Geneology International

Tag: focus

  • a Focus on Current and Emerging Therapies

    a Focus on Current and Emerging Therapies

    Abstract

    Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

    Key Words: follicular lymphoma; treatment; novel therapies

    Introduction

    Follicular lymphoma (FL) is an incurable B-cell lymphoid neoplasm with significant biological and clinical heterogeneity. As the most common indolent lymphoma and second most common non-Hodgkin lymphoma (NHL), it has a relapsing and remitting course with risk of transformation to aggressive disease.1,2 Most patients present with advanced disease and will eventually
    require treatment for symptomatic disease. Given the range of clinical behaviors, the decision of when to treat is equally important as how to treat, noting that therapeutic goals include meaningful remission, symptom palliation, and prolongation of life.

    While the majority of patients have survival approximating 2 decades, a subset of patients have aggressive disease with poor outcomes.3 Unfortunately, baseline identification of these patients remains challenging. Approximately 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients with FL have progressive disease within 2 years of initial chemoimmunotherapy and a 5-year overall survival (OS) of 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.4 Cumulative toxicity from repeated exposure to palliative cytotoxic chemotherapy also contributes to morbidity and mortality. While anti–CD20-based chemoimmunotherapy remains an important standard of care, more rational and biologically driven agents are either approved or in development. In this review, we examine the current approach to the diagnosis and treatment of FL with a focus on targeted therapy and other novel agents.

    Current Standards for Diagnosis

    A diagnosis of FL requires histologic examination of a lymph node biopsy for assessment of nodal architecture and grading.5 FL is characterized by neoplastic germinal center B-cells growing in densely packed follicles with distortion of the normal nodal architecture. Grading depends on the number of centroblasts/high-power field. Grade 1-3a are considered indolent, whereas 3b is more aggressive and clinically approached as diffuse large B-cell lymphoma (DLBCL).6 The classic immunophenotype includes the B-cell antigens CD19, CD20, and CD79a; lymphoid progenitor marker, CD10; and nuclear proteins, BCL-2 and BCL-6. Unlike mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, it is negative for CD5.

    Molecular Testing

    Cytogenetically, FL is characterized by the translocation t(14;18), which occurs in up to 90{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of cases, as a result of aberrant V(D)J recombination. This results in BCL-2 protein overexpression and increased cell survival (Figure 1).7 As a hallmark of FL, it is necessary, but alone insufficient, for lymphomagenesis.8-10 An important recent finding is early mutations in genes coding for chromatin modifying proteins.11-13 These ‘epimutations’ are a second hallmark of FL and include: KMT2D (~70-80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), CREBBP (~65-70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), EZH2 (~25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and EP300 (~14{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}).12,14 These transcriptionally repressive mutations result in increased germinal center proliferation, differentiation block, and immune evasion.15-17 Along with the BCL2 translocation, these mutations are early events occurring in a common progenitor cell.

    Through divergent clonal evolution, other mutations are subsequently acquired including mutations in genes involved in immune modulation (TNFRSF14); JAK-STAT signaling (STAT6, SOCS1); and B-cell receptor–NF-kB signaling (CARD11, TNFAIP3, MYD88).12 While conventional karyotyping and fluorescent in situ hybridization (FISH) for t(14;18) are part of the standard evaluation for FL, genomic sequencing is limited to testing for the EZH2 mutation when tazemetostat is being considered.18 Nonetheless, next-generation sequencing has revealed the diverse mutational landscape of FL and provides insight into disease pathogenesis, as well as opportunities for more precise therapeutic strategies.

    Stratification for Treatment Selection

    The treatment of FL must consider individual parameters and balance the risk of cumulative toxicity versus remission and palliation of symptoms. The conventional approach to FL is clinical observation until there is an indication to treat, typically based on criteria of the Groupe d’Etude des Lymphomes Folliculaires (GELF) or National Comprehensive Cancer Network (NCCN).19,20 There are several prognostic indices in FL including the Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI-2, and m7-FLIPI, but none dictate the timing or type of treatment at an individual patient level.14,21,22

    The m7-FLIPI and gene expression profiling panels include genomic features, but have varied performance and are not validated for clinical practice.23 Staging with positron emission tomography (PET) imaging helps to identify the extent of disease and preferred sites for biopsy when histologic transformation to DLBCL is suspected, as this occurs in up to 15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients.3 The assumption here is that higher uptake values correspond with more rapid cell turnover and aggressive histology. This is somewhat controversial, and PET alone does not appear to predict histologic transformation.24 Nonetheless, PET imaging does result in disease upstaging in approximately 10{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of cases, which often has treatment implications.25,26

    Therapy Selection

    First-line Treatment

    For patients with stage I-II disease, there are several options including observation, rituximab (Rituxan), chemoimmunotherapy, or radiation, with the majority of patients having similar excellent long-term survival regardless of initial approach.27 Approximately 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients have advanced disease (stage III or IV) at diagnosis.3,28 Asymptomatic patients with low disease burden may be actively monitored. When treatment is indicated for patients with low tumor-burden advanced disease, rituximab monotherapy is often used, given the high overall response rate (ORR; complete remission [CR] plus partial remission [PR]) of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, low toxicity, and long median time to treatment failure of approximately 4 years, which delays the need for cytotoxic therapy.29

    When selecting initial treatment for patients with high tumor burden and symptomatic advanced FL, there are several considerations regarding the chemotherapy backbone, the anti-CD20 antibody, the use of maintenance strategies, and whether to opt for a nonchemotherapy regimen (Figure 2). Based on the StiL (NCT00991211) and BRIGHT (NCT00877006) trials, bendamustine and rituximab (BR) or rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), are both options with ORR >90{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.30,31

    BR has become a preferred option based on superior progression-free survival (PFS) over R-CHOP (70 vs 31 months, respectively) and it is also not associated with alopecia, anthracycline-associated cardiotoxicity, vinca alkaloid-associated neuropathy, or steroid-associated risks. R-CHOP may be preferred in cases where occult transformation is suspected, or immune suppression associated with bendamustine is to be avoided. In patients treated with R-CHOP or rituximab with cyclophosphamide, vincristine, and prednisone (R-CVP), maintenance therapy with rituximab every
    8 weeks for 2 years compared with placebo improves PFS, but not OS, based on the PRIMA study (NCT00140582).32

    It is unclear whether this extends to patients treated with BR. In the GALLIUM study (NCT01332968), chemoimmunotherapy with obinutuzumab (Gazyva) versus rituximab improved PFS, with no difference in OS, but did result in high grade 3-5 adverse events, including infusion-related events and infections.33,34 The use of maintenance therapy is controversial, and even more so during the COVID-19 pandemic. Among surveyed physicians who treat indolent lymphomas with a maintenance therapy strategy, 53{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} hold rituximab maintenance to allow for vaccination.35 Lenalidomide (Revlimid)with rituximab is an alternative to chemoimmunotherapy with similar response rates, PFS, and OS to chemoimmunotherapy (R-CHOP, BR, or R-CVP).36 Similar to chemoimmunotherapy, it is a fixed-duration treatment, but with a much longer time frame at 18 months. It remains an option for patients wishing to avoid cytotoxic chemotherapy.

    Relapsed/Refractory Treatment

    There is no standard treatment or sequence of treatments for relapsed/refractory FL (RR-FL), but the number of options is increasing. Approximately 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients have early relapse and progression of disease within 24 months (POD24), and these patients have poor outcomes.4 Unfortunately, upfront identification of these patients is not possible, and more effective treatments for these patients are needed. For all patients with RR-FL, a chemoimmunotherapy regimen (BR, R-CHOP, or R-CVP) different from the first-line therapy is an option.

    There is limited data on R-CHOP after BR, but second-line BR in patients with indolent NHL with previous rituximab (39{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) or CHOP (54{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) had an ORR of 82{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and PFS of 34 months.37 Rituximab monotherapy is also effective for some patients with low tumor burden and previous rituximab-based regimens with an ORR 55{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 64{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and PFS of 14 months.38,39 Obinutuzumab with either bendamustine or CHOP may improve outcomes by overcoming rituximab refractoriness, especially for relapses within 6 to 12 months.40,41 In transplant-eligible patients with chemosensitive disease to first salvage, consolidative autologous stem cell transplantation (auto-SCT) appears to improve long-term survival based on several retrospective analyses.

    Among patients with POD24, auto-SCT has an improved 5-year OS of approximately 77{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 59{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} among those without auto-SCT.42 Similar results were observed for patients undergoing auto-SCT within 1 year of treatment failure, with a 5-year OS of 73{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} compared with 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} without auto-SCT.43 It should be noted, however, that the benefit of auto-SCT may simply be due to a favorable response to second-line therapy and randomized studies are needed.

    In the era of increased alternative treatments, the use of auto-SCT has been substantially reduced. The use of allogeneic-SCT, a historical option with curative potential in FL, has also declined. While the preferred therapy for high-risk patients with early relapse has yet to be defined, targeted therapy beyond anti-CD20 monoclonal antibodies has been reshaping the treatment landscape of FL since 2014 (Table 1), with several new trials focusing on this population, including a US Intergroup Study S1608 (NCT03269669).

    Lenalidomide

    Lenalidomide is an immunomodulatory drug with direct cytotoxicity to lymphoma cells via inhibition of the E3 ubiquitin ligase, cereblon, as well as indirect antitumor effects mediated through changes in the tumor microenvironment.44 Lenalidomide with rituximab is an active regimen in rituximab-sensitive relapsed FL, as demonstrated in the AUGMENT trial (NCT01938001) with an ORR of 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 35{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) compared with an ORR of 55{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 20{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) for rituximab alone.39 The combination had a 2-year OS and median PFS of 95{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 39.4 months compared with 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 13.9 months, respectively, for rituximab alone. The combination had a higher incidence of all grades of infections (63{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 49{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively), neutropenia (58{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 23{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and cutaneous reactions (32{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 12{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}). Of the grade 3 or 4 adverse events, a higher incidence of neutropenia (50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} vs 13{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) was also observed with the combination. This study led to the regulatory approval of lenalidomide with rituximab in patients with RR-FL.

    PI3K Inhibitors

    Inhibition of PI3K signaling has been a largely successful approach, with 4 FDA-approved agents in RR-FL.45 PI3K mediates proximal intracellular B-cell receptor signaling, as well as cell survival signals received from the tumor microenvironment. Idelalisib (δ isoform inhibitor; Zydelig) was the first of these agents to be approved and a major breakthrough in the RR-FL space. The ORR was 57{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with a median duration of response (DOR) of 12.5 months and median PFS of 11 months in very heavily pretreated patients.46 Unfortunately, significant toxicities, including neutropenia, diarrhea, transaminitis, and pneumonia, limited its development. Copanlisib (pan-isoform inhibitor; Aliqopa); duvelisib (δ and γ isoform inhibitor; Copiktra); and umbralisib (δ isoform and CK1 ε inhibitor; Ukoniq) are also approved for RR-FL with comparable efficacy and improved toxicity profiles.47-49 They all have an ORR ranging from 42{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 59{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, median DOR of 10 to 12 months, and median PFS of 9.5 to 11 months. They have regulatory approval for patients with multiply relapsed FL, based on activity in the heavily pretreated setting.

    Tazemetostat

    Approximately 25{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients with FL have a gain of function mutation in the histone methyltransferase protein, EZH2, with consequent increased expression of genes involved in cell proliferation.12,14,50 Although it contributes to lymphomagenesis, EZH2 gene mutations are associated with improved PFS.50 Tazemetostat (Tazverik) is an EZH2 inhibitor that targets this epimutation. It is the first biomarker-directed therapy in FL and has been approved as a third-line option in RR-FL, with an ORR of 69{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and CR rate of 13{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.51 With a median follow-up of 22 months, the median PFS was 13.8 months, and median OS was not reached. It also appears to have activity in patients without an EZH2 gene mutation, with ORR of 35{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and similar median PFS and OS. There were few significant treatment-related adverse events, with 3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients having grade 3 or 4 myelosuppression and a low discontinuation rate of 8{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. Its favorable toxicity profile makes it an attractive oral option.

    CAR T-Cell Therapy

    While targeted agents have clinical activity in RR-FL, long-term remission is still lacking and most require prolonged treatment courses. CAR T-cell therapy has revolutionized the treatment of aggressive lymphomas like DLBCL, and is also now an option for RR-FL, although follow-up remains short. Axicabtagene ciloleucel (axi-cel; Yescarta) is an anti-CD19 CAR T-cell
    therapy that received accelerated approval in March 2021 for adult patients with RR-FL (≥ 2 lines of prior therapy) based on the results of the phase 2 study ZUMA-5.52 In a preliminary report of updated results (median follow-up of 31 months), 86 patients with RR-FL had an ORR of 94{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 79{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), median DOR and PFS of 38.6 months and 39.6 months, respectively, while OS was not reached.53 The incidence of cytokine release syndrome (CRS) and neurotoxicity grade ≥ 3 were 6{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} and 15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, respectively.

    The phase 2 ELARA trial (NCT03568461) evaluating tisagenlecleucel (tisa-cel) in patients with RR-FL (≥ 2 lines of prior therapy) had an ORR 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 69{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) without any grade ≥ 3 CRS, and only 3{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} with grade ≥ 3 neurotoxicity.54 At a median follow-up of 16.9 months, the median DOR, PFS, and OS were not reached, but 1-year PFS was 67{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. The phase 2 TRANSCEND FL trial (NCT04245839) using lisocabtagene maraleucel is ongoing. One of the most crucial challenges is patient selection for CAR T, which remains a costly and
    aggressive approach. Long-term follow-up and real-world data for CAR T-cell therapy from the commercial setting will be important guides influencing patient selection.

    Emerging and Novel Therapies

    Beyond the commercially approved targeted therapies in FL, there are multiple emerging agents that target the biology of FL (Figure 3). These are reviewed briefly in the following section, which also highlights novel investigational use of these treatments in FL (Table 2).

    Antibody-Drug Conjugates

    Antibody-drug conjugates (ADCs) offer an appealing means of antigen-based drug delivery, with several in development. In a phase 2 study in patients with RR-FL, the anti-CD79b ADC, polatuzumab vedotin, (pola; Polivy) was combined with rituximab and resulted in an ORR of 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR 45{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with a 9.4-month DOR.55 The PFS was 15.3 months with a 2-year OS of 88{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}. The most common grade 3-4 adverse events were neutropenia (15{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) and diarrhea (10{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}); however, although no grade 3-4 neuropathy was observed, 40{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} had grade 1-2 neuropathy.

    In preliminary reports of early-phase studies evaluating pola combinations in RR-FL, pola with BR did not improve treatment response.56 Pola with obinutuzumab/lenalidomide had an ORR of 76{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), while pola with obinutuzumab/venetoclax had an ORR of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 57{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and long-term results with updated survival are anticipated.57,58 In a phase 1 study including 14 patients with RR-FL, the anti-CD19 ADC, loncastuximab tesirine (Zynlonta), had an ORR of 79{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and cytopenias were the most common adverse effect.59

    Checkpoint Inhibitors

    Although checkpoint blockade monotherapy has low response rates in RR-FL, combinations may be more active. A phase 1/2 trial (NCT02631577) using obinutuzumab, atezolizumab (Tecentriq), and lenalidomide (G-atezo-len) in patients with RR-FL reported an ORR of 78{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 72{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), median DOR of 38 months, and 2-year PFS of 65{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.60 Cytopenias were the most common grade ≥ 3 adverse event and occurred in 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of patients. While the majority of toxicities were manageable, the discontinuation rate of any study drug was 29{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}.

    In a preliminary report of pembrolizumab with rituximab in patients with RR-FL (NCT02446457), the ORR was 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 60{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), and although safe, the benefit of pembrolizumab (Keytruda) over rituximab monotherapy was unclear, as this trial included patients with rituximab-sensitive disease.61 In the frontline phase 2 trial (1st FLOR study; NCT03245021), immune priming with nivolumab (Opdivo), followed by rituximab and nivolumab had an ORR of 92{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 54{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), with a favorable toxicity profile.62 Larger studies and a longer follow-up are needed to clarify the role of checkpoint inhibitors as first-line nonchemotherapy options.

    Novel Antibodies and Combinations

    Antibodies with novel targets are also under investigation in FL. The anti-CD47 antibody, magrolimab (Hu5F9-G4), blocks CD47 on lymphoma cells to enhance macrophage-mediated phagocytosis. In a phase 1 study of patients with RR-NHL, which included 7 patients with RR-FL, magrolimab with rituximab resulted in an ORR of 71{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (5/7) and CR rate of 43{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (3/7).63 Although small, these numbers are encouraging, with many patients having rituximab-refractory disease. The phase 2 portion of this study (NCT02953509) is currently recruiting.

    Another trial investigating venetoclax (Venclexta) with obinutuzumab and magrolimab (VENOM) in relapsed/refractory indolent lymphomas is recruiting, and the results are eagerly anticipated (NCT04599634). Tafasitamab (Monjuvi) is an anti-CD19 antibody approved in combination with lenalidomide for relapsed/refractory DLBCL, but has low activity as a monotherapy in FL.64 A phase 3 trial (InMIND) of tafasitamab plus lenalidomide/rituximab versus lenalidomide/rituximab alone in patients with RR-FL or marginal zone lymphoma will determine whether there is a role for tafasitamab in RR-FL (NCT04680052).

    Bispecific Antibodies

    Bispecific antibodies or bispecific T-cell engagers (BiTes) are novel protein constructs with separate B-cell (CD20) and T-cell targeting (CD3) domains. Mosunetuzumab, glofitamab, odronextamab, and epcoritamab are bispecific antibodies being investigated in early-phase RR-FL trials (Table 3), which have shown promising results with ORR ranging from 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 100{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR from 50{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} to 75{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) in heavily pretreated patients.65-69 Bispecific antibodies provide an off-the-shelf form of T-cell mediated therapy, with the goal of achieving the durable remissions seen with CAR T-cell therapy. Unlike CAR T-cell therapy, they appear to have a lower risk of CRS and neurotoxicity, and favorable responses in patients relapsing after CAR T-cell therapy. The optimal clinical use of bispecific antibodies remains unknown, and trials including novel combinations in FL are ongoing: mosunetuzumab and lenalidomide (NCT04246086); and epcoritamab with lenalidomide/rituximab or BR (NCT04663347).

    BCL2 and Epigenetic Targeting

    While BCL2 translocation and epigenetic dysregulation are both frequent features in FL, the efficacy of existing agents has been modest. The BCL2 inhibitor, venetoclax, had low monotherapy activity in FL with an ORR of 38{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 14{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}),70 but combination strategies are in development. A preliminary report of the first trial to combine a Bruton tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), with venetoclax in RR-FL showed an ORR of 83{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 33{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}) with manageable toxicity (NCT02956382).71 Several frontline trials using venetoclax-based combinations include the following: venetoclax, oral azacitidine (CC-486), and obinutuzumab (NCT04722601); venetoclax, lenalidomide, and obinutuzumab (NCT03980171); and venetoclax, ibrutinib, and obinutuzumab (NCT04450173).

    The phase 2 PrECOG 0403 trial with frontline venetoclax, bendamustine, and obinutuzumab (NCT03113422) for patients with high tumor-burden FL (n = 56) showed an ORR of 93{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} (CR of 73{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}), 2-year estimated PFS of 86{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, and 2-year estimated OS of 94{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} at a median follow-up of 21 months.72 Despite the efficacy, the rate of ≥ grade 3 adverse events was high, at 84{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c}, most notably due to tumor lysis, cytopenias, and infections. Unfortunately, this toxicity will preclude its use, but alternative dosing strategies to mitigate adverse effects are being explored. Tazemetostat is also being evaluated in combination with rituximab (NCT04762160), and in combination with lenalidomide and rituximab (NCT04224493).

    Conclusions

    While chemoimmunotherapy, lenalidomide with rituximab, or rituximab alone are standard first or subsequent line options for advanced FL, the treatment choices for RR-FL have evolved over the last several years. Additional agents for multiply relapsed patients include PI3K inhibitors, tazemetostat, and CAR T-cell therapy. Patient selection for CAR T-cell therapy is evolving, and the optimal sequencing with other therapies remains unknown. There are many emerging investigational products, including ADCs, anti-CD47 monoclonal antibodies, bispecific antibodies, checkpoint-based therapy, and novel combination strategies that are being evaluated. Individualized approaches, trial end points with quality-of-life measures, and information to guide sequencing of available regimens and agents are all desperately needed. These efforts, coupled with ongoing discovery in the biology of FL, are imperative to improving outcomes for patients with FL.

    AUTHOR AFFILIATIONS:

    Kirk E. Cahill, MD1; and Sonali M. Smith, MD1

    1Department of Medicine, Section of Hematology/Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL.

    Funding: None

    Corresponding author

    Sonali M. Smith, MD; Elwood V. Jensen Professor in Medicine; Chief, Section of Hematology/Oncology; Department of Medicine; The University of Chicago Medicine; 5841 S. Maryland Ave., MC 2115; Chicago, IL 60637; Email: [email protected]

    References

    1. Link BK, Maurer MJ, Nowakowski GS, et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol. 2013;31(26):3272-3278. doi:10.1200/JCO.2012.48.3990
    2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443-459. doi:10.3322/caac.21357
    3. Batlevi CL, Sha F, Alperovich A, et al. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J. 2020;10(7):74. doi:10.1038/s41408-020-00340-z
    4. 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
    5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569
    6. Vaidyanathan G, Czuczman MS. Follicular lymphoma grade 3: review and updates. Clin Lymphoma Myeloma Leuk. 2014;14(6):431-435. doi:10.1016/j.clml.2014.04.008
    7. Weiss LM, Warnke RA, Sklar J, Cleary ML. Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas. N Engl J Med. 1987;317(19):1185-1189. doi:10.1056/NEJM198711053171904
    8. Limpens J, de Jong D, van Krieken JH, et al. Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Oncogene. 1991;6(12):2271-2276.
    9. Aster JC, Kobayashi Y, Shiota M, Mori S, Sklar J. Detection of the t(14;18) at similar frequencies in hyperplastic lymphoid tissues from American and Japanese patients. Am J Pathol. 1992;141(2):291-299.
    10. Roulland S, Navarro JM, Grenot P, et al. Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis. J Exp Med. 2006;203(11):2425-2431. doi:10.1084/jem.20061292
    11. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298-303. doi:10.1038/nature10351
    12. Okosun J, Bodor C, Wang J, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46(2):176-181. doi:10.1038/ng.2856
    13. Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189-195. doi:10.1038/nature09730
    14. Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16(9):1111-1122. doi:10.1016/S1470-2045(15)00169-2
    15. Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A. 2015;112(10):E1116-1125. doi:10.1073/pnas.1501199112
    16. Zhang J, Vlasevska S, Wells VA, et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017;7(3):322-337. doi:10.1158/2159-8290.CD-16-1417
    17. Ortega-Molina A, Boss IW, Canela A, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med. 2015;21(10):1199-1208. doi:10.1038/nm.3943
    18. Tazverik. Prescribing information. Epizyme; 2020. Accessed August 24, 2021. https://bit.ly/3fGgbQv
    19. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15(3):1110-1117. doi:10.1200/JCO.1997.15.3.1110
    20. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 5.2021. Accessed January 20, 2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
    21. Solal-Celigny P. Follicular Lymphoma International Prognostic Index. Curr Treat Options Oncol. 2006;7(4):270-275. doi: 10.1007/s11864-006-0036-3
    22. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27(27):4555-4562. doi:10.1200/JCO.2008.21.3991
    23. Mozas P, Rivero A, Lopez-Guillermo A. Past, present and future of prognostic scores in follicular lymphoma. Blood Rev. 2021;50:100865. doi:10.1016/j.blre.2021.100865
    24. Mir F, Barrington SF, Brown H, et al. Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study. Blood. 2020;135(15):1214-1218. doi:10.1182/blood.2019001091
    25. Le Dortz L, De Guibert S, Bayat S, et al. Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma. Eur J Nucl Med Mol Imaging. 2010;37(12):2307-2314. doi:10.1007/s00259-010-1539-5
    26. Luminari S, Biasoli I, Arcaini L, et al. The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi. Ann Oncol. 2013;24(8):2108-2112. doi:10.1093/annonc/mdt137
    27. Michallet AS, Lebras LL, Bauwens DD, et al. Early stage follicular lymphoma: what is the clinical impact of the first-line treatment strategy? J Hematol Oncol. 2013;6:45. doi:10.1186/1756-8722-6-45
    28. Nooka AK, Nabhan C, Zhou X, et al. Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Ann Oncol. 2013;24(2):441-448. doi:10.1093/annonc/mds429
    29. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014;32(28):3096-3102. doi:10.1200/JCO.2014.56.5853
    30. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
    31. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952. doi:10.1182/blood-2013-11-531327
    32. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51. doi:10.1016/S0140-6736(10)62175-7
    33. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331-1344. doi:10.1056/NEJMoa1614598
    34. Hiddemann W, Barbui AM, Canales MA, et al. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018;36(23):2395-2404. doi:10.1200/JCO.2017.76.8960
    35. Messmer M, Wagner-Johnston N. COVID-19 vaccination in patients on rituximab: a survey of lymphoma physicians at NCI designated cancer centers. Leuk Lymphoma. 2021;62(12):3019-3022. doi:10.1080/10428194.2021.1941939
    36. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi:10.1056/NEJMoa1805104.
    37. Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016;17(1):57-66. doi:10.1016/S1470-2045(15)00447-7
    38. Tobinai K, Igarashi T, Itoh K, et al. Rituximab monotherapy with eight weekly infusions for relapsed or refractory patients with indolent B cell non-Hodgkin lymphoma mostly pretreated with rituximab: a multicenter phase II study. Cancer Sci. 2011;102(9):1698-1705. doi:10.1111/j.1349-7006.2011.02001.x
    39. 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(14):1188-1199. doi:10.1200/JCO.19.00010
    40. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093. doi:10.1016/S1470-2045(16)30097-3
    41. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013;122(7):1137-1143. doi:10.1182/blood-2013-01-481341
    42. 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
    43. 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
    44. Gribben JG, Fowler N, Morschhauser F. Mechanisms of action of lenalidomide in B-cell non-hodgkin lymphoma. J Clin Oncol. 2015;33(25):2803-2811. doi:10.1200/JCO.2014.59.5363
    45. Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 2018;18(3):148-167. doi: 10.1038/nrc.2017.121
    46. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδinhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. doi:10.1056/NEJMoa1314583
    47. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905. doi:10.1200/JCO.2017.75.4648
    48. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. doi:10.1200/JCO.18.00915
    49. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kdelta/CK1epsilon inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39(15):1609-1618. doi:10.1200/JCO.20.03433
    50. Huet S, Xerri L, Tesson B, et al. EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J. 2017;7(4):e555. doi:10.1038/bcj.2017.32
    51. 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(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
    52. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2020;136(suppl 1):40-41. doi:10.1182/blood-2020-136834
    53. Neelapu SS, Chavez JC, Sehgal AR, et al. Long-term follow-up analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Blood. 2021;138(suppl 1):93-93. doi:10.1182/blood-2021-148473
    54. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. Published online December 17, 2021. doi:10.1038/s41591-021-01622-0
    55. Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019;6(5):e254-e265. doi:10.1016/S2352-3026(19)30026-2
    56. Sehn LH, Kamdar M, Herrera AF, et al. Randomized phase 2 trial of polatuzumab vedotin (pola) with bendamustine and rituximab (BR) in relapsed/refractory (r/r) FL and DLBCL. J Clin Oncol. 2018;36(suppl 15):7507. doi:10.1200/JCO.2018.36.15_suppl.7507
    57. Diefenbach C, Kahl BS, Banerjee L, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed/refractory follicular lymphoma: primary analysis of the full efficacy population in a phase Ib/II trial. Blood. 2019;134(suppl 1):126. doi:10.1182/blood-2019-123669
    58. Bannerji R, Yuen S, Phillips TJ, et al. Polatuzumab vedotin + obinutuzumab + venetoclax in patients with relapsed/refractory (R/R) follicular lymphoma (FL): Primary analysis of a phase 1b/2 trial. J Clin Oncol. 2021;39(suppl 15):7534. doi:10.1200/JCO.2021.39.15_suppl.7534
    59. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512
    60. Morschhauser F, Ghosh N, Lossos IS, et al. Obinutuzumab-atezolizumab-lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma: final analysis of a Phase Ib/II trial. Blood Cancer J. 2021;11(8):147. doi:10.1038/s41408-021-00539-8
    61. Nastoupil LJ, Westin JR, Fowler NH, et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study. J Clin Oncol. 2017;35(suppl 15):7519. doi:10.1200/JCO.2017.35.15_suppl.7519
    62. Hawkes EA, Lee ST, Chong G, et al. Immune priming with nivolumab followed by nivolumab and rituximab in first-line treatment of follicular lymphoma: The phase 2 1st FLOR study. J Clin Oncol. 2021;39(suppl 15):7560. doi:10.1200/JCO.2021.39.15_suppl.7560
    63. Advani R, Flinn I, Popplewell L, et al. CD47 Blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med. 2018;379(18):1711-1721. doi:10.1056/NEJMoa1807315
    64. Jurczak W, Zinzani PL, Gaidano G, et al. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1266-1272. doi:10.1093/annonc/mdy056
    65. Budde LE, Sehn LH, Matasar MJ, et al. Mosunetuzumab monotherapy is an effective and well-tolerated treatment option for patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of therapy: pivotal results from a phase I/II study. Blood. 2021;138(suppl 1):127. doi:10.1182/blood-2021-145872
    66. Morschhauser F, Bishton M, Eyre TA, et al. Mosunetuzumab in combination with lenalidomide has a manageable safety profile and encouraging activity in patients with relapsed/refractory follicular lymphoma: initial results from a phase Ib study. Blood. 2021;138(suppl 1):129. doi:10.1182/blood-2021-145694
    67. Morschhauser F, Carlo-Stella C, Dickinson M, et al. Glofitamab as monotherapy and in combination with obinutuzumab induces high complete response rates in patients (pts) with multiple relapsed or refractory (R/R) follicular lymphoma (FL). Blood. 2021;138(suppl 1):128. doi:10.1182/blood-2021-148778
    68. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8
    69. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a Human CD20 x CD3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Blood. 2020;136(suppl 1):42-43. doi:10.1182/blood-2020-136659
    70. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320
    71. Ujjani CS, Lai C, Leslie LA, et al. Ibrutinib and venetoclax in relapsed and refractory follicular lymphoma. Blood. 2020;136(suppl 1):46-47. doi:10.1182/blood-2020-136219
    72. Portell CA, Jegede O, Wagner-Johnston ND, et al. Phase II study of venetoclax in combination with obinutuzumab and bendamustine in patients with high tumor burden follicular lymphoma as front line therapy (PrECOG 0403). Blood. 2021;138(suppl 1):814. doi:10.1182/blood-2021-145217
  • This New Year Focus on Financial Health: Tips to Becoming Financially Fit

    This New Year Focus on Financial Health: Tips to Becoming Financially Fit

    By Michelle Lawrence, Chase Community and Business enterprise Progress Government Director

    Whether you are wanting to turning into financially impartial, scheduling for a prolonged awaited family vacation, or preserving for a down payment to purchase your first dwelling, we want 2022 to turn into the yr you turned common with some of the instruments and skills to aid make your money journey as sleek as doable. 

    Handling your revenue can be overwhelming but it doesn’t have to have to be. Comprehension factors like balancing a check ebook, budgeting, preserving, and even constructing your credit rating rating are expertise that can enable you at any phase of your lifestyle. Even in these tricky situations with the pandemic when so several of us are going through increased uncertainty all-around our funds and work security, it is these types of moments exactly where being familiar with core money skills can be the difference maker. 

    Set Goals. It is not about what you make, it’s about what you maintain. A greenback put into a price savings account with compounded fascination, will be value additional tomorrow. Set an close intention for your funds, perhaps it’s managing you to a extravagant evening meal once a thirty day period, or a little something larger sized these types of as conserving for a home, auto or a wedding. Plans are significant since they can support impression the pondering at the rear of your spending. 

    Make the most of Investing Tools. Chase’s Autosave permits buyers to make automatic transfers to discounts accounts. From $10 a 7 days or $100 a month, you pick how significantly revenue you want to help you save and in what cadence. When the income by no means enters your examining account, you’re a great deal much less very likely to invest it.

    Chase’s monetary plans hub gives an interactive calculator that maps out a timeline to arrive at personal savings goals and highlights how the Autosave software can enable you take care of a normal cost savings program to remain on monitor and fulfill your ambitions. Other sources are also readily available, these kinds of as budget worksheets to watch and track regular monthly expending, guidance on working with the Credit rating Journey software to develop and guard credit, as nicely as history on small-price checking accounts made to deliver entry for anybody who has had difficulties having or maintaining an account in the past.

    Question Your Regional Advocates. In Washington D.C. and Baltimore, we’ve employed a few group professionals – a new job made by the lender – who get the job done with the neighborhood and modest companies to boost awareness of accessible means, and aid connect you with money overall health applications, products and solutions and solutions. 

    With our new Community Middle Branch in Skyland Town Heart, buyers can study additional about interactive plans on matters these types of as funds building, house buying strategies, job interview and career lookup expertise, or how to fund a smaller business enterprise. Contrary to standard branches, these localized hubs are designed especially for the local community and with the intent to near gaps in accessibility to economical schooling, sources and access to money for achieving milestones like acquiring a home, setting up a modest business enterprise or spending for instruction.

    Reserved Funds for Minority Business enterprise Proprietors. 41{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of Black-owned corporations shut their doorways owing to the Pandemic, and COVID-19 has only worsened the disparities and inequities that desire an intentional reprioritization of cash. Through our Business owners of Color Fund, in partnership with the Washington Place Neighborhood Investment Fund and the Latino Financial Enhancement Heart, JPMorgan Chase is operating to supply extra accessibility to money to long term entrepreneurs, current business house owners and communities who have traditionally and unfairly struggled to secure it.

    Equitable Household Lending. Residence equity is also a important contributor to families’ wealth, producing it very important that we improve assets ownership amid Black communities. A person way we hope to do this is via our Chase DreaMaker home loan, which would make making use of for your 1st home loan or refinancing a present-day 1 a lot more attainable with a lesser down payment, and by presenting lessened home finance loan insurance, much more adaptability all-around your credit score, probable support grants and homebuyer training courses. 

    No issue exactly where you are monetarily, budgeting and preserving are two essential behaviors that can support all of us bounce back again from life’s unpredicted times or continue to keep on monitor to assure you satisfy your objectives. That is why we are right here to assist every person have open up discussions about what it suggests to turn out to be monetarily healthier and present support, applications and tips to get there. Economic well being is a journey, and we can assist you believe about a program for now and the upcoming. 

    For extra methods, info and accessibility to instruments that can aid you realize your fiscal aims and milestones, visit chase.com/individual/financial-ambitions

    Sponsored articles from JPMorgan Chase & Co.

    Help us Continue to explain to OUR Story and be part of the AFRO family as a member – subscribers are now members!  Join in this article! 

  • Sauce Magazine – 11 St. Louis businesses that focus on self-care for a fresh start to the new year

    Sauce Magazine – 11 St. Louis businesses that focus on self-care for a fresh start to the new year

    11 St. Louis corporations that aim on self-care for a fresh new get started to the new year

    Companion Written content

    By Sauce Staff // January 7, 2022

    The New Calendar year is often a good time to set your intentions for the future. Irrespective of whether you are wanting for some tasty, nutrient-loaded food stuff and beverages, a nutritious medication alternate or some self-care at a spa, these local companies will help you get to your plans.

    Refreshing Thyme Market at City Foundry STL
    Get a fresh commence to your yr at Fresh new Thyme Marketplace! Proudly positioned at City Foundry STL, New Thyme is your new neighborhood grocery keep. They are targeted on bringing fresh new, inexpensive and regional products to Midtown St. Louis and beyond. You will appreciate the entire grocery variety, meat and deli counters, as well as the substantial pure and natural alternatives. Be sure to go to the in-keep café, property to Iron Drop, which attributes artisanal scratch-made biscuits and cautiously curated craft roasted espresso menus, and Ace Sushi with scrumptious sushi made refreshing each day, hot foods possibilities and boba tea. Look at out the $5 sushi rolls just about every Thursday.
    Fresh new Thyme’s food items doesn’t only appear, smell and style fantastic – it’s also very good for you. Get all the vitamins you need to have and all the flavors you crave while supporting trustworthy companions, brand names and farmers. Store confidently and permit your hunger tutorial the way figuring out that each and every item in the retailer has been hand-chosen with treatment.
    Prevent by the organic dwelling segment this January for a sale on vitamins and overall body treatment, when you can get 30{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} off all people objects in the retail outlet from Jan. 5 to 11, 2022 – take edge of this incredible offer!
    3701 Foundry Way, Suite 201, St. Louis, 314.597.4400, freshthymefoundry.com

    Contemporary Gatherings Cafe + Farm at Saint Louis University
    Fresh Gatherings Cafe + Farm is a student-operate cafe operated by the Office of Nourishment and Dietetics that is open up to the community and situated on SLU’s Health-related Campus. The cafe sources from its natural and organic city farm on campus and from neighborhood farmers and growers in Missouri and Illinois. It is open up for breakfast and lunch with a complete-support coffee bar. Lover favorites contain oat milk lattes, breakfast burritos and croissants, but there are also everyday sizzling lunch specials, seize-and-go sandwiches, salads, soups and baked products. Fresh Gatherings Cafe + Farm exemplifies SLU’s Jesuit principles in assistance of improvement of the full person. They believe that in the value of very good food to nourish the head, body and spirit. The main software in diet and culinary arts allows students to mix their two passions into a job.
    3404 Rutger St., St. Louis, freshgatheringscafe.com, @freshgatherings, @slunutrition1818

    the therapeutic hamsa spa & medspa // photograph courtesy of the healing hamsa

    Fulfill Foodstuff & Drinks
    Dr. Angela Zeng’s perception that “food is better medicine” prompted her to produce a line of terrific tasting, functional juices and smoothies using whole plant components. She hopes to inspire customers’ awareness of the opportunities of integrative and holistic drugs. From her delicious Karuna smoothies to her Karviva ACE Sport beverages and new Karviva Unwined alcohol-no cost wine different, each individual beverage is encouraged by historic knowledge and backed by modern day science. The company’s wellness beverages present a large array of item added benefits ranging from restoration of digestive and immune health and fitness with prebiotics and anti-oxidants to providing thoroughly clean protein and supplying sustained electrical power. The beverages can be identified in regional suppliers including Schnucks, Entire Foodstuff Market place, Dierbergs, Straubs and Contemporary Thyme.
    mykaruna.com

    Indigo Massage & Wellness
    At Indigo Therapeutic massage & Wellness, a comforting practical experience commences as shortly as you stroll in the doorway. Clients frequently tout how calming the area is with its stunning blue and inexperienced décor, defused lighting and pleasant aromas, as well as the comfy seating and the professionalism of the staff members. Opt for from a range of services, from therapeutic massages, CBD facials and acupuncture to overall body wraps and reflexology. Join the Indigo wellness application for a monthly credit score for a discounted therapeutic massage this membership can even be shared with your spouse. Program forward for Valentine’s Working day and e book a massage or get a partners therapeutic massage reward card. In addition, all workers customers at Indigo are totally vaccinated to aid put your worried brain at ease.
    1901 Arsenal St., St. Louis 7200 Manchester Street, Maplewood, 314.276.9882, indigomassagetherapy.com

    Jane Dispensary
    Jane Dispensary is a healthcare cannabis boutique on the Delmar Loop that gives a innovative experience though educating the general public and supporting to take out the stigma of hashish, which can be an integral element of a wholesome lifestyle. Marijuana has a myriad of overall health added benefits and particularly assists with irritation – both in the basic populace and for these with inflammatory autoimmune health conditions this sort of as rheumatoid arthritis, variety 1 diabetic issues, irritable bowel syndrome, celiac condition and several a lot more. When aiming to lower swelling with cannabis, it’s crucial to decide on a merchandise with a higher CBD to THC ratio as CBD is the most effective anti-inflammatory cannabinoid. Quit by the Jane storefront to communicate with a hashish specialist to find the ideal merchandise to fulfill your requirements.
    6662 Delmar Blvd., College Metropolis, janedispensary.com

    Lona’s Lil Eats
    If you appreciate Asian soul foodstuff with a flare but want to indulge in a wholesome way, Lona’s Lil Eats’ homestyle meals are light but gratifying and keep your body fueled all day extensive. There are a great deal of vegan, vegetarian and gluten-no cost options, and customization is encouraged. Sauces – which variety from sweet or savory to sour or spicy – give full-bodied flavors, and any entree can be created into a salad if you’re trying to get the job done more veggies into your diet plan. Furthermore, every thing is made refreshing with no preservatives or MSG. To up your antioxidant ingestion, full your food with the broad collection of teas, from green and white to oolong and black.
    2199 California Ave., St. Louis, 314.925.1888, lonaslileats.com

    photograph courtesy of rootberry

    Rootberry
    As a substitute of location not possible targets loaded with sacrifice and compromise, how about you just “eat more plants additional usually?” Rootberry is St. Louis’ new plant-driven meals corporation that capabilities a rotating menu of chef- and nutritionist-created entrees, shareables and desserts that are completely ready to consume or heat in minutes. Get properly with these restaurant-high quality, nutrient dense foods this sort of as Rootberry’s shepherd’s pie, wintertime squash risotto, Aztec enchiladas, tikka masala and extra. And, even though Rootberry features salads, they are absolutely unexpected like Spring Roll In A Bowl or the soy-ginger superfood salad. The most effective aspect? Rootberry is offered for delivery to your property or workplace. Check out their web site, pick what appears fantastic to you, choose your delivery day and time, and take pleasure in. (No subscription needed, BTW.) You can also discover it in the prepared meals segment in the deli of all Dierbergs Marketplaces. Rootberry is a neighborhood firm producing mouth watering meals that is not just excellent for you – it is great for the world far too. So never get worried about getting vegan, vegetarian or flexitarian this 12 months – simply delight in consuming terrific food stuff … that just comes about to be 100{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} plant-centered.
    St. Louis, rootberry.com

    Source Juicery
    Locating healthier options outdoors the metropolis can in some cases be a obstacle, but Resource Juicery allows you love the benefit of clean up having on the go. And with the pandemic nevertheless surging, there is by no means been a better time to emphasis on being balanced. Supply delivers a myriad of healthy seize-and-go possibilities, from chilly-pressed juice and wellness pictures to nut milks, smoothies, salads and breakfast staples like oats and parfaits. Attempt a one- to 3-day juice cleanse with the solution to include meal packs or protein packs like grilled hen and electric power bites. All goods are gluten-no cost, and there are numerous vegan choices too. Resource delivers an effortless on line purchasing process with curbside pickup or contactless home shipping and delivery to the Edwardsville region. Walk-in buying is also welcome.
    228 N. Primary St., Edwardsville, 618.650.9080, sourcejuicery.com

    Terrabis
    Terrabis is a health care cannabis dispensary in O’Fallon, Hazelwood, Creve Coeur, Springfield and Kansas Town. Did you know a study examine on hashish and bodily exercise was printed in Frontiers in General public Health and fitness? It discovered that 80{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} of cannabis buyers mix hashish and work out. 78{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} say it raises satisfaction. 70{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} say it boosts recovery, and 52{fe463f59fb70c5c01486843be1d66c13e664ed3ae921464fa884afebcc0ffe6c} say it motivates them to workout. Balanced residing and supporting an active life-style is every thing we’re about. The identify Terrabis brings together the word Terra, which stands for Earth Earth, and the term Bis, which are the past 3 letters of their favorite plant, hashish. With each other, Terrabis stands for a healthier earth and represents their adventurous spirit. They motivate you to #ExploreMore of the outdoor, as perfectly as their products, to reside a more healthy and happier life.
    A number of places. terrabis.co, @terrabis_hq

    The Healing Hamsa
    When it will come to wholesome life, self-care is a crucial aspect that should not slide to the wayside. The Healing Hamsa is a location the place professional medical aesthetics meet magical experiences with remedies ranging from a selection of facials and chemical peels to microneedling and over and above. Wellness weekends, non-public occasions and couples ordeals are also readily available, and the Healing Hamsa is exceptionally very pleased to be inclusive and prides itself on the continuing instruction to serve clientele of all ethnic backgrounds. In addition, the spa presents robes, cozy slippers and bottomless beverages while you wait around for your treatment(s) to start off. So upcoming time you are needing a minimal excess self-care, appear verify out this small business created on superior-close experiences and an emphasis on being equipped to retreat and chill out.
    4400 Chouteau Ave., St. Louis, 314.450.8399, healinghamsa.com

    The Pasta Residence Co.
    The Pasta House Co. has prolonged been synonymous with Italian foods in St. Louis as it is celebrating 48 decades in small business, but did you know the home of the golden toasted ravioli also has a variety of balanced options? From an assortment of salads and vegetable-forward dishes like eggplant parmigiano to an full gluten-absolutely free menu, Pasta Dwelling aims to supply a little something for every person. Consider a spouse and children meal beginning at just $29.99 and involves pasta, their popular salad, toasted ravioli and bread and butter. At Pasta Household, you can dine in, buy takeout for curbside pickup, or even get delivery. For greater get-togethers, inquire about catering possibilities.
    Several locations, pastahouse.com

  • At Sweet Birch Herbals in Ashfield, the focus in on the power of nature for good

    At Sweet Birch Herbals in Ashfield, the focus in on the power of nature for good

    ‘People have advanced with plants for hundreds of yrs,” Hannah Jacobson-Hardy of Sweet Birch Herbals in Ashfield reminds us. “And organic medication is nonetheless the most utilized therapeutic observe in the globe.”

    As a result of Sweet Birch Herbals, Jacobson-Hardy aims to preserve her community rooted to the teaching, healing and all-about properly-getting that nearby plants and herbs can give.

    “I expand medicinal herbs and make goods from them,” she describes, “and I educate courses about gardening, foraging, and producing herbal items so you can have your possess apothecary.”

    Jacobson-Hardy is also the girl powering one more neighborhood item, Comprehensive Moon Ghee, a line of various kinds of ghee (clarified butter) she will make with grass-fed milk from regional cows.

    For Sweet Birch Herbals, the centre of exercise is Jacobson-Hardy’s homestead and farm on Creamery Highway in Ashfield.

    “My home is about 3 acres, so it’s compact, but a good deal of house for growing herbs,” she says. “Right by the highway there is a minor barn with a farm retail store and animals, a greenhouse where by I’ll grow ginger and turmeric next 12 months, and then a massive discipline planted with elderberries, flowers and garlic.” Up the hill are a lot more gardens, properly mulched and fertilized with manure from her animals to develop healthful soil without tilling.

    “The apothecary (where by herbs and solutions are saved) is in the basement of the property in which it is cooler,” she says, “and we have a small kitchen area down there for earning solutions.”

    Teas and tinctures, lotions and salves, syrups and ciders — these are most of what Sweet Birch Herbals helps make and sells. The potency of new herbs is fleeting, but preserving an herb in 1 of these kinds captures its essence and usefulness in something that’s shelf-steady.

    “I test to mature every thing I can listed here for generating these,” Jacobson-Hardy claims, “but from time to time which is not achievable. Like this calendar year I purchased ginger and turmeric from Outdated Close friends Farm in Amherst. I love connecting with and obtain a lot from other neighborhood farms.”

    On the schooling aspect, Sweet Birch Herbal’s core providing is a yearlong apprenticeship led by Jacobson-Hardy. Contributors join both a starting, intermediate or superior cohort of 10 other people to deepen their understanding of herbs and takes advantage of.

    “We satisfy when a month for a complete day, March by November,” Jacobson-Hardy points out. “It’s a ton of fingers-on finding out — harvesting from the gardens and forest, cooking factors, creating ferments, creating your possess herbal medications.”

    Although apprenticeships are entire for subsequent year, Jacobson-Hardy also teaches a person-working day workshops in the course of the 12 months, at the farm in Ashfield and by request at other destinations throughout the area.

    Jacobson-Hardy’s very own journey in herbal schooling draws broadly from her earlier. She credits her mother and father and grandparents, who taught her to mature, locate, cook and maintain foodstuff and herbs from a youthful age, for instilling an comprehension that “health arrives from what we place in our bodies.” Later, a diploma in plant and soil science from UMass Amherst and time learning with other community herbalists helped tune her recognition of how plants help persons.

    Still finally, Jacobson-Hardy suggests it’s the crops by themselves that are the greatest teachers, as men and women have just scratched the area in comprehending their array of features, properties and employs.

    “There’s a degree of humility that comes from doing work with crops and herbalism,” she claims, “because no particular person is definitely a learn. There is always a lot more to study.”

    The thought that everyone’s a amateur to some diploma can make exploring herbalism for the to start with time a lot less overwhelming. “A great way to integrate herbs into your each day existence is by means of your typical cooking schedule,” Jacobson-Hardy states. Plenty of culinary herbs have medicinal benefits, these types of as aiding digestion or getting antibacterial.

    She also indicates familiarizing yourself with natural teas to fully grasp the outcomes of different plants. (Constantly consult a health-related specialist right before experimenting with much more potent natural medications.)

    For those people who’d rather use herbs in pre-created products and solutions like tinctures, teas, oils and so on, Sweet Birch Herbals is one of many local organizations making them with nearby ingredients.

    “Elderberry syrups are a single of the most well-known issues this time of calendar year,” Jacobson-Hardy says. “They raise the immune method, are antiviral, and style truly great blended into seltzer drinking water or tea. We also make a rose product and a lavender cream, both of which are great for hydrating the skin as the air dries out. And teas are always common.”

    For these looking ahead to the vacations on today’s Small Enterprise Saturday, they also have gift bins that incorporate a handful of merchandise. And from Entire Moon Ghee, “chocolate and maple ghee are actually well known stocking stuffers,” Jacobson-Hardy claims.

    “Plus I just manufactured a batch of balsam fir essential oil with balsam boughs from Pieropan Xmas Tree Farm listed here in Ashfield,” she claims, “and it’s so pleasant. It makes the complete home scent like the holidays.”

    Sweet Birch Herbals has a self-serve farm stand open from dawn to dusk on internet site in Ashfield. They also provide on the web by means of their web-site, in individual at the Northampton Winter Farmers Marketplace, and as a result of several nearby merchants in the Valley (their site, sweetbirchherbals.com, has a comprehensive listing).

    Many persons use herbal medicine as portion of a program of self-treatment. Jacobson-Hardy sees a true comprehension as encompassing that, as effectively as treatment for issues a great deal better.

    “Ever given that I was a very little woman, I’ve loved character,” she states. “It’s my content put, the place I sense entire and protected. Seeing it degraded, I felt the way I could depart the earth a superior put was by education and learning. Connecting persons to the earth, nature and vegetation, and educating that we are not individual. Then it’s tougher to damage the earth. Simply because we see it’s portion of us.”

    Jacob Nelson is communications coordinator for CISA (Community Associated in Sustaining Agriculture). For much more ideas about locally grown and produced items this vacation period, check out buylocalfood.org/discover-it-regionally.