lunes, 26 de agosto de 2019

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®) 4/8 –Health Professional Version - National Cancer Institute

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Aggressive Mature B-cell NHL

Burkitt and Burkitt-like Lymphoma/Leukemia

Incidence

In the United States, Burkitt and Burkitt-like lymphoma/leukemia account for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibit a consistent, aggressive clinical behavior.[1-3] The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,4] (Refer to Table 1 for more information about the incidence of Burkitt lymphoma by age and sex distribution.)

Tumor biology

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYConcogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[3,5,6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[7]
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
  • Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[8-11]
  • Mutations in TP53 are observed in one-third to one-half of cases.[8,10]
  • Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[8,10]
  • Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[8,12]
A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases; however, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, apoptosis, CCND3, and TP53.[13]
The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[14]
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[15]
Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkittlymphoma/leukemia cases have a gene expression signature similar to Burkitt lymphoma/leukemia.[16,17] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[16,18]
Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues.[14] In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[19,20] Most patients present in the adolescent and young adult age range with localized nodal disease, and outcomes appear favorable in the small number of cases identified. Cases show a very high proliferative index and can show a focal starry sky pattern. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma; mutations commonly observed in Burkitt lymphoma (e.g., ID3, TCF3, and CCND3) are uncommon in Burkitt-like lymphoma with 11q aberration.[19] Conversely, mutations in GNA13 appear to be common (up to 50%) in patients with Burkitt-like lymphoma with 11q aberration and are less common in patients with Burkitt lymphoma.

Clinical presentation

The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring.[3,4] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread are seen.

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for Burkitt lymphoma/leukemia.

Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia

The treatment of Burkitt and Burkitt-like lymphoma/leukemia is the same as treatment for diffuse large B-cell lymphoma. The following discussion is pertinent to the treatment of both types of childhood NHL.
Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens.[21-25]
Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)
Current treatment strategies are based on risk stratification, as described in Table 4. Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma.[21,23]
Table 4. FAB/LMB and BFM Staging Schemas for B-cell NHL
 StratumDisease Manifestation
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphomes Malins B; NHL = non-Hodgkin lymphoma.
aBased on results of the FAB/LMB-96 study, a serum LDH level more than twice the upper limit of normal has been used to define a group B high-risk group in the international B-cell NHL study ANHL1131 (NCT01595048).[22]
FAB/LMB International Study [22,23,26]ACompletely resected stage I and abdominal stage II
BaMultiple extra-abdominal sites
Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease); epidural masses (stage III Murphy staging) are treated as group B unless there is evidence of dural invasion
CMature B-cell ALL (>25% blasts in marrow) and/or CNS disease
 
BFM Group [27]R1Completely resected stage I and abdominal stage II
R2Nonresected stage I or II and stage III with LDH <500 IU/L
R3Stage III with LDH 500–999 IU/L
Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L
R4Stage III, IV, B-cell ALL with LDH >1,000 IU/L
Any CNS disease
The following studies have contributed to the development of current treatment regimens for pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma.
Evidence (chemotherapy):
  1. Berlin-Frankfurt-Münster (BFM) studies
    1. Localized disease (R1 and R2 groups): The BFM group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[21,27] For unresected stage I or stage II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[21,27]
      • In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[27]
      • In the NHL-BFM-95 study, it was demonstrated that prolonging the duration of methotrexate infusion did not improve outcome for patients with low-stage disease.[21]
      • Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients.[21]
    2. Advanced/disseminated disease (R3 and R4 groups): In the NHL-BFM-95 study, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[21]
      • EFS with best therapy in NHL-BFM-95 was 93% for R3 and R4 group patients.[21]
      • Inferior outcome was observed for patients with CNS disease at presentation (70% 3-year EFS).[27]
  2. French Society of Pediatric Oncology Lymphomes Malins B (LMB) and French-American British (FAB) studies
    1. Localized disease (group A): Patients with completely resected stage I and abdominal stage II (group A) disease who received two cycles of multiagent chemotherapy, without intrathecal chemotherapy or rituximab had an excellent outcome (COG-C5961 [FAB/LMB-96]).[26][Level of evidence: 2A]
      • The 3-year EFS was 98% for stage I or stage II.[22]
    2. Advanced disease (group B): For unresected stage I through IV disease (without CNS or leukemic disease), the above-mentioned FAB/LMB-96 study demonstrated that reducing the duration of therapy to four cycles of chemotherapy after a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[22]
      • The 3-year EFS was 90% for stage III and 86% for stage IV (CNS-negative and nonleukemic) patients.
      • Patients with a lactate dehydrogenase (LDH) level more than twice the upper limit of normal had an EFS of 86% compared with 96% in those with lower LDH levels.
    3. Disseminated disease (group C): For patients with leukemic or CNS involvement in the FAB study, reduction in the cumulative dose of therapy and the number of maintenance cycles resulted in inferior outcome.[23]
      • Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.
      • Patients who were CNS positive but marrow negative did better, with an EFS of 82%, while those with combined marrow and CNS disease at diagnosis had an EFS of only 61%.
      • This study identified the response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.
Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[21-23,27]
Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma both express high levels of CD20.[5]
Evidence (rituximab):
  1. Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with diffuse large B-cell lymphoma (CAN-NCIC-LY9).[28] (Refer to the Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
  2. In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma/leukemia.[29][Level of evidence: 2Div]
  3. A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL.[30]; [24][Level of evidence: 3iiiA]
    • Compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak levels of rituximab in younger patients.
  4. An international randomized phase III trial that evaluated the benefit of adding rituximab to standard therapy was closed early.[31]
    • Superior results were observed in the rituximab arm, with 94% EFS for this high-risk group of patients (stage III with elevated LDH and stage IV).
Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are described in Table 5.
Table 5. Standard Treatment Options for Burkitt and Burkitt-like Lymphoma/Leukemia and Diffuse Large B-cell Lymphoma
TrialStratumDisease ManifestationsTreatment
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS= central nervous system; COG = Children's Oncology Group; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphomes Malins B; NHL = non-Hodgkin lymphoma; POG = Pediatric Oncology Group.
POG-8314/POG-8719/POG 9219 [32] Grossly resected stage I and II (completely resected abdominal stage II disease)Three cycles of outpatient chemotherapy (no radiation or maintenance therapy)
 
COG-C5961(FAB/LMB-96) [22,23,26] COG-ANHL1131 (Inter-B-NHL Ritux 2010) [31]ACompletely resected stage I and abdominal stage IITwo cycles of chemotherapy
BMultiple extra-abdominal sitesPrephase + four cycles of chemotherapy (reduced-intensity arm)
Nonresected stage I and II, III (normal LDH)
Stage III (elevated LDH), marrow <25% blasts, no stage IV CNS diseasePrephase + four cycles of chemotherapy (reduced-intensity arm) + six doses of rituximab
CMature B-cell ALL (>25% blasts in marrow) and/or stage IV CNS diseasePrephase + six cycles of chemotherapy (full-intensity arm) + six doses of rituximab
 
GER-GPOH-NHL-BFM-95 [21,27]R1Completely resected stage I and abdominal stage IITwo cycles of chemotherapy
R2Nonresected stage I/II and stage III with LDH <500 IU/LPrephase + four cycles of chemotherapy (4-hour methotrexate infusion)

Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia

There is no standard treatment option for patients with recurrent or progressive disease. For recurrent or refractory B-lineage NHL, survival is generally 10% to 30%.[23,33-37] A review of patients treated on the LMB-89, LMB-96 (NCT00002757), and LMB-2001 trials identified 67 of 1,322 patients who relapsed. A multivariate analysis demonstrated that the following factors were associated with better survival:[37]
  • One site of disease at relapse.
  • Diffuse large B-cell lymphoma histology.
  • Initial good-risk disease (i.e., group A or group B with normal LDH).
  • Duration of complete remission of more than 6 months.
Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma include the following:
  1. R-ICE (ifosfamide, carboplatin, and etoposide plus rituximab).[38]
  2. CYVE (high-dose cytarabine and etoposide) for relapsed group A and group B disease.[37]
  3. Allogeneic or autologous stem cell transplantation (SCT).[39,40]
  4. Bispecific antibody (anti-CD20, anti-CD3).[41]
Chemoresistance makes remission difficult to achieve.
Evidence (treatment of recurrent Burkitt and Burkitt-like lymphoma/leukemia):
  1. A study from the United Kingdom for children with relapsed or refractory mature B-cell NHL and B-cell acute lymphoblastic leukemia showed the most favorable outcomes for those who received rituximab and an autologous SCT. However, the study could not distinguish whether this relationship reflected that children who survived were those who remained well enough to tolerate chemotherapy and rituximab, achieved a response, and were eligible for transplantation.[42]
  2. The COG conducted a study of 20 patients (14 of whom had Burkitt lymphoma/leukemia) using R-ICE to treat relapsed/refractory B-cell NHL (Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma).[38][Level of evidence: 3iiA]
    • Study results showed a complete remission/partial remission rate of 60%.
  3. The Japanese Pediatric Leukemia/Lymphoma Study Group performed a phase II study using R-ICE in 28 patients.[43]
    • The investigators observed a 70% complete and partial response rate.
  4. A retrospective review of patients with relapsed disease treated in the LMB-89, LMB-96, and LMB-2001 trials were analyzed. Group A and group B patients received the CYVE regimen as initial salvage therapy, and group C patients received ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab.[37]
    • The complete and partial remission rate was 64%; 2 of 3 group A patients responded, 19 of 29 group B patients responded, and 3 of 5 group C patients responded.
If remission can be achieved, high-dose therapy plus SCT remains the best option for survival. However, the benefit of autologous versus allogeneic SCT is unclear.[35,39,44,45]; [46][Level of evidence: 2A]; [47][Level of evidence: 3iiiDii]
Patients not in remission at the time of transplant fare significantly worse.[37,39,46] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a transplant option should not be pursued in these patients.[48]
(Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation).
Evidence (SCT therapy):
  1. An analysis of data from the Center for International Blood and Marrow Transplant Research demonstrated the following:[39]
    • No difference using either autologous or allogeneic donor stem cell sources, with 2-year EFS of 50% for diffuse large B-cell lymphoma and 30% for Burkitt lymphoma/leukemia patients who survived to have a transplant.
    • Some graft-versus-lymphoma effect has been implied by the lower relapse rate in the allogeneic SCT patients; however, that was balanced by the higher treatment-related mortality.
  2. A small, single-center, prospective study used autologous transplantation followed by reduced-intensity allogeneic SCT to treat relapsed NHL.[40]
    • The study reported an EFS of 60%.

Treatment options under clinical evaluation for Burkitt/Burkitt-like leukemia/lymphoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Diffuse Large B-cell Lymphoma

Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)

Incidence

Diffuse large B-cell lymphoma is an aggressive mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,49] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,50] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)

Tumor biology

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[51]
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
  • The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[7,52,53] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[54]
  • Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[52]
  • As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[16,18]
  • In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[18,55]
  • A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[56] Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.[57]

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt or Burkitt-like lymphoma/leukemia, although more often it is localized, and less often it involves the bone marrow or CNS.[49,50,58] (Refer to the Clinical presentationsection in the Burkitt and Burkitt-like Lymphoma/Leukemia section of this summary for more information.)

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for diffuse large B-cell lymphoma.

Treatment options for diffuse large B-cell lymphoma

As with Burkitt and Burkitt-like lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 5. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemiasection of this summary for information about the treatment of diffuse large B-cell lymphoma.

Treatment options for recurrent diffuse large B-cell lymphoma

The treatment of recurrent diffuse large B-cell lymphoma is the same as the treatment of recurrent Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia section of this summary for more information.

Treatment options under clinical evaluation for diffuse large B-cell lymphoma

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Primary Mediastinal B-cell Lymphoma

Incidence

In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases.[50,59-61]

Tumor biology

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[62] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
  • Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[62]
  • Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.
Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[63,64] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
  • Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[65-67]
  • Genomic alterations in CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, are common in primary mediastinal B-cell lymphoma and lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.[68]
  • Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[69]
    • The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[60,61]
    • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[70,71]
    • The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[69]
  • Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.[60,61]

Clinical presentation

As the name would suggest, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension) and can be associated with superior vena cava syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys; however, CNS and marrow involvement are exceedingly rare.[72]

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for primary mediastinal B-cell lymphoma.

Treatment options for primary mediastinal B-cell lymphoma

Treatment options for primary mediastinal B-cell lymphoma include the following:
  1. Dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R).
Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma fared significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS of 66%, compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[73][Level of evidence: 2A] Similarly, in the NHL-BFM-95 trial, patients with primary mediastinal B-cell lymphoma had an EFS of 50% at 3 years.[21] However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival rates.[74]
Evidence (DA-EPOCH-R):
  1. A single-arm study in young adults utilized the DA-EPOCH-R regimen (usually six cycles) with filgrastim and no radiation therapy.[74][Level of evidence: 2A]
    • The 5-year EFS was 93%, and overall survival (OS) was 97%.
    • At short-term follow-up, there was no evidence of cardiac toxicity, despite a high cumulative dose of doxorubicin for those who went through most of the anthracycline-dose escalations.
    • An important finding in this study was the prognostic value of end-of-therapy imaging. Nine of 12 patients who had residual mediastinal masses at the end of therapy had positive positron emission tomography scans. Seven of these nine patients had the masses resected, but no viable tumor was found.
    • A concern for using this regimen is the significantly higher cumulative doses of alkylating agents and anthracyclines administered than those used in previous regimens.
  2. A single-arm modification of DA-EPOCH-R (usually six cycles with filgrastim and no radiation therapy) was completed by the BFM group, in which the cumulative doxorubicin dose was kept at 360 mg/m2 and intrathecal chemotherapy was added.[75]
    • The study showed a 2-year OS of 92% among the 15 consecutive pediatric patients treated.
  3. A multicenter, retrospective study of 38 pediatric patients (aged <21 years) and 118 adult patients treated with DA-EPOCH-R observed the following:[76]
    • Pediatric patients had a 3-year EFS of 81% and a 3-year OS of 91%. These results were not significantly different from the results observed in adults.

Treatment options for refractory or relapsed primary mediastinal B-cell lymphoma

The U.S. Food and Drug Administration granted accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more previous lines of therapy. The approval was based on data from 53 patients (median age, 33 years; range, 20–61 years). The overall response rate was 41%, which included 12% complete responses and 29% partial responses.[77]

Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
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