Chronic Myeloid Leukaemia



Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterised by anaemia, leucocytosis and splenomegaly. The natural history of CML is characterised by three phases chronic phase, accelerated phase (AP) and blast phase (BP). CML is characterised by the presence of fusion gene BCR-ABL1 that results from the t(9;22) translocation. This gene encodes for a constitutionally active tyrosine kinase that has been shown to drive the CML stem cells. The diagnosis of CML can not be made in the absence of this gene.  Onset of AP signals a change in the biological behaviour of disease. The disease follows a more agressive course that culminates in blast phase. The blast phase mresembles an acute leukaemia and is a terminal event in the natural history of CML. Inhibitors of BCR-ABL1 prevent the emergence of accelerated and blast phase and have dramatically improved the outcome of CML.

Etiology and Epidemiology

CML constitutes about 15% of all leukaemias. The incidence increase with age and the disease is slightly more common in males. The incidence of the disease does not show geographic variation. The only know etiological factor for CML is exposure to radiation.

Pathogenesis

CML is characterised by the presence of Philedelphia chromosome [t(9;22)(q34;q11)] which results from a reciprocal translocation between the long arms of chromosomes 9 and 22 (figure 1). The ABL1 proto-oncogene is located on chromosome 9 at q34. Chromosome 22 has the BCR gene at 22q11. The ABL1 gene translocates downstream to the BCR gene as a result of the t(9;22)(q34;q11) translocation. This results in the formation of the BCR-ABL1 fusion gene (see The BCR-ABL1 Gene).

Molecular Biology of CML

 

The expression of the ABL1 tyrosine kinase is tightly regulated. The t(9;22)(q34;q11) results in the N terminal segment of the ABL1 gene being replaced by that of the  BCR gene. This results in the ABL1 tyrosine kinase being constitutively expressed. The size of the N terminal amino acids contributed by BCR determine the length and the clinical properties of the fusion gene.

A model of pathogenesis of CML has to account for three features of the disease

  1. Uncontrolled proliferation of leucocytes accompanied sometimes with the proliferation of platelets
  2. Progression from a relatively stable phase of proliferation, the chronic phase, to a agressive  phase charecterized by increasing leucocytes counts, anaemia and falling platelet counts ultimately culminating in a acute leukaemia like picture, the blast phase. Unlike the chronic phase that shows myeloid and sometimes platelet proliferation, the blast phase may show a myeloid, lymphoid or rarely megakaryocytic lineage.
  3. Failure of tyrosine kinase inhibitors to errdicate the malignant clone despite pronounced and prolonged supression of the BCR-ABL1 positive clone.

The precise mechanism how BCR-ABL1 leads to chronic myeloid leukaemia is not known. Activation of phosphatidylinositol kinase (PI3K), RAS/Mitogen activated protein kinase (RAS/MAPK) and JAK/STAT pathway has been demonstrated in BCR-ABL1 positive cells. These pathways have been implicated in malignant transformation of cells and are believed to be responsible for the malignant phenotype of CML. Progression of CML from chronic phase to accelerated phase and eventually blast phase marks change in the disease that makes it progressively less responsive to drugs inhibiting BCR-ABL1 kinase. Cells with BCR-ABL1 fusion gene have an increase in the reactive oxygen species predisposing them to DNA damage. Progression from chronic phase to acclerated phase and eventually blast phase is associated with the cell accquiring additional mutations. This is known as clonal evolution. Reactive oxygen species induced DNA damage is believed to result in clonal evolution which results in progression to accelerated phase and blast phase resulting in treatment failure.

CML Pathogenesis-600px

Imatinib, an inhibiter of ABL1 tyrosine kinase has been in use for over a decade. Treatment of CML patients with Imatinib results in normalisation of blood counts, regression of splenomegaly and a decrease in the number of cells showing BCR-ABL1 fusion gene. The BCR-ABL1 kinase expressing cells are suppresses to undetectable levels in about 40% of the patients creating an impression that disease has been eradicated. If treatment is discontinued in such patients cells expressing BCR-ABL1 fusion reappear in 50-60% of such patients. These observations have been interpreted as suggesting that the CML stem cells have mechanisms that survive inhibition by Imatinib and other inhibitors of ABL1 tyrosine kinase. Studies to identify and target these pathways to erradicate CML stem cells with an goal to curing CML are undertaken. Some of the pathways that have shown a promise are Alox5pathway, the sonic hedgehog pathway (SHH), the Wnt/β-catenin pathway, the JAK/STAT pathway, the TGF-Beta/FOXO/BCL-6 pathway (Stem Cells International Volume 2013 (2013),  Article ID 724360, 12 pages)

Clinical Manifestations

Presentations

The manifestation of CML included

  1. Anaemia
  2. Fatigue, weight loss, fever, night sweats because of a hyper metabolic state induces by high leucocyte counts
  3. Bone pain
  4. Abdominal pain, early satiety and fullness because of splenomegaly. The pain is usually a tugging pain but sharp pain may indicate a splenic infarct. Splenic rupture though described is a rare event.
  5. Leucostasis because of very high white blood cell counts may present with neurological deficits, respiratory insufficiency or priapism.
  6. Incidental discovery for a haemogram performed for another reason is becoming a common presentation in populations that have a good healthcare system.

Splenomegaly is commonly seen. Historically CML is associated with massive splenomegaly (splenomegaly below the umbilicus). Today this may be seen only in communities with suboptimal health care and diagnosis is delayed. Hepatomegaly may be seen in some patients.

CML-Phases

Stages of Disease

CML has three stages, chronic Phase, accelerated phase and blast phase. Before the introduction of definitive therapy (Initially interferon, currently inhibitors of BCR-ABL1 kinase) every patient progressed from chronic phase to accelerated phase and finally to blast phase. The blast phase was terminal. The WHO definitions of the phases are listed in table 1. Acclerated phase definition is defined differently by different authors. Definitions may differ in the details but recognise the following

  1. Increasing WBC counts with appearance of new anomalies. These may be basophilia, eosinophilia or increase in the immature forms particularly blasts and promyelocytes. Progression of patients on BCR-ABL1 kinase inhibitors is accompanied by appearance mutations in BCR-ABL1.
  2. Increasing splenomegaly

The TKIs have dramatically reduced the rate of progression to accelerated phase or blast crisis. 4.6% for Dasatinib (DASSISION trial 5 year follow up), 3.5% for nilotinib (ENESTnd)and 8% imatinob (IRIS trial 8 Year follow up). Patients who do not achieve an early response to TKIs have a higher risk of progression.

Investigation

Haemogram

A complete haemogram should be performed in all patients. Patients of CML have leucocytosis with shift to the left and often have eosinophilia and/or basophilia. Platelet counts are often slightly increased but may be normal high or occasionally low. There is mild to moderate anaemia. The differential count of peripheral blood depends on the phase of disease. Patients with chronic phase have <10% blasts and ≤ 20% basophilis. Patients with accelerated phase have 10-19% blasts or >20% basophilic. Patients with blast crisis have ≥20% blasts.

Bone Marrow

Bone marrow studies are not needed for diagnosis of CML. This can be made by demonstration of BCR-ABL1 on peripheral blood. Bone marrow studies are essential for determining the phase of disease. The bone marrow of a patients of chronic phase of CML shows a high myeloid to erythroid ratio with a normal myeloid maturation. Dysplasia is not a feature of CML and suggests the diagnosis of myeloproliferative disease/mydlodysplasia overlap.  The chronic phase is characterised by <10% blasts. The megakaryocytes are smaller with reduced lobulation and may be increased in number. Bone marrow of patients from accelerated phase show myeloid hyperplasia with myelodysplasia and a blast percentage between 10-19%. Megakaryocytes may be seen in clusters or sheets. Bone marrow from patients with blast phase shows ≥20% blasts.

Risk Scores

Risk scores help in prognosticating the patients and should be performed at diagnosis. The three scores are listed in table 2. Hasford and Sokal scores are prognostic scores for predicting outcomes of CML patients. The  EUTOS score was developed to predict the outcome of patients receiving imatinib at 18 months of therapy and was reported to perform better than Sokal and Hasford scores. It has not been validated by other investigators.

CML Prognostic Scores

Table 2. CML Prognostic (Risk) Scores

 

Treatment

The approval of imatinib in May 2001 by the US FDA saw CML become the first disease to benefit from targeted therapy. The 8 year survival of patients in chronic phase has improved from 6% in 1975 to 42%-65% from 1983-2000 and 87% for patients diagnosed after 2001 (Blood 119:1981-87;2012). Before the introduction of imatinib the treatments used for patients of CML included (in chronological order) splenic radiation, arsenic, busulfan, hydrourea and a combination of interferon and cytarabine. With the exception of interferon and cytarabine none of the other therapies suppress the BCR-ABL1 positive clone.  The IRIS trial established imatinib, an inhibitor of BCR-ABL1 tyrosine kinase as the first line treatment for chronic myeloid leukaemia. DASSISION trial and the ENESTen trials established dasatinib and nilotinib as front line therapy.
 The aims of therapy is prevent progression of disease to accelerated phase and blast phase. This can be achieved by
  1. Inducing a haematological remission
  2. Inducing a molecular remission
  3. Eradicating the CML stem cell

Tyrosine kinase inhibitors (TKIs) are the first line of treatment in all patients of CML. The use of imatinib in pregnancy is associated with increase in malformations. These include malformations of the skeleton, respiratory system, kidney and gastrointestinal the gastrointestinal tract. The risk of exompholous is increased by almost 1000 times. Imatinib and other TKIs are contraindicated in pregnancy. The treatment of pregnant woman is challenging. Interferon may be used after the period of organogenesis. Women who have not completed their family are encouraged to do so early and should be switched to TKI. Women in the childbearing age on TKI should be made to understand that contraception is mandatory.

Tyrosine Kinase Inhibitors (TKI)

Many inhibitors of BCR-ABL1 tyrosine kinase have been developed. Out of these imatinib, dasatinib and nilotinib are approved for use in the first line setting. Dasatinib and nilotinib can be used for patients who relapse on imatinib. Busotinib and ponatinib are approved for use relapsed CML. The TKIs drugs used in CML are listed in the table below.

 Dose Indications Adverse Effects
Imatinib
  1. Chronic Phase CML: 400mg
  2. CML AP/BP: 400mg od the doses may be increased to 600mg-800mg/day. The 800mg dose is administered in two daily doses
  3. Ph+ALL: 600mg od
  4. PDGFRA mutated MDS/MPD: 400mg/day
  5. GIST: 400mg/day
  6. HES/CEL: 400mg od
  1.  CML First line therapy for chronic, accelerated and blast phase
  2. Ph+ve ALL
  3. Gastrointestinal stromal tumour
  4. MDS/MPD with PDGFA gene rearrangements
  5. Hypereosainophilic syndrome/chronic eosinophilic leukaemia
  1. Skin depigmentation
  2. Nausea, vomiting
  3. Periorbital oedema
  4. Fluid retention manifesting as effusions and oedema
  5. Myalgias
  6. Diarrhoea
  7. Insomnia, deprtesson
Dasatinib
  1. Chronic Phase: 100mg od
  2. Accelerated and blast phase: 140mg od
  1. CML first line and second line therapy
  2. Ph+ve ALL resistance or intolerance to prior tyrosine kinase therapy
  1. Myelosupression
  2. Bleeding
  3. Fliud retention manifestion as oedema and pleural effusion
  4. Diarrhoea, nauseas vomiting
  5. Fatigue
  6. Insomnia, depression
  7. Elevated transaminases
  8. Hypocalcaemia, hypophosphataemia
  9. QTc prolongation
Nilotinib
  1. CML Chronic Phase 300mg bd
  2. CML chronic phase resistant/intolerant to other TKIs: 400mg bd
  3. AP/BC: 400mg bd
CML first line and second line therapy

 

  1. Myelosupression
  2. Fatigue, asthenia, anorexia
  3. Prolonged QTc
  4. Electrolyte anomalies – hypophosphatemia, hypokalemia, hypocalcaemia, hyponatraemia
  5. Elevated transaminases
Bosutinib
  1. CML chronic phase: 500 mg orally once daily with food. Escalation to 600 mg daily in patients who do not respond.
  2. Dose in Hepatic impairment: Reduce 200 mg daily
CML failure or intolerance to firstling therapy
  1. Diarrhoea
  2. Nausea/vomiting
  3. Abdominal pain
  4. Myelosupression
  5. Skin rash
  6. Elevated Transaminases
  7. Fliud retention manifestion as oedema and pleural effusion
  8. Fatigue
Ponatinib
45mg reduce dose to 30mg in patients taking strong CYP3A inhibitors
  1. CML first line and second line therapy
  2. Ph+ve ALL resistance or intolerance to prior tyrosine kinase therapy
  3. The only TKI active against the T315I BCR-ABL1 mutation
  1. Arterterial thrombosis including myocardial infraction. Toxicity may be seen in up to 10% of the patients
  2. Cardiac toxicity – arrhythmias, pericardial effusions
  3. Elevated transaminases,  liver failure
  4. Pancrititis
  5. Hypertension
  6. Fluid retention,
  7. Gastrointestinal perforation
  8. Tumour lysis syndrome
Omacetaxine (Non TKI, inhibitor of protein synthesis)
 1.25mg/m2 SC bd for 14 consecutive days every 28 days till haematological response. Continue as 1.25mg/m2 sc bd for seven days every 28 days after as maintenance CML chronic or acclerated phase resistant to two more TKI
  1. Myelosupression – thrombocytopenia, neutropenia and anaemia
  2. Impaired glucose tolerance with hyperglycaemia in upto 11%
  3. Diarrhoea, nausea, vomiting abdominal pain
  4. Fatigue asthenia, arthralgia peripheral oedema
  5. Injection site reactions

A newly diagnosed patients should be initiated on treatment with Imatinib (400mg od), dasatinib (100mg od)  or nilotinib (300mg bd). Dasatinib and nilotinib. Busotinib and  ponatinib can be used in patients progressing on these the first line drugs. Ponatinib is indicated in the T315I mutations. Patients carrying this mutation do not respond to any of the other TKI.

Monitoring Therapy

Patients are monitored for response by clinical examination, haemogram and determining the levels of the BCR-ABL1 transcript. The BCR-ABL1 transcript is measured by RT-PCR. The response definitions are given in table below

Response Definitions

Complete Haematological Response
  1. WBC counts < 10 X 109/L
  2. Platelet Count < 450 X 109/L
  3. No immature myeloid cells on the peripheral blood differential count
  4. Basophils less than 5%
  5. no splenomegaly
Cytogenetic Response
  1. Complete (CCyR) 0% Ph+
  2. Partial Cytogenic Response  (PCyR) 1-35%
  3. Major Cyogenic response 36%-65%
  4. Minor Cytogenic Response 66%-95%
  5. No Cytogenic Response >95%
Molecular Response
  1. Early molecular response (EMR) – BCR-ABL1 transcripts ≤10% by QPCR (IS) at 3 and 6 months.
  2. Major molecular response (MMR) – BCR-ABL1 transcripts 0.1% by QPCR (IS) or ≥3-log reduction in BCR-ABL1 mRNA from the standardized baseline, if QPCR (IS) is not available.
  3. Complete molecular response (CMR) – no detectable BCR-ABL mRNA by QPCR (IS) using an assay with
  4. a sensitivity of at least 4.5 logs below the standardized baseline. CMR is variably described, and is best defined by the the assay’s level of sensitivity (eg. MR 4.5).
Relapse Resistance
  1. Any sign of loss of response (defined as hematologic or cytogenetic relapse)
  2. 1-log increase in BCR-ABL transcript levels with loss of MMR (two consecutive samples to be tested)
  3. loss of CCyR

The haematological and cytogenetic milestones in the treatment of CML have been described by the NCCN and ELN.  Secondary resistance to TKIs results from point mutations. Mutations analysis of the kinase domain of ABL should be performed in case of failure to achieve or loss of a milestone. Mutations that result in resistance to the first line TKIs are characterised and mutational analysis serves as a guide to choose second line therapy. The T315I mutation imparts resistance to all TKIs except ponatinib.

The TKI treatment needs to be continued lifelong. Attempts to withdraw treatment in patients who have achieved prolonged deep molecular response have shown that the disease returns in a majority of the patients on discontinuation of treatment.

Allogenic stem cell transplant was the mainstay of treatment of CML before the introduction of TKIs. The availability of many TKIs has diminished the role of allogenic stem cell transplant. Allogenic stem cell transplant is indicated only in patients who progress on TKIs.

Prognosis

Introduction of imatinib altered the prognosis of CML by converting it form a progressive ad fatal disease to a chronic disease. The 8 year survival of CML on imatinib is 85%. Those progressing on imatinib can be treated with other TKIs.

 

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The BCR-ABL1 Gene


CML Pathogenesis-600pxBCR-ABL1 is a fusion gene formed as a result of the t(9;22)(q34;q11) chromosomal translocation, the translocation that results in the formation of the Philadelphia chromosome. The Abelson murine leukaemia viral oncogene homolog 1 (ABL1) gene from 9q34 is translocated downstream to a region at 22q11 known as breakpoint cluster (BCR). The fusion gene encodes for a constitutionally active tyrosine kinase that has been shown to drive the expression chronic myeloid leukaemia phenotype. BCR-ABL1 gene has also been on implicated in the pathogens is of acute lymphoblastic leukaemia and in rare cases of acute myeloid leukaemia. The gene has been targeted with unparalleled success by the first tyrosine kinase inhibitor approved in clinical practice, imatinib.

 Molecular Biology of BCR-ABL

The ABL1 proto-oncogene is located on chromosome 9 at q34. Chromosome 22 has the BCR gene at 22q11. The ABL1 gene translocated downstream to the BCR gene as a result of the t(9;22)(q34;q11) translocation. ABL1-BCR translocation also occurs and may express but is of no clinical significance.

 

Molecular Biology of CML

The BCR-ABL1 fusion gene and it’s variants

The breakpoint of the ABL1 gene may be upstream exon 1a, between exon 1a and 1b or downstream exon 1b but it is almost always upstream exon 2. With rare exceptions all transcripts of BCR1-ABL1 gene have exon 2-11 of the ABL1 gene. The BCR breakpoints are variable and determine the size as well as the pathogenic properties of the BCR-ABL1 gene.. The breakpoint on the BCR gene are clustered in three regions known major cluster, minor cluster and micro cluster (Table 1). Depending on the location of breakpoint  on the BCR gene three types of protein are synthesized. The p210 transcript is associated with CML and some patients with Philadelphia positive acute lymphoblastic leukaemia. The shorter p190 transcript is associated with philedelphia positive acute lymphoblastic leukaemia and some patients of chronic myeloid leukaemia. The CML that carry this mutation show monocytosis and have a more aggressive course. The p230 is the largest and the rarest of the BCR-ABL1 transcripts. It is associated with a more indolent course and is found in patients with the rare chronic neutrophilic leukaemia. Atypical transcripts e1a3, e13a3 and e6a2 have been described.

Table 1: The BCR-ABL1 fusion genes

 Major Cluster  Minor Cluster  Micro-Cluster
 Synonym M-Cluster m-cluster µ-cluster
Location exons 12-16 Between alternative exon 2, e2’ and e2 between exons e19 and e20
Protein p210 p190 p230
Associated Leukaemia  CML, e14a2 shown to have thrombocytosis in some studies., Ph+ ALL  Ph + ALL; CML that tends to have monocytosis and an agressive course  Chronic Neutrophilic Leukaemia, Small reports describing patients with a course resembling classical CML

Mutagenicity of BCR-ABL1

ABL1 is a nuclear kinase whose activity is tightly regulated by the cell. BCR-ABL1 translocation results loss of regulation and the kinase is  cosntitutively active. Sustitution of ABL1 at the N termnal by segments of the BCR gene result in the synthesis of a protein that has the capacity to dimerise. Dimerisation transphosphorylates and then aurtophsophorylates the the kinase fully activating it. The precise mechanism how BCR-ABL1 leads to chronic myeloid leukaemia is not known but activation of  phosphatidylinositol kinase, RAS/Mitogen activated protein kinase and JAK/STAT pathway has been demonstrated in BCR-ABL1 positive cells. These pathways are involved in cellular growth and differentiation. The BCR-ABL1 kinase also phosphorylates proteins involved in adhesion and migration and this may have a role in premature release of myeloid cells in circulation. CML cells have a two to sixfold increase in reactive oxygen species and have impaired DNA repair. Reactive oxygen species can induce DNA double strand breaks. The results is additional mutations and these are believed to be responsible for blast crisis and acclerates phase.

Tyrosine kinase inhibitors targeting the BCR-ABL1 protein induce a remission in most patients of CML. About half the patients who have achieved sustained complete molecular response relapse on discontinuation of the tyrosine kinase inhibitors. This suggests that the stemat least some CML stem cells are not BCR-ABL1 dependent for growth. Experimental observations support this hypothesis.

Targeting the BCR-ABL1 Gene

The BCR-ABL1 gene was the first gene to be targeted by a tyrosine kinase inhibitor, imatinib. Imatinib was followed by dasatinib, nilotinib, Busotinib and Panotinob. Imatanib, Dasatinib and Nilotinib are approved to first line use. Imatinib has resulted in a 85% 8 year survival. Dasatinib and nolitinib are active in imatinib resistant CML and are now approved for first line use. Drug resistance results from mutations in BCR-ABL1 kinase. The T315I mutation or the gatekeeper mutations impaires access of TKIs to the BCR-ABL1 kinase making most drugs inactive. Panotinib can inhibit the T315I mutation.

 

Further Reading

Barnes DJ Melo JV. Molecular Basis of Chronic Myleoid Leukaemia. In Chronic Myeloproliferative Disorders: Cytogenetic and Molecular Anomalies. Bain Barbra J (Ed) 2003.

Dasatinib


Dasatinib is a thiazole carboxamide oral multikinase inhibitor that inhibits BCR-ABL and SRC kinases that is used for the treatment of chronic myeloid leukaemia and BCR-ABL positive acute lymphoblastic leukaemia.

Mechanism of Action

The kinases inhibited by dasatinib include

  1. BCR-ABL
  2. SRC family (SRC, LCK, YES, FYN)
  3. c-KIT
  4. Epirin A receptor
  5. Platelet derived growth factor β (PDGF-β) receptors

BCR-ABL kinase inhibition
As an inhibitor of BCR-ABL kinase dasatinib is 325 times more potent than imatinib and 16 times more potent than nilotinib. Unlike imatininb and nilotinib dasatinib binds the active and the inactive configurations of the enzyme. It is effective against mutations that have destabilized the inactive configuration. Unlike imatinib chronic inhibition of the kinase in not achieved and does not appear to be necessary for action. Activity of dasatinib appears to be related to the peak levels and the side effects to the nadir. In keeping with this observation, once a day therapy with dasatinib is as effective and less toxic than the same dose administered in two daily doses. Though dasatinib targets cells that are more premature than imatinib, it has no action against the CML stem cell. Dasatinib therapy, like imatinib and nilotinib, is needed lifelong. Dasatinib is ineffective against cells carrying the T315I mutation.

Inhibition of Other Kinases
Dasatinib has immunomodulatory effects. Inhibition of PDGF-β receptors may be responsible for the chylous effusion seen with dasatinib.

Pharmacokinetics

Dasatinib is rapidly absorbed on oral administration and peak levels are achieved in 0.5-3 hours. Absorption is not affected by food. The solubility of dasatinib decreases with increasing pH.  It is highly protein bound (96%). The volume of distribution is large (2505L) indicating extensive extravascular distribution. The concentrations achieved depend on the total dose and schedule. Once a day therapy results in doubling of Cmax and halving of Cmin. Efficacy of dasatinib is related to the average concentration. The toxicity of dasatinib increases with age and with Cmin. These observations suggest that once a day therapy would be efficacious and less toxic and this is borne out in clinical trials (Haematologica. 2010; 95: 232–240). Animal studies show that dasatinib crosses the blood brain barrier and achieves therapeutic concentrations in the CSF. In patients of Ph+ve ALL the CSF levels have ranged from 5-28% of plasma levels and this has correlated with sustained responses in patients with Ph +ve CML in BC or Ph +ve ALL (Blood 2008; 112:1005-12). Dasatinib is metabolized by the liver and the metabolites are eliminated in the feces. There are no active metabolites. Only about 4% of the drug is eliminated in the urine mostly in the form of metabolites. No dose reduction is needed for liver of kidney dysfunction.

Drug Interactions

Four potential processes at that drugs can interact with dasatinib include absorption, protein binding, drug metabolism and effect of the QT interval.

  1. Dasatinib and Inhibitors of acid secretion: Famotidine decreases dasatinib exposure by 61%. H-2 antagonists and proton pump inhibitors should not be used with dasatinib. Antacids may be used but an interval of at least 2 hours must separate dasatinib and antacids.
  2. Protein Binding: Dasatinib is highly protein bound. Displacement from protein binding has the potential tom increase the dasatininb levels. No such interaction has been identified.
  3. Dasatinib Metabolism: Dasatinib is a substrate for and an inhibits CYP3A4 and dasatinib levels may be affected by inhibitors and inducers of CYP3A4.
    1. Inhibitors of CYP3A4: Ketoconazole may increase the exposure to dasatinib. Other drugs that may show a similar effects include iraconazole, voraconazole, verapamil, erythromycin, clarythromycin and cyclosporine.
    2. Inducers of CYP3A4: Rifampicin induces CYP3A4 and reduces exposure to dasatinib by  80%.  Phenobarbital, phenytoin, carbamazepine are expected to have the same effect.
  4. Drugs prolonging QT interval: Dasatinib prolongs the QT interval and should be used with caution with other agents that prolong QT.
  5. Others: Dasatinib increases the simvastatin by about 20%

Adverse Effects

  1. Myelosupression: Myelosupression manifests as neutropenia and /or thrombocytopenia and is more frequent in patients with advanced CML or acute lymphoblastic leukaemia. It is less common when the drug is administered at a dose of 100mg once a day dose than other dosing schedules. It is reversible of withholding the drug.
  2. Fluid Retention: Fluid retention is seen in about one-third of the patients. About 4-10% have severe fluid retention. The incidence of pleural effusions is lower when the drug is administered at a dose of 100mg once a day.
  3. Cardiopulmonary toxicity: Cardiopulmonary toxicity manifests as congestive cardiac failure, QT prolongation and pulmonary hypertenssion. Pericardial effusions may be seen.
  4. Hepatotoxicity: Hepatic toxicity manifests as elevated transaminases.
  5. Musculoskeletal system: Musculoskeletal toxicity manifests as arthralgia and myalgia and cramps.
  6. Gastrointestinal toxicity: Gastrointestinal toxicity includes nausea, vomiting, dyspepsia, diarrhoea and gastrointestinal bleed.
  7. Others:  Fatigue, asthenia and anorexia may be seen. Dasatinib use has been associated with hypocalcaemia and hypophosphataemia

Indication

  1. Chronic Myeloid Leukaemia: Dasatinib is indicated for chronic phase, accelerated phase and blast crisis of chronic myeloid leukaemia. It may be used in first line setting or in patients who progress or are intolerant to imatinib. It is not effective in the T515I mutation.
  2. Ph +ve Acute Lymphoblastic Leukaemia resistant or intolerant to previous TKI therapy.

Dose

  1. Chronic myeloid Leukaemia:
    1. Chronic Phase: 100mg once a day. The dose may be increased to a maximum of 140mg once a day.
    2. Acclerated Phase and Blast Crisis: 140mg once a day. The dose may be increased to a maximum of 180mg once a day.
  2. Ph +ve Acute Lymphoblastic Leukaemia: 140mg once a day. The dose may be increased to a maximum of 180mg once a day.

For dose modification for neutropenia and thrombocytopenia refer to sprycel.com.