Keywords
dasatinib - second-generation TKI in CML - chronic myeloid leukemia
Introduction
The Philadelphia (Ph) chromosome which is the shortened chromosome 22 is formed due to the juxtaposition of a part of the Break point cluster region BCR gene in chromosome 22 to the Abelson murine leukemia virus ABL gene part in chromosome 9.[1] The presence of this characteristic reciprocal translocation t(9, 22) is required for the diagnosis of chronic myeloid leukemia (CML). Imatinib, a tyrosine kinase inhibitor (TKI), was a game changer in the management of CML. However, some patients fail to respond to imatinib or develop resistance over time. There are a few second-generation (2G) TKIs like dasatinib, nilotinib, and bosutinib approved for use in CML. These 2G TKIs are approved for either in the first-line or the second-line. Recently the generic version of dasatinib has been approved for use in India. Hence, we have reviewed the key features of dasatinib which was earlier known as BMS 354825.
Mechanism of Action and Pharmacokinetics
Mechanism of Action and Pharmacokinetics
Dasatinib is a potent, orally active, small-molecule inhibitor of multiple kinases, including BCR–ABL, (sarcoma) Src family kinases, c-KIT, and platelet-derived growth factor receptor (PDGFR-β5). It does not require conformational changes in the ABL binding domain in contrast to imatinib and hence is active against imatinib-resistant mutations. The absorption is not affected by the food intake and hence can be taken either before food or after food. Dasatinib is metabolized by cytochrome P450 enzyme 3A4(CYP3A4). The terminal half-life is around 5 to 6 hours. Enzyme inhibitors increase the drug levels, leading to increased toxicity. Concomitant use of proton pump inhibitors decreases the bioavailability of dasatinib while concurrent administration of CYP3A4 inhibitors like azoles can increase bioavailability.[2] Preclinical and clinical studies have demonstrated improved central nervous system penetration of dasatinib ([Table 1]).[3]
Table 1
Dose modifications for concurrent use with enzyme inhibitors
|
Setting
|
Current dose (mg)
|
Recommended dose (mg)
|
|
Concomitant use with enzyme inhibitors
|
140
|
40
|
|
100
|
20
|
|
70
|
20
|
Sensitive and Resistant ABL Kinase Domain Mutation
Sensitive and Resistant ABL Kinase Domain Mutation
Approximately 10 to 15% of patients with CML chronic phase (CP) develop resistance to imatinib. One of the mechanisms of imatinib resistance is the development of mutations in the ABL kinase domain. Mutations that are sensitive and resistant to dasatinib are mentioned in [Table 2].
Table 2
Common sensitive and resistant mutations for dasatinib
|
aIC50: Half maximal inhibitory concentration.
|
|
Sensitive mutation (IC50a<2)
|
Y253F, E279K, D276G, M351T, F359V, H396P, H396R, G398R
|
|
Moderately resistant (IC50 2–4)
|
E255V, Q252H, L384M, L486S
|
|
Resistant mutation (IC50 > 10)
|
T315A, T315I,F317L/I/V/C, V299L
|
Food and Drug Administration–Approved Indications
Food and Drug Administration–Approved Indications
Adults
-
First-line TKI in Ph + CML—CP, accelerated phase (AP), or blast phase (BP)—100-mg once daily (OD) in CP and 140 mg OD in AP and BP.
-
Second-line TKI in CML in any phase with imatinib resistance or intolerance.
-
First-line in Ph + acute lymphoblastic leukemia (ALL) along with intensive therapy, 140 mg OD.
Pediatrics
-
First-line TKI in CML CP (≥ 1 year of age), 60 to 80 mg/m2 OD.
-
Newly diagnosed Ph + ALL in combination with chemotherapy, 80 mg/m2 OD.
Other Indications (Off-Label)
Common Toxicity and Dose Adjustments
Common Toxicity and Dose Adjustments
-
Hematological toxicities are among the most common side effects of dasatinib. Cytopenias are common during therapy and occur at increased frequency in those of Ph + ALL and accelerated/blast phase of CML than in the CP. Higher rates of cytopenias are also reported following switching to dasatinib after imatinib failure. Cytopenias are more common in the first few weeks or months of treatment and improve once the leukemic clones are cleared. Hematological monitoring with complete blood count (CBC) is recommended weekly for the first 4 to 6 weeks. In the absence of cytopenias, CBC can be monitored once in every 2 weeks or monthly until month 3. In patients with advanced phase CML, more frequent monitoring is advised ([Tables 3 and 4]).
-
Dasatinib can inhibit platelet aggregation and can cause bleeding manifestations like gastrointestinal bleeding (5%). Dasatinib should be used with caution in patients receiving aspirin or anticoagulants.[6]
[7]
[8]
-
Pleural effusion: The mechanism of pleural effusion is believed to be immune mediated. Other mechanisms include off-target inhibition of PDGFR-β and SRC family kinase. PDGFR-β inhibition leads to reduced interstitial fluid pressure and inhibition of SRC leads to change in vascular permeability. The effusion is exudative and lymphocyte rich. The risk factors associated with increased risk of pleural effusion include older age (>65 years),[9] previous history of cardiovascular disease, hypertension, twice daily schedule, higher dose, and advanced-phase CML. It can happen at any time during treatment, the median time in the DASISION trial being 114 weeks. The median duration of pleural effusion is around 4 weeks. Around 60% of those who develop pleural effusion can have recurrence of effusion. The management of effusion depends on the symptoms, presence of risk factors, and the extent of hematological response achieved. Diuretics and steroids have been used in the management, although the rationale for their use is not established. Only a minority of patients require treatment discontinuation due to pleural effusion (6% patients in DASISION trial). The management of pleural effusion is shown in [Table 5].
-
Cardiac toxicity is briefed below:
-
Prolongation of cardiac ventricular repolarization (QTc; 1%), dysrhythmias can occur. Electrolyte imbalances (hypokalemia or hypomagnesemia) should be corrected before starting treatment. Caution should be exerted while using drugs that prolong the QTc interval as it may predispose to life-threatening arrhythmias. All patients should get baseline electrocardiogram (ECG). In case of QTc > 440 ms or prolongation of >30 ms from baseline, weekly monitoring of ECG is preferred. Dasatinib should be stopped in case of QTc > 500 ms or prolongation of >50 ms from baseline and ECG monitored weekly. Dasatinib is resumed when QTc ≤ 450 ms in two consecutive ECGs.[11]
-
Congestive heart failure (2%) can occur or worsen due to fluid retention.
-
Pulmonary arterial hypertension (PAH; <1%) warrants discontinuation of the drug. It is reversible in most cases once the drug is stopped.[11]
-
Pericardial effusion (1%) due to fluid retention.
Table 3
Incidence of common toxicities[6]
[7]
|
Toxicity
|
Incidence
|
|
All grade (%)
|
Grades 3, 4 (%)
|
|
Haematology
|
|
Anemia
|
90
|
10
|
|
Neutropenia
|
65
|
21
|
|
Febrile neutropenia
|
4
|
|
|
Thrombocytopenia
|
70
|
19
|
|
Fluid retention
|
|
Superficial edema
|
22
|
|
|
Pleural effusion
|
28
|
5
|
|
Cardiovascular
|
|
Pericardial effusion
|
3
|
1
|
|
Pulmonary hypertension
|
<1
|
5
|
|
Pulmonary edema
|
2
|
|
|
Congestive cardiac failure
|
2
|
1
|
|
Cardiac Ischemia
|
3.9
|
|
|
Cardiac arrhythmias
|
7
|
|
|
Bleeding diathesis
|
|
Gastrointestinal bleed
|
2
|
|
|
Central nervous system bleed
|
<1
|
|
|
Other toxicities
|
|
Rash
|
14
|
|
|
Fatigue
|
8
|
|
|
Myalgia
|
23
|
|
|
Diarrhea
|
17
|
1
|
Table 4
Dose modifications for hematological toxicity[7]
|
Setting
|
Hematologic toxicity
|
Recommendations
|
|
Abbreviations: BP, blast phase; ALL, acute lymphoblastic leukemia; AP, accelerated phase; CP, chronic phase; CML, chronic myeloid leukemia; OD, once daily; Ph, Philadelphia; ANC, absolute neutrophil count.
|
|
CML CP 100-mg OD
|
ANC <500 or platelet <50,000
|
1. Interrupt dasatinib until ANC >1,000 and platelets >50,000 and resume at the original starting dose.
2. For recurrence, interrupt dose, resume dasatinib at 80-mg OD and then for further recurrence, reduce dose to 50-mg OD.
|
|
CML AP, BP, Ph + ALL
|
ANC <500 or platelet <10,000
|
1. Check if toxicity is disease related.
2. If not related to disease interrupt dasatinib until ANC > 1,000 and platelets >20,000 and resume the original dose.
3. For recurrence, interrupt dose, resume dasatinib at 100-mg OD (second episode) or 80-mg OD (third episode).
|
Table 5
Recommendations for the management of pleural effusion[10]
|
Grade
|
Management
|
Dose interruption/dose reduction
|
|
Grade 1
|
1. Observe.
2. Repeat chest X-ray once in 3 months for 1 year.
|
Nil
|
|
Grade 2
|
1. Steroids—prednisolone 40 mg/day for 4–5 days.
2. Diuretics.
|
1. Interrupt dose until effusion resolves to grade1.
2. Resume at a 20% reduced dose.
|
|
Grades 3 and 4
|
1. Thoracentesis if required.
2. Steroids and diuretics.
|
1. Interrupt dose until effusion resolves to Grade1.
2. Resume at a 20% reduced dose.
3. Consider stopping the drug for recurrent effusions (grade 3 or 4) even after 2 dose reductions.
|
-
Gastrointestinal toxicity can occur in the form of diarrhea (22%), nausea (8%), vomiting (5%), and abdominal pain. These toxicities usually occur in the initial weeks of therapy and resolve with symptomatic treatment.[11]
-
Dose modifications for hepatic and renal dysfunction: patients with severe hepatic impairment (Child–Pugh C) and severe renal impairment (creatinine more than three times the upper limit of normal) have not been included in trials and there are no specific clinical trials for the use of dasatinib in patients with renal and hepatic impairment. However, the amount of dasatinib and its metabolites excreted through kidney is low and hence, no dose modifications are recommended for patients with hepatic and renal dysfunction.
Monitoring during Therapy
Monitoring during Therapy
CBCs should be monitored once in 2 weeks for CP and once weekly for advanced phase CML for the first 2 months and then once in 3 months. In case of Ph-positive ALL, the CBC is done according to the recommendations of the protocol used.
Liver function tests and renal function tests should be done once in 2 weeks for the first 2 months and then whenever clinically indicated. In Ph-positive ALL, these tests may be required more frequently as per the protocol used.
Chest X-ray and ECG are recommended only if clinically indicated.
Points to Ponder in Dosing
Points to Ponder in Dosing
OD is preferred, as it is found to be as efficacious as BD dosing with lesser adverse events, especially pleural effusion and also requires lesser dose interruptions.[12] The dasatinib is available in tablet formulations in the following strengths 20, 50, 70, and 100 mg. The tablets should be consumed whole and should not be crushed or cut.
A lower dose of dasatinib (50-mg OD) in CP, CML is found to be more efficacious in a single phase-2 study from the MD Anderson Cancer Centre when compared with the historical cohort of the DASISION study. The rates of molecular responses were higher than historical controls who received a dose of 100 mg (major molecular remission [MMR or MR3] at 1 year was 81%; four log reductions [MR4] at 1 year was 55%). Randomized controlled trials are needed to confirm the above results.[13]
Stopping Tyrosine Kinase Inhibitor
Stopping Tyrosine Kinase Inhibitor
Treatment-free remission (TFR) has evolved as a treatment goal in patients with a sustained deep molecular response (DMR). It helps to avoid the toxicity associated with long-term TKI use and also decreases the financial burden of long-term medication. This strategy requires motivated patients and close monitoring of BCR–ABL transcript levels. Patients usually regain molecular responses following treatment reinitiation, in case of loss of MMR during the stop phase. TFR as a goal is possible with imatinib and 2G TKIs. With the use of 2G TKIs, more proportion of patients can achieve a deep molecular response and such responses happen earlier compared with the use of imatinib. Hence more patients are eligible for the TFR strategy. Selected trials on the use of TKI discontinuation with dasatinib are shown in [Table 7].
Table 6
Key trials with the use of dasatinib
|
Study
|
Setting
|
Design
|
Result
|
|
Abbreviations: OS, overall survival; ALL, acute lymphoblastic leukemia; AP, accelerated phase; BD, twice daily; BP, blast phase; CP, chronic phase; CML, chronic myeloid leukemia; MMR, major molecular remission; OD, once daily; Ph, Philadelphia; CCyR, complete cytogenetic response, EFS, Event free survival.
|
|
DASISION[15]
|
CML–CP, first line
n = 519
|
Dasatinib 100 vs. imatinib 400 mg OD
|
1 year CCyR 77 vs. 66% (p = 0.007)
5-year MMR 76 vs. 64% (p < 0.0022
|
|
CCCG-ALL2015[16]
|
Newly diagnosed pediatric Ph-positive ALL
n =189
|
Dasatinib 80 mg/m2 vs. imatinib 300 mg/m2/day
|
4 year EFS 71 vs. 48.9% (p = 0.005)
4-year OS 88.4 vs. 69.4% (p = 0.004)
|
|
CA180–034[17]
|
CML–CP second line after imatinib failure or intolerance
n = 670
|
Dasatinib 100 mg OD vs. 50 mg BD vs. 140 mg OD vs. 70 mg BD
|
MMR at 7 years
100 mg OD: 43.7%
50 mg BD: 41.6%
140 mg OD: 40.7%
70 mg BD: 41.07%
|
|
CA180–035[18]
|
CML AP/BP
n = 317
|
Dasatinib 140 mg OD vs. 70 mg BD
|
1 year MMR 66 vs. 68%
Pleural effusion 20 vs. 39%, (p < 0.001)
|
Table 7
Key trials evaluating the role of treatment-free remission
|
Abbreviations: MMR, major molecular remission; MR4, four log reductions; TFR, treatment- free remission; L, line of treatment.
|
|
DADI[19]
|
setting: 1/2 L after imatinib failure. n = 63
|
Criteria for stop: MR4 for 1 year.
Criteria for restart: loss of MR4
|
3-year TFR 36%
|
|
DASFREE[20]
|
setting: 1L/subsequent lines
n = 84
|
Criteria for stop: MR 4.5 for 1 year
Criteria for restart: loss of MMR
|
2-year TFR 46%
|
Dasatinib in Pregnancy and Breastfeeding
Dasatinib in Pregnancy and Breastfeeding
There is a paucity of clinical data on the safety of dasatinib in pregnancy. Pregnancy-related issues include miscarriage, intrauterine growth retardation, and placental abruption. Fetal effects include the development of hydrops fetalis, skeletal malformations, and cytopenias. Dasatinib should be avoided during pregnancy and lactation.[14] There is limited data on the pregnancy outcome of female partners of men who are taking dasatinib.
Conclusion
Dasatinib is a potent 2G TKI with better responses in the management of chronic myeloid leukemia. With the availability of generic dasatinib, the cost of treatment has considerably come down, thereby increasing the reach of the drug to the poor and downtrodden.
