Posts Tagged ‘CHR’
Antineoplastic Agents
Overview
Although conventional cytotoxic drugs are the mainstay of therapy for most cancers, immunotherapies (and more recently, the protein tyrosine kinase inhibitor imatinib) have played a more prominent role in chronic myelogenous leukemia. Accordingly, few antineoplastic agents are in active development for chronic myelogenous leukemia. We discuss only ChemGenex’s version of homoharringtonine (Ceflatonin) in this section. The Chinese Academy of Medical Science has also launched a version of homoharringtonine.
Mechanism Of Action
Conventional cytotoxic agents interrupt the DNA replication and repair processes required for functional cell division. They act in several ways, including alkylating DNA, resulting in strand breakage; inhibiting crucial enzymes required for DNA strand formation; and interfering with spindle formation. Homoharringtonine inhibits the initiation of protein, DNA, and RNA biosynthesis.
Homoharringtonine
Homoharringtonine (ChemGenex’s Ceflatonin, formerly CGX-653) is an intravenous formulation of a natural product derived from the cephalotaxus evergreen tree. Homoharringtonine affects several cellular pathways, including the regulation of genes associated with apoptosis and angiogenesis. In the several years prior to the launch of imatinib, homoharringtonine was extensively investigated for chronic-phase chronic myelogenous leukemia, in first- and second-line therapy, alone, and in combination with interferon-a and/or cytarabine (Pfizer’s Cytosar-U, generics). ChemGenex has initiated a combination Phase II trial of homoharringtonine and imatinib in chronic myelogenous leukemia patients who are developing resistance to imatinib. Phase II trials are ongoing in the acute myelogenous leukemia setting.
A preclinical study in four paired imatinib-sensitive/resistant cell lines investigated the potency of homoharringtonine, cytarabine, daunorubicin, and hydroxyurea, alone or in combination with imatinib. Primary blasts from advanced-stage, imatinib-refractory chronic myelogenous leukemia patients were studied using semi-solid media clonogenic assays to test the sensitivity of the tumor cells to homoharringtonine. Investigators found that homoharringtonine achieved major inhibition of chronic myelogenous leukemia cell-line proliferation.
In a clinical trial, homoharringtonine, combined with interferon-a in the first-line setting, achieved a CHR in 85% of patients, a cytogenetic response in 21% of patients, and an major cytogenetic response in 49% of patients. Combined with low-dose cytarabine as a second-line treatment, homoharringtonine induced a CHR among 72% of patients, major cytogenetic response in 15% of patients, and cytogenetic response in 5% of patients. In a triple-therapy study among patients with early chronic-phase chronic myelogenous leukemia, 90 patients received treatment with interferon-a, cytarabine, and homoharringtonine. Patients received 5 million units (MU)/m2 interferon-a and cytarabine 10 mg, both subcutaneously daily, and homoharringtonine 2.5 mg/m2 by continuous infusion over 24 hours daily on days 1-5 every 28 days. After a median duration of 16.5 months of therapy, 78 patients switched to imatinib 400 mg orally daily.
With the triple regimen, 94% of patients achieved a CHR and 74% achieved a cytogenetic response. The cytogenetic response was complete (Ph-positive cells 0%) in 22% of treated patients and major in 46% of treated patients. Significant myelosuppression occurred, resulting in major dose reductions. After 12 months of therapy, the median interferon-a dosage was 1.6 MU/m2 daily, the median cytarabine dosage was 1.85 mg daily, and the median number of homoharringtonine-treated days was two every month. Only three patients developed blastic-phase disease while receiving the triple regimen. After switching to imatinib, and after a median follow-up of 46 months from the start of triple therapy, 63% of patients achieved a cytogenetic response and a further 13% achieved an major cytogenetic response. Nine percent of patients had entered the blastic phase. Investigators estimate that five-year survival will stand at 88%.
In a small Phase I/II trial, nine patients with Ph-positive accelerated-phase chronic myelogenous leukemia previously treated with imatinib received treatment with a semi-synthetic formulation of homoharringtonine by daily subcutaneous injection for seven days, every 28 days. With a median follow-up of 12 months, 80% of patients had achieved a second chronic phase, and 67% of patients had achieved a complete hematologic response. No patient achieved a cytogenetic response. According to investigators, homoharringtonine was well tolerated with minimal nonhematologic toxicity. Grade IV neutropenia was observed in three patients, and grade IV thrombocytopenia requiring platelet support occurred in two patients. All patients were monitored for mutations in the ABL kinase domain, and, in one patient, a kinase domain mutation detected at the start of treatment was no longer detectable after six months of treatment.
One problem facing older drugs in clinical trials for chronic myelogenous leukemia, such as homoharringtonine and arsenic trioxide, is that physicians would rather place patients in clinical trials testing the new tyrosine kinase inhibitors and use these older agents only as last resorts. However, the primary limitations of homoharringtonine are its hematologic toxicity and its relatively low incidence of CCRs. The hematologic toxicity has restricted the dose of homoharringtonine in clinical trials, and most patients ultimately received only two days, rather than the planned five days, of treatment per month. Homoharringtonine’s hematologic toxicity profile will probably preclude a role in combination with imatinib in the first-line setting.
Hypomethylating Agents
Overview
Hypermethylation of DNA in the regulatory area of selected genes has been shown to be common in neoplasia and is associated with tumor resistance or progression.
Both 5-azacytidine (Pfizer’s Vidaza/Mylosar) and decitabine (Supergen and MGI Pharma’s Dacogen) are potent DNA methylation inhibitors and have shown significant antileukemic activity in myeloid malignancies, including acute myelogenous leukemia and myelodysplastic syndrome. In chronic myelogenous leukemia, these agents have been used mostly in the accelerated and blastic phases.
Mechanism Of Action
The Pa promoter of abl and several other genes that are central to the development of chronic myelogenous leukemia are hypermethylated in a significant proportion of patients, and methylation increases with disease progression. The p15 gene is hypermethylated with chronic myelogenous leukemia progression, and different patterns of hypermethylation for myeloid and lymphoid blastic phases have been reported. Therefore, hypomethylating agents may play a role in treating chronic myelogenous leukemia. Decitabine
Decitabine is a DNA methyltransferase inhibitor under development by Supergen and MGI Pharma for the potential treatment of a range of hematologic malignancies, solid tumors, and sickle cell disease. Decitabine has shown activity in accelerated-phase and blastic-phase chronic myelogenous leukemia as a single agent and is now being investigated in combination with other chemotherapeutic agents and imatinib. The agent is in Phase II trials for the treatment of chronic myelogenous leukemia.
Decitabine is a cytidine analogue that exerts potent DNA hypomethylating effects through its covalent binding to DNA methyltransferase. Decitabine is cytotoxic at high doses, hypomethylating at low doses, and has clinical activity in myeloid malignancies that appears to be optimal at low doses.
In a Phase II study, the activity of decitabine mono therapy (at 15 mg/m2 intravenously [IV] over one hour daily, five days a week for two weeks) in patients who were either imatinib-intolerant or had chronic myelogenous leukemia that was refractory to imatinib was evaluated. Thirty-five patients were enrolled (12 in the chronic phase, 17 in the accelerated phase, and 6 in the blastic phase). CHRs were seen in 12 patients (34%), partial hematologic responses were seen in 7 patients (20%), and hematologic improvement was seen in 4 patients (11%); there was an overall hematologic response rate of 65% (83% in the chronic phase, 59% in the accelerated phase, and 50% in the blastic phase). MCRs were observed in 7 patients (20%), and minor cytogenetic responses were seen in 9 patients (26%), with an overall cytogenetic response rate of 46%. Median response duration was three months. The only common grade 3 or 4 toxicities observed were related to myelosuppression. There were two deaths in the study, both related to thrombocytopenia and hemorrhage.
Another study showed synergy between imatinib and decitabine. Ten patients who presented with untreated accelerated or blastic-phase chronic myelogenous leukemia were treated with a combination of decitabine (15 mg/m2, IV, for 10 days) and imatinib (600 mg po daily). Of the ten patients enrolled, six were evaluable; two patients achieved CHR, and one patient achieved a minor cytogenetic response.
If approved for the treatment of chronic myelogenous leukemia, decitabine will likely be used in accelerated-phase and blastic-phase disease that is unresponsive to imatinib therapy. The agent is unlikely to be used alone and will be used in combination with imatinib and other therapies.
Farnesyl Transferase Inhibitors
Overview
One of the best-recognized downstream events resulting from the tyrosine kinase activity of BCR-ABL in chronic myelogenous leukemia patients is the activation of ras. Ras, which is synthesized as an inactive protein in the cytoplasm, is activated through a prenylation process that allows attachment to the cellular membrane. This process is mediated most prominently by farnesyl transferase and alternatively through geranyl protein transferase. Mutations of ras and Ras protein activation are frequent features of malignant transformation. Approximately 30% of human cancers have been associated with ras mutations. The frequency of these mutations varies in hematologic malignancies from 5% to 15% in acute lymphoblastic leukemia and up to 65% in chronic myelogenous leukemia. Therefore, inhibition of Ras activation has been investigated as an antineoplastic therapy. One approach to ras inhibition is inhibiting farnesyl transferase via farnesyl transferase inhibitors (FTIs). Preclinical studies have demonstrated that FTIs have significant anti-chronic myelogenous leukemia activity.
Mechanism Of Action
The actual mechanism of action of FTIs is not yet clear because the inhibition of Ras farnesylation does not account for all of the FTIs’ actions. For example, FTIs do not require the presence of mutant Ras protein to produce antitumor effects. Several other proteins have been implicated as downstream targets that mediate the antitumorigenic effects of FTIs. The regulation of RhoB, a small GTPase that acts downstream of Ras and is involved in many cellular processes, including cytoskeletal regulation and apoptosis, has been proposed as a mechanism of FTI-mediated antitumorogenesis. Additional proteins involved in cytoskeletal organization are also known to be farnesylated, including the centromere proteins CENP-E and CENP-F, protein tyrosine phosphatase, and lamins A and B. Therefore, one possible mode of action of FTIs may be their inhibiting effects on cellular reorganization and mitosis.
In addition to inhibiting cellular reorganization and mitotic pathways, it is known that FTIs indirectly modulate several important signaling molecules, including transforming growth factor (TGF) βRII, MAPK/ERK, PI3K/AKT2, Fas (CD95), and vascular endothelial growth factor. The regulation of these effectors can lead to the modulation of signaling pathways involving cell growth, proliferation, and apoptosis.
Tipifarnib
Janssen Pharmaceutica and its parent company, Johnson & Johnson, are developing tipifarnib (R-115777, Zarnestra), an orally bioavailable non-petidomimetic FTI for the treatment of various hematologic malignancies, including acute myelogenous leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia. Tipifarnib inhibits farnesyl transferase, preventing Ras from being altered and locating in the cell membrane. Therefore, Ras is not activated, and the signal for cell growth is not transmitted.
A Phase I study suggested that tipifarnib’s mechanism of action may involve inhibiting angiogenesis and decreasing the expression and secretion of vascular endothelial growth factor. This study investigated the tolerability and efficacy of tipifarnib + imatinib in patients with chronic-phase chronic myelogenous leukemia who have failed imatinib. The starting dosage was tipifarnib 300 mg twice daily for 14 days every 21 days and imatinib 300 mg daily, with subsequent levels 300 mg + 400 mg once daily, 400 mg + 400 mg twice daily, and 500 mg + 400 mg three times daily, respectively. The median age was 63 years, and the median time from diagnosis was 68 months. All the patients had failed imatinib, nine had failed interferon-a, and six had failed other therapies. The maximally tolerated dose (MTD) was imatinib 400 mg daily and tipifarnib 400 mg twice daily. One patient died early (16 days on treatment) of unknown causes, nine discontinued therapy after a median of 12 three-week cycles, and six continued therapy after a median of 11+ cycles. Eleven patients started with abnormal WBC counts and nine achieved normalization during therapy. One patient achieved a cytogenetic response, one patient achieved an major cytogenetic response (with a T315I mutation), and two patients displayed minor cytogenetic responses. Two patients lost the response after nine months, and two had ongoing responses more than 12 months after commencing therapy. The researchers concluded that this combination is well tolerated and demonstrates antileukemia activity.
Lonafarnib
Schering-Plough’s lonafarnib is an orally bioavailable nonpetidomimetic FTI. The compound is in Phase II trials for a variety of difficult-to-treat solid tumors and leukemias and in Phase I for chronic myelogenous leukemia.
Lonafarnib inhibits the proliferation of imatinib-resistant, BCR-ABL-positive cell lines as well as colony formation of cells from imatinib-resistant chronic myelogenous leukemia patients. It also sensitizes imatinib-resistant cells to apoptosis with imatinib.
A Phase I study investigated lonafarnib in combination with imatinib for patients with chronic myelogenous leukemia who had failed imatinib therapy. The starting dosage for chronic-phase chronic myelogenous leukemia was imatinib 400 mg daily + lonafarnib 100 mg twice daily; for the accelerated and blastic phases dosage was 600 mg daily and 100 mg twice daily. A total of 22 patients were treated: 9 in the chronic phase, 10 in the accelerated phase, and 3 in the blastic phase. Prior therapy included imatinib (n = 22), interferon-a therapy (n = 16), and other agents (n = 7). Median age was 59 years, and median time from diagnosis was 51 months. Patients received therapy for a median of 23 weeks.
Among 6 patients in the chronic phase evaluable for hematologic response, 1 patient had a CHR and 1 patient achieved an major cytogenetic response. Among patients in the accelerated and blastic phases, 4 had hematologic responses: one CHR (with mutation F359V), one partial hematologic response (no mutation), and two hematologic improvements (one patient with lymphoid blastic-phase disease achieved marrow cytogenetic response, and one patient with accelerated-phase disease achieved CHR with incomplete platelet recovery). The researchers concluded that the combination of lonafarnib and imatinib is well tolerated and shows early evidence of activity in this refractory population.
Cytotoxic Agents
Overview
Chemotherapy uses anticancer or “cytotoxic” drugs to destroy cancer cells by disrupting their growth. Cytarabine is commonly used in combination with interferon-a and in chemotherapy regimens to treat blastic-phase chronic myelogenous leukemia. The cytotoxic agents hydroxyurea and busulfan were the treatments of choice until interferon-a was introduced into the chronic myelogenous leukemia market twenty years ago. The older agents are less costly than interferon-a or imatinib and are orally administered.
Once chronic myelogenous leukemia enters the blastic phase, no treatment is particularly effective for controlling the disease. Clinicians use a wide variety of multidrug regimens that are based on the treatments for acute myelogenous leukemia and acute lym-phocytic leukemia. Commonly used cytotoxic agents are idarubicin (Pfizer’s Zavedos/Idamycin), daunorubicin (Sanofi-Aventis’s Cerubidin, Bedford’s Cerubidine, generics), and vincristine (Eli Lilly’s Oncovorin, generics).
Mechanism Of Action
Chemotherapeutic drugs work by damaging cancer cells as they undergo division, or mitosis, and preventing their further reproduction. Cells that are at rest (e.g., most normal cells) are much less vulnerable to chemotherapeutic damage. The cell cycle is composed of four distinct phases, G1, S, G2, and Go, during which the cell prepares for and undergoes mitosis. Combination chemotherapy includes drugs that damage cells at different stages in the process of cell division. Using more than one drug increases the chance of killing a greater number of cells. Chemotherapy also affects healthy body tissues that grow constantly (e.g., skin, hair, digestive system), a factor that explains the side effects, such as hair loss, suffered by patients.
Cytarabine
In the treatment of chronic-phase chronic myelogenous leukemia, cytarabine (Pfizer’s Cytosar-U, generics) is generally used in conjunction with interferon-a. The addition of cytarabine to interferon-a increases the toxicity of the treatment; whether the combination of the two therapies increases response rates is controversial.
Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA via multiple mechanisms including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and, most importantly, incorporation into DNA. Cytotoxicity is highly specific for the S phase of the cell cycle.
One study analyzed the efficacy of daily treatment with interferon-a (5 MU/m2) combined with LDAC (10 mg) (IFN+LDAC) in 140 patients with Ph-positive early chronic chronic myelogenous leukemia. Results were compared with those in patients receiving interferon-a with or without intermittent LDAC (seven days per month). CHRs were observed in 92% of patients treated with IFN+LDAC, and cytogenetic responses were observed in 74% (major in 50%, complete in 31%). The estimated four-year survival rate was 70%. The incidence of CHR was higher with IFN+LDAC than with intermittent or no LDAC (92% versus 84% versus 80%, respectively); similar results were noted for cytogenetic response (74% versus 73% versus 58%, respectively). Also, the time to achievement of a major cytogenetic response was significantly shorter than was obtained with previous interferon-a regimens.
Another study randomized 721 patients with Ph-positive, early chronic-phase chronic myelogenous leukemia to receive treatment with either hydroxyurea (50 mg/kg) and interferon-a (5 MU/m2/d) or hydroxyurea, interferon-a, and monthly courses of LDAC (20 mg/m2 for 10 days/month). The rate of CHR was 66% in the IFN+LDAC group versus 55% in the interferon-a/hydroxyurea group. The cytogenetic response rate was 66% in patients treated with LDAC (major in 41%, complete in 15%), which was significantly higher than the 52% response rate (major in 24%, complete in 9%) among patients treated with interferon-a/hydroxyurea. Patients in the IFN+LDAC group had a significantly better survival rate than patients in the interferon-a/hydroxyurea group: three-year survival rates were 86% versus 79%.
Cytarabine is generally administered as an intravenous preparation. An oral form of cytarabine is available in Japan.
Hydroxyured
Hydroxyurea (also known as hydroxycarbamide) (Bristol-Myers Squibb’s Hydrea, generics) effectively produces rapid hematologic responses and controls overall tumor burden in chronic myelogenous leukemia, as assessed by white blood cell count and spleen size. Although up to 80% of patients achieve hematologic remissions with hydroxyurea, cytogenetic responses are rare, and when they occur, are normally transient. Hydroxyurea is superior to busulfan, but inferior to interferon-a therapy, in terms of both survival rates (median survival 56 months with hydroxyurea and 44 months with busulfan) and toxicity. Hydroxyurea is also used to treat acute myeloid leukemia, head and neck cancers (before radiotherapy treatment), and ovarian cancer.
Hydroxyurea acts primarily as an inhibitor of ribonucleotide reductase. Inhibition of this protein leads to the depletion of essential DNA precursors. Another proposed mechanism of cytotoxicity involves direct chemical damage to DNA by hydroxyurea or a metabolite. Hydroxyurea also inhibits repair of DNA damaged by chemotherapy or radiation, offering potential synergy between hydroxyurea and radiation or alkylating agents. Laboratory studies suggest that hydroxyurea acts selectively against the episomes responsible for drug resistance. Hydroxyurea is specific for the S-phase of the cell cycle.
Because of its rapid onset of action, hydroxyurea can be used to reduce the leukemic burden in newly diagnosed patients before initiating interferon-a or progenitor stem-cell transplantation. Hydroxyurea is also used in patients with refractory disease or those who are intolerant of first-line therapy.
Common side effects associated with hydroxyurea are threefold. They include a temporary drop in bone marrow function, causing a fall in white blood cell count that increases the risk of severe infection; a drop in red cell count (anemia), causing fatigue and shortness of breath; and a drop in platelet numbers in the blood, causing bleeding or bruising.
Busulfan
Low-dose therapy with busulfan (GlaxoSmithKline’s Myleran) was once the mainstay of treatment for chronic myelogenous leukemia. The superior survival rates produced by imatinib, interferon-a, and hydroxyurea have reduced busulfan’s role to that of myeloablative therapy prior to allo-Stem-cell transplantation. This medication is also used to treat other disorders of the blood or bone marrow (e.g., myeloproliferative disorder, thrombocytosis, myelofibrosis).
Busulfan is a bifunctional alkylating agent that has been in clinical use since 1959. Carbonium ions rapidly form after systemic absorption of busulfan, leading to alkylation of DNA. This alkylation results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA. The antitumor activity of busulfan is cell cycle phase-nonspecific. Selective effects on granulocytopoesis are not well understood.
In the treatment of chronic myelogenous leukemia, busulfan is most commonly used in high doses as a myeloablative agent in patients receiving progenitor stem-cell transplantation. The dose of busulfan in this setting depends on the protocol, ranging from 8 to 16 mg/kg given over four days. The major dose-limiting effects of busulfan are myelotoxicity and pancytopenia. Myelotoxicity may be increased in patients who are recovering from the effects of prior chemotherapy or those who have received radioactive phosphorus or radiation to marrow-bearing bones.
Busulfan can lower the body’s ability to fight an infection, as well as prevent normal blood clotting. Other side effects associated with busulfan include hyperpigmentation, pulmonary toxicity, abnormal gonadal function, seizures, and veno-occlusive disease.
Protein Tyrosine Kinase Inhibitors
Overview
Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of tyrosine residues. These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling, and neurite outgrowth. Unregulated activation of these enzymes, through mechanisms such as point mutations or overexpression, can lead to various forms of cancer as well as to benign proliferative conditions. More than 70% of the known oncogenes and protooncogenes involved in cancer encode PTKs.
A number of protein tyrosine kinase inhibitors have been developed and approved for cancer treatment. These include inhibitors of c-Abl (imatinib, for treatment of chronic myelogenous leukemia); HER2 (trastuzumab [Genentech/Roche's Herceptin], for treatment of breast cancer); vascular endothelial growth factor receptor (bevacizumab [Genentech/Roche's Avastin], for treatment of metastatic colorectal cancer); and the epidermal growth factor receptor (EGFR) gefitinib (AstraZeneca’s Iressa, also known as cetuximab (ImClone/Merck & Co./BMS’s Erbitux), for treatment of lung and colorectal cancer, respectively.
Mechanism Of Action
The rationale for developing tyrosine kinase inhibitors for the treatment of cancer is based on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. In chronic myelogenous leukemia, affected cells have a consistent cytogenetic abnormality, the Philadelphia chromosome, which carries a BCR-ABL fusion gene encoding a tyrosine kinase oncoprotein. Imatinib mesylate is a specific inhibitor of this oncoprotein.
Imatinib
Imatinib mesylate (Novartis’s Gleevec/Glivec, formerly STI-571) was first launched in the United States in May 2001 for the treatment of blastic- and accelerated-phase chronic myelogenous leukemia and chronic-phase disease after failure of interferon-a therapy. Imatinib had previously been awarded fast-track status for the myeloid blastic phase indication of chronic myelogenous leukemia and granted orphan drug designation in the United States, European Union, and Japan. In December 2002, the FDA approved the product for first-line therapy in all phases of chronic myelogenous leukemia, after data from the imatinib arm of the International Randomized Study of Interferon Versus ST-1571 (IRIS; discussed subsequently) showed high cytogenetic response rates and delay in disease progression, suggesting that imatinib improves long-term survival. The dose of 400 mg per day of imatinib administered orally, the same dose used in the IRIS trial, is considered standard therapy for patients with newly diagnosed chronic myelogenous leukemia in the chronic phase. In February 2002, the FDA also approved imatinib for the treatment of inoperable and metastatic malignant gastrointestinal stromal tumors. The product is also being investigated for the potential treatment of other cancers that express tyrosine kinases, including acute lymphocytic leukemia and certain solid tumors.
Imatinib is a 2-phenylamino-pyrimidine derivative that specifically inhibits the tyrosine kinase activity of the ABL proteins c-ABL and BCR-ABL. The BCR-ABL fusion gene present in chronic myelogenous leukemia encodes an oncoprotein, p210BCR-ABL, that has dysregulated tyrosine kinase activity that is central to the pathogenesis of chronic myelogenous leukemia. Imatinib competitively inhibits the interaction of adenosine triphosphate (ATP) with these oncoproteins, thereby lessening their ability to phosphorylate and activate downstream target proteins.
The initial approval of imatinib was based on data from Phase II studies involving approximately 1,230 patients in 32 centers located in five countries. The trial endpoints included hematologic and cytogenetic response rates. In one study, a total of 532 patients with late chronic-phase chronic myelogenous leukemia in whom previous therapy with interferon-a had failed were treated with 400 mg of oral imatinib daily. Imatinib induced MCRs in 60% (69% of these patients displayed a cytogenetic response) and CHRs in 95% of the patients. The time to onset of an major cytogenetic response ranged from 2.4 months to 19 months, and the median time to a CHR was 0.7 months. After a median follow-up of 18 months, chronic myelogenous leukemia had not progressed to the accelerated or blastic phases in an estimated 89% of patients, and 95% of the patients were still alive. Only 2% of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred.
Data from some ongoing Phase III IRIS trials demonstrated superior response rates in imatinib-treated patients compared with interferon-a. The IRIS study was the largest study of chronic myelogenous leukemia patients ever conducted, enrolling 1,106 patients (553 randomized to each treatment arm) with newly diagnosed Ph-positive chronic myelogenous leukemia between June 2000 and January 2001 in 16 countries. The study compared imatinib at 400 mg per day with interferon-a plus subcutaneous low-dose cytarabine (LDAC) (IFN+LDAC) as first-line treatments; patients were allowed to cross over to the other treatment arm if they experienced loss of response, lack of response, or intolerance to the treatment. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression.
After a median follow-up, the estimated rate of an major cytogenetic response at 18 months was 87% in the imatinib group and 35% in the IFN+LDAC-treated group. The estimated rates of cytogenetic response were 76% and 14%, respectively. At 18 months, the estimated rate of freedom from progression to accelerated or blastic-phase chronic myelogenous leukemia was 97% in the imatinib group and 91% in the combination-therapy group. Imatinib was better tolerated than IFN+LDAC. It is worth noting that 89% of patients receiving IFN+LDAC had already switched to imatinib therapy after a median of only 8 months into the study. Therefore, the survival benefit with imatinib compared with IFN+LDAC has not yet become apparent with long-term follow-up because most patients treated with IFN+LDAC are benefiting early on from the added sequential imatinib therapy.
An additional follow-up to the IRIS trial at 42 months confirmed durable response with first-line imatinib therapy while demonstrating the effect of cytogenetic response on long-term outcomes. Of newly diagnosed patients treated with imatinib, 98% had achieved CHR, while 91% had achieved an major cytogenetic response, and 84% had achieved a cytogenetic response. For patients who had achieved cytogenetic response and a thousandfold (3 log) or greater reduction in BCR-ABL transcript level (i.e., a molecular response) at 12 months, the probability of remaining progression-free was 98% at 42 months. This probability compared with 90% for patients with cytogenetic response and less than a thousandfold reduction in BCR-ABL transcript level, and 75% for patients who had not achieved cytogenetic response. Responses to imatinib were found to be durable at the 42-month follow-up; an estimated 91% of patients maintained CHR, 91% of patients maintained major cytogenetic response, and 87% of patients maintained cytogenetic response.
A follow-up study monitored the molecular response for a median of 42 months in all 28 patients enrolled in the IRIS trial in Australia and New Zealand who commenced imatinib as their first-line therapy. The study’s aim was to determine if the BCR-ABL levels continued to decrease after 24 months. A cytogenetic response (approximately equivalent to a greater than 2-log reduction of BCR-ABL) was achieved in 24 of the 28 patients. Of the four patients without a cytogenetic response, all had disease progression, and in one patient a BCR-ABL mutation was detected, followed by rapid progression to blastic-phase disease. The data demonstrate that, although the frequency of achieving an major molecular response increased between 12 and 42 months, most of the improvement occurred between 12 and 24 months. Thirteen patients achieved an major molecular response by 12 months, and all 13 achieved a 4-log reduction (equivalent to undetectable levels of BCR-ABL transcripts) at 42 months. These results suggest that, in patients achieving an major molecular response by 12 months, leukemic cell mass is still decreasing after 3.5 years of imatinib therapy.
Common side effects of imatinib treatment are superficial edema, nausea, and muscle cramps. Some patients may experience severe toxicity, leukopenia, thrombocytopenia, and anemia. The most common adverse events experienced in the IRIS trial were hematologic and hepatic toxicities and included severe (NCI grades 3/4) neutropenia (16.2%), anemia (4.0%), thrombocytopenia (9.3%), and elevated liver enzymes (5.4%). Other drug-related adverse events occurred in 15.8% of patients.
Another study, conducted by researchers at the M.D. Anderson Cancer Center in Houston, Texas examined the optimal dose of imatinib therapy. In this trial, 222 previously untreated early chronic-phase chronic myelogenous leukemia patients were split into two groups. One group of patients was treated with the 400 mg daily dose of imatinib, while another group was treated with 800 mg daily. Patients in the higher-dose group had an estimated progression-free survival rate of 99% at 12 months compared with 92% in the standard dose group. Researchers concluded that the 800 mg daily imatinib dose resulted in higher rates of CCRs and MMRs. Extramedullary toxicity (toxicity outside the bone marrow) was similar in the two groups, but myelosuppression was more common with the higher dose. At 12 months, the median actual dose for the high-dose group was still 800 mg daily, with 36% of evaluable patients having required dose reduction, compared with 14% of those treated with the standard dose.
Acquired resistance to imatinib among patients with chronic-phase disease appears to be rare and can often be overcome by increasing the dose. In a follow-up study, 261 patients with chronic myelogenous leukemia in chronic-phase post-interferon-a failure received an escalated daily dose of 600-800 mg of imatinib orally after demonstrating a poor response or relapse at the standard dose (400 mg daily). Among patients treated for hematologic resistance or relapse, 65% achieved a complete or partial hematologic response. Among patients treated for cytogenetic resistance or relapse, 56% achieved a complete or major cytogenetic response.
In contrast, 70% of patients in myeloid blast crisis exhibit resistance to imatinib. Furthermore, all patients in lymphoid blast crisis relapse within six months of responding to imatinib. This resistance appears to arise from a variety of mechanisms, including acquired mutations in the ABL kinase domain, BCR-ABL overexpression, P-glycoprotein overexpression reducing the cellular uptake of imatinib, selection of preexisting mutant cells, and possibly, excessive degradation of the BCR-ABL protein.
Several studies have shown that imatinib is not as effective in the treatment of accelerated and blastic-phase chronic myelogenous leukemia as it is in the treatment of chronic-phase disease. A Phase II study investigated the hematologic and cytogenetic responses of 260 patients in myeloid blast crisis treated with 400-600 mg imatinib daily. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least four weeks in 31% of patients, including CHRs in 8%. In patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced MCRs in 16% of patients, and 7% of the responses were complete. Median survival time was 6.9 months. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions.
Another Phase II study involving 235 patients showed that imatinib 400-600 mg daily induced hematologic and cytogenetic responses in accelerated-phase chronic myelogenous leukemia. Imatinib induced a hematologic response in 82% of patients and sustained hematologic responses lasting at least four weeks in 69%, and complete responses in 34%. The rate of major cytogenetic response was 24%; complete responses were achieved by 17%. Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. In comparison with 400 mg, imatinib doses of 600 mg led to more cytogenetic responses (28% compared with 16%), longer duration of response (79% compared with 57% at 12 months), time to disease progression (67% compared with 44% at 12 months), and overall survival (78% compared with 65% at 12 months) with no clinically relevant increase in toxicity.
Several groups have investigated the combination of imatinib plus LDAC using the hypothesis that resistance to imatinib would be less frequent. The chronic myelogenous leukemia French Group performed a Phase II trial to determine the safety and tolerability of the combination in 30 previously untreated patients in chronic-phase chronic myelogenous leukemia. Treatment was administered in 28-day cycles. Patients were treated continuously with imatinib at a dose of 400 mg daily. LDAC was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m2/day via subcutaneous injection. Adverse events were frequently observed: grade 3 or 4 hematologic toxicities and nonhematologic toxicities occurred in 53% and 23% of patients, respectively. At 6 months, 100% of patients achieved a CHR, and the cumulative incidence of cytogenetic response at 12 months was 83%. The researchers concluded that the combination was safe and promising, given the rates of response.
The STI-571 Prospective International Randomized Trial (SPIRIT) is a Phase III study underway to compare imatinib monotherapy, imatinib plus cytarabine, and imatinib plus interferon-a as first-line treatment in randomized, newly diagnosed chronic myelogenous leukemia patients.