Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

2022 ◽  
Author(s):  
Abdelrahman H. Elsayed ◽  
Xueyuan Cao ◽  
Amit K. Mitra ◽  
Huiyun Wu ◽  
Susana Raimondi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Patient Specific ◽  
High Dose ◽  
Nucleotide Polymorphisms ◽  
Standard Regimen ◽  
Poor Outcome ◽  
High Hazard Ratio ◽  
Acute Myeloid

PURPOSE To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

Patient-specific microRNA expression profiles as a marker for minimal residual disease in acute myeloid leukemia

Hematology ◽  
2013 ◽  
Vol 19 (1) ◽  
pp. 18-21 ◽  
Author(s):  
Velizar Shivarov ◽  
Angel Stoimenov ◽  
Branimir Spassov ◽  
Svetlana Angelova ◽  
Monika Niagolov ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Patient Specific ◽  
Minimal Residual ◽  
Acute Myeloid

scholarly journals Molecular Minimal Residual Disease Detection in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-30-SCI-30
Author(s):  
Peter Valk
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Fusion Transcript ◽  
Patient Specific ◽  
Molecular Abnormalities ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Acute Myeloid

Abstract Minimal residual disease (MRD) detection based on the standardized molecular monitoring of the t(9;22)-related BCR-ABL1 fusion transcript is well established for patients with chronic myeloid leukemia (CML). The levels of BCR-ABL1 serve as a guide to tailor treatment of the CML patient. In acute myeloid leukemia (AML) MRD detection based on polymerase chain reaction (PCR) approaches targeted towards the acquired molecular abnormalities is less well established. MRD measurement of the CBFB-MYH11 and RUNX1-RUNX1T1 fusion transcripts after induction therapy has been shown to be of some clinical importance. However, these transcripts can persist during long term complete remission, without having an effect on treatment outcome. In contrast, sequential MRD monitoring of the PML-RARA fusion transcript in acute promyelocytic leukemia (APL) is a strong predictor of relapse. Initial molecular MRD studies were limited to these favorable AML subtypes. Due to the discovery of novel recurrent abnormalities in AML the potential of molecular MRD detection has increased substantially. Although, certain acquired mutations, such as those in NPM1, are known for a number of years, only recently the application of these molecular abnormalities for MRD detection has been investigated in larger clinical trials. By NPM1 mutant MRD detection we can now recognize patients with higher risk of relapse. Highly sensitive targeted detection of the hotspot mutations in AML subsets is feasible by means of real-time PCR, but detection of patient specific mutations with this technology is still challenging. Next generation sequencing (NGS) revealed that AML is an extremely heterogeneous disease, as illustrated by the multitude of acquired mutations, but this technology has also opened possibilities for detection of MRD in virtually every patient. With NGS there is no need for patient specific assays since practically all mutations are detected. These molecular abnormalities, as single marker or in combination, will most certainly improve MRD monitoring of AML. However, it remains yet to be determined how MRD levels are assessed and which combination of markers in a MRD detection result in clinically relevant information, requiring extensive validation in large clinical AML trials. Smaller studies already demonstrated the variable dynamics of MRD during treatment and associations between somatic mutations persistence and risk of relapse. However, clonal hematopoiesis of undetermined potential, i.e., preleukemic mutations that may persist after treatment, provides an extra layer of complexity to the applicability of MRD detection. For example, the clinical applicability of MRD detection in the setting of mutant DNMT3A and IDH mutations is likely less effective due to the persistent DNMT3A and IDH mutant preleukemic cells following treatment. However, should all mutations be cleared after treatment or can preleukemic mutations in otherwise normal hematopoiesis persist without resulting in relapse? Taken together, there is need for molecular approaches to understand the dynamics of residual disease in AML during treatment. Disclosures No relevant conflicts of interest to declare.

Identification of the Novel Chromosomal Translocation t(17;19)(q23;q13) in a Pediatric Patient with Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4344-4344
Author(s):  
Deborah L. Shardy ◽  
Mohammed F. Azim ◽  
Rizwan C. Naeem ◽  
Sharon E. Plon
Keyword(s):  
Acute Myeloid Leukemia ◽  
Reciprocal Translocation ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Chromosomal Translocation ◽  
Therapeutic Interventions ◽  
High Dose ◽  
Artificial Chromosomes ◽  
Acute Myeloid

Abstract Chromosomal rearrangements have been associated with many hematologic malignancies. Identification of the genes involved in several of these rearrangements has provided information about the development of malignancy and has led to therapeutic interventions. Historically, a considerable number of pediatric acute myeloid leukemia (AML) cases have been reported as cytogenetically normal. However, with improved cytogenetic techniques and the use of fluorescent in situ hybridization (FISH), new translocations are now being identified. We present the case of a 10-year-old male with AML (FAB subtype M1) and a subtle chromosomal translocation. G-band karyotype analysis revealed a balanced, reciprocal translocation between chromosomes 17 and 19 involving bands 17q23 and 19q13. This translocation was present in 20 out of 20 bone marrow cells examined. Peripheral blood chromosome analysis ruled out a constitutional chromosomal abnormality. Metaphase FISH with telomere-region specific probes for chromosomes 17 and 19 confirmed the reciprocal translocation between 17q and 19q. This patient was treated according to the SJCRH AML 2002 protocol and was randomized to receive high-dose cytarabine. Because he had minimal residual disease following induction therapy, he also received Gemtuzumab Ozogamicin. The patient was in cytogenetic remission for one year after completion of therapy, and then he relapsed with the original leukemic clone and additional cytogenetic abnormalities. The t(17;19)(q23;q13) has not been reported previously in malignancies or other disorders, and therefore identification of the genes at the chromosomal breakpoints may provide new insights into the pathogenesis of AML. As an initial step to map the breakpoint regions, we performed FISH with a commercially available probe encompassing the CRX, GLTSCR2, and GLTSCR1 loci on 19q13 (Vysis, Downers Grove, IL). This revealed that the 19q breakpoint is centromeric to these loci. We are further mapping the translocation breakpoint region on chromosome 19q using FISH-mapped bacterial artificial chromosomes (BACs).

scholarly journals Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment

2020 ◽  
Vol 21 (16) ◽  
pp. 5626
Author(s):  
Laurène Fenwarth ◽  
Elise Fournier ◽  
Meyling Cheok ◽  
Thomas Boyer ◽  
Fanny Gonzales ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Response Prediction ◽  
Gemtuzumab Ozogamicin ◽  
Nucleotide Polymorphisms ◽  
Molecular Alterations ◽  
Leukemia Treatment ◽  
Set Up ◽  
Acute Myeloid

Gemtuzumab ozogamicin (GO, Mylotarg®) consists of a humanized CD33-targeted antibody-drug conjugated to a calicheamicin derivative. Growing evidence of GO efficacy in acute myeloid leukemia (AML), demonstrated by improved outcomes in CD33-positive AML patients across phase I to III clinical trials, led to the Food and Drug Administration (FDA) approval on 1 September 2017 in CD33-positive AML patients aged 2 years and older. Discrepancies in GO recipients outcome have raised significant efforts to characterize biomarkers predictive of GO response and have refined the subset of patients that may strongly benefit from GO. Among them, CD33 expression levels, favorable cytogenetics (t(8;21), inv(16)/t(16;16), t(15;17)) and molecular alterations, such as NPM1, FLT3-internal tandem duplications and other signaling mutations, represent well-known candidates. Additionally, in depth analyses including minimal residual disease monitoring, stemness expression (LSC17 score), mutations or single nucleotide polymorphisms in GO pathway genes (CD33, ABCB1) and molecular-derived scores, such as the recently set up CD33_PGx6_Score, represent promising markers to enhance GO response prediction and improve patient management.

Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations

2010 ◽  
Vol 85 (12) ◽  
pp. 926-929 ◽  
Author(s):  
Dana Dvorakova ◽  
Zdenek Racil ◽  
Ivana Jeziskova ◽  
Ivo Palasek ◽  
Marketa Protivankova ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Patient Specific ◽  
Minimal Residual ◽  
Acute Myeloid

Safety and activity of venetoclax in combination with high-dose cytarabine in children with relapsed or refractory acute myeloid leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10004-10004 ◽  
Author(s):  
Seth E Karol ◽  
Thomas Alexander ◽  
Soumyasri Das Gupta ◽  
Stanley B. Pounds ◽  
Kristin Canavera ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

10004 Background: Venetoclax is an orally available BCL-2 antagonist with demonstrated activity in adults with newly diagnosed or relapsed acute myeloid leukemia (AML). Here, we describe the first use of venetoclax 1) in combination with high-dose cytarabine and idarubicin 2) in patients 2-22 years old with relapsed AML. Methods: Patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in this Phase 1 study with a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1-28 and low-dose (LD: 100 mg/m2 every 12 hours x 20 doses) or high-dose (HD: 1000 mg/m2 every 12 hours x 8 doses) cytarabine beginning on day 8 (Table). Patients who had previously received < 270 mg/m2 of doxorubicin equivalents also received idarubicin 12 mg/m2 on day 8 in dose level 4; other patients were enrolled on the expansion cohort at dose level 3. Non-hematologic CTCAE grade 3 or higher toxicities were intensity limiting (ILT), excluding those anticipated with HD cytarabine. Results: Among 18 evaluable patients, a single ILT (prolonged hematological suppression beyond day 50) was observed (Table). Toxicities were consistent with the underlying cytotoxic chemotherapy, with 14 patients experiencing a total of 40 grade 3 toxicities including 6 documented infections and 23 episodes of febrile neutropenia. There was 1 grade 4 fungal sepsis. The recommended phase 2 dose of venetoclax was 360 mg/m2 (max 600 mg) when combined with HD cytarabine or HD cytarabine/idarubicin. Of the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy, end-of-cycle marrow responses included 7 CR/CRi and 3 PR. Minimal residual disease negative remissions occurred in 4 patients. BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to further characterize the promising activity of these combinations are underway. Conclusions: Venetoclax combined with cytarabine or cytarabine/idarubicin is active and well tolerated in pediatric patients with relapsed/ refractory AML. Clinical trial information: NCT03194932. [Table: see text]

Comparative analysis of Ig and TCR gene rearrangements at diagnosis and at relapse of childhood precursor-B–ALL provides improved strategies for selection of stable PCR targets for monitoring of minimal residual disease

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2315-2323 ◽  
Author(s):  
Tomasz Szczepański ◽  
Marja J. Willemse ◽  
Bas Brinkhof ◽  
Elisabeth R. van Wering ◽  
Mirjam van der Burg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Patient Specific ◽  
Gene Rearrangements ◽  
Secondary Acute Myeloid Leukemia ◽  
Minimal Residual ◽  
Selection Of ◽  
Acute Myeloid

Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements are excellent patient-specific polymerase chain reaction (PCR) targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL), but they might be unstable during the disease course. Therefore, we performed detailed molecular studies in 96 childhood precursor-B–ALL at diagnosis and at relapse (n = 91) or at presumably secondary acute myeloid leukemia (n = 5). Clonal Ig and TCR targets for MRD detection were identified in 94 patients, with 71% of these targets being preserved at relapse. The best stability was found for IGK-Kde rearrangements (90%), followed byTCRG (75%), IGH (64%), and incompleteTCRD rearrangements (63%). Combined Southern blot and PCR data for IGH, IGK-Kde, and TCRDgenes showed significant differences in stability at relapse between monoclonal and oligoclonal rearrangements: 89% versus 40%, respectively. In 38% of patients all MRD-PCR targets were preserved at relapse, and in 40% most of the targets (≥ 50%) were preserved. In 22% of patients most targets (10 cases) or all targets (10 cases) were lost at relapse. The latter 10 cases included 4 patients with secondary acute myeloid leukemia with germline Ig/TCR genes. In 5 other patients additional analyses proved the clonal relationship between both disease stages. Finally, in 1 patient all Ig/TCR gene rearrangements were completely different between diagnosis and relapse, which is suggestive of secondary ALL. Based on the presented data, we propose stepwise strategies for selection of stable PCR targets for MRD monitoring, which should enable successful detection of relapse in most (95%) of childhood precursor-B–ALL.

scholarly journals Is There Still a Role for Autologous Stem Cell Transplantation for the Treatment of Acute Myeloid Leukemia?

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 59 ◽  
Author(s):  
Felicetto Ferrara ◽  
Alessandra Picardi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Supportive Therapy ◽  
Current Evidence ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Consolidation Phase ◽  
Acute Myeloid

After intensive induction chemotherapy and complete remission achievement, patients with acute myeloid leukemia (AML) are candidates to receive either high-dose cytarabine-based regimens, or autologous (ASCT) or allogeneic (allo-SCT) hematopoietic stem cell transplantations as consolidation treatment. Pretreatment risk classification represents a determinant key of type and intensity of post-remission therapy. Current evidence indicates that allo-SCT represents the treatment of choice for high and intermediate risk patients if clinically eligible, and its use is favored by increasing availability of unrelated or haploidentical donors. On the contrary, the adoption of ASCT is progressively declining, although numerous studies indicate that in favorable risk AML the relapse rate is lower after ASCT than chemotherapy. In addition, the burden of supportive therapy and hospitalization favors ASCT. In this review, we summarize current indications (if any) to ASCT on the basis of molecular genetics at diagnosis and minimal residual disease evaluation after induction/consolidation phase. Finally, we critically discuss the role of ASCT in older patients with AML and acute promyelocytic leukemia.

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