The treatment of hematologic malignancies is rapidly changing, and primary therapy for multiple myeloma (MM), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML) has evolved steadily over the past 5 years. Biologic advances have led to a better understanding of drug resistance and the emergence of an assortment of targeted therapies.
The molecular pathways have been the focus of much research over the past 20 years. “Markers, receptors, and ways to transport drugs are important components of the cell, and we are learning what they do and, more important, how to manipulate them,” pronounced B. Douglas Smith, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.
The use of targeted therapies has revolutionized the way in which leukemias are treated. In addition to improving our understanding of signaling pathways in the development of leukemia and drug resistance, the emergence of targeted therapies offers patients more treatment options with less toxicity than do older approaches. “There are a lot of different agents that are now under development, some of which have been approved for therapy, for dealing with abnormalities on the cancer cell,” reported Dr. Smith. When combined with cytotoxics, these innovative agents may overcome drug resistance and target minimal residual disease, he added.
The biologic and therapeutic implications of the use of targeted therapies must be considered as well. Such therapies should ideally impact the primitive cancer stem cell in order to avoid the problem of emerging drug resistance, according to Dr. Smith. For the treatment of AML, it is unlikely that a single agent will be effective, in contrast to the effectiveness of single agent imatinib in the treatment of CML. So the question is how to use new generations of agents effectively in combination. Another concern is the fact that “targeted” does not mean without adverse effects. Finally, clinical trials should incorporate meaningful biologic correlatives into realistic designs; biologic correlates can often provide valuable insights into the underlying pathophysiology.
The importance of encouraging patients to participate in clinical trials cannot be overemphasized, urged Dr. Smith. The link between laboratory studies and clinical work is an essential component of the development of future therapeutic advances. The 2006 National Comprehensive Cancer Network (NCCN) clinical practice guidelines note that there is no standard treatment for AML, and participation in clinical trials is recommended during first-line as well as post-remission therapies.
The most common molecular abnormality of AML is the FLT3-activating mutation, a member of the PDGFR family of receptors; Dr. Smith deemed it as “one of the worst prognostic factors” in AML. Thus, inhibition of the abnormal FLT3 protein has emerged as a target of therapy. Oral FLT3 inhibitors such as lestaurtinib (CEP-701), midostaurin (PKC412), and tandutinib (MLN518) have been evaluated in patients with relapsed or refractory AML with such mutations. Dr. Smith reported that they have been “clinically active” in approximately 30%40% of patients.
More recently, the use of lestaurtinib has been studied in combination with chemotherapy in patients with relapsed AML in a randomized, open-label trial (Levis M et al. Blood 2005;106:403). This trial enrolled 49 patients, nearly half of whom received chemotherapy plus lestaurtinib, with the others receiving chemotherapy only. Lestaurtinib appeared to be well tolerated, its addition causing a slight increase in gastrointestinal side effects (nausea and dyspepsia) but few withdrawals as a result of drug-related adverse events. The clinical results were compared with the results of the laboratory studies that focused on plasma levels of the drug and cell sensitivity. There were complete remissions in 6 of 8 patients with both adequate plasma concentrations and sensitive cells.
“In fact, these correlative studies perfectly mirrored the clinical responses seen,” Dr. Smith stated. “A new direction might be to take agents that are selective and target abnormalities in leukemia cells and begin to combine them to optimize their effect,” he added.
The incidence of AML is higher in people older than age 65 than in younger individuals, and the chance of developing AML by the age of 70 is nearly 1 in 7,000, Dr. Smith stated. Moreover, certain factors associated with age, such as an increase in DNA damage and exposure to environmental toxins, a decrease in detoxifying enzyme activity, and a decrease in immune surveillance, complicate the clinical picture even further.
“In fact, we know that our older patients don’t do as well with therapies,” Dr. Smith explained, and so, essentially, elderly patients with newly diagnosed AML have traditionally not been treated with standard therapies. With these growing numbers, however, it has been challenging to develop effective therapies for elderly patients with AML that increase tumor selectivity while decreasing toxicity.
Several farnesyltransferase inhibitors (FTIs), such as lonafarnib (SCH66336), BMS214662, and tipifarnib (R115777), have been assessed in clinical trials for various hematologic malignancies (see table). In early phase I trials of tipifarnib in patients with relapsed AML, response rates of up to 30% have been achieved at different dosing levels, according to Dr. Smith, and in phase II studies of older (median age, 73 years) patients with AML, response rates of between 10% and 15% were obtained, with a median duration of 31.5 weeks. Of note, 80% of the 171 patients in the phase II trial were considered to be at poor risk (based on age, cytogenetic analysis, and MDS).
Combination therapy with tipifarnib and etoposide in elderly (older than age 70) patients with poor-risk, newly diagnosed AML appears to be a fairly well tolerated and clinically active approach. In one dose-escalating study on 48 patients (median age, 77 years), the dosage regimen was 300, 400, or 600 mg of tipifarnib twice daily for 14 or 21 days along with 100, 150, or 200 mg of etoposide on days 13 and 810. Responses were seen at all dosing levels.
At the end of cycle 2, the complete response rate in patients with a median age of 80 years was 23%, and a 30% response rate was achieved with a higher dose of tipifarnib (³ 400 mg twice daily); the rate of treatment-related deaths was 15%. Although the rate of hospitalization was high (36%) in the study group, this finding was not unexpected, given the poor-risk, older study population, Dr. Smith asserted. This trial continues to accrue patients to determine the best dosing combination.
The development of effective vaccine strategies is yet another treatment direction for leukemia. The components of a true immune attack include an active immune system, recognition between the cells (“self“ versus “nonself”), an immune system stimulus (antigen), and an adjuvant stimulus. Since myeloid malignancies are relatively immunoresponsive, “CML is an ideal disease to target the impact of immunotherapy,” Dr. Smith stated.
Derived from a CML erythrocyte cell line, K562/granulocyte macrophage colony-stimulating factor (GM-CSF) vaccine offers potential target antigens; the addition of the potent cytokine GM-CSF enhances the immune system, explained Dr. Smith. In a pilot study of K562/GM-CSF immunotherapy in 19 adults with chronic-phase CML (median age, 52 years) who had been taking imatinib for at least 12 months, four injections of the vaccine were administered at 3-week intervals. Eligibility criteria included a major cytogenetic response and a measurable disease burden, which was assessed every 6 weeks for 6 months via fluorescence in situ hybridization (FISH) or the polymerase chain reaction (PCR).
Overall response rates of 53% were achieved, with a median follow-up of 14 months, Dr. Smith reported. Two of the 4 patients who were FISH positive and 8 of the 15 patients who were FISH negative but PCR positive responded. Although no hematologic or autoimmune toxicities were noted, all patients experienced mild skin reactions at the injection site. In an anecdotal report from his clinical practice, Dr. Smith said that a 57-year-old woman with previously treated chronic-phase CML has achieved “an impressive response” with a series of four K562/GM-CSF vaccinations and imatinib.
Dr. Smith considered this immunotherapeutic approach to be a safe alternative that may improve individual responses in patients on imatinib. Molecular remissions can be obtained with minimal toxicity. Furthermore, these vaccine “responses” have been demonstrated in an assortment of settings: with or without prior interferon treatment, in the presence of a FISH-positive or FISH-negative disease burden, and during or after vaccination. Finally, vaccination may eliminate residual leukemia after cytoreduction with imatinib.
New trials are being conducted with K562/GM-CSF as a booster therapy in patients with CML; with J05115 in those with MDS; and in elderly subjects with AML who are destined to relapse after remission. “This group of trials together will lend some important insights in how to target the immune system and get it involved in therapy,” Dr. Smith concluded.