Myeloproliferative neoplasms with concomitant chronic myeloid leukemia are associated with TKI resistance and poor outcomes.
Gagnon LL., Duminuco A., Stagno F., Sobas M., Fominykh M., Virchis A., Nicolini F-E., Hildt J., Bentley H., Godfrey AL., Shih L-Y., Chee A., Mead A., Lewandowski K., Sobieralski P., Hannah G., Reyal Y., Cummin T., Piszcz J., Yip K., Frewin R., Narayanan S., Rahman D., Ajayi A., Cervi P., Byrne J., Taylor T., Lebowa W., Pavlu J., Arami S., Ceesay M., Chraniuk D., Delage R., Condorelli A., Santana C., Radia DH., de Lavallade H., Milojkovic D., Harrison C., Harrington P.
Chronic myeloid leukemia (CML) and Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are generally distinct clonal disorders, with the co-occurrence of BCR::ABL1 rearrangement with concomitant Ph-negative MPN rarely reported. Here we describe the largest known international cohort of Ph-negative MPN and coexisting CML providing important insights into this rare clinical scenario. We performed an international, multicenter, retrospective analysis of patients with concomitant BCR::ABL1 rearrangement and Ph-negative MPN, identifying 61 cases from 30 centers in 7 countries, over a 29-year period (1996-2025). Thirty-one patients (50.8%) had Ph-negative MPN preceding CML, 18 patients (29.5%) had CML preceding Ph-negative MPN, and 12 patients (19.7%) had Ph-negative MPN and CML diagnosed simultaneously. We observed increased TKI resistance and myelofibrotic transformation, especially in patients initially diagnosed with Ph-negative MPN. In this group, 35.4% (n = 11) progressed to MF, 2 patients to blast-phase MPN, and 69.2% (n = 18) failed to achieve a complete cytogenetic response. The rare e1a2 BCR::ABL1 transcript was notably prevalent which is associated with TKI resistance and a more aggressive disease course in CML. We described superior survival in those with Ph-negative MPN preceding CML, with median OS not reached, compared with 277 months for CML preceding Ph-negative MPN and 100 months for those diagnosed simultaneously (p = 0.05).