Management of Acute Myeloid Leukemia (AML) in Older Patients

Purpose of Review: The acute myeloid leukemia (AML) treatment landscape has rapidly evolved over the past few years. These changes have several implications for the care of older adults (≥ 60 years), who have inferior clinical outcomes. We review decision-making in older adults, focusing on patient- and disease-related factors. We then summarize current treatment options, including multiple recently approved therapies, based on hypothetical clinical scenarios. Recent Findings: In lieu of using chronological age to determine fitness, we highlight the importance of standardized fitness assessments using geriatric assessments. Next, we review intensive and lower-intensity treatment options in the upfront setting. We focus on multiple newly approved medications, including venetoclax, midostaurin, CPX-351, gemtuzumab, glasdegib, enasidenib, and ivosidenib, and their specific indications. Lastly, we briefly discuss supportive care of older adults with AML. Summary: Outcomes of older adults with AML remain poor; fortunately, there are many new promising treatment options. Personalized treatment plans based on patient- and disease-specific factors are essential to the care of older adults with AML

Spontaneous Remission in an Older Patient with Relapsed FLT3 ITD Mutant AML

Spontaneous remission (SR) of acute myeloid leukemia (AML) is a very rare phenomenon. AML characterized by FLT3 internal tandem duplication (FLT3 ITD) is typically associated with an aggressive clinical course with rapid progression, relapse, and short overall survival in the absence of transplantation. We report here the first case of SR of FLT3 ITD mutant AML in the literature. Our patient was an elderly woman with relapsed NPM1 and FLT3 ITD mutant AML whose disease underwent SR for a brief duration without precipitating cause. We review the potential immune mechanisms underlying SR in AML and discuss the implications for novel immunotherapeutic approaches for FLT3 mutant AML

Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches

TCR Antigen–Induced Cell Death Occurs from a Late G1 Phase Cell Cycle Check Point

AbstractDeletion of antigen-activated T cells after an immune response and during peripheral negative selection after strong T cell receptor (TCR) engagement of cycling T cells occurs by an apoptotic process termed TCR antigen-induced cell death (AID). By analyzing the timing of death, cell cycle markers, BrdU-labeled S phase cells, and phase-specific centrifugally elutriated cultures from stimulated Jurkat T cells and peripheral blood lymphocytes, we found that AID occurs from a late G1 check point prior to activation of cyclin E:Cdk2 complexes. T cells stimulated to undergo AID can be rescued by effecting an early G1 block by direct transduction of p16INK4a tumor suppressor protein or by inactivation of the retinoblastoma tumor suppressor protein (pRb) by transduced HPV E7 protein. These results suggest that AID occurs from a late G1 death check point in a pRb-dependent fashion

Engraftment Properties of CG-SH cells.

<p><b>(A)</b> Sequencing chromatogram demonstrating the <i>RUNX1</i> mutation in CG-SH. <b>(B)</b> Percent hCD45+ engraftment achieved in the bone marrow (BM), peripheral blood (PB), and spleen of non-irradiated NSG mice receiving 1e6 CG-SH cells directly from cell culture via tail vein injection. Each symbol represents a single animal analyzed 6 weeks after transplantation. The horizontal black bars indicate mean engraftment. <b>(C)</b> Limiting dilution analysis of CG-SH and M9-ENL cells to determine the lowest cell dose necessary to achieve engraftment in each cell population. 1e1 – 1e6 cells were injected into non-irradiated NSG mice (5 mice per cell dose) and engraftment levels analyzed 10 weeks post- transplantation.</p

Residual Disease in CG-SH Xenografts Treated with a 5-day regimen of Anthracycline/Cytarabine-Based Chemotherapy.

<p><b>A and B.</b> Flow cytometric plots demonstrating the level of CG-SH engraftment in the bone marrow, peripheral blood, and spleen of a representative saline-treated control mouse <b>(A)</b> and a representative chemotherapy-treated mouse <b>(B)</b>. Treatment was initiated five weeks after tail vein injection of 1e6 CG-SH cells into non-irradiated NSG mice. Mice were analyzed four days after the completion of chemotherapy. <b>(C)</b> Quantification of the impact of chemotherapy in a cohort of CG-SH- xenografted mice. Each symbol represents a single mouse analyzed four days after the completion of treatment. Control mice were treated with saline. <b>(D)</b> Bone marrow histology four days after the completion of chemotherapy in CG-SH xenografts. Magnification is at 20x (left panels) and 40x (right panels), respectively. <b>(E)</b> Chemotherapy fails to eradicate leukemia-initiating cells in CG-SH xenografts. Leukemic cells were harvested from the bone marrow of chemotherapy-treated CG-SH xenografts or saline-treated controls and tested for their ability to engraft secondary NSG recipients. Non-irradiated secondary recipients were transplanted with unsorted cell populations containing 5e4 CG-SH cells and engraftment was determined 6 weeks later. All data were analyzed by the comparison of means using unpaired t-test. ***p = 0.0001, ****p<0.0001, ns = not significant.</p