US Pharm. 2007;32(7)(Oncology suppl):26-31.

ABSTRACT: Chronic myelogenous leukemia (CML) is a hematologic malignancy associated with chromosomal abnormalities, including the Philadelphia chromosome (Ph). The aim of initial therapies was to reduce the presence of the CML clone using myelosuppressive remedies. Although these treatments may have provided some level of disease control, the chance for a cure was minimal. Allogeneic stem cell transplantation offers an effective cure for patients with CML, but the morbidity and mortality linked to transplant-related complications, as well as donor availability, limit this option. The use of interferon-alpha is also an effective treatment that is limited by tolerability. New targeted therapies, such as imatinib and dasatinib, which inhibit the enzymatic activity of Ph, offer patients relatively well-tolerated treatment options with a high likelihood of response. The objective of this article is to describe the history of therapeutic options available for CML and the role of current targeted therapies.

Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results in uncontrolled myeloproliferation.1 The disease was first described in 1845, and in 1960, the molecular cause of the disease was determined through the discovery of the Philadelphia chromosome (Ph), named for the city in which it was identified. This was the first time that a chromosomal rearrangement could be linked specifically to the development of a particular cancer.2 Ph is created through the translocation of a section of human chromosome 9 that contains the ABL kinase domain with a specific breakpoint cluster region (BCR) on chromosome 22. This translocation results in BCR-ABL, a constitutively active oncogenic tyrosine kinase, which imparts the ability of cells containing this abnormality to hyperproliferate. Eventually, these cells are released into the periphery as differentiated leukemic white blood cells. 3,4 Although BCR-ABL is not found in all patients with CML, it is present in more than 90%, as well as in 10% to 15% of patients with acute lymphoblastic leukemia (ALL).2 Aside from Ph, other genetic defects have been observed in over 80% of patients in the blast crisis (BC) phase of CML, the most aggressive phase of the disease.

Phases of CML
CML primarily affects the elderly; the median age at diagnosis is 65 years.5 The diagnosis of CML is often made following the identification of leukocytosis, prompting further evaluation and subsequent identification of immature blasts and promyelocytes. Patients are classified into one of three phases based on the level of clonal expansion of blast cells and promyelocytes in the peripheral blood and bone marrow. The chronic phase (CP) of CML represents an early phase with a lower level of myeloproliferation compared to advanced stages. Of the approximately 4,600 patients diagnosed with CML in the United States each year, more than 90% are in this phase.5 Although patients are generally asymptomatic in CP, expansion of the CML clone may lead to malaise, weight loss, and an enlarged spleen.5 Patients can remain in CP for three to five years, but progression to the accelerated phase (AP) signals a shift to a more aggressive form of CML, marked by genetic instability of the clone and increased volume of blasts and promyelocytes. 2 Physical symptoms representing the transition to AP are often not apparent to patients. The duration of this phase is generally four to six months before the progression to BC. In this phase, there are ?30% blasts in the bone marrow or peripheral blood. Extramedullary sites of blast cell proliferation are likely. Patients in BC may have complaints of fever, night sweats, weight loss, anorexia, and fatigue. Splenomegaly is often present, and patients may experience bone pain and show signs of infection. Median survival of patients in BC is three to six months.5

Goals of Treatment
Treatment for CML has changed in recent years due to advances in the understanding of the molecular basis of the disease and technology, facilitating the discovery of therapy aimed at inhibiting factors related to pathogenesis and disease progression. The two basic goals of treatment in patients with CML involve the hematologic and cytogenetic responses (Table 1). A complete hematologic response during CP is defined as normalization of peripheral blood counts and absence of all signs and symptoms of leukemia. The absence of response is aptly indicated as no response. In the advanced stages of CML (AP and myeloid BC), a major hematologic response can be a complete hematologic response if there are less than 5% blasts in the bone marrow, a normalization of blood counts, and no other signs and symptoms of leukemia. A major hematologic response may also include patients who present with no evidence of leukemia but with the absence of normalized platelets or white blood cell counts. A minor hematologic response is defined as less than 15%  blasts in bone marrow or peripheral blood, less than 30% blasts plus promyelocytes in bone marrow and peripheral blood, less than 20% basophils in peripheral blood, and no extramedullary involvement other than the spleen or liver. Progression indicates the evolution of patients from AP to BC or the increase in number of blasts in patients who are in BC after at least four weeks of treatment.

For a complete cytogenetic response, the absence of Ph in the bone marrow is required. A partial cytogenetic response is the detection of 1% to 35% Ph-positive (Ph+) metaphases. A minor cytogenetic response is 36% to 65% Ph+ metaphases, a minimal response is 66% to 95% Ph+ metaphases, and no response is more than 95% Ph+ metaphases. A major cytogenetic response includes patients who have achieved either a complete or partial cytogenetic response. 6,7


Evolution of Therapy
Fowler's Solution: With the identification of CML and a basic understanding of the disease, pharmacologic therapy began to be employed to control the disease. Fowler's solution, arsenic trioxide dissolved in potassium bicarbonate, was first described as a remedy for CML in 1878.8 When a leukemic patient was given the solution for a 10-week period, leukocytosis was shown to decrease, then return after discontinuation of therapy, and respond again after reinstitution of the arsenic. Fowler's solution became a common treatment for CML and other hematologic malignancies until the turn of the century, when advances in the understanding of radiation led to the application of splenic irradiation, which was used as first-line therapy for CML until the 1950s.8,9 Arsenic solution made a brief return as a treatment for CML in the 1930s, but reports of toxicity reduced its use.8 Although these early therapeutic options were able to reduce the levels of blast cells in patients, there was almost no chance for a cure of CML.

Busulfan:The discovery of busulfan in the 1950s provided another option.10 Typically, busulfan was first administered in intermittent oral doses ranging up to 6 mg per day. Patients were monitored for a reduction in leukocytosis during therapy.11 The intermittent pattern of dosage was aimed to limit toxicity such as skin pigmentation, pulmonary fibrosis, reproductive disorders, and wasting syndrome. When a patient's blood counts decreased to levels considered unsafe, the drug was discontinued. If a disease-related rise in white blood cell count was observed, busulfan was reinitiated. Although remissions may have lasted several weeks to years in early treatment courses, the remissions ultimately became shorter with each relapse. When intermittent therapy was deemed to have lost its effect, continuous busulfan dosing was prescribed. Other medications were used, such as 6-mercaptopurine, uracil mustard, and dibromomannitol, but were of limited therapeutic benefit and never became mainstays of therapy.11,12

Hydroxyurea: In the 1950s, hydroxyurea was found to have antitumor activity and was tested against a variety of malignancies, including CML.13 During the 1960s, multiple studies found hydroxyurea to be beneficial in controlling leukocytosis in patients with CML who relapsed after first-line use of busulfan. However, patients who responded eventually progressed to the BC phase of the disease.11 In 1972, clinical studies found hydroxyurea to be a viable first-line therapy.11 A retrospective review of patients treated with either busulfan or hydroxyurea published in 1982 found hydroxyurea to be just as effective as busulfan, with a possible increase in survival.14 Although busulfan and hydroxyurea offered patients a chance for improved survival, both agents failed to prevent the inevitable advancement of CML to the BC phase.

Allogeneic Stem Cell Transplantation (SCT): The goal of treatment for CML began to shift in the 1970s with allogeneic SCT. This procedure offered a means to eradicate Ph through various myelosuppressive and immunosuppressive treatment combinations, termed conditioning regimens, of chemotherapy and radiation.15,16 Thus, a realistic chance for a cure became available. In allogeneic SCT, antigenetically matched donor stem cells are transfused into patients after the myelosuppressive conditioning regimen is given. The donor cells then replace and rebuild the patient's hematopoietic system and mount a complex, immune-mediated reaction against remaining malignant cells.

Allogeneic SCT is most successful early in the course of disease; hence, patients undergoing transplantation in CP have an improved chance of survival when compared to AP patients, and AP patients fair better than patients in BC.17 Allogeneic SCT is highly effective in achieving cytogenetic and hematologic responses; the relapse rate after a sibling SCT is less than 20% for patients transplanted in CP.18 The five-year disease-free survival rate in a similar group of patients who received stem cells from unrelated donors (which is considered to carry a higher risk of treatment-related complications) was also between 80% and 90%.5 Therefore, it is important that SCT be conducted as early in the progression of CML as possible. Current practice continues to maintain this understanding, and allogeneic SCT remains a common treatment modality.18 Although SCT offers a possible cure for CML, this option is limited by donor availability and treatment complications, such as hepatic veno-occlusive disease, graft-versus-host disease, and potentially fatal infections.

Interferon-Alpha: The limitations of SCT have led to the evaluation of other therapeutic options with the potential outcome of a cure. In the 1980s, interferon-alpha offered patients with CP-CML a possibility for hematologic and cytogenetic responses with the elimination of Ph.19,20 Currently, interferon-alpha (Roferon-A) is approved for the treatment of CML in CP with an initial dose of 3 MU daily for three days, followed by an increase to 6 MU daily for three days, and then an increase to the target dose of 9 MU daily for the duration of treatment.21 Common side effects of interferon-alpha include flu-like symptoms, such as fever, fatigue, myalgia, chills, arthralgia, and headache, as well anorexia, depression, nausea and vomiting, and diarrhea. 21

In the mid-1990s, the addition of monthly courses of low-dose cytarabine (20 mg/m2 per day for 10 consecutive days repeated monthly) was found to significantly improve survival over interferon-alpha alone when given to patients with CP-CML.22 Patients receiving interferon-alpha plus cytarabine were found more likely to achieve a hematologic response at six months and a major cytogenetic response at 24 months, compared to interferon-alpha alone. Furthermore, patients given the combination who achieved a partial or complete cytogenetic response were found to have a longer overall survival, compared to those with a minor or no response, thus demonstrating the importance of a cytogenetic response to therapy. Additional studies evaluating the ability of interferon-alpha and low-dose cytarabine to achieve hematologic and cytogenetic responses and improve survival in patients with CP-CML have confirmed these results. 23,24 However, toxicity associated with interferon-alpha often limits the utility of this agent. Side effects often lead to intolerance of interferon and discontinuation of therapy.22

Targeted Therapy
Imatinib (Gleevec): In the 1990s, based on the hypothesis that selective inhibition of BCR-ABL tyrosine kinase activity might be effective in the treatment of Ph+ leukemias, along with a better appreciation of the interactions of the ATP-binding site of BCR-ABL, several small molecules with therapeutic potential were developed.25 One of these compounds (originally named CGP-57148 and then STI-571) was found to inhibit the BCR-ABL kinase containing clones in vitro and led to their destruction via apoptosis. 25-27 This compound represented the first targeted therapy created specifically to inhibit the molecular abnormality believed responsible for pathogenesis. In 2001, STI-571, now called imatinib, was approved for use based on studies that found the drug provided Ph+ CML patients with a safe and effective treatment option.28 Phase I studies showed that imatinib produced major cytogenetic and hematologic responses in patients who had not responded to previous treatment with interferon-alpha due to relapse or intolerance of side effects.29 Imatinib was even found to benefit patients who did not respond to hydroxyurea, busulfan, or interferon plus cytarabine.29 This study, among others, provided strong examples of how significant a role targeted therapy could have in the possible cure for CML.30

The efficacy of imatinib in the treatment of newly diagnosed patients with CP-CML who have not received treatment has also been demonstrated in comparison to the preexisting standard of interferon plus low-dose cytarabine.31 A randomized phase III trial of 1,106 patients enrolled within six months of their diagnosis with CP-CML found that those who received imatinib were statistically more likely to achieve a complete hematologic and cytogenetic response, compared to patients who received interferon plus cytarabine. Furthermore, after 12 months of treatment, patients who received imatinib were less likely to have disease progression. Although survival rates were comparable for the two groups, the quality of life related to adverse effects of treatment was better in patients taking imatinib.31

Imatinib is approved for use in adult and pediatric patients with newly diagnosed Ph+ CML in CP, as well as in Ph+ patients in any phase of CML after therapeutic failure of interferon. Imatinib is also indicated for use in pediatric patients with Ph+ CML in CP who have recurred after SCT or are resistant to interferon therapy.32 Imatinib is available in 100- and 400-mg tablets. The recommended dosage is 400 mg per day in adult patients in CP, and 600 mg daily in adult patients in AP or BC. The pediatric daily dose in newly diagnosed patients is 340 mg/m 2 (not to exceed 600 mg per day). Dosing in children with disease recurrence in CP after SCT or interferon resistance is 260 mg/m2 per day.32 Common side effects in patients taking imatinib include fluid retention, nausea, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, headache, and joint pain. Cytopenias may also occur, especially at doses greater than 600 mg daily, and are more likely to be severe in advanced stages of CML.32

Imatinib clearly revolutionized the treatment of CML, but limitations in its spectrum of activity have become apparent. Although patients with CML obtain durable cytogenic responses to imatinib, relapses have been observed, especially in patients who begin treatment during AP and BC.6,33,34 Relapse during treatment with imatinib is often found to be related to resistance caused by amino acid point mutations occurring within the kinase domain of BCR-ABL. In fact, these point mutations at over 40 different amino acid positions account for acquired resistance in 50% to 90% of patients.5,7 The degree of resistance to imatinib when started in CP has been predicted to occur at a rate of 4%; this rate is higher in advanced stages of CML.35 Resistance to imatinib occurs due to the disruption of critical interactions between imatinib and BCR-ABL that occur from changes in amino acid sequences. 33,36 The result is the reactivation of BCR-ABL, which leads to downstream signaling of malignant processes and proliferation of clones containing the abnormal kinase.34 Other proposed mechanisms of resistance to imatinib include amplification of the BCR-ABL gene, overexpression of BCR-ABL mRNA, increased efflux of imatinib via p -glycoprotein–mediated actions, and activation of additional proteins such as those belonging to the SRC family of kinases.34,37

Dasatinib (Sprycel): This SRC family kinase inhibitor is structurally distinct from imatinib.33 Dasatinib was approved by the FDA for use in 2006 and offers promise in the treatment of CML and Ph+ ALL because of its activity against many of the mutant forms of BCR-ABL that are resistant to imatinib. This broader spectrum of activity is due to the ability of dasatinib to bind to the inactive form of BCR-ABL, similarly to imatinib, but also to the active conformation of the protein.6 This expanded activity is due to dasatinib's advantage of less sensitive molecular interactions and subsequent fewer restrictions required for binding.38

Clinical evaluation of dasatinib has been performed in patients who have either relapsed after responding to imatinib or were unable to tolerate the drug due to side effects. In an early phase I, nonrandomized study examining doses of dasatinib ranging from 15 mg daily to 120 mg twice daily in adult patients with CML or Ph+ ALL who were resistant to or could not tolerate treatment with imatinib, 44% achieved a complete hematologic response and 21% a major cytogenetic response.6 Notably, 81% of patients who had a major cytogenetic response to imatinib also attained this response taking dasatinib before they relapsed. In addition, many patients who did not have a cytogenetic response with imatinib cytogenetically responded to dasatinib. Typically, doses of at least 50 mg daily were required for the hematologic responses, while higher doses were needed for major cytogenetic responses. The duration of responses in patients in CP or AP was between two and 19 months, and 43% of patients in myeloid BC were still in major hematologic response for five to 12 months at the time the data were originally published.6 One observed advantage of dasatinib over imatinib is the activity in patients with imatinib-resistant mutations. Of the 60 patients who had mutations in BCR-ABL at baseline, dasatinib was able to invoke a hematologic or cytogenetic response in all except those patients carrying the T315I mutation. These results showed that dasatinib offers strong antileukemic activity in patients with CML or Ph+ ALL, regardless of phase or BCR-ABL genotype, who had been unable to continue treatment with imatinib.6

The START trials are a series of comprehensive studies to further ascertain the potential for dasatinib in the treatment of Ph+ leukemias.39,40-43 The phase II START trial involved five separate arms to evaluate the effects of dasatinib in patients in different stages of CML or Ph+ ALL who were resistant or intolerant to imatinib treatment. In the open-label, nonrandomized START-C, -A, -B, and -L arms, patients were initiated on 70 mg of dasatinib orally twice daily. The dosage was escalated to 90 or 100 mg twice daily in patients who were determined to have a poor initial response, or dosage was decreased to 50 and 40 mg twice daily if persistent drug-related toxicity was observed. In each arm, patients taking dasatinib achieved hematologic and cytogenetic responses. Notably, patients in CP were more likely to achieve responses than patients in either AP or BC.39-42

START-R, the final arm, is the first randomized, comparative trial of dasatinib versus imatinib.43 Patients with CML in CP that were deemed resistant to 400 to 600 mg of imatinib were randomized to receive either 70 mg of dasatinib twice daily or high-dose imatinib at 800 mg per day. The primary endpoint was major cytogenetic response after 12 weeks of therapy. Preliminary data on the first 36 patients are available. Of these patients, 22 received dasatinib and 14 received imatinib. Toxic effects requiring dose reduction occurred in eight (36%) of the patients receiving dasatinib and in one patient (7%) in the imatinib arm. Regarding response to therapy, 21 patients (95%) who received dasatinib and 13 patients (93%) taking imatinib achieved a complete hematologic response. At 12 weeks, seven patients (32%) taking dasatinib and one patient (7%) taking imatinib attained the primary outcome of a major cytogenetic response. Thirteen patients (two taking dasatinib and 11 taking imatinib) required therapeutic crossover due to adverse effects.43 Although still preliminary, these results appear promising for patients with resistance to doses of imatinib of 600 mg daily or less.

Dasatinib is approved by the FDA for use in the treatment of patients with chronic, accelerated, or myeloid or lymphoid blast phases of CML or with Ph+ ALL that has developed resistance or intolerance to previous therapy.44 The recommended starting dose is 140 mg per day administered orally as 70-mg doses twice daily, morning and evening without regard to meals. Dasatinib is available as oral tablets that should be swallowed whole, not crushed, cut, or chewed. The dasatinib dosage may be increased or decreased in 20-mg increments based on disease response and tolerability. It is available in three tablet strengths: 20, 50, and 70 mg.44

Resistance created by BCR-ABL mutations appears to be a limitation of all known tyrosine kinase inhibitors. Even dasatinib, which seems to have the broadest spectrum of activity, is not effective against the T315I mutation. However, the most challenging goal in the treatment of CML may reside in elimination of the pathologic stem cells. The quiescent nature of these cells may make them inherently resistant to kinase inhibitors.45,46 In vitro analysis has shown dasatinib to have only a moderate ability to eradicate cells within the stem cell compartment. Combining tyrosine kinase inhibitors with drugs that work by different mechanisms may ultimately be the answer, potentially offering a higher chance for a cure through the targeting of multiple malignant functions in CML cells.47-49 Kinase-independent pathways may also have an important role in the pathology of CML, allowing cells to proliferate despite adequate exposure to tyrosine kinase inhibitors. This may also explain why patients in more advanced stages of CML are less likely to respond to treatment with a tyrosine kinase inhibitor.50

Nilotinib (AMN107): Nilotinib, a third selective tyrosine kinase inhibitor, is currently still under investigation, but clinical study has been performed to evaluate its safety and tolerability, as well as antileukemic activity.51 The phase I dose-ranging study evaluated 106 patients with Ph+ imatinib-resistant CML in various phases who were assigned to receive one of nine doses (daily dose of 50, 100, 200, 400, 600, 800, or 1,200 mg; twice-daily doses of 400 or 600 mg). No dose-limiting side effects were observed for doses up to 600 mg daily, suggesting this to be the maximum tolerated dose. Hematologic responses were observed in all three phases of CML (BC, 39%; AP, 72%; CP, 92%). Major cytogenetic responses occurred as well (BC, 18%; AP, 20%; CP, 53%). Nilotinib is active in patients with all observed variants of BCR-ABL except the T315I mutation.51 Therefore, nilotinib, similar to dasatinib,  appears to be a second-line therapy for patients who have relapsed or not tolerated initial therapy with imatinib.

Conclusion
The evolution in management for CML has taken several steps over the past 150 years. Some of these steps, such as the tyrosine kinase inhibitors, represent revolutionary innovations based on the increased understanding of molecular mechanisms of CML. These selective therapies offer more safety and reliability than existing options. Future advances in the treatment of CML will determine how these novel therapies best fit into existing niches or even alter treatment patterns. For example, dasatinib and nilotinib are currently used as second-line targeted therapy after imatinib failure or intolerance. The question remains as to whether these newer tyrosine kinase inhibitors are as effective as existing first-line therapy. Similarly, the development of additional tyrosine kinase inhibitors that provide enhanced activity against all BCR-ABL forms would be helpful to eliminate existing gaps, such as the T315I mutation. The investigational agent MK-0457 (VX-680) is an aurora kinase inhibitor with tyrosine kinase–inhibiting activity, which has been observed in vivo to provide activity against this particular form of BCR-ABL.52 It may be possible to use multiple tyrosine kinase inhibitors concomitantly to provide broader coverage and slow the development of resistance. Similarly, due to the existence of chromosomal changes that occur in CML in addition to BCR-ABL, more drugs will likely be developed that will help provide a multipronged effort on different targets involved in the pathogenesis of the CML.

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