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Leukaemia is disease of blood cells. In which replacement of bonemarrow with malignant, leukaemic cells. Which is defined as chronic myeloproliferative disorder charecterised by neutrophilic leukocytosis, which is a rare disease seen more prominently in some areas of india and world. It follows a biphasic or triphasic course - chronic phase, accelerated phase and blast crisis. Median survival is around 3-5years.various phases in its pathogenesis, which is common in adults and rare in children.CML is classically associated with the presence of Philadelphia (Ph) chromosome, it results from reciprocal translocation of genetic material (containing proto-oncogene c-abl) from chromosome 9 to chromosome 22 (at the breakpoint of the bcr locus). It is the hallmark of CML and is found in 95% of patients. The choice of treatments is based on a patient's age, overall health and related factors. The anti-cancer drugs interferon, cytarabine, and hydroxyurea were the main CML treatments before imatinib became available in 2001, but are now infrequently used.many other drugs are being used in the treatment of CML. Novel drug targets and noveltherapies are being identified to improve the treatment procedure.
It is a malignant disorder of the haematopoietic tissues characterised by increased numbers of white blood cells in the bone marrow and peripheral blood.
Its course may be varied from few days or weeks to years depending on the type.
The cells produced are called leukaemia cells which aggregate with other wbc, rbc and platelets preventing them to do their normal function.
There are different types of leukaemias.
They are classified in to various types depending upon severity and the type of wbc cells they effect.
There are two major types of leukaemias. They are :
1)chronic leukaemia: this type of leukaemia will not express its symptoms until the physician identifies in a regular check up and until leukaemia cells are produced large in number, which expresses symptoms like swollen lymph nodes, infections etc.
2)acute leukaemia: in this type leukaemia cells doesn't function as wbc, they increase rapidly and worsens.
Leukaemia can start in lymphoid cells this is called as lymphoid, lymphocytic or lymphoblastic leukaemia and which effect myeloid cells are called myeloid or myelogenous leukaemia .
There are four common types of leukaemias:
Chronic lymphocytic leukaemia
Chronic myeloid leukaemia
Acute lymphocytic or lymphoblastic leukaemia
Acute myeloid leukaemia
Hair cell leukaemia
Although the causes are not known, but some risk factors may have increased chance of getting leukaemia.
They are different types
Radiation : such as atomic bomb explotions and other radiations
Radiation therapy: diagnostic x-rays, CT-scans etc.
Smoking: cigarette smoking
Chemotherapy: drugs used for cancer therapy
Downs syndrome and other inherited diseases
Myelodysplastic syndrome and other blood disorder
Human T-cell leukemia virus type I (HTLV-I)
Family history of leukaemia
Of all the leukaemias the most common type seen in india is chronic myelogenous leukaemia.
Chronic myelogenous leukaemia:
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells.
Symptoms depend upon number of leukaemia cells produced and place where they effect.
Chronic leukaemia doesnot show signs and symptoms until they are identified by doctors routine checkup.
Acute leukaemia atients reach doctor due to sickness, headache, vomiting, confusion, loss of muscle control, seizures.
Other symptoms related to kidneys, heart, testes, lungs , digestive system.
Common symptoms are :
Swollen lympth glands
Fever or night sweats
Feeling weak or tired
Bleeding and bruising
Swelling or discomfort in the abdomen
Pain in bones or joints
phases of chronic myeloid leukaemia:
Chronic pase cml
Chronic phase: in this phase there are less than 5% of blasts are seen in blood and bone marro, lasts for several years.
Accelerated phase: more than 5% and less than 30% blasts are seen in blood and bone marrow, they grow faster.
Blastic phase: 30% blasts are seen in blood and bone marrow, it develops to acute leukaemia.
Patients may have symptoms like fever, malaise, enlarged spleen, weight loss.
Relapsing cml: it is progression of disease from a stable remission. Which include increase in myeloid or blast cells, cytogenetic positivity and FISH positivity.
cml is a rare disease which effects less than 150000 people in us population, it is listed as rare disease by office of rare diseases of national institution of health, it occurs in 1-2 persons in 100000 and affects people of all ages, which is common in middle age and even children which is common in males than females.
It is a mycroproliferative disorder of 10-12% of leukaemia.
In india it is less seen in western countries, in Manipur , Mizoram , south west coast -goa, udipi, thrissur it is high.
1 in 2000 people are effected and about 5000 to 6000 cases are repoted a year.
Its rate increases as the age increases an average of 60 in men and 70 in females and on the basis of race it varies.
The patients live for five years and the prevalence is five times it is the survival rate.
Annually its incidence is 1 and 1.5 cases per one lakh and its prevalence is 1 in 7000.
Molecular biology and pathogenesis:
Cml is charectirised by the presence of Philadelphia (ph) chromosome - first determined by nowell and bungerford in 1990.
Reciprocal translocation of genetic material (containing proto -oncogene c-abl) from chromosome 9 to chromosome 22 (at breakpoint of the bcrlocus).
In few cases large deletions are seen adjacent to the translocation break point on the derivative 9 chromosome.
ABL proteins are non receptor thirosine kinases plays a major role in signal transduction and the regulation of cell growth.
Structural abnormalities of ABL and BCR facilitate the leukemogenic transformation of Bcr-Abl, which results in bcr/abl encodes for a fusion protein (p210)with elevated and dysregulated tyrosin kinase activity.
The normal p145ABL exchange between the cytoplasm and the nucleus.
The activity and intracellular localization of p145 ABL in regulated by integins.
BCR/ABL: acts as a mitogen by activating res(oncogene) signal transduction pathway leading to increase in C-Mye and C-Fos and subsequent increase in gene transcriptiommnn amd activation of cylind complexes.
Cycline dependent kinases allows the cells to move from G1 phase of cell cycle to S Phase.
BCR/ABL inhibits apoptosis thus leading to accumulation of cells.
A4b intergins are impotant for the adhesion of normal progenitor to the marrow micro environment, which effects the progenitor proliferation and differentiation.
BCR/ABL blocks normal integrin function and there by reduces adhesion of progenitor cell to stromal elements.
So that the stem cells escape physiological inhibitiory regulation.
Disease transformation is charecterized by additional cytogenetic and molecular changes.
Cytogenic changes like trisomy 8,iso chromosomes 17q and double ph chromosome.
Molecular abnormalities include abnormalities in p53,RBI , C-MYL, RAS, AML-EVI-I.
Alterations in p53 are associated exclusively with myeloid transformation and abnormalities of RBI are associated with lymphoid transformation.
Diagnosis: patients must be diagnosed before going to treatment to identify the stage/phase of the cml.
Factors considered for choosing a diagnostic test:
Severity of symptoms
Previous tests results
The types of tests used are:
Blood tests, bone marrow biopsy, cytogenetics, fluorescent insitu hybridization
(FISH) , polymerase chain reaction (PCR), imaging tests like CT- scan , X-ray.
Treatment of cml is based upon the stage/phase of the disease. It may be of varied types like chemotherapy, surgery, immunotherapy, stemcell/bone marrow transplantation.
There are several drugs which are being used in the treatment of CML , the are as follows
Fowler solution (arsenicals) was the first treatment in 1856.
Which was followed by radiotherapy, used for controlling CML,continued till 1950.
Busurfan replaced radiotherapy in 1953,
Hydroxyurea was introduced in CML therapy in 1972. Because of its toxicity it became the better agent for treatment of CML.
In 1980 interferon shown to be effective which became first line of treatment for CML.
Busurfan which acts on stem cell results in controlling, the cell count, it is avoided in patients who ae preparing for BMT.
Hydroxyurea is used by which the cell count is decreased rapidly by acting on proliferating cells.
INFA2 a and 2b are used in treatment of CML, it acts by induction of FAS and its ligand on CML progenitor, which induces cell death in early stemcell population , recognition of CML cells by cellular immune system, INF has a prolong survival by delaying blast crisis.
INF a with cytosine arabinoside (Ara-c):
This drug combination improves cytogenic response and improves survival.
The daily dose is INFa and low dose of Ara-c.
Chemotherapy with newer agent :
Attachement of a 40kba polyethylene glycol polymer to the IFNa-2b molecule results in a drug with good activity compound to IFN-ab, with longer half life.
YNK01 (ocfosfats): a oral prodrug of arac-c, which over come the limitation of systemic deamination and hydrophilic property, thus drug resists the deoxycytidine deaminase
Homoharringtonine (HHT): A plant alkaloid used in treatment of CML,in patient who are resistant to IFN combination of both showed good results in haematologic remission and cytogenic response.
Decidabine: a hypomethylating agent used in CML.
STI571: orally active tyrosine kinase inhibitor, a combination of STI571 with IFN, DNR, Ara-c show better result than STI571 alone.
Other agents like farnesyl transferase inhibitis azidothymidine, topotecan and all transretinoic acid (ATRA) are under development.
Inhibition of BR/ABL gene products:
Antesense oligonucleotide: (AS-ODN) therapy:
They act by inhibiting transcription of target gene.
They are unstable and susceptible to nucleus digestion.
This also targets ARBL,shc, p120GAP and CMYC.
These can be targeted against BCR/ABLmRNA.
Maxizyme , cleaves bcr-abl, Mrna only in cells with bcr-abl junction sequence.
Catalytic RNA subunit of RNase p:
M1-RNA these will recognise and cleave specifically the chimeric molecules created by chromosomal abnormalities.
Phosphatidyl inositol- 3kinase (PI-3kinase):
They are involved in cell proliferation.
The process involved in this treatment is
Contraduction of a patients haematopoietic stem cells with adrug resistance gene and antiBCR ABL anti kinase sequence.
A part from all the above treatments the first generation drug imatinib was developed in preference to interferon alfa plus cytarabine which are used earlier to imatinib.
Many trials had been conducted on the imatinib to prove its efficacy.
This was proved by a five year study in comparison with interferon alfa which was a multicentre, randomized , crossover , open label study in large proportions.
The study showed that the patients receiving imatinib showed major cytogenetic molelularresponse
Wich was estimated by scoring system devised by socal and colleagues.
The blast crisis or accelerated phase has not progressed in majority of patients.
The analysis of the study performed ata median follow[ showed that imatinib can be used as a initial therapy for firstly diagnosed CML.
A new drug DASATINIB was developed after imatinib was conformed to show some limitations.
Trial conductedon DASATINIB which is a highly potent BCR-ABL kinase inhibitor has frsulted complete cytogenetic response which was higher than that of imatinib.
The molecular response was high than compared with imatinib with in short span of time.
DASATINIB will improve th ongterm outcome among patients with newly diagnosed chronic phase CML.
Another drug NILOTINIB and orally bioavailable derivative of IMATINIB, is a tyrosine kinase inhibitor with improved target specificity, was developed for the treatment of CML.
This is a structurally modified imatinib drug i.e nilotinib will also act by inhibiting BCR-ABL by binding to an inactive, DFG- out conformation of the ABLkinase domain, thus blocks the TKP of proteins involved in BCR-ABL signed transduction.
It has greater potency over KIT and PDGF receptor kinase. A total responce was achieved in short time period.
DASATINIB given to patient with CML-CP post imatinib failure produced a major cytogenetic response rate of 45% at 6months, and complete cytogenetic response rate of 33%.
With NILOTINIB the estimated 5-year survival rate was 95% , over all cytogenic response was 96%.
Apart from these drugs recently new therapeutics and new drug targets are being identifying developed.
Limitations of currently available treatment:
Limitations for the present drugs are that they (imatinib) doesn't keep many patients from eventually moving into the disease later, more severe stage,and certain cells that set events in motion towards CML are able to resist the drug are not known.
A biochemical abnormality like hyperbilirbinemia followed by transient elevations in ALT, AST and serum lipase was seen in treatment with the drug nilotinib.
It does not have activity against targets such as the SVC-family of tyrosine kinase.
Another limitation of imatinib is that it is not known why it is not able to eradicate the malignant clone.
Imatinib cannot completely inhibit BCR-ABL kinase activity.
Another limitations of all the drugs used in treatment were side effects each and every drug show side effects this makes to think to prefer which drug is effective for the treatment of CML.
These side effects may be nausea,vomiting, diarrhoea, breast enlargement may occur in small number of males, skin rashes,mild anemia, women with preganancy who take imatinib may develop complications in the faetus.
About nilotinib, taking the medication with food can lead to excessive amounts of the drug in the bloodstream and is not recommended.rashes may appear, changes in heart rhythm known as QT prolongation.
With interferon there may be few side effects like chil fever,and flu like symptoms may appear.
NOVEL DRUG TARGETS:
Introduction of second generation thyrokinase inhibition re establisher response in approximately half of the patients who are receiving the existing drugs will show some improvement.
Understanding the mechanisms of TKI induced apoptosis in CML cells which helps in modulating the apoptosis by extracellular factors. This was inhibited by protein synthesis inhibition in bothK 562 and CML CD 34+ cells.
Mutations in the kinase domain (KD) of Bcr-Abl that impain drug binding as major mechanism of acquired drug resistance.
Wnt proteins (glycoprotiens) bind to the frizzed receptors and LRP5/6 co-receptors.
By stabilizing the critical mediator B-catonin plays a role in cell proliferation and differentiation.
These became the new targets in the treatment of CML
MToR a novel bifunctional target.
Digestion of growth inhibitory and VEGF- suppressive effects of rapamycin.
Polo like kinase (PIK-1) as a novel drug target which plays a essential role in mitosis. Expressed in phosphorylated form in CML cell line K562 and protein in CML cells silencing PLK will lead to stop of cycle arrest. Over writing the imatinib resistance with the PLK 1 inhibitor B12536.
NOVEL DRUG THERAPIES:
Sprycel is approved for use only in patients who have failed gleeve treatment which is a Bristol-myer squibb. Which act as thyrosine kinase inhibitor.
Vincristine and prednisone (VP) has produced remissions in 30% of patient wit chronic CML in blast transformation (CML-BT), these will effect production of granulocytes which are considered to be free of myclotoxicity.
P-glycoprotein mediated drug, efflux is a resistance mechanism of chronic myeloid leukaemia cells to treatment with imatinib mesylate.
By decreased p-glycoprotein (pgp) positive leukaemia cells .
Modulation of Pgp by cyclosporine A restored imaitnib cytotoxicity. Pgp modulation in the imatinib treatment of a patient with BCR-abl positivease
MDR1 is considered in the diversity of resistance development to imaitnib treatment.
Combined ABl inhibitor therapy for minimizing drug resistance in chronicML, src/abl inhibitor with imatinib will overcome the resistance.
The BVR-adl gene expression as tyrosine kinase was discovered in 1986 by a team led by nobel laureate david Baltimore.
Alternative for bone marrow transplantation with unmatched donor tissue is receiving a transplant that uses umbilical cord blood which is rich in stem cells.
Biological therapy: increases immunity power by interferon.
Brotezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-K and NOD/SCID repopulating cells.
Brotezomib is antiproliferative and induces apoptosis in chronic phase, targets primitive CML cells,which effects CD 34+38- longterm culture initiating (LTC-X) and non obese diabetic/sugar combind immunodificient (NOD/SCID)repopulating cells.
This proves that bortezomib is effertive in resistant and advanced disease
Autologous cytokine induced killer cells (CIK) for CML patient on standard drug therapy.
Multi target kinase inhibitor AP24534 which show haematologic, cytogenetic and molecular antileukaemia activity by ARIAD pharmaceutical company.
STI571 (IRIS) show rapid complete cytogenetic response (CCR) and a major molecular response (MMR).
Treatment by targeting activity transcription factor 3 by galectin 9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia.
Sequential treatment with flavoliridol synergistically enhances phyrolol-1,5-benzoxazepine induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imaitnib treatment which showed synergic enhancement opoptosis in CML cells including those expressing the imatinib resistant T3151 mutant, flavopiridol reduced the number of polyploidy cells formed in response to PBox treatment.
Critical assessment of new treatment:
The present treatment of CML shows much advanced and is still evolving in various aspects. The treatment with various drugs in the early stages of the disease shows improvement of life. A combinational drug therapy also shown better results, in the early stage of drug development. Present treatment with single drug also showing a varied difference in treatment which shows divers route of targets for the disease. Present treatments are reaching the needs of patients with this disease by improving their immunity by biological therapy , decreasing the count of lympho blasts and proliferation of the lymphocytic cells.
There is a need of further research in mechanism of the disease in which the action of the thirosine kinase which plays a major role in development of the disease. Identifying the various factors of the symptoms of the disease will further help in development of new drugs.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells. The incidence of CML is 1 to 2 cases per 100,000 people per year; in the Western Hemisphere, CML accounts for 15% of leukemias in adults. Discovery of the specific karyotypic abnormality of the Philadelphia (Ph) chromosome in the pathogenesis of CML has led to a better understanding of the disease and hence to an advancement of targeted therapeutics. Availability of imatinib as an accepted targeted therapy in newly diagnosed patients has changed the treatment paradigm in CML. The majority of CML patients in chronic phase achieve excellent and durable responses with standard-dose imatinib. Mechanisms of primary and secondary resistance to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical use. It is important that at any time the CML treatment and response remain optimal and thus patients on imatinib require continuous monitoring for early detection of resistance. This review will discuss the treatment and guidelines for monitoring CML patients in the imatinib era.