Review on Pathophysiological and Pharmacotherapeutic approach on Chronic Myeloid Leukemia

 

Kiranmai Gudimetla1*, Orsu Prabhakar2, Abhisek Pal1

1GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad, Telangana.

2GITAM Institute of Pharmacy, GITAM Deemed to be University, Visakhapatnam, Andhra Pradesh.

*Corresponding Author E-mail: kiranmai.gudimetla@gitam.edu

 

ABSTRACT:

Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell malignant clonal disorder resulting in elevation of erythroid cells and platelets in peripheral blood and clear myeloid hyperplasia in the bone marrow. Philadelphia (Ph) chromosome detection forms the major diagnosis in CML. It displays the translocation t(9; 22) that generates the oncogene bcr/abl. Constitutive tyrosine kinase activity is been exhibited by the oncoprotein (BCR/ABL) which supports growth and continued existence in cells of CML. Incidence remains almost constant worldwide and it is the most commonest in India majorly in adults. Clinically, Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) are the three phases of CML. The drugs used in the treatment of CML are known as Tyrosine Kinase Inhibitors (TKI’S). The primary drug which directly target BCR-ABL tyrosine kinase activity was Imatinib. Imatinib resistance is the major drawback of this drug due to mutations. Imatinib binding is prevented by BCR-ABL kinase domain mutations, BCR-ABL gene amplification or over-expression, clonal progression, and reduced bioavailability of imatinib or cell exposure. Stem cell transplantation is the only curative approach till date. In patients who cannot undergo transplantation, the BCR-ABL tyrosine kinase inhibitor STI571 (Gleevec, Imatinib), immune therapy or interferon-alpha and other cytoprotective drugs are used. Currently available data shows that Imatinib is a better compound compared to second line drugs in producing complete molecular and cytogenetic responses. The resistance against STI571 has been reported which has to be tested with mutational analysis for the treatment for using an accurate regimen. Current researchers are consequently challenging to inhibit or work against STI571 resistance by the development of new molecules or combination of molecules contributing for further improvement in the treatment of CML and for better understanding of resistant mechanisms. These strategies, whether will guide to curative treatment in CML in the future remains unclear.

 

KEYWORDS: Chronic Myeloid Leukemia, Tyrosine Kinase Inhibitors, Imatinib, BCR-ABL Onco-protein, Stem Cell Transplantation.

 

 


PURPOSE OF REVIEW:

The introduction of Imatinib has transformed the treatment of CML. In early chronic phase CML patients, depending on the good tolerability and response rates shown it has been developed as the standard first-line therapy. Currently approved for use in chronic-phase (CP) disease are only four agents.

 

The selection of drug has been rendered more difficult due to the drug resistance which may be due to point mutations or other changes. The recent advances in the therapy and the selection of a first-line agent among the available TKI’s are reviewed here.

 

INTRODUCTION:

Chronic Myeloid Leukemia (CML) is the most common myelo proliferative neoplasm with an incidence of 10-20 cases per million in a year. It initiates from pluripotent stem cell which gives rise to myeloid and lymphoid cells. Philadelphia (Ph) chromosome (Fig:1) detection forms the major diagnosis in CML. The Philadelphia chromosome (Ph) was developed by the reciprocal translocation t(9; 22) (q34; q11) and was first identified in 1960 in a patient with CML1. Translocation of the proto-oncogene tyrosine-protein kinase (ABL1) gene located on chromosome 9 to the breakpoint cluster region (BCR) gene located on chromosome 22 results in a BCR-ABL1 fusion gene on the Philadelphia chromosome2. The molecular consequence of the Ph chromosome is the generation of the BCR ABL oncogene which encodes for the chimeric BCR-ABL oncoprotein, which promotes the growth of leukemic cells with constitutive kinase activity3.

 

Fig 1: Formation of Philadelphia Chromosome

 

Molecular Mechanisms:

The BCR-ABL Tyrosine Kinase activity has proved to have a profound effect on characteristic changes of CML from its molecular pathogenesis and also the signaling pathways. The major functions of malignant cells are uncontrolled proliferation, decreased apoptosis, and activation of anti-apoptotic molecules which forms the major targets for therapy. Increased cell proliferation in CML is through RAS pathway activation and decreased apoptosis is through STAT5 pathway activation, inhibition of the pro-apoptotic molecule is through BAD via AKT, due to deregulation of cell adhesion, with premature release into the circulation of immature myeloid cells (CRKL effect), angiogenesis changes and increased instability of genome are the major changes related with CML progression (Fig: 2)4. Incidence remains almost constant worldwide and it is the most common leukemia in India among adults. An annual incidence of CML is 1.6 cases per one lakh inhabitants in a year, with a slight high proportion in males, and the medium age at appearance is 55 years. In 20 years aged patients very-few cases had been recorded and may be less than 20%5. Higher incidence of CML is seen in survivors during atomic bomb attack and patients treated with radiation therapy for malignancies. The different pathways associated with BCR-ABL signal transduction are the RAS pathway, mitogen activated protein kinase pathway, phosphatidyl-inositol-3kinase pathway, and extracellular signal regulated kinase pathway, signal transduction and activator of transcription 5 and kB nuclear factor pathway6.

 

SRC Kinase Family:

Cell growth regulation is contributed by the family of proteins in SRC kinase. Receptors involved in this pathway are such as SRC, YES, FYN, YRK, BLK, HCK, LYN and LCK are the homologous intracellular receptors7. There are proteins that are phosphorylated by HCK, LYN and FYN kinases (SRC family) which phosphorylate SH3-SH2 regions of BCR-ABL containing multiple tyrosine residues, thereby increasing their activity. Imatinib resistance during progression of CML is also due to LYN and HCK over expressions and sometimes may also due to activation of LYN and HCK8.

 

Fig 2: Molecular mechanisms in BCR-ABL protein

 

Chronic, accelerated and blast crisis are the three different phases of CML. In blast phase of CML the leukemic clone progressively loses its ability to differentiate9. Below 10% blasts are immature white blood cells, which can be seen in blood and bone marrow in the chronic phase which last for several years. In chronic phase of CML about 90% of people have been diagnosed with blasts. Because of mutations in the CML cells and additional DNA damage in accelerated phase most patients will have blasts in both the blood and bone marrow up to 10-19%. Basophils in the peripheral blood may be more than 20% which may have changes in the Philadelphia chromosome in addition to the new cytogenetic changes. Targeted therapy, chemotherapy, and immunotherapy are the available systemic therapies for CML. A person may receive only one type of therapy at a time or a combination of systemic therapies given at the same time.

 

Targeted therapy blocks proliferation of cancer cells and their growth while restricting damage to healthy cells. The major targets of targeted therapy in cancer treatment are particular genes, tissue or the proteins that are related to growth of cancer cells. Monoclonal antibodies are the drugs used in targeted therapy, generally which are administered orally. The unique protein called the BCR-ABL tyrosine kinase enzyme is the major target for CML. The drugs, tyrosine kinase inhibitors targets BCR-ABL. Chemotherapy uses anti-cancer (cytotoxic) drugs to damage leukemia cells by disrupting the growth and proliferation. Chemotherapy is only occasionally used for CML. The drug therapy that activates the immune system is immunotherapy. The immune system naturally synthesizes interferons. Interferons can also be synthesized in-vitro. The growth and division of cancer cells can be reduced by interferons. Interferons are used as the first line treatment for the patients prior to the introduction of tyrosine kinase inhibitors in patients who could not receive allogeneic stem cell transplantation. Currently TKIs are more effective due to their affinity and efficacy and they have fewer side effects and so are preferred than interferon in the treatment of CML. Immunotherapy is now an option for those patients who cannot withstand the side effects of TKI therapy.

 

Clinical Presentation and Diagnosis:

Chronic phase (CP), Accelerated phase (AP) and Blast phase (BP) are the three different phases of CML. The clinical symptoms are not specific to any of the three phases and include fever, fatigue, bone pain, night sweats, weight loss, splenomegaly, thrombocytopenia, functional neutropenia in which patients are at high risk of bacterial and fungal infections with normal absolute neutrophil counts and may have neutrophils functioning abnormally and also high risk of bleeding because of thrombocytopenia10. Markers commonly used in laboratory include leukocytosis, with relative thrombocytopenia and anemia. WBC counts will be greater than 100,000 μL in CML patients. In the Accelerated Phase or Blast Phase of the disease symptomatic manifestations occur most frequently11, and hyper viscosity with symptoms of final organ failure may be shown by patients12 which is a rare presentation involving any organ in addition to soft tissues, bones, liver and eyes. It is termed as extramedullary blast crisis13-14.

 

Diagnosis:

Complete Blood Picture, Aspiration of Bone Marrow, Biopsy and Cytogenetic Analysis are the major diagnostic tests in CML. FISH (Fluorescence In Situ Hybridization) is a more sensitive method for detecting the presence of BCR-ABL gene than the standard cytogenetic tests.

 

Initial Treatment of Chronic Phase CML:

The treatment of choice for eligible patients is allogeneic stem cell transplant (alloSCT) which achieved a durable disease-free survival of 50–85% in patients approximately due to a graft versus leukemia effect15. Treatment related mortality of 5–20% can be seen in many long-term survivors and significant morbidity has been associated due to its exceptional toxicity profile, mainly opportunistic infections due to immune suppression in graft versus host disease. Now-a-days allogeneic stem cell transplant is now preferred in patients if failure of treatment with TKI’s is observed and in advanced stage of CML.

 

Primary Management of Chronic Phase of CML:

The standard primary treatment of CML includes Imatinib, Dasatinib, Nilotinib and Bosutinib. These are commercially available TKIs. In the first stage of CML that is Chronic Phase imatinib 400–800mg a day, nilotinib 300mg twice daily or dasatinib 100mg daily forms the major options. Selection of TKI is supposed to be based on phase of CML, goals of the treatment, age, side effects and also the comorbidities. The adverse drug event profile of the existing drugs should not be taken into consideration. Overall survival after five years is 85%–95% with all the TKIs. The endurance difference between first line drug imatinib and second generation TKIs are not significant.

 

Kinase Inhibitors:

Imatinib is the drug that directly targets the BCR-ABL tyrosine kinase. It is a small-molecule which is the first tyrosine kinase enzyme inhibitor16. Depending on the pharmacological response and the excellent acceptability shown, it is used as the first-line standard drug for patients in beginning stages of first phase i.e, chronic phase17. The proposed pre-treatment predictor for the access of imatinib entry into the cell is organic cation transporter-1 [OCT-1] expression. The measurement of OCT-1 and its corresponding RNA expression is higher in superior survival of patients treated with imatinib18. Recent research results confirm that, heterogeneity of tumor according to different molecular and cellular targets resulted in failure of numerous cases of targeted therapy. In recent nanoparticle-based research, the use of nanoparticles in diagnostic and therapeutic applications of cancer has gained the momentum19. Targeting molecules downstream of BCR-ABL is an alternative approach for the therapy.

 

Imatinib Resistance and Second-line Treatment:

Mutations of BCR-ABL kinase domain inhibiting imatinib binding, progression of clones, intensification of BCR-ABL or excess of expression and reduced imatinib mesylate bioavailability or exposure of the cell are different pathophysiologic mechanisms for imatinib resistance (Fig:3). In imatinib resistance T315I, Y253F/H, and E255K/V are the major mutations and also clonal evolution are the most important mechanisms20. Patients failing Imatinib therapy in chronic myeloid leukemia due to mutations have been reported are 36% to 55.7%21. Mutation frequency ranged in between 27%-55%, 50% -59.2% and 47.6-79.4% in chronic, accelerated and blast phases respectively22.

 

Fig 3: Resistance mechanisms by imatinib

 

Imatinib resistance may be of two types primary and secondary. In primary resistance, the patient does not respond to the treatment, whereas response is exhibited by the patient initially in secondary resistance, and later reversion occurs. The mechanisms of resistance are independent of BCR-ABL protein. Point mutations and sequence amplification in ABL molecule are dependent on BCR-ABL molecule because of which imatinib bonds are impeded due to its conformational changes23. Major reasons for primary imatinib resistance are poor OCT-1 cell transporter activity and the expression of P-glycoprotein which affects the efflux of drug24. Alpha-1 acid glycoprotein (AGP) binding of imatinib25, decreases its activity and stimulation of other signaling pathways26. Point mutations are the mainly frequent cause of secondary resistance in nearly 35% - 70% of long-sufferings in oncogene of BCR-ABL27. Second-generation TKI were developed to treat imatinib resistant or intolerable patients. In AP-CML the optimal therapeutic approach alters depending on whether the patient is TKI-naive or has developed beginning of chronic phase though taking a TKI. Cell cytogenetic response has been achieved by treatment-naïve patients up to eighty to ninety percent28. The major options of therapy are using a tyrosine kinase inhibitor or allogeneic stem cell transplant.

Second-Generation Tyrosine Kinase Inhibitors:

Dasatinib:

It has a strong inhibitory action against active BCR-ABL conformation except for the T315I mutation, the SRC and ABL kinases and most of the mutant forms. It is a piperizinyl derivative29. The commonly encountered adverse events are myelotoxicity, neutropenia and thrombocytopenia 21%, 19% and 10% respectively. Non-hematologic adverse effects include pleural effusion, diarrhoea, rash, and headache 10%, 17%, 11%, 12% respectively30. At the once daily dose studies show similar response rates in relation to pleural effusion31.

 

Nilotinib:

It is an amilopyrimidine derivative further potent and selective than imatinib, inhibits tyrosine kinase activity except for the T315I mutation and BCR-ABL, PDGF, c-kit. Majority of the altered forms of ABL can be inhibited by Nilotinib32-37. Hypophosphatemia, elevated lipase, hyperglycemia and elevated total bilirubin 16%, 17%, 12% and 8% respectively are the most common laboratory abnormalities and it is well tolerated by the patients. Neutropenia (31%), thrombocytopenia (31%), and anemia (10%), pleural or pericardial effusion are major hematological changes which occurred in less than 1%38.

 

Bosutinib:

SRC family kinases can be inhibited as well as Src, Lyn and Hck by bosutinib. Platelet derived growth factor and vascular endothelial growth factor receptors has also revealed activity against bosutinib. It is an inhibitor of ATP competitive BCR-ABL tyrosine kinase. In murine myeloid cell lines expression, 16 out of 18 imatinib-resistant forms of Bcr-Abl are been inhibited except T315I and V299L mutant forms by bosutinib39.

 

Ponatinib:

Ponatinib is a multi-targeted tyrosine-kinase inhibitor and the only TKI against ABL1 in mutations of T315I and of elevated potency. T315I mutation is resistant to current therapies such as imatinib also. In the therapy of different types of tumors, Ponatinib is very effective.

 

Omacetaxine:

It is a non-tyrosine kinase protein-synthesis inhibitor, and in patients with T315I mutation it is very active. It is given by parenteral route in a cycle of 28 days and 14 days that is FDA approved for patients who have failed ≥2 TKIs.

 

Blast Phase CML:

When central nervous system is involved, Imatinib is inadequate as it does not cross blood brain barrier40. Higher rate of cell cytogenetic response in MBP (26%) and LBP (46%), is achieved with dasatinib 140mg once daily, but responses are temporary, with a <12mo for MBP and <6mo for LBP of median survivility41.

Dasatinib is a highly lipophilic drug that crosses the blood-brain barrier. But, for prophylaxis of diseases related to brain and spinal cord that is central nervous system, regular treatment that is systemic chemotherapy, intrathecal chemotherapy, and radiotherapy should be given. Nilotinib 400mg BID is not approved for this indication as it is related with poor results when compared to dasatinib42. Ponatinib is associated with positive response in profoundly pre-treated patients, with T315I mutations. Bosutinib is used for blast phase which is also accepted and may induce mean cytogenetic response and hematologic response 37% and 28% respectively43.

 

The Stop Imatinib which is also known as STIM, trial investigated the hazard of reversion in patients on imatinib mesylate where the patients have shown complete molecular response for more than two years and have withdrawn the treatment. For evidence of molecular relapse, hundred patients had a center follow-up of nearly 50 months and were examined closely in the most recent update. Within 7 months of stopping imatinib, molecular relapse overall 61% and events occurring 95% has been experienced44. With nilotinib, 48 weeks after stopping, 51.6% that is 98 patients remained in primary endpoint or MMR45.

 

For trying a precise inhibitor of tyrosine kinase in patients with CML the presence of the Philadelphia chromosome or BCR-ABL fusion protein, the tyrosine kinase activity forms the major principle in the treatment.

 

RECENT FINDINGS:

The toxicity profiles and potency of complete report on of seminal trials have shown the long-standing usefulness of Tyrosine Kinase Inhibitors and their considerable differences in their therapeutic efficacy. The deeper molecular responses are generated by dasatinib and nilotinib predominantly in the midst of patients with complexity of the disease than imatinib. At one year with bosutinib similar results have been obtained. Bosutinib at a dose of 400mg daily well balanced in the efficacy and toxicity profile prompting the recent approval. Numerous studies have confirmed that Kinase inhibitors can be carefully discontinued in patients with deep responses for extended periods. In CP CML achievement of treatment-free remission is an ideal goal.

 

CONCLUSION:

The development of an extremely efficient targeted therapy with enhanced understanding of CML history revolutionized the treatment of CML. CP patients now-a-days have an extended predictable endurance with imatinib, unlike 15 years ago. Second-generation TKI’s are effective when imatinib resistance occurs. Even second generation TKI’s are not successful in patients because of point mutations or any other mechanisms. Majorly T315I mutation is a big confront in the treatment. For patients who develop intolerance or resistance because of imatinib, clinical decisions related with the treatment should be taken into account after performing mutation analysis. Early diagnosis and appropriate treatment with suitable initial dosing is essential so that resistance can be prevented. Therapeutic strategies such as dose acceleration and combination therapy are done to manage the resistance to achieve individual optimal levels. The consideration of each patient’s exclusive  co -morbidities and preferences on the basis of different parameters like disease complexity, potency, efficacy and toxicity profile of each one of the TKI, enables accurate individualized therapeutic management in chronic phase CML. The development of new molecules or combination of molecules contributes to the further improvement in the treatment of CML and for better understanding of resistant mechanisms.

 

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Received on 05.09.2019            Modified on 13.10.2019

Accepted on 17.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6): 2971-2976.

DOI: 10.5958/0974-360X.2020.00526.0