Созылмалы миелолейкоз: себептері, диагностикасы және емдеуі

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome. CML is largely treated with targeted drugs called tyrosine kinase inhibitors (TKIs) which have led to dramatically improved long term survival rates since 2001. These drugs have revolutionized treatment of this disease and allow most patients to have a good quality of life when compared to the former chemotherapy drugs. In Western countries, CML accounts for 15–25% of all adult leukemias and 14% of leukemias overall (including the pediatric population, where CML is less common). Some (<10%) are diagnosed during the accelerated stage which most often presents bleeding, petechiae and ecchymosis. Exposure to ionising radiation appears to be a risk factor, based on a 50 fold higher incidence of CML in Hiroshima and Nagasaki nuclear bombing survivors. In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p210 is short for 210 kDa protein, a shorthand used for characterizing proteins based solely on size). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr abl fusion gene product is also a tyrosine kinase. The fused BCR ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the BCR ABL protein and its action as a tyrosine kinase, targeted therapies (the first of which was imatinib) that specifically inhibit the activity of the BCR ABL protein have been developed. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr abl as the cause of CML. As a result of this translocation, the chromosome looks smaller than its homologue chromosome, and this appearance is known as the Philadelphia chromosome chromosomal abnormality. Thus, this abnormality can be detected by routine cytogenetics, and the involved genes BCR ABL1 can be detected by fluorescent in situ hybridization, as well as by PCR. The small subset of patients without detectable molecular evidence of BCR ABL1 fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML. CML must be distinguished from a leukemoid reaction, which can have a similar appearance on a blood smear.

CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention, CML typically begins in the chronic phase, and over the course of several years progresses to an accelerated phase and ultimately to a blast crisis. Blast crisis is the terminal phase of CML and clinically behaves like an acute leukemia. Drug treatment will usually stop this progression if early. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome).

The only curative treatment for CML is a bone marrow transplant or an allogeneic stem cell transplant. Other than this there are four major mainstays of treatment in CML: treatment with tyrosine kinase inhibitors, myelosuppressive or leukapheresis therapy (to counteract the leukocytosis during early treatment), splenectomy and interferon alfa 2b treatment.

In the past, antimetabolites (e. g., cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used as treatments of CML in the chronic phase, but since the 2000s have been replaced by Bcr Abl tyrosine kinase inhibitors drugs that specifically target BCR ABL, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. Despite the move to replacing cytotoxic antineoplastics (standard anticancer drugs) with tyrosine kinase inhibitors sometimes hydroxyurea is still used to counteract the high leukocyte counts encountered during treatment with tyrosine kinase inhibitors like imatinib; in these situations it may be the preferred myelosuppressive agent due to its relative lack of leukemogenic effects and hence the relative lack of potential for secondary haematologic malignancies to result from treatment. IRIS, an international study that compared interferon/cytarabine combination and the first of these new drugs imatinib, with long term follow up, demonstrated the clear superiority of tyrosine kinase targeted inhibition over existing treatments.

The first of this new class of drugs was imatinib mesylate (marketed as Gleevec or Glivec), approved by the US Food and Drug Administration (FDA) in 2001. Imatinib was found to inhibit the progression of CML in the majority of patients (65–75%) sufficiently to achieve regrowth of their normal bone marrow stem cell population (a cytogenetic response) with stable proportions of maturing white blood cells. Because some leukemic cells (as evaluated by RT PCR) persist in nearly all patients, the treatment has to be continued indefinitely. Since the advent of imatinib, CML has become the first cancer in which a standard medical treatment may give to the patient a normal life expectancy.

To overcome imatinib resistance and to increase responsiveness to TK inhibitors, four novel agents were later developed. The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR ABL protein, and was approved in 2007, by the U. S. Food and Drug Administration (FDA) to treat CML in people who were either resistant to or intolerant of imatinib. A second TK inhibitor, nilotinib, was approved by the FDA for the same indication. In 2010, nilotinib and dasatinib were also approved for first line therapy, making three drugs in this class available for treatment of newly diagnosed CML. In 2012, radotinib joined the class of novel agents in the inhibition of the BCR ABL protein and was approved in South Korea for people resistant to or intolerant of imatinib. Bosutinib received US FDA and EU European Medicines Agency approval on 4 September 2012, and 27 March 2013, respectively for the treatment of adults with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy. Asciminib (Scemblix) was approved for medical use in the United States in October 2021.

While capable of producing significantly improved responses compared with the action of imatinib, neither dasatinib nor nilotinib could overcome drug resistance caused by one particular mutation found to occur in the structure of BCR ABL1 known as the T315I mutation (in other words, where the 315th amino acid is mutated from a threonine residue to an isoleucine residue). Two approaches were developed to the treatment of CML as a result:

In 2007, Chemgenex released results of an open label Phase 2/3 study (CGX 635 CML 202) that investigated the use of a non BCR ABL targeted agent omacetaxine, administered subcutaneously (under the skin) in patients who had failed with imatinib and exhibited T315I kinase domain mutation. This is a study which is ongoing through 2014. In September 2012, the FDA approved omacetaxine for the treatment of CML in the case of resistance to other chemotherapeutic agents. Independently, ARIAD pharmaceuticals, adapting the chemical structures from first and second generation TK inhibitors, arrived at a new pan BCR ABL1 inhibitor which showed (for the first time) efficacy against T315I, as well as all other known mutations of the oncoprotein. The drug, ponatinib, gained FDA approval in December 2012 for treatment of patients with resistant or intolerant CML. Just as with second generation TK inhibitors, early approval is being sought to extend the use of ponatinib to newly diagnosed CML also.

In 2005, encouraging but mixed results of vaccination were reported with the BCR/ABL1 p210 fusion protein in patients with stable disease, with GM CSF as an adjuvant.

Before the advent of tyrosine kinase inhibitors, the median survival time for CML patients had been about 3–5 years from time of diagnosis. With the use of tyrosine kinase inhibitors, survival rates have improved dramatically. A 2006 follow up of 553 patients using imatinib (Gleevec) found an overall survival rate of 89% after five years. A 2011 followup of 832 patients using imatinib who achieved a stable cytogenetic response found an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Fewer than 1% of patients died because of leukemia progression.

The American Cancer Society estimates that in 2014, about 5,980 new cases of chronic myeloid leukemia were diagnosed, and about 810 people died of the disease. This means that a little over 10% of all newly diagnosed leukemia cases will be chronic myeloid leukemia. The average risk of a person getting this disease is 1 in 588. The disease is more common in men than women, and more common in whites than African Americans. The average age at diagnosis is 64 years, and this disease is rarely seen in children.