This is an open label, phase 1 study for AML subjects with relapsed or refractory disease or subjects in morphologic remission with MRD+ after first line therapy with venetoclax+HMA. A preliminary dose-finding cohort will be followed by 3 expansion cohorts.

Cohort 1 will be a conventional 3+3 dose-escalation study to determine maximum tolerated (MTD) or recommended dose of mitoxantrone when used with venetoclax+azacitidine. Subjects who are refractory to first-line therapy with venetoclax+HMA, or who respond and then relapse after first line therapy with venetoclax+HMA, will enroll in the study and receive a subsequent cycle of venetoclax+azacitidine at the dose and schedule being administered per the standard of care, along with a starting dose of 4mg/m2 of mitoxantrone administered IV on days 1-4. Depending on the absence or frequency of dose-limiting toxicities, additional patients will be enrolled at the appropriate dose levels, increasing by 2mg/m2 per cycle, per the 3+3 design until the MTD or a dose of 10mg/m2 of mitoxantrone is reached. The dose escalation phase will conclude when the MTD is determined; if the MTD is not reached, a recommendation for a dose of mitoxantrone in combination with venetoclax+azacitidine will be made based on toxicity and efficacy data.

After the establishment of the MTD or recommended dose of mitoxantrone, an expansion cohort (cohort 2) will open. 10 subjects who are refractory to first-line therapy with venetoclax+HMA, or who respond and then relapse after first line therapy with venetoclax+HMA, will enroll in the study and receive a subsequent cycle of venetoclax+azacitidine at the dose and schedule being administered per the standard of care, with the determined MTD/recommended dose of IV mitoxantrone given on days 1-4. On day 28 +/- 7 days of this cycle, a bone marrow biopsy will be repeated. In the absence of a ≥50% blast reduction from baseline, the subject will discontinue the study. If a CR, CRi, MLFS or blast reduction from baseline of ≥50% occurs, the subject can continue sequential cycles of venetoclax+azacitidine at the dose and schedule being administered per the standard of care, with the MTD/recommended dose of mitoxantrone on days 1-4, for up to 3 total cycles. No subject will receive \>3 cycles of mitoxantrone. After mitoxantrone cycles have been completed, subjects will receive a bone marrow biopsy after the third cycle, and then continue bone marrow biopsies with MRD assessments every 6 months, until disease progression or the administration of any therapy other than venetoclax+azacitidine, at which time the subject will be discontinued from the study.

In cohort 3, subjects who are in a morphologic remission with MRD+ after ≤3 cycles of standard of care venetoclax+HMA will enroll and receive mitoxantrone on days 1-4 at a dose to-be-determined that is below the MTD from cohort 1, concurrently with venetoclax+azacitidine, at the dose and schedule being administered per the standard of care, over a 28-day treatment cycle. A bone marrow biopsy with MRD assessment will be performed on day 28 +/- 7 days. If MRD conversion to negative occurs, subsequent treatment cycles will continue to administer venetoclax+azacitidine, at the dose and schedule being administered per the standard of care, with the to-be-determined dose of mitoxantrone on days 1-4, for a maximum of three total cycles of mitoxantrone. If MRD conversion to negative does not occur, the next cycle may escalate the mitoxantrone dose to a level to-be-determined and not exceeding the MTD, with venetoclax+azacitidine at the dose and schedule being administered per the standard of care. If MRD conversion to negative occurs, subsequent treatment cycles will continue to administer venetoclax+azacitidine, at the dose and schedule being administered per the standard of care, with the to-be-determined dose of IV mitoxantrone on days 1-4, for a maximum of three total cycles of mitoxantrone. If MRD conversion to negative does not occur, the next cycle may escalate the mitoxantrone to a level to-be-determined and not exceeding the MTD, with venetoclax+azacitidine at the dose and schedule being administered per the standard of care. Subjects will not receive \>3 cycles of mitoxantrone. After mitoxantrone cycles have been completed, subjects will continue bone marrow biopsies with MRD assessments every 6 months, until disease progression or the administration of any therapy other than venetoclax+azacitidine, at which time the subject will be discontinued from the study.

In cohort 4, subjects who are in a morphologic remission with MRD+ after \>3 cycles of standard of care venetoclax/HMA will enroll 28-50 days after the start of the previous venetoclax/HMA cycle. They will receive mitoxantrone IV on days 1-4 at a dose to-be-determined that is below the MTD from cohort 1; on day 14, the subject will start venetoclax+azacitidine at the dose and schedule being administered per the standard of care. On day 42 +/- 7 days, a bone marrow biopsy, with MRD assessment, will be repeated. If MRD conversion to negative occurs, subsequent treatment cycles will continue to administer venetoclax+azacitidine, at the dose and schedule being administered per the standard of care, with the to-be-determined dose of IV mitoxantrone on days 1-4, for a maximum of three total cycles of mitoxantrone. If MRD conversion to negative does not occur, the next cycle will retain the same schedule, and may escalate the mitoxantrone to a dose level to-be-determined and not exceeding the MTD. If MRD conversion to negative occurs, one additional cycle of mitoxantrone at this dose, with venetoclax+azacitidine at the dose and schedule being administered per the standard of care, will be given. If MRD conversion to negative does not occur, the next cycle will retain the same schedule, and may escalate the mitoxantrone to a level to-be-determined and not exceeding the MTD. No subject will receive \>3 cycles of mitoxantrone. After mitoxantrone cycles have been completed, subjects will continue bone marrow biopsies with MRD assessments every 6 months, until disease progression or the administration of any therapy other than venetoclax+azacitidine, at which time the subject will be discontinued from the study.