scholarly journals Factors Associated with Clinical Outcomes after Venetoclax-Based Combination Therapy in Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-43
Author(s):  
Yazan F. Madanat ◽  
Hetalkumari Patel ◽  
Omik Patel ◽  
Jingsheng Yan ◽  
Jude Khatib ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Combination Therapy ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Grade ◽  
Newly Diagnosed ◽  
Factors Associated ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Background Outcomes of older patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) remain poor with an overall survival (OS) of <12 months (mo). The combination of venetoclax (ven) and azacitidine (aza) for such newly diagnosed AML pts in the confirmatory VIALE-A trial demonstrated an improvement in OS compared with aza alone. However, this trial excluded pts with prior hypomethylating (HMA) therapy, as well as pts with relapsed/refractory (R/R) disease. Therefore, the outcomes of those pts remain unknown. We thus investigated the outcomes of pts treated with ven-based therapy in the newly diagnosed and R/R settings. Methods Pts diagnosed with AML or high-grade myeloid neoplasms (MN) between 2/2018 - 5/2020 who completed at least one cycle of ven-based therapy were included. Clinical data were collected and targeted next generation sequencing evaluating a panel of ~80 genes commonly mutated in myeloid malignancies was performed. Responses were assessed using the IWG criteria, and OS was calculated from cycle one day one until the date of last follow-up/death. Categorical variables were compared using Fisher's exact test. Univariable and multivariable Cox- and logistic-regression were used to assess factors associated with response and OS. Results Fifty pts were prescribed ven at our center, and eight were excluded as they received less than one full cycle of therapy. Of the 42 pts included, the majority (91%) had AML and 9% had high-grade R/R MDS or CMML. Median age at diagnosis was 66 years (28-88) and 23 pts (55%) were female. Per ELN risk stratification, most (81%) pts had poor, 14% had intermediate, and 5% had favorable-risk disease. Forty percent had de novo-, 52% had secondary/therapy-related AML (t-AML) and 8% had R/R MN. Twenty one (50%) pts received venetoclax for newly diagnosed AML, and of those nine (43%) had prior HMA therapy. Of the other 21 (50%) pts who received venetoclax in the R/R setting, 10 (48%) received prior HMA therapy. Median duration of prior HMA therapy was 6 cycles (1-24). Ven was given in combination with HMA, low dose cytarabine (LDAC), or IC in 35 (83.3%), 6 (14.3%), and 1 (2.4%) pt respectively. Forty pts were evaluable for response. Complete response (CR) or CR with incomplete count recovery (CRi) rate was 47.5%. CR/CRi rates were significantly different based on ven combination (IC> HMA > LDAC, p=.001), AML status (de novo > t-AML > s-AML, p=.025), ELN risk and cytogenetic group (favorable > intermediate > poor, p=.001 and p=.004 respectively). CR/CRi rates were lower for pts receiving prior HMA, p=.012. CR/CRi rates were higher for pts with FLT3 (p=.040) and NPM1 mutations (p=.04). There was a trend for lower CR/CRi for pts with TP53 mutations, p=.095. [Table 1] Newly diagnosed vs R/R disease status, number of mutations (≤3 vs >3), and prior treatment with IC for AML had no impact on CR/CRi rates. There was no difference in median OS (mOS) between newly diagnosed vs R/R pts: 10.9mo vs 9.5mo respectively, p=.61. OS was significantly different based on response (CR vs CRi vs MLFS/PR vs PD with mOS not reached, 13.2, 9.5, and 2.3 mo respectively, p<.001. OS was longer for pts with de-novo AML> t-AML> s-AML with mOS of 15.6, 10.9, and 2.8 mo respectively, p=.007. Lastly, mOS was significantly shorter for pts with prior HMA exposure vs not at 5.0 vs 15.6 mo respectively, p=.003. [Figure 1] Multivariable analysis (MVA) for response demonstrated ELN cytogenetic intermediate vs high risk to be the only factor associated with CR/CRi, p=.004. MVA for OS showed prior HMA exposure and ELN poor cytogenetic risk to be the only two factors associated with shorter OS, p=.022 and p=.007 respectively. Conclusions In summary, this study of real world outcomes with ven combination therapy in AML has revealed disease features predictive of clinical outcomes. Remarkably, we observed no difference in response rates or OS between pts with newly diagnosed AML or R/R disease, which may be in part reflective of a population with high disease risk less likely to respond to upfront therapy. Additionally, we identify in a MVA disease factors predictive of response to therapy such as ELN cytogenetic risk and prior HMA exposure, the latter of which was not previously evaluated in clinical trials. Together, these observations highlight the clinical potential of ven combinations for R/R AML, as well as the need for novel therapeutic strategies to overcome the poor outcomes of pts with prior HMA exposure. Disclosures Patel: Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Agios: Consultancy.

scholarly journals Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1364-1364 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Kelda Gardner ◽  
Genevieve Alcorn ◽  
Mary-Elizabeth M. Percival ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Intensive Therapy ◽  
Treatment Intensity ◽  
High Grade ◽  
Intensive Chemotherapy ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a >10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight </≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Sorafenib In Pediatric Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1073-1073
Author(s):  
Hiroto Inaba ◽  
Jeffrey E Rubnitz ◽  
Elaine Coustan-Smith ◽  
Lie Li ◽  
Brian D Furmanski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Pediatric Acute Myeloid Leukemia ◽  
Rtk Signaling ◽  
Acute Myeloid

Abstract Abstract 1073 Background: Aberrant receptor tyrosine kinase (RTK) signaling arising from genetic abnormalities, such as FLT3-internal tandem duplications (FLT3-ITD), is an important mechanism in the development and growth of acute myeloid leukemia (AML) and is often associated with a poor outcome. Hence, inhibition of RTK signaling is an attractive novel treatment option, particularly for disease that is resistant to conventional chemotherapy. We evaluated the clinical activity of the multikinase inhibitor sorafenib in children with de novo FLT3-ITD–positive AML or relapsed/refractory AML. Methods: Fourteen patients were treated. Six patients with newly diagnosed FLT3- ITD–positive AML (aged 9–16 years; median, 12 years) received 2 cycles of remission induction therapy and then started sorafenib (200 mg/m2 twice daily for 20 days) the day after completing induction II (low-dose cytarabine, daunorubicin, and etoposide). Nine patients (aged 6–17 years; median, 9 years) with relapsed AML (including one treated on the above regimen) received sorafenib alone (2 dose levels; 200 and 150 mg/m2) twice daily for the first week of therapy, concurrently with clofarabine and cytarabine on days 8–12, and then alone from days 13 to 28. Sorafenib pharmacokinetics were analyzed at steady-state on day 8 of sorafenib in patients with newly diagnosed AML and on day 7 in patients with relapsed AML. In patients with relapsed AML, the effect of sorafenib on signaling pathways in AML cells was assessed by flow cytometry. Results: All 6 newly diagnosed patients, including 2 whose AML was refractory to induction I, achieved a complete remission (CR) after induction II; 5 had negative minimal residual disease (MRD; <0.1% AML cells in bone marrow) after induction II. Both patients in this group who relapsed achieved second remissions, one with sorafenib alone and one on the relapse regimen described above. Of the 9 patients with relapsed AML, 6 (4 with FLT3-ITD) were treated with sorafenib 200 mg/m2. All 6 had a >50% decrease in blast percentage and/or bone marrow cellularity after 1 week of sorafenib. After concurrent sorafenib and chemotherapy, 5 of the 9 patients with relapsed AML achieved CR (2 had negative MRD) and 2 achieved a partial remission (PR; 5%-25% AML cells in bone marrow); all 4 patients with FLT3-ITD had a CR or PR. After sorafenib treatment, 6 patients underwent HSCT while 2 with FLT3-ITD who could not receive HSCT were treated with single-agent sorafenib and have maintained CR for up to 8 months. Hand-foot skin reaction (HFSR) or rash occurred in all patients and improved with cessation of sorafenib. Dose-limiting toxicity (DLT, grade 3 HFSR and/or rash) was observed in 3 of the 6 patients with relapsed AML treated with 200 mg/m2 of sorafenib; no DLT was observed at 150 mg/m2. The effect of sorafenib on downstream RTK signaling was tested in the leukemic cells of 4 patients: in most samples, phosphorylation of S6 ribosomal protein and 4E-BP1 was inhibited. The mean (± SD) steady-state concentration (Css) of sorafenib was 3.3 ± 1.2 mg/L in the newly diagnosed group and 6.5 ± 3.6 mg/L (200 mg/m2) and 7.3 ± 3.6 mg/L (150 mg/m2) in those with relapsed AML. In both groups, the mean conversion of sorafenib to sorafenib N-oxide was 27%-35% (approximately 3 times greater than previously reported), and mean sorafenib N-oxide Css was 1.0–3.2 mg/L (2.1-6.7 μM). In a 442-kinase screen, the inhibitory profiles of sorafenib N-oxide and sorafenib were similar, and FLT3-ITD phosphorylation was potently inhibited by both forms (sorafenib N-oxide Kd = 0.070 μM; sorafenib Kd = 0.094 μM). Sorafenib N-oxide inhibited the growth of an AML cell line with FLT3-ITD (IC50 = 0.026 μM) and 4 AML cell lines with wild-type FLT3 (IC50 = 3.9–13.3 μM) at approximately half the potency of sorafenib. Conclusion: In children with de novo FLT3-ITD and relapsed/refractory AML, sorafenib given alone or with chemotherapy induced dramatic responses and inhibited aberrant RTK signaling in leukemic cells. Sorafenib and its active metabolite (sorafenib N-oxide) likely contribute to both efficacy and toxicity. These results warrant the incorporation of sorafenib into future pediatric AML trials. Disclosures: Inaba: Bayer/Onyx: Research Funding. Off Label Use: Sorafenib and clofarabine: both used for treatment of pediatric acute myeloid leukemia.

The Size of the Dendritic Cell Population At Diagnosis Worsens Prognosis in Acute Myeloid Leukemia – Bigger Is Not Better

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4870-4870
Author(s):  
Marta I Pereira ◽  
Ana I Espadana ◽  
Emília Cortesão ◽  
Gilberto P Marques ◽  
Catarina Geraldes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
World Health ◽  
Biological Behavior ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Dc Component ◽  
Acute Myeloid

Abstract Abstract 4870 Background: Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010). DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant. It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims: This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods: We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms. Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples. Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%). OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results: We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033). In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p < 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035). The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion: In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval. We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML). If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion: Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. Disclosures: No relevant conflicts of interest to declare.

Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells in Human Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-11-SCI-11
Author(s):  
Ravi Majeti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clonal Evolution ◽  
Founder Mutations ◽  
Hematopoietic Stem ◽  
Relapsed Disease ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic progenitors with poor clinical outcomes. Recent genome-scale sequencing efforts have determined that on average, an individual AML case is associated with 5 somatic mutations in recurrently mutated genes. This finding raises the important question of how AML develops from normal hematopoietic stem and progenitor cells. Given that AML is characterized by the sequential acquisition of genetic lesions in a single lineage of cells, and that all cells in the myeloid lineage, apart from HSC, are short-lived, we proposed a model in which serial acquisition of mutations occurs in self-renewing HSC. We investigated this model and the nature of founder mutations through the genomic analysis of de novo AML and patient-matched residual HSC. Using exome sequencing, we defined mutations present in individual AML genomes from 19 cases, and screened for these mutations in the residual HSC. We identified multiple mutations present in residual HSC retaining normal multilineage differentiation in vivo, including mutations in IDH1/2, TET2, DNMT3A, and genes encoding the subunits of the cohesin complex. Through single cell analysis, we determined that as we hypothesized, a clonal progression of multiple mutations occurs in HSC. From these studies, we identified patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, while mutations in "proliferative" genes such as FLT3 and KRAS occur late. Using this approach, we identified pre-leukemic HSC in a larger cohort of AML patients, and determined that their frequency within the stem cell compartment at the time of diagnosis varied widely from undetectable to nearly 100% of the cells. Stratifying these patients into two groups with either high or low frequencies of pre-leukemic HSC demonstrated that patients in the high group had much worse overall and relapse-free survival than those in the low group, indicating that the presence of pre-leukemic HSC may be critical for eventual clinical outcomes. To further investigate the response of pre-leukemic HSC to treatment, we analyzed the persistence of pre-leukemic mutations in patients in remission and found CD34+ progenitor cells and various mature cells that harbor pre-leukemic mutations. These findings indicate that pre-leukemic HSC can survive induction chemotherapy, identifying these cells as a potential reservoir for the re-evolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease, and show that some of these patterns are consistent with involvement of pre-leukemic HSC. Thus, our studies of pre-leukemic HSC reveal the clonal evolution of AML genomes from founder mutations, suggest a potential mechanism contributing to relapse, and constitute a cellular reservoir that may need to be targeted for more durable remissions. Disclosures Majeti: Forty Seven, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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