Targeted Therapies in the Management of Leukemia and Lymphoma
Targeted Therapies in the Management of Leukemia and Lymphoma
ABSTRACT: The treatment of malignancies now includes therapies that target various components of the malignant cells. The targeted therapies used to treat leukemias and lymphomas include monoclonal antibodies, tyrosine kinase inhibitors, histone deacetylase inhibitors, hypermethylation inhibitors, and proteasome inhibitors. While each of the drugs in each class of agents has similar toxicities, some of the agents within the classes may have unique side effects. For example, the monoclonal antibodies can each cause an infusion reaction, but rarely, rituximab (Rituxan) can reactivate hepatitis B, an effect that has not been noted with other monoclonal antibodies. Nurses need to be aware of the potential side effects of each of the agents in order to manage the toxicities and educate patients about actions they can take to minimize their risk of the side effects.
The treatment of leukemias and lymphomas has evolved significantly over the last few decades. Previously, treatment for these diseases consisted of a variety of chemotherapy agents, given alone or in combination. More recently, new drugs with specific targets in or on the surface of cancer cells have been identified. These “targeted therapies” are now a mainstay of treatment for leukemias and lymphomas. Targeted cancer therapies are agents that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and division. Targeted therapies can cause cancer cell death directly by inducing apoptosis, or indirectly by stimulating the immune system to recognize and kill cancer cells. In addition, targeted therapies can be conjugated so they can deliver toxic substances to the cancer cell. Some of these new targeted therapies include monoclonal antibodies, and other major categories of agents that impede cell growth: inhibitors of tyrosine kinase, of histone deacetylase (HDAC), of proteasomes, and of hypermethylation.
Monoclonal Antibodies 101
Antibodies are proteins that are produced by B lymphocytes in response to foreign proteins, called antigens. They are Y-shaped, with two main portions: the Fab region and the Fc region. The Fab region is the segment that binds to the antigen. The Fc region is a constant component of the antibody. Antibodies function as a marker that binds to the antigen so that the antigen molecules can be recognized and destroyed by phagocytes. Initially, monoclonal antibodies (MoAbs) were murine, indicating that they only contained mouse components. Newer MoAbs contain various components of humans and an animal component, which is often mouse. The amount of each component varies. Chimeric antibodies have a structure that is least 50% human, while the remainder is mouse DNA encoding the binding portion of a monoclonal antibody. Humanized antibodies are antibodies from nonhuman species whose protein sequence has been modified to increase its similarity to an antibody produced naturally in humans. More than 90% of a humanized antibody is human. Human antibodies are fully human. MoAbs are made by identical immune cells which are clones of a parent cell. It is possible to produce MoAbs that specifically bind to any substance (antigen). For an antibody to be effective, it needs to target an antigen that is abundantly expressed on the malignant cell. Once it binds to the cell, the antibody induces cell death through a variety of mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and apoptosis. Multiple monoclonal antibodies have been developed for the treatment of lymphomas and leukemias.
Monoclonal Antibody Agents Used in Treatment of Leukemia and Lymphoma
CD20 is a cell-surface glycoprotein that is highly expressed on B cells. Elevated levels of freely circulating CD20 have been reported in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that was approved by the US Food and Drug Administration (FDA) in 1997. It was the first monoclonal antibody for the treatment of human malignancy to be approved by the FDA. Its initial approval was as a single agent administered at a dose of 375 mg/m2 on a weekly times 4 schedule for relapsed or refractory, follicular or low-grade NHL. The reported response rate was 48%, with 6% complete responses (CRs) and a median duration of response of about 1 year. Subsequent studies confirmed its effectiveness as a single agent in both the upfront and refractory disease settings. Its addition to standard chemotherapy regimens has prolonged the survival of patients with diffuse large B cell NHL and follicular NHL.[3–6] Response rates with use of rituximab in CLL have only been modest, at about 12%. The potential reason for the lower response rates in CLL seems to relate primarily to a lower level of CD20 expression in CLL compared with that in other lymphomas. Alternate dosing schedules have been investigated in CLL, including a three-times-weekly schedule or higher doses administered with each infusion (ie, 500 mg/m2).
Attempts to improve the efficacy of rituximab have included strategies to alter the dosing schedule of rituximab, administering rituximab on a maintenance schedule, and the development of other agents that target CD20. Methods to intensify the dose or schedule of rituximab include administration of treatment combinations more frequently, as in an every-2-week schedule. While the responses were higher, so were the toxicities seen with these schedules.[7,8]
Maintenance therapy is another method to enhance the benefit of rituximab following induction therapy. Administration of rituximab—either following treatment with rituximab as a single agent or after chemotherapy that is given along with rituximab—has been shown to improve overall response rates and the rate of CRs.[9,10] In patients with diffuse large B cell NHL, however, maintenance rituximab given after initial treatment including rituximab has not been shown to be beneficial. In patients with low-grade lymphomas, two schedules for maintenance rituximab that have been demonstrated to be useful include a weekly times 4 course of rituximab every 6 months for 2 years or a single dose of rituximab given every 2 months. The optimal schedule has not been identified.
Toxicity. Mild to moderate infusion reactions occur in the majority of patients during the first rituximab infusion. Cytokine release is believed to be at least partially responsible for most of the infusion reactions precipitated by rituximab. Levels of inflammatory cytokines have been shown to increase significantly during the administration of rituximab. Symptoms of the infusion-associated reaction to rituximab can include fever, chills, and rigors. Other symptoms associated with rituximab infusion reactions include nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. These reactions generally occur within 30 to 120 minutes from the beginning of the first infusion. The reaction resolves with slowing or interruption of the rituximab infusion and with supportive care such as administration of diphenhydramine, acetaminophen, and IV saline. The incidence of infusion reactions is highest with the first infusion and decreases with each subsequent infusion. The rate of infusion reactions with the first infusion is 77% and is 30% with the fourth infusion. (See Table 1 for nursing management strategies of infusion reactions from monoclonal antibodies.) Pain at the injection site has been reported in less than 5% of patients receiving rituximab.
Tumor lysis has been reported following treatment with rituximab. The risk of tumor lysis seems to be greater in patients with high levels of circulating malignant cells or high tumor burden. Myelosuppression due to rituximab alone is infrequent (2% to 4%) and reversible. It is increased in frequency when rituximab is combined with chemotherapy; however, a higher rate of neutropenia is not noted when rituximab is combined with chemotherapy. Lymphocyte depletion occurs in 70% to 80% of patients, and may be responsible for an increased rate of infection in which no specific organism can be identified. The median duration of lymphopenia is approximately 14 days, and the median duration of neutropenia of 13 days. Bacterial, viral, and fungal infections have been reported following rituximab therapy; however, serious infections have been reported to occur in only 2% of patients.[13,14]
Hepatitis B virus reactivation, with hepatic failure and death, has been reported with rituximab. The median time to the diagnosis of hepatitis was about 4 months after the initiation of rituximab. Cardiac toxicity, with chest pain and arrhythmias, has been reported rarely, especially in patients with cardiac comorbidities. The relationship between cardiac toxicity and rituximab therapy has been difficult to establish.
Ofatumumab (Arzerra) is a fully human anti-CD20 monoclonal antibody. It has a stronger complement-dependent cytotoxicity, a slower disassociation rate, and more stability in binding to B cells than rituximab in vitro. Ofatumumab was approved by the FDA in 2009 for patients with CLL who are refractory to both fludarabine (Fludara) and alemtuzumab (Campath). In patients with CLL that was refractory to fludarabine, the overall response rate (ORR) was 47%, with a response rate of 43% in patients who had previously received rituximab and 53% in those who were rituximab-naive. Additional studies are ongoing with the use of ofatumumab in combination with chemotherapeutic regimens.
Toxicity. The most common adverse reactions from ofatumumab are infusion reactions and infections that are primarily grade 1 or 2. Infusion reactions are relatively common with early doses but subside with subsequent infusions. Additional side effects include neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious toxicities are infections, neutropenia, and pyrexia, with infection being the most common cause for discontinuation of the drug.
Brentuximab vedotin (Adcetris) is a novel antibody–drug conjugate consisting of an anti-CD30 antibody conjugated to a potent antimicrotubule agent. It is administered as a 30-minute infusion every 3 weeks. An ORR of 75% with brentuximab vedotin has been reported in Hodgkin lymphoma, with a 34% CR rate. An ORR of 86% has been reported in patients with anaplastic large cell lymphoma, with 57% CRs.
Toxicity. In a phase I study of brentuximab vedotin, the most common reported side effects included fatigue (36%); pyrexia (33%); and diarrhea, nausea, neutropenia, and peripheral neuropathy (22% each). Patients with peripheral neuropathy typically presented with grade 1 or 2 sensory findings, such as numbness or tingling of the hands or feet. The median time to onset of symptoms was 9 weeks. Resolution of neuropathy symptoms was noted in 63% of the patients who developed peripheral neuropathy.
Alemtuzumab (Campath) is a humanized monoclonal antibody against CD52, which is a marker on both normal and malignant B and T cells and on the majority of monocytes, macrophages, and natural killer cells. It was approved in 2001 for relapsed and refractory CLL/small lymphocytic lymphoma (SLL), and for previously untreated CLL patients in 2007. The dosing schedule starts at 3 mg on day 1, then increased to 10 mg on day 2 and 30 mg three times per week for a total of 8 to 12 weeks. Alemtuzumab can be given either by the IV or subcutaneous route. The majority of patients treated via the IV route experience infusion reactions. Alemtuzumab administered subcutaneously has shown biologic activity comparable to that seen with the IV route. While some have reported diminished infusion reactions with the subcutaneous route, others have reported similar infusion reaction rates except for fewer reports of chills when alemtuzumab was given subcutaneously, as compared with IV administration.[22,23] Prophylactic antibacterial and antiviral antibiotics need to be given along with alemtuzumab therapy. In a large international study of patients who had failed to respond to fludarabine, the ORR in CLL patients following treatment with alemtuzumab was 33%, with 2% of patients achieving a CR. Median time to progression for patients who responded to treatment was 9.5 months. The median peripheral blood lymphocyte count decreased by more than 99.9%, but alemtuzumab has been found to be less effective in patients with bulky lymph nodes that are more than 5 cm in diameter. The authors noted that, in prior studies, patients with poor performance status did markedly worse than they observed in their study, with increased hematologic and infectious toxicity. Alemtuzumab is being investigated in combination with other agents.
Toxicity. The most common adverse events with alemtuzumab are cytopenia and infection, as a consequence of profound cellular immune suppression. Profound lymphopenia occurs by 2 to 4 weeks following initiation of treatment, and it may persist for more than a year. Severe neutropenia occurs in about one-third of patients, typically between weeks 4 and 8, and usually resolves in 2 to 3 weeks. Reactivation of herpes virus infections, including cytomegalovirus (CMV), represents the most common opportunistic infection in patients receiving alemtuzumab. Patients should receive prophylaxis against opportunistic infections and be monitored for CMV reactivation. Septicemia has been reported in about 15% of patients.
Notably, in the study by Keating et al, nonresponders to alemtuzumab had an increased risk of severe infection. Infusion reactions in that study resulted in discontinuation of alemtuzumab in 6% of patients. The most common infusion-related reactions with alemtuzumab were rigors in 89% of patients, fever in 83%, nausea in 47%, vomiting in 33%, and hypotension in 15%. Other frequently reported symptoms of infusion reactions include rash, fatigue, urticaria, dyspnea, pruritus, headache, and diarrhea.