Diffuse Large B-Cell Lymphoma (DLBCL)


R-CHOP is a chemoimmunotherapy regimen consisting of a combination of Rituxan® (rituximab) with cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin® (vincristine), and prednisone. It is used to treat both indolent and aggressive forms of non-Hodgkin lymphoma. 

R-CHOP as the First-Line Standard of Care

R-CHOP chemoimmunotherapy has been the standard for treating diffuse large B-cell lymphoma (DLBCL) for 2 decades, with a cure rate of approximately 70% in patients with DLBCL. The regimen includes a first-day treatment of intravenous (IV) rituximab at 375 mg/m2, IV cyclophosphamide at 750 mg/m2, IV doxorubicin at 50 mg/m2, IV vincristine at 1.4 mg/m2 with a dose cap of 2 mg, and oral prednisone at 100 mg daily on days 1 through 5.1,2

According to National Comprehensive Cancer Network (NCCN) guidelines, patients who have DLBCL with early bulky disease or advanced disease should receive 6 cycles of R-CHOP with or without radiotherapy. However, low-risk patients (stages I and II) can receive 4 cycles of R-CHOP with 2 additional doses of rituximab. R-CHOP may be administered in a 14- or 21-day cycle and may be followed by radiation therapy. For patients with an absolute contraindication to anthracyclines, etoposide can be substituted for hydroxydaunorubicin (ie, R-CEOP rather than R-CHOP). A long-term study found that R-CEOP is a valid alternative to R-CHOP in this setting, with the potential for cure.3,4

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How R-CHOP Works

R-CHOP is a systemic treatment, so it spreads throughout the body and the drugs kill rapidly dividing cells, such as cancer cells. Cyclophosphamide belongs to a class of drugs called alkylating agents; these are used to treat a variety of cancers, including breast cancer, multiple myeloma, and lymphoma. Cyclophosphamide is metabolized to an active form that inhibits protein synthesis through DNA and RNA crosslinking, preventing the division and growth of cancer cells.

Hydroxydaunorubicin is an anthracycline that can be used to treat many types of cancer, including breast, lung, and ovarian cancers. It blocks the activity of an enzyme, called topoisomerase 2, to halt the growth and division of cancer cells.6

Vincristine belongs to a group of drugs, called vinca alkaloids, that prevent cell division and tumor growth. It is used to treat many types of cancer, including advanced-stage breast cancer, lymphomas, and leukemia. It is injected intravenously, usually once a week, and can be used with other chemotherapeutic drugs. The length of the treatment depends upon the body’s response to the drug. Some of the side effects are nausea, vomiting, loss of hair, loss of appetite, sores in the mouth, and stomach pain.7

Prednisolone is an oral corticosteroid that helps to reduce inflammation, nausea, vomiting, allergic reactions, thrombocytopenia, and hypercalcemia. It decreases vasodilation, permeability of capillaries, and leukocyte migration to sites of inflammation. It mediates changes in gene expression and leads to multiple downstream effects including inhibition of neutrophil apoptosis.8

Rituximab is a chimeric type 1 monoclonal antibody directed against CD20, which is present on the surface of both normal and malignant B lymphocytes. Its mechanisms of action include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and the direct induction of apoptosis, which result in the elimination of cancerous B lymphocytes. Rituximab is approved by the US Food and Drug Administration for use in combination with anthracycline-based chemotherapy in patients with previously untreated DLBCL.9

The CHOP regimen was the standard of care for DLBCL in the 1990s,10 but then it was discovered that the addition of rituximab to this chemotherapy regimen improved the prognosis of patients with B-cell lymphomas.11 Rituximab, cyclophosphamide, hydroxydaunorubicin, and vincristine are given intravenously, whereas the steroid prednisolone is taken orally as a tablet.

R-CHOP in Clinical Studies

The clinical benefit of R-CHOP in DLBCL has been demonstrated in several clinical trials. The Groupe d’Etude des Lymphomes de l’Adulte (GELA) conducted a phase 3 trial comparing the use of R-CHOP to CHOP in older patients aged 60 to 80 years with DLBCL. The complete response rate was significantly higher in the patients treated with R-CHOP than in those treated with CHOP alone (76% vs 63%; P=.005). After a median follow-up of 2 years, event-free survival and overall survival were significantly longer (P <.001 and P=.007, respectively) in the patients treated with R-CHOP than in those treated with CHOP alone. These results were confirmed in a longer follow-up study.12,13

Another trial, RICOVER-60, compared 6 cycles of CHOP-14 (every 2 weeks) with and without rituximab in 1222 randomized patients. The results showed a higher rate of 3-year event-free survival when rituximab was added to 6 cycles of CHOP-14 (66.5% vs 47.2%).14

The MabThera International trial was a comparative (R-CHOP-like vs CHOP-like alone) phase 3 trial that included patients 18 to 60 years old. The study found that in the patients who were treated with R-CHOP, the 3-year event-free survival rate (79% vs 59%) and overall survival rate (93% vs 84%) were higher.15 

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References

  1. Definition of R-CHOP regimen–NCI Drug Dictionary. National Cancer Institute. Accessed August 29, 2022.
  2. Visco C, Li Y, Xu-Monette Y, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26:2103-2113. doi:10.1038/leu.212.83
  3. Candelaria M, Dueñas-Gonzalez A. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma. Ther Adv Hematol. 2021;12:2040620721989579. doi:10.1177/2040620721989579
  4. Moccia AA, Schaff K, Freeman C, et al. Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. Blood Adv. 2021;5(5):1483-1489.  doi:10.1182/bloodadvances.2020002982
  5. Ogino MH, Tadi P. Cyclophosphamide. StatPearls [Internet]. Updated July 4, 2022.
  6. Doxorubicin. MedlinePlus Drug Information. Accessed August 29, 2022.
  7. Vincristine injection. MedlinePlus Drug Information. Accessed August 29, 2022.
  8. Prednisolone. C21H28O5. PubChem. Accessed August 29, 2022.
  9. Hanif N, Anwer F. Rituximab. StatPearls [Internet]. Updated May 1, 2022.
  10. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002-1006. doi:10.1056/NEJM199304083281404
  11. Bezombes C, Fournié JJ, Laurent G. Direct effect of rituximab in B-cell-derived lymphoid neoplasias: mechanism, regulation, and perspectives. Mol Cancer Res. 2011;9(11):1435-1442. doi:10.1158/1541-7786.MCR-11-0154
  12. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. doi:10.1056/NEJMoa011795
  13. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23(18):4117-4126. doi:10.1200/JCO.2005.09.131
  14. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-116. doi:10.1016/S1470-2045(08)70002-0
  15. Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379-391. doi:10.1016/S1470-2045(06)70664-7

Reviewed by Debjyoti Talukdar, MD, on 8/30/2022.

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