What are the non-platinum-based chemotherapy regimens used in the treatment of diffuse large B-cell lymphoma (DLBCL)?

Updated: Aug 20, 2020
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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In the past, 4 non–platinum-containing regimens were used in the salvage regimen in preparation for HDC-ASCS. The antitumor activity of regimens such as methylprednisolone, ifosfamide, mitoxantrone, and etoposide (MINE); ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD); ifosfamide, epirubicin, and etoposide (IEV), or busulphan, etoposide, cytarabine, and melphalan (Mini-BEAM) is comparable to that observed with platinum-based regimen. [136, 137, 138, 139] Response rates to any of these 3 regimens in relapsed/refractory DLBCL (never exposed to rituximab) vary from 64-75%, and the safety profile is similar to platinum-containing regimens. [136, 137, 138, 139]

On the other hand, the use of these regimens has declined overtime for several reasons, such as (1) the restriction of anthracyclines in salvage regimens across previously CHOP/R-CHOP–treated patients to avoid cumulative cardiotoxicity, (2) the protection of stem cells by restricting the use of melphalan or busulphan in the salvage regimen prior to stem cell collection, and (3) the need to decrease nonhematological and hematological toxicity from high-dose ifosfamide-containing regimens by combining this agent with a platinum compound.

The most commonly used non–platinum-containing regimens are primarily gemcitabine based. These particular regimens are well tolerated in elderly patients, in patients with limited bone marrow reserve (ie, relapsed/refractory after HDC-ASCT), or those patients with multiple comorbid conditions. The hematological toxicity observed in clinical trials evaluating the efficacy and toxicity of nonplatinum gemcitabine-based regimens is significantly lower than in platinum-containing regimens. Grade 3-4 neutropenia and thrombocytopenia has been reported in only 20% and 10-25% of the patients, respectively. [140, 141]

Another strategy used by other investigators is to modify the schedule of administration of previously used agents. A good example of this approach is the development of the infusional regimen of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH), with or without rituximab. Wilson et al demonstrated that EPOCH was highly effective (74% overall response rate, with 24% CR) in relapsed/refractory aggressive non-Hodgkin lymphoma, with acceptable hematological and nonhematological toxicity. [142] The incident of cardiac toxicity was extremely low (3%), despite the fact that 94% of the patients enrolled had prior anthracycline exposure. [142, 143] Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell non-Hodgkin lymphoma treated with rituximab-EPOCH. [144]

The emergence of rituximab resistance is starting to be observed in patients with relapsed/refractory DLBCL. The evaluation of other biologically active monoclonal antibodies targeting CD20 (eg, ofatumumab), monoclonal antibodies directed against other key regulatory surface receptors (ie, CD40, CD22), or small-molecule inhibitors (eg, lenalidomide, proteasome inhibitors, mammalian target of rapamycin [mTOR] inhibitors) in combination with systemic chemotherapy is necessary to broaden the therapeutic armamentarium against relapsed/refractory DLBCL.

In summary, the incorporation of rituximab to standard doses of CHOP has resulted in improved clinical outcomes when compared with standard chemotherapy in patients with DLBCL and has raised the bar with respect to which new therapies are being evaluated in patients with aggressive lymphomas. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as frontline treatment of DLBCL is beyond dispute, previously accepted biomarkers of response (eg, Bcl-2 expression, IPI) also need reevaluation to raise new challenges in the therapeutic treatment of those patients in whom chemoimmunotherapy fails or who have relapse after chemoimmunotherapy.

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