Development of the ABL kinase inhibitor dasatinib (BMS-354825) in imatinib-resistant Philadelphia chromosome-positive leukemias
Abramson Cancer Center of the University of Pennsylvania
Last Modified: April 27, 2006
Presenter: Charles L. Sawyers
Presenter's Affiliation: University of California at Los Angeles, Los Angeles, CA
Type of Session: Clinical Plenary
- Chronic myeloid leukemia (CML) is associated with the 9;22 reciprocal chromosomal translocation (aka the Philadelphia chromosome). This translocation results in the fusion protein, BCR-ABL, which is a constitutively active tyrosine kinase.
- Imatinib is an orally available ABL kinase inhibitor that reliably induces durable hematologic and cytogenetic remissions in patients with chronic phase disease. Patients in blast crisis can also respond, but these disease remissions are much less durable.
- Relapsed disease after imatinib therapy is associated with mutations in the kinase domain of BCR-ABL.
- Structural studies of ABL-imatinib complexes show that imatinib can only bind the kinase in the “closed” conformation. Resistance occurs as a result of mutations in the BCR-ABL protein that prevent the kinase from taking on this “closed” conformation.
- Dasatinib is an orally available inhibitor of ABL that can bind both the “open” and “closed” conformations. In vitro, it has activity against CML clones with mutated BCR-ABL (except for one mutation, T315I, which lies in a binding pocket that contacts both imatinib and dasatinib).
- Dasatinib also inhibits SRC, KIT, PDGFR among others, and is 325-times more potent than imatinib against ABL.
- These pre-clinical observations prompted Phase I and II evaluation of dasatinib in patients with CML who had relapsed on imatinib.
Material and Methods
- The results of several early phase trials were compiled and presented:
- Phase I dose escalation trial of dasatinib in 84 imatinib-resistant/intolerant patients with CML in late chronic phase (CP) or accelerated phase (AP), myeloid blast crisis (MBC), lymphoid blast crisis (LBC), or patients with Philadelphia chromosome- positive ALL
- Phase II study at 4 international studies in similar groups of patients
- Randomized Phase II of dasatinib vs. high-dose imatinib (with history of suboptimal response to standard dose imatinib)
- In patients with MBC, LBC, or ALL, major hematologic responses were defined as fewer than 5% bone marrow blasts.
- Major cytogenetic responses were defined as less than or equal to 35% Philadelphia chromosome-positive cells.
- Phase I study:
- Complete hematologic responses were seen in 37/40 (93%) of CP patients and major hematologic responses were seen in 31/44 (70%) of those in blast crisis/ALL.
- Major cytogenetic responses were seen in 45% of CP patients and 25% of those in blast crisis/ALL. Responses lasted a median of >12 months in CP patients and 8 months in AP patients, but lasted less than 6 months in LBC and ALL patients.
- Inhibition of a blood biomarker of BCR-ABL target (called phospho-CRKL) was short-lived with once-a-day treatment. A twice-a-day group was added, but there was no difference in responses between once/day vs. twice/day.
- Responses were seen in patients with each of the different mutations, except no responses were seen in patients with the T315I mutation, which is consistent with the in vitro cross-resistance to both imatinib and dasatinib.
- Phase II: similar response rates were observed.
- -Myelosuppression in 50% of CP patients, 79% of AP patients. It was suggested that this was a marker of response rather than a true toxicity. The myelosuppression was reversible by withholding doses temporarily.
- Pleural effusions: 12-18%.
- Further mutational analysis in this large group of patients revealed 4 novel mutations that were seen in at least 2 patients. Mutations were found in 14% of intolerant patients suggesting that mutations may be associated with CML development, not just a result of imatinib-treatment. Mutations were found in 55% of resistant patients, 9% of whom had the cross-resistant T315I mutation.
- Several additional mutations were identified in patients who initially responded to dasatinib, but then relapsed (T315A, V299L).
- The observation that dasatinib can induce responses in imatinib-resistant CML indicates that BCR-ABL is a persistent and critical factor in this disease, even after relapse following imatinib therapy. Identification of molecular mechanisms of resistance can lead to strategies for second-line treatment.
- The story of imatinib as a targeted agent for BCR-ABL continues to be a roadmap for other targeted therapies. Identification of mutations in the targets proteins of biologic therapy can teach us about mechanisms of resistance or response, as was seen with gefitinib and EGFR mutations.
- Should imatinib and dasatinib be used sequentially or concurrently to decrease emergence of resistance? This question remains to be answered.
- The problem of the cross-resistant T315 mutant may require targeted drug development, and some biologic agents already in preclinical development (e.g. BIRB-796) may target this mutant and merit further study.