Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia.

Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD-; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.

Pharmacological evidence for multiple sites of action of pressure in mice.

The ability of eight diverse pharmacological agents to ameliorate the high pressure nervous syndrome (HPNS) in mice was studied. Data were obtained for the end points: coarse tremors, complete spasms, clonic convulsions, tonic convulsions, and death. The three anesthetics examined (nitrogen, urethane, and phenobarbital) gave good protection against all end points but especially against tonic convulsions. Furthermore, marked increases (greater than 90 atm) were recorded in the lethal pressure in spite of a fixed linear compression. Some detailed differences among the anesthetics were also noted. Of the anticonvulsants, phenytoin protected against tonic convulsions but actually exacerbated some other end points. Diazepam gave some protection against all phases except the tremors, as did trimethadione. Tetrahydrocannabinol and chlorpromazine had little effect. The pharmacological profiles of these end points are all different, suggesting they represent the effects of pressure at separate and distinct sites in the central nervous system. The HPNS cannot be regarded as a single syndrome.