Introduction

Imatinib (IMAT) made possible complete marrow remissions of CML beginning in 1998. By 2001, relapses in non-marrow sites (CNS and many other organs) were reported in IMAT patients in marrow remission, which proved resistant to RT and systemic or intrathecal chemotherapy routinely used over 70 years. Sequelae include blindness, paralysis, spread of resistance to marrow, and death. Since the debut of dasatinib (DAS), a dual BCR::ABL1/SRC kinase inhibitor, in 2004, clearing of extramedullary leukemia (EML) by DAS in IMAT-resistant patients has been reported in numerous individual cases. As DAS is the first agent to produce complete remissions of resistant EML, we undertook to ascertain the durability of responses to DAS and to explore differences in DAS and IMAT.

Methods

All reports of patients with EML in any organ published 2004-2025 given DAS alone or added to routine approaches were reviewed. Response durations were elicited from authors. Results of our prior RNAseq study of specimens of EML in breast in AML and ALL patients were reviewed.

Results

165 patients with EML in any site who received DAS were identified in the literature, 70% presented after IMAT failure and 35 after transplants. Diagnoses were BCR::ABL1 (Ph‘+): 99 CML, 39 ALL, 4 AML, 3 biphenotypic leukemia, 7 lymphoblastic lymphoma; 13 had Ph‘- diseases. Age range was 2-80 years, 24 were under 21. DAS dose was usually 140 mg/d. Complete remission (CR) of EML was reported in 159 patients, confirmed by MRI, CSF, PET/CT in 11, autopsy in 2. CR sites include meninges, brain, bones, skin, ovary, heart, pancreas. In 6 patients, EML CR was not documented: in 3, disease progressed, in 2, visual and motor impairment was unchanged, and 1 died on DAS. Follow-up was obtainable from 56 authors. Response duration was knowable for 144 patients. 91 obtained CR lasting a few months to 11+ years, 38 for 2+-11+ years, (17 for >4 years). 12 of the 38 2-year survivors had undergone transplants after CR. 20 patients died in CR (2 myocardial infarctions, 10 infections, 2 transplant complications, 1 cancer, 1 accident, 1 hemorrhage, and 3 cause unknown). Relapse occurred in 34 patients:6 in same and 6 in other sites, 14 in marrow(M), 4 in EM +M, and 4 in unknown sites. Maintaining adequate dose appeared to be a factor in EML relapse. BCR::ABL1 mutations were reported in 12 relapses, 8 were T3151.

Among genes significantly overexpressed in EML tissue compared to normal tissue in our prior RNAseq study were SRC family kinase (SFK) LCK and PECAM-1 (CD31).

Discussion

Leukemia growth in non-marrow sites is an under-investigated lethal aspect of leukemias, known over 200 years but never a focus of specific treatment development. EML is an important cause of treatment failure and estimated to occur in 10-30% of leukemia patients; survival is typically <1 year. We report that DAS has produced lengthy CRs of EML, many in IMAT-resistant patients, and that LCK and PECAM-1 are upregulated in EML tissues. Overexpression of SFKs like LCK, and of PECAM-1 has previously been reported to be associated with IMAT resistance and with inhibition of IMAT-induced apoptosis in murine CML cells, respectively. We hypothesize that overexpression of LCK and PECAM-1 may contribute to IMAT resistance of EML and to the susceptibility of EML to DAS treatment. LCK is an oncogenic SFK found in choroid plexus, nerves, some cancers, and some Ph'-negative AML marrows. PECAM-1 has roles as a regulator of apoptosis, and in transendothelial migration and extramedullary dissemination of AML. PECAM-1 is phosphorylated in an SFK-dependent manner and both LCK and PECAM-1 are tyrosine phosphorylated by BCR::ABL1. DAS was developed as a LCK inhibitor (and BCR::ABL1 inhibitor) and DAS treatment completely prevents PECAM-1 phosphorylation. Therefore, it is not unreasonable to speculate that IMAT-driven overexpression of LCK and PECAM-1 may lead to enhanced LCK-mediated PECAM-1 tyrosine phosphorylation which promotes leukemia survival and migration to extramedullary sites, both of which deleterious outcomes can be inhibited by DAS.

Trials designed to identify EML in all leukemia patients by PET/CT and the use of EML-targeted DAS therapy for documented involvement, could improve patient survival and open new avenues of research.

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2025
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