Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Porkka, Kimmo; Koskenvesa, Perttu; Lundán, Tuija; Rimpiläinen, Johanna; Mustjoki, Satu; Smykla, Richard; Wild, Robert A.; Luo, Roger T.; Arnán, Montserrat; Brethon, Benoît; Eccersley, Lydia; Hjorth‐Hansen, Henrik; Höglund, Martin; Klamová, Hana; Knutsen, Håvar; Parikh, Suhag; Raffoux, Emmanuel; Gruber, Franz; Brito‐Babapulle, Finella; Dombret, Hervé; Duarte, Rafael F.; Elonen, Erkki; Paquette, Ron; Zwaan, C. Michel; Lee, Francis Y. F.

doi:10.1182/blood-2008-02-140665

Cited by 366 publications

(268 citation statements)

References 33 publications

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“…This is likely to represent a significant clinical problem as the brain is a frequent site of relapse in melanoma. However, secondgeneration tyrosine kinase inhibitors such as dasatinib have shown some promise in Philadelphia chromosome-positive leukaemia patients with CNS involvement (Porkka et al, 2008). Furthermore, studies have looked at modulating the distribution of drugs such as imatinib by targeting P-glycoprotein and other drug protein transporters (Breedveld et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

et al. 2010

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BACKGROUND: Mutations in KIT are more frequent in specific melanoma subtypes, and response to KIT inhibition is likely to depend on the identified mutation. METHODS: A total of 32 patients with metastatic acral or mucosal melanoma were screened for mutations in KIT exons 11, 13 and 17. RESULTS: KIT mutations were found in 38% of mucosal and in 6% of acral melanomas. Three patients were treated with imatinib and one with sorafenib. All four patients responded to treatment, but three have since progressed within the brain. CONCLUSIONS: The observed clinical responses support further investigation of KIT inhibitors in metastatic melanoma, selected according to KIT mutation status.

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Section: Discussionmentioning

confidence: 99%

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

et al. 2010

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“…Finally, dasatinib could also reach sanctuary areas like cerebrospinal fluids, which has not been found by other TKIs. 41,42 The response to TKI is the most important prognostic factor and it is the basis of continuing or changing the treatment. The responses are defined as "optimal," "failure" or "warning."…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison

Firwana

Sonbol

Diab

et al. 2015

Intl Journal of Cancer

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Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR 0.1% IS ) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR 4.5 0.0032% IS ) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm of blood stem cells. It accounts for 10-15% of new leukemia diagnoses with 5,980 new cases expected each year. 1 CML is associated with a reciprocal chromosomal translocation between the ABL oncogene on chromosome 9 and the BCR on chromosome 22.2 BCR-ABL oncoprotein has active ABL tyrosine kinase activity which leads to cell cycle deregulation, affecting differentiation and DNA repair, which results in increased proliferation, resistance to apoptosis and an alteration of their adhesion properties, and eventually leads to

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“…51 Finally, Porkka et al reported that dasatinib is capable of increasing survival in a K562 intracranial chronic myeloid leukemia (CML) mouse model, whereas imatinib is not. 52 Overall, these results indicate that a more active CNS prophylaxis must be administered when using imatinib as front-line therapy.…”

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confidence: 99%

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

et al. 2016

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In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0-79.3 vs. 20%, 95%CI: 5.8-69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3-82.6 vs. 20%, 95%CI: 5.8-69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2-38.6 vs. 60.0%, 95%CI: 21.6-84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1 p190 patients showed a significantly faster molecular response than BCR-ABL1 p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

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Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Cited by 366 publications

References 33 publications

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

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