Dasatinib as an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults

ABSTRACT

Introduction: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy.

Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined.

Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1⁺ patients or is attributed to inhibition of the fusion protein alone, or a combined effect on several kinases, and whether dasatinib-containing combination treatment should be preferred in these patients instead of other emerging strategies, e.g. monoclonal antibodies.

Trial registration: ClinicalTrials.gov identifier: NCT02744768.

Trial registration: ClinicalTrials.gov identifier: NCT02143414.

Trial registration: ClinicalTrials.gov identifier: NCT02494882.

Trial registration: ClinicalTrials.gov identifier: NCT02420717.

Trial registration: ClinicalTrials.gov identifier: NCT02815059.

Trial registration: ClinicalTrials.gov identifier: NCT00103701.

Trial registration: ClinicalTrials.gov identifier: NCT00337454.

Trial registration: ClinicalTrials.gov identifier: NCT00816283.

Trial registration: ClinicalTrials.gov identifier: NCT03564470.

Trial registration: ClinicalTrials.gov identifier: NCT03414450.

Trial registration: ClinicalTrials.gov identifier: NCT01256398.

Trial registration: ClinicalTrials.gov identifier: NCT00792948.

Trial registration: ClinicalTrials.gov identifier: NCT00036738.

Trial registration: ClinicalTrials.gov identifier: NCT01883219.

Trial registration: ClinicalTrials.gov identifier: NCT03624530.

Trial registration: ClinicalTrials.gov identifier: NCT01643603.

Trial registration: ClinicalTrials.gov identifier: NCT01643603.

Trial registration: ClinicalTrials.gov identifier: NCT02888990.

Trial registration: ClinicalTrials.gov identifier: NCT02888977.

KEYWORDS:

• Acute lymphoblastic leukemia
• BCR-ABL
• chemotherapy
• clinical studies
• dasatinib
• imatinib
• immunomodulation

Box 1. Drug summary

Table

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded. The authors receive financial support for their research from the Norwegian Cancer Society, Helse-Vest and University of Bergen.