lunes, 26 de agosto de 2019

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®) 5/8 –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



Lymphoblastic Lymphoma

Incidence

Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL).[1-3] (Refer to Table 1 for more information about the incidence of lymphoblastic lymphoma by age and sex distribution.)

Tumor Biology

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[3,4]
As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity at 6q.[5,6]

Clinical Presentation

As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.
Pleural and/or pericardial effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and occasionally other sites, such as lymphoid tissue of Waldeyer ring, testes, bone, or subcutaneous tissue. Abdominal involvement is less than what is observed in Burkitt lymphoma/leukemia.
Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have T-cell acute lymphoblastic leukemia (ALL), and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL.[7] The debate centers on whether they truly represent the same disease.[8] It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Prognostic Factors

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

Standard Treatment Options for Lymphoblastic Lymphoma

Current data do not suggest superiority for the following treatment options.
Standard treatment options for lymphoblastic lymphoma include the following:
  1. GER-GPOH-NHL-BFM-95: Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and CNS radiation therapy for CNS-positive patients only. Treatment duration for T-cell and B-cell precursor lymphoblastic lymphoma is 24 months.[9,10]
  2. COG-A5971 (NCT00004228): Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, and 6-thioguanine.[11,12]
    1. Stage I or II (arm A0; localized disease): Modified Children's Cancer Group (CCG) BFM regimen (prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and reduced number of intrathecal treatments during maintenance).
    2. Stage III or IV (2 × 2 randomization):
      First randomization
      • Arm A1 (disseminated disease, no CNS disease): Modified CCG BFM regimen without intensification. No high-dose methotrexate administered during the interim maintenance phase, but intrathecal therapy is administered throughout the maintenance phase.
      • Arm B1 (disseminated disease, no CNS disease): GER-GPOH-NHL-BFM-95 regimen without intensification and without intrathecal therapy during maintenance.
      Second randomization
      • Arm A2 (disseminated disease, no CNS disease): Modified CCG BFM regimen (arm A1) with intensified induction and delayed intensification.
      • Arm B2 (disseminated disease, no CNS disease): GER-GPOH-NHL-BFM-95 regimen (arm B1) with intensified induction and delayed intensification. Patients with CNS disease were nonrandomly treated on arm B2 with the addition of radiation therapy.
    Equivalent outcomes were observed for arms A1, B1, A2, and B2.
Patients with low-stage (stage I or stage II) lymphoblastic lymphoma have long-term disease-free survival (DFS) rates of about 60% with short, pulsed chemotherapy followed by 6 months of maintenance, with an overall survival (OS) rate higher than 90%.[13,14] However, with the use of an ALL approach and induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma.[9-11]
Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[9,10,12] Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena cava obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)
Evidence (high-stage treatment regimens for lymphoblastic lymphoma):
  1. In the GER-GPOH-NHL-BFM-90 study, the 5-year DFS was 90%, and there was no difference in outcome between stage III and stage IV patients.[9] Patients with precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy.[2]
  2. In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly.[10]
    • There were no significant increases in CNS relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.
    • Of interest, the probability of 5-year event-free survival (EFS) was worse in NHL-BFM-95 (82%) than in NHL-BFM-90 (90%). It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of subsequent neoplasms observed in NHL-BFM-95. NHL-BFM-95 also had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome, although this difference was not statistically significant.
  3. A trial (A5971 [NCT00004228]) of stage III and stage IV lymphoblastic lymphoma patients evaluated two strategies for CNS prophylaxis, without the use of CNS irradiation. Patients were randomly assigned to receive high-dose methotrexate in interim maintenance (BFM-95) or intrathecal chemotherapy throughout maintenance (CCG-BFM).[12][Level of evidence: 1iiA]
    • The overall incidence of CNS relapse was 1.2%, and there was no difference between the treatment arms for CNS relapse, DFS, or OS.
    • The benefit of intensifying induction therapy with continuous infusion daunomycin earlier in induction/delayed intensification phases and the addition of cyclophosphamide was also studied in a randomized fashion. Intensification of therapy did not improve DFS or OS, but increased grade III and grade IV toxicities.
The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. In the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[15][Level of evidence: 1iiA] Of note, all of these patients received prophylactic cranial radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[10,12] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect the outcome and showed cardioprotective benefit on the basis of echocardiographic and laboratory assessments.[16][Level of evidence: 2A]
In addition to the NHL-BFM-95 trial, a single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL.[17] However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group do not support this finding.[12,18,19]

Treatment Options for Recurrent Lymphoblastic Lymphoma

For patients with recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.[18,20]; [21][Level of evidence: 2A]; [22,23][Level of evidence: 3iiiA] As in patients with Burkitt lymphoma/leukemia, chemoresistant disease is common.
There are no standard treatment options for patients with recurrent or progressive disease.
Treatment options for recurrent lymphoblastic lymphoma include the following:
  1. Nelarabine or nelarabine-containing chemotherapy regimens (nelarabine, cyclophosphamide, and etoposide).[24-26]
  2. ICE (ifosfamide, carboplatin, and etoposide).[27]
  3. Allogeneic stem cell transplantation (SCT).[28]
Evidence (treatment of recurrent lymphoblastic lymphoma):
  1. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[24]
  2. A phase IV multicenter study of patients with relapsed T-cell leukemia/lymphoma (n = 28, 11 lymphoma) were treated with single-agent nelarabine.[25]
    • A complete response rate of 36% was observed.
  3. Two small series have treated patients with relapsed T-cell leukemia/lymphoma using nelarabine, cyclophosphamide, and etoposide.[26,29]
    1. One study treated 27 patients.[26]
      • A partial/complete response rate of 85% was observed.
      • However, 13% of patients developed greater than grade 3 neurotoxicity, and three patients died of neurotoxicity.
      • Of the four lymphoma patients, one patient achieved a partial remission, but all patients eventually had disease progression.
    2. The other study treated seven patients.[29]
      • The partial/complete response rate was 100%.
      • Of the two lymphoma patients, both achieved partial responses but later progressed.
  4. A BFM study showed an OS rate of 14% for patients relapsing after BFM front-line therapy; all patients who survived had undergone an allogeneic SCT.[23]
  5. A Center for International Blood and Marrow Transplant Research analysis demonstrated that EFS was significantly worse when an autologous (4%) versus allogeneic (40%) donor stem cell source was used, with all failures resulting from progressive disease.[28]

Treatment Options Under Clinical Evaluation for Lymphoblastic 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 are examples of national and/or institutional clinical trials that are currently being conducted:
  • NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years. Patients are classified into one of three risk groups (standard, intermediate, or very high) on the basis of the amount of minimal detected disease at diagnosis, radiographic response, and minimal residual disease status at day 29. The objectives of the trial include the following:
    • To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is administered during the induction phase (four doses) and again during the delayed intensification phase (four doses).
    • To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.
    • To determine whether prophylactic cranial radiation can be omitted in patients with T-cell lymphoblastic lymphoma without CNS3 disease at diagnosis.
  • COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL or Localized B-lineage Lymphoblastic Lymphoma): In this study, all patients with stage I and stage II B-cell lymphoblastic lymphoma are treated with average-risk ALL therapy.
    All lymphoma patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with intrathecal chemotherapy.
    The objective for enrolled lymphoma patients is to collect biological data on B-cell lymphoblastic lymphoma and evaluate the effect of dose de-escalation on OS.
  • 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.
References
  1. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 35-50. Also available online. Last accessed April 12, 2019.
  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 131 (1): 39-49, 2005. [PUBMED Abstract]
  3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PUBMED Abstract]
  4. Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000. [PUBMED Abstract]
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  7. Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127 (20): 2375-90, 2016. [PUBMED Abstract]
  8. Meyer JA, Zhou D, Mason CC, et al.: Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
  9. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000. [PUBMED Abstract]
  10. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006. [PUBMED Abstract]
  11. Termuhlen AM, Smith LM, Perkins SL, et al.: Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1229-33, 2012. [PUBMED Abstract]
  12. Termuhlen AM, Smith LM, Perkins SL, et al.: Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group. Br J Haematol 162 (6): 792-801, 2013. [PUBMED Abstract]
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  14. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997. [PUBMED Abstract]
  15. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011. [PUBMED Abstract]
  16. Asselin BL, Devidas M, Chen L, et al.: Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol 34 (8): 854-62, 2016. [PUBMED Abstract]
  17. Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001. [PUBMED Abstract]
  18. Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008. [PUBMED Abstract]
  19. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008. [PUBMED Abstract]
  20. Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005. [PUBMED Abstract]
  21. Michaux K, Bergeron C, Gandemer V, et al.: Relapsed or Refractory Lymphoblastic Lymphoma in Children: Results and Analysis of 23 Patients in the EORTC 58951 and the LMT96 Protocols. Pediatr Blood Cancer 63 (7): 1214-21, 2016. [PUBMED Abstract]
  22. Mitsui T, Mori T, Fujita N, et al.: Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 52 (5): 591-5, 2009. [PUBMED Abstract]
  23. Burkhardt B, Reiter A, Landmann E, et al.: Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group. J Clin Oncol 27 (20): 3363-9, 2009. [PUBMED Abstract]
  24. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005. [PUBMED Abstract]
  25. Zwaan CM, Kowalczyk J, Schmitt C, et al.: Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol 179 (2): 284-293, 2017. [PUBMED Abstract]
  26. Kuhlen M, Bleckmann K, Möricke A, et al.: Neurotoxic side effects in children with refractory or relapsed T-cell malignancies treated with nelarabine based therapy. Br J Haematol 179 (2): 272-283, 2017. [PUBMED Abstract]
  27. Kung FH, Harris MB, Krischer JP: Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study. Med Pediatr Oncol 32 (3): 225-6, 1999. [PUBMED Abstract]
  28. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010. [PUBMED Abstract]
  29. Commander LA, Seif AE, Insogna IG, et al.: Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 150 (3): 345-51, 2010. [PUBMED Abstract]
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