Long-Term Follow-Up Indicates Survival with Addition of Rituxan® to CHOP in NHL

Long-Term Follow-Up Indicates Continued Improvement in Survival with Addition of Rituxan® to CHOP in NHL

R-CHOP Treatment of Non-Hodgkin’s Lymphoma

C. Dean Buckner, MD, Founding Member, Fred Hutchinson Cancer Center; Medically reviewed 10/2018

Rituxan® (rituximab) has become an integral part of the treatment of patients with B-cell NHL and when combined with cyclophosphamide, doxorubicin, Oncovin® and prednisone (R-CHOP) is the standard of care for many types of lymphoma.

NHL is a cancer of the lymph tissue, which is part of the body’s immune system. Lymph tissue is present in lymph nodes, lymph vessels, blood and bone marrow, which exist throughout the body. It is also found in organs such as the thymus, tonsils and spleen. Lymphocytes, the main cells in the lymph system, exist in two forms: B and T-cells. Each of these cells serves a specific function in aiding the body fight infection. The large majority of NHL cases involves cancer of the B-lymphocytes and is characterized by the excessive accumulation of these atypical cells. As a result, blood and lymph tissue is overcrowded, and the normal formation and function of blood and immune cells is suppressed. Additionally, the cancerous lymphocytes themselves do not function normally, further decreasing the body’s ability to fight infection.

Rituxan is a monoclonal antibody (protein designed in a laboratory) that binds to proteins on the surface of B-lymphocytes. This binding action stimulates the immune system to kill B-cells and causes the B-cells themselves to expire. A significant benefit of this approach is that Rituxan only targets cancer cells (B-cells), thus sparing healthy cells from destruction. In contrast, chemotherapy and radiation do not differentiate between cancer cells and healthy cells in the body, leading to potentially destructive side effects.

R-CHOP Improves Survival for Young Patients with Diffuse Large B Cell Lymphoma

According to an article published in the Lancet Oncology, the addition of Rituxan® (rituximab) to CHOP-like chemotherapy regimens improves survival in young patients with diffuse large B-cell lymphoma.

Researchers affiliated with the MabThera International Trial Group (MInT), which is a group that consists of physicians from 18 countries, conducted a clinical trial to evaluate compare R-CHOP to the CHOP alone in younger patients with DLBCL. This trial included 824 patients who were aged 18-60 years. Patients treated with R-CHOP had improved survival over those treated with CHOP alone:

  • At 3 years, event-free survival was achieved in 79% of patients treated with R-CHOP compared with only 59% of patients treated with CHOP only.
  • Overall survival at 3 years was 93% for patients treated with R-CHOP compared with 84% of patients treated with CHOP only.

R-CHOP Improves Survival in Elderly Patients with Diffuse Large Cell NHL

Researchers in France reported five-year data from a clinical trial evaluating the effectiveness of adding Rituxan to CHOP in elderly patients with B-cell NHL. This trial included 399 patients who had not received prior treatment. They were aged between sixty and eighty years. Patients were treated with either Rituxan plus CHOP (R-CHOP) or CHOP only. At five years, overall survival was greater in patients treated with R-CHOP-58 percent versus only 45 percent in patients treated with CHOP alone. The average duration of survival had not yet been reached at the time of publication in the group treated with R-CHOP. An average duration of survival of 3.1 years in patients treated with CHOP was observed. Cancer-free survival was also significantly improved in the group of patients treated with R-CHOP, compared to those treated with CHOP only. The addition of Rituxan to CHOP was well tolerated in this group of patients.

According another study published in Lancet Oncology, the addition of Rituxan® to the chemotherapy combination referred to as CHOP improves survival compared with CHOP alone in the treatment of elderly patients with aggressive B-cell non-Hodgkin’s lymphoma.

To compare different approaches to administering CHOP with or without Rituxan in the treatment of elderly patients with diffuse large B-cell lymphoma, researchers in Germany conducted a study among more than 1,000 patients between the ages of 61 and 80 years. Patients were divided into four treatment groups: 1) six cycles of CHOP alone; 2) eight cycles of CHOP alone; 3) six cycles of CHOP with Rituxan (CHOP-R); 4) eight cycles of CHOP-R. Patients were treated with radiation therapy if they had sites of bulky disease.

  • Six cycles of CHOP-R resulted in the best survival compared with the other three regimens.
  • Eight cycles of CHOP alone did not improve survival compared with six cycles of CHOP alone.
  • The addition of Rituxan to chemotherapy resulted in improved survival in both the six- and eight-cycle CHOP regimens.

The researchers concluded that six cycles of CHOP-R provides improved survival over eight cycles of CHOP-R or any regimen containing CHOP alone in elderly patients with aggressive B-cell NHL. These results confirm that six cycles of R-CHOP appears to be the optimal treatment regimen for these patients.

R-CHOP Improves Outcomes as Initial Therapy in Follicular Lymphoma

Researchers from Germany reported the results of a clinical trial to evaluate the use of Rituxan as initial therapy for 428 patients with newly diagnosed follicular lymphoma who were treated with either Rituxan plus CHOP (R-CHOP) or CHOP alone as initial therapy. Results indicated that the addition of Rituxan improved outcomes:

  • Complete disappearances of detectable cancer (complete responses) were achieved in 20% of patients treated with R-CHOP, versus 17% of patients treated with CHOP.
  • Partial disappearances of detectable cancer (partial responses) were achieved in 77% of patients treated with R-CHOP, versus 73% of patients treated with CHOP.
  • Overall survival at 2 years was 95% for patients treated with R-CHOP and 90% for patients treated with CHOP.

Treanda More Effective than Standard R-CHOP for Non-Hodgkin’s Lymphoma

The combination of Treanda® (bendamustine) and Rituxan® (rituximab) more than doubled progression-free survival compared with standard R-CHOP therapy among patients with indolent lymphoma and mantle cell lymphoma.

Treanda is a chemotherapy agent that combines the action of two types of agents, which attack cancerous cells through distinct pathways. It is approved for the treatment of recurrent NHL and CLL. Treanda is currently being evaluated for use in other types of cancer as well as in the initial treatment of NHL.

This phase III clinical trial evaluated the use of Treanda in the initial treatment of NHL. The study included 514 patients with previously untreated follicular, indolent, or mantle cell lymphomas who were randomly assigned to receive treatment with R-CHOP or with Treanda plus Rituxan. Earlier data suggested that Treanda plus Rituxan was as effective as R-CHOP and less toxic. Longer-term results indicate that the combination improves progression-free survival (PFS).

After a median follow-up of 45 months, the median PFS in the Treanda/Rituxan group was 69.5 months compared to 31.2 months in the R-CHOP group. Overall survival was similar between the two groups; however, nearly half of the R-CHOP patients whose disease continued to progress were allowed to cross over and receive the Treanda/Rituxan regimen. Because survival for indolent lymphomas tends to be very long, PFS is the most reliable measure of clinical benefit from therapies.

The researchers concluded that Treanda/Rituxan is more effective and less toxic than R-CHOP in the initial treatment of indolent and mantle cell lymphoma.

Treanda Plus Rituxan is Not Inferior to R-CHOP and R-CVP for advanced NHL

The combination of Treanda® (bendamustine) and Rituxan® was found to be noninferior to the commonly used chemotherapy regimens R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) in patients with previously untreated advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL), according to the results of a study presented at the 54th Annual Meeting of the American Society of Hematology in Atlanta, Georgia.

R-CHOP and R-CVP are two commonly used treatment approaches for NHL. Research has been ongoing to evaluate other treatment approaches in an effort to improve effectiveness and reduce side effects. Treanda is a chemotherapy agent that combines the action of two types of agents, which attack cancerous cells through distinct pathways. It is approved for the treatment of recurrent NHL and chronic lymphocytic leukemia (CLL). Treanda has been widely used in Europe for decades, but only became available in the U.S. in 2008. It is currently being evaluated for use in other types of cancer as well as in the initial treatment of NHL.

Previous research has indicated that Treanda/Rituxan offers a significant improvement in progression-free survival over R-CHOP in follicular NHL and MCL and this treatment regimen has become the standard in Germany. Researchers conducted the BRIGHT study, which compared the safety and efficacy of Treanda/Rituxan with standard treatment regimens of R-CHOP and R-CVP as first-line treatment for indolent NHL or MCL in order to confirm the results of the earlier study.

The study included 419 evaluable patients, 213 who were randomly assigned to receive Treanda/Rituxan and 206 who were randomized to either R-CHOP or R-CVP. The study used complete response as the primary endpoint, and showed no difference between the two treatment arms. The complete response rate for Treanda/Rituxan was 31 percent compared with 25 percent in the control group. The complete response ratio of 1.26 met the definition of noninferiority, but was not statistically significant for superiority. Overall response rates were 97 percent for Treanda/Rituxan compared with 91 percent for R-CHOP/R-CVP.

The toxicity profiles for Treanda/Rituxan and R-CHOP/R-CVP are distinct and the researchers suggest that toxicity should be considered in treatment selection. Patients in the Treanda/Rituxan arm experienced a higher incidence of nausea/vomiting, pyrexia, chills, drug hypersensitivity reactions, decreased appetite, rash, and pruritus. These patients experienced increased grade 3 or higher adverse events that included hypersensitivity reactions, opportunistic infection, and respiratory/thoracic disorders. Patients in the R-CHOP/R-CVP arms experienced a higher incidence of constipation, paresthesia, peripheral neuropathy, and alopecia. These patients experienced more frequent febrile neutropenia, alopecia, and neuropathy. More deaths occurred in the Treanda/Rituxan group (six patients, due to pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) than in the R-CHOP/R-CVP group (one patient, due to sepsis).

The researchers concluded that in patients with advanced indolent NHL and MCL, Treanda/Rituxan produces a complete response rate that is noninferior to that of R-CHOP/R-CVP. In the subgroup of patients with MCL, Treanda/Rituxan produces a significantly higher complete response rate (51% vs 24%). High overall response rates were attained in both treatment groups.

R-CHOP Induction Plus Rituxan Maintenance Improves Remission in Older Patients with Mantle Cell Lymphoma

Induction therapy with R-CHOP followed by maintenance with Rituxan® nearly doubled the remission duration in older patients with mantle cell lymphoma, according to the results of a study published in the New England Journal of Medicine.

Mantle cell lymphoma is a subset of NHL that accounts for approximately 5%–10% of all lymphomas. Older patients with mantle cell lymphoma typically have a poor long-term prognosis, with relapse or disease progression occurring within two to three years.

Researchers conducted a randomized clinical trial that included 560 patients age 60 or older with stage II to IV mantle cell lymphoma. The patients were randomly assigned to six cycles of Rituxan, fludarabine, and cyclophosphamide (R-FC) every 28 days or eight cycles of R-CHOP every 21 days. Patients who experienced a response then underwent a second randomization to maintenance therapy with Rituxan or interferon alfa, given until disease progression.

The primary analysis included 485 patients—246 who were assigned to R-FC and 239 who were assigned to R-CHOP. The median age of patients was 70 years. The results indicated that both groups had similar remission rates. More patients in the R-FC group demonstrated complete remission (40% vs. 34%); however, there was also a higher rate of progressive disease (14% vs. 5%) in the R-FC group. Four-year overall survival was significantly higher in the R-CHOP group—62 percent compared to 47 percent in the R-FC group.

Patients who responded to treatment underwent a second randomization and 143 patients received maintenance therapy with Rituxan while 131 received maintenance with interferon alfa. The results indicated that the remission duration was significantly longer in the Rituxan group compared to the interferon group. Rituxan reduced the risk of progression or death by 45 percent compared to interferon.

The researchers concluded that R-CHOP induction followed by maintenance therapy with Rituxan is effective for older patients with mantle-cell lymphoma.

Adding Revlimid to R-CHOP May Improve Outcomes of Selected Patients with NHL

The addition of Revlimid® (lenalidomide) to R-CHOP the standard treatment for NHL can overcome the negative prognostic effect of the non–germinal B-cell phenotype in diffuse large B-cell lymphoma which is associated with significantly worse outcomes with R-CHOP therapy compared with the germinal B-cell subtype.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, which is a cancer that begins in the cells of the immune system. The most widely used treatment for DLBCL is R-CHOP.

In this clinical study, 60 adults with untreated stage II to IV CD20-positive diffuse large B-cell lymphoma were treated with oral Revlimid in addition to standard-dose R-CHOP every 21 days for six cycles. All patients also received Neulasta® to reduce the risk of infection and ensure the chemotherapy could be delivered on time. The investigators designated this treatment new regimen as R2CHOP.

Among 60 evaluable patients receiving R2CHOP, 98% responded to treatment and 80% had complete disappearance of their cancer. 59% survived without evidence of cancer 2 years from treatment and 78% survived overall.

Diffuse large B-cell lymphomas were further classified as germinal B-cell vs non–germinal B-cell in the R2CHOP patients and compared to 87 patients with diffuse large B-cell lymphoma from a historical control group who were treated with conventional R-CHOP.

Both progression-free survival and overall appeared to be improved in non–germinal B-cell subtype treated with R2CHOP compared to the historical controls.

The investigators concluded that R2CHOP demonstrated promising efficacy in the treatment of diffuse large B-cell lymphoma and that the addition of Revlimid appears to appears to improve the outcome of the non–germinal B-cell phenotype.

Epratuzumab plus R-CHOP Highly Active in Diffuse Large B-Cell Lymphoma

Addition of epratuzumab to R-CHOP (Rituxan®, cyclophosphamide, doxorubicin, vincristine, and prednisone) appears highly active as initial therapy for diffuse B-cell lymphoma. Epratuzumab is an investigative agent that is targeted against the CD-22 antigen, which is a component found on B-cells. The binding of epratuzumab to the CD-22 antigen stimulates a patient’s immune system to help kill cancer cells. Furthermore, other biologic mechanisms are also thought to provide anticancer activity with the use of epratuzumab.

Researchers from the Mayo Clinic conducted a clinical trial to evaluate the addition of epratuzumab to R-CHOP as initial therapy for diffuse large B-cell lymphoma. This study included 15 patients, the majority of whom had advanced disease.

  • Anticancer responses were achieved in 87% of patients.
  • A complete anticancer response was achieved in 67% of patients.
  • At one year overall survival was 100% and progression-free survival was 93%.
  • At two years overall survival and progression-free survival rates were 86%.
  • Severely low levels of immune cells occurred in 93% of patients; 73% of patients required dose reductions due to side effects.
  • At 30 months follow-up, 87% of patients remained alive.

The researchers concluded that the addition of epratuzumab to R-CHOP as initial therapy for diffuse large B-cell lymphoma appears to provide high anticancer activity. Future trials further evaluating this novel regimen are warranted.

R-CHOP Followed by Zevalin®/Rituxan® Promising for Untreated Follicular NHL

Use of Zevalin® plus Rituxan® following the treatment regimen referred to as R-CHOP significantly improves the rates of anticancer responses among patients with advanced, previously untreated follicular NHL.

Zevalin is comprised of ibritumomab, a monoclonal antibody that is attached to a radioactive substance called Yttrium 90 (90Y). The monoclonal antibody portion of Zevalin binds to proteins (CD 20 antigens) found only on the surface of B-cells. When Zevalin binds to the cancer cells, the immune system is stimulated to attack the cancer cells while the attached 90Y destroys these cells by spontaneous radiation emission.

Researchers speculate that Zevalin may also produce anticancer effects through additional mechanisms not fully understood at present. •This type of treatment not only provides anticancer treatment through separate strategies, but also delivers greater amounts of radiation to the cancer cells than external radiation therapy. Additionally, radiation exposure to normal cells is minimized.

Zevalin is currently being studied in several clinical trials for use with differing schedules within treatment regimens for several types of hematologic malignancies. Researchers from the University of Pittsburgh recently conducted a trial to evaluate the addition of Zevalin plus Rituxan to R-CHOP in 30 patients with previously untreated follicular NHL.

•Complete disappearances of cancer were achieved in 35.7% of patients after treatment with R-CHOP; this rate improved to 89.3% of patients following treatment with Zevalin and Rituxan. At 20 months, progression-free survival was nearly 80% and the addition to Zevalin and Rituxan was well tolerated.

The researchers concluded that the addition of Zevalin and Rituxan to R-CHOP significantly improves responses in patients with previously untreated follicular NHL. Longer follow-up will help determine the true clinical effectiveness of this treatment strategy.

R-CHOP is safe and effective for the treatment of AIDS-related NHL.

Individuals diagnosed with the acquired immune deficiency syndrome (AIDS) have a significantly increased risk of developing non-Hodgkin’s lymphoma (NHL). NHL is a cancer that originates in the immune system.

There was initially some concern regarding the safety of the addition of Rituxan to CHOP for patients with AIDS-related NHL. This is because Rituxan binds to important immune cells, called B-cells. B-cells are the most common types of cancerous present in NHL. Rituxan causes the immune system, as well direct biologic properties, to kill B-cells. Since AIDS patients already have compromised immune systems, physicians have been concerned that the use of Rituxan may increase the risk of infection for these patients.

Researchers from France conducted a clinical trial evaluating the safety and effectiveness of R-CHOP for the treatment of AIDS-related NHL. This trial included 61 patients.

  • Complete disappearances of detectable cancer were achieved in 40 patients.
  • Partial disappearances of detectable cancer were achieved in five patients.
  • Progressive cancer occurred in seven patients.
  • At two years the overall survival rate was 75%.
  • Severely low levels of immune cells accompanied by fever occurred in approximately 13% of patients.
  • Only one patient died from infection.

The researchers concluded that the addition of Rituxan to CHOP is a safe and effective treatment option for patients with AIDS-related NHL.

References:

  1. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract 3.
  2. Rummel MJ, von Gruenhagen U, Niederle N et al. Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with follicular, indolent and mantle cell lymphomas: results of a randomized phase III study of the Studygroup Indolent Lymphomas (StiL). Presented at the 50th Annual Meeting of the American Society of Hematology, December 6-9 2008, San Francisco, CA. Abstract 2596.
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  8. 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. Journal of Clinical Oncology. 2005; 23;4117-4126.
  9. DeMonaco N, Wu M, Osborn J, et al. Phase 2 Trial of CHOP-Rituximab Followed by 90Y ibritumomab Tiuxetan (Zevalin) and Rituximab in Patients with Previously Untreated Follicular Non-Hodgkin Lymphoma. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology (ASCO). June 2006. Abstract # 7589.
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