Leukaemia is disease of blood cells. In which replacing of bonemarrow with malignant, leukaemic cells. Which is defined as chronic myeloproliferative upset charecterised by neutrophilic leucocytosis, which is a rare disease seen more conspicuously in some countries of India and universe. It follows a biphasic or triphasic class – chronic stage, accelerated stage and blast crisis. Median endurance is around 3-5years.various stages in its pathogenesis, which is common in grownups and rare in children.CML is classically associated with the presence of Philadelphia ( Ph ) chromosome, it consequences from mutual translocation of familial stuff ( incorporating proto-oncogene c-abl ) from chromosome 9 to chromosome 22 ( at the breakpoint of the bcr venue ) . It is the trademark of CML and is found in 95 % of patients. The pick of interventions is based on a patient ‘s age, overall wellness and related factors. The anti-cancer drugs interferon, cytarabine, and hydroxyurea were the chief CML interventions before imatinib became available in 2001, but are now infrequently used.many other drugs are being used in the intervention of CML. Novel drug marks and noveltherapies are being identified to better the intervention process.
It is a malignant upset of the hematopoietic tissues characterised by increased Numberss of white blood cells in the bone marrow and peripheral blood.
Its class may be varied from few yearss or hebdomads to old ages depending on the type.
The cells produced are called leukemia cells which aggregate with other leukocyte, red blood cell and thrombocytes forestalling them to make their normal map.
There are different types of leukemia.
They are classified in to assorted types depending upon badness and the type of leukocyte cells they consequence.
There are two major types of leukemia. They are:
1 ) chronic
2 ) ague
1 ) chronic leukemia: this type of leukemia will non show its symptoms until the physician identifies in a regular cheque up and until leukaemia cells are produced big in figure, which expresses symptoms like conceited lymph nodes, infections etc.
2 ) ague leukemia: in this type leukemia cells does n’t work as leukocyte, they increase quickly and worsens.
Leukaemia can get down in lymphoid cells this is called as lymphoid, lymphocytic or lymphoblastic leukemia and which consequence myeloid cells are called myeloid or myelogenous leukemia.
There are four common types of leukemia:
Chronic lymphocytic leukemia
Chronic myeloid leukemia
Acute lymphocytic or lymphoblastic leukemia
Acute myeloid leukemia
Hair cell leukemia
Although the causes are non known, but some hazard factors may hold increased opportunity of acquiring leukemia.
They are different types
Radiation: such as atomic bomb explotions and other radiations
Radiation therapy: diagnostic X raies, CT-scans etc.
Smoke: coffin nail smoke
Chemotherapy: drugs used for malignant neoplastic disease therapy
Downs syndrome and other familial diseases
Myelodysplastic syndrome and other blood upset
Human T-cell leukaemia virus type I ( HTLV-I )
Family history of leukemia
Of all the leukaemias the most common type seen in India is chronic myelogenous leukemia.
Chronic myelogenous leukemia:
Chronic myelogenous leukaemia ( CML ) is a myeloproliferative upset characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to distinguish. Consequently, the peripheral blood cell profile shows an increased figure of granulocytes and their immature precursors, including occasional blast cells.
Symptoms depend upon figure of leukaemia cells produced and topographic point where they consequence.
Chronic leukemia doesnot show marks and symptoms until they are identified by physicians everyday medical examination.
Acute leukemia atients reach physician due to sickness, concern, purging, confusion, loss of musculus control, ictuss.
Other symptoms related to kidneys, bosom, testicles, lungs, digestive system.
Common symptoms are:
Swollen lympth secretory organs
Fever or dark workout suits
Feeling weak or tired
Bleeding and bruising
Swelling or uncomfortableness in the venters
Pain in castanetss or articulations
stages of chronic myeloid leukemia:
Chronic pase cml
Chronic stage: in this stage there are less than 5 % of blasts are seen in blood and bone marro, lasts for several old ages.
Accelerated stage: more than 5 % and less than 30 % blasts are seen in blood and bone marrow, they grow faster.
Blastic stage: 30 % blasts are seen in blood and bone marrow, it develops to acute leukemia.
Patients may hold symptoms like febrility, unease, enlarged lien, weight loss.
Get worsing cml: it is patterned advance of disease from a stable remittal. Which include addition in myeloid or blast cells, cytogenetic positiveness and FISH positiveness.
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 establishment of wellness, it occurs in 1-2 individuals in 100000 and affects people of all ages, which is common in in-between age and even kids which is common in males than females.
It is a mycroproliferative upset of 10-12 % of leukemia.
In India it is less seen in western states, in Manipur, Mizoram, south west seashore -goa, udipi, thrissur it is high.
1 in 2000 people are effected and about 5000 to 6000 instances are repoted a twelvemonth.
Its rate additions as the age increases an norm of 60 in work forces and 70 in females and on the footing of race it varies.
The patients live for five old ages and the prevalence is five times it is the survival rate.
Annually its incidence is 1 and 1.5 instances per one hundred thousand and its prevalence is 1 in 7000.
Molecular biological science and pathogenesis:
Cml is charectirised by the presence of Philadelphia ( pH ) chromosome – foremost determined by nowell and bungerford in 1990.
Reciprocal translocation of familial stuff ( incorporating proto -oncogene c-abl ) from chromosome 9 to chromosome 22 ( at breakpoint of the bcrlocus ) .
In few instances big omissions are seen next to the translocation interruption point on the derivative 9 chromosome.
ABL proteins are non receptor thirosine kinases plays a major function in signal transduction and the ordinance of cell growing.
Structural abnormalcies of ABL and BCR facilitate the leukemogenic transmutation of Bcr-Abl, which consequences in bcr/abl encodes for a merger protein ( p210 ) with elevated and dysregulated tyrosin kinase activity.
The normal p145ABL exchange between the cytol and the karyon.
The activity and intracellular localisation of p145 ABL in regulated by integins.
BCR/ABL: Acts of the Apostless as a mitogen by triping RESs ( transforming gene ) signal transduction pathway taking to increase in C-Mye and C-Fos and subsequent addition in cistron transcriptiommnn amd activation of cylind composites.
Cycline dependant kinases allows the cells to travel from G1 stage of cell rhythm to S Phase.
BCR/ABL inhibits programmed cell death therefore taking to accretion of cells.
A4b intergins are impotant for the adhesion of normal primogenitor to the marrow micro environment, which effects the primogenitor proliferation and distinction.
BCR/ABL blocks normal integrin map and at that place by reduces adhesion of primogenitor cell to stromal elements.
So that the root cells escape physiological inhibitiory ordinance.
Disease transmutation is charecterized by extra cytogenetic and molecular alterations.
Cytogenic alterations like trisomy 8, iso chromosomes 17q and dual pH chromosome.
Molecular abnormalcies include abnormalcies in p53, RBI, C-MYL, RAS, AML-EVI-I.
Changes in p53 are associated entirely with myeloid transmutation and abnormalcies of RBI are associated with lymphoid transmutation.
Diagnosis: patients must be diagnosed before traveling to intervention to place the stage/phase of the cml.
Factors considered for taking a diagnostic trial:
Badness of symptoms
Previous trials consequences
The types of trials used are:
Blood trials, bone marrow biopsy, cytogenetics, fluorescent insitu hybridisation
( FISH ) , polymerase concatenation reaction ( PCR ) , imaging trials 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 organ transplant.
There are several drugs which are being used in the intervention of CML, the are as follows
Fowler solution ( arsenicals ) was the first intervention in 1856.
Which was followed by radiation therapy, used for commanding CML, continued till 1950.
Busurfan replaced radiation therapy in 1953,
Hydroxyurea was introduced in CML therapy in 1972. Because of its toxicity it became the better agent for intervention of CML.
In 1980 interferon shown to be effectual which became first line of intervention for CML.
Busurfan which acts on root cell consequences in commanding, the cell count, it is avoided in patients who ae fixing for BMT.
Hydroxyurea is used by which the cell count is decreased quickly by moving on proliferating cells.
INFA2 a and 2b are used in intervention of CML, it acts by initiation of FAS and its ligand on CML primogenitor, which induces cell decease in early stemcell population, acknowledgment of CML cells by cellular immune system, INF has a prolong endurance by detaining blast crisis.
INF a with C arabinoside ( Ara-c ) :
This drug combination improves cytogenic response and improves endurance.
The day-to-day dosage is INFa and low dosage of Ara-c.
Chemotherapy with newer agent:
Attachement of a 40kba polythene ethanediol polymer to the IFNa-2b molecule consequences in a drug with good activity compound to IFN-ab, with longer half life.
YNK01 ( ocfosfats ) : a unwritten prodrug of arac-c, which over come the restriction of systemic deaminization and hydrophilic belongings, therefore drug resists the deoxycytidine deaminase
Homoharringtonine ( HHT ) : A works alkaloid used in intervention of CML, in patient who are immune to IFN combination of both showed good consequences in haematologic remittal 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 consequence than STI571 entirely.
Other agents like farnesyl transferase inhibitis azidothymidine, topotecan and all transretinoic acid ( ATRA ) are under development.
Inhibition of BR/ABL cistron merchandises:
Antesense oligonucleotide: ( AS-ODN ) therapy:
They act by suppressing written text of mark cistron.
They are unstable and susceptible to nucleus digestion.
This besides targets ARBL, shc, p120GAP and CMYC.
These can be targeted against BCR/ABLmRNA.
Maxizyme, cleaves bcr-abl, Mrna merely in cells with bcr-abl junction sequence.
Catalytic RNA fractional monetary unit of RNase P:
M1-RNA these will recognize and split specifically the chimeric molecules created by chromosomal abnormalcies.
Phosphatidyl inositol- 3kinase ( PI-3kinase ) :
They are involved in cell proliferation.
The procedure involved in this intervention is
Contraduction of a patients hematopoietic root cells with adrug opposition cistron and antiBCR ABL anti kinase sequence.
A portion from all the above interventions the first coevals drug imatinib was developed in penchant to interferon alfa plus cytarabine which are used earlier to imatinib.
Many tests had been conducted on the imatinib to turn out its efficaciousness.
This was proved by a five twelvemonth survey in comparing with interferon alfa which was a multicentre, randomized, crossing over, unfastened label survey in big proportions.
The survey showed that the patients having imatinib showed major cytogenetic molelularresponse
Wich was estimated by hiting system devised by socal and co-workers.
The blast crisis or accelerated stage has non progressed in bulk of patients.
The analysis of the survey performed ata average follow [ showed that imatinib can be used as a initial therapy for foremost diagnosed CML.
A new drug DASATINIB was developed after imatinib was conformed to demo some restrictions.
Trial conductedon DASATINIB which is a extremely powerful 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 clip.
DASATINIB will better th ongterm result among patients with freshly diagnosed chronic stage CML.
Another drug NILOTINIB and orally bioavailable derived function of IMATINIB, is a tyrosine kinase inhibitor with improved mark specificity, was developed for the intervention of CML.
This is a structurally modified imatinib drug i.e nilotinib will besides move by suppressing BCR-ABL by adhering to an inactive, DFG- out conformation of the ABLkinase sphere, therefore blocks the TKP of proteins involved in BCR-ABL signed transduction.
It has greater authority over KIT and PDGF receptor kinase. A entire responce was achieved in short clip period.
DASATINIB given to patient with CML-CP station 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 endurance rate was 95 % , over all cytogenic response was 96 % .
Apart from these drugs late new therapeutics and new drug marks are being placing developed.
Restrictions of presently available intervention:
Restrictions for the present drugs are that they ( imatinib ) does n’t maintain many patients from finally traveling into the disease subsequently, more terrible phase, and certain cells that set events in gesture towards CML are able to defy the drug are non known.
A biochemical abnormalcy like hyperbilirbinemia followed by transeunt lifts in ALT, AST and serum lipase was seen in intervention with the drug nilotinib.
It does non hold activity against marks such as the SVC-family of tyrosine kinase.
Another restriction of imatinib is that it is non known why it is non able to eliminate the malignant ringer.
Imatinib can non wholly suppress BCR-ABL kinase activity.
Another restrictions of all the drugs used in intervention were side effects each and every drug show side effects this makes to believe to prefer which drug is effectual for the intervention of CML.
These side effects may be sickness, purging, diarrhea, breast expansion may happen in little figure of males, skin roseolas, mild anaemia, adult females with preganancy who take imatinib may develop complications in the faetus.
About nilotinib, taking the medicine with nutrient can take to inordinate sums of the drug in the blood stream and is non recommended.rashes may look, alterations in bosom beat known as QT protraction.
With interferon there may be few side effects like chil febrility, and grippes like symptoms may look.
NOVEL DRUG TARGETS:
Introduction of 2nd coevals thyrokinase suppression re establisher response in about half of the patients who are having the bing drugs will demo some betterment.
Understanding the mechanisms of TKI induced programmed cell death in CML cells which helps in modulating the programmed cell death by extracellular factors. This was inhibited by protein synthesis suppression in bothK 562 and CML CD 34+ cells.
Mutants in the kinase sphere ( KD ) of Bcr-Abl that impain drug binding as major mechanism of acquired drug opposition.
Wnt proteins ( glycoprotiens ) bind to the frizzed receptors and LRP5/6 co-receptors.
By stabilising the critical go-between B-catonin plays a function in cell proliferation and distinction.
These became the new marks in the intervention of CML
MToR a fresh bifunctional mark.
Digestion of growing inhibitory and VEGF- suppressive effects of rapamycin.
Polo like kinase ( PIK-1 ) as a fresh drug mark which plays a indispensable function in mitosis. Expressed in phosphorylated signifier in CML cell line K562 and protein in CML cells hushing PLK will take to halt of rhythm apprehension. Over composing the imatinib opposition with the PLK 1 inhibitor B12536.
NOVEL DRUG THERAPIES:
Sprycel is approved for usage merely in patients who have failed gleeve intervention which is a Bristol-myer squibb. Which act as thyrosine kinase inhibitor.
Vincristine and Orasone ( VP ) has produced remittals in 30 % of patient humor chronic CML in blast transmutation ( CML-BT ) , these will consequence production of granulocytes which are considered to be free of myclotoxicity.
P-glycoprotein mediated drug, outflow is a opposition mechanism of chronic myeloid leukemia cells to intervention with imatinib mesylate.
By decreased p-glycoprotein ( pgp ) positive leukemia cells.
Transition of Pgp by cyclosporine A restored imaitnib cytotoxicity. Pgp transition in the imatinib intervention of a patient with BCR-abl positivease
MDR1 is considered in the diverseness of opposition development to imaitnib intervention.
Combined ABl inhibitor therapy for minimising drug opposition in chronicML, src/abl inhibitor with imatinib will get the better of the opposition.
The BVR-adl cistron look as tyrosine kinase was discovered in 1986 by a squad led by nobel laureate David Baltimore.
Alternative for bone marrow organ transplant with odd giver tissue is having a graft that uses umbilical cord blood which is rich in root cells.
Biological therapy: additions unsusceptibility power by interferon.
Brotezomib induces programmed cell death in crude chronic myeloid leukaemia cells including LTC-K and NOD/SCID repopulating cells.
Brotezomib is antiproliferative and induces programmed cell death in chronic stage, marks primitive CML cells, which effects CD 34+38- longterm civilization initiating ( LTC-X ) and non corpulent diabetic/sugar combind immunodificient ( NOD/SCID ) repopulating cells.
This proves that bortezomib is effertive in immune and advanced disease
Autologous cytokine induced slayer cells ( CIK ) for CML patient on standard drug therapy.
Multi mark 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 aiming activity written text factor 3 by galectin 9 induces programmed cell death and overcomes assorted types of intervention opposition in chronic myelogenous leukaemia.
Consecutive intervention with flavoliridol synergistically enhances phyrolol-1,5-benzoxazepine induced programmed cell death in human chronic myeloid leukemia cells including those immune to imaitnib intervention which showed synergic enhancement opoptosis in CML cells including those showing the imatinib immune T3151 mutation, flavopiridol reduced the figure of polyploidy cells formed in response to PBox intervention.
Critical appraisal of new intervention:
The present intervention of CML shows much advanced and is still germinating in assorted facets. The intervention with assorted drugs in the early phases of the disease shows betterment of life. A combinable drug therapy besides shown better consequences, in the early phase of drug development. Present intervention with individual drug besides demoing a varied difference in intervention which shows frogmans path of marks for the disease. Present interventions are making the demands of patients with this disease by bettering their unsusceptibility by biological therapy, diminishing the count of lympho blasts and proliferation of the lymphocytic cells.
There is a demand of farther research in mechanism of the disease in which the action of the thirosine kinase which plays a major function in development of the disease. Identifying the assorted factors of the symptoms of the disease will foster aid in development of new drugs.
Chronic myeloid leukaemia ( CML ) is a myeloproliferative upset characterized by clonal enlargement of pleuripotent hematopoetic root cells. The incidence of CML is 1 to 2 instances per 100,000 people per twelvemonth ; in the Western Hemisphere, CML accounts for 15 % of leukaemia in grownups. Discovery of the specific karyotypic abnormalcy of the Philadelphia ( Ph ) chromosome in the pathogenesis of CML has led to a better apprehension of the disease and hence to an promotion of targeted therapeutics. Availability of imatinib as an recognized targeted therapy in freshly diagnosed patients has changed the intervention paradigm in CML. The bulk of CML patients in chronic stage accomplish first-class and lasting responses with standard-dose imatinib. Mechanisms of primary and secondary opposition to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical usage. It is of import that at any clip the CML intervention and response remain optimum and therefore patients on imatinib require uninterrupted monitoring for early sensing of opposition. This reappraisal will discourse the intervention and guidelines for supervising CML patients in the imatinib epoch.