Chronic Myeloid Leukemia

Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less welldefined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1- driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.

Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

P=N/A, N=1, Completed, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Completed | N=10 --> 1

P1, N=18, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Dec 2027 --> Mar 2028

A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.

In immunosuppressed patients being treated with dasatinib, haemorrhagic colitis can mask an underlying infection.Tissue biopsy constitutes a key tool for promptly diagnosing cytomegalovirus colitis, enabling clinicians to start treatment early and thus prevent adverse outcomes.

Knocking out Ptbp2 in CML cell lines and patient samples decreased Polk levels; when treated with hydroxyurea, these samples exhibited increased DNA damage, evidenced by long comet tails and elevated γH2AX foci, a DNA damage marker; however, re-expressing Polk in Ptbp2-KO cells restored the phenotype...Cells with high levels of Ptbp2 and Polk showed increased sister chromatid exchanges and BrdU incorporation in ex vivo tests, while multinucleated cells with multipolar spindles appeared in in vivo tests. Our results confirm the key role of the Ptbp2-Polk-MRE11 axis in promoting genomic instability and supporting the survival of cells with higher malignancy.

Before the first TKI discontinuation, all six patients had received imatinib treatment for a median of 82.5 months (range, 40-87 months) and maintained a sustained deep molecular response, specifically MR(4.5), for a median of 34.5 months (range, 24-62 months)...All four patients who had resumed TKI treatment for >6 years and maintained MR(4.5) for >5 years achieved a sustained second TFR of ≥21 months; among these, three had received second-generation TKI for >1 year during the resumption of TKI treatment. The other two patients lost MMR at 4 and 3 months, respectively, after the second TKI discontinuation but regained MR(4.5) at 2 and 3 months, respectively, after resuming TKI treatment again.

CML patients achieving early hematological response to TKI therapy had significantly better survival outcomes. In contrast, non-responders, particularly those harboring BCR-ABL kinase domain mutations, demonstrated poorer survival. The S348L mutation was the most common variant in this cohort. Early mutation detection may help guide therapeutic adjustments and improve outcomes in TKI-resistant CML.

Circulating miRNAs are valuable biomarkers for TKI resistance in CML. Targeting HMGB1-associated miRNAs, together with combined CBD and IM treatment, may help re-establish apoptotic regulation and overcome resistance mechanisms.

P2, N=313, Active, not recruiting, Center for International Blood and Marrow Transplant Research | Recruiting --> Active, not recruiting