Abstract:The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimu… Show more
“…Nevertheless, numerous studies have demonstrated the persistence of cML leukemic cells in the BM niche following treatment, even in patients with undetectable levels of the BCR-ABL1 transcript by RT-qPcR. The persistence of these cells in patients with CML has also been confirmed in clinical practice, where molecular relapse is experienced in ~50% of patients undergoing TKI discontinuation programs (39)(40)(41)(42). Residual leukemic cells may be quiescent stem cells, detectable only by cd26 recognition methods (43), or active cML cells.…”
due to the discovery of their role in intra-cellular communications, exosomes, which carry information specific to the cell of origin, have garnered considerable attention in cancer research. Moreover, there is evidence to suggest the possibility of isolating different exosome sub-populations based on target antigens at the cell surface. Philadelphia chromosome-positive (Ph +) chronic myeloid leukemia (cML) is a clonal myeloproliferative neoplasia characterized by the breakpoint cluster region-proto-oncogene 1 tyrosine-protein kinase (BcR-ABL1) fusion-gene, derived from the t (9;22) translocation. Tyrosine kinase inhibitors (TKIs) target BcR-ABL1 protein and induce major or deep molecular responses in the majority of patients. despite the fact that several studies have demonstrated the persistence of leukemic cells in the bone marrow niche, even following treatment, TKIs prolong patient survival time and facilitate treatment-free remission. These characteristics render cML a plausible model for investigating the feasibility of tumor-derived exosome fraction enrichment. In the present study, patients in the chronic phase (cP) of CML were treated with TKIs, and the quantification of the BCR-ABL1 exosomal transcript was performed using digital PcR (dPcR). The possibility of tumor-derived exosomes enrichment was confirmed, and for the first time, to the best of our knowledge, the detection of the BcR-ABL1 transcript highlighted the presence of active leukemic cells in patients with CP-CML. According to these findings, tumor-derived exosomes may be considered a novel tool for the identification of active leukemic cells, and for the assessment of innovative monitoring focused on the biological functions of exosomes in cML.
“…Nevertheless, numerous studies have demonstrated the persistence of cML leukemic cells in the BM niche following treatment, even in patients with undetectable levels of the BCR-ABL1 transcript by RT-qPcR. The persistence of these cells in patients with CML has also been confirmed in clinical practice, where molecular relapse is experienced in ~50% of patients undergoing TKI discontinuation programs (39)(40)(41)(42). Residual leukemic cells may be quiescent stem cells, detectable only by cd26 recognition methods (43), or active cML cells.…”
due to the discovery of their role in intra-cellular communications, exosomes, which carry information specific to the cell of origin, have garnered considerable attention in cancer research. Moreover, there is evidence to suggest the possibility of isolating different exosome sub-populations based on target antigens at the cell surface. Philadelphia chromosome-positive (Ph +) chronic myeloid leukemia (cML) is a clonal myeloproliferative neoplasia characterized by the breakpoint cluster region-proto-oncogene 1 tyrosine-protein kinase (BcR-ABL1) fusion-gene, derived from the t (9;22) translocation. Tyrosine kinase inhibitors (TKIs) target BcR-ABL1 protein and induce major or deep molecular responses in the majority of patients. despite the fact that several studies have demonstrated the persistence of leukemic cells in the bone marrow niche, even following treatment, TKIs prolong patient survival time and facilitate treatment-free remission. These characteristics render cML a plausible model for investigating the feasibility of tumor-derived exosome fraction enrichment. In the present study, patients in the chronic phase (cP) of CML were treated with TKIs, and the quantification of the BCR-ABL1 exosomal transcript was performed using digital PcR (dPcR). The possibility of tumor-derived exosomes enrichment was confirmed, and for the first time, to the best of our knowledge, the detection of the BcR-ABL1 transcript highlighted the presence of active leukemic cells in patients with CP-CML. According to these findings, tumor-derived exosomes may be considered a novel tool for the identification of active leukemic cells, and for the assessment of innovative monitoring focused on the biological functions of exosomes in cML.
“…[110]). has been achieved [111,112]. However, the length and frequency of intervals to allow catchup growth in children on TKI treatment still have to be defined and at least in our rat model, this approach did not recover the biomechanical strength of the long bones.…”
Section: Hypothesized Model Of Osseous Damage and Clinical Relevance mentioning
confidence: 81%
“…Our animal model also revealed that intermittent imatinib treatment mitigated skeletal effects on the growing bone, thus pointing toward a possibility to improve the risk-benefit ratio of long-term TKI exposure in pediatric patients. First clinical data in adults look promising but further studies must be carried out to determine whether the intermittent exposure is also sufficiently effective for the control of CML [111,112]. Regarding pediatric patients, the results from the juvenile animal model and the clinical experience from adult patients with CML should be combined.…”
Section: Experimental Animal Models Of Human Diseases -An Effective Tmentioning
The tyrosine kinase (TK) inhibitor (TKI) imatinib provides a highly effective treatment for chronic myeloid leukemia (CML) targeting at the causative oncogenic TK BCR-ABL1. However, imatinib exerts off-target effects by inhibiting other TKs that are involved, e.g., in bone metabolism. Clinically, CML patients on imatinib exhibit altered bone metabolism as a side effect, which translates into linear growth failure in pediatric patients. As TKI treatment might be necessary for the whole life, long-term side effects exerted on bone and other developing organs in children are of major concern and not yet studied systematically. Here, we describe a new juvenile rat model to face this challenge. The established model mimics perfectly long-term side effects of TKI exposure on the growing bone in a developmental stage-dependent fashion. Thus, longitudinal growth impairment observed clinically in children could be unequivocally modeled and confirmed. In a "bench-to-bedside" manner, we also demonstrate that this juvenile animal model predicts side effects of newer treatment strategies by second generation TKIs or modified treatment schedules (continuous vs. intermittent treatment) to minimize side effects. We conclude that the results generated by this juvenile animal model can be directly used in the clinic to optimize treatment algorithms in pediatric patients.
“…1 ); 23 reporting non-standard dosing of oral SACT in solid tumours and 11 in haematological malignancies. Four studies were late phase clinical trials [ 20 – 23 ], 15 were cohort studies and 15 were case reports. Non-standard dosing was identified for eleven different oral SACT, as reported in Tables 3 - 5 .…”
Section: Resultsmentioning
confidence: 99%
“…Non-standard dosing strategies reported were dose interruptions, dose reductions and a variety of other strategies. Dose interruption strategies were the most common non-standard dosing strategy described (14 studies), dose reductions (9 papers), and other dosing strategies (11 studies, of which, two reported the use of alternate day dosing of lenalidomide [ 11 , 23 ]). Fig.…”
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