Curing Chronic Myelogenous Leukemia Essay

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Chronic Myelogenous Leukemia (CML): Treatment Options

Patients suffering from chronic myelogenous leukemia (CML) experience recurrent infections, anemia, and thrombocytopenia, signs and symptoms often manageable without professional help. Accordingly, patients often failed to seek medical care until late in the disease course and would have had a poor prognosis in the 20th century. Today, a number of effective treatments are available, including the highly effective kinase inhibitor imatinib. Kinase inhibitors suppress the activity of the fusion protein p210BCR-ABL, which is the product of a chromosomal translocation between chromosomes 9 and 22. Over half of all CML patients will become symptom free with the use of kinase inhibitors and live a long and productive life, but a smaller percentage will require more aggressive and riskier treatment approaches, among which is allogeneic hematopoietic stem cell transplantation following high dose chemotherapy.

Introduction

CML Etiology

Chronic myelogenous leukemia (CML) is a progressive disease that impairs the normal function of blood cells (National Cancer Institute, 2015a). The bone marrow in a healthy person contains hematopoietic stem cells, from which blood cells will develop. The two primary lineages derived from hematopoietic stem cells are myeloid and lymphoid, with the latter generating a number of critical immune cells. The terminal lymphoid cell types are B. And T. lymphocytes and natural killer cells. By contrast, the myeloid precursor can differentiate into red blood cells, platelets, eosinophils, basophils, and neutrophils. The latter three cell types are collectively called granulocytes (blasts) and are also critical for immune function. In patients with CML, granulocytes proliferate and overpopulate the bone marrow and circulatory compartments, leading to impaired functioning of other myeloid and lymphoid cell types. The result is recurrent infections, anemia, and thrombocytopenia (bleeding problems), due to impaired immunity, red blood cell function, and platelet activity, respectively.

The most common cause of CML is a translocation between chromosomes 9 and 22 in a bone marrow stem cell or myeloid precursor (National Cancer Institute, 2015a). The resulting chromosome 22 is called the Philadelphia or Ph chromosome. The translocation brings a portion of the Abelson proto-oncogene ABL, a non-receptor tyrosine kinase, next to the BCR gene, such that two new genes are created on chromosome 9 and 22: BCR-ABL on 22 and ABL-BCR on 9 (Levitan et al., 2003). Most research has focused on the activity of the BCR-ABL gene product, p210BCR-ABL, which is a 210 kDa cytoplasmic fusion protein with constitutive tyrosine kinase activity. The p210BCR-ABL kinase in turn induces dysregulated proliferation of granulocytes.

CML Epidemiology

CML is the rarest of the four major types of leukemia in the United States, with a prevalence estimated to have been 33,990 in 2011 (Leukemia & Lymphoma Society, 2015). In 2014, an estimated 5,980 new cases of CML were diagnosed, representing 11.4% of all leukemia cases. Other estimates suggest the prevalence is much higher, with 160,000 individuals suffering from CML in the United States in 2014 (Sweet, Pinilla-Ibarz, & Zhang, 2014). Although individuals of any age can develop CML, only 3.1% occur in individuals under 20-years of age (Leukemia & Lymphoma Society, 2015). Men are slightly more at risk and represent 52% of all cases, while the risk for all types of leukemia is highest among non-Hispanic Whites. The five-year survival rate for CML was 59.9%, compared to 25.4% for acute myeloid leukemia, 70% for acute lymphoblastic leukemia, and 83.5% for chronic lymphocytic leukemia. In 2014, an estimated 810 CML Americans died from this disease.

CML Pathophysiology

Individuals often fail to recognize that they are suffering from CML, sometimes for months and years (Mayo Clinic Staff, 2014). Unfortunately, the later the disease is diagnosed and treated, the poorer the prognosis. The signs and symptoms of CML include unusually easy bleeding, fatigue, fever, unintentional weight loss, poor appetite, pale skin, night sweats, and pain or a feeling of fullness below the ribs on the left side. Patients presenting with any of these symptoms will undergo a number of tests, starting with a physical examination to check vital signs and the presence of an enlarged spleen (National Cancer Institute, 2015a). A complete blood count with differential will be performed to check for abnormal counts of red blood cells, platelets, hemoglobin, and the different types of white blood cells. Other tests performed may include blood chemistry profile and bone marrow biopsies, followed by cytogenetic analysis, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction.

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The latter three tests can be used to check for chromosomal abnormalities and the presence of a fusion gene between BCR and ABL.

The factors affecting prognosis are age, disease phase, percent blasts in blood or bone marrow, spleen size, and overall health (National Cancer Institute, 2015a). The three phases of CML are chronic, accelerated, and blastic, with chronic being the mildest form of the disease. Less than 10% of blood and bone marrow cells are blast cells (granulocytes) in the chronic phase, but this increases to between 10 and 19% in the accelerated phase. In the blastic phase, at least 20% of blood and bone marrow cells are blasts.

Treatments and Medications

A standard CML treatment option is chemotherapy, which seeks to kill cancer cells systemically or regionally with the administration of cytotoxic drugs. The use of chemotherapy to treat CML predates the use of kinase inhibitors by several decades, but during the early years the drug cocktails used rarely altered disease course because the leukemic myeloid precursors were not destroyed (Santos et al., 2011). The addition of interferon-? To chemotherapy represented the first real breakthrough, since a small number of patients achieved complete cytogenic remission (CCyR; loss of detectable levels of Ph chromosome) in the bone marrow and blood and lived longer. Alternatively, high dose chemotherapy can be used to destroy all bone marrow cells in preparation for a hematopoietic stem cell transplant. This approach carries significant risks, but its potential for CCyR is high enough for it to be a standard treatment option for younger patients with a matched donor.

The most common treatment approach is the use of kinase inhibitors, including imatinib mesylate, nilotinib, dasatinib, and ponatinib (National Cancer Institute, 2015b). Treatment with imatinib is a standard, first-line treatment option for most CML patients due to increased patient survival and drug tolerability. The first clinical trials with imatinib for CML patients were very promising and revealed major cytogenic response (MCyR; 35% or less of bone marrow cells positive for the Ph chromosome) in 87% of patients and a CCyR in 76% of patients (Santos et al., 2011). After 8 years, 55% of the patients who participated in the imatinib clinical trial were still taking the drug and 83% remained CCyR. Since the imatinib clinical trial results were published in 2002, a number of studies have revealed that 30 to 40% of patients will require additional treatments due to an existing or acquired kinase inhibitor resistance. These patients will have the option of attempting higher doses of imatinib, taking second or third generation kinase inhibitors, or having an allogenic hematopoietic stem cell transplant following chemotherapy- or radiation-mediated killing of bone marrow cells. The use of second and third generation kinase inhibitors have also been promising and are gradually being used as a first-line therapy for CML patients.

Other options include biologics, which involve the use of natural biological agents to stimulate an immune response against the leukemic stem cells or myeloid precursors in the bone marrow and blood (National Cancer Institute, 2015b; Llander, Hekim, & Mustjoki, 2014). Although kinase inhibitor therapy has been highly effective for a large percentage number of patients, none are truly considered to be cured; whereas, an effective immune response against cells producing p210BCR-ABL and other leukemia antigens have curative potential (Llander et al., 2014) . A related treatment is donor lymphocyte infusions, which is used to transfer healthy white blood cells from donors into the circulatory system of CML patients (National Cancer Institute, 2015b). The donated lymphocytes then attack the leukemic cells. It is important to note that kinase inhibitors tend to suppress immune activation, so the simultaneous use of kinase inhibitors and donor lymphocyte infusions would probably not be recommended (Santos et al., 2011). Even though kinase inhibitors result in long-term survival of CML patients, most patients continue to take these drugs indefinitely. Notably, there have been patients that have stopped taking these drugs and have had a partial cytogenetic relapse, but remain symptom free. Santos and colleagues (2011) suggest that the immune system in these patients, in particular NK-cells, are controlling the growth and expansion of leukemic cells and are therefore these patients have been effectively cured.

Summary

With the development of kinase inhibitors, most CML patients can live normal lives and a few may be effectively cured. A smaller percentage of patients, especially.....

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