Primary mediastinal B-cell lymphoma (PMBCL) is a rare but aggressive mature B-cell lymphoma arising from thymic B cells. Although previously thought to be a subtype of diffuse large B-cell lymphoma (DLBCL), it exhibits clinicopathologic characteristics that have led to its recognition as a distinct entity by the WHO.1 PMBCL represents approximately 2% to 4% of non-Hodgkin lymphoma, with a predominance among females.2 PMBCL exhibits a number of clinical and biologic characteristics that are similar to classic Hodgkin lymphoma (cHL), including a peak incidence in adolescents and young adults, presentation as a mediastinal mass, alterations in nuclear factor-κB (NF-κB) and JAK/STAT signaling, and upregulation of PD-L1. This review discusses the biology, diagnosis, and treatment of PMBCL in children and young adults and summarizes future directions to advance outcomes in this distinct lymphoma subtype.
Biology of PMBCL
The morphologic and immunophenotypic appearance of PMBCL in children is similar to that observed in adult patients.3 The neoplastic cells in PMBCL are large with round to oval hyperchromatic or vesicular nuclei and scant to abundant pale cytoplasm. The infiltrate is diffuse, but often the cells are compartmentalized by fine to dense fibrous tissue (Figure 1A). Commonly, a subset of the lymphoma cells are pleomorphic and may resemble Reed-Sternberg cells. The neoplastic cells express pan-B-cell markers (CD20, CD79a, CD19) as well as transcriptional regulators of the B-cell program (BOB.1, PU.1, OCT-2, PAX5, BCL6, MUM1/IRF4).3 CD30 and CD23 are expressed in 77% and 67%, respectively, of childhood cases of PMBCL. However, the CD30 expression by the neoplastic PBMCL cells, in contrast to that seen on Reed-Sternberg cells in cHL, is heterogenous and relatively dim3 (Figure 1B). PMBCL is associated with a variety of genetic abnormalities, including gains/amplifications at chromosome 9p24.1, including the JAK2/PDCD1LG2/PDCD1LG1 locus, which is seen in most cases and can be identified by karyotyping (Figure 2).
Histology and immunophenotype of primary mediastinal large B-cell lymphoma. (A) The neoplastic cells are large with clear-to-eosinophilic cytoplasm. There is a diffuse pattern, usually with compartmentalization of the tumor cells by relatively delicate fibrous bands (hematoxylin-eosin, original magnification ×20). (B) The neoplastic cells are of B-cell origin based on expression of pan-B-cell markers, such as CD20; they lack expression of T-cell markers, such as CD3. The neoplastic B cells, such as in this case, are usually CD10-negative, BCL6-positive, and MUM1-positive, consistent with a nongerminal center origin. However, CD10 expression, in contrast to this case, can be seen in a minority of instances. The tumor cells are usually CD23-positive, exhibit dim heterogeneous expression of CD30, and are positive for PD-L1 and PD-L2 (latter not shown). The proliferation rate (Ki67) is variable but is usually high (immunoperoxidase, original magnification ×20).
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Histology and immunophenotype of primary mediastinal large B-cell lymphoma. (A) The neoplastic cells are large with clear-to-eosinophilic cytoplasm. There is a diffuse pattern, usually with compartmentalization of the tumor cells by relatively delicate fibrous bands (hematoxylin-eosin, original magnification ×20). (B) The neoplastic cells are of B-cell origin based on expression of pan-B-cell markers, such as CD20; they lack expression of T-cell markers, such as CD3. The neoplastic B cells, such as in this case, are usually CD10-negative, BCL6-positive, and MUM1-positive, consistent with a nongerminal center origin. However, CD10 expression, in contrast to this case, can be seen in a minority of instances. The tumor cells are usually CD23-positive, exhibit dim heterogeneous expression of CD30, and are positive for PD-L1 and PD-L2 (latter not shown). The proliferation rate (Ki67) is variable but is usually high (immunoperoxidase, original magnification ×20).
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Histology and immunophenotype of primary mediastinal large B-cell lymphoma. (A) The neoplastic cells are large with clear-to-eosinophilic cytoplasm. There is a diffuse pattern, usually with compartmentalization of the tumor cells by relatively delicate fibrous bands (hematoxylin-eosin, original magnification ×20). (B) The neoplastic cells are of B-cell origin based on expression of pan-B-cell markers, such as CD20; they lack expression of T-cell markers, such as CD3. The neoplastic B cells, such as in this case, are usually CD10-negative, BCL6-positive, and MUM1-positive, consistent with a nongerminal center origin. However, CD10 expression, in contrast to this case, can be seen in a minority of instances. The tumor cells are usually CD23-positive, exhibit dim heterogeneous expression of CD30, and are positive for PD-L1 and PD-L2 (latter not shown). The proliferation rate (Ki67) is variable but is usually high (immunoperoxidase, original magnification ×20).
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Karyotype of primary mediastinal large B-cell lymphoma. The red arrow indicates amplification at chromosome 9p24.1, which includes the JAK2/PDCD1LG2/PDCD1LG1 locus. (Courtesy of Susan Mathew, PhD, Cytogenetics Laboratory, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York.)
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Karyotype of primary mediastinal large B-cell lymphoma. The red arrow indicates amplification at chromosome 9p24.1, which includes the JAK2/PDCD1LG2/PDCD1LG1 locus. (Courtesy of Susan Mathew, PhD, Cytogenetics Laboratory, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York.)
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Karyotype of primary mediastinal large B-cell lymphoma. The red arrow indicates amplification at chromosome 9p24.1, which includes the JAK2/PDCD1LG2/PDCD1LG1 locus. (Courtesy of Susan Mathew, PhD, Cytogenetics Laboratory, Weill Cornell Medicine/New York Presbyterian Hospital, New York, New York.)
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Genomics of PMBCL
PMBCL is distinct from other subtypes of DLBCL in terms of clinical and immunophenotypic characteristics. Genomic and molecular studies have further confirmed its standing as a distinct entity, but have also shown several commonalities with cHL,4,5 suggesting a relationship between these 2 entities.
Early efforts to characterize PMBCL through gene expression profiling identified common gains or amplifications involving 2p16 (REL/BCL11A, 41%) and 9p24 (JAK2/PD-L2, 59%).3 Similar to what has been observed for cHL, more extensive genomic analyses identified recurrent driver mutations leading to constitutive activation of oncogenic signaling via NF-κB (TNFAIP3, NFKBIE, NFKB2, IKBKB) and JAK/STAT (STAT6, PTPN1 IL4R, JAK1, CISH).4,6–8 Also similar to cHL, multiple studies have identified recurrent amplifications involving 9p24.1 resulting in overexpression of PD-L1, and thereby promoting an immune evasion phenotype in PMBCL.9,10 This phenotype was further highlighted by studies identifying genomic alterations in B2M, CIITA, CD58, CD274, PDCD1LG2, which have direct roles in major histocompatibility complex (MHC) expression/stability, NK interaction, and T-cell–mediated immune responses.4 Chapuy et al6 identified several genomic alterations more common to PMBCL relative to cHL, impacting epigenetic modifiers (ZNF217, EZH2), transcription factors (PAX5, IRF2BP2), and TP53. Overall, these findings have driven efforts to overcome the immune evasion capabilities of these tumors through inhibition of the PD-1/PD-L1 pathways in addition to other immunotherapeutics aimed at enhancing T-cell–mediated killing.
Initial Presentation and Diagnostic Workup
Patients typically present with symptoms related to bulky, localized mediastinal masses, which also frequently directly involve the chest wall, lung, pleura, or pericardium. Many patients also have associated pleural or pericardial effusions. Involvement of the bone marrow or central nervous system (CNS) at initial presentation are uncommon.11,12 Elevated levels of lactate dehydrogenase and overt B symptoms are observed in a subset of patients.11,12 For histologic diagnosis, an excisional biopsy is preferred but is often not feasible because patients can present with respiratory and cardiac compromise. In this setting, an image-guided percutaneous needle biopsy is also appropriate. Staging workup should include a baseline FDG-PET/CT (Figure 3). Bilateral bone marrow biopsy and lumbar puncture should also be considered. Workup and staging should be expedited to allow for rapid initiation of therapy, because patients can present with a significant burden of disease. Staging for PMBCL varies between pediatric and adult practices and must be considered when interpreting data across age groups. Use of the St. Jude NHL staging classification system13 is common practice among many pediatric groups, whereas the Lugano staging classification system is commonly used in adults.14 More recently, an international multidisciplinary panel developed a revised international pediatric NHL staging system (IPNHLSS) and response criteria to address staging and response of distinct pediatric histologic entities with considerations for contemporary molecular diagnostics and advanced imaging.15,16
FDG-PET/CT of a pediatric patient with primary mediastinal large B-cell lymphoma. Fused (A) coronal and (B) axial views. Images obtained with patient consent.
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
FDG-PET/CT of a pediatric patient with primary mediastinal large B-cell lymphoma. Fused (A) coronal and (B) axial views. Images obtained with patient consent.
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
FDG-PET/CT of a pediatric patient with primary mediastinal large B-cell lymphoma. Fused (A) coronal and (B) axial views. Images obtained with patient consent.
Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2023.7004
Clinical Management of Adult Patients With PMBCL
There is no single standard of care for adults with PMBCL. Most approaches include rituximab combined with an anthracycline-containing regimen ± radiation therapy (RT) (Table 1). The most common chemotherapy regimens used in the United States are R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) and dose-adjusted (DA) EPOCH-R (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin/rituximab). R-CHOP has historically been given in combination with RT; however, recent approaches have sought to reduce exposure to RT given the risk for long-term toxicity. Outcomes in prospective trials evaluating R-CHOP ± RT have demonstrated progression-free survival (PFS) ranging from 78% to 84%.17–20 A single-center phase II trial of DA-EPOCH-R without RT conducted in adults with PMBCL demonstrated excellent outcomes (3-year PFS, 93%).21 A retrospective multicenter analysis of DA-EPOCH-R demonstrated a 3-year event-free survival (EFS) of 87%.12 Caution should be taken in comparing outcomes across trials, however, and there have been no randomized phase III trials in PMBCL comparing R-CHOP and DA-EPOCH-R.
Summary of Up-Front Therapies in Adult Patients With PMBCL
Clinical Management in Pediatric Patients
Data specific to pediatric patients with PMBCL treated on prospective trials is limited because patients with PMBCL have historically been treated on the same trials as those with Burkitt lymphoma and DLCBL, which are more common diagnoses in children. A summary of the outcome data for pediatric patients with PMBCL treated on various regimens is provided in Table 2. Seidemann et al22 evaluated a subset of 30 pediatric patients with PMBCL treated on consecutive trials of the NHL-Berlin-Frankfurt-Münster (NHL-BFM) Study Group from 1886 to 1999 and reported a probability of EFS of 0.7. A similar analysis was performed on patients enrolled on FAB/LMB96. Among 42 patients with mediastinal large B-cell lymphoma treated on that prospective trial, the 5-year EFS was 66% (95% CI, 49%–78%), which was inferior compared with the 5-year EFS in patients with DLBCL on the same trial (85%; 95% CI, 71%–92%; P≤.001).23
Summary of Studies in Pediatric Patients With PMBCL
Following the promising results of the NCI phase II trial of DA-EPOCH-R in adults with PMBCL, this regimen has been evaluated in pediatric patients.21 A single-arm, prospective, international phase II trial of DA-EPOCH-R was conducted, enrolling children aged ≤18 years with PMBCL. In total, 46 patients with a median age of 15.6 years were enrolled, with a 4-year EFS of 69.6% (95% CI, 55.2%–80.9%) and overall survival (OS) of 84.8% (95% CI, 71.8%–92.4%).11 These outcomes were not different when compared with historic outcomes in pediatric patients treated on traditional NHL chemotherapy regimens. In a multi-institutional retrospective analysis evaluating the use of DA-EPOCH-R, 38 pediatric patients (median age, 16 years) were reported with a 3-year EFS of 81.0%. A comparison with the EFS among adult patients (n=118) did not demonstrate a statistical difference (3-year EFS, 87.4%; P=.338).12
More recently, the NHL-BFM Study Group reported outcomes of pediatric patients with PMBCL treated on the 3 trials: NHL-BFM 95, which used B-NHL–type combination chemotherapy (n=52); B-NHL-BFM-04, which included intensified B-NHL therapy (n=29) and later DA-EPOCH-R (n=16); and the NHL-BFM Registry 2012 on which patients were treated with DA-EPOCH-R (n=52). Treatment with DA-EPOCH-R resulted in superior outcomes (5-year EFS, 84%; 95% CI, 72%–91%) compared with intensified B-NHL therapy on B-NHL-BFM-04 (5-year EFS, 59%; 95% CI, 39%–74%; P=.016) and B-NHL therapy on the NHL-BFM 95 trial (5-year EFS, 39%; 95% CI, 19%–60%; P≤.001).24
Dourthe et al25 reported on the recent French experience on the LMB2001 trial, which treated patients with 4 to 8 cycles of Lymphomes Malins B (LMB)–based chemotherapy without RT. A total of 42 patients were enrolled with a median age of 15 years (range, 8–18 years), with 21 receiving rituximab. The 5-year EFS and OS for the entire cohort was 88.1% (95% CI, 75.0%–94.8%) and 95.2% (95% CI, 84.0%–98.7%), respectively, with a trend toward a superior outcome in patients receiving rituximab (5-year EFS, 81.0% [95% CI, 60.0%–92.3%] vs 95.2% [95% CI, 77.3%–99.2%]; hazard ratio, 0.24; 95% CI, 0.03–2.2).
Ultimately, like adults with PMBCL, a standard approach to up-front therapy is yet to be identified and various approaches are reasonable.
RT in PMBCL
PMBCL is a radiation-sensitive malignancy; however, the role of RT, particularly in the up-front setting, is not clearly defined. Retrospective analyses comparing OS rates in adults with PMBCL treated with rituximab + chemotherapy ± RT present conflicting results on the impact of RT on OS.26,27 Early results from the UNFOLDER trial from the German Lymphoma Alliance (GLA) indicated that adults with PMBCL randomly assigned to treatment with R-CHOP without RT had an increased risk of a partial response.28 The role for RT in the setting of more dose-intensive regimens in combination with rituximab, such as DA-EPOCH-R, is less clear.19,21
Pediatric data on the use of RT in initial management of PMBCL is limited. The prospective pediatric studies outlined earlier, including the prospective DA-EPOCH-R trial,11 and the LMB25 and BFM24 approaches, do not include RT. In the retrospective analysis on the use of DA-EPOCH-R, RT was only administered in a small subset of pediatric patients (4/36 patients) highlighting the limited use of RT among pediatric patients treated outside of clinical trials.12
An ongoing prospective, randomized phase III trial being conducted by the International Extranodal Lymphoma Study Group (IELSG) is evaluating the role of RT following rituximab-containing chemotherapy regimens in adult patients with PMBCL (ClinicalTrials.gov identifier: NCT01599559).
Overall, when determining a chemotherapy and radiation plan for patients with PMBCL, the balance of efficacy and long-term toxicity should be considered. Higher-intensity chemotherapy regimens may allow for the omission of RT, which is associated with late effects including cardiac toxicity and secondary malignancy. Cardiac toxicity is also a risk with any anthracycline-containing chemotherapy regimen and the total cumulative anthracycline dose should be considered as well.
Role for FDG-PET Imaging in PMBCL
The utilization of metabolic response as determined by interval or end-of-treatment (EoT) PET/CT scans is now widely used in the management of lymphomas.14 However, the role of PET imaging in prognostication and determining the need for consolidative RT in PMBCL is not defined. Numerous studies in adults have indicated a negative EoT PET, defined as a Deauville response score of 1 to 3, is associated with a strong likelihood of prolonged EFS.12,29,30 Hayden et al31 retrospectively identified 113 adults treated with R-CHOP ± RT across the pre-PET and post-PET era. In patients with a negative EoT PET, the 5-year time to progression was 91%. Martelli et al32 prospectively enrolled 125 patients for central review of EoT PET imaging following chemoimmunotherapy, and negative PET imaging predicted a 5-year PFS/OS of 98%/100%.
In contrast, the utility of a positive PET scan remains unclear. Data from the pediatric phase II trial for DA-EPOCH-R demonstrated that the positive predictive value of an EoT PET/CT was 63.6% (95% CI, 30.8%–89.1%).11 Similarly, in adults treated on the phase II trial of DA-EPOCH-R, Melani et al33 identified 25 patients with a positive EoT PET/CT, with only 5 (20%) experiencing a subsequent treatment failure. Serial PET imaging off-therapy indicated that further improvement in FDG activity occurred over time in patients with a positive EoT PET who did not experience a later progression, supporting a possible monitoring strategy for these patients.33 Regardless, based on these data, a repeat biopsy should be strongly considered before starting additional therapy for patients suspected of having refractory disease based on EoT PET alone.
Emerging Biomarkers in PMBCL: Circulating Tumor DNA
Given the limited predictive value of FDG-PET in PMBCL, additional biomarkers predictive of response could help to better identify patients at risk for relapse.11,33 Circulating tumor DNA (ctDNA) is widely being evaluated as a potential biomarker across the field of oncology, with potential applications in diagnosis, prognosis, response assessment, and remission monitoring. Currently data on ctNDA in PMBCL are limited, but studies thus far have found a high degree of concordance between primary biopsies of patients and mutational profile observed in matched ctDNA. The most common mutations identified in PMBCL tumors and ctDNA in one study were B2M (61%), SOCS1 (61%), GNA13 (44%), STAT6 (44%), NFKBIA (39%), ITPKB (33%), and NFKBIE (33%).34 Schroers-Martin et al35 analyzed 197 cases of lymphomas in adult patients and identified higher levels of cfDNA in those with PMBCL and mediastinal gray zone lymphoma, relative to DLBCL, cHL, and transformed low-grade lymphomas. A subsequent multicenter study analyzed samples from 217 patients with DLBCL (n=193) or PMBCL (n=24) and demonstrated that pretreatment levels of ctDNA had prognostic significance in both the up-front and relapsed settings in this combined cohort.36 Furthermore, among patients receiving initial therapy, a reduction in these levels was predictive of outcome. This was predictive at both an early molecular response timepoint (EFS among patients with a 2-log decrease after one cycle vs <2-log decrease: 83% vs 50% [P=.0015], respectively) and a later major molecular response (EFS among patients with 2.5-log decrease after 2 cycles vs <2.5-log decrease: 82% vs 46% [P=.001], respectively).36 ctDNA is currently being collected from patients enrolled on the phase III trial comparing chemotherapy alone versus chemotherapy + nivolumab in children and adults with previously untreated PMBCL (ClinicalTrials.gov identifier: NCT04759586). This may help to define the future role for ctDNA in PMBCL.
Management of Relapsed or Refractory PMBCL
Most patients who do not experience a response to initial therapy will experience early disease progression, with recurrences commonly occurring within 8 months of initial therapy, and more than half of progressions occurring in <1 year.37 Sites of relapse vary and can include the mediastinum or new nodal and/or extranodal regions, including the lung, liver, kidney, and adrenal glands. Although CNS disease is rare at initial presentation, CNS relapse of PMBCL can occur and most commonly presents as parenchymal brain lesions.
The approach to second-line therapy in PMBCL currently mirrors that of relapsed or refractory (R/R) DLBCL, with rituximab-containing regimens such as R-ICE (ifosfamide/carboplatin/etoposide) and R-DHAP (dexamethasone/cytarabine/cisplatin) followed by consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT), and results in 3-year EFS and OS rates of 65% and 68%, respectively, in adult studies.38 RT is often strongly considered, particularly for patients with disease restricted to the mediastinum in whom RT was not previously used. Allogeneic transplantation is an option for patients experiencing disease progression following ASCT or who have chemorefractory disease, and is associated with 5-year PFS and OS rates of 34% (95% CI, 17%–52%) and 45% (95% CI, 26%–63%), respectively, in adults.39 Novel agents are now being used in second- and third-line therapy and should also be considered.
Novel Agents in PMBCL
The recent emergence of novel agents has altered the approach to R/R PMBCL and offers the opportunity to advance outcomes in up-front therapy as well. Recurrent translocation and amplification events involving 9p24.1 result in increased expression of PD-L1 and PD-L2, making checkpoint inhibitors an attractive therapeutic option.9,10 As such, adults with PMBCL were included on the phase IB KEYNOTE-013 and phase II KEYNOTE-170 studies, which evaluated pembrolizumab as a single agent in R/R PMBCL. Patients with PMCBL had an objective response rate (ORR) of 48% (complete response [CR] rate, 33%) and 45% (CR rate, 13%) on the phase Ib and II trials, respectively.40 Based on these results, pembrolizumab is now FDA-approved in children and adults with PMBCL that has relapsed after 2 prior therapies.41
Brentuximab vedotin (BV), an antibody–drug conjugate targeting CD30, is also a rational therapeutic approach in PMBCL, because most cases express CD30. A phase II trial evaluated BV monotherapy in patients with R/R PMBCL (n=15) and demonstrated tolerability but minimal efficacy, with a 13% ORR.42 BV has also been studied in combination with nivolumab.43,44 It has been shown that BV may enhance the antitumor effect of checkpoint inhibition through depletion of regulatory T cells that have upregulated CD30.43 In a phase II trial of combination BV/nivolumab in 36 patients with R/R PBMCL, the ORR was 70% (95% CI, 51%–85%) and CR rate was 43%.44
CD19, which is a commonly expressed antigen in PMBCL, also represents a promising therapeutic target for emerging immunotherapies. Multiple studies have been conducted using autologous anti-CD19 CAR T cells for the treatment of R/R mature B-cell lymphomas in adults, including PMBCL. The multicenter phase II trial for axicabtagene ciloleucel enrolled 111 patients with mature B-cell lymphoma, including 24 with PMBCL, resulting in an ORR of 84% and CR rate of 54%. Notably, at a median follow-up of 15.4 months, 42% of patients had an ongoing response.45 Similar results were achieved in the TRANSCEND NHL 001 trial evaluating a separate CD19-directed CAR T-cell therapy, lisocabtagene maraleucel, in patients with R/R mature B-cell lymphomas, with 15 of 256 having PMBCL, demonstrating an ORR of 73% (95% CI, 66.8%–78.0%) and CR rate of 53% (95% CI, 46.8%–59.4%) across the entire cohort.46 Currently there are limited data in pediatric patients with PMBCL. A pediatric/adolescent young adult phase II, single-arm, global trial evaluating tisagenlecleucel in patients with CD19+ R/R mature B-cell lymphoma has recently completed accrual, but results are still pending.47
Bispecific T-cell engagers (BITEs) are emerging as promising agents for the treatment of B-cell NHL, with a number of agents in development.48 These agents bring T cells into direct contact with tumor cells through dual binding of CD3 on T cells and either CD19 or CD20 on B-cell tumors. Recent trials investigating these agents in R/R aggressive and indolent B-NHL have resulted in promising CR rates, ranging from 19% to 45%.49–51 However, a limited subset of patients with R/R PMBCL have been included in these studies, and dedicated trials will likely be needed to understand the potential role for these agents in PMBCL.
Novel agents also have the potential to improve outcomes for patients with previously untreated PMBCL. Given the success of immune checkpoint inhibition in the relapsed setting, there is currently an ongoing randomized phase III trial evaluating chemotherapy alone versus chemotherapy + nivolumab for children and adults with previously untreated PMBCL (ClinicalTrials.gov identifier: NCT04759586). This trial is being conducted across the National Clinical Trials Network (NCTN) with representatives from all cooperative groups, including pediatric and adult patients.
Summary and Future Directions
PMBCL is now recognized as a distinct NHL subtype with molecular and clinical features that overlap with cHL. With a peak incidence in adolescents and young adults, and no data to suggest significant differences in the biology of the disease in children and adults, this disease provides the opportunity for pediatric and adult groups to work together to advance outcomes. The development of novel therapies that target key vulnerabilities in PMBCL, including immune checkpoint blockade and CD19-directed CAR T-cell therapy, provides the potential to improve outcomes and reduce the reliance on toxic therapies in this vulnerable population. Still some key unanswered questions remain in PMBCL, including: What is the role for PET/CT in dictating therapy? Can genomic or radiographic biomarkers be used identify high- and low-risk populations? Can novel therapies replace radiation or high-dose chemotherapy in up-front therapy? Given the rare nature of this disease, collaboration will be essential to help answer these questions and improve outcomes for both children and adults with PMBCL.
References
- 1.↑
Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022;36:1720–1748.
- 2.↑
Burkhardt B, Zimmermann M, Oschlies I, et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 2005;131:39–49.
- 3.↑
Oschlies I, Burkhardt B, Salaverria I, et al. Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 2011;96:262–268.
- 4.↑
Mottok A, Hung SS, Chavez EA, et al. Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood 2019;134:802–813.
- 5.↑
Bea S, Zettl A, Wright G, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 2005;106:3183–3190.
- 6.↑
Chapuy B, Stewart C, Dunford AJ, et al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood 2019;134:2369–2382.
- 7.↑
Feuerhake F, Kutok JL, Monti S, et al. NFκB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood 2005;106:1392–1399.
- 8.↑
Guiter C, Dusanter-Fourt I, Copie-Bergman C, et al. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood 2004;104:543–549.
- 9.↑
Joos S, Otaño-Joos MI, Ziegler S, et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 1996;87:1571–1578.
- 10.↑
Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014;123:2062–2065.
- 11.↑
Burke GAA, Minard-Colin V, Aupérin A, et al. Dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab therapy in children and adolescents with primary mediastinal B-cell lymphoma: a multicenter phase II trial. J Clin Oncol 2021;39:3716–3724.
- 12.↑
Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose- adjusted EPOCH-R. Br J Haematol 2017;179:739–747.
- 13.↑
Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980;7:332–339. https://www.ncbi.nlm.nih.gov/pubmed/7414342
- 14.↑
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059–3068.
- 15.↑
Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J Clin Oncol 2015;33:2106–2111.
- 16.↑
Rosolen A, Perkins SL, Pinkerton CR, et al. Revised international pediatric Non-Hodgkin lymphoma staging system. J Clin Oncol 2015;33:2112–2118.
- 17.↑
Rieger M, Österborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol 2011;22:664–670.
- 18.↑
Gleeson M, Hawkes EA, Cunningham D, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. Br J Haematol 2016;175:668–672.
- 19.↑
Moskowitz C, Hamlin PA Jr, Maragulia J, et al. Sequential dose-dense RCHOP followed by ICE consolidation (MSKCC protocol 01–142) without radiotherapy for patients with primary mediastinal large B cell lymphoma. Blood 2010;116:420.
- 20.↑
Moskowitz CH, Schöder H, Teruya-Feldstein J, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in advanced-stage diffuse large B-cell lymphoma. J Clin Oncol 2010;28:1896–1903.
- 21.↑
Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH- rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013;368:1408–1416.
- 22.↑
Seidemann K, Tiemann M, Lauterbach I, et al. Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol 2003;21:1782–1789.
- 23.↑
Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 2013;121:278–285.
- 24.↑
Knörr F, Zimmermann M, Attarbaschi A, et al. Dose-adjusted EPOCH- rituximab or intensified B-NHL therapy for pediatric primary mediastinal large B-cell lymphoma. Haematologica 2021;106:3232–3235.
- 25.↑
Dourthe ME, Phulpin A, Auperin A, et al. Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study. Haematologica 2022;107:2173–2182.
- 26.↑
Giri S, Bhatt VR, Pathak R, et al. Role of radiation therapy in primary mediastinal large B-cell lymphoma in rituximab era: a US population-based analysis. Am J Hematol 2015;90:1052–1054.
- 27.↑
Jackson MW, Rusthoven CG, Jones BL, et al. Improved survival with combined modality therapy in the modern era for primary mediastinal B-cell lymphoma. Am J Hematol 2016;91:476–480.
- 28.↑
Held G, Thurner L, Poeschel V, et al. Role of radiotherapy and dose- densification of R-CHOP in primary mediastinal B-cell lymphoma: a subgroup analysis of the unfolder trial of the German Lymphoma Alliance (GLA). J Clin Oncol 2020;38(Suppl):Abstract 8041.
- 29.↑
Pinnix CC, Dabaja B, Ahmed MA, et al. Single-institution experience in the treatment of primary mediastinal B cell lymphoma treated with immunochemotherapy in the setting of response assessment by 18fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 2015;92:113–121.
- 30.↑
Filippi AR, Piva C, Giunta F, et al. Radiation therapy in primary mediastinal B-cell lymphoma with positron emission tomography positivity after rituximab chemotherapy. Int J Radiat Oncol Biol Phys 2013;87:311–316.
- 31.↑
Hayden AR, Tonseth P, Lee DG, et al. Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach. Blood 2020;136:2803–2811.
- 32.↑
Martelli M, Ceriani L, Zucca E, et al. [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 study. J Clin Oncol 2014;32:1769–1775.
- 33.↑
Melani C, Advani R, Roschewski M, et al. End-of-treatment and serial PET imaging in primary mediastinal B-cell lymphoma following dose-adjusted EPOCH-R: a paradigm shift in clinical decision making. Haematologica 2018;103:1337–1344.
- 34.↑
Rivas-Delgado A, Nadeu F, Andrade-Campos M, et al. Cell-free DNA for genomic analysis in primary mediastinal large B-cell lymphoma. Diagnostics (Basel) 2022;12:1575.
- 35.↑
Schroers-Martin JG, Kurtz DM, Soo J, et al. Determinants of circulating tumor DNA levels across lymphoma histologic subtypes. Blood 2017;130:Abstract 4018.
- 36.↑
Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol 2018;36:2845–2853.
- 37.↑
Aoki T, Shimada K, Suzuki R, et al. High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma. Blood Cancer J 2015;5:e372.
- 38.↑
Vardhana S, Hamlin PA, Yang J, et al. Outcomes of relapsed and refractory primary mediastinal (thymic) large B cell lymphoma treated with second-line therapy and intent to transplant. Biol Blood Marrow Transplant 2018;24:2133–2138.
- 39.↑
Herrera AF, Chen L, Khajavian S, et al. Allogeneic stem cell transplantation provides durable remission in patients with primary mediastinal large B cell lymphoma. Biol Blood Marrow Transplant 2019;25:2383–2387.
- 40.↑
Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol 2019;37:3291–3299.
- 41.↑
FDA. FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. Accessed November 1, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-treatment-relapsed-or-refractory-pmbcl
- 42.↑
Zinzani PL, Pellegrini C, Chiappella A, et al. Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: results from a phase 2 clinical trial. Blood 2017;129:2328–2330.
- 43.↑
Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2018;131:1183–1194.
- 44.↑
Zinzani PL, Santoro A, Gritti G, et al. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the phase II CheckMate 436 study. J Clin Oncol 2019;37:3081–3089.
- 45.↑
Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531–2544.
- 46.↑
Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020;396:839–852.
- 47.↑
Minard V, Maude SL, Buechner J, et al. Bianca: phase II, single-arm, global trial to determine efficacy and safety of tisagenlecleucel in pediatric/young adult (YA) patients (Pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). J Clin Oncol 2020;38(Suppl):Abstract e22504.
- 48.↑
Bock AM, Nowakowski GS, Wang Y. Bispecific antibodies for non-Hodgkin lymphoma treatment. Curr Treat Options Oncol 2022;23:155–170.
- 49.↑
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;398:1157–1169.
- 50.↑
Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Eng J Med 2022;387:2220–2231.
- 51.↑
Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol 2022;387:2220–2231.
- 52.
Shah NN, Szabo A, Huntington SF, et al. R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis. Br J Haematol 2018;180:534–544.
