Dasatinib (SPRYCEL)

Oral multitargeted kinase inhibitor of BCR-ABL, SRC, c-KIT, ephrin, and PDGFR-ß.

Safe and effective for CML.

Trade name is Sprycel.

Oral agent with protein binding of 96%.

Hepatic metabolism with a half-life of 1.3 to 5 hours.

Excretion by fecal route ( 85%) and renal (4%).

An oral multi- BCR/Abl and Src family tyrosine kinase inhibitor approved for first line use in patients with chronic myelogenous leukemia (CML)[1] and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Main targets of therapy are BCR/Abl, Src, c-Kit, ephrin receptors, and several other tyrosine kinases.

Up to 325 times more potent than imatinib in killing cells dependent on BCR/ABL.

Responses were maintained in 95% of patients with chronic-phase CML, with a median follow-up time of >12 months.

Compared to imatinib there is a higher rate of complete cytogenetic response of 77% compared to 66% for imatininb.

Compared to imatininib there is a higher rate of MMR, 46% vs 28%.

At 3 years 66% of patients had MMR and only 3% progressed to accelerated or blast phase disease compard to 5% with imatinib.

In patients with accelerated-phase CML, 82% remain in remission, with a median follow-up of only 5 months.

Nearly all patients with CML in blast crisis or Ph+ ALL relapse within 6 months.

Responses are seen in patients with all BCR/Abl genotypes, with the exception of T315I mutation, which confers resistance to dasatinib, nilotinib and imatinib in vitro.

Approved for chronic, accelerated, and blast phases of CML and for Philadelphia chromosome positive acute lymphoblastic leukemia resistant to prior therapy.

Has a 325 fold increased potency than imatinib in inhibiting BCR-ABL kinase.

Has a 2-log increased kinase inhibition in potency compared to imatinib and is active against most imatinib resistant BCR-ABL mutations, with the exception of T315I.

Can bind to both active and inactive conformation of the ABL kinase domain, which imatinib and nilotinib cannot.

It is active in many kinase domain mutations resistant to imatinib.

Durable hematologic and cytogenetic responses seen in imatinib resistant patients or in those intolerant of imatinib with chronic phase CML (START-C trial).

In a phase I study therapy in imatinib resistant patients it induced complete hematologic remissions in 92% of patients and a major cytogenetic response in 60%.

More effective than high dose imatinib in chronic phase CML patients resistant to conventional doses of imatinib, with improved cytogenetic and molecular response rates and progression free survival.

Most common adverse reactions include peripheral edema, gastrointestinal symptoms and myelosuppression.

Cardiac dysfunction including QT prolongation, and tumor lysis syndrome have been reported.

Common toxic effects are neutropenia and myelosuppression.

Reversible pulmonary arterial hypertension is rare complication.

Pleural effusions may occur and patients may require thoracentesis or pleurodesis treatment.

Adverse events include diarrhea, peripheral edema, and headache.

Pleural effusion occurs at a higher rate in those with CML-accelerated phase (50%) than with chronic myelogenous leukemia-blast phase (33%)or CML-chronic phase (29%).

Abnormal liver function tests may occur transiently.

Pulmonary arterial hypertension has been reported.

Dyspnea, rash and congestive heart failure may occur.

pulmonary hypertension may be associated.

Pleural effusion seen in 14-30% of patients.

Compared to imatinib, dasatinib more likely to cause thrombocytopenia and pleural effusions.

In a review of 138 patients with CML treated with this agent 35% developed pleural effusions, particularly in patients with accelerated or blast phase disease.

Twice daily treatment may increase risk of pleural effusion.

Pleural effusion is minimized with 100 mg single daily dosing compared to other schedules, in patients with pleural effusion (Porkka K).

Can cause scrotal and penile edema.

In a study of 519 patients with treatment naïve CML randomized to dasatinib 100 mg once daily or imatinib 400 mg once daily: the median time to major molecular response was faster in the dasatinib arm 6.3 versus 9.2 months for imatinib, a higher major molecular response 45% versus 28%, respectively-suggesting this agent as initial therapy may lead to improved long-term clinical benefits (Kantarjian H et al).

In the above study the overall twelve-month survival was 97.2% for dasatinib and 98.8% for imatinib, complete cytogenetic response rate was twice as high for dasatinib .

This agent induces a complete cytogenetic response in approximately 50% of patients who do not have a response to imatinib or cannot tolerate it (Hochhaus A, Shah NP).

Dasatinib compared to imatinib induced significantly faster and higher rates of complete cytogenetic response and major molecular response given to newly diagnosed patients with chronic CML (Kantarjian H).

In the above study of 519 patients the rate of complete cytogenetic response was 77% for dasatinib and 66% for imatinib, and the rate of major molecular response rate was 46% vs 28%: achieving complete cytogenetic response within 12 months is associated with better long-term progression free survival, dasatinib may improve long-term outcomes among patients with newly diagnosed CML.

Adding the tyrosine kinase inhibitor dasatinib to standard aromatase inhibitor therapy with letrozole doubled progression-free survival (PFS) compared with letrozole alone in women with hormone receptor-positive, HER2-negative metastatic breast cancer.

Dose 100 mg/day orally.

In pediatric AML Philadelphia chromosome positive, dasarinib had superior results to



Induction and consolidation in first line treatment of PH-positive acute lymphoblastic leukemia in adults with dasatinib and blinatumab is associated with a high incidence of molecular response and survival (complete response 98%, immediate follow up of 18 months survival 95% and disease free survival was 88%).

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