Patients with aggressive non-Hodgkin’s lymphoma (NHL) that has progressed after initial treatment have what is called relapsed disease. Patients with relapsed NHL can be divided into two broad categories:
- Patients who do not experience a complete disappearance or remission of their cancer following a complete course of chemotherapy treatment
- Patients who achieve a complete remission to initial treatment and then experience a cancer recurrence
Relapse of NHL may occur several months to years after the initial remission; however, the majority of relapses occur within two years of initial treatment.
Patients with relapsed NHL are typically re-treated with chemotherapy using drugs that are different from those administered for initial treatment. High-dose chemotherapy with stem cell transplantation has been shown to produce better outcomes than re-treatment with conventional chemotherapy.1 Outcomes may be improved further with the addition of the targeted therapy, Rituxan® (rituximab). 2, 3
Rituxan also appears to benefit some patients when administered alone or with conventional chemotherapy. 4
About this NHL Treatment Information
The following is a general overview of treatment for relapsed, aggressive NHL. Treatment may consist of chemotherapy, high-dose chemotherapy with stem cell transplantation, targeted therapy, or a combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatment techniques, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival.
In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. New techniques for treating relapsed NHL that are being actively investigated are discussed under Strategies to Improve Treatment .
Circumstances unique to each patient’s situation may influence how these general treatment principles are applied. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
- High-dose Treatment with Autologous Stem Cell Transplant
- Targeted Therapy
- Conventional Chemotherapy
- Managing Side Effects of Treatment
- Strategies to Improve Treatment for Relapsed NHL
High-Dose Treatment with Autologous Stem Cell Transplant (ASCT) for Relapsed NHL
More chemotherapy has been shown to kill more cancer cells in the treatment of patients with NHL. Since conventional doses of chemotherapy appear to cure some patients with NHL, some doctors believe that more intensive regimens that deliver chemotherapy more frequently and/or at higher doses may cure even more patients. However, high-dose chemotherapy kills critical red and white blood cells. To help rebuild the blood cells, patients commonly undergo an autologous stem cell transplant (ASCT) after high-dose therapy. An ASCT involves collecting the patients own stem cells, which are cells that grow into blood cells. The stem cells are collected prior to therapy and stored, then administered to the patient after high-dose therapy.
High-dose therapy with ASCT appears to cure approximately 40% of patients with NHL, which is a marked improvement over conventional chemotherapy, which cures fewer than 20% of patients.
High-dose therapy with ASCT vs. conventional chemotherapy: A direct comparison of conventional chemotherapy versus high-dose chemotherapy with ASCT in the treatment of patients with relapsed NHL demonstrated that nearly half of the patients who received the high-dose treatment survived five years or more without cancer compared to 10% of the patients treated with conventional chemotherapy. 
This important clinical trial has established high-dose chemotherapy with ASCT as the standard of care in the treatment of relapsed NHL.
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional therapy may offer the advantage of increasing the intensity of treatment delivered to the cancer and improving outcomes without increasing treatment-related side effects.
Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.
Rituxan® (rituximab): Treatment with Rituxan can produce anticancer responses in patients with relapsed NHL, even if they have already received and had an anticancer response to Rituxan. For these patients, Rituxan is typically administered in combination with chemotherapy.
For patients who have not already received Rituxan, administration of this drug alone has been shown to produce anticancer responses in approximately 40% of patients. 
Patients with relapsed NHL who do not undergo high-dose chemotherapy with ASCT and/or targeted therapy are typically retreated with conventional chemotherapy.
Managing Side Effects of Treatment
The standard treatment for NHL, chemotherapy, not only destroys cancer cells but also normal cells that grow rapidly such as blood cells, cells in the hair follicles, or cells in the mouth and intestines. Damage to blood cells can result in neutropenia, a condition characterized by abnormally low blood levels of infection-fighting white blood cells. Neutropenia increases the risk of contracting bacterial and fungal infections. Managing neutropenia is important because, in some cases, this side effect can be severe enough that chemotherapy treatment may need to be delayed or the dose reduced, which decreases some patients’ chance for cure.
Chemotherapy-induced neutropenia can be prevented in most patients with the administration of blood cell growth factors, which are substances produced by the body to stimulate blood cell production. There are two white blood cell growth factors that have been produced in a laboratory and approved by the Food and Drug Administration for the prevention of chemotherapy-induced neutropenia: Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). Clinical trials have shown that Neulasta and Neupogen reduce the severity and duration of neutropenia associated with chemotherapy for the treatment of NHL. Neulasta is as effective as Neupogen and it is administered only once every chemotherapy cycle, whereas Neupogen is administered daily. , 
For more in-depth information, go to Managing Side Effects.
Strategies to Improve Treatment of Relapsed NHL
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of relapsed, aggressive NHL will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of relapsed, aggressive NHL include the following:
- Adding Targeted Therapy to Stem Cell Transplant
- Advances in Stem Cell Transplantation
- New Targeted Therapies
- Advances in Chemotherapy
- Combination Chemotherapy
- Phase I Clinical Trials
Adding Targeted Therapy to Stem Cell Transplant
Rituxan is a targeted therapy that can locate cancer cells and kill them directly. Because Rituxan is associated with minimal side effects, it can be combined with high-dose chemotherapy to kill more cancer cells without increasing the overall side effects of treatment.
Adding Rituxan to high-dose chemotherapy appears to improve outcomes. Results of a clinical trial indicate that more than half of patients (53%) with relapsed disease who were treated with high-dose chemotherapy plus Rituxan followed by ASCT experienced a complete response to treatment. This was twice as many complete responses compared to a similar group of patients treated with the same chemotherapy without Rituxan; only 27% of these patients experienced complete responses. 
The addition of high-dose Rituxan prior to and following an ASCT appears to improve survival in the treatment of patients with recurrent, aggressive NHL. Patients treated with Rituxan survived longer and were cancer free longer compared to a similar group of patients who underwent the same treatment without Rituxan (see table 1). 
Table 1 Addition of High-Dose Rituxan Improves Survival
|High-dose Rituxan with ASCT||High-dose therapy and ASCT without Rituxan|
|Survived 2 years or more||80%||53%|
|Cancer free for 2 years or more||67%||43%|
Advances in Stem Cell Transplantation
Research continues to find ways to make stem cell transplants safer and more effective. One approach is developing new chemotherapy regimens or ways to deliver the high-dose chemotherapy that patients receive before stem cell transplantation.
High-dose chemotherapy consisting of hyperfractionated cyclophosphamide (administered every 12 hours for three days), high-dose cytarabine, and high-dose methotrexate followed by stem cell transplatation has been shown to produce complete anticancer responses in more than half (64%) of patients with relapsed, aggressive NHL. The 28 patients involved in this study had relapsed after prior anthracycline-based chemotherapy. Following the above described treatment, nearly half (46%) survived three years or more without cancer recurrence. 
Allogeneic stem cell transplantation: Transplanting stem cells from one individual to another is called an allogeneic transplant. This procedure is associated with more complications than an ASCT, which involves reinfusing the patient’s own stem cells. For this reason, an allogeneic transplant may be most suited for patients who are younger or more fit, and capable of tolerating the potential side effects of treatment.
In the treatment of patients with relapsed immunoblastic lymphoma, a type of aggressive NHL that occurs predominantly in younger patients, allogeneic transplantation appears to be just as effective as an autologous transplant. Fewer of the patients who underwent allogeneic transplants experienced a relapse of their cancer after treatment. However, this apparent advantage was effectively offset by a higher risk of transplant-related deaths among the patients who underwent allogeneic transplants. Both types of transplants were associated with a 40% chance of long-term survival (five years or more). There was a lower relapse rate following allogeneic transplants, but this was offset by increased transplant-related deaths. 
New Targeted Therapy
Zevalin® (ibritumomab): Zevalin is a radioactive monoclonal antibody. It is approved for the treatment of low-grade (indolent) NHL that is recurrent or refractory.
Zevalin uses two mechanisms to target and kill cancer cells: The monoclonal antibody locates and binds to CD 20 protein found on the surface of B-cells, stimulating the immune system to attack the cancer cells. The attached radioactive material (Yttrium 90) kills the cancer by delivering radiation directly to the cells. This method delivers more radiation to the cancer cells and less radiation to the normal cells compared to conventional external radiation therapy.
When evaluated with patients who had received three to seven prior regimens, stem cell transplantation, and had stopped responding to Rituxan, treatment with Zevalin produced anticancer responses in half of patients, and detectable cancer disappeared in 20% of the patients. 
Zevalin with stem cell transplant: The addition of Zevalin to high-dose chemotherapy prior to an autologous stem cell transplant appears to be a promising treatment for recurrent NHL. More than three-quarters (77%) of patients treated with this approach experienced a complete disappearance of their cancer that lasted two years or more. Overall, 92% of patients survived 5 years or more. 
Rituxan and epratuzumab: Epratuzumab is a type of targeted therapy called a monoclonal antibody that targets the CD22 antigen, a protein that is found on the surface of B-lymphocytes and particularly on B-cell cancers. The combination of Rituxan and epratuzumab appears to be well tolerated and potentially effective in the treatment of patients with relapsed or refractory B-cell NHL. While only six patients out of the 23 involved in this study had aggressive NHL (the rest had indolent, or low-grade disease), half of them experienced a complete disappearance of detectable cancer after the combination treatment. The most common side effects of treatment were fever, shivering, and fatigue. 
Avastin® (bevacizumab): Avastin is a type of targeted therapy that causes its anticancer effect by starving cancer cells of the blood that they need to survive and grow. This drug is FDA-approved for the treatment of patients with advanced colon cancer in combination with chemotherapy. Avastin has demonstrated modest anticancer activity as a single agent in the treatment of aggressive, relapsed NHL. Future studies are planned to evaluate Avastin in combination with chemotherapy for patients with advanced NHL.
Bexxar® (131-I tositumomab): Bexxar is a monoclonal antibody linked to a radioactive substance called iodine 131. The monoclonal antibody locates and attaches to the cancerous B-cells in the body; the iodine 131 then delivers radiation directly to the cancer cell. Bexxar has been approved by the FDA for treatment of patients with low-grade lymphoma whose cancer has progressed following primary therapy. Research also suggests that it is active in the treatment of relapsed, aggressive NHL. 
Results of an early clinical trial suggest that addition of Bexxar to high-dose chemotherapy carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplant may be an effective therapy for patients with relapsed NHL. Of the 23 patients involved in this trial, 57% experienced complete anticancer responses. More than 50% of the patients lived three years or more and nearly 40% were free of cancer. 
Advances in Chemotherapy
The development of high-dose chemotherapy has already contributed to improving some patients’ chance for cure. Delivering chemotherapy more frequently than the typical three-week cycle may also kill more lymphoma cells. A chemotherapy cycle is a treatment followed by a period of no treatment. The purpose of the interval between treatments is to allow time for recovery of normal cells that may have been damaged. However, cancer cells may also recover during this period. Delivering chemotherapy more frequently may kill more lymphoma cells.
In addition, researchers continue to investigate new drugs and new combinations, or regimens.
Treanda™ (bendamustine hydrochloride): Treanda is a chemotherapy agent that does not interfere with other commonly used chemotherapy agents called alylating agents. Treanda has been used in Germany for many years for the treatment of patients with NHL, chronic lymphocytic leukemia (CLL), multiple myeloma, breast cancer, and other solid tumors such as lung cancer.
When Treanda was administered to patients who had stopped responding to prior therapy, three-quarters (74%) experienced an anticancer response and over one-third (39%) had a complete disappearance of detectable cancer. 
Velcade® (bortezomib): A new chemotherapy drug, called Velcade, is approved for the treatment of patients with relapsed multiple myeloma and appears to be active in the treatment of NHL. In a small clinical trial, Velcade produced anticancer responses in 19% of patients with relapsed NHL. 
Doxil® (liposomal doxorubicin): Anthracyclines, such as doxorubicin, are among the most active anticancer compounds, especially for the treatment of NHL and breast cancer. However, these drugs may cause long-term damage to the heart. There have been attempts to decrease the cardiotoxicity of doxorubicin by changing the way it is formulated. Doxil delivers doxorubicin encapsulated in a small amount of lipid, or fat.
Pixantrone: Another anthracycline that causes cardiotoxicity is mitoxantrone. Pixantrone is a new drug that eliminates the part of the mitoxantrone molecule that may cause this damage, while retaining the portion that is the active anticancer agent. Early clinical trials conducted in patients with relapsed lymphoma who had received high doses of doxorubicin indicate that additional treatment with pixantrone did not cause any further heart damage. The 21 patients in this study were treated with up to six cycles of pixantrone. One-third of patients experienced a complete anticancer response and approximately one-third more had a partial anticancer response. 
Eloxatin® (oxaliplatin): Eloxatin is a platinum compound that causes less damage to the kidneys than cisplatin. Researchers from London have reported that Eloxatin can be substituted for cisplatin in the DHAP regimen without any apparent loss of activity. 
A second study found that Eloxatin administered as a single agent produced anticancer responses in patients with recurrent or relapsed NHL. Of the 23 patients with aggressive, refractory NHL, 32% of experienced an anticancer response to treatment, two of which were complete responses. Patients who had previously responded to platinum agents responded to Eloxatin.  Taken together, the findings of these two studies suggest that Eloxatin offers real advantages over Platinol and can be administered to patients previously treated with Platinol.
Gemzar® (gemcitabine), cisplatin, and dexamethasone: Gemzar is a chemotherapy drug that is active in the treatment of several different cancer types, including lymphomas, and has been shown to cause fewer side effects than some other chemotherapy drugs. Results of a clinical trial indicate that the combination chemotherapy consisting of Gemzar, cisplatin, and dexamethasone produced anticancer responses in approximately half (49%) of patients with recurrent or refractory NHL. 
GEM-P (Gemzar, cisplatin, methylprednisolone): A Gemzar-base regimen, GEM-P, has been shown to produce anticancer responses in 80% of patients with refractory lymphoma. More than 60% of patients treated with this regimen lived one year or more.  If these findings are confirmed in further clinical trials, GEM-P may prove to be more active than DHAP in the treatment of refractory disease.
DICE (Dexamethasone, ifosfamide, cisplatin, etoposide): DICE produced responses in the treatment of patients with relapsed NHL who had not responded to an autologous transplant. Overall, 40% of patients lived three years or more after treatment. 
Gemzar and Rituxan: The combination of Gemzar and Rituxan may offer the advantage of fewer side effects than other therapies for relapsed disease. In the treatment of seven patients with aggressive NHL that had relapsed after CHOP, treatment with Gemzar and Rituxan resulted in two complete remissions and three partial remissions. 
Phase I Clinical Trials
Phase I clinical trials involve a small number of patients for whom other standard therapies have failed or no known alternative therapy is available. Phase I therapy may produce anticancer effects and a small number of patients may be helped. However, the primary goals of this type of trial are to determine the dose that can be administered to patients, the manner in which the drug works in the body, and the side effects related to different doses.
 Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. New England Journal of Medicine. 1995;333(32):1540-1545.
 Rothe A, Schulz H, Elter T, et al. Rituximab monotherapy is effective in patients with poor risk refractory aggressive lnon-Hodgkin’s lymphoma. Haematologica. 2004;89:875-876.
 Lopez A, de Sevilla A, Castaigne S, et al. Pegfilgrastim supports delivery of CHOP-R chemotherapy administered every 14 days: a randomized phase II study. Proceedings from the 46th meeting of the American Society of Hematology (ASH). Blood. 2004;104:904a,Abstract #3311.
 Vose J, Crump M, Lazarus H. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. Journal of Clinical Oncology. 2003;21: 514-519.
 Green M, Koelbl H, Baselga J. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Annals of Oncology. 2003:14:29-35.
Kewalramani T,Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103(10):3684-8.
 Khouri I, Saliba R, Hosing C, et al. Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Hodgkin’s Lymphomas. Journal of Clinical Oncology. 2005; 23: pp. 2240-2247.
 Todeschini G, Tecchio C, Pasini F, et al. Hyperfractionated cyclophosphamide and high-doses of arabinosylcytosine and methotrexate (HyperCHiDAM Verona 897). An intensive and effective regimen for patients with aggressive, refractory or recurrent non-Hodgkin lymphomas after anthracycline-containing regimens. Cancer. 2005;104:555-560.
 Levine JE, Harris RE, Loberiza FR, et al, A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood. 2003;101:2476-2482.
 Joyce J, Schuster M, McCook B, et al. Experience with Yttrium 90 Ibritumomab Tiuxetan (Zevalin®) After Autologous Stem Cell Transplant (ASCT) in Patients with Non-Hodgkin’s Lymphoma (NHL). Proceedings from the 2005 annual meeting of the American Society of Clinical Oncology. Abstract #6669.
 Nademanee A, Forman S, Molina A, et al. A phase ½ trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplant in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood. 2005;106:2896-2902
 Leonard JP, Coleman M et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2005;23:5044-5051.
 Stopeck AT, Bellamy W, Unger J, et al. Phase II trial of single agent bevacizumab (Avastin) in patients with relapsed, aggressive non-Hodgkin’s lymphoma (NHL): Southwest Oncology Group Study S0108. Proceedings from the 41st annual meeting of the American Society of Clinical Oncology, Orlando FL. 2005; Abstract #6592.
 Horning S, Younes S, Jain V, et al. Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab. Journal of Clinical Oncology. 2005; 23: 712-719.
 Vose JM, Bierman PJ, Enke C, et al. Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2005;73:461-467.
 Friedberg JW, Cohen P, Cheson BD, et al. Bendamustine HCL (Treanda) results in high rate of objective response in patients with rituximab-refractory and alkylator-refractory indolent B-cell non-Hodgkin’s lymphoma (NHL): results from a phase II multicenter single-agent study (SDX-105-01). Blood. 2005;106:70a, abstract number 229.
 Goy A, Younes A, McLaughlin P, et al. Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology. 2005; 23: 667-675.
 Herbrecht R, Borchmann P, Wilhelm M, et al. Preliminary phase II results of pixantrone (BBR) in combination with cyclophosphamide, vincristine and prednisone in patients with relapsed aggressive non-Hodgkin’s lymphoma. Proceedings of the American Society of Hematology. Blood. 2004;104:682a, abstract number 2489.
 Webb A, Cunningham D, Hill M, et al. An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin’s lymphoma. British Journal of Haematology. 2001;115:786-792.
 Oki Y, McLaughlin P, Pro B, et al. Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin’s lymphoma. Cancer. 2005;104:781-787.
Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer. 2004;101(8):1835-42.
 Chau I, Harries M, Cunningham D, et al. Gemcitabine, cisplatin and methylprednisolone chemotherapy (GEM-P) is an effective regimen in patients with poor prognostic primary progressive or multiply relapsed Hodgkin’s and non-Hodgkin’s lymphoma. British Journal of Haematology. 2003; 120/6:970.
 Biagi JJ, Herbert KE, Smith C, et al. A phase II study of dexamethasone, ifosfamide, cisplatin and etoposide (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma. Leukemia Lymphoma. 2005;46:197-206.
 Wenger C, Stern M, Herrmann R, et al. Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non Hodgkin’s lymphoma? Leukemia Lymphoma. 2005;46:71-75.