Mature B-cell non-Hodgkin lymphomas (B-NHLs) comprise approximately 7% of all pediatric cancers. The most common types are Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma.1,2 Patients treated with French-American-British mature lymphoma B 96 (FAB/LMB96) therapy experienced 97% ± 0.5% (group A), 89% ± 1.2% (group B), and 79% ± 2.7% (group C) event-free survival (EFS) with short, intensive, multiagent chemotherapy, as we have previously reported.3–6 In a trial conducted by the Children’s Oncology Group (COG), the addition of rituximab to chemotherapy up-front in patients with stage III/IV disease improved EFS to 95%,7 whereas in another COG trial the addition of rituximab to chemotherapy up-front in patients with Burkitt leukemia/lymphoma with central nervous system (CNS) and/or bone marrow involvement improved EFS to 90%, as we have previously reported.8 An international phase III randomized trial in children with stage III and IV mature B-NHL also showed a marked advantage in EFS and overall survival (OS) in patients who received rituximab in addition to LMB therapy.9 Thankfully, the number of children who experience relapse is small, because the prognosis remains dismal, with OS rates of 27% to 36%, as reported by our group and others.1,10–12
Failure Definition
Risk classification in the FAB/LMB96 trial was delineated as follows: low-risk (group A), defined as resected stage I and abdominal completely resected stage II disease; high-risk (group C), defined as bone marrow involvement L3 blasts ≥25% and/or CNS disease; intermediate-risk (group B), defined as all others.3,6,13 Recently, we reported a new staging classification that incorporates new histologic entities, extranodal dissemination, improved diagnostic methods, and advanced imaging technology, and a new CAYA-specific response classification in the International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS) and the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC), respectively.14,15
Patients with primary refractory disease are those who never attain a complete response (CR) with standard multiagent chemoimmunotherapy.
Reduction
FAB/LMB96 therapy reduction (administered to patients in groups B and C) is comprised of a 7-day low-dose reduction phase with cyclophosphamide/vincristine/prednisone (COP). We define reduction failure as a <20% response to COP or COP dose–equivalent steroid pretreatment.3,13
Progression
Patients with progression are those with a >25% increase in sum product of greatest perpendicular diameters on CT or MRI, Deauville score 4 or 5 on FDG-PET with an increase in lesional uptake from baseline, or development of new morphologic evidence of disease in bone marrow or cerebral spinal fluid.14,15
Relapse
Patients who have experienced a relapse are those who have attained a CR with subsequent evidence of disease.
Standard of Care Reinduction and Consolidation Strategies
Although there is no universal standard of care reinduction strategy for relapsed/refractory (R/R) disease, the most common regimens used include ifosfamide/carboplatin/etoposide (ICE) and cytarabine/etoposide (CYVE), with the more recent addition of rituximab.10,13,16–18 In their retrospective review of the 67 (5%) patients enrolled in the SFOP/SFCE LMB89, FAB/LMB96, and LMB2001 trials who experienced relapse, Jourdain et al17 demonstrated an overall response rate (ORR; CR + partial response [PR]) of 66% to 67% in group A and B patients treated with CYVE after relapse and 60% in group C patients treated with ICE after relapse. Other first salvage regimens used in group C patients included VENOMID (vindesine/mitoxantrone/methylprednisolone/ifosfamide) and ICN (ifosfamide/carboplatin/mitoxantrone), as well as high-dose methotrexate and intrathecal chemotherapy potentially followed by an additional chemotherapy regimen in patients with CNS relapse. The COG demonstrated the safety and efficacy of their rituximab + ICE (R-ICE) regimen in 20 patients with R/R B-NHL and mature B-cell acute lymphoblastic leukemia (B-ALL), with a 60% CR/PR.16 Woessmann et al19 analyzed the 157 patients with R/R Burkitt lymphoma and Burkitt leukemia included in studies or registries of the Non-Hodgkin’s Lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) study group from Austria, the Czech Republic, Germany, and Switzerland between 1986 and 2016. The most common initial salvage regimens used were R-ICE; ifosfamide, carboplatin, idarubicin/mitoxantrone, paclitaxel, and rituximab (R-ICI/ICN); and rituximab, vincristine, idarubicin, ifosfamide, carboplatin, and dexamethasone (R-VICI). The 3-year survival rate was 11% ± 3% before 2000 to 27% ± 5% after 2000.
Consolidation with stem cell transplant is now considered the standard of care in patients with mature R/R B-NHL who can achieve a CR or PR.19–22
The ideal type of transplant, however, is not universally agreed upon. Although autologous stem cell transplantation (autoSCT) has historically been considered first-line therapy for children, adolescents, and young adults (CAYAs) with R/R B-NHL,21,22 a number of centers are now utilizing allogeneic stem cell transplantation (alloSCT) to capitalize on a graft-versus-lymphoma effect.23 There have also been several studies utilizing tandem autoSCT/alloSCT in adults with R/R NHL24–27 and one study in CAYAs.28 The latter study was conducted by our group as part of a prospective multicenter study and yielded a 70% EFS in patients with NHL who underwent sequential myeloablative autoSCT with subsequent alloSCT. Five of those patients had mature B-NHL. Our center combined the data of the 5 patients with R/R B-NHL with an additional 7 patients treated with the same regimen plus or minus the addition of radioimmunotherapy with ibritumomab tiuxetan and found that patients experienced an 83.3% EFS.29
Future Reinduction, Consolidation, and Maintenance Strategies
Novel agents with activity against B-NHL include antibody–drug conjugates (ADCs), monoclonal antibodies, checkpoint inhibitors, T-cell engagers, CAR-T-cells, CAR-natural killer (NK) cells, and cell signaling inhibitors. These agents are being incorporated into reinduction, consolidation and maintenance phases of therapy.
Antibody–Drug Conjugates
CD19, CD20, CD22, and CD79 A/B are B-cell markers and thus are highly expressed in all mature B-cell malignancies.30 CD38 is expressed highly in Burkitt lymphoma and is also expressed in non-Burkitt lymphoma NHL.31 CD30 is less uniformly expressed in B-NHL, though is expressed in a number of DLBCLs and variably in other B-NHLs, including Burkitt lymphoma.32
Loncastuximab tesirine is an ADC comprised of a humanized anti-CD19 antibody conjugated to SG3199, a pyrrolobenzodiazepine dimer cytotoxin.33 The safety and anticancer activity of loncastuximab tesirine in combination with gemcitabine, lenalidomide, polatuzumab vedotin, or umbralisib in patients aged >18 years with R/R B-NHL is currently being evaluated in a multiarmed phase Ib, multicenter study (LOTIS-7; ClinicalTrials.gov identifier: NCT04970901). It will also be used with modified R-ICE in treatment arm II of the Glo-BNHL trial (NCT05991388), which is not yet recruiting.34
Polatuzumab vedotin (PV) is an ADC comprised of a humanized anti-CD79b conjugated to monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor that precludes cell division.35 We have an open trial at our institution evaluating the safety and efficacy of post-autoSCT PV maintenance in patients aged ≥12 years with poor-risk and R/R B-NHL. Patients will receive a conditioning regimen consisting of either carmustine, etoposide, cytarabine, and melphalan, or cyclophosphamide, carmustine, and etoposide, and then undergo disease evaluation post-autoSCT. Patients with CR, PR, or stable disease will continue on to 8 cycles of PV maintenance with the first dose administered between days 30 to 60 post-autoSCT (NCT04491370).36
Zilovertamab vedotin (ZV) is a humanized ADC comprised of an ROR1 antibody conjugated to a MMAE. A recent phase I study of 32 adults with previously treated lymphoid malignancies demonstrated that 47% of patients with mantle cell lymphoma achieved a response, and 60% of the 5 patients with DLBCL achieved a response with dose-escalating ZV administered every 3 weeks until progression or unacceptable toxicity.37 There is a currently open phase II/III randomized multicenter trial for patients aged >18 years with R/R DLBCL to determine the safety and efficacy of ZV combined with standard of care options: (1) ZV in combination with R-GemOx (rituximab, gemcitabine, oxaliplatin) versus R-GemOx alone, and (2) ZV in combination with BR (bendamustine, rituximab) versus BR alone (NCT05139017).
Inotuzumab ozogamicin (InO) is an ADC comprised of a humanized anti-CD22 antibody linked to calicheamicin. A total of 79 adult patients with R/R NHL achieved a 39% ORR with InO monotherapy in a phase I trial.38 A randomized phase III study (NCT01232556) in 338 adults with R/R CD20+/CD22+ aggressive B-NHL who were not candidates for high-dose chemotherapy comparing R-InO with investigator’s choice rituximab + bendamustine or rituximab + gemcitabine revealed that there was no significant difference in progression-free survival (PFS) or OS.39 Patients who have received InO and proceed to hematopoietic SCT (HSCT) have a significant risk of sinusoidal obstructive syndrome of the liver.40 There is currently a multicenter phase I/II study using InO as maintenance post-HSCT in patients aged 16 to 75 years post-allogeneic HSCT for acute lymphoblastic leukemia or post-autologous HSCT for high-risk NHL (NCT03104491).
Monoclonal Antibodies
Minard-Colin et al9 recently published on the significant improvement in EFS and OS in CAYAs with high-grade, high-risk mature B-NHL achieved in the international study when rituximab was added to standard FAB chemotherapy versus FAB therapy alone, and consistent with the results of our 2 prior COG rituximab and FAB chemotherapy pilot trials.7,8 CAYAs with stage II and III B-NHL with low lactate dehydrogenase (≤2 × upper limit of normal) (good-risk group B) enjoyed a 100% EFS when treated with anthracycline dose-intensity reduction (50 mg/m2) and substitution with dose-dense rituximab, as we have recently reported.41 Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody specifically developed to overcome rituximab resistance,42 has demonstrated enhanced antibody-dependent cellular cytotoxicity to rituximab.43 We have an open trial at our center combining obinutuzumab and ICE (O-ICE) in CAYAs with R/R CD20+ mature NHL (ClinicalTrials.gov identifier: NCT02393157). The 6 patients enrolled thus far, all with Burkitt lymphoma, tolerated O-ICE well with no grade ≥3 adverse events, and 5 of the 6 patients were able to successfully proceed to HSCT.44 Tafasitamab, an Fc-modified humanized anti-CD19 monoclonal antibody, was proven to be safe and efficacious when added to R-CHOP in adults with newly diagnosed high-intermediate- and high-risk DLBCL45 and has been used in combination therapies as well.46 Daratumumab is a CD38 monoclonal antibody that is most commonly used for multiple myeloma. It has also been evaluated in pediatric patients with T-cell acute lymphoblastic leukemia, T-cell lymphoblastic lymphoma, and NK/T-cell lymphomas. CD38 is highly expressed on a subset of B-NHLs as well. A phase II study of daratumumab monotherapy in R/R mantle-cell lymphoma, DLBCL, and follicular lymphoma (FL) only demonstrated a 6.7% ORR.47 It should, however, be studied in combination therapy trials in patients with R/R B-NHL. In a recent ACCELERATE forum, naked monoclonal antibodies were not deemed to be the most promising agents in the R/R setting.48
Checkpoint Inhibitors
Many tumors harness the immune system’s mechanism of self-tolerance to actuate immune evasion. Checkpoint inhibitors restore T-cell–mediated immunity enabling antitumor response.
There are currently 10 immune checkpoint inhibitors approved by the FDA: (1) 4 anti–PD-1s: pembrolizumab, nivolumab, cemiplimab, and dostarlimab; (2) 3 anti–PD-L1s: atezolizumab, durvalumab, and avelumab; (3) 2 anti–CTLA-4s: ipilimumab and tremelimumab; and (4) 1 LAG-3 inhibitor approved in combination with nivolumab (for metastatic melanoma in children aged ≥12 years).49 PD-1 inhibition seems to be efficacious in particular subsets of NHL, including primary mediastinal B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, and Epstein Barr virus–positive lymphoma. ADVL1412 is a phase I/II study to determine safety, pharmacokinetics, and efficacy of nivolumab in CAYAs with recurrent or refractory, non-CNS solid tumors. In the NHL cohort, PD-L1 expression ranged from 1% to 100% of tumor cells in 8 of the 10 patients evaluated.50 Studies are ongoing to better delineate which patients will have optimal responses to checkpoint inhibitor therapy.51,52
T-Cell and NK-Cell Engagers
T-cell and NK-cell engagers are drugs with bispecific or trispecific binding sites to bring T cells or NK cells, respectively, together with their target on a malignant cell. Blinatumomab is a CD19 and CD3 bispecific antibody approved by the FDA for second-line treatment of R/R B-ALL and minimal residual disease in B-ALL. It has demonstrated activity in adults with R/R B-NHL with a median OS of 4.6 years and a median PFS of 6.7 months.53 Blinatumomab was successfully used as a bridge to transplant in 3 of 9 adults with R/R Burkitt lymphoma.54 Mosunetuzumab is a humanized CD20 and CD3 bispecific antibody. It was recently shown in a first-in-human single-agent trial to achieve durable responses with a low toxicity profile in adults with R/R B-NHL, with best ORR and CR rates in patients with aggressive B-NHL of 34.9% and 19.4%, respectively.55 There is an adult study underway using mosunetuzumab as consolidation post-autoSCT in patients with R/R aggressive B-NHL (ClinicalTrials.gov identifier: NCT05412290). There are no currently open or listed pediatric trials utilizing mosunetuzumab. Odronextamab, a fully humanized IgG4-based CD20 × CD3 bispecific antibody, demonstrated an ORR and CR of 53% in patients with DLBCL without prior CAR T-cell therapy who received doses of ≥80 mg, and an ORR of 33% and a CR of 27% in patients with prior CAR T-cell therapy.56 The only listed pediatric trial utilizing odronextamab is Regeneron’s compassionate use program for patients of all ages with R/R DLBCL or FL (NCT05619367). It will also be used in treatment arm I of Glo-BNHL (NCT05991388), which is not yet recruiting.34 Glofitamab, a CD20 × CD3 bispecific antibody with CD20 bivalency and CD3 monovalency, provided pretreated adults with R/R B-NHL who received the recommended phase II dose an ORR of 65.7% (57.1% of which were a CR). Of those patients who were in a CR, 84.1% were still in CR with a maximum of 27.4 months observation.57 Results of phase II of the phase I–II study were just published; 39% of patients achieved a CR with a median time to CR of 42 days and a PFS of 37%. Of the 52 patients who had prior CAR T-cell therapy, 35% attained a CR.58 There is a currently open phase I/II trial evaluating the safety and efficacy of glofitamab in combination with R-ICE in CAYAs (ages 6 months to 30 years) with R/R mature B-NHL (iMATRIX GLO; NCT05533775). Epcoritamab, a CD20 × CD3 bispecific antibody administered subcutaneously, provided patients who received the full dose in the phase I/II dose-finding study an ORR of 88%, with 38% achieving a CR with no grade ≥3 cytokine release syndrome (CRS) events and no dose-limiting toxic effects.59 There is an open trial in CAYAs aged 1 to 25 years with R/R B-NHL administering single-agent epcoritamab for up to 3 years (NCT05206357).
AFM13 is a CD16A × CD30 bispecific antibody that binds CD30+ malignant cells to NK cells. In a study of CD30 expression in pediatric neoplasms, variable CD30 staining was demonstrated in DLBCLs.60 A phase II trial using AFM13 monotherapy in patients with relapsed HL demonstrated an ORR of 16.7% and a 12-month PFS of 12.6%.61 There is a currently open trial for patients aged 15 to 75 years with R/R CD30+ Hodgkin lymphoma or NHL using AFM13 combined with modified umbilical cord blood NK cells (NCT04074746).
Chimeric Antigen Receptor Therapy (CAR-T and CAR-NK)
There are now 4 FDA-approved anti-CD19 CAR-T cell therapies for adults with R/R large B-cell lymphoma, FL, or mantle cell lymphoma based on the ZUMA-1, ZUMA-2, ZUMA-5, ZUMA-7, TRANSFORM, and TRANSCEND studies.62 Despite excellent response rates, approximately 60% of adults with R/R DLBCL treated with anti-CD19 CAR-T cells will experience relapse. Various strategies are now being trialed to increase efficacy and prevent relapse, including a combination of checkpoint inhibitors with CAR-T cells and multiple antigen targeting.63 Roddie et al64 described their experience using dual targeting CD19/CD22 CAR-T cells in patients with R/R B-cell lymphoma. These CARs ± pembrolizumab demonstrated durable remissions beyond 12 months in 54.4% of complete responders.
There are currently no FDA-approved CARs for pediatric B-NHL. Rivers et al65 reported early response data on 8 pediatric patients with R/R B-NHL (DLBCL, Burkitt lymphoma, gray zone B-cell lymphoma, and primary mediastinal B-cell lymphoma) aged 4 to 18 years who were treated with anti-CD19 CAR-T cells with an EGFR suicide construct. Although there were 2 patients who attained a CR, these responses were not durable. The BIANCA trial (ClinicalTrials.gov identifier: NCT03610724) is a phase II, single-arm, international trial to determine efficacy and safety of tisagenlecleucel in CAYAs (age <25 years) with R/R B-NHL that was completed this year with 33 patients enrolled. Preliminary results on 5 patients infused with tisagenlecleucel deemed the manufacture feasible with a manageable safety profile (no grade ≥3 CRS), though 1 patient did die of progressive disease.66 Liu et al67 evaluated the safety and feasibility of sequential disparate B-cell antigen–targeted CAR T-cell therapy for pediatric R/R Burkitt lymphoma. A total of 23 patients received the initial CD19 CAR T-cell infusion, with those who did not achieve an ongoing CR subsequently receiving ≥1 sequential infusions of CAR T-cell therapy that targeted CD22, followed by CD20 based on disease status and CAR T-cell persistence after each infusion. The 18-month PFS was an impressive 78% in patients with bulky disease and 60% in those with CNS involvement. There are a number of ongoing pediatric B-NHL CAR T-cell trials (Table 1).
CAR T-Cell Trials for Pediatric B-Cell Non-Hodgkin Lymphoma
CAR-NK cells are being studied as well in B-cell malignancies and have the potential to overcome some of the limitations associated with CAR-T cells68 (Table 2). Liu et al69 administered HLA-mismatched anti-CD19 cord blood–derived CAR-NK cells to 11 patients with R/R CD19-positive cancers (NHL or chronic lymphocytic leukemia). CAR-NKs were armed with interleukin-15 expression to enhance CAR expansion and persistence and an inducible caspase 9 safety switch. A total of 73% of patients attained a response and no patients experienced CRS, neurotoxicity, or graft-versus-host disease (GVHD). FT596 is a CAR-NK derived from induced pluripotent stem cells that also expresses a high-affinity, noncleavable CD16 and a recombinant fusion of IL-15 and IL-15 receptor alpha.70 It will be used in combination with rituximab or obinutuzumab for patients with R/R CLL or B-cell lymphoma in a phase I dose-finding study that is active though not yet recruiting (NCT04245722). CAR-NK cells lend themselves more feasibly to off-the-shelf options.
CAR-NK Cell Trials for NHL
Combining CAR-T and CAR-NK cell therapy with both autoSCT and alloSCT is an exciting prospect as well. There is an open phase I trial in adults with high-risk intermediate B-NHL who will undergo a myeloablative autoSCT per institutional standard followed by an infusion of CD19-CAR-specific/truncated EGFR lentiviral vector-transduced T cells on day 2 or 3 (NCT01815749). Brudno et al71 published their experience administering donor-derived anti-CD19 CAR-T cells to patients with B-cell malignancies who experienced relapse posttransplant. A total of 8 of 10 patients attained a remission post–CAR T-cell infusion, although the response rate was highest for patients with B-ALL. None of the patients experienced GVHD post CAR T-cells. Administration of donor-derived CAR-T cells could be a potential maintenance strategy for patients with B-NHL post-alloHSCT while awaiting immune reconstitution and consequent graft-versus-lymphoma effect.
Cell Signaling Inhibitors
Cell signaling inhibitors are now more commonly being incorporated in adult B-NHL trials. Ibrutinib, an oral covalent Bruton tyrosine kinase (BTK) inhibitor, has demonstrated significant activity in activated B-cell DLBCL and less activity in germinal center B-cell DLBCL. The second-generation BTK inhibitor acalabrutinib was recently studied in combination with a STAT3 inhibitor in adults with R/R DLBCL, with an ORR of 24%.72 The next-generation BTK inhibitor zanubrutinib proved to be tolerable in a majority of adults with treated B-cell malignancies unable to tolerate ibrutinib or acalbrutinib.73 Results of the global phase III SPARKLE trial, evaluating the addition of ibrutinib to R-ICE or R-VICI in pediatric patients versus R-ICE or R-VICI alone, demonstrated no EFS benefit with the addition of ibrutinib, as we previously reported.74 Lenalidomide, an oral immunomodulatory agent, has activity in DLBCL as well, with best ORRs of up to 28%.46,75 It has been shown to enhance the antibody-dependent cell-mediated cytotoxicity of rituximab and to have activity in CNS lymphoma.75 The RE-MIND study, comparing tafasitamab + lenalidomide (L-MIND) with a real-world lenalidomide monotherapy cohort in patients with R/R DLBCL ineligible for stem cell transplant, demonstrated a CR rate of 39.5% in the combination therapy arm versus 13.2% in the lenalidomide monotherapy group.46,76 Although lenalidomide has safety data in pediatrics, there are no current data for its use in pediatric B-NHL.
BCL2 overexpression is common in B-NHL, providing another target. Venetoclax is a selective potent BCL2 inhibitor that has activity in B-NHL.77 A novel phase I study design of venetoclax in R/R malignancies (ClinicalTrials.gov identifier: NCT03236857), including pediatric NHL, just completed, although no results are published yet. In this phase I multipart study, pediatric patients in the R/R NHL cohort in part 2 were planned to initially receive venetoclax monotherapy, and after the first assessment may receive venetoclax in combination with chemotherapy (rituximab and/or dexamethasone and/or vincristine) beginning week 4 (day 22).78 Bortezomib, a proteasome inhibitor that can suppress NF-κB activity, was recently demonstrated to improve PFS and OS when combined with R-CHOP in patients with activated B-cell DLBCL (OS, 67% with R-CHOP vs 80% with RB-CHOP) and patients with molecular high-grade DLBCL (5-year PFS, 29% with R-CHOP vs 55% with RB-CHOP).79 The COG did look at adding bortezomib to ifosfamide and vinorelbine (IVB) in pediatric patients with relapsed Hodgkin lymphoma, and although study accrual was suspended after 26 enrollments due to lack of efficacy in the interim monitoring, there did seem to be an improved OS of 91% after 2 to 4 cycles of IVB.80
Future Directions
In this age of bounty with myriad agents active against pediatric B-NHL, the path forward for CAYAs with R/R disease will lie in combination therapy tested in international collaborations, such as Glo-BNHL, given the mercifully small number of patients experiencing relapse.34 Incorporating biomarkers, circulating tumor DNA/cell-free DNA, and different pathways for different B-NHL subsets will play a vital role as well.
Acknowledgments
The authors thank Virginia Davenport, RN, for her excellent assistance in the preparation of this manuscript.
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