Updates to the Management of Patients With Relapsed or Refractory Indolent Follicular and Marginal Zone Lymphomas

Presenters: Ann S. LaCasce and Ariela Noy

Although follicular lymphoma (FL) and marginal zone lymphoma (MZL) share similarities, the 2 diseases have distinct biologic differences that affect their presentation and treatment. Stage I disease is more common in MZL than in FL due to marginal zone biology, for example, and stage I MZL is curable by surgery or radiation therapy. Newer therapies for both FL and MZL provide chemotherapy-free options, but they are not identical. Brüton’s tyrosine kinase inhibitors are active in relapsed or refractory MZL but not in FL, for example. CAR T-cell therapy has just been approved for treatment of FL and is an ongoing area of investigation for both diseases.

At the NCCN 2022 Annual Conference, Ann S. LaCasce, MD, MMSc, Director, Dana-Farber/Mass General Brigham Fellowship in Hematology/Oncology, Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, and Ariela Noy, MD, Member and Attending Physician, Memorial Sloan Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, discussed novel treatment approaches for the management of patients with follicular lymphomas (FLs) and marginal zone lymphomas (MZLs). Although the diseases share similarities, FL and MZL have distinct biological differences that affect presentation and treatment. Dr. LaCasce summarized the data from clinical trials on the use of targeted therapies for relapsed or refractory (R/R) FLs, and Dr. Noy reviewed the safety and efficacy of novel treatment options for R/R MZLs.

R/R Follicular Lymphoma

For patients with FL grade 1 to 2, there are several chemotherapy options available in the second-line setting. Preferred regimens include bendamustine + obinutuzumab or rituximab (for patients with no prior bendamustine); CHOP (cyclophosphamide/hydroxydaunorubicin/vincristine/prednisone) + obinutuzumab or rituximab; CVP (cyclophosphamide/vincristine/prednisone) + obinutuzumab or rituximab; and lenalidomide + rituximab.1 “The immunomodulatory drug lenalidomide + rituximab is an appropriate and appealing regimen for patients who have early relapse after standard chemoimmunotherapy,” said Dr. LaCasce, who noted several different mechanisms of action for lenalidomide.

Results of the phase III AUGMENT trial in relapsed FL showed improved progression-free survival (PFS) with combination lenalidomide + rituximab compared with rituximab alone (hazard ratio [HR], 0.46; P<.001).2 The addition of lenalidomide to rituximab was also associated with a trend in improvement in overall survival. “As expected, the combination regimen had higher rates of neutropenia, but infection rates were similar,” she said. “There was also a higher incidence of low-grade rash in the lenalidomide arm, but no difference in the rates of deep vein thrombosis, pulmonary embolism, or secondary malignancies.”

Third-Line and Subsequent Therapies

In the third-line setting of FL, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for B-Cell Lymphomas list several novel agents, including PI3K inhibitors (copanlisib and umbralisib), the EZH2 inhibitor tazemetostat, and anti–CAR T-cell therapy. However, as of April 15, 2022, TG Therapeutics announced the voluntary withdraw of umbralisib (UKONIQ) from sale for the approved indications of adult patients with MZL who have received at least one prior anti-CD20–based regimen and for adult patients with FL who have received at least 3 prior systemic therapies.3 Umbralisib was initially granted accelerated approval for these indications in February 2021. The decision to withdraw umbralisib from sale was primarily based on the withdrawal of the Biologics License Application/supplemental New Drug Application for combination ublituximab and umbralisib in chronic lymphocytic leukemia.

Lastly, ibrutinib and venetoclax have both demonstrated disappointing activity in R/R FL, said Dr. LaCasce.

PI3K Inhibitors

Several PI3K inhibitors have been studied as single agents in R/R indolent lymphoma; however, only copanlisib and umbralisib are approved for patients with FL. In a phase II study of copanlisib, the overall response rate (ORR) was 59% in patients with FL, with a complete remission rate of 14% and a median PFS of 11.0 months.4 As Dr. LaCasce explained, copanlisib is given intravenously and has a completely different toxicity profile compared with other PI3K inhibitors. In the phase II study, 50% of patients experienced hyperglycemia of any grade, and 34% experienced grade 3 hyperglycemia. Hypertension occurred in 61% of patients, with 30% experiencing grade 3 hypertension. “This agent is appealing for patients who do not have poorly controlled diabetes and those who may prefer an intravenous therapy,” said Dr. LaCasce.

A subsequent study comparing rituximab + copanlisib versus placebo in relapsed indolent lymphomas demonstrated a significant difference in PFS (HR, 0.52; P<.0001). Median PFS was approximately 50% at 12 months.5

The other PI3K inhibitor, umbralisib, showed meaningful clinical activity in heavily pretreated patients with indolent non-Hodgkin lymphoma (NHL).6 Of the 208 patients enrolled, 56% had grade 1–3a FL, and the study population had a median of 3 (range, 1–10) prior therapies. The ORR for umbralisib was 45%, with a complete response rate of 6%; median PFS was 10.6 months. The toxicity profile of any grade included neutropenia (16%), diarrhea (59%), and increased liver enzymes (20%).

EZH2 Inhibition

EZH2, an epigenetic modifier, is important in both mutant and wild-type FL. Approximately 20% of patients with FL have EZH2 gain-of-function mutations.7

In a phase II study, the EZH2 inhibitor tazemetostat demonstrated clinically meaningful and durable responses, with ORRs of 70% and 35% in EZH2-mutant and wild-type populations, respectively.8 Median PFS was 13.8 months in patients with EZH2-mutated disease and 11.1 months in those with wild-type disease. According to Dr. LaCasce, tazemetostat is also well tolerated, with a significantly favorable toxicity profile.

“Tazemetostat is a good option in patients who are elderly or who do not have bulky or rapidly progressive disease, including those with wild-type EZH2, who may do well with stable disease for a period of time,” she said.

CAR T-Cell Therapy

According to Dr. LaCasce, CAR T-cell therapy has had a dramatic effect on aggressive B-cell lymphomas in the R/R setting. In the ZUMA-5 study, axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with R/R indolent NHL.9 Despite nearly 70% of patients being refractory to their last regimen and 24% having had a prior autologous stem cell transplant, the ORR was 94%, and 8% achieved complete remission. Moreover, the median PFS was not reached in R/R FL.

“This is a very exciting result that changes the field of R/R FL,” said Dr. LaCasce. “Although we need longer follow-up, there is the possibility of durable remission, making this an appealing option for young patients.” According to Dr. LaCasce, providers must consider a variety of patient and disease factors when applying these results to individual patients.

R/R Marginal Zone Lymphoma

MZL is the third most common type of NHL, representing as many as 15% of NHL cases, explained Dr. Noy. Although there are similarities to FL, biological differences of MZL affect presentation and treatment. Stage I disease is more common in MZL than in FL, for example, and stage I disease is curable by surgery or radiation therapy.

“Indolent lymphomas are generally incurable when they present with disseminated disease, but patients can live for years or even decades,” said Dr. Noy, who noted that judicious use of therapy is warranted to preserve quality of life.

There are 3 common subtypes of MZL: extranodal MZL of mucosa-associated lymphoid tissue lymphoma, nodal MZL, and splenic MZL. Beyond first-line therapy, however, treatment options converge among subtypes.

Second-Line and Subsequent Therapies

The NCCN Guidelines for B-Cell Lymphomas list several suggested treatment regimens. Patients who are generally well can receive chemoimmunotherapy with bendamustine + rituximab or bendamustine + obinutuzumab, although these regimens are not recommended for those previously treated with bendamustine. Other recommended regimens include BTK inhibitors (ibrutinib or zanubrutinib), CHOP + rituximab, or lenalidomide + rituximab. For patients who are elderly or infirm, preferred options include Brüton’s tyrosine kinase (BTK) inhibitors, lenalidomide + rituximab, or rituximab.1

Although discussed at the NCCN Guidelines Panel meeting as an option, the company voluntarily withdrew the drug April 15, 2022, based on data from a randomized CLL trial.3 PI3Kinase inhibitors are no longer in use for MZL.

BTK Inhibitors

In patients with previously treated MZL, single-agent ibrutinib induced durable responses with a favorable benefit/risk profile.10 With 60 patients enrolled, the study was small, said Dr. Noy, but the results were significant. ORRs at 12 and 24 months were nearly 60%, but complete responses were relatively few, and median PFS was 15.7 months.11

“Biomarker analysis showed that patients who received single-agent rituximab alone without prior chemotherapy enjoyed the best PFS, but those who had combined chemoimmunotherapy had a far lower PFS, which is typically only about 12 months,” said Dr. Noy.

In September 2021, the second-generation BTK inhibitor zanubrutinib received FDA approval based on data from the MAGNOLIA study, which showed a similar ORR of approximately 60%, but a higher complete response rate of 20%.12 Complete metabolic response was seen in 26% of patients. Data from other trials also suggest that zanubrutinib has a superior safety profile.13,14

Rituximab + Lenalidomide

The phase III AUGMENT trial, which examined rituximab ± lenalidomide in R/R indolent lymphoma, enrolled 63 patients with MZL in addition to those 295 with FL. Although a PFS improvement was seen among patients with FL, no improvement was seen in those with MZL with the addition of lenalidomide, but this could be a reflection of the small sample size: 295 patients (82%) had FL, and 63 (18%) had MZL.2

Data from the MAGNIFY trial, which were presented at the 2021 American Society of Hematology Annual Meeting & Exposition, however, showed response rates of 60%, including complete responses in 40% of patients with MZL who received lenalidomide + rituximab followed by maintenance.15 Moreover, duration of response was nearly 40 months. “We need to see what happens with this study going forward,” said Dr. Noy. “This is only the completion of the induction phase, demonstrating once again the power of lenalidomide and rituximab in combination.”

PI3K Inhibitor: Umbralisib

The PI3K inhibitor umbralisib is also FDA approved for MZL. In a phase II study of 69 patients with MZL who had ≥1 prior therapy, including an anti-CD20–containing regimen, the ORR was 49%, including 16% complete responses.16 Median duration of response has still not been reached. Although discussed at the NCCN Guidelines Panel meeting, TG Therapeutics voluntarily withdrew umbralisib from sales based on data from a randomized chronic lymphocytic leukemia trial.3

CAR T-Cell Therapy

Finally, CAR T-cell therapy is an ongoing area of investigation. The ZUMA-5 trial, which led to the approval of axicabtagene ciloleucel for FL, also enrolled patients with MZL. The ORR was 96% among patients with MZL treated with CAR T-cell therapy, and 74% of patients experienced a complete response.9 However, axicabtagene ciloleucel is not yet approved for MZL.

“We need to think of treatment for indolent diseases as a marathon rather than a sprint,” said Dr. Noy. “It’s also important to consider both the toxicity of treatment and patient preferences as we go forward.”

References

  • 1.

    Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 2.2022. Accessed March 20, 2022. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 2.

    Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019;37:11881199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL [press release]. Morrisville, NC: Associated Press; April 15, 2022.

    • Search Google Scholar
    • Export Citation
  • 4.

    Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma [published correction in J Clin Oncol 2018;36:521]. J Clin Oncol 2017;35:38983905.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction in Lancet Oncol 2021; 22:e239]. Lancet Oncol 2021;22:678689.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol 2021;39:16091618.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Bollard J, Massoma P, Vercherat C, et al. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors. Oncotarget 2015;6:3673136745.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 2020;21:14331442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23:91103.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:22242232.

  • 11.

    Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv 2020;4:57735784.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Opat S, Tedeschi A, Linton K, et al. The MAGNOLIA trial: zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma. Clin Cancer Res 2021;27:63236332.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Tam CS, Opat S, D'Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020;136:20382050.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Song Y, Zhou K, Zou DH, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study [published online March 18, 2022]. Blood, doi: 10.1182/blood.2021014162

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Lansigan F, Andorsky DJ, Coleman M, et al. Completed induction phase analysis of MAGNIFY: phase 3b study of lenalidomide + rituximab (R 2) followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. Blood 2021;138(Suppl 1):812.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: a multicenter, open label, registration directed phase II study [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 7506.

    • Crossref
    • Search Google Scholar
    • Export Citation

Disclosures: Dr. LaCasce has disclosed serving on the product/speakers bureau for Research to Practice. Dr. Noy has disclosed serving as a scientific advisor for ADC Therapeutics, Epizyme, EUSA, Janssen Pharmaceutica Products, LP, MorphoSys AG, and TG Therapeutics; receiving honoraria from Medscape and Pharmacyclics; receiving consulting fees from Physicians' Education Resource; and receiving grant/research support from Rafael Pharma.

Correspondence: Ann S. LaCasce, MD, MMSc, Dana-Farber Cancer Institute, 450 Brookline Avenue, M227, Boston, MA 02215. Email: alacasce@partners.org; and Ariela Noy, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Email: noya@mskcc.org
  • 1.

    Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 2.2022. Accessed March 20, 2022. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 2.

    Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019;37:11881199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL [press release]. Morrisville, NC: Associated Press; April 15, 2022.

    • Search Google Scholar
    • Export Citation
  • 4.

    Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma [published correction in J Clin Oncol 2018;36:521]. J Clin Oncol 2017;35:38983905.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Matasar MJ, Capra M, Özcan M, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction in Lancet Oncol 2021; 22:e239]. Lancet Oncol 2021;22:678689.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol 2021;39:16091618.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Bollard J, Massoma P, Vercherat C, et al. The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors. Oncotarget 2015;6:3673136745.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 2020;21:14331442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23:91103.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:22242232.

  • 11.

    Noy A, de Vos S, Coleman M, et al. Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis. Blood Adv 2020;4:57735784.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Opat S, Tedeschi A, Linton K, et al. The MAGNOLIA trial: zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma. Clin Cancer Res 2021;27:63236332.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Tam CS, Opat S, D'Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020;136:20382050.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Song Y, Zhou K, Zou DH, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study [published online March 18, 2022]. Blood, doi: 10.1182/blood.2021014162

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Lansigan F, Andorsky DJ, Coleman M, et al. Completed induction phase analysis of MAGNIFY: phase 3b study of lenalidomide + rituximab (R 2) followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. Blood 2021;138(Suppl 1):812.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: a multicenter, open label, registration directed phase II study [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 7506.

    • Crossref
    • Search Google Scholar
    • Export Citation
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