Treatment for Indolent, Recurrent Adult NHL
Standard Treatment Options for Indolent, Recurrent Adult NHL
Chemotherapy (single agent or combination)
Radiolabeled anti-CD20 monoclonal antibodies
Palliative radiation therapy
Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL
Current Clinical Trials
In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 1 year. Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates. Patients who experience a relapse with indolent lymphoma can often have their disease controlled with single agent or combination chemotherapy, rituximab (an anti-CD20 monoclonal antibody), lenalidomide, radiolabeled anti-CD20 monoclonal antibodies, or palliative radiation therapy.[2,3] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.
In a retrospective review of 325 patients between 1972 and 1999, the risk of histologic transformation was 30% by 10 years from diagnosis. In this series, high risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.
A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate (11%) to a higher-grade histology. The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series describes a better prognosis for patients with transformation than was experienced by patients in the prerituximab era.
(Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for descriptions of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials should be considered.Standard Treatment Options for Indolent, Recurrent Adult NHL
Standard treatment options for indolent, recurrent adult NHL include the following:
- Chemotherapy (single agent or combination).
- Radiolabeled anti-CD20 monoclonal antibodies.
- Palliative radiation therapy.
Significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, both as single agents and in combination with other drugs.[8-13] Patients may respond to the original induction regimen again, especially if the duration of remission exceeds one year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.Rituximab
- In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after retreatment with combination chemotherapy (with or without rituximab during induction) or rituximab alone; all trials showed prolongation of response duration,[19-21] and one trial demonstrated improvement in median progression-free survival (PFS) (3.7 years vs. 1.3 years, P < .001) and OS (74% vs. 64%, P = .07) at 5 years with a median follow-up of 39 months favoring maintenance rituximab.
Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab, have also been reported before and after cytotoxic chemotherapy.[23-28][Level of evidence: 1iiDiii]
A prospective trial of 409 patients with follicular lymphoma who responded to induction chemotherapy were randomly assigned to yttrium-90 ibritumomab or no further consolidation; with a median follow-up of 7.3 years, the 8-year PFS favored ibritumomab (41% vs. 22% [HR, 0.47; P < .001), but there was no difference in OS.[Level of evidence: 1iiDiii]Palliative radiation therapy
Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy for patients with indolent and aggressive relapsed disease.Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL
Treatment options under clinical evaluation include the following:
- Stem cell transplant. In many institutions, autologous or allogeneic stem cell transplantations are being used for patients whose disease has relapsed. Such an approach is still under evaluation but should be considered in the context of a clinical trial.[31-35]
Evidence (stem cell transplant):
- The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like induction chemotherapy and then randomly assigned them to autologous stem cell transplantation versus interferon maintenance. With a median follow-up of 4.2 years, the 5-year PFS was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[Level of evidence: 1iiDiii]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin's lymphoma: implications for marrow transplantation. J Clin Oncol 10 (6): 942-7, 1992. [PUBMED Abstract]
- Peterson BA: Current treatment of follicular low-grade lymphomas. Semin Oncol 26 (5 Suppl 14): 2-11, 1999. [PUBMED Abstract]
- Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PUBMED Abstract]
- 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]
- Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PUBMED Abstract]
- 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]
- Link BK, Maurer MJ, Nowakowski GS, et al.: Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 31 (26): 3272-8, 2013. [PUBMED Abstract]
- Hochster HS, Kim KM, Green MD, et al.: Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10 (1): 28-32, 1992. [PUBMED Abstract]
- Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 10 (3): 371-7, 1992. [PUBMED Abstract]
- Redman JR, Cabanillas F, Velasquez WS, et al.: Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma. J Clin Oncol 10 (5): 790-4, 1992. [PUBMED Abstract]
- Tsimberidou AM, McLaughlin P, Younes A, et al.: Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100 (13): 4351-7, 2002. [PUBMED Abstract]
- Tulpule A, Schiller G, Harvey-Buchanan LA, et al.: Cladribine in the treatment of advanced relapsed or refractory low and intermediate grade non-Hodgkin's lymphoma. Cancer 83 (11): 2370-6, 1998. [PUBMED Abstract]
- Klasa RJ, Meyer RM, Shustik C, et al.: Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20 (24): 4649-54, 2002. [PUBMED Abstract]
- Davis TA, White CA, Grillo-López AJ, et al.: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 17 (6): 1851-7, 1999. [PUBMED Abstract]
- Piro LD, White CA, Grillo-López AJ, et al.: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10 (6): 655-61, 1999. [PUBMED Abstract]
- Davis TA, Grillo-López AJ, White CA, et al.: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18 (17): 3135-43, 2000. [PUBMED Abstract]
- Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PUBMED Abstract]
- Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PUBMED Abstract]
- van Oers MH, Van Glabbeke M, Giurgea L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 28 (17): 2853-8, 2010. [PUBMED Abstract]
- van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PUBMED Abstract]
- Martinelli G, Schmitz SF, Utiger U, et al.: Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28 (29): 4480-4, 2010. [PUBMED Abstract]
- Witzig TE, Wiernik PH, Moore T, et al.: Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 27 (32): 5404-9, 2009. [PUBMED Abstract]
- 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]
- Witzig TE, Flinn IW, Gordon LI, et al.: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol 20 (15): 3262-9, 2002. [PUBMED Abstract]
- Ansell SM, Ristow KM, Habermann TM, et al.: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol 20 (18): 3885-90, 2002. [PUBMED Abstract]
- Davies AJ, Rohatiner AZ, Howell S, et al.: Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 22 (8): 1469-79, 2004. [PUBMED Abstract]
- 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]
- Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006. [PUBMED Abstract]
- Morschhauser F, Radford J, Van Hoof A, et al.: 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol 31 (16): 1977-83, 2013. [PUBMED Abstract]
- 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]
- Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000. [PUBMED Abstract]
- Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000. [PUBMED Abstract]
- Khouri IF, McLaughlin P, Saliba RM, et al.: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111 (12): 5530-6, 2008. [PUBMED Abstract]
- Sebban C, Brice P, Delarue R, et al.: Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 26 (21): 3614-20, 2008. [PUBMED Abstract]
- Thomson KJ, Morris EC, Milligan D, et al.: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28 (23): 3695-700, 2010. [PUBMED Abstract]
- Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PUBMED Abstract]