martes, 30 de julio de 2019

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute 9/9

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute

National Cancer Institute

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



Treatment for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL





Patients with aggressive stage I or aggressive, contiguous stage II diffuse large B-cell lymphoma are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).


Standard Treatment Options for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

Standard treatment options for aggressive stage I and aggressive, contiguous stage II adult non-Hodgkin lymphoma (NHL) include the following:
  1. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without IF-XRT.

R-CHOP with or without IF-XRT

The confirmation of efficacy for rituximab in advanced-stage disease has suggested the use of R-CHOP with or without radiation therapy but its use is only supported by retrospective comparisons.[1][Level of evidence: 3iiiDiii]
  • R-CHOP (four to six cycles).
  • R-CHOP (three to six cycles) + IF-XRT.
Evidence (R-CHOP with or without IF-XRT):
  1. In a randomized prospective trial of 334 patients with nonbulky (≤7 cm) stage I or stage II diffuse large B-cell lymphoma (DLBCL), after receiving four to six cycles of R-CHOP-14 (R-CHOP delivered every 2 weeks), patients were randomly assigned to receive or not receive 40 Gy of radiation therapy.[2]
    • After a median follow-up of 64 months, the 5-year event-free survival (EFS) (89%–92%, P = .18) and 5-year overall survival (OS) (92%–96%, P = .32) were the same.[2][Level of evidence: 1iiA]
    Similar to the results of randomized studies of radiation therapy in the prerituximab era, radiation therapy can be deferred in nonbulky early-stage patients. For patients unable to tolerate prolonged-course chemotherapy, three cycles of R-CHOP plus radiation therapy has produced equivalent results based on single-arm retrospective trials.[1]
  2. In a randomized prospective trial, published only in abstract form, of 592 patients younger than 60 years with nonbulky (<7.5 cm) stage I or stage II DLBCL, patients were randomly assigned to four versus six cycles of R-CHOP.[3]
    • With a 66-month median follow-up, the 3-year EFS was 89% in both arms (P = NS) and the 3-year OS was 98% in both arms (P = NS).[3][Level of evidence: 1iiA]
    • For patients with favorable early-stage DLBCL, four cycles of R-CHOP is sufficient.
Conclusion: For patients with favorable prognosis nonbulky (<7 cm) stage I or stage II DLBCL, four cycles of R-CHOP is sufficient. For patients with unfavorable prognosis, six cycles of R-CHOP or three cycles of R-CHOP and 40 Gy of radiation therapy can be utilized. Early-stage patients with bulky disease (>7.5 cm) have not been studied in randomized trials; combined modality therapy with R-CHOP for four to six cycles plus radiation therapy is usually chosen.

Treatment Options Under Clinical Evaluation for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

Treatment options under clinical evaluation include the following:
  • R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).[4,5]

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. Persky DO, Unger JM, Spier CM, et al.: Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 26 (14): 2258-63, 2008. [PUBMED Abstract]
  2. Lamy T, Damaj G, Soubeyran P, et al.: R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 131 (2): 174-181, 2018. [PUBMED Abstract]
  3. Poeschel V, Held G, Ziepert M, et al.: Excellent outcome of young patients (18–60 years) with favourable-prognosis diffuse large B-cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of rituximab: results of the 592 patients of the flyer trial of the Dshnhl/GLA. [Abstract] Blood 132 (Suppl 1): A-781, 2018. Also available online. Exit Disclaimer Last accessed January 14, 2019.
  4. Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005. [PUBMED Abstract]
  5. Ketterer N, Coiffier B, Thieblemont C, et al.: Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol 24 (4): 1032-7, 2013. [PUBMED Abstract]

Treatment for Aggressive, Noncontiguous Stage II/III/IV Adult NHL





The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.[1]
The following drug combinations are referred to in this section:
  • R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.
  • R-ACVBP: rituximab, an anti–CD20 monoclonal antibody, + doxorubicin + cyclophosphamide + vindesine + bleomycin + prednisone.


Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Standard treatment options for aggressive, noncontiguous stage II/III/IV adult NHL include the following:
  1. R-CHOP.
  2. Other combination chemotherapy.

R-CHOP

The following studies established R-CHOP as the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL).[2] Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.[3]
Evidence (R-CHOP):
  1. R-CHOP showed improvement in event-free survival (EFS) and overall survival (OS) compared with CHOP alone in 399 advanced-stage patients with DLBCL older than 60 years (EFS, 57% vs. 38%; P = .002, and OS, 70% vs. 57%; P = .007 at 2 years).[4][Level of evidence: 1iiA] At 10-years' median follow-up, the OS of patients who received R-CHOP compared with patients who received CHOP was 44% versus 28%, P < .0001.[5]
  2. Similarly, for 326 evaluable patients younger than 61 years, R-CHOP showed improvement in EFS and OS compared with CHOP alone (EFS, 79% vs. 59%, P = .001, and OS, 93% vs. 84%, P = .001 at 3 years).[6][Level of evidence: 1iiA]
  3. A randomized study (DSHNHL-1999-1A [NCT00052936]) of 1,222 patients older than 60 years compared R-CHOP given every 2 weeks for six or eight cycles with CHOP given every 2 weeks for six or eight cycles.[7] With a median follow-up of 72 months, the EFS favored R-CHOP given every 2 weeks for six or eight cycles (EFS at 6 years, 74% vs. 56%; P < .0001). The OS favored R-CHOP for only six cycles because of increased toxicity in the eight-cycle arm (OS at 6 years, 90% vs. 80%; P = .0004).[7][Level of evidence: 1iiA] There was no comparison with standard R-CHOP or CHOP given every 3 weeks.
  4. A trial (NCT00140595) of 380 patients younger than 60 years with DLBCL and an age-adjusted International Prognostic Index (IPI) rating of 1 randomly assigned treatment of patients to ACVBP and R-ACVBP plus consolidation with methotrexate, ifosfamide, etoposide, and cytarabine versus CHOP and rituximab.[8] With a median follow-up of 44 months, 3-year OS favored R-ACVBP (92% vs. 84%; hazard ratio, 0.44; 95% confidence interval (CI), 0.28–0.81, P = .007).[8][Level of evidence: 1iiA] The significantly worse toxicities with R-ACVBP, the narrow target population (<60 years with either elevated lactate dehydrogenase (LDH) or stage III-stage IV disease, but not both), and the lack of a confirmatory trial may inhibit adoption of R-ACVBP as a new standard of care.[9]
Clinical trials continue to explore modifications of R-CHOP. There is no validated trial for interim positron emission tomography–based treatment intensification.[10]

Stage IE or IIE gastric DLBCL

Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[11-14][Level of evidence: 3iiiDiv]

Prognostic factors

The National Comprehensive Cancer Network (NCCN) IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[15]
  • Age <40 years: 0; 41–60 years: 1; 61–75 years: 2; >75 years: 3.
  • Stage III/IV: 1.
  • Performance status 2/3/4: 1.
  • Serum LDH normalized: 0; >1x to 3x: 1; >3x: 2.
  • Number of extranodal sites ≥2: 1.
Risk scores:
  • Low (0 or 1): 5-year OS, 96%; PFS, 91%.
  • Low intermediate (2 or 3): 5-year OS, 82%; PFS, 74%.
  • High intermediate (4 or 5): 5-year OS, 64%; PFS, 51%.
  • High (>6): 5-year OS, 33%; PFS, 30%.
Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[16] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.[17]
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYCgene, or both, confer a particularly poor prognosis.[18-21] Patients at high risk of relapse may be considered for clinical trials.[22] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[23,24]

Treatment of tumor lysis syndrome

Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure.[25] Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.[26]

CNS prophylaxis

Central nervous system (CNS) prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[27] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[28,29]
Evidence (CNS prophylaxis):
  1. A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence.[30]
    • Patients with both risk factors had a 17% probability of CNS recurrence at 1 year after diagnosis (95% CI, 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[30][Level of evidence: 3iiiDiii]
Patients with diffuse, small, noncleaved-cell/Burkitt's lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.

Hepatitis B

Patients with a resolved hepatitis B virus (HBV) infection (HBsAg negative + HBcAb positive) are at risk of reactivation of HBV and require monitoring of HVB DNA. Prophylactic nucleoside therapy lowered HBV reactiation from 10.8% to 2.1% in a retrospective study of 326 patients.[31]

Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Treatment options under clinical evaluation include the following:
  1. Bone marrow transplant (BMT) or stem cell transplantation (SCT).
    Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[32-39]; [40-42][Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.
    Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[33,39] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.[43]
  2. Radiation therapy consolidation to sites of bulky disease.
    After R-CHOP induction chemotherapy (or similar regimens), the addition of IF-XRT to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[44-46] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

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. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PUBMED Abstract]
  2. Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005. [PUBMED Abstract]
  3. Cunningham D, Hawkes EA, Jack A, et al.: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381 (9880): 1817-26, 2013. [PUBMED Abstract]
  4. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002. [PUBMED Abstract]
  5. Coiffier B, Thieblemont C, Van Den Neste E, et al.: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116 (12): 2040-5, 2010. [PUBMED Abstract]
  6. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006. [PUBMED Abstract]
  7. Pfreundschuh M, Kuhnt E, Trümper L, et al.: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12 (11): 1013-22, 2011. [PUBMED Abstract]
  8. Récher C, Coiffier B, Haioun C, et al.: Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378 (9806): 1858-67, 2011. [PUBMED Abstract]
  9. Casasnovas RO, Ysebaert L, Thieblemont C, et al.: FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood 130 (11): 1315-1326, 2017. [PUBMED Abstract]
  10. Dührsen U, Müller S, Hertenstein B, et al.: Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial. J Clin Oncol 36 (20): 2024-2034, 2018. [PUBMED Abstract]
  11. Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PUBMED Abstract]
  12. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PUBMED Abstract]
  13. Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PUBMED Abstract]
  14. Kuo SH, Yeh KH, Wu MS, et al.: Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood 119 (21): 4838-44; quiz 5057, 2012. [PUBMED Abstract]
  15. Zhou Z, Sehn LH, Rademaker AW, et al.: An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123 (6): 837-42, 2014. [PUBMED Abstract]
  16. Møller MB, Christensen BE, Pedersen NT: Prognosis of localized diffuse large B-cell lymphoma in younger patients. Cancer 98 (3): 516-21, 2003. [PUBMED Abstract]
  17. Maurer MJ, Ghesquières H, Link BK, et al.: Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials. J Clin Oncol 36 (16): 1603-1610, 2018. [PUBMED Abstract]
  18. Cuccuini W, Briere J, Mounier N, et al.: MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood 119 (20): 4619-24, 2012. [PUBMED Abstract]
  19. Johnson NA, Slack GW, Savage KJ, et al.: Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3452-9, 2012. [PUBMED Abstract]
  20. Green TM, Young KH, Visco C, et al.: Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3460-7, 2012. [PUBMED Abstract]
  21. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PUBMED Abstract]
  22. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PUBMED Abstract]
  23. Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
  24. Lossos IS, Czerwinski DK, Alizadeh AA, et al.: Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350 (18): 1828-37, 2004. [PUBMED Abstract]
  25. Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008. [PUBMED Abstract]
  26. Cortes J, Moore JO, Maziarz RT, et al.: Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol 28 (27): 4207-13, 2010. [PUBMED Abstract]
  27. Glantz MJ, Cole BF, Recht L, et al.: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16 (4): 1561-7, 1998. [PUBMED Abstract]
  28. Fisher RI, Gaynor ER, Dahlberg S, et al.: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328 (14): 1002-6, 1993. [PUBMED Abstract]
  29. Bernstein SH, Unger JM, Leblanc M, et al.: Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group. J Clin Oncol 27 (1): 114-9, 2009. [PUBMED Abstract]
  30. van Besien K, Ha CS, Murphy S, et al.: Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 91 (4): 1178-84, 1998. [PUBMED Abstract]
  31. Kusumoto S, Arcaini L, Hong X, et al.: Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood 133 (2): 137-146, 2019. [PUBMED Abstract]
  32. Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000. [PUBMED Abstract]
  33. Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997. [PUBMED Abstract]
  34. Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998. [PUBMED Abstract]
  35. Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997. [PUBMED Abstract]
  36. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001. [PUBMED Abstract]
  37. Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002. [PUBMED Abstract]
  38. Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003. [PUBMED Abstract]
  39. Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004. [PUBMED Abstract]
  40. Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006. [PUBMED Abstract]
  41. Stiff PJ, Unger JM, Cook JR, et al.: Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369 (18): 1681-90, 2013. [PUBMED Abstract]
  42. Chiappella A, Martelli M, Angelucci E, et al.: Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18 (8): 1076-1088, 2017. [PUBMED Abstract]
  43. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
  44. Held G, Murawski N, Ziepert M, et al.: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 32 (11): 1112-8, 2014. [PUBMED Abstract]
  45. Kahl BS: Bulky aggressive B-cell lymphoma: to radiate or not to radiate--that is the question. J Clin Oncol 32 (11): 1097-8, 2014. [PUBMED Abstract]
  46. Phan J, Mazloom A, Medeiros LJ, et al.: Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 28 (27): 4170-6, 2010. [PUBMED Abstract]

Treatment for Lymphoblastic Lymphoma (LBL)/Acute Lymphocytic Leukemia (ALL)





LBL is a very aggressive form of non-Hodgkin lymphoma (NHL), which often occurs in young patients but not exclusively. LBL is the lymphomatous manifestation of ALL. The treatment paradigms are based on trials for ALL because LBL and ALL are considered different manifestations of the same biologic disease. LBL is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the central nervous system (CNS). (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.) Intensive combination chemotherapy with CNS prophylaxis is the standard treatment of this aggressive histologic type of NHL. Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed.
The most important aspects of the pretreatment staging workup include careful review of the following pathological specimens:
  • Bone marrow aspirate.
  • Biopsy specimen.
  • Cerebrospinal fluid cytology.
  • Lymphocyte marker.


Standard Treatment Options for LBL/ALL

Standard treatment options for LBL include the following:
  1. Intensive therapy.
  2. Radiation therapy.
(Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

Intensive therapy

Standard treatment is intensive combination chemotherapy with CNS prophylaxis.

Radiation therapy

Radiation therapy is sometimes given to areas of bulky tumor masses.

Treatment Options Under Clinical Evaluation for LBL/ALL

New treatment approaches are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

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.

Treatment for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma





Diffuse, small, noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[1]


Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma

Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:
  1. Aggressive multidrug regimens.
  2. CNS prophylaxis.

Aggressive multidrug regimens

Standard treatment for diffuse, small, noncleaved-cell/Burkitt lymphoma is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (such as diffuse large cell).[2-4] Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase.
Evidence (aggressive multidrug regimens):
  • Aggressive combination chemotherapy patterned after that used in childhood Burkitt lymphoma has been very successful for adult patients. More than 60% of advanced-stage patients were free of disease at 5 years.[4-7]
  • Rituximab has been incorporated into these aggressive combination chemotherapy regimens. A nonrandomized, single-arm, prospective, multicenter trial of 363 patients, aged 16 years to 85 years, showed a 5-year progression-free survival of 71% and a 5-year overall survival of 80%.[3][Level of evidence: 3iiiA]

CNS prophylaxis

Patients with diffuse, small, noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients, usually given as four to six intrathecal injections.[8] (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information).
Evidence (CNS prophylaxis):
  • In a series of 41 patients treated with systemic and intrathecal chemotherapy, 44% of those who presented with CNS disease and 13% of those who relapsed with CNS involvement became long-term disease-free survivors.[9] CNS relapse patterns were similar whether or not patients received radiation therapy, but increased neurologic deficits were noted among those patients who received radiation therapy.

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. Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004. [PUBMED Abstract]
  2. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PUBMED Abstract]
  3. Hoelzer D, Walewski J, Döhner H, et al.: Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 124 (26): 3870-9, 2014. [PUBMED Abstract]
  4. Dunleavy K, Pittaluga S, Shovlin M, et al.: Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 369 (20): 1915-25, 2013. [PUBMED Abstract]
  5. Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PUBMED Abstract]
  6. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PUBMED Abstract]
  7. Mead GM, Sydes MR, Walewski J, et al.: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13 (8): 1264-74, 2002. [PUBMED Abstract]
  8. Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PUBMED Abstract]
  9. Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin's lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996. [PUBMED Abstract]

Treatment for Aggressive, Recurrent Adult NHL



Standard Treatment Options for Aggressive, Recurrent Adult NHL

In a retrospective review of multiple international trials, 636 patients were identified as having refractory diffuse large B-cell lymphoma (DLBCL), which was defined as progression or stable disease during or just at completion of full-course chemotherapy or relapse within 1 year after autologous stem cell transplantation (SCT).[1] With subsequent therapy the objective response rate was 26%, complete response (CR) rate was 7%, median overall survival (OS) was 6.3 months, and only 20% of patients were alive at 2 years.
Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
  1. Bone marrow or stem cell transplantation.
  2. Re-treatment with standard agents.
  3. Palliative radiation therapy.

Bone marrow or stem cell transplantation

Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed.[2] Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[3-7]
Evidence (BMT):
  1. In a prospective, randomized study, (EORTC-PARMA), 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival (EFS) was significantly improved with transplantation (46% vs. 12%). OS was also significantly better with transplantation (53% vs. 32%).[8][Level of evidence: 1iiA] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.
    In general, patients who responded to initial therapy and who responded to conventional therapy for relapse before the BMT have had the best results.[9]
  2. In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[10][Level of evidence: 3iiiA]
Peripheral stem cell transplantation (SCT) has yielded results equivalent to standard autologous SCT.[11,12] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[13][Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous SCT can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[14,15]; [16][Level of evidence: 3iiiDiv]
Evidence (peripheral SCT):
  • In a randomized prospective trial, 396 patients with DLBCL in first relapse or who were refractory to first-line therapy received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous SCT; there was no difference in 3-year EFS or OS.[17][Level of evidence: 1iiA]
  • In a randomized prospective trial, 619 patients with relapsed or refractory aggressive lymphoma received either R-DHAP or R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin) followed by autologous SCT; at a median follow-up of 53 months, there was no difference in EFS or OS, but patients who received R-GDP reported less toxicity.[18][Level of evidence: 1iiC]

Re-treatment with standard agents

In general, re-treatment with standard agents rarely produces a cure in patients whose lymphomas relapse.[19] Several salvage chemotherapy regimens are available.[20-22]
  • Rituximab alone can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).[23]; [24][Level of evidence: 3iiiDiv]
  • Radiolabeled anti-CD20 monoclonal antibodies, such as iodine I 131-tositumomab (no longer commercially available) and yttrium Y 90-ibritumomab tiuxetan, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.[25,26]; [27][Level of evidence: 3iiiDiv]
  • In two phase II trials, 49 patients showed a 19% to 35% overall response rate to lenalidomide with or without rituximab.[28,29][Level of evidence: 3iiiDiv]
Relapse with indolent lymphoma
Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma.[25,26] Not infrequently, an aggressive lymphoma may relapse as a small cell (indolent) lymphoma. Such a situation occurs with indolent lymphoma in the bone marrow and aggressive lymphoma in a nodal site. Patients may present in such a manner, and chemotherapy might successfully eradicate the peripheral disease while failing to eliminate the small cell component from the bone marrow. The clinical significance and natural history of this pattern of disease is not well defined.
CAR T-cell therapy
Multiple trials describe patients with refractory large B-cell lymphoma who underwent an infusion of T cells that were engineered to express a chimeric antigen receptor (CAR) to target the CD19 antigen expressed on the malignant B cells using three different constructs: axicabtagene ciloleucel, tisagenecleucel, and lisocabtagene maraleucel.[30-32] Each study reported a 50% to 60% CR, but the long-term durability of response is yet to be determined.[30][Level of evidence: 3iiiDiv] This represents a therapeutic option for patients with otherwise refractory or resistant disease. Patients who respond adequately may receive an autologous SCT or allogeneic SCT consolidation.

Palliative radiation therapy

In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy.[33] Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[34]

Treatment Options Under Clinical Evaluation for Aggressive, Recurrent Adult NHL

Treatment options under clinical evaluation include the following:
  • SCT. The indolent lymphomas may relapse with an aggressive histology (i.e., histologic conversion). The durability of the second remission may be short, and clinical trials, such as autologous or allogeneic peripheral SCT, can be considered.[35-38]

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. Crump M, Neelapu SS, Farooq U, et al.: Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 130 (16): 1800-1808, 2017. [PUBMED Abstract]
  2. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
  3. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
  4. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PUBMED Abstract]
  5. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PUBMED Abstract]
  6. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994. [PUBMED Abstract]
  7. Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PUBMED Abstract]
  8. Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PUBMED Abstract]
  9. Vellenga E, van Putten WL, van 't Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008. [PUBMED Abstract]
  10. Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PUBMED Abstract]
  11. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PUBMED Abstract]
  12. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PUBMED Abstract]
  13. Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PUBMED Abstract]
  14. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011. [PUBMED Abstract]
  15. Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PUBMED Abstract]
  16. Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008. [PUBMED Abstract]
  17. Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010. [PUBMED Abstract]
  18. Crump M, Kuruvilla J, Couban S, et al.: Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32 (31): 3490-6, 2014. [PUBMED Abstract]
  19. Larouche JF, Berger F, Chassagne-Clément C, et al.: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol 28 (12): 2094-100, 2010. [PUBMED Abstract]
  20. Rodriguez MA, Cabanillas FC, Velasquez W, et al.: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13 (7): 1734-41, 1995. [PUBMED Abstract]
  21. Rizzieri DA, Sand GJ, McGaughey D, et al.: Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma. Cancer 100 (11): 2408-14, 2004. [PUBMED Abstract]
  22. Kewalramani T, Zelenetz AD, Nimer SD, et al.: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103 (10): 3684-8, 2004. [PUBMED Abstract]
  23. Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998. [PUBMED Abstract]
  24. Tobinai K, Igarashi T, Itoh K, et al.: Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol 15 (5): 821-30, 2004. [PUBMED Abstract]
  25. Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PUBMED Abstract]
  26. Witzig TE, Gordon LI, Cabanillas F, et al.: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20 (10): 2453-63, 2002. [PUBMED Abstract]
  27. Wiseman GA, Gordon LI, Multani PS, et al.: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 99 (12): 4336-42, 2002. [PUBMED Abstract]
  28. Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011. [PUBMED Abstract]
  29. Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 26 (30): 4952-7, 2008. [PUBMED Abstract]
  30. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PUBMED Abstract]
  31. Schuster SJ, Bishop MR, Tam CS, et al.: Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 380 (1): 45-56, 2019. [PUBMED Abstract]
  32. Locke FL, Ghobadi A, Jacobson CA, et al.: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20 (1): 31-42, 2019. [PUBMED Abstract]
  33. Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PUBMED Abstract]
  34. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]
  35. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]
  36. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
  37. Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
  38. Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]

NHL During Pregnancy



General Information About NHL During Pregnancy

Non-Hodgkin lymphomas (NHL) occur more frequently than Hodgkin lymphoma in an older population. This age difference may account for fewer reports of NHL in pregnant patients.[1]

Stage Information for NHL During Pregnancy

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (Refer to the Stage Information for Adult NHL section of this summary for more information.)

Treatment Option Overview for NHL During Pregnancy

Table 5. Treatment Options for Non-Hodgkin Lymphoma (NHL) During Pregnancy

Indolent NHL During Pregnancy

Treatment may be delayed for those women with an indolent NHL.

Aggressive NHL During Pregnancy

Immediate therapy

According to anecdotal case series, most NHL in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1,3-5] Consequently, some investigators favor immediate therapy, even during pregnancy.[5] In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta.[6] One-half of the patients received therapy antepartum, and the 6-month survival was reported at 53%, with a live-birth rate of 83%.[6][Level of evidence: 3iiiDiv]
A multicenter retrospective analysis of 50 patients described pregnancy termination in 3 patients, deferral of therapy to postpartum in 15 patients (median 30 weeks gestation), and antenatal therapy applied to the remaining 32 patients (median 21 weeks gestation, all done after the first trimester).[7] With a median follow-up of 41 months, the 3-year progression-free survival was 53%, and overall survival was 82%, using R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or modifications of this regimen.[7][Level of evidence: 3iiiDiv]

Early delivery when feasible

For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy.

Termination of pregnancy

Termination of pregnancy in the first trimester may be an option that allows immediate therapy for women with aggressive NHL.
Evidence (treatment effect on children exposed in utero):
  • With follow-up ranging from several months to 11 years, children who were exposed to high-dose doxorubicin-containing combination chemotherapy in utero (especially during the second and third trimester) have been found to be normal.[5,8-10] For most of the chemotherapeutic agents used for the treatment of NHL, there are no data regarding long-term effects on children exposed in utero.
  • In one anecdotal case, a newborn exposed to a rituximab-containing regimen in utero was born with no circulating B lymphocytes. The newborn was otherwise normal and recovered the circulating B lymphocytes by age 6 months with no unusual or persisting intercurrent infections.[11]


References
  1. Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PUBMED Abstract]
  2. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PUBMED Abstract]
  3. Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin's lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985. [PUBMED Abstract]
  4. Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin's lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991. [PUBMED Abstract]
  5. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PUBMED Abstract]
  6. Horowitz NA, Benyamini N, Wohlfart K, et al.: Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. Lancet Oncol 14 (7): e275-82, 2013. [PUBMED Abstract]
  7. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PUBMED Abstract]
  8. Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin's lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990. [PUBMED Abstract]
  9. Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin's lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991. [PUBMED Abstract]
  10. Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990. [PUBMED Abstract]
  11. Mandal PK, Dolai TK, Bagchi B, et al.: B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen. Indian J Pediatr 81 (10): 1092-4, 2014. [PUBMED Abstract]

Changes to This Summary (07/25/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Indolent NHL
Added text to state that an alternative prognostic index using only beta-2-microglobulin and initial bone marrow involvement has the disadvantage of requiring an invasive test not usually required outside the context of a clinical trial (cited Bachy et al. as reference 15).
Added Lockmer et al. as reference 21.
Added text to state that patients with lymphoplasmacytic lymphoma should be checked for associated hepatitis C virus infection.
Added text to state that in the rare case of lymphoplasmacytic lymphoma involving the central nervous system, ibrutinib resulted in an 85% response rate in an anecdotal series of 28 patients (cited Castillo et al. as reference 65 and level of evidence 3iiiDiv).
Added text to state that a prognostic index for all of the marginal zone lymphomas has three adverse prognostic factors: age 70 years or older, stage III or stage IV disease, and high lactate dehydrogenase (LDH) level (cited Thieblemont et al. as reference 74). Also added that fewer than 10% of patients transform to a higher-grade lymphoma; risk factors in one retrospective review included elevated LDH, more than four nodal sites at the time of initial diagnosis of marginal zone lymphoma, and failure to achieve complete response after initial treatment (cited Alderuccio et al. as reference 75).
Aggressive NHL
Added Mehta-Shah et al. as reference 69.
Added Schmitz et al. as reference 114.
Added text to state that mantle cell lymphoma may be divided into two clinical subtypes: a classical version with lymphadenopathy with high SOX-11 expression that manifests with an aggressive clinical course and a worse prognosis versus a leukemic, non-nodal version with low SOX-11 expression and a more indolent course and a better prognosis (cited Clot et al. as reference 177). Also added that there is frequent overlap on presentation with these subtypes, and the therapeutic implication remains unclear; however, both of these versions can converge later in their course into a blastoid phenotype or treatment-resistant phenotype due to genomic instability and selection (cited Dreyling et al. as reference 178).
Added Gerson et al. and Ruan et al. as references 185 and 190, respectively.
Added Shimada et al. as reference 226.
Treatment Option Overview for Adult NHL
Added text to state that patients with a resolved hepatitis B virus (HBV) infection are at risk of reactivation of HBV and require monitoring of HBV DNA. Also added that prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients (cited Kusumoto et al. as reference 10).
Treatment for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL
Added Brady et al. as reference 6.
Treatment for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Added text about results of a prospective randomized trial of 447 patients with indolent and mantle cell lymphoma (cited Flinn, van der Jagt et al. as reference 23 and level of evidence 1iiDiii).
Added Flinn, Miller et al. as reference 52.
Added Leonard et al. as reference 54.
Treatment for Indolent, Recurrent Adult NHL
Added Lockmer et al. and Canellos as references 19 and 21, respectively.
Revised text to state that with a median follow-up of 31.8 months, the 2-year overall survival favored the obinutuzumab combination (cited Cheson et al. as reference 26 and level of evidence 1iiA). Also added text to state that the contribution of maintenance therapy to the outcome could not be assessed in this design.
Added Hepatitis B as a new subsection.
Treatment for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
Added R-ACVBD to list of drug combinations for patients with advanced stages of aggressive non-Hodgkin lymphoma.
Added Casasnovas et al. as reference 9.
Revised text to state that clinical trials continue to explore modifications of R-CHOP. Also added text to state that there is no validated trial for interim positron emission tomography–based treatment intensification (cited Dührsen et al. as reference 10).
Added Hepatitis B as a new subsection.
Treatment for Aggressive, Recurrent Adult NHL
Revised text to state that multiple trials describe patients with refractory large B-cell lymphoma who underwent an infusion of T cells that were engineered to express a chimeric antigen receptor to target the CD19 antigen expressed on the malignant B cells using three different constructs: axicabtagene ciloleucel, tisagenecleucel, and lisocabtagene maraleucel (cited Schuster et al. and Locke et al. as references 31 and 32, respectively). Also revised text to state that each study reported a 50% to 60% complete response, but the long-term durability of response is yet to be determined.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Adult Non-Hodgkin Lymphoma Treatment is:
  • Eric J. Seifter, MD (Johns Hopkins University)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Adult Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389492]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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