Leonard told HemOnc Today when the study was presented. “This does not necessarily apply to all patients; certainly, some patients opt not to have maintenance therapy, and we do not have data on this particular antibody in this setting without maintenance.

“Additionally, this study will bring more information to light as to whether the preferred chemotherapy approach is to partner with an anti-CD20 antibody treatment,” Leonard added.

Watch and wait

Management for patients with asymptomatic follicular lymphoma may not include therapy. Some opt for another approach: watch-and-wait.

A study by Ardeshna and colleagues, published in The Lancet Oncology, compared three strategies among patients with advanced-stage, asymptomatic, nonbulky follicular lymphoma: rituximab induction, rituximab induction plus maintenance, and watch-and-wait.

Researchers observed significant differences in the time to start of new treatment among the groups. Forty-six percent of patients in the watch-and-wait group did not need treatment at 3 years, compared with 88% of the maintenance rituximab group (HR = 0.21; 95% CI, 0.14-0.31) and 78% of the rituximab induction group (HR = 0.35; 95% CI, 0.22-0.56).

“Watch-and-wait is the standard of care for asymptomatic follicular lymphoma patients,” Smith said. “With over 5 years of follow-up [in the Ardeshna and colleagues’ study], there is improved PFS, but no difference in OS. This is very important for patients and physicians to understand.”

However, because most of the data on this approach are derived from the pre-rituximab era, watch-and-wait is no longer as commonly used, Barta said.

Also, patients with long life expectancies tend to undergo treatment to improve quality of life. Watch and wait may be considered for patients who have shorter life expectancies because of the impact therapy might have on quality of life.

In the Ardeshna trial, patients who received maintenance rituximab demonstrated significant improvements in the Mental Adjustment to Cancer scale score (P = .0004) and Illness Coping Style score (P = .0012) between baseline and month 7.

“The watch-and-wait approach is used less commonly as treatment with rituximab in asymptomatic low-tumor patients can prolong the time to first chemotherapy,” Barta said. “[It also] may help improve quality of life in anxious patients who have difficulties with coping with their diagnosis of lymphoma and the idea of observation alone.”

Transformation ‘a function of time’

Approximately 2% to 3% of patients with follicular lymphoma will progress to a more aggressive histology each year — equating to about 30% of cases over 10 years — in a process known as transformation.

The average time between diagnosis of low-grade lymphoma and transformation is 3 to 6 years, but transformation can occur many years later.

Certain biologic factors — such as high lactate dehydrogenase, high FLIPI score, bulkier tumors at presentation and advanced age — are associated with increased risk for transformation.

Transformation occurs due to early driver mutations in progenitor clones, Ghosh said. Mutations are enriched for genes involved in chromtin regulation. Further, mutations in genes involved in cell cycle regulation such as p53, EZH2, MLL2, CREBBP and alterations in tumor microenvironment also are implicated.

“However, there is no standard molecular panel that can predict transformation,” Ghosh said.

A patient’s lifetime risk for transformation is as high as 30% to 40%, according to Fowler.

“We need to identify biologic markers that will predict patients who will transform, because then we can intervene with some of the novel therapies,” he said.

Standard chemotherapy does not change a patient’s risk for transformation, but it remains unclear whether novel agents, immunotherapies or other targeted therapies affect risk.

An analysis of the National LymphoCare Study — conducted by Wagner-Johnston and colleagues and published in Blood — evaluated transformation risk among 2,652 patients. Overall, 14.3% of patients transformed over a median 6.8 years of follow-up.

Risk for transformation appeared similar between patients treated with R-CHOP or R-CVP (adjusted HR = 0.94; 95% CI, 0.62-1.42). The risk was only reduced among patients who received maintenance rituximab (HR = 0.67; 95% CI, 0.46-0.97), and those who initiated treatment at diagnosis rather than undergoing observation (HR = 0.58; 95% CI, 0.46-0.75).

“We have imperfect ways of prognosticating risk for progression prior to initiation of treatment,” Barta said. “However, we have learned through results from the [National LymphoCare Study] that patients who relapse within 2 years after completion of initial chemoimmunotherapy are at high risk for poor outcomes.”

The researchers concluded that transformation incidence appears similar in the modern era compared with historical data, suggesting that chemoimmunotherapy does not affect its occurrence. Still, although patients who experienced transformation faced worse outcomes than those who did not, survival does appear to be improving over time.

Whether treatment reduces risk for transformation remains controversial. Several studies have showed treatment with an anthracycline or rituximab decreased transformation risk, whereas others showed no difference.

“There is no clear prospective data and no clear definitive data that there is any treatment that mitigates the risk for transformation,” Smith said.

Transformation underscores the urgency for the development of new treatments, according to Kwak, who called transformation “purely a function of time.”

“The longer the patient has the disease, the higher risk for transformation,” Kwak said. “Once there is transformation to aggressive type, the prognosis becomes much less favorable. It is not hopeless because there are treatments, but they are not as effective and it is harder to manage the disease once it transforms.”

Future targets, clinical trials

As understanding of disease biology increased after the introduction of rituximab, researchers began studying many novel agents and combinations for various stages of follicular lymphoma.

For instance, idelalisib is being studied in two phase 3 trials in combination with rituximab; in combination with bendamustine in previously treated patients; in a phase 1 trial in combination ONO/GS-4059 (ONO Pharmaceutical Co. and Gilead), an investigational Bruton’s tyrosine kinase inhibitor; and as monotherapy in previously treated patients.

Other kinase inhibitors in the pipeline include TGR-1202 (TG Therapeutics), AMG 319 (Amgen), duvelisib (Infinity Pharmaceuticals), copanlisib (Bayer) and venetoclax (Venclexta; AbbVie, Genentech), a B-cell lymphoma-2 inhibitor. Duvelisib and copanlisib are in phase 3 development for non-Hodgkin lymphoma, including follicular lymphoma.

“We are heading into an exciting time in the study of follicular lymphoma,” Fowler said. “For the first time in many decades, we have a lot of new, novel, active drugs that are not very toxic. The challenge now is trying to figure out how to best use these drugs in combination without additive toxicity and hopefully with greater benefit for patients.”

Lenalidomide has been studied in follicular lymphoma. In the phase 2 study of rituximab plus lenalidomide in previously untreated indolent NHL, Fowler and colleagues from MD Anderson Cancer Center reported very high response rates and complete responses. Further, results of the SAKK 35/10 study showed a higher complete remission rate with the addition of lenalidomide to rituximab in previously untreated follicular lymphoma.

Ghosh is anticipating results of the phase 3 RELEVANCE clinical trial — led by Fowler — which is investigating rituximab and lenalidomide vs. investigator’s choice of chemoimmunotherapy.

“Although the RELEVANCE study was not restricted to high-risk follicular lymphoma, it will be interesting to see if lenalidomide and rituximab can lead to deeper and more durable remissions compared with rituximab and standard chemotherapy,” Ghosh said.

Insights into follicular lymphoma pathogenesis also may lead to other treatment advances. For instance, researchers have found that acquisition of translocation t(14;18) is a very early event in pathogenesis, Smith said.

“In fact, nearly one-quarter of the population may harbor clonal B cells with this rearrangement,” she said. “Understanding the factors leading to malignant manifestation is being intensely studied. In addition, the bone marrow may be the reservoir for malignant cells when the disease is clinically in remission. The future of follicular lymphoma will be to understand the biologic and genetic events leading to relapse and to perhaps target these cells.”

Clinicians also hope that precision medicine can begin to guide more patient care in follicular lymphoma.

“The patients who would benefit the most from precision medicine are the high-risk patients most at risk for relapsing early,” Kwak said. “With advances in next-generation sequencing of patients’ tumors, it should be possible to not only identify mutations that will predict what drugs work against those tumors, but also the sequencing information will allow the development of new personalized treatments.”

Precision medicine also can stand to benefit more than just high-risk patients, Smith said.

“I definitely hope that precision medicine is a future possibility for follicular lymphoma, with benefit for nearly all patients affected by this disease,” Smith said. “Although precision medicine in oncology has mostly focused on high-risk patients ... it is equally important that we identify the low-risk patients who can be spared exposure to costly and potentially toxic interventions.” – by Melinda Stevens

Click here to read the , “Does chemotherapy still have a role in follicular lymphoma treatment?”

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For more information:

Stefan K. Barta, MD, MS, MRCP, can be reached at stefan.barta@fccc.edu.

Nathan H. Fowler, MD, can be reached at nfowler@mdanderson.org.

Nilanjan Ghosh, MD, PhD, can be reached at nilanjan.ghosh@carolinashealthcare.org.

Larry W. Kwak, MD, PhD, can be reached at lkwak@coh.org.

John P. Leonard, MD, can be reached at jpleonar@med.cornell.edu.

Sonali M. Smith, MD, can be reached at smsmith@medicine.bsd.uchicago.edu.

Disclosures: Barta reports research funding from Celgene, Merck and Seattle Genetics, and a consultant role with Janssen. Fowler reports advisory roles with Celgene, Janssen and Roche, and research funding from Celgene, Gilead Sciences, Janssen and Roche. Ghosh reports consultant roles with AbbVie, Celgene, Gilead Sciences, Pharmacyclics and Seattle Genetics. Kwak reports equity from Antigenics/Agenus and Xeme BioPharma, and consultant roles with Celltrion, Sellas and Xeme BioPharma. Leonard reports consultant roles with AbbVie, Biotest, Bristol-Myers Squibb, Celgene, Genmab, Gilead Sciences, Juno, Nanostring, Regeneron, Sunesis, Sutro and Teva. Smith reports consultant roles with Celgene, Gilead Sciences, Juno, Pharmacyclics and TG Therapeutics.