Targeted Therapies: Implications for Treating Hematologic Malignancies

At a symposium held in conjunction with the Twenty-Seventh Annual Congress of the Oncology Nursing Society, three specialists in oncology nursing presented recent data on the use of targeted therapies to treat hematologic malignancies. Topics included the use of monoclonal antibodies to treat non-Hodgkin’s lymphoma, antibody- targeted chemotherapy to treat acute myelogenous leukemia, and tyrosine kinase inhibition to treat chronic myelogenous leukemia.

This program was supported by an educational grant from Wyeth Pharmaceuticals.

Speakers

Monoclonal Antibody in the Treatment of Non-Hodgkin’s Lymphoma  

Approximately 300,000 Americans are living with non-Hodgkin’s lymphoma (NHL), a disease that has grown in incidence by 15% over the last 15 years. Non-Hodgkin’s lymphoma, which is characterized by malignant proliferation of lymphoid cells of the immune system, is derived from B cells in approximately 85% of cases. For this reason, the CD20 antigen, which is expressed only on B cells, is an important target for treatment of non-Hodgkin’s lymphoma, according to Jill M. Contardi, RN, Infusion Room Staff Nurse, Seattle Cancer Care Alliance, Seattle, Washington. For this reason, monoclonal antibody therapies that target CD20 have become an important treatment option for patients with some types of non-Hodgkin’s lymphoma.

Monoclonal Antibody Therapy for Low-Grade Non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma is typically categorized by disease grade (Table 1), as well as immunophenotype, cytogenetics, and other factors. For stage I and II low-grade non-Hodgkin’s lymphoma, treatment options generally include watchful waiting, excision, regional radiation therapy, and chemotherapy. For stage III and IV low-grade non-Hodgkin’s lymphoma, options are combination chemotherapy, high-dose chemotherapy, stem cell transplantation, and biologic therapies, such as rituximab. Rituximab, a chimeric humanized murine monoclonal antibody, is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive B-cell non-Hodgkin’s lymphoma as well as for retreatment, 8-week therapy, and treatment of bulky disease. Rituximab operates by targeting the CD20 antigen found on the surface of both normal and malignant B cells. “CD20 is indeed a useful target in treating B-cell non-Hodgkin’s lymphoma. CD20 is expressed only on B cells, it stays on the membrane of the target cell, and it is not internalized by the cell once bound to antibody,” Ms. Contardi said. In a pivotal study by McLaughlin and colleagues, patients with relapsed or refractory CD20-positive low-grade or follicular lymphoma received 375 mg/m2 rituximab once/week for 4 weeks. Results showed a complete response of 6% and partial response of 42%, with a time to disease progression of 13.2 months. Others have found similar results (Piro et al; Davis et al). In addition, studies to treat patients with high-grade lymphoma with chemotherapy plus rituximab have shown promise (Coiffier et al 2002).

Toxicity and Patient Education with Rituximab
A thorough and careful nursing assessment is essential before, during, and after administration of rituximab (Table 2). “The potential adverse reactions with rituximab are different than those with chemotherapy, and patients should be educated as to what signs and symptoms they can anticipate,” Ms. Contardi explained. Common adverse reactions with rituximab include flu-like symptoms, cardiovascular events, tumor lysis syndrome/renal dysfunction, hypersensitivity reactions, and mucocutaneous reactions. Hematologic side effects are less common, and may include severe neutropenia (and resulting infection 2%), thrombocytopenia, and anemia (2%-6%). “In addition, B lymphocyte levels are decreased, with recovery occurring within 9 to 12 months,” Ms. Contardi said.

Before discharge, nurses should explain the potential reactions and safety issues with rituximab treatment. Trouble breathing, changes in cardiac signs and symptoms, fever, skin changes, or urinary changes should be reported immediately. Home medications and precautions concerning hematologic effects (especially if also receiving chemotherapy) should be discussed, along with the necessary avoidance of pregnancy, breastfeeding, and exposure to live vaccines. Patients should be encouraged to call with any questions or concerns. “In addition to verbal discussion, written instructions for patients are often helpful,” Ms. Contardi pointed out.

In closing, Ms. Contardi noted that rituximab continues to be a valuable treatment option for patients with certain types of low-grade lymphoma and bulky disease, and is currently under study for use in patients with certain types of high-grade lymphoma. In addition, a recent phase III study has yielded good response rates with another monoclonal antibody agent, ibritumomab tiuxetan, which consists of a monoclonal antibody attached to a radioisotope. It is hoped that patients with bulky disease, and low-grade and intermediate-grade CD20-positive non-Hodgkin’s lymphoma will benefit from the research continuing in this area.

Table 1. Classification of Non-Hodgkin’s Lymphoma by Grade
Low-Grade Lymphoma
  • Diffuse small-cell lymphocytic; follicular small cleaved-cell; follicular mixed types
Intermediate-Grade Lymphoma
  • Follicular large-cell; diffuse small cleaved; diffuse mixed small- and large-cell; diffuse large-cell types
High-Grade Lymphoma
  • Immunoblastic lymphoma; Burkitt’s; lymphoblastic lymphoma; small noncleaved cell

Table 2. Nursing Assessment with Rituximab Administration

• General assessment
• Pretreatment vital signs with O2 saturation
• Laboratory tests: CBC with differential, chemistries
• Cardiac monitoring if positive cardiac history noted
• Assessment of whether home medications were taken or held (eg, allopurinol, antihypertensives)
• Assessment of transportation plan
• Review of S/S of reactions to be reported
• Premedication with 650 mg acetaminophen, 25/50 mg po/IV diphenhydramine 30 to 60 minutes prior to start
• Anaphylaxis medications at bedside
• Airway, O2 supplies

Antibody-Targeted Chemotherapy in Acute Myeloid Leukemia

Acute myelogenous leukemia (AML) is an aggressive malignancy that occurs most frequently in persons older than 60 years, and has a median survival time of 1 to 2 years. Treatment regimens for acute myelogenous leukemia include induction chemotherapy, consolidation chemotherapy, and stem cell transplantation. Because CD33 is expressed by leukemic blast cells in more than 80% of patients with acute myelogenous leukemia, antibody-targeted chemotherapy targeting CD33 has also become an important treatment option for select patients with this disease, said Program Chair Kathleen Shannon-Dorcy, RN, MN, Research Nurse, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Antibody-Targeted Chemotherapy for Acute Myelogenous Leukemia
Acute myelogenous leukemia is a clonal hematopoietic malignancy, originating in the bone marrow and involving cells of the myeloid lineage, and is characterized by overproduction of myeloblasts and impaired production of normal cells. While the mean survival time with acute myelogenous leukemia is only 1 to 2 years, 40% of patients younger than 65 years are cured. Chemotherapy regimens used to treat acute myelogenous leukemia can result in cure or increased survival time, but also carry toxicities such as alopecia, mucositis, cardiovascular toxicity, thrombocytopenia, and infection. In addition, stem cell transplantation procedures can be too invasive for many older patients. “However, antibody-targeted chemotherapy allows the benefit of specifically targeting the CD33 marker expressed on the surface of leukemic cells in more than 80% of patients with acute myelogenous leukemia,” Ms. Shannon-Dorcy said.

Gemtuzumab ozogamicin is the first and only antibody-targeted chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) for use in patients with acute myelogenous leukemia. Gemtuzumab consists of a highly specific and minimally immunogenic humanized murine anti-CD33 monoclonal antibody that is conjugated with a highly potent cytotoxic agent, calicheamicin. Gemtuzumab’s monoclonal antibody component targets the CD33 antigen—expressed on the leukemic cells but not on the pluripotent stem cells or nonhematologic cells—thus delivering the cytotoxic calicheamicin directly to the cancer cells. Gemtuzumab is indicated for use in patients with relapsed acute myelogenous leukemia who are 60 years or older or who are unable to tolerate chemotherapy. Indeed, phase II studies have shown overall remission rates of approximately 30% in patients receiving gemtuzumab (gemtuzumab package insert). Adverse events observed with gemtuzumab may include fever, chills, nausea, vomiting, asthenia, diarrhea, abdominal pain, headache, stomatitis, dyspnea, and hypokalemia (Data on file. Wyeth Pharmaceuticals).

Nursing Management Strategies: Gemtuzumab Administration
In patients who have relapsed acute myelogenous leukemia and are undergoing gemtuzumab treatment, careful nursing assessment and management strategies are essential (Table 1). Important points to remember are to alert the pharmacy that gemtuzumab will be required, to schedule administration early in the day, and to schedule administration early or mid-week. “Because of the immediate neutropenia and thrombocytopenia that occurs, monitoring is necessary and scheduling administration before the weekend is not recommended,” Ms. Shannon-Dorcy said. In addition, with gemtuzumab, the anti-tumor agent works inside the cell; therefore, corticosteroids may be used.

Conclusion
According to Ms. Shannon-Dorcy, continuing research results with gemtuzumab have been promising. This agent is currently being studied as a single agent in cases of APL in which patients have high-risk cytogenetics, and in combination regimens for induction therapy in acute myelogenous leukemia (Table 2). “These potential treatment options provide us with cautious optimism for the future. We continue, one step at a time, to work toward the elimination of cancer from the lives of our patients,” Ms. Shannon-Dorcy concluded.

Table 1. Nursing Assessment and Management Strategies with Gemtuzumab

Patient Care
  • Patient should be scheduled for early morning administration
  • Provide hydration at maintenance
  • Give two doses 14 days apart
  • Instruct patient regarding immediate neutropenia and thrombocytopenia
Nursing Assessment
  • Vital signs, pre- and post-administration
  • Pretreatment laboratory tests: CBC, LFTs, electrolytes. Monitor post-infusion
  • Premedicate with diphenhydramine 50 mg po, methylprednisolone 50 mg IV.
  May repeat 4 hours after first dose
Clinical Implications after Administration
  • Rapid neutropenia and thrombocytopenia
  • Prophylaxis with ciprofloxacin, ceftriaxone for fever, amphotericin B
  • Transient elevation in liver function tests

Table 2. Current Clinical Trials of Gemtuzumab Ozogamicin

• Gemtuzumab as single agent in consolidation therapy in patients with high-risk cytogenetics
• Untreated APL
• Gemtuzumab in combination therapies for the treatment of acute myelogenous leukemia
   – Sequential administration with MICE induction therapy in elderly patients
  – Low-dose gemtuzumab with cytarabine and daunorubicin in induction therapy (phase I)
  – Low-dose gemtuzumab in combination with H-DAT 3 + 10 induction therapy in adults < 60 years

Tyrosine Kinase Inhibition in the Treatment of Chronic Myeloid Leukemia

Chronic myelogenous leukemia (CML) is a malignancy in which too many white blood cells are produced, are released into the circulation, and do not undergo apoptosis. High response rates to treatment may occur in all phases of disease, and cytogenetic advances over the last two decades have resulted in the development of targeted treatment options for patients with chronic myelogenous leukemia, said Carol S. Viele, RN, MS, Clinical Nurse Specialist, Hematology/Oncology/Bone Marrow Transplant, and Assistant Clinical Professor, Department of Physiological Nursing, University of California, San Francisco. According to Ms. Viele, the identification of Bcr-Abl tyrosine kinase, an enzyme causing aberrant cell growth and division in chronic myelogenous leukemia, has allowed the development of a therapeutic agent that may act against this specific protein.

The Role of Tyrosine Kinase
Chronic myelogenous leukemia occurs at a median age of 45 to 55 years, with 85% of patients being diagnosed in the chronic phase of disease. The clinical course of chronic myelogenous leukemia is well characterized, with the chronic phase (with stabilization of disease) lasting 4 to 6 years, the accelerated stage (begins to produce more abnormal cells) lasting a median of 1 year, and the blast or blast crisis phase (terminal phase of illness) approximately 3 to 6 months. Several cytogenetic findings have helped to improve the treatment options for certain patients with chronic myelogenous leukemia. It is well known that 95% of persons with chronic myelogenous leukemia have the Philadelphia chromosome, or translocation of chromosomes 9 and 22. In turn, this t (9;22) abnormality creates the constitutive abnormal tyrosine kinase, Bcr-Abl tyrosine kinase. “It is now known that Bcr-Abl tyrosine kinase is the single molecular abnormality that causes the transformation to the malignant clone. Tyrosine kinase triggers a signal transduction cascade, resulting in cell growth and proliferation,” the speaker explained.

Indeed, in chronic myelogenous leukemia, as part of the signal transduction pathway, phosphorylation leads to stimulation of tyrosine kinase substrate called Bcr-Abl, which in turn leads to uncontrolled proliferation and reduced apoptosis of white blood cells (Table 1). By inhibiting the signal transduction of tyrosine kinase, stimulation and phosphorylation of this enzyme do not occur, and thus chronic myelogenous leukemia does not develop.

Targeted Treatment Strategies
Imatinib mesylate was developed as a targeted therapy, designed to inhibit tyrosine kinase and disrupt the signal transduction pathway leading to development of chronic myelogenous leukemia (Table 1). Imatinib inhibits proliferation and induces apoptosis in Bcr-Abl-positive cell lines. In addition, imatinib also inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF), stem-cell factor (SCF), c-kit, and PDGF- and SCF-mediated cellular events (imatinib package insert). In 2001, U.S. Food and Drug Administration (FDA) approved the use of imatinib as an oral therapy for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis, accelerated phase, or chronic phase after unsuccessful interferon-alpha therapy. Imatinib has been shown to produce high response rates in patients with chronic myelogenous leukemia for whom interferon has failed or cannot be tolerated. In addition, three phase II open- labeled, multicenter studies showed imatinib 400 to 600 mg to yield complete hematologic response rates ranging from 93% (chronic phase) to 7% (blast phase) and major cytogenetic response rates ranging from 61% (chronic phase) to 15% (blast phase).

The most frequently observed side effects of imatinib include skin rash, nausea and vomiting, muscle cramping, diarrhea, and edema. “Importantly, one of the main nursing points to note is that imatinib affects cytochrome P450 metabolism, mainly via CYP3A4, and thus may have interactions with other drugs such as warfarin and acetaminophen. Administering imatinib with these agents may alter clearance. Inhibitors of clearance include erythromycin, clarithromycin, and ketoconazole, while inducers of clearance include dexamethasone, phenytoin, and St. John’s wort. It is therefore important to be aware, from both the patient and the pharmacy, of what medications each patient is taking,” Ms. Viele explained (Druker et al, ASH meeting educational symposium 2001).

Conclusion
Imatinib has been shown to have a favorable safety profile and good rates of hematologic and cytogenetic responses in all phases of chronic myelogenous leukemia. In addition, the FDA recently approved imatinib for use in patients with kit-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Studies of imatinib in patients with small-cell lung cancer, prostate cancer, glioma, and breast cancer are ongoing. According to Ms. Viele, “The continued study and use of targeted therapy in chronic myelogenous leukemia and other cancers may indeed change the course of cancer treatment in the future.”

Table 1. The Role of Signal Transduction in Chronic Myelogenous Leukemia

Signal Transduction
  • Any biochemical communication from one part of a cell to another
Signal Transduction Inhibition
  • A process by which signal transduction is stopped, bringing the cell back to its normal condition
Signaling Proteins
  • Tyrosine kinases are enzymes that trigger a signal transduction cascade, resulting in cell growth and proliferation