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Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

Treatment for Indolent, Recurrent Adult NHL

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.[1]

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.[4] 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.[5] 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.[6]

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.[7] 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)

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 1 year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.


Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[14-17] Rituximab can also be combined with combination chemotherapy.[18]

Evidence (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.[20]


Responses of 20% to 30% have been reported for lenalidomide, especially for follicular lymphoma and small lymphocytic lymphoma.[22][Level of evidence: 3iiiDiv]

Radiolabeled anti-CD20 monoclonal antibodies

Durable responses to radiolabeled monoclonal antibodies, such as yttrium-90 ibritumomab (commercially available) and iodine-131 tositumomab (commercially unavailable), 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.[29][Level of evidence: 1iiDiii]

Palliative radiation therapy

Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy in two fractions for patients with indolent and aggressive relapsed disease.[30] In a prospective randomized trial, treatment with 4 Gy was inferior to treatment with 24 Gy in 12 fractions in PFS (77% vs. 92%, P < .0001).[31][Level of evidence: 1iiDiii]

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.[32-36]

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.[37] 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.[37][Level of evidence: 1iiDiii]

Current Clinical Trials

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.


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  • Updated: April 24, 2015