Diffuse Large B-Cell Lymphoma (Non-Hodgkin Lymphoma) Treatment Protocols 

Updated: Apr 14, 2016
  • Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Treatment Protocols

Treatment recommendations for patients with diffuse large B-cell lymphoma (DLBCL) begin with evaluating the extent of the disease, performance status of the patient, and histologic subtypes. Treatment of localized and advanced disease varies considerably.

Below is a general treatment algorithm for DLBCL, followed by treatment recommendations for different stages of disease and for relapsed or refractory disease. [1, 2, 3]

General DLBCL treatment algorithm

Diagnosis of DLBCL:

  • Staging/IPI score/bulky disease
  • Assess end-organ function
  • Establish therapy endpoints (ie, cure vs palliation)

Stage I/II (nonbulky) disease:

  • Rituximab (R) plus cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) for 3-4 cycles
  • Follow with involved field radiation therapy (IFRT)
  • If positron emission tomography (PET) is positive after 4 cycles, administer 2 more cycles before IFRT
  • If relapse occurs, see step 4

Advanced-stage (stage III-IV) or bulky stage II disease:

  • R+CHOP every 21 d for 6 cycles, with or without IFRT for bulky sites
  • Prophylactic intrathecal (IT) chemotherapy in selected cases or
  • Clinical trial with correlative science studies (eg, R+CHOP-like and other biological agents or small molecules and/or other novel monoclonal antibodies [mAbs] or immunoconjugates)

In cases of relapse:

  • Staging/IPI score/bulky disease
  • Assess end-organ function

In relapse patients, collect lymphoid tissue and store for future analysis or current research evaluating gene profiling, proteomic analysis, biomarkers of disease (MUM-1, Bcl-6, and CD10), and preclinical studies with novel agents

Relapse patients eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT):

  • Platinum-based salvage chemotherapy, [4] including rituximab, ifosfamide, carboplatin, and etoposide (RICE) for 2-3 cycles or
  • Rituximab plus cisplatin, cytarabine, and dexamethasone (DHAP) for 2-3 cycles
  • If partial or complete response is achieved, use HDC and ASCT
  • Observation or clinical trials evaluating agents in the maintenance setting may be recommended
  • If patient relapses, consider clinical trials evaluating novel agents (eg, bortezomib, lenalidomide, or immunoconjugates) or
  • Radioimmunotherapy (RIT)

Relapse patients not eligible for HDC and ASCT:

  • Palliative chemotherapy (gemcitabine-based therapy
  • Clinical trials evaluating novel agents (eg, bortezomib, lenalidomide, or immunoconjugates) or
  • RIT

Treatment recommendations for early-stage disease

Stage I and selected stage II:

Patients without adverse risk factors present:

  • R+CHOP: Combined therapy with rituximab 375 mg/m 2 IV on day 1 plus  cyclophosphamide 750 mg/m 2 IV on day 1 or 3 plus  doxorubicin 50 mg/m 2 IV on day 1 or 3 plus  vincristine 1.4 mg/m 2 (maximum dose, 2 mg) IV on day 1 or 3 plus  prednisone 40 mg/m 2 PO on days 1-5 or 3-8; every 21d for 3 cycles [5]
  • Radiographic studies including functional imaging (eg, PET scan) to document response to treatment should be done before initiation of IFRT and/or at the end of therapy
  • Always confirm residual PET abnormalities with biopsy before modifying therapy

Patients with adverse risk factors present:

  • R+CHOP: Combined therapy with rituximab plus  cyclophosphamide 750 mg/m 2 IV on day 1 or 3 plus  doxorubicin 50 mg/m 2 IV on day 1 or 3 plus  vincristine 1.4 mg/m 2 (maximum dose, 2 mg) IV on day 1 or 3 plus  prednisone 40 mg/m 2 PO on days 1-5 or 3-8; every 21d for 3 cycles followed by IFRT [5] or
  • R+CHOP: Rituximab 375 mg/m 2 IV on day 1 plus  cyclophosphamide 750 mg/m 2 IV on day 1 or 3 plus  doxorubicin 50 mg/m 2 IV on day 1 or 3 plus  vincristine 1.4 mg/m 2 (maximum dose, 2 mg) IV on day 1 or 3 plus  prednisone 40 mg/m 2 PO on days 1-5 or 3-8; every 21d for 6 cycles with or without IFRT [6]
  • Radiographic studies including functional imaging (eg, PET scan) to document response to treatment should be done before initiation of IFRT and/or at the end of therapy
  • Always confirm residual PET abnormalities with biopsy before modifying therapy

Treatment recommendations for advanced-stage disease

Stages III-IV:

  • R+CHOP: Rituximab 375 mg/m 2 IV on day 1 plus  cyclophosphamide 750 mg/m 2 IV on day 1 or 3 plus  doxorubicin 50 mg/m 2 IV on day 1 or 3 plus  vincristine 1.4 mg/m 2 (maximum dose, 2 mg) IV on day 1 or 3 plus  prednisone 40 mg/m 2 PO on days 1-5 or 3-8; every 21d for 6 cycles with or without IFRT [6, 7]
  • Consider radiation therapy to bulky sites of disease at the end of chemoimmunotherapy

Prophylactic intrathecal chemotherapy (selected cases)

Prophylactic IT chemotherapy with low-dose methotrexate (eg, 12 mg) should be routinely administered to DLBCL patients with the following characteristics [8, 9] :

  • More than one extranodal site of disease
  • Testicular or breast involvement, regardless of stage
  • Lymphoblastic variants
  • Oropharyngeal or paraspinal sites of involvement
  • Bone marrow involvement
  • Concomitant infection with HIV

Treatment recommendations for relapsed or refractory disease

Patients eligible for HDC-ASCT (treatment goal = cure):

A vast number of regimens are used in the treatment of patients with relapsed or refractory DLBCL. These are primarily based on chemotherapy agents that are not cross-resistant to those used in the front-line setting, with or without rituximab. The goal of salvage regimens is to achieve maximum tumor burden cytoreduction in preparation for HDC with ASCT (HDC-ASCT). [10]

  • RICE: Rituximab 375 mg/m 2 day 1 plus  ifosfamide 5 g/m 2 on day 2 plus  carboplatin AUC 5 plus  etoposide 100 mg/m 2 daily on days 1-3; every 14 d [11] (see also the Carboplatin AUC Dose Calculation [Calvert formula] calculator) or
  • ICE: Ifosfamide 5 g/m 2 on day 2 plus  carboplatin AUC 5 plus  etoposide 100 mg/ m 2 daily on days 1-3; every 14d [12] or
  • GDP: Gemcitabine 1000 mg/m 2 on days 1 and 8 plus  dexamethasone 40 mg on days 1-4 plus  cisplatin 75 mg/m 2 on day 1; every 21d [13] or
  • GEM-P: Gemcitabine 1000 mg/m 2 on days 1 and 8 plus  methylprednisolone 1000 mg/m 2 on days 1-5 plus  cisplatin 100 mg/m 2 on day 15; every 28 d [14, 15] or
  • Gem-P: Gemcitabine 1000 mg/m 2 on days 1 and 8 plus  cisplatin 100 mg/m 2 on day 1; every 21d [16, 17] or
  • R+GEMOX: Rituximab 375 mg/m 2 plus  gemcitabine 1000 mg/m 2 plus  oxaliplatin 100 mg/m 2 on day 1; every 14 d [17] or
  • ESHAP: Etoposide 40 mg/m 2/day plus  methylprednisolone 500 mg/day plus  cisplatin 25 mg/m 2/day by continuous IV infusion (CIVI) for 4 d  plus  cytarabine (Ara-C) 2 g/m 2 on day 5 [18] or
  • DHAP: Dexamethasone 40 mg on days 1-4 plus  cytarabine 2 g/m 2 every 12h for 2 doses on day 2 plus  cisplatin 100 mg/m 2 on day 1; every 21d [19] or
  • R-DHAP: Dexamethasone 40 mg on days 1-4 plus  cytarabine 2 g/m 2 every 12h for 2 doses on day 2 plus  cisplatin 100 mg/m 2 on day 3; every 21 d plus  rituximab 375 mg/m 2 weekly for 4 wk starting on day 1 of first cycle [20] or
  • R-DHAP-VIM-DHAP: Cisplatin 100 mg/m 2 on day 1 by continuous IV infusion plus  cytarabine 2 g/m 2 every 12 h for 2 doses on day 2 plus  dexamethasone 40 mg/day on days 1-4; VIM = etoposide 90 mg/m 2 on days 1, 3, and 5 plus  ifosfamide 1200 mg/m 2 IV on days 1-5 plus  methotrexate 30 mg/m 2 IV on days 1 and 5; rituximab 375 mg/m 2 is administered on day 5 of the DHAP courses or on day 6 of the VIM course [21] or
  • DHAP-VIM-DHAP: Cisplatin 100 mg/m 2 on day 1 by continuous IV infusion plus  cytarabine 2 g/m 2 every 12 h for 2 doses on day 2 plus  dexamethasone 40 mg/day on days 1-4; VIM = etoposide 90 mg/m 2 on days 1, 3, and 5 plus  ifosfamide 1200 mg/m 2 IV on days 1-5 plus  methotrexate 30 mg/m 2 IV on days 1 and 5 [21]

Patients not eligible for HDC-ASCT (treatment goal = palliation):

  • GV: Gemcitabine 1000 mg/m 2 plus  vinorelbine 30 mg/m 2 on days 1 and 8; every 21 d [22] or
  • GVP: Gemcitabine 1000 mg/m 2 plus  vinorelbine 30 mg/m 2 on days 1 and 8 plus  prednisone 100 mg on days 1-8; every 21d [23] or
  • ViGePP: Vinorelbine 25 mg/m 2 plus  gemcitabine 800 mg/m 2 on days 1 and 8 plus  procarbazine 100 mg/m 2 on days 1-7 plus  prednisone 60 mg/m 2 on days 1-15; every 28 d [24] or
  • IEV: Ifosfamide 2500 mg/m 2 plus  etoposide 150 mg/m 2 on days 1-3 plus  epirubicin 100 mg/m 2 on day 1; every 21 d [24, 25] or
  • MINE: Ifosfamide 2660 mg/m 2/day on days 1-3 plus  etoposide 300 mg/m 2 in 1 dose on days 1-3; followed by ifosfamide 3300mg/m 2 on days 1-3 plus  mitoxantrone 20 mg/m 2 on day 1 if less than complete response is achieved [26] or
  • IVAD: Ifosfamide 1500 mg/m 2 plus  etoposide 100 mg/m 2 plus  cytarabine 100 mg/m 2 plus  dexamethasone 40 mg on days 1-5; every 21d [27] or
  • Mini-BEAM: Busulfan 60 mg/m 2 on day 1 plus  etoposide 75 mg/m 2 on days 2-5 plus  cytarabine 100 mg/m 2 every 12h on days 2-5 plus  melphalan 30 mg/m 2 on day 6; every 28d [28, 29] or
  • EPOCH: Doxorubicin 10 mg/m 2 plus  etoposide 50 mg/m 2 plus  vincristine 0.4 mg/m 2 by continuous IV infusion on days 2-4 plus  cyclophosphamide 750 mg/m 2 on day 6 plus  prednisone 60 mg/m 2 on days 1-6; every 21 d [30] or
  • R-EPOCH: Rituximab 375 mg/m 2 IV on day 1 plus  doxorubicin 15 mg/m 2 plus  etoposide 65 mg/m 2 plus  vincristine 0.5 mg/day by continuous IV infusion on days 2-4 plus  cyclophosphamide 750 mg/m 2 on day 5 plus  prednisone 60 mg/m 2 on days 1-14; every 21d [31] or
  • Lenalidomide 25 mg PO on days 1-21; every 28 d until progression or unacceptable toxicity [32]