Responses can be achieved with a combination of the MEK inhibitor selumetinib and dexamethasone in patients with relapsed/refractory RAS-pathway mutated acute lymphoblastic leukemia: Results of a parallel cohort, dose-finding and expansion phase I/II trial

Background Relapsed/refractory acute lymphoblastic leukemia (ALL) remains a major clinical challenge. We have previously shown that relapsed leukemias frequently carry RAS-pathway activating mutations that could be targeted by MEK-inhibitors in combination with glucocorticosteroids. Methods Based on these pre-clinical results, we designed a phase I/II trial to evaluate the safety and preliminary efficacy of dexamethasone in combination with the MEK-inhibitor selumetinib for the treatment of relapsed/refractory RAS-pathway mutated ALL. The trial recruited both children and adults. Treatment consisted of oral selumetinib and dexamethasone in 28-day cycles. Results Initial study participants experienced serious adverse events due to infections, with three deaths from sepsis and pneumonia. Urgent safety measures were therefore introduced. This included reduction of the dexamethasone dose and frequency and the introduction of mandatory infectious prophylaxis. Nevertheless, twelve patients were recruited (four children, all B-immunophenotype; eight adults, 6/8 T-ALL). Nine patients were evaluable for response of whom four achieved a morphological complete remission after four weeks of treatment. Two of the responding patients (T- immunophenotype) remained stable on the combination for three and five cycles, respectively. The leukemic blasts of one responding patient were further characterized at time of progression, revealing persistence of the original NRAS mutation and upregulation of cell cycle/division genes as a potential targetable resistance mechanism. The study was stopped due to poor recruitment highlighting the challenges of academic multi-national early phase clinical trials in rare patient populations. Conclusion The combination of MEK-inhibitors with corticosteroids merits further investigation in RAS-pathway activated acute lymphoblastic leukemia, particularly T-ALL.