scholarly journals The Effect of Traumatic Diagnostic Lumbar Puncture in De Novo Pediatric Acute Myeloid Leukemia - a Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4016-4016
Author(s):  
Donna L Johnston ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
William G Woods ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Red Blood Cells ◽  
Lumbar Puncture ◽  
Systemic Therapy ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Study Entry ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Background - In many adult protocols for acute myeloid leukemia (AML), the standard of care is to perform a lumbar puncture (LP) at the time of diagnosis only if there are central nervous system (CNS) symptoms present, and if absent, the LP is performed after a period of systemic therapy in order to avoid contamination of the cerebrospinal fluid (CSF) with circulating blasts in the case of a traumatic LP, or is not done at all. This differs from the practice in pediatric AML protocols where LP is performed as part of the diagnostic workup and intrathecal (IT) cytarabine given at the time of the diagnostic LP, as well as during therapy, similar to the pediatric ALL approach. We sought to determine the effect of an initial traumatic LP in a large cohort of pediatric patients with de novo AML. Methods - Treatment protocols COG AAML03P1 and AAML0531 enrolled 1344 patients with diagnostic LP and outcome data available. In these protocols, patients identified to be CNS2 (0-5 WBC with blasts present) or CNS3 (>5 WBC with blasts or CNS symptoms at diagnosis) prior to systemic therapy received additional IT therapy, while CNS1 (no blasts) patients received IT therapy only at the beginning of most courses of chemotherapy. Patients were analyzed for CNS status as well as diagnostic LP red cell count. A diagnostic LP with greater than 100 red blood cells was considered traumatic. The effect of traumatic LP on outcome was analyzed. Results - Among these patients, 949 were CNS1, 217 were CNS2 and 178 were CNS3. In looking at percentage of patients with more than 100 RBC in the CSF, there were 52 (5.48%) CNS1, 12 (5.53%) CNS2 and 55 (30.9%) CNS3 (three group comparison, p<0.001). As well, in patients with 6 to 100 RBC in the CSF in each CNS group there was a significant difference with 150 (15.81%) CNS1, 64 (29.49%) CNS2 and 45 (25.28%) CNS3 patients, (p<0.001). Figure 1 shows the number of patients in each CNS group with number of RBC in the diagnostic LP. The number of RBC in the CSF did not correlate with the degree of peripheral blood hyperleukocytosis. The outcomes of patients with traumatic initial LP showed that patients who had a traumatic initial LP did not have a significantly different OS (HR 1.14, p=0.405) or EFS (HR 1.22, p=0.132) from study entry, nor RR (HR 1.06, p=0.769) or TRM (HR 1.30, p=0.510) compared to those with an atraumatic LP. This was similarly seen in the subgroups, CNS1, CNS2, and CNS3. In examining patients with 0 RBC in their initial CSF, OS was similar among the CNS1, CNS2 and CNS3 patients (62.6%, 62.7% and 66.4% respectively, p=0.974). The OS was also similar for patients with <100 RBC (64.5% ± 2.8%) and >100 RBC (63.0% ±9.1%). In examining outcomes of CNS3 patients with a traumatic tap, there were no significant differences in OS, EFS, or RR among those with traumatic tap and those without. Overall though, multivariable analyses showed that CNS3 patients had significantly worse EFS from study entry compared to CNS1 and CNS2 patients (HR 1.58, p<0.001) due to a higher RR (HR 1.64, p=0.003). The CNS3 patients with traumatic LP had similar OS and EFS compared to those without traumatic LP (OS 63.5% ± 15.2% vs 60.8% ± 11.4% respectively, and EFS 43.4% ± 15.3% vs 35.5% ± 10.9% respectively). Conclusion - There were significantly more CNS3 patients with >100 RBC in the CSF than in the other 2 CNS groups. Outcome for these patients with traumatic LP vs those with atraumatic LP however were not different for EFS, OS or RR for all 3 CNS groups. It is likely that more than half of the CNS3 patients received extra IT therapy due to traumatic LP. In the majority of cases these IT therapies were given with sedation, potentially unnecessarily. The concern though that a traumatic initial LP contributes to worse outcome in CNS3 patients is not warranted. Delaying initial LP to align with adult practice, when peripheral blasts are cleared, would not change prognosis, but may lessen the number of patients who need additional IT therapy from traumatic LPs, thus sparing a significant proportion of children unnecessary procedures and CNS directed chemotherapy. Figure 1 Number of Red Blood Cells in the CSF, CNS Status and Number of Patients in Each Grouping Figure 1. Number of Red Blood Cells in the CSF, CNS Status and Number of Patients in Each Grouping Disclosures No relevant conflicts of interest to declare.

scholarly journals NPM1 and FLT3-ITD/TKD Gene Mutations in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Shano Naseem ◽  
Jogeshwar Binota ◽  
Neelam Varma ◽  
Harpreet Virk ◽  
Subhash Varma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Total Leucocyte Count ◽  
Molecular Testing ◽  
Therapeutic Implications ◽  
Number Of Patients ◽  
Flt3 Mutations ◽  
Acute Myeloid

Background: A number of mutations have been reported to occur in patients with acute myeloid leukemia (AML), of which NPM1 and FLT3 genes mutations are the commonest and have important diagnostic and therapeutic implications. Material and Methods: Molecular testing for NPM1 and FLT3 genes was performed in 92 de-novo AML patients. The frequency and characteristics of NPM1 and FLT3 mutations were analyzed. Results: Nucleophosmin 1(NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutations were seen in 22.8% and 16.3% of patients, respectively. Amongst FLT3 mutations, FLT3-ITD mutation was seen in 8.7% cases, FLT3- TKD in 5.4%, and FLT3-ITD+TKD in 2.2% cases. Certain associations between the gene mutations and clinical characteristics were found, including in NPM1 mutated group- female preponderance, higher incidence in M4/M5 categories and decreased expression of CD34 and HLA-DR; and in FLT3-ITD mutated group- higher age of presentation, higher total leucocyte count and blast percentage. Conclusion- AML patients with NPM1 and FLT3 mutations have differences in clinical and hematological features, which might represent their different molecular mechanism in leukemogenesis. The frequency of NPM1 and FLT3 mutations in this study was comparable to reports from Asian countries but lower than that reported from western countries. However, as the number of patients in the study was less, a larger number of patients need to be studied to corroborate these findings.

The Presence of Central Nervous System Disease at Diagnosis in Pediatric Acute Myeloid Leukemia Does Not Affect Outcome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1827-1827
Author(s):  
Donna L. Johnston ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Beverly J. Lange ◽  
William G. Woods
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Nervous System ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Study Entry ◽  
Pediatric Acute Myeloid Leukemia ◽  
Cns Disease ◽  
Acute Myeloid

Abstract Introduction: The presence of disease in the central nervous system (CNS) in pediatric acute myeloid leukemia (AML) is often thought to confer a worse prognosis. This study examined the outcome of children with AML who had CNS disease at diagnosis. Methods: Patients enrolled on Children’s Oncology Group protocols 2891 (N=836)and 2961 (N=901) being treated for de novo AML were classified for the presence of CNS disease at diagnosis as: CNS1 (less than 5 WBC in the CSF with no blasts), CNS2 (less than 5 WBC in the CSF with blasts) or CNS3 (5 or more WBC in the CSF with blasts). CNS disease at diagnosis was then analysed for survival, patient characteristics and outcome using univariate analysis. Patients on these protocols were treated with intrathecal chemotherapy and not radiation therapy for their CNS disease. Results: For both AML protocols, the overall survival and event free survival were highest in patients with CNS2 disease but this was not significantly different from the survival of the CNS1 and CNS3 patients. Overall survival from 2891 study entry for all de novo patients Overall survival from 2891 study entry for all de novo patients Overall survival from 2961 study entry for all de novo patients Overall survival from 2961 study entry for all de novo patients Patients with CNS 2 and 3 disease were of significantly lower median age than CNS1 patients (p=0.001 in 2891 and p=0.005 in 2961). There was a significantly higher WBC count at diagnosis (p=0.001 in both studies), presence of hepatomegaly (p=0.001 in both studies), presence of splenomegaly (p=0.003 in 2891 and p=0.001 in 2961), FAB M2 morphology (p=0.001 in both studies) and FAB M4 morphology (p=0.001 in both studies) in patients with CNS2 and 3 disease compared to CNS 1 patients. Also, CNS2 and 3 patients had a significantly higher incidence of abnormal chromosome 16 (p=0.002 in 2891 and p=0.001 in 2961). In protocol 2891 significantly more CNS2 and 3 patients had hyperdiploid cytogenetics compared to CNS1 patients (p=0.016), and in protocol 2961 there were significantly more patients with t(8;21) in the CNS1 group (p=0.007). In terms of overall outcome, there was a significantly higher incidence of isolated CNS relapse in patients with CNS3 disease at diagnosis in the 2891 protocol (p=0.001), and in patients with both CNS2 and 3 disease at diagnosis in the 2961 protocol (p=0.001). Conclusion: Patients with CNS disease at diagnosis have similar survival to those without CNS disease, although they have an increased incidence of isolated CNS relapse. More aggressive CNS directed therapy may be warranted in this patient population.

scholarly journals A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Filgrastim in Remission Induction and Consolidation Therapy for Adults With De Novo Acute Myeloid Leukemia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4710-4718 ◽  
Author(s):  
Gerhard Heil ◽  
Dieter Hoelzer ◽  
Miguel A. Sanz ◽  
Klaus Lechner ◽  
John A. Liu Yin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Iii ◽  
Remission Induction ◽  
Induction Treatment ◽  
Consolidation Therapy ◽  
Double Blind ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract The safety and efficacy of filgrastim as an adjunct to acute myeloid leukemia (AML) induction and consolidation therapy was assessed in this prospective double-blind, randomized, placebo-controlled, multicenter trial. A total of 521 consecutive de novo AML patients aged 16 or more years were randomized to receive filgrastim (5 μg/kg/d subcutaneously) or placebo after standard induction as well as consolidation chemotherapy. Blinded study drug was given from 24 hours after chemotherapy until the absolute neutrophil count was ≥1.0 × 109/L for 3 consecutive days. The overall complete remission rate was 68%. After a median follow-up of 24 months (range 5 to 40) the median disease-free survival was 10 months (95% confidence interval [CI], 8.7 to 10.8) and the median overall survival was 13 months (95%CI, 12.2 to 14.6). These did not differ between treatment groups. Patients receiving filgrastim experienced neutrophil recovery 5 days earlier after induction 1 than those receiving placebo (P < .0001). This was accompanied by reductions in the duration of fever (7 v 8.5 days; P = .009), parenteral antibiotic use (15 v 18.5 days; P = .0001), and hospitalization (20 v 25 days; P = .0001). Similar reductions were seen after induction 2 and the consolidation courses. There was a significant reduction in the number of patients requiring systemic antifungal therapy in the filgrastim group during induction treatment (34% v 43%; P = .04). In conclusion, filgrastim is safe in that it had no negative impact on the prognosis of the AML patients. In addition, it effectively reduced the duration of neutropenia, leading to significant clinical benefits by reducing the duration of fever; requirement for parenteral anti-infectives, specifically amphotericin B; and the duration of hospitalization.

scholarly journals A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Filgrastim in Remission Induction and Consolidation Therapy for Adults With De Novo Acute Myeloid Leukemia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4710-4718 ◽  
Author(s):  
Gerhard Heil ◽  
Dieter Hoelzer ◽  
Miguel A. Sanz ◽  
Klaus Lechner ◽  
John A. Liu Yin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Iii ◽  
Remission Induction ◽  
Induction Treatment ◽  
Consolidation Therapy ◽  
Double Blind ◽  
Number Of Patients ◽  
Acute Myeloid

The safety and efficacy of filgrastim as an adjunct to acute myeloid leukemia (AML) induction and consolidation therapy was assessed in this prospective double-blind, randomized, placebo-controlled, multicenter trial. A total of 521 consecutive de novo AML patients aged 16 or more years were randomized to receive filgrastim (5 μg/kg/d subcutaneously) or placebo after standard induction as well as consolidation chemotherapy. Blinded study drug was given from 24 hours after chemotherapy until the absolute neutrophil count was ≥1.0 × 109/L for 3 consecutive days. The overall complete remission rate was 68%. After a median follow-up of 24 months (range 5 to 40) the median disease-free survival was 10 months (95% confidence interval [CI], 8.7 to 10.8) and the median overall survival was 13 months (95%CI, 12.2 to 14.6). These did not differ between treatment groups. Patients receiving filgrastim experienced neutrophil recovery 5 days earlier after induction 1 than those receiving placebo (P < .0001). This was accompanied by reductions in the duration of fever (7 v 8.5 days; P = .009), parenteral antibiotic use (15 v 18.5 days; P = .0001), and hospitalization (20 v 25 days; P = .0001). Similar reductions were seen after induction 2 and the consolidation courses. There was a significant reduction in the number of patients requiring systemic antifungal therapy in the filgrastim group during induction treatment (34% v 43%; P = .04). In conclusion, filgrastim is safe in that it had no negative impact on the prognosis of the AML patients. In addition, it effectively reduced the duration of neutropenia, leading to significant clinical benefits by reducing the duration of fever; requirement for parenteral anti-infectives, specifically amphotericin B; and the duration of hospitalization.

scholarly journals In Patients with Acute Myeloid Leukemia, Hidac Administered on Days 1, 2 and 3 of Consolidation Course Is As Efficacious As Hidac Given on Days 1, 3 and 5, but Is Better Tolerated

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3378-3378
Author(s):  
Baher Krayem ◽  
Avraham Frisch ◽  
Nurit Horesh ◽  
Ronit Leiba ◽  
Tsila Zuckerman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Neutropenic Fever ◽  
Risk Category ◽  
Consolidation Therapy ◽  
Blood Products ◽  
Packed Red Blood Cells ◽  
Acute Myeloid

Abstract Introduction: High-dose Ara-C (HiDAC) is a post-remission consolidation protocol commonly used in patients with acute myeloid leukemia (AML). The optimal regimen of HiDAC administration is not fully established. Recent studies suggest that a short and condensed schedule of HiDAC consolidation therapy given on days 1, 2 and 3 (HiDAC123) may be superior to the traditional days 1, 3 and 5 regimen (HiDAC135). The current retrospective study compared the impact of these two therapeutic approaches on the outcomes of AML patients treated at the Rambam Leukemia Unit. Methods: This retrospective cohort analysis included patients diagnosed with AML between the years 2015-2020 who were candidates for aggressive chemotherapy. Fifty-seven patients received a total of 76 courses of HiDAC135 mainly between 2015 and 2017, while 77 other patients received a total of 135 courses of HiDAC123 mainly between 2017 and 2020. The HiDAC dose in the two groups was 3 g/m 2 for patients aged less than 55 years, and 1.5 g/m 2 for patients aged 55-65 years. Patient demographics, the ELN leukemia risk category and NPM1 status were compared. The analysis also included data on complications per course of HiDAC therapy, need for hospitalization, the number of days of hospitalization if needed, the occurrence of neutropenic fever per course, the need for blood products (packed red blood cells and platelets), neurotoxicity and death within the 28 days of the course. Results: The HiDAC123 and HiDAC135 groups were comparable in terms of the ELN risk category and NPM1 status. The groups significantly differed in age (median of 49.8 years and 55.9 years, respectively; p=0.01), which was most likely to be related to the use of venetoclax and azacitidine during the period when HiDAC123 was prescribed. Similar percentage of patients achieved complete remission (CR) after induction chemotherapy (93.5% and 94.7%, in the HiDAC123 and HiDAC135 groups, respectively). There were no differences in the overall survival (OS) and event-free survival (EFS) between the two groups (Figure 1). Significantly more patients in the HiDAC135 group were hospitalized for more than 4 days compared with the HiDAC123 group (51.3% vs 31.9%; p=0.008) and significantly more patients in the HiDAC135 group needed more than 2 units of packed red blood cells than in the HiDAC123 group (38.2% vs 21.5%, p=0.011). There was no difference in the percentage of patients in need of platelet transfusion. Likewise, there was no difference between the two groups in either the number of hospitalizations post-HiDAC therapy, the occurrence of neutropenic fever events or the incidence of death within the first 28 days after the HiDAC therapy. Conclusions: The present analysis demonstrates that HiDAC123 is as safe and efficacious as HiDAC135 in terms of OS and EFS and is associated with shorter hospitalization and lower requirement for blood products. These results show that HiDAC123 could be the regimen of choice as consolidation therapy in AML patients. Figure 1 Figure 1. Disclosures Zuckerman: Orgenesis Inc.: Honoraria; BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Ofran: Pfizer: Consultancy; AbbVie: Consultancy; Medison Israel: Consultancy; Astellas: Consultancy; Janssen: Consultancy.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

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