Small Molecule Tyrosine Kinase Inhibitors with BCR-ABL and C-Kit as Targets

Neha Vapiwala, MD and Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania?

Imatinib mesylate

Drs. Peter Nowell and David Hungerford, two Philadelphia researchers, were experimenting with cells from various types of leukemia when one noticed a smaller-than-normal chromosome number 22 on the cancer cells of two individuals with chronic myelogenous leukemia (CML). They published their research in 1960, describing this abnormality ultimately found in 9 out of 10 CML patients they studied. The findings were confirmed by a group in the United Kingdom, and the abnormality was subsequently named the Philadelphia Chromosome, for the city in which it was discovered. Nowell and Hungerford had demonstrated that this genetic change was required for the development of CML, a novel and often unaccepted concept at that time. Targeted Therapy - Part 1

In 1972, another researcher, Janet Rowley, MD, would discover the missing piece of chromosome number 22 attached to another chromosome, number 9, thereby identifying the first known "chromosomal translocation". The 9;22 chromosomal translocation is found on the leukemic cells of more than 95% of patients with CML. As the field of genetics grew, it was discovered that the gene abl (pronounced "able"), normally located on chromosome 9, had attached itself to the gene bcr (pronounced "b-c-r") on chromosome 22. The bcr-abl gene is constitutively active (meaning it does not require activation by other proteins), and sends signals to activate proteins and enzymes which speed up cellular division and can lead to the formation of abnormal white blood cells that proliferate to the point that they interfere with normal blood cell production, leading to leukemia.

After the Philadelphia chromosome mutation and defective bcr-abl protein were discovered, researchers screened chemical libraries to find a drug that would inhibit that protein. The result was known as 2-phenylaminopyrimidine, which was then tested and modified to become imatinib. In May of 2001, imatinib was approved by the FDA for the initial therapy for CML and later, Philadelphia chromosome (Ph)- positive acute lymphoblastic leukemia (ALL), by targeting the bcr-abl protein, preventing further development of leukemia cells. In the same month, it made the cover of TIME magazine as a "magic bullet" to cure cancer. Although these agents have not been successful in curing CML, TKIs have been shown to achieve long-term disease control in a majority of treated patients and have become the initial treatment of choice. There are 10 current FDA- approved indications for imatinib and a full review of all these indications is beyond the scope of this review. However, we will review the critical oncological uses for this medication and select important clinical trials.

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a cancer of the blood, where abnormally high numbers of ineffective white blood cells known as "blast cells" accumulate in the circulation and limit normal blood cell production. These cells include: red blood cells, white blood cells, and the cells responsible for producing platelets, which are essential for normal blood clotting. There are three phases of chronic myeloid leukemia: 1) Chronic phase: 85% of patients present in this stage where there are less than 5% immature blast cells in the bone marrow. This phase generally lasts for years and is controllable with oral chemotherapy medications. 2) Accelerated phase: during the accelerated phase, maturation of white blood cells becomes more affected as there are 10-19% blast cells in the blood or bone marrow. In this phase, the number of abnormal cells in the body is more difficult to control with medications as these cells increasingly accumulate mutations. 3) Blast phase: in blast crisis (blast phase), there are more than 20-30% blast cells in the blood or bone marrow with progressively less functional blood cell production. Before recent advances in treatment, blast crisis typically occurred within 4-5 years after diagnosis and was often unresponsive to treatment.

Treatment options for patients with CML are quite complex and depend on the phase of disease, availability of a bone marrow donor and patient choice. Overall, treatment can be broken down into three main categories: 1) treatment with oral TKIs such as imatinib, dasatinib, or nilotinib. 2) Potential cure with hematopoietic cell transplantation (also called bone marrow transplantation or BMT), usually after the disease stops responding or relapses during treatment. 3) Treatment to reduce symptoms with other medications and chemotherapy (hydroxyurea or interferon alpha with or without a chemotherapy agent known as cytarabine). Although TKIs are not curative of CML, they are able to achieve long-term control of the disease in the majority of patients and have become the initial treatment of choice for almost all people with newly diagnosed CML.

Initial trials of imatinib evaluated patients intolerant of interferon therapy (which up until that point had been the standard of care). The phase III IRIS trial was published in the New England Journal of Medicine in March 2003, where patients with the new diagnosis of chronic phase CML were treated with imatinib or interferon alfa plus low-dose chemotherapy with another chemotherapy drug known as cytarabine. The results were updated at the American Society of Hematology (ASH) annual meeting in 2008. Results from this trial and subsequent update indicated that despite significant contamination from crossover between the two treatment arms (meaning that patients who were not originally intended to get imatinib eventually did, thus making interpretation of study results more complicated), imatinib treatment produced higher response rates with more durable responses (longer lasting) with less toxicity. The so-called crossover prevented the trial from demonstrating an overall survival benefit but retrospective analyses (studies looking back on the use of the medication) have pointed to significantly better survival at 3 years. These results helped establish imatinib as the initial treatment of choice for patients with CML in chronic phase. At the present, there are ongoing clinical trials assessing whether the more potent inhibitors, dasatinib and nilotinib (see below), might be employed either alone or in combination with imatinib or other agents as initial therapy of chronic phase CML.

For patients in accelerated or blast phase, the prognosis is quite poor (and worse for patients previously treated with imatinib). Most patients undergo treatment in an attempt to return the patient to a second chronic phase with some then going on to receive bone marrow transplantation. The use of imatinib has been demonstrated to be effective in inducing a second chronic phase in some patients and has also been shown to reduce the risk of subsequent relapse in those patients that underwent bone marrow transplantation.

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Just as with CML, acute lymphoblastic leukemia (ALL) is a cancer of blood cells (sometimes referred to as lymphoblastic lymphoma when the disease primarily involves lymph nodes rather than the blood and bone marrow). ALL involves a type of white blood cell called a lymphocyte and the ‘acute’ refers to the typically rapid progression seen in this disease, which requires immediate treatment. Just as with CML, some patients with AML have the Philadelphia chromosome (Ph+). Results from a phase II trial published in the Journal of Clinical Oncology in January of 2006 demonstrated that patients treated with even single-agent imatinib had a complete response (CR) rate of 96%.

Gastrointestinal Stromal Tumors

Disordered TKs are implicated in the development of both solid (e.g., lung cancer) and hematological malignancies (e.g., CML). However, researchers quickly discovered that imatinib does not have only one function and one target. The efficacy of imatinib in advanced gastrointestinal stromal tumors (GIST) tumors was established after its initial approval for patients with CML. GIST tumors represent a very small percentage of gastrointestinal malignancies (1-3%) and are categorized as tumors of connective tissue. Unlike most gastrointestinal tumors (such as colonic cancer), these cancers do not arise from the linings of organs but instead come from cells called the interstitial cells of Cajal (ICC), which are normally part of the autonomic nervous system of the intestine.

Most (50-80%) GISTs arise from a mutation in the c-kit gene, which encodes a receptor for a growth factor termed stem cell factor (scf). The c-kit product/CD117 is expressed on ICCs and a large number of other cells (e.g., bone marrow cells, mast cells, melanocytes). Mutations permit c-kit to function independent of scf activation, which leads to a high rate of cell division and genomic instability. It is likely that more mutations are needed for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process.

Rather than tyrosine kinase inhibition, as in CML, imatinib fights GISTs through inhibition of this pathway. Following the increasing use of imatinib in CML patients, it became evident that molecularly targeted therapy with imatinib induced dramatic, rapid, and sustained clinical benefit in GISTs by blocking signaling via c-kit. Long-term results were published in February 2008 in the Journal of Clinical Oncology from a phase II trial of patients where the median survival of patients with advanced GIST increased from an average of 18 to 57 months. Unfortunately, most patients who initially respond eventually acquire resistance via additional mutations with a median time to progression of approximately 2-3 years.

Other Uses of Imatinib

The myelodysplastic syndromes (MDS) are a group of blood disorders associated with disorganized and ineffective blood cell production with a risk of deterioration into acute leukemias. Just as imatinib exerts its benefit in treating GIST tumors through c-kit, a receptor known as platelet derived growth factor receptor alpha (PDGFR) is activated in some patients with MDS. Imatinib has been shown to be capable of inducing dramatic clinical and molecular responses in diseases associated with either PDGFR fusion protein such as the myeloproliferative disorders.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous soft tissue sarcoma. Approximately 85-90% of DFSPs are low grade, while the remainder contain a higher-grade component (which is usually known as a fibrosarcoma), and are considered to be intermediate-grade sarcomas. Although they rarely metastasize (<5%), many of these tumors recur locally. The vast majority of cases of DFSP have a characteristic chromosomal translocation, t(17;22), which places platelet-derived growth factor beta (PDGFB) under the control of a protein that results in constant activation of PDGFR. At the 2009 annual meeting of the American Society of Clinical Oncology (ASCO), results were reported on a combined analysis of two phase II trials in advanced DFSP where imatinib was found to be active in DFSP tumors harboring t(17;22) with a response rate approaching 50%.

Toxicities and Precautions of Imatinib Therapy

Although imatinib is typically well tolerated, many patients with CML ultimately develop resistance to this medication. The estimated 2-year incidence of resistance is as high as 80% in the blastic phase, 40-50% in the accelerated phase, and 8-10% in the chronic phase. Resistance typically occurs through increased expression of the bcr-abl protein or mutations in the fusion gene itself. Although the long-term side effects of imatinib have not yet been completely ascertained, clinical experience suggests that it is generally very well tolerated. Overall, side effects such as swelling, nausea, rash and musculoskeletal pain are common, but mild. Severe congestive heart failure (CHF) is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their heart.

Here are the following current FDA approved indications for imatinib mesylate:

  1. Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase.
  2. First-line treatment of Ph-positive CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy.
  3. Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy. Note: there are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival
  4. Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
  5. Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements
  6. Adult patients with aggressive systemic mastocytosis (ASM).
  7. Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase.
  8. Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP)
  9. First-line treatment of kit (CD117)-positive unresectable and/or metastatic malignant GIST.
  10. Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST

Selected dosing recommendations for imatinib mesylate:

  1. Adult CML: 400 mg/day for chronic phase, 600 mg/day for accelerated phase or blast crisis.
  2. Adult ALL: 600 mg/day
  3. GIST: 400 or 600 mg/day.
  4. Pediatric CML: 260 mg/m2/day given once per day or split into two daily doses.

Dasatinib and Nilotinib

If a patient either stops responding or is intolerant of imatinib therapy, second-generation TKIs have more recently become available: dasatinib and nilotinib. Dasatinib, also known as Sprycel (experimental name BMS-354825), is another orally active TKI with several distinct molecular targets including: bcr-abl, Src, c-Kit and PDGFR and is more than 300 times more potent than imatinib against cells expressing wild type bcr-abl (preclinical data). Dasatinib binds to both the active and inactive forms of bcr-abl (as opposed to imatinib, which only binds to the inactive state). In preclinical evaluations, dasatinib demonstrated activity against 18 of 19 bcr-abl mutants. With respect to these second generation TKIs as first line therapies, more mature data needs to be collected prior to FDA approval.

Clinical trials are in progress to assess whether the second-generation inhibitors might be used either alone or in combination with imatinib or other agents as initial therapy of chronic phase CML. However, at the present time, the use of these agents is restricted to patients that have failed imatinib therapy either due to relapse of disease or drug intolerance. Many of these patients will respond to these newer agents as demonstrated in phase I/II trials. Based on these trials, dasatinib and nilotinib are approved for the treatment of chronic or accelerated phase CML with resistance or intolerance to prior therapy, including imatinib. Dasatinib is also approved for the treatment of blast phase CML with resistance or intolerance to prior imatinib. Updated results from a phase II trial were reported in the Journal of Clinical Oncology in July of 2009 demonstrating improved 1-year progression-free survival and overall survival rates. In that trial, dasatinib was generally well tolerated; the most frequent non-hematologic severe treatment-related adverse event was diarrhea (52%).

Here are the following current FDA approved indications for dasatinib:

1.  Adults with all phases of CML with resistance or intolerance to prior therapy, including imatinib.

2.  Adults with Ph+ ALL with resistance or intolerance to prior therapy.

Dosing recommendations for dasatinib: 70 mg twice daily (140 mg/day).

As with dasatinib, nilotinib (Tasigna, AMN107) is a second generation TKI with multiple targets, including: bcr-abl, c-Kit and PDGFR. The only current FDA approved indication for nilotinib is for use in chronic phase or accelerated phase Ph+ CML for adult patients resistant to or intolerant of prior imatinib therapy. A recent update of a phase I trial published in the journal Blood in November 2007 reported an estimated survival of 95% at 12 months. Side effects were mostly mild with low white blood cells and platelets being the most common toxicities. The dosing for nilotinib is 400 mg twice daily without food.

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