Antibodies Used in the Treatment of Lymphomas and other Hematological Malignancies
In the following section, we will cover antibody therapies used in the treatment of lymphomas and other hematological malignancies, including chronic lymphocytic leukemia and acute myeloid leukemia. Despite advances in cancer biology, immunology, and radiobiology, hematological malignancies are often incurable. In both lymphomas and leukemias, the immune system plays a unique role, since disordered immune cells are the source of these cancers. The success of the first drug that we will discuss, rituximab, in the treatment of non-Hodgkin lymphomas prompted the development of numerous other agents designed to treat hematological malignancies as well as many of the agents that we have already discussed for the treatment of solid malignancies in previous sections. Of all the agents in our list of monoclonal antibodies in Table 2, rituximab has the distinction of being the first FDA approved targeted agent and has been shown to increase survival in follicular lymphomas and to cut lymphoma-associated deaths in patients with CD20+ aggressive lymphomas in half. In this section, we will review the current role of monoclonal antibodies in the treatment of different hematological malignancies. Of note, some of the antibodies that will be discussed in this section contain a radioactive molecule. These antibody therapies retain their antibody-antigen specificity and take advantage of targeted delivery of localized radiation to further enhance cell killing. As in previous sections, our discussion will be limited to agents currently possessing FDA approval for anticancer indications.
Rituximab is the first monoclonal antibody therapy approved by the US Food and Drug Administration (FDA) for the treatment of cancer, back in 1997. It targets the CD20 protein found on the surface of normal and cancerous B-cells. (B-cells are a part of the immune system, some of which differentiate into cells that produce antibodies, which we discussed in the context of the production of targeted antibody therapy). About 85% of all non-Hodgkin's lymphomas (NHLs) are of the B-cell type (the other 15% are T-cell type). Of the B-cell NHLs, more than 95% express the CD20 target. Thus, rituximab is used in patients with CD20-positive non-Hodgkin's lymphoma.
Lymphomas are cancers of the lymphatic system, which is comprised of collections of lymph nodes located throughout the body that filter the blood and combat infection and disease. Just as with solid malignancies, these cancers arise from disordered cells that multiply uncontrollably; unlike solid malignancies, lymphomas arise within the lymph nodes. There are two general types of lymphomas: Hodgkin's disease (HD, named after its discoverer Dr. Thomas Hodgkin) and non-Hodgkin's lymphoma (NHL). It is the latter for which rituximab is used. Unlike HD, which tends to follow a predictable pattern of disease spread, NHL is less predictable and more likely to spread to areas outside the lymph nodes. In 2009, there were approximately 66,000 new cases and 19,500 deaths from NHL and 8,510 new cases and 1,290 deaths from HD. The majority of NHLs occur in adults 40 to 70 years old. Unlike HD, NHL is typically grouped into three categories – indolent, aggressive and highly aggressive. Survival of untreated indolent lymphomas is measured in years and represent 35-40% of all lymphomas, of which the most predominant is follicular lymphoma. Half of NHLs fall into the aggressive category including: diffuse large B cell lymphoma (DLBCL) and many mantle cell lymphomas. Highly aggressive lymphomas represent about 5% of NHLs and will not be discussed in this section.
Interestingly, the chemotherapeutic backbone used in the treatment of both NHL and HD has largely remained unchanged since the 1970s. The CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) is still the most widely used in NHL and the ABVD regimen (adriamycin, bleomycin, vinblastine, and dacarbazine) is the most widely used in the treatment of HD. However, none of the traditional cytotoxic chemotherapeutic regimens used in the management of either lymphomas or leukemias take the biology of the cancers into account, which changed with the implementation of rituximab.
In previous sections, we have explored many of the targets of monoclonal antibody therapies such as the EGF and HER2 receptors. CD20, a surface antigen found in as many as 95% of B cells was therefore an ideal therapeutic target for the first truly targeted anticancer therapy. Since its approval in 1997, rituximab has been used in tens of thousands of patients and continues to be extensively studied across hundreds of clinical trials. FDA approval of rituximab was largely based on an open-label, single-arm, multicenter trial published the Journal of Clinical Oncology in 1998 with 166 patients with tissue-confirmed low-grade or follicular NHL that had recurred following initial therapy (also known as relapse). In that trial, the overall response rate was 48% in treated patients and the rate of partial response was 72%. These results were promising enough to pave the way for some of the following trials we will discuss and helped secure FDA approval.
Rituximab is a major component in the treatment of follicular lymphomas, which are the second most common NHL (DLBCL is the most common) and many of which are indolent. Rituximab is an integral component in the treatment of follicular lymphomas, and may be given as a single agent or along with cytotoxic chemotherapy. Of note, there have been no randomized trials comparing the effectiveness of various rituximab-based chemotherapy combinations. One of the trials with the longest follow-up was most recently updated in the Journal of Clinical Oncology in December 2004 and reported 9 year follow-up for patients enrolled on a phase II trial assessing response of patients with histologically confirmed, low-grade or follicular B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. In this trial, patients received both CHOP chemotherapy and six cycles of rituximab. The overall response rate was 100%, and 87% of patients achieved a complete response or unconfirmed complete response.
Rituximab has also been demonstrated to be beneficial in relapsed or refractory follicular lymphoma. A randomized phase III trial published in the journal Blood in 2006 randomized 465 patients to either CHOP for 6 cycles with or without rituximab. Patients treated with CHOP plus rituximab had significantly higher rates of overall (85 versus 72%) and complete (30 versus 16%) rates of response. These patients also had a longer median progression-free survival (33 versus 20 months) compared to patients receiving CHOP only.
Mantle Cell Lymphoma
Patients diagnosed with mantle cell lymphoma (MCL) have variable clinical courses – some behave indolently, while some behave aggressively. The role of rituximab in the treatment of newly diagnosed MCL has not been completely established. A recent Cochrane review examined 7 randomized trials (although these included patients with follicular and other indolent lymphomas) and found improved overall survival (OS) in patients treated with chemotherapy regimens containing rituximab. A recent systematic review of the initial treatment of patients with MCL from UpToDate reports that for patients with MCL "we suggest the addition of rituximab to combination chemotherapy rather than chemotherapy alone. This is primarily due to the low risk of toxicity related to the addition of rituximab and a possible but uncertain benefit in overall survival. Rituximab can be incorporated into either conventional chemotherapy regimens or aggressive treatment programs."
For patients with recurrent or relapsed MCL, although there are no large phase III trials that have evaluated the incorporation of rituximab into standard chemotherapy regimens, there have been prospective phase II trials investigating the use of single agent rituximab in MCL patients. One such study was published in the Journal of Clinical Oncology in January 2000 and found an overall response rate of 37% with a 14% complete response rate. At a median follow-up from treatment of 1.3 years, the projected median duration of response was 1.2 years, supporting the use of rituximab.
Diffuse Large B Cell Lymphoma
DLBCL is the most common NHL subtype and accounts for nearly 30% of all NHL patients. Median survival can be measured in months if the patient does not receive treatment. Through the use of chemotherapy regimens such as CHOP, disease free survival rates of 35 to 45% at four years are possible. These numbers have been further enhanced with the incorporation of rituximab. A study published in the New England Journal of Medicine in January 2002 examined patients aged 60-80 with DLBCL and randomly assigned nearly 400 patients to either 8 cycles of CHOP versus 8 cycles of CHOP plus rituximab. At a median follow-up of 2 years, overall survival times were significantly higher in the rituximab-containing arm without greater treatment toxicity. Although the optimal number of cycles is undefined, rituximab-containing CHOP or CHOP-like regimens provide improved survival to the same regimens without rituximab, regardless of patient age.
Chronic Lymphocytic Leukemia
The most recently approved indication for rituximab is for use in patients with chronic lymphocytic leukemia (CLL), which is a cancer of the blood where abnormally high numbers of ineffective white blood cells known as lymphocytes accumulate in the lymph nodes, spleen and liver. These abnormal cells interfere with normal immune function, and can be fatal if untreated. On February 18, 2010, the FDA granted approval to rituximab for use in combination with fludarabine and cyclophosphamide (FC) for the treatment of previously treated and untreated patients with CLL. The approval was based on a clinically meaningful and statistically significant increase in progression-free survival (PFS) observed in two randomized multicenter open-label trials (CLL8 and REACH) in patients randomized to receive either FC or the combination of FC plus rituximab (R-FC).
Other uses of Rituximab
There are a number of other clinical uses for rituximab, which are beyond the scope of this review. However, the medication is being used to treat rheumatoid arthritis and is FDA approved for this indication and has been used in a number of other autoimmune diseases. Rituximab is also being explored for use in patients that have undergone solid organ transplantation.
Toxicities and Precautions in Rituximab Therapy
Rituximab therapy does impose a risk of hepatitis B reactivation among patients positive for certain hepatitis antigens or antibodies and appropriate blood work needs to be collected prior to the initiation of therapy. Some cases of reactivation of latent JC virus have also been reported, some of which have resulted in a condition known as progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease characterized by progressive neurological deterioration from demyelination of the central nervous system. Other rare toxicities, such as pulmonary fibrosis, have also been reported. As with other incompletely human antibody therapies, infusional reactions are also possible and are frequent with rituximab therapy since it is a chimeric antibody. Not surprisingly, studies are being conducted with second and third generation anti-CD20 antibodies, which are though to be less immunogenic and therefore better tolerated than rituximab. Finally, precautions against tumor lysis syndrome should also be considered in some patients with aggressive or highly aggressive lymphomas. In this condition, the rapid killing of cancer cells results in the accumulation of cellular byproducts in the blood stream, which can cause renal failure and electrolyte imbalances.
In summary, here are the currently approved FDA indications for rituximab:
- Non-Hodgkin lymphoma: as a single agent for the treatment of relapsed or refractory low-grade or follicular NHL and for treatment of patients with CD20 positive NHL and for the treatment of patients with non-progressing low-grade CD20 positive NHL following first-line chemotherapy with CVP chemotherapy, or in conduction with CVP for first-line treatment of previously untreated CD20, B-cell follicular NHL and in combination with CHOP or other anthracycline-based chemotherapy regimens for the treatment of previously untreated diffuse, large B-cell CD20 positive NHL.
- In combination with fludarabine and cyclophosphamide (FC), for the treatment of previously untreated and previously treated patients with chronic lymphocytic leukemia (CLL).
- Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies
Dosing recommendations for rituximab:
- The dose for both NHL and CLL indications is 375 mg/m2. The dose as a component of Zevalin (Ibritumomab tiuxetan) is 250 mg/m2
- The dose for RA in combination with methotrexate is two 1000 mg IV infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg IV or equivalent glucocorticoid is recommended 30 minutes prior to each infusion.
90Y-Ibritumomab and 131I-Tositumomab
Introduction and Clinical Use
90Y-Ibritumomab tiuxetan (Zevalin) and 131I-Tositumomab (Bexxar) are mouse monoclonal antibodies against CD20 that have been joined with radioisotopes of yttrium or iodine. In theory, these medications deliver the same anti-CD20 specific therapy as rituximab plus each has a radioactive portion of the antibody, which can deliver a second "hit" to the affected cell. In June 2003, the US FDA approved tositumomab for patients with CD20-positive, follicular non-Hodgkin's lymphoma with relapsed or refractory lymphoma. In a study of 60 patients with previously treated relapsed or resistant low-grade or transformed low-grade NHL, a single dose of tositumomab resulted in an overall response rate of 65%, with 20% of patients achieving a complete response.
A treatment course of tositumomab involves a total of four infusions given over 7-14 days, and is divided into two basic phases or steps: dosimetric and therapeutic. The first set of infusions includes administration involves non-radioactive antibody (essentially rituximab), designed to improve bodily distribution of later doses of the drug by increasing its accumulation in the tumor. Next is the dosimetric infusion with the antibody and a very small amount of radioactive isotope. This is done to determine the rate of clearance of radioactivity from the body. Then, based on the clearance rate, the amount of radioactivity needed for a specific patient to reach a desired therapeutic total body dose can be calculated. Finally, about 7-14 days after the dosimetric step, the patient returns for the actual treatment, the therapeutic step. This includes two infusions (making a total of 4) and again starts with the non-radioactive antibody, followed by the pre-calculated, patient-specific radioactive drug needed to deliver the desired total body dose of radiation. Following the treatment itself, up to three whole body gamma scans are performed on days 0, 2 to 4, and potentially on days 6 to 7 as well. These are done to assess for altered biodistribution of the radiation and to evaluate the rate of clearance for each individual patient. The total body clearance rate of the radioisotope depends on the size of the tumor, the presence of spleen enlargement, and the level of bone marrow involvement.
Ibritumomab is also a radiolabelled anti-CD20 antibody used for the treatment of relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma (NHL). It was actually approved by the FDA before tositumomab, in February 2002, making it the first radioimmunotherapy drug to receive FDA approval. Unlike tositumomab, dosing does not involve a dosimetric step but is instead calculated based on a patient's body weight and baseline platelet count.
Recently, extended follow-up data for the ibritumomab "First-line Indolent (FIT)" study were presented at the American Society of Hematology (ASH) Annual Meeting in 2008, and demonstrated continued improvement in progression-free survival (PFS) following ibritumomab consolidation therapy for patients with follicular B-cell non-Hodgkin's lymphoma who achieved a response to first-line therapy over chemoradiotherapy alone. Patients achieving a complete remission (CR) after induction chemotherapy receiving ibritumomab consolidation achieved a PFS survival benefit of greater than 67 months, compared to 30.8 months in the control arm. Additionally, ibritumomab consolidation did not adversely affect the use of various effective second-line treatments including stem cell transplants in relapsed patients. In September 2009, ibritumomab received approval from the FDA for an expanded label for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieved a partial or complete response to first-line chemotherapy.
Toxicities and Precautions in Ibritumomab and Tositumomab Therapy
Patient selection is critical before treatment with radioimmunotherapy: patients should not have more than 25% bone marrow involvement and need to have adequate platelet and neutrophil counts. As with the administration of any radioactive solution into the body, there are precautions that need to be taken during the administration of these intravenous agents, such as the use of acrylic shielding. Tositumomab emits both gamma and beta radiation and is rapidly eliminated via the urine and gastrointestinal (GI) tract. During the infusional and immediate post-treatment period, patients are usually isolated in a specially prepared room with limited access and lead shielding is used. Family members must maintain a distance of several feet with no physical contact for 3 to 4 days.
There are also precautions that patients need to take once they are safe to go home following treatment. Because of the high clearance of radioactive iodine-131 in urine, patients need the use of their own bathroom following completion of therapy and should flush the toilet twice with each use. Patients need to shower daily, wash hands frequently, and should have their own dishes/silverware, clothing and sheets that are used and cleaned separately from other members of the household. Patients should be at least 6 feet from other people and should avoid close contact with infants, children, and pregnant women. While emitting radiation, patients should not share a common bed and should avoid car trips longer than 2 hours.
Radiation safety with ibritumomab is more straightforward as this medication only uses beta radiation, which has a much shorter range than the gamma radiation used with tositumomab and a half-life of 2.7 days with a slow clearance rate. As with tositumomab, patients should have a private bathroom and follow toileting precautions. Condom use is important, although intimate contact is not advised. Because iodine has an affinity for thyroid tissue, patients are at risk for delayed hypothyroidism, which will require periodic monitoring by a physician for life.
Despite all of these precautions, the treatment itself is typically well tolerated. As with the infusion of any immunological agent, infusion-related adverse reactions such as fever, chills, and urticaria are possible. Because of the foreign mouse protein component to these two mediations (these antibodies are neither humanized or chimeric), patients are typically premedicated in the infusion suite. Additionally, treatment with radioimmunotherapy can cause a "flare" reaction following treatment with worsening inflammation of the lymph node involvement in the patients, which can last for several days but is not an indication of treatment failure. Because of the immunological and radioactive nature of these products, a large amount of bone marrow is irradiated and treatment results in severe and prolonged cytopenias in most patients, which is typically worst 4-7 weeks following treatment with recovery of blood counts at 8-12 weeks. Treatment with these agents is not associated with hair loss or persistent nausea or vomiting. Mucocutaneous (mouth, throat, eyelids, and nose) reactions are uncommon. As with any other therapy using radiation, there is a possibility of secondary cancers from this type of treatment, such as myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). These cancers occur in approximately 4% of patients treated with tositumomab and may be slightly lower in patients treated with ibritumomab (roughly 1.3% over 9 years), although many of these patients have been treated previously with chemotherapy making it difficult to be completely sure of the cause of the second cancer.
In summary, here is the currently approved FDA indication for 90Y-Ibritumomab and 131I-Tositumomab: patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with rituximab-refractory non-Hodgkin"s lymphoma. Additionally, as of September 2009, ibritumomab received approval from the FDA for an expanded label use for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieved a partial or complete response to first-line chemotherapy.
Ofatumumab (Azerra, OMB12517) is a fully humanized monoclonal antibody against CD20 with a different target on B cells than rituximab. As we have previously discussed, the CD20 molecule is highly expressed in both normal and malignant B cells and when bound by an antibody, sends a signal across the membrane, which may result in cell death. Ofatumumab is currently under development for treating chronic lymphocytic leukemia (CLL) and has also shown potential in treating follicular non-Hodgkin"s lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis, and relapsing remitting multiple sclerosis. As discussed in the section on rituximab, CLL is a cancer of the blood, where abnormally high numbers of ineffective white blood cells known as lymphocytes accumulate in lymph nodes, spleen and liver. These abnormal cells interfere with normal immune function, and can be fatal if untreated.
Ofatumumab was approved by the FDA as a fast track medication in October 2009 for patients suffering from CLL who have not responded to currently available therapies, in part based on results from Hx-CD20-406, a single-arm, multicenter trial in 154 patients with relapsed or refractory CLL to both fludarabine and alemtuzumab were treated with ofatumumab. The response rate was 42% with a median response duration of 6.5 months. Safety and dosing had previously been investigated in a phase I/II trial where patients with refractory or relapsing CLL were given 4 weekly infusions of ofatumumab at 3 different doses published in the journal Blood in February 2008.
The most serious side effects of ofatumumab included increased susceptibility of infections, including progressive multifocal leukoencephalopathy (PML), a generally fatal disease of the brain almost exclusively found in immunocompromised patients, which is caused by activation of the JC virus. Patients at high risk for Hepatitis B should be screened before being treated with ofatumumab and patients with evidence of inactive hepatitis should be monitored for reactivation of the infection during and after completing treatment. Common adverse reactions include neutropenia, pneumonia, fever, cough, diarrhea, anemia, fatigue, and rash.
Alemtuzumab (Campath) is a recombinant DNA-derived humanized monoclonal antibody against CD52 that was first approved for use in patients with B-cell chronic lymphocytic leukemia (B-CLL) in 2001. CD52 is a surface antigen expressed by B cells, T cells, macrophages and monocytes (all forms of white blood cells). One of the more important trials with alemtuzumab was published in the Journal of Clinical Oncology in December of 2007. This phase III trial examined nearly 300 patients with stage I-IV CLL assigned to either alemtuzumab or an alkylating chemotherapy agent known as chlorambucil. At a median follow-up of 25 months, patients treated with alemtuzumab had a higher overall response rate (83 versus 55%) and complete remission (24 versus 2%) rate, as well as longer progression-free survival (15 versus 12 months).
Alemtuzumab is also used in some conditioning regimens for bone marrow transplantation and kidney transplantation as well as in the treatment of some patients with cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis.
A significant complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections; in particular, reactivation of cytomegalovirus. As with many antibody therapies, alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash.
The currently approved FDA indication for alemtuzumab is as single agent therapy for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).
Gemtuzumab (Mylotarg, CMA-676) is a humanized, chimeric antibody against CD33 for use in the treatment of acute myelogenous leukemia (AML). CD33 is an adhesion protein found on the surface of leukemic myeloid blasts but not on normal blood stem cells making it an attractive target for antibody therapy. Patients with relapsed or refractory AML typically have a poor outcome. In this population, chemotherapeutic salvage regimens confer complete remission (CR) in less than 50% of patients, with a 3-year overall survival (OS) rate of less than 30%. In addition, patients whose first CR (CR1) duration is less than 1 year or who do not achieve CR have a worse outcome and may benefit little from autologous or allogeneic stem-cell transplantation.
In May of 2000, gemtuzumab was granted accelerated approval by the FDA for use in patients age 60 or older with CD33+ AML in first relapse who are not otherwise considered candidates for cytotoxic chemotherapy. In a trial published in the Journal of Clinical Oncology in November of 2008, patients treated with refractory or relapsed AML using gemtuzumab plus intermediate-dose cytarabine, and mitoxantrone were able to achieve a high rate of objective response and improved outcome.
An accelerated approval requires follow up studies on the drug to confirm the benefit seen in earlier studies. Follow up studies determined that there was no improvement in outcomes and there were a higher number of deaths in the gemtuzumab arm. Rates of one particular side effect, veno-occlusive disease (VOD), were higher in the follow up studies compared with the original studies. In this condition, some of the small veins in the liver are blocked, leading to weight gain, hepatomegaly (swollen liver), fluid around the liver, increased bilirubin, and occasionally kidney failure. More common side effects of treatment with gemtuzumab include infusional reactions such as fevers, chills, nausea and vomiting and severe myelosuppression (low blood counts). Less commonly, gemtuzumab can result in longer-term pulmonary complications.
As a result of the follow up studies on this agent, the manufacturer has voluntarily withdrawn gemtuzumab from the market and it is no longer available available to patients in the United States.