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.

scholarly journals Gemtuzumab ozogamicin can reduce minimal residual disease in patients with childhood acute myeloid leukemia

Cancer ◽  
2013 ◽  
Vol 119 (22) ◽  
pp. 4036-4043 ◽  
Author(s):  
Carol O'Hear ◽  
Hiroto Inaba ◽  
Stanley Pounds ◽  
Lei Shi ◽  
Gary Dahl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Gemtuzumab Ozogamicin ◽  
Childhood Acute Myeloid Leukemia ◽  
Minimal Residual ◽  
Acute Myeloid

scholarly journals Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4566
Author(s):  
Michele Gottardi ◽  
Giorgia Simonetti ◽  
Alessandra Sperotto ◽  
Davide Nappi ◽  
Andrea Ghelli Luserna di Rorà ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematological Malignancy ◽  
Residual Disease ◽  
Gemtuzumab Ozogamicin ◽  
Post Transplantation ◽  
Blast Cells ◽  
Pharmaceutical Agents ◽  
Acute Myeloid ◽  
Made In

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.

scholarly journals Is Need Chemotherapy Titration During Acute Myeloid Leukemia Treatment?

2021 ◽  
pp. 1-5
Author(s):  
Ali Amanati ◽  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Residual Disease ◽  
Rare Complication ◽  
Intensive Chemotherapy ◽  
Leukemia Treatment ◽  
Minimal Residual ◽  
Acute Myeloid

Persistent marrow aplasia is a rare complication with poor prognosis after intensive chemotherapy for acute myeloid leukemia. We present a 14-year-old boy with acute myeloid leukemia (AML), was complicated by chemotherapy induced persistent aplasia and he was expired because of prolonged neutropenia and pulmonary Aspergilosis. In this review we explain causes of persistent post chemotherapy persistent aplasia and prevention of this phenomenon during treatment with consideration of minimal residual disease (MRD) and response to question about chemotherapy titration dose.

Targeted immunotherapy with gemtuzumab ozogamicin (GO) following reduced intensity allogeneic stem cell transplantation (RI AlloSCT) to reduce minimal residual disease (MRD) in children with acute myeloid leukemia (AML): MRD monitoring by Wilms tumor gene

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9532-9532
Author(s):  
E. Roman ◽  
M. Olszewski ◽  
M. Kletzel ◽  
M. Bhatia ◽  
B. Bradley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Wilms Tumor ◽  
Gemtuzumab Ozogamicin ◽  
Average Risk ◽  
Peripheral Blood Stem Cells ◽  
The Impact ◽  
Targeted Immunotherapy ◽  
Acute Myeloid

9532 Background: RI vs myeloablative (MA) AlloSCT in adults with AML is associated with significantly less transplant related mortality but increased rate of relapse, presumably secondary to MRD (Alyea et al; Blood, 2005). Quantification of the WT1 has been used successfully to detect MRD in children with acute myeloid leukemia (AML) (Kletzel et al; Pediatr Dev Pathol, 2002). GO has induced ORR in >30% of patients with overt relapsed CD33+ AML and may have a better effect in the setting of MRD (Sievers et al; J Clin Oncol, 2001). We have shown that RI AlloSCT followed by 2 doses of GO in average risk AML has resulted in >94% donor chimerism (Roman/Cairo, Clin Can Res, 2005). We explored changes in MRD prior to and after consolidation with 2 doses of GO targeted immunotherapy in children with average risk AML post RI AlloSCT. Methods: 11 pts, 11 years (0.5–21) with CD33+ (8 CR1, 3 CR2) received fludarabine 30 mg/m2x6d and busulfan 3.2–4 mg/kgx2d. Donors: 7 6/6 HLA related peripheral blood stem cells (RPBSC), 1 5/6 RPBSC, 1 6/6 related cord blood (CB) and 2 4/6 unrelated CB. GOx2 was administered =60d post AlloSCTx2 (8wks apart), at 4.5–7.5 mg/m2 (dose escalation). Samples were collected for WT1 analysis prior to and after each dose of GO (n=5). WT1 levels were determined by quantitative RT-PCR and compared with WT1 expression in a K562 leukemia line. Positive MRD was a ratio of K562 WT/patient's WT1>0.5. Results: The MTD for GO post RI AlloSCT has not been reached. 8/11 are NED (3 deaths: 1 relapse, 1 graft failure, 1 cGVHD) Pre GO WT1–0.079±0.07 (n=5), pre GO-dose #2–0.012±0.016 (n=3). One of these patients had detectable MRD (WT1–1.56) prior to the GO-dose #2, no MRD at 1year and is alive and in remission at 2 years post GOx2. The fifth patient entered transplant with +MRD (WT-0.866), relapsed after the first dose of GO and died of relapse prior to receiving the second dose. Conclusions: Targeted therapy with GOx2 may be useful in eradicating MRD in patients post RI AlloSCT. A larger cohort is necessary to assess the impact of GO (at the MTD) on MRD post RI AlloSCT in children with AML. No significant financial relationships to disclose.

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.

Drug therapy for acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1154-1163 ◽  
Author(s):  
Martin S. Tallman ◽  
D. Gary Gilliland ◽  
Jacob M. Rowe
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Optimal Dose ◽  
Dose Schedule ◽  
Gemtuzumab Ozogamicin ◽  
Leukemic Cells ◽  
Farnesyl Transferase ◽  
Acute Myeloid

AbstractAlthough improvement in outcomes has occurred in younger adults with acute myeloid leukemia (AML) during the past 4 decades, progress in older adults has been much less conspicuous, if at all. Approximately 50% to 75% of adults with AML achieve complete remission (CR) with cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only approximately 20% to 30% of the patients enjoy long-term disease survival. Various postremission strategies have been explored to eliminate minimal residual disease. The optimal dose, schedule, and number of cycles of postremission chemotherapy for most patients are not known. A variety of prognostic factors can predict outcome and include the karyotype of the leukemic cells and the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance and mutations in or over expressions of specific genes such as WT1, CEBPA, BAX and the ratio of BCL2 to BAX, BAALC, EVI1, KIT, and FLT3. Most recently, insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents and have ushered in an exciting new era of antileukemia therapy. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyl transferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, and apoptosis inhibitors.

scholarly journals Post-Induction Treatment for Acute Myeloid Leukemia: Something Change?

2021 ◽  
Vol 23 (9) ◽  
Author(s):  
Sonia Jaramillo ◽  
Richard F. Schlenk
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Gemtuzumab Ozogamicin ◽  
Induction Treatment ◽  
Optimal Timing ◽  
Recent Developments ◽  
Acute Myeloid

Abstract Purpose of Review Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of conventional chemotherapy and a broadening use of allogeneic hematopoietic cell transplantation (allo-HCT) whereas the results remained dismal and very stable in patients older than 60 years. The current review highlights the recent developments in standard intensive post-remission chemotherapy, evidence for the use of recently approved agents, and discusses the relevance of measurable residual disease (MRD) measurement in treatment adaptation. Recent Findings Current approvals of midostaurin, venetoclax, gemtuzumab ozogamicin, VYXEOS, ivosidenib, enasidenib, glasdegib, and CC-486 have changed the structure, aim, and schedule of consolidation therapy, and new, well-tolerated agents are being evaluated as maintenance therapies. Furthermore, MRD assessment has been implemented to guide the duration and type of consolidation and maintenance therapy as well as indicate the optimal timing of allo-HCT. Summary Novel therapies have changed the structure and perspective of post-remission therapy in AML for both young and elderly patients. In addition, MRD assessment could guide the type, duration, and intensity of consolidation and maintenance therapy.

Sign in / Sign up

Export Citation Format

Share Document