Comprehensive Genomic Analysis of Noonan Syndrome and Acute Myeloid Leukemia in Adults: A Review and Future Directions

2020 ◽  
Vol 143 (6) ◽  
pp. 583-593
Author(s):  
Muhned S. Alhumaid ◽  
Majed J. Dasouki ◽  
Syed O. Ahmed ◽  
Halah AbalKhail ◽  
Samya Hagos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Noonan Syndrome ◽  
Myeloid Leukemia ◽  
Genomic Analysis ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Young Adult Patient ◽  
Acute Myeloid

Acute myeloid leukemia (AML) in the setting of Noonan syndrome (NS) has been reported before without clear guidelines for treatment or prognosis in these subgroups of patients, most likely due to its rarity and incomplete understanding of the pathogenesis of both diseases. In the current era of next-generation sequencing-based genomic analysis, we can better identify patients with NS with more accurate AML-related prognostic markers. Germline mutations in <i>PTPN11</i> are the most common cause of NS. Somatic mutations in <i>NPM1</i> occur frequently in AML. Here, we describe a young adult patient with a novel combined germline <i>PTPN11</i> and somatic <i>NPM1</i>, <i>IDH1</i>,<i></i>and<i> BCL6</i> mutations who presented with fatal AML. In addition, a 50.5-Mb interstitial deletion of 7q21.11-q33 in tumor DNA was detected by chromosomal microarray analysis. While mutations in the transcriptional repressor <i>BCL6</i> are known to contribute to the pathogenesis of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), its novel identification in this patient suggests an expanded role in aggressive AML. The identification of key molecular aberrations including the overexpression of SHP2, which drives leukemogenesis and tumorigenesis, has led to the development of novel investigational targeted SHP2 inhibitors.

scholarly journals A National Multicenter Evaluation of the Clinical Utility of Optical Genome Mapping for Assessment of Genomic Aberrations in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Brynn Levy ◽  
Linda B. Baughn ◽  
Scott Chartrand ◽  
Brandon LaBarge ◽  
David Claxton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genome Mapping ◽  
Genomic Structure ◽  
World Health ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Accurate Identification ◽  
Genomic Aberrations ◽  
Acute Myeloid

AbstractDetection of hallmark genomic aberrations in acute myeloid leukemia (AML) is essential for prognosis and patient management. Clinical practice guidelines for identifying such structural variants (SVs), established by the World Health Organization (WHO), European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN), rely substantially on cytogenetic/cytogenomic techniques such as karyotyping, fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA). However, these techniques are limited by the need for skilled personnel as well as significant time and labor, making them cost-prohibitive for some patients. Optical genome mapping (OGM) addresses these limitations and allows for the accurate identification of clinically significant SVs using a novel, high throughput, inexpensive methodology. In a single assay, OGM offers a significantly higher resolution than karyotyping with comprehensive genome-wide analysis comparable to CMA and the added unique ability to detect balanced SVs that are missed by microarray. Here, we report the performance of OGM in a cohort of 100 AML cases, which were previously characterized by karyotype alone or karyotype and FISH. CMA was performed as an additional test in some cases. OGM identified all the clinically relevant SVs and CNVs reported by these standard cytogenetic methods. Moreover, OGM identified clinically relevant SVs in 11% of cases that had been missed by the routine methods. In 24% of cases, OGM refined the underlying genomic structure reported by traditional cytogenomic testing (13%), identified additional clinically relevant variants (7%) or both (4%). Three of 48 (6.25%) cases reported with normal karyotypes were shown to have cryptic translocations involving gene fusions. Two of these cases included fusion between NSD1-NUP98. Based on the comprehensive genomic profiling of the AML patients in this multi-institutional study, we recommend that OGM be considered as a first-line test for detection and identification of clinically relevant SVs.

scholarly journals Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiang Zhang ◽  
Jiejing Qian ◽  
Huafeng Wang ◽  
Yungui Wang ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Underlying Mechanism ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Dominant Mutation ◽  
First Line Therapy ◽  
Line Therapy ◽  
Acute Myeloid

AbstractVenetoclax (VEN) plus azacitidine has become the first-line therapy for elderly patients with acute myeloid leukemia (AML), and has a complete remission (CR) plus CR with incomplete recovery of hemogram rate of ≥70%. However, the 3-year survival rate of these patients is < 40% due to relapse caused by acquired VEN resistance, and this remains the greatest obstacle for the maintenance of long-term remission in VEN-sensitive patients. The underlying mechanism of acquired VEN resistance in AML remains largely unknown. Therefore, in the current study, nine AML patients with acquired VEN resistance were retrospectively analyzed. Our results showed that the known VEN resistance-associated BCL2 mutation was not present in our cohort, indicating that, in contrast to chronic lymphocytic leukemia, this BCL2 mutation is dispensable for acquired VEN resistance in AML. Instead, we found that reconstructed existing mutations, especially dominant mutation conversion (e.g., expanded FLT3-ITD), rather than newly emerged mutations (e.g., TP53 mutation), mainly contributed to VEN resistance in AML. According to our results, the combination of precise mutational monitoring and advanced interventions with targeted therapy or chemotherapy are potential strategies to prevent and even overcome acquired VEN resistance in AML.

scholarly journals A Case of Acute Myeloid Leukemia Concurrent With Untreated Chronic Lymphocytic Leukemia

2017 ◽  
Vol 37 (4) ◽  
pp. 336-338
Author(s):  
Hye-Young Lee ◽  
Chan-Jeoung Park ◽  
Enkyung You ◽  
Young-Uk Cho ◽  
Seongsoo Jang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
Myeloid Leukemia ◽  
Lymphocytic Leukemia ◽  
Acute Myeloid

scholarly journals Mesenchymal Stem Cells (MSCs) Intensify the Impact of KIR Ligand-Mismatching on Acute Graft-Versus-Host Disease Post HSCT in Patients with Acute Myeloid Leukemia but Not with Acute Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Yu Zhang ◽  
Shaozhen Chen ◽  
Jinhua Ren ◽  
Xiaofeng Luo ◽  
Zhizhe Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Objectives: Mesenchymal stem cells (MSCs) and killer cell immunoglobulin-like receptor (KIR) ligand-mismatch, which can trigger the alloreactivity of natural killer (NK) cells, have been shown to be protective for severe acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no prospective or retrospective studies exploring their relationship. Here, we investigated the potential influence of KIR matching, MSCs and their coaction on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of allo-HSCT. Methods: Data from 154 patients with acute myeloid and lymphocytic leukemia treated with allo-HSCT between May 2015 and May 2020 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 93 male patients (60.3%) and 61 female (39.7%), with a median age of 24 years (1-59 years), 104 cases of acute myeloid leukemia (AML; 67.5%) and 50 cases with acute lymphocytic leukemia (ALL; 32.5%). Eighty-one patients (52.6%) underwent MSCs infusion on day+1. The sources of MSCs were human placenta or human bone marrow. MSCs infusion dose ranged from 0.5 to 3x106/kg of recipient weight. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results: At the time of transplantation, 65 cases (42.2%) were in remission, while 89 (57.8%) had active disease. aGVHD occurred in 31 patients (20.1%) and recurrence arose in 21 patients (13.6%), but no significant cGVHD was observed. After adjusting for age, disease-risk, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that KIR ligand-matching was associated with an increased risk of aGVHD compared to KIR ligand-mismatching (p=0.023) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD in ALL patients, and on OS and RR in both AML and ALL patients. MSCs was associated with much lower recurrence rate (RR) (p=0.049), even when the recipients were not in remission at the time of HSCT. Furthermore, MSCs reduced the incidence of aGVHD in both AML and ALL patients, although it did not reach statistical significance (p=0.19). The combination of KIR ligand-mismatching and MSCs infusion significantly suppressed aGVHD occurrence in AML patients (p=0.033). More importantly, MSCs infusion intensified the suppression effect of KIR ligand-mismatching on aGVHD in AML patients (p=0.047). In the KIR ligand-mismatch group, the incidence of aGVHD was 10.3% when patients received MSCs, compared to 25.6% in those who did not. However, combining KIR ligand-mismatch and MSCs injection had no significant effect on aGVHD in ALL patients, or on OS and RR in both AML and ALL patients. Conclusions: KIR ligand-mismatch, MSCs infusion and their combination significantly reduced the risk of aGVHD after allo-HSCT in AML patients. It confirms the relationship between MSCs injection and lower RR. These data provide a clinically applicable strategy where co-transplantation with MSCs and triggering of allo-NK cells by KIR ligand-mismatching can ameliorate aGVHD, thus improving allo-HSCT outcome in AML patients. Disclosures No relevant conflicts of interest to declare.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

scholarly journals Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy

2019 ◽  
Vol 10 ◽  
pp. 204062071988282 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Drug Administration ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

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