Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance.

Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.

Impact of patrilocality on contrasting patterns of paternal and maternal heritage in Central-West Africa.

Despite their ancient past and high diversity, African populations are the least represented in human population genetic studies. In this study, uniparental markers (mtDNA and Y chromosome) were used to investigate the impact of sociocultural factors on the genetic diversity and inter-ethnolinguistic gene flow in the three major Nigerian groups: Hausa (n = 89), Yoruba (n = 135) and Igbo (n = 134). The results show a distinct history from the maternal and paternal perspectives. The three Nigerian groups present a similar substrate for mtDNA, but not for the Y chromosome. The two Niger-Congo groups, Yoruba and Igbo, are paternally genetically correlated with populations from the same ethnolinguistic affiliation. Meanwhile, the Hausa is paternally closer to other Afro-Asiatic populations and presented a high diversity of lineages from across Africa. When expanding the analyses to other African populations, it is observed that language did not act as a major barrier to female-mediated gene flow and that the differentiation of paternal lineages is better correlated with linguistic than geographic distances. The results obtained demonstrate the impact of patrilocality, a common and well-established practice in populations from Central-West Africa, in the preservation of the patrilineage gene pool and in the affirmation of identity between groups.

Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy.

Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.