Experts Debate Best Strategies for Early-Relapsing Follicular Lymphoma

Targeted Therapies in OncologySeptember 2019
Volume 8
Issue 12

&quot;Early-relapsing lymphoma is a problem, there is no debate about that. The hard part is in trying to manage these patients effectively,&rdquo; Jonathon B. Cohen, MD, MS, told an audience at the 2019 Debates and Didactics in Hematology and Oncology conference held in Sea Island, Georgia.<br /> &nbsp;

Jonathan B. Cohen, MD, MS

Jonathan B. Cohen, MD, MS

Jonathan B. Cohen, MD, MS

&ldquo;Early-relapsing lymphoma is a problem, there is no debate about that. The hard part is in trying to manage these patients effectively,&rdquo; Jonathon B. Cohen, MD, MS, told an audience at the 2019 Debates and Didactics in Hematology and Oncology conference held in Sea Island, Georgia.1

To identify which patients are best suited for each therapy, 3 oncologists from Winship Cancer Institute of Emory University in Atlanta, Georgia, including Cohen, reviewed the data in favor of each approach for use in patients with relapse or refractory follicular lymphoma that occurs within 2 years of frontline therapy.

Evidence of Poor Prognosis

Male gender, poor Karnofsky performance status, high Follicular Lymphoma International Prognostic Index (FLIPI) score, high baseline b2-microglobulin, and certain mutations have predictive power for poor prognosis, but currently, no system takes into account all these factors for determining a high-risk population. However, studies have shown statistically significant associations between early relapse and poor prognosis in follicular lymphoma.

Amelia A, Langston, MD

Amelia A, Langston, MD

Amelia A, Langston, MD

In one analysis of data from the National LymphoCare Study (NLCS), patients with stage II to IV follicular lymphoma (n = 588) treated with first-line rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) whose disease progressed within 2 years of diagnosis had worse outcomes than patients in the reference group. Patients who were classified in the group with early progressive disease were more likely to be male, have high-risk FLIPI scores, elevated lactate dehydrogenase levels, and stage III or IV disease than the reference group (TABLE).2 Rates of overall survival (OS) at 2 years in patients with early progression versus those in the reference group were 68% and 97%, respectively; at 5 years, the corresponding rates of OS were 50% and 90%.2

&ldquo;This is a distinct group of patients with a bad prognosis, and they need something beyond more chemoimmunotherapy,&rdquo; Amelia A. Langston, MD, said during her section of the debate, in which she highlighted the benefits of hematopoietic stem cell transplant in patients with follicular lymphoma.

The Case for Transplant

Among patients with early relapse, data indicate clinical benefit with autologous hematopoietic stem cell transplant (autoHSCT), and this is seen most in patients who receive transplant early after first signs of relapse.

&ldquo;Early relapse or primary treatment failure of follicular lymphoma after initial therapy is not the follicular lymphoma that we have come to know,&rdquo; said Langston, medical director of the Winship Cancer Institute of Emory University. &ldquo;It is not an indolent situation and it needs alternative therapies.&rdquo;

Evidence for AutoHCT

A retrospective analysis of 2 cohorts of patients with follicular lymphoma and early treatment failure (ETF), defined as failure to achieve at least partial response after frontline chemoimmunotherapy or progression within 2 years of front-line chemoimmunotherapy, examined patients who received autoHSCT (n = 175) and those who did not (n = 174). The rates of 5-year OS in patients with and without autoHSCT were 67% and 60%, respectively (P= .16). Selecting for patients with early transplant (n = 123), defined as having transplant within 1 year of ETF, showed a 5-year survival rate of 73% and was associated with a statistically significant improvement in OS in a multivariate analysis.3

Another retrospective study of 162 patients &le;65 years experiencing disease progression within 2 years of front-line therapy showed a significant survival benefit at 5 years in those who had autoHSCT versus no transplant (51% vs 19%, respectively; HR, 0.38; 95% CI, 0.24-0.62;P<.0001). In patients with assessable response to cytoreductive second-line therapy, the response rates were higher in those who received subsequent transplant than in those who did not.4 &ldquo;Success [of the transplant] depends on chemotherapy sensitivity at the time of transplant,&rdquo; Langston said.

Evidence for AlloHCT

Langston briefly reviewed allogeneic hematopoietic stem cell transplant (alloHSCT) as a potentially curative option for patients with chemotherapy-refractory disease but noted that these patients may also be well suited for clinical trial enrollment. Eligibility for alloHCT is typically limited to a subset of patients who are fit at the time of transplant.

In one study of ETF follicular lymphoma, patients with matched-sibling donor (MSD) alloHSCT had similar rates of OS at 5 years (73%) compared with patients who received autoHSCT (70%), but relapse rates in the first group were lower. However, the probability of nonrelapse mortality was significantly lower for autoHSCT compared with either MSD or matched-unrelated donor transplant (P<.0001).5

AlloHSCT may be limited to a group of patients &ldquo;with a poor prognosis who are young, fit, and not eligible for other approaches,&rdquo; Langston said, because it comes with significant transplant-related morbidity and mortality. She concluded by saying that patients who fail to respond to second-line therapy after early relapse, those who are unable to mobilize autologous cells, and those with donor options and social support may be the best suited for alloHCT.

Christopher R. Flowers, MD, MS

Christopher R. Flowers, MD, MS

Christopher R. Flowers, MD, MS

Clinical Trial

Because follicular lymphoma is rarely cured and patients typically exhibit a pattern of continuous relapse, Christopher R. Flowers, MD, MS, made the case for treating patients on a clinical trial. &ldquo;There are many new treatment options for this patient population, in particular in a randomized controlled trial that will, hopefully, answer questions in the early-relapsing patient population,&rdquo; Flowers, director of Emory&rsquo;s Lymphoma Program at Winship, said during his presentation.

Flowers is also the ECOG lead of the randomized phase II S1608 trial (NCT03269669) that is looking at follicular lymphoma in the early relapsed or refractory setting. Participants who received frontline therapy of bendamustine or R-CHOP will receive obinutuzumab (Gazyva) in combination with 1 of 3 additional therapies: lenalidomide (Revlimid); umbralisib (TGR-1202); or either CHOP or bendamustine, depending on the patient&rsquo;s frontline therapy.


The efficacy of umbralisib is still under investigation, but Flowers cited a phase I trial that showed the single-agent PI3K inhibitor produced an objective response rate (ORR) of 53% in 17 patients with relapsed or refractory follicular lymphoma, including 2 complete responses.6

&ldquo;Umbralisib is more selective in its activity in PI3Kd,&rdquo; Flowers said. Approved PI3K inhibitors, such as idelalisib (Zydelig) and duvelisib (Copiktra), have less selective inhibition of this isoform than umbralisib,6 as well as higher rates of grade &ge;3 adverse events (AEs), although this needs to be validated by a randomized trial. &ldquo;[S1608] is one such trial that is attempting to address that in early relapsing patients with follicular lymphoma,&rdquo; he said.


Another investigational agent, the anti-CD47 antibody Hu5F9-G4 (magrolimab), inhibits cancer cells through blockade of a &ldquo;don&rsquo;t eat me&rdquo; signal that enables macrophage immune invasion. Results of a phase Ib/II dose-escalation trial presented at the 2018 American Society of Clinical Oncology Annual Meeting showed that Hu5F9-G4 with rituximab produced an ORR of 71% in 7 patients with relapsed or refractory follicular lymphoma, including 3 complete responders.7

Patients treated with Hu5F9-G4 had a manageable safety profile, with the most common AEs being on-target anemia, infusion-related reactions, fever, chills, and headache. No autoimmune AEs were seen, and treatment discontinuation due to AEs occurred in 1 patient (4.5%).7

Applying these findings to the use of clinical trials overall, Flowers said: &ldquo;Some of the new challenges are trying to direct the most appropriate treatment and treatment sequences for early-relapsing patients and build on some principles [of the transplant discussion] by looking at genomic profiles across patients and identifying who may be appropriate for autoHCT or alloHCT but always considering the role of a clinical trial.&rdquo;

Cellular Therapies

A large number of patients who have early progression of disease will transform to non-Hodgkin lymphoma (NHL), said Cohen, medical director of infusion services at Winship. For these patients, cellular therapies may be appropriate.

&ldquo;Some patients will relapse and have indolent-behaving disease, but many have transformed NHL,&rdquo; said Cohen. &ldquo;When we talk about early relapse of disease, this becomes an increasingly relevant topic.&rdquo;

In an analysis of patients with follicular lymphoma treated with frontline bendamustine and rituximab (n = 296), 12% of patients progressed within 2 years of treatment. Of those, 27 of a total of 35 patients also had transformed disease.8

&ldquo;Those patients that relapse early with transformed disease are the ones that are at the highest risk and for whom I will think about CAR [chimeric antigen receptor] T-cell therapy,&rdquo; he said.

Cohen acknowledged the strengths of both prior treatments for patients with relapsed follicular lymphoma, adding that clinical trials are a beneficial option for those who are eligible for enrollment. Although transplant can extend survival, he said, this option is limited to patients with disease control, which can be difficult to achieve in patients with early relapse. In addition, there is a high rate of relapse within a few years of autoHCT and a nonrelapse mortality of up to 30% with alloHCT.

&ldquo;Retreating these patients with chemotherapy is unlikely to be a successful approach, [and] something else needs to be done,&rdquo; Cohen said.

In a phase I/II clinical trial of anti-CD19 CAR T-cell therapy in patients with relapsed or refractory follicular lymphoma (n = 8) and transformed NHL (n = 13), complete remission (CR) rates of 88% and 46%, respectively, were observed. All patients with follicular lymphoma who achieved CR had ongoing responses at 24 months.9

&ldquo;This highlights the fact that this can be an effective therapy in patients with follicular lymphoma,&rdquo; Cohen said. &ldquo;The key is identifying who are the right ones to receive it.&rdquo;

Impressive response rates of about 50% have also been observed with the autologous T-cell product ACTR707 with rituximab in a patient population that includes diffuse large B-cell and follicular lymphomas in the phase I UNUM ATTCK trial (NCT03189836).

&ldquo;Many patients have transformed disease if you look for it. If you identify it, these patients can be considered for CAR T-cell therapy and can be referred. Those who do not have transformed disease are candidates for investigational approaches that may include cellular therapies,&rdquo; Cohen concluded.


  1. Cohen JB, Flowers CR, Langston AA. How should you treat patients with early relapse of FL? Presented at: 2019 Debates and Didactics in Hematology and Oncology; July 24-28, 2019; Sea Island, GA.
  2. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study.J Clin Oncol. 2015;33(23):2516-2522. doi: 10.1200/JCO.2014.59.7534.
  3. Casulo C, Friedberg JW, Ahn KW, et al. Autologous transplantation in follicular lymphoma with early therapy failure: a National LymphoCare Study and Center for International Blood and Marrow Transplant Research analysis.Biol Blood Marrow Transplant.2018;24(6):1163-1171. doi: 10.1016/j.bbmt.2017.12.771.
  4. Jurinovic V, Metzner B, Pfreundschuh M, et al. Autologous stem cell transplantation for patients with early progression of follicular lymphoma: a follow-up study of 2 randomized trials from the German Low Grade Lymphoma Study Group.Biol Blood Marrow Transplant. 2018;24(6):1172-1179. doi: 10.1016/j.bbmt.2018.03.022.
  5. Smith SM, Godfrey J, Ahn KW, et al. Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure.Cancer. 2018;124(12):2541-2551. doi: 10.1002/cncr.31374.
  6. Burris HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kd and casein kinase-1e inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study.Lancet Oncol. 2018;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2.
  7. Advani RH, Flinn I, Popplewell L, et al. Activity and tolerability of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: initial phase 1b/2 results.J Clin Oncol. 2018;36(suppl 15; abstr 7504). doi: 10.1200/JCO.2018.36.15_suppl.7504.
  8. Freeman CL, Savage KJ, Villa D, et al. Frontline therapy with bendamustine and rituximab (BR) in follicular lymphoma: prognosis among patients with progression of disease by 24 months (POD24) is poor with majority having transformed lymphoma.Blood. 2018;132(suppl 1; abstr 2873). doi: 10.1182/blood-2018-99-113675.
  9. Hirayama AV, Gauthier J, Hay KA, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy [published online ].Blood. 2019;134(7):636-640. doi: 10.1182/blood.2019000905.
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