Leukemia is the neoplastic proliferation of the hematopoietic cells. These cells are undifferentiated or partially differentiated stages of maturation. As a consequence of the immature leukocytes excessive proliferation, these cells eventually replace the normal blood-forming elements, resulting in the patient presenting with clinical and laboratory evidence of leukopenia, anemia, and thrombocytopenia.
In terms of incidence, chronic myelogenous leukemia (CML) is the second most frequent form of myeloid leukemia after acute myeloid leukemia (AML), accounting for approximately the third of all incident cases of myeloid leukemias. However, the CML prognosis is good, resulting in the number of prevalent cases of CML outnumbering those of AML based on survival data analysis from the United States (SEER, 2011). Although, the risk of developing CML is very low, its status as a chronic disease implies a disproportionately large burden of disease and period of treatment, with many CML patients being maintained on a course of drug therapy for many years (Hochhaus A, 2008).
CML is identified by the ICD-10 code C92.1, three phases of CML are defined, in ascending order of severity as follows: chronic, accelerated, blastic. Most patients eventually progress to an accelerated phase and finally develop a blast crisis. The majority of patients who develop a blast crisis have a myeloid lineage to develop acute myeloid lymphoma. In contrast, less than 20% of patients progress through blast crisis with a lymphoid lineage to acute lymphocytic lymphoma.
Given the systemic nature of leukemia, the primary treatment modality is chemotherapy. Stem cell transplantation (SCT) is sometimes utilized for the treatment of CML, similar to its use for the treatment of the acute leukemias, but it’s now used less frequently for CML, basically because these patients are often elderly, and in part due to the introduction of Gleevec® (imatinib mesylate, Novartis).
The Gleevec launch has change the treatment guidelines for CML. While originally indicated for use in advanced patients, it has moved forward to treat patients in earlier disease stage. Gleevec, a specific inhibitor of the BCR-ABL tyrosine kinase, is the primary chemotherapy agent used to treat CML.
Usually, chemotherapy has not been proven to increase survival in CML, but it does significantly improve the life quality. The complete remission is not appropriate for CML treatment with chemotherapy, because the chromosome abnormalities persist or only transiently disappear during therapy. The goal of therapy has primarily been to relieve symptoms and to control disease.
Stem Cell Transplantation
Allogeneic SCT (allo SCT), which used a donor, as opposed to autologous SCT (auto SCT), which uses the patient’s own stem cells following chemotherapy, results in the lowest incidence of leukemic relapse. This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD).
Interferon alfa (IFNα) and hydroxyurea are standard treatments used to stabilize patients prior to SCT. Two retrospective series following allo SCT from a human leukocyte antigen (HLA)-matched unrelated donor showed a five-year relapse rate of 3% to 10% and a five-year overall survival rate of 31% to 57% (most deaths were treatment-related). Cyclosporine and methotrexate are used to prevent GVHD, and the relapse incidence at five years ranges from 20% to 30%. However, if T-cell depletion is used to minimize GVHD, relapse increases to 60% to 70%.
Tyrosine Kinase Inhibitors
Gleevec has revolutionized the treatment of CML patients. The drug targets the abnormal BCR-ABL kinase chromosomal translocation. Patients with this translocation, the Ph chromosome, are said to be Ph+. Gleevec does not cure CML, but effectively suppresses it and prolongs the lives of these patients. It inhibits proliferation and induces apoptosis of BCR-ABL-positive cells. Besides Gleevec, these patients can be treated with regimens containing IFNα, cytarabine, and/or hydroxyurea if they are eligible for transplantation. The prognosis of accelerated and blast- phase patients has been improved by Gleevec based on historical controls.
Sprycel® (dasatinib, Bristol-Myers Squibb) is a tyrosine kinase inhibitor, like Gleevec, that targets BCR-ABL.
Sprycel interact with forms of the enzyme that do not respond to Gleevec, such as those with mutations. Until 2006, once patients no longer responded to Gleevec, they had a poor prognosis with few remaining options. Long-term follow-up of the pivotal Gleevec trial showed that 3.3% of chronic-phase patients become refractory or insensitive to Gleevec in the first year of therapy, 7.5% become refractory/insensitive in the second year, 4.8% in the third year, 1.5% in the fourth year, and 0.9% in the fifth year. Of patients who receive Gleevec as second-line therapy after first-line interferon therapy, 25% experience progressive disease at 48 months. Of newly diagnosed patients in accelerated and blast phases treated with Gleevec, 24% and 66%, respectively, do not reach hematologic remission. This revealed unmet patients need in who do not respond or lose response to Gleevec. Sprycel was approved in 2006 for use in these patients, and was recently approved by the FDA for newly diagnosed patients.
Tasigna® (nilotinib, Novartis) is another tyrosine kinase inhibitor of BCR-ABL approved for the treatment of Gleevec-resistant/-intolerant patients. It was designed by Novartis to have a higher affinity for BCR-ABL than Gleevec, thereby earning itself the nickname “Super Gleevec.”
CML Drug Development Opportunities
As dasatinib (Bristol-Myers Squibb/Otsuka’s Sprycel) and nilotinib (Novartis’s Tasigna) start to be used more frequently in the first-line setting for chronic myeloid leukemia (CML), following their 2010 FDA approval in this setting, some experts raise concerns that fewer treatment choices will be available for patients who become refractory to up-front treatment. Although imatinib (Novartis’s Gleevec/Glivec) has been used for the past decade as first-line treatment for patients with CML, U.S. and European approvals of the second-generation tyrosine kinase inhibitors (TKIs) (i.e., dasatinib
and nilotinib) in 2010 as first-line therapies for CML patients will alter the CML treatment landscape.
Robust molecular responses, in comparison with imatinib, were observed for nilotinib in the ENESTnd trial and for dasatinib in DASISION trial (Kantarjian H, 2011; Larson RA, 2011). US and European KOL indicates that they will continue to prescribe imatinib over the second-generation TKIs because more long-term data are available for imatinib as a first-line therapy than for the second-generation TKIs and because reimbursement may be an issue with the second-generation TKIs in this setting.
Interviewed oncologists, KOL, and experts think that intermediate and high-risk patients as well as patients with primary resistance to imatinib in particular might benefit the most from a more potent second-generation TKI as up-front treatment. Using a potent second generation TKI as first-line therapy typically means that the less potent imatinib will never be used during a patient’s course of treatment so a line of therapy is lost with use of up-front dasatinib or nilotinib. In addition, many unanswered questions remain regarding the long-term use of second generation TKIs—in particular, some experts are concerned about an increasing incidence of hard-to treat BCR-ABL mutations (e.g., T315I). In addition to the T315I mutation, other BCR-ABL mutations arise in the course of TKI treatment, and switching to another non-treatment-resistant TKI is typically the best solution. However, patients may be limited by which TKIs they receive based on risk factors, mutational status, and/or comorbidities. Therefore, it remains necessary to develop additional treatments that not only improve outcomes for CML patients who have become refractory to initial treatment with a TKI but also for a wide variety of patients with different health characteristics. Several therapies are in development for treatment refractory CML, some of which address the therapeutic needs of patients with the T315I mutation.
Although they will target a subset of patients in an indication that has low incidence, treatments fulfilling these unmet needs will be commercially compelling because they will be able to command premium pricing and are treatments that patients take for many years. Although dasatinib and nilotinib are both frequently used to treat patients who become refractory to initial treatment with a TKI, we selected dasatinib as the comparator for our target product profile study. In the United States, these treatments are both widely prescribed for CML.
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