Abstract: Mature B-cell non-Hodgkin lymphomas (B-NHLs) comprise approximately 40% to 60% of all NHLs among children, adolescents, and young adults. Although overall survival with mature B-NHL approaches 90% in children younger than 15 years and 70% to 80% in adolescents and young adults, it is achieved with the use of intense therapeutic regimens, many of which lead to long-term effects that last for years after the patient’s initial diagnosis and treatment. Chronic health issues, poor performance outcomes, impaired quality of life, and decreased fertility have all been associated with mature B-NHL therapy. As the role of targeted therapy in this population is elucidated, data continue to show that it can be incorporated safely into chemotherapy backbones, allowing a decrease in cytotoxic chemotherapy doses. These trends support ongoing efforts to find innovative combinatorial strategies that integrate new cell surface targets and use new classes of drugs, such as monoclonal antibodies, antibody-drug conjugates, checkpoint inhibitors, T-cell and natural killer–cell engagers, and chimeric antigen receptor T-cell therapy.
Introduction
Mature B-cell non-Hodgkin lymphomas (B-NHLs) in children, adolescents, and young adults (CAYAs) consist mostly of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) and comprise approximately 40% to 60% of all NHLs in these age groups.1-3 BL is seen predominately in children younger than 15 years, and DLBCL occurs predominantly in CAYAs (15-39 years). The overall survival (OS) rates of patients with mature B-NHL approach 90% in children younger than 15 years and 70% to 80% in adolescents/young adults.1-3 These survival rates reflect the use of chemotherapy with or without radiotherapy without the use of targeted immunotherapy.
Unfortunately, although the survival rates in these patients are impressive, many people who receive intense therapy regimens experience adverse effects that persist for years after their initial diagnosis and treatment.4 A review of the existing literature regarding late effects in NHL survivors, including chronic health issues, poor performance outcomes, impaired quality of life, decreased fertility, and increased mortality, cited 2 separate reports showing that approximately two-thirds of survivors experienced at least one chronic health condition and that more than one-third had a life-threatening issue.5 When compared with community controls, NHL survivors experienced more than double the number of chronic health issues by age 50 years, the most common of which were hypertension, dyslipidemia, cardiac arrhythmias, peripheral nervous system disorders, and structural heart defects.5 The Childhood Cancer Survivor Study reported that among 23,601 childhood cancer survivors, the cumulative incidence of grade 3 to 5 health care conditions from 1990 to 1999 was 17.7% (95% CI, 15%-22.5%) in those with a history of NHL.6 These results emphasize that the significantly improved OS rates in CAYAs with NHL come at a significant cost of multiple chronic health conditions—most importantly, cardiovascular disease, neurocognitive deficits, and secondary malignancies—and a diminished health-related quality of life.6-17
Reassuringly, reports have shown that as the intensity of therapy has decreased over time, survivors of cancer have experienced fewer serious chronic health conditions, and mortality rates have also declined.6,18 Cairo and colleagues first reported on the safety and efficacy of short, intensive multiagent chemotherapy and involved-field cranial radiation (only for patients with central nervous system [CNS] disease) in patients with intermediate- or high-risk mature B-NHL, which produced a 2-year event-free survival (EFS) rate of 80%.19 The cumulative doses of doxorubicin in the intermediate- and high-risk groups were 180 and 240 mg/m2, respectively.19 The cumulative doses of cyclophosphamide in the intermediate- and high-risk groups were 5.8 and 6.8 g/m2, respectively.19,20 In an international cooperative group randomized study (FAB/LMB96) involving the Children’s Oncology Group (COG), French Society of Pediatric Oncology, and United Kingdom Children’s Cancer Study Group, Cairo and colleagues demonstrated significant reductions of cyclophosphamide in the intermediate-risk group B patients from 5.8 to 3.3 g/m2 and of doxorubicin from 180 to 120 mg/m2, with similar efficacy.21-23 These trends support ongoing efforts to find newer, innovative targeted therapies for mature B-NHL that will allow a decrease in cumulative chemotherapy and radiation exposure while superior survival is maintained. To decrease cytotoxic chemotherapy, innovative combinatorial strategies of multitarget treatment will need to be explored. Fortunately, mature B-NHL cells are known to have many surface proteins and signaling pathways, each ripe for targeting (Figure, Table).
Monoclonal Antibodies
Monoclonal antibodies are therapeutic agents that target the cell surface receptors on cancer cells. They either induce apoptosis directly and/or enhance antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity. Monoclonal antibodies have been used for both solid and hematologic cancers.24
Rituximab
Rituximab, an anti-CD20 monoclonal antibody, has become an integral component of therapy in B-NHL in adults, both as monotherapy and in combination with multiagent chemotherapy. Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody.25,26 After binding to CD20 on the B lymphocyte, rituximab causes cell death by means of one of the following 3 methods: (1) enhancing complement-dependent cytotoxicity; (2) enhancing antibody-dependent cellular toxicity; or (3) inducing apoptosis. A landmark paper published in The New England Journal of Medicine demonstrated clear efficacy when rituximab was used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy in elderly patients with DLBCL.27 This large multicenter trial employed the standard regimen, with rituximab at a dose of 375 mg/m2 administered on day 1 of each CHOP cycle for 8 cycles. The complete response (CR) rate for those who received rituximab was 76% and was 63% for those who did not. The 2-year OS rates were 70% and 57%, respectively.27
Rituximab therapy has also been used in the CAYA population through various COG studies. Cairo and colleagues found that variables such as advanced stage, elevated lactate dehydrogenase (LDH), presence of primary mediastinal B-cell lymphoma (PMBL), and combined bone marrow and CNS disease were associated with inferior survival.28 Following this report, the pilot study ANHL01P1 from the COG restricted eligibility to patients in French-American-British (FAB) group B who had advanced disease (stage III/IV) and FAB group C. Therapy consisted of FAB B4 or C1, as previously described, with the addition of rituximab. Rituximab was administered as 2 doses of 375 mg/m2 in each induction cycle and 1 dose of 375 mg/m2 in each consolidation cycle.21,23 The 3-year EFS rates were 95% (95% CI, 79%-98%) for all group B stage III/IV patients and 90% (95% CI, 75%-96%) for all group C patients.29
The larger Intergroup-COG phase 2 follow-up study randomized CAYAs with high-risk mature B-NHL to an FAB/LMB96 backbone with or without rituximab. The study closed early because interim results showed superiority of the rituximab regimen: a 1-year EFS rate of 94.2% for those who received rituximab vs 81.5% for those who received chemotherapy alone (hazard ratio [HR], 0.44; P=.006).30
The final analysis, published in The New England Journal of Medicine, showed similar results. The EFS rate was 93.9% (95% CI, 89.1%-96.7%) in those who received rituximab vs 82.3% (95% CI, 75.7%-87.5%) in the chemotherapy-alone group; the 3-year OS rate was 95.1% (95% CI, 90.5%-97.5%) in those who received rituximab vs 87.3% (95% CI, 81.2%-91.6%) in the chemotherapy-alone group.31 Given the overall improvement in EFS with the addition of rituximab to a standard chemotherapy backbone, the subsequent question would be whether it is possible to decrease the cumulative doses of upfront chemotherapy, thereby reducing the risk and occurrence of late effects.
In a recent study by Goldman and colleagues, anthracycline and several intrathecal (IT) chemotherapy doses were reduced and rituximab was added to FAB chemotherapy in group B low-risk patients (LDH <2 × the upper limit of normal [ULN]).32 In this study, rituximab was given as previously described, but the cumulative dose of doxorubicin was reduced from 120 to 50 mg/m2, and IT liposomal cytarabine was administered after systemic methotrexate clearance in each induction cycle, with the total number of IT injections reduced from 9 to 5. No serious adverse events were attributed to the protocol therapy among 19 patients (2 stage II and 17 stage III with LDH <2 × ULN).32 All patients completed therapy with no reported events, and the EFS rate was 100% at a median of 48 months (range, 12-84 months) from trial enrollment.32
Obinutuzumab
Obinutuzumab (Gazyva, Genentech) is a type II monoclonal antibody with greater antibody-dependent cellular cytotoxicity than that of rituximab, at least in xenograft models.26,33 It has been approved for therapy in chronic lymphoblastic leukemia (CLL) in combination with chlorambucil,34 and it has been used in patients with mature B-NHL, specifically adults with DLBCL, in a phase 3 study that randomized them to receive either obinutuzumab or rituximab with a CHOP backbone. The results showed similar outcomes, with 2-year EFS rates of 59.8% vs 56.6% (P=.123), respectively, and a 2-year progression-free survival (PFS) rate of 83.1% for the entire cohort. It was also noted that the patients in the obinutuzumab arm had more frequent grade 3 to 5 infections than did those in the rituximab arm (21% vs 12%); obinutuzumab was therefore determined not to be superior to rituximab.35
Obinutuzumab is also being trialed in pediatric patients with relapsed mature B-NHL. A current study has combined obinutuzumab with ifosfamide, carboplatin, and etoposide for patients with relapsed mature B-NHL. Thus far, reports have shown that of the 6 patients who were treated, 5 had an overall response that allowed them to proceed to hematopoietic stem cell transplant.36 This study is currently enrolling patients (NCT02393157).
Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) are a specific form of targeted therapy in which a monoclonal antibody is combined with a cytotoxic small molecule that can cause cell death following cell internalization.37
Polatuzumab Vedotin
Polatuzumab vedotin (PV; Polivy, Genentech) is an ADC that targets the surface antigen CD79b on human B cells.38,39 In addition to the humanized immunoglobulin G1 component, it includes an antimitotic agent, monomethyl auristatin E (MMAE). MMAE is known to inhibit cell division by blocking the polymerization of tubulin.38,40,41 PV was incorporated into phase 2 studies in combination with other chemotherapy agents, as well as rituximab, in patients with relapsed/refractory (R/R) DLBCL. Of the 39 patients enrolled on this arm of the study, 54% had an objective response, whereas 21% had a CR.40 Tilly and colleagues went on to show that PV was generally well tolerated; the most common adverse events were neutropenia, anemia, and diarrhea, with no grade 5 events.40 PV also has been used to treat de novo DLBCL. In a phase 3 study, adult patients with previously untreated DLBCL were randomized to receive PV plus rituximab (R)-CHP or R-CHOP. The 2-year PFS rate was significantly higher in the PV-R-CHP group (76.7%) than in the R-CHOP group (70.2%). The authors were also able to show that the safety profiles were similar in the 2 arms. They concluded that in patients with previously untreated intermediate- or high-risk DLBCL, the substitution of PV in place of vincristine resulted in a lower risk for disease progression, relapse, or death.42 PV is also being trialed in upfront therapy for newly diagnosed mature B-NHL. In the recently opened RADICAL study, the investigators are enrolling pediatric and adolescent/young adult patients with intermediate- or high-risk mature B-NHL to a protocol that adds targeted immunotherapy with PV to FAB/LMB96 chemotherapy with rituximab, while also decreasing anthracycline doses (NCT05253495).43
Loncastuximab Tesirine
Loncastuximab tesirine (Zynlonta, ADC Therapeutics) is an ADC that targets CD19. It is made up of a humanized anti-CD19 monoclonal antibody linked to a pyrrolobenzodiazepine dimer toxin, SG3199, via a cathepsin-cleavable valine-alanine linker.44,45 The drug works by first binding to CD19, after which it is internalized. Once inside the cell, the pyrrolobenzodiazepine dimer toxin is released following cleavage of the linker, so that it can form DNA crosslinks that ultimately lead to apoptosis of the cell.45 Early phase 1 studies determined the dosing of this medication but were also able to report response rates. Among the 183 patients in the study, the overall response rate (ORR) was 45.6%, with 26.7% of the responses CRs.44 Among the patients with DLBCL, the ORR was 42.3%.44 These results led to a phase 2 study, LOTIS-2, in which loncastuximab was administered to patients with pretreated R/R DLBCL.45 At a median follow-up of approximately 8 months, the ORR was 48.3%, with 24.8% of the responses CRs. Among those in CR, the 2-year OS and PFS rates were 68.2% and 72.5%, respectively.45 A follow-up study, LOTIS-3, added ibrutinib (Imbruvica, Pharmacyclics/Janssen) to loncastuximab in 35 patients with R/R DLBCL and showed an ORR of 57.1%, with 34.3% of the responses CRs.46 Finally, the phase 3 LOTIS-5 study, which is currently open, will randomize patients with R/R DLBCL to receive loncastuximab combined with rituximab or immunochemotherapy including rituximab, gemcitabine, and oxaliplatin (NCT04384484). Loncastuximab is being utilized in CAYA patients with R/R B-NHL in combination with modified rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE) in the currently recruiting treatment arm II of Glo-BNHL (NCT05991388).47
Brentuximab Vedotin
Brentuximab vedotin (BV; Adcetris, Seagen) is an ADC that targets CD30. It is composed of a monoclonal antibody component, anti-CD30, coupled with MMAE, a cytotoxic microtubule-disturbing agent, via a protease cleavable linker.48,49 BV has been used for the last few decades, but most of the data for this drug have been obtained in patients with Hodgkin lymphoma (HL) or anaplastic large cell lymphoma. Trials that incorporated BV into frontline pediatric therapies for HL (COG AHOD1331) showed superiority in the BV arm compared with the standard of care, with EFS rates of 92.1% vs 82.5%, respectively.50 With the large success of the addition of BV in HL, groups began to investigate whether CD30 might be a target in other types of lymphoma. Slack and colleagues published work showing that of the 385 cases of de novo DLBCL they studied, 95 (25%) expressed CD30, making it a potential target in this population of patients.51 Results from the ECHELON-3 study showed statistically significant improvements in PFS and OS with BV plus lenalidomide and rituximab vs placebo plus lenalidomide and rituximab.52 This finding ultimately led to approval of the combination by the US Food and Drug Administration (FDA) for patients who have R/R DLBCL after failure of 2 previous forms of therapy and are ineligible for autologous hematopoietic stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy.
Zilovertamab Vedotin
Zilovertamab vedotin is an ADC specifically targeting the receptor tyrosine kinase–like orphan receptor 1 (ROR1).53,54 The drug consists of a monoclonal antibody, a cleavable linker, and MMAE.54 Much of the research with this medication has been done in mantle cell lymphoma, but a 35-person phase 1 study by Wang and colleagues included 5 patients with DLBCL.54 Of the 5 evaluable patients with DLBCL, 3 had an objective tumor response—specifically, 1 partial response and 2 CRs. These results have led to the incorporation of this drug into several other studies, including the phase 1/2 LIGHTBEAM-U01 substudy 01A evaluating the safety and efficacy of zilovertamab vedotin for CAYA patients with hematologic or solid tumors (NCT06395103). The phase 2 waveLINE-004 study is looking specifically at patients with R/R DLBCL and will also evaluate efficacy and safety (NCT05144841).
Checkpoint Inhibitors
Checkpoint inhibitors are monoclonal antibodies that target checkpoint proteins to restore T-cell–mediated immunity, thereby enhancing antitumor response.55
Programmed Death 1
The inhibition of programmed death 1 (PD-1) has proved effective in certain subsets of NHL, including Epstein-Barr virus–positive lymphoma, T-cell/histiocyte–rich large B-cell lymphoma, and PMBL. In the open-label, multicenter phase 1/2 CheckMate 436 study, administration of the combination of nivolumab (Opdivo, Bristol Myers Squibb) plus brentuximab to patients at least 15 years of age with R/R PMBL led to an ORR of 73.3%.56 Nivolumab has been reported to have only modest efficacy in patients with DLBCL that failed to respond to or who were ineligible for autologous stem cell transplant (ORRs of 10% and 3%, respectively).57 In the phase 1/2 study ADVL1412, which was designed to determine safety, pharmacokinetics, and efficacy in CAYAs with R/R non-CNS solid tumors, programmed death ligand 1 (PD-L1) expression ranged from 1% to 100% of tumor cells in 8 of the 10 patients evaluated in the NHL cohort.58
Relatlimab
Relatlimab is a checkpoint inhibitor that targets LAG3, thereby reducing LAG3-mediated immune response inhibition. Relatlimab combined with nivolumab (Opdualag, Bristol Myers Squibb) augments the antitumor immune response via dual checkpoint blockade with increased T-cell proliferation and cytokine secretion. This combination has been effective in patients with melanoma59 and is currently being trialed in a phase 1/2 study of CAYA patients with R/R HL or NHL (NCT05255601). Ongoing studies are looking to identify those patients who will have optimal responses to checkpoint inhibitor therapy.60,61
T-Cell and NK-Cell Engagers
T-cell and natural killer (NK)–cell engagers have bispecific or trispecific binding sites that bring T cells or NK cells to their target on a malignant cell to attack the malignant cell in a manner that does not depend on the major histocompatibility complex (MHC).
CD19-Targeting Agent
Blinatumomab. Blinatumomab (Blincyto, Amgen) is a CD19- and CD3-targeting bispecific antibody approved by the FDA for the second-line treatment of R/R precursor B-cell acute lymphocytic leukemia (pre-B-ALL), for measurable residual disease in pre-B-ALL, and most recently for the consolidation phase of multiphase chemotherapy for patients with Ph-negative pre-B-ALL. The drug has demonstrated activity in adults with R/R B-NHL (median OS of 4.6 years and median PFS of 6.7 months).62 Blinatumomab also achieved an ORR of 37% in patients with R/R B-NHL when it was administered in a stepwise 70-day cycle (9, then 28, then 112 μg/d) and an optional second 28-day cycle.63 In addition, it has been used as a bridge to transplant in 3 of 9 adults with R/R BL.64
CD20-Targeting Agents
Epcoritamab. Epcoritamab (Epkinly, Genmab/AbbVie) is a subcutaneously administered CD20×CD3 bispecific antibody. A phase 1/2 dose-finding study demonstrated an ORR of 88% in patients who received the full dose, with a CR achieved in 38%, no grade 3 or higher cytokine release syndrome (CRS) events, and no dose-limiting toxic effects.65 Long-term follow-up of this study recently reported an ORR of 63.1% and a CR rate of 40.1%.66 An open trial is using single-agent epcoritamab for up to 3 years in CAYAs aged 1 to 25 years with R/R B-NHL (NCT05206357).
Glofitamab. Glofitamab (Columvi, Genentech) is a CD20×CD3 bispecific antibody with CD20 bivalency and CD3 monovalency. Pretreated adults with R/R B-NHL who received the recommended phase 2 dose of glofitamab attained an ORR of 65.7%, and 57.1% of the responses were CRs. Most of the patients (84.1%) who at first were in CR were still in CR after a maximum of 27.4 months of observation.67 More than one-third of the patients (39%) achieved a CR, with a median time to CR of 42 days and a PFS rate of 37%. Of the 52 patients who had prior CAR T-cell therapy, 35% attained a CR.68 Real-world data were consistent with these results and reported that the ORR in 70 patients with R/R DLBCL was 47%, with a CR rate of 27% in this multinational study.69 The currently open phase 1/2 iMATRIX GLO trial in CAYAs aged 6 months to 30 years with R/R mature B-NHL is evaluating the safety and efficacy of glofitamab in combination with R-ICE (NCT05533775).
Mosunetuzumab. Mosunetuzumab (Lunsumio, Genentech) is a humanized CD20 and CD3 bispecific antibody. This drug, in a first-in-human phase 1/2 single-agent dose escalation trial in adults with R/R B-NHL, was shown to produce an ORR of 36.4% with a low toxicity profile.70 An ongoing adult study is using mosunetuzumab as consolidation after autologous stem cell transplant in patients with R/R aggressive B-NHL (NCT05412290).
Odronextamab is a fully humanized IgG4-based CD20×CD3 bispecific antibody. In patients who had DLBCL without prior CAR T-cell therapy and received doses of 80 mg or higher, the ORR and the CR rate were 53%. In patients who had DLBCL with prior CAR T-cell therapy and received doses of 80 mg or higher, the ORR was 33% and the CR rate was 27%.71 Odronextamab is being used in CAYA patients with R/R B-NHL in the currently recruiting treatment arm I of Glo-BNHL (NCT05991388).47
CD30-Targeting Agent
AFM13. AFM13 is a CD16A×CD30 bispecific antibody that binds NK cells to CD30-positive malignant cells. Variable CD30 staining was demonstrated in DLBCLs in a study of CD30 expression in pediatric neoplasms.72 A phase 2 trial in which AFM13 monotherapy was used in patients with relapsed HL demonstrated an ORR of 16.7% and a 12-month PFS rate of 12.6%.73 Currently, an open although not yet recruiting phase 1/2 trial for patients 15 to 75 years old with R/R CD30-positive HL or NHL is using AFM13 in combination with modified umbilical cord blood NK cells (NCT04074746).
Chimeric Antigen Receptor Therapy (T-Cell and NK-Cell)
CAR cells are cells engineered from a patient’s own T cells to express a synthetic receptor that targets tumor antigens in a non–MHC-dependent manner. These cells then expand in vivo to provide short- and long-term disease control.
CD19-Targeting Agents
The ZUMA-1, ZUMA-2, ZUMA-5, ZUMA-7, TRANSFORM, and TRANSCEND studies led to FDA approval of 4 anti-CD19 CAR T-cell therapies for adults with R/R large B-cell lymphoma, follicular lymphoma, or mantle cell lymphoma.74 Despite excellent response rates, approximately 60% of adults with R/R DLBCL treated with anti-CD19 CAR T-cell therapy will experience relapse. Disparate strategies that include using armored CARs, combining checkpoint inhibitors with CAR T-cell therapy, and targeting multiple antigens are now being trialed to increase efficacy and prevent relapse.75 Off-the-shelf allogeneic CAR T-cell therapy with the use of clustered regularly interspaced short palindromic repeats (CRISPR) editing is being trialed as well.76
Currently, no CARs for pediatric B-NHL are approved by the FDA. Numerous challenges, including financial and regulatory challenges, account for the lack of approval. An average vein-to-vein time of 3 to 6 weeks is often too long and unfeasible for CAYAs with aggressive mature B-NHL.77 ACCELERATE, an international organization with multiple stakeholders, facilitates interaction among academia, industry, patient advocates, and regulators to advance the timely investigation of new anticancer drugs for children and adolescents. At their most recent meeting, participants discussed a number of these challenges as well as potential solutions, such as new academic and biopharma hybrid development models, the decentralization of manufacturing, and the coordination of early development models to avoid often-duplicative efforts.78
ZUMA-4 evaluated the safety and efficacy of brexucabtagene autoleucel (Tecartus, Kite Pharma) in patients aged 21 years or younger with R/R B-ALL or R/R B-NHL, with results pending. Rivers and colleagues reported early response data on 8 pediatric patients with R/R B-NHL (DLBCL, BL, gray zone B-cell lymphoma, or PMBL) aged 4 to 18 years who were treated with anti-CD19 CAR T-cell therapy with an epidermal growth factor receptor (EGFR) suicide construct, and only 2 patients attained a CR that was not durable.79 The BIANCA trial (NCT03610724), a single-arm, international phase 2 trial to determine the efficacy and safety of tisagenlecleucel (Kymriah, Novartis) in CAYAs (<25 years old) with R/R B-NHL, enrolled 33 patients. Preliminary results on 5 patients infused with tisagenlecleucel deemed the agent feasible, with a manageable safety profile (no grade >3 CRS). One of these 5 patients did die of progressive disease.80
Donor-derived CAR T-cell therapy might be a maintenance strategy for patients with B-NHL after allogeneic hematopoietic stem cell transplant while they await immune reconstitution and consequent graft-versus-lymphoma effect, and it has been used in the setting of relapse after transplant. Among 20 patients with B-cell malignancies who experienced relapse after allogeneic transplant, 8 attained a remission with donor-derived anti-CD19 CAR T-cell therapy, although the response rate was highest for patients with B-ALL. None of these patients experienced graft-versus-host disease after CAR T-cell therapy.81
CAR NK-cell therapy also is being studied in B-cell malignancies and has the potential to overcome some of the limitations associated with CAR T-cell therapy, including the development of an off-the-shelf product.82 Cord blood–derived NK cells expressing anti-CD19 CAR and interleukin 15 (IL-15) to enhance CAR expansion and persistence were safely administered to 37 patients aged 8 to 70 years with CD19-positive B-cell malignancies in a recent phase 1/2 trial, and 1-year OS and PFS rates of 68% and 32%, respectively were attained.83 HLA-mismatched, anti-CD19, cord blood–derived CAR NK cells armed with IL-15 and an inducible caspase 9 safety switch were administered safely to 11 patients who had R/R CD19-positive cancers (NHL or CLL), with 73% of patients attaining a response and no patients experiencing graft-versus-host disease, CRS, or neurotoxicity.84 FT596 is a CD19 CAR NK-cell product 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.85 It was used in combination with rituximab or obinutuzumab to treat patients with R/R CLL or B-cell lymphoma in a dose-finding phase 1 study that has been terminated; results are pending (NCT04245722). The phase 1 ANCHOR trial is recruiting patients aged 3 to 75 years with R/R B-cell malignancies for treatment with allogeneic NK T-cell therapy expressing a CD19-specific CAR and IL-15. Patients in the aggressive or highly aggressive lymphoma arm of the non-ALL cohort must have experienced R/R disease after 2 or more lines of therapy, including a CD20 antibody and an anthracycline, and must be ineligible for autologous stem cell transplant (NCT03774654).
CD22-Targeting Agents
A phase 1 dose-finding study of CD22 CAR T-cell therapy in patients with large B-cell lymphoma who either had experienced relapse after CD19 CAR T-cell therapy or had CD19-negative lymphoma demonstrated a promising ORR of 66% and a CR rate of 52% at the recommended phase 2 dose.86 PLAT-07 is an ongoing multicenter phase 1/2 trial utilizing SCRI-CAR22v2 in patients 0 to 30 years of age with refractory or recurrent CD22-positive leukemia or lymphoma (NCT04571138). An ongoing phase 2 trial in adults is evaluating the safety and efficacy of CRG-022 at a dose of 1×106 CAR+ T cells per kilogram in patients with R/R LBCL whose disease has progressed after CD19 CAR T-cell therapy (NCT05972720).
CD19-, CD20-, and CD22-Targeting Agents (Dual and/or Sequential Targeting)
Dual-targeting CD19/CD22 CAR T-cell therapy with and without pembrolizumab was trialed in patients who had R/R B-cell lymphoma and demonstrated durable remissions beyond 12 months in 54.4% of complete responders.87
The safety and feasibility of sequential disparate B-cell antigen–targeted CAR T-cell therapy for pediatric R/R BL were evaluated as well. A total of 23 patients received the initial CD19 CAR T-cell infusion; those who did not achieve an ongoing CR subsequently received 1 or more sequential infusions of CAR T-cell therapy targeting CD22 followed by CD20 according to disease status and CAR T-cell persistence after each infusion. The 18-month PFS rate was a promising 78% in patients with bulky disease and was 60% in those with CNS involvement.88
CD70-Targeting Therapy
CD70 is a type 2 transmembrane glycoprotein that is highly expressed in myriad tumors, including hematologic malignancies. The combination of fourth-generation CD19-targeting CAR T-cell therapy and fourth-generation CD70-targeting CAR T-cell therapy attained a CR in an adult with R/R primary CNS lymphoma.89 A CD70-targeting fourth-generation IL-15–secreting CAR showed promise against CD19-negative B-cell lymphoma in vitro and in vivo in preclinical studies.90 St. Jude is currently enrolling pediatric patients aged 21 years or younger in their DIRECT70 trial, which is using a CD70-targeting CAR T-cell treatment for patients with CD70-positive hematologic malignancies who are CD19-negative or for whom a CD19-targeting CAR T-cell therapy is not available (NCT06326463).
Pediatric trials are needed that incorporate CAR T-cell/NK-cell therapy in the upfront setting for certain high-risk patients, thereby potentially preventing relapse and toxicities caused by multiple lines of cytotoxic chemotherapies, as was done in the ZUMA-12 trial for adults with high-risk large B-cell lymphoma.91
Conclusion
Many targeted therapies are available for mature B-NHL, although many have yet to be approved in pediatrics. Given the poor survival of patients with R/R disease, studies in these patients are being conducted with caution. Although targeted therapies, such as PV, are slowly being approved for the upfront treatment of adult B-NHL, the process is much slower in pediatrics. More studies, such as the RADICAL study mentioned earlier, are needed that incorporate targeted therapies in the upfront management of pediatric mature B-NHL. The goal of these studies is to improve outcomes and reduce cytotoxic chemotherapy, thereby minimizing the most toxic side effects and late effects of therapy. Given the thankfully small number of patients with R/R disease, international collaborative efforts such as Glo-BNHL, a prospective international multicenter platform clinical trial designed to evaluate the efficacy and safety of the most promising novel agents as monotherapy or in combination with existing therapies, are required.47 The horizon remains bright for CAYAs with mature B-NHL and may one day hold promise of a chemotherapy-free regimen of targeted therapy and an even further reduction in R/R disease.
Disclosures
Dr. Cairo serves as a consultant for Jazz Pharmaceuticals and AbbVie; is a member of the speakers’ bureau of Jazz Pharmaceuticals and Amgen; and receives research funding from Jazz Pharmaceuticals, AbbVie, Merck, Miltenyi Biotec, Servier, Omeros, and Janssen. Drs. Audino and Gardenswartz have no disclosures.
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