martes, 30 de julio de 2019

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute 8/9

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute

National Cancer Institute

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

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 2 years.[1] Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates.[2]
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.[3,4] 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 can be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type.[5] 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.[6] 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.[7]
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.[8] 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 can be considered.


Standard Treatment Options for Indolent, Recurrent Adult NHL

Standard treatment options for indolent, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
  1. Chemotherapy (single agent or combination).
  2. Rituximab.
  3. Obinutuzumab.
  4. Lenalidomide.
  5. Radiolabeled anti-CD20 monoclonal antibodies.
  6. Palliative radiation therapy.

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.[9-14] 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

Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[15-19] Rituximab can also be combined with combination chemotherapy.[20,21]
Evidence (rituximab):
  1. In three randomized, prospective studies involving previously treated patients with relapsed indolent lymphoma, patients were randomly assigned to rituximab maintenance after re-treatment with combination chemotherapy (with or without rituximab during induction) or rituximab alone.[22-24]
    • All trials showed prolongation of response duration,[22-24] 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.[23]

Obinutuzumab

Obinutuzumab is a CD20-binding monoclonal antibody with alternative epitope binding.
Evidence (obinutuzumab):
  1. In a randomized prospective trial (NCT01059630) involving 396 patients with rituximab-refractory indolent lymphoma (mostly follicular lymphoma), patients received obinutuzumab plus bendamustine followed by obinutuzumab maintenance therapy for 2 years versus bendamustine alone with no maintenance therapy.[25,26][Level of evidence: 1iiA]
    • With a median follow-up of 31.8 months, the 2-year OS favored the obinutuzumab combination (74.5% vs. 65.1%) (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.47–0.96; P = .027). The median PFS also favored the obinutuzumab combination (25.8 months [95% CI, 19.5–41.1 months] vs. 14.1 months [95% CI, 12.6–16.0 months]) (HR, 0.57; 95% CI, 0.44–0.73; P < .001).[26][Level of evidence: 1iiA]
    • The contribution of maintenance therapy to the outcome could not be assessed in this design.

Lenalidomide

Responses of 20% to 56% have been reported for lenalidomide, especially in patients with follicular lymphoma and small lymphocytic lymphoma, with even higher responses noted for the combination of lenalidomide and rituximab.[27,28][Level of evidence: 3iiiDiv]

Radiolabeled anti-CD20 monoclonal antibodies

Durable responses to radiolabeled monoclonal antibodies, such as yttrium Y 90 (90Y)-ibritumomab tiuxetan (commercially available) and iodine I 131-tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[29-31][Level of evidence: 1iiDiii] However, the cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia is higher (4% vs. 1%; P+/02) in one of the randomized trials versus nonradiolabeled antibody with chemotherapy.[31]
Evidence (radiolabeled anti-CD20 monoclonal antibodies):
  1. In a prospective trial of 409 patients with follicular lymphoma who responded to induction chemotherapy, patients were randomly assigned to 90Y-ibritumomab tiuxetan or no further consolidation.[32]
    • With a median follow-up of 7.3 years, the 8-year PFS favored 90Y-ibritumomab tiuxetan (41% vs. 22% [hazard ratio, 0.47; P < .001]), but there was no difference in OS.[32][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.[33] 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).[34][Level of evidence: 1iiDiii]

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.[35]

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 (SCT) are being used for patients whose disease has relapsed. Such an approach is still under evaluation but can be considered in the context of a clinical trial.[36-40]
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 SCT versus interferon maintenance.[41] 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.[41][Level of evidence: 1iiDiii]

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
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  21. 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]
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  40. 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]
  41. 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]
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