Clinicopathological Features of Acute Myeloid Leukemia in a Patient with Phase III Clinical Trial of Tofacitinib (Xeljanz) Therapy for Ulcerative Colitis: A Case Study with Literature Review

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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Accuracy of adverse event reporting on a phase III clinical trial for pediatric acute myeloid leukemia: A report from the Children’s Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.10028 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 10028-10028

Author(s):

Tamara P. Miller ◽

Yimei Li ◽

Marko Kavcic ◽

Todd Allen Alonzo ◽

Matt Hall ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Event ◽

Myeloid Leukemia ◽

Adverse Event Reporting ◽

Phase Iii ◽

Oncology Group ◽

Event Reporting ◽

Pediatric Acute Myeloid Leukemia ◽

Phase Iii Clinical Trial ◽

Acute Myeloid

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International Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.8562 ◽

2014 ◽

Vol 32 (18) ◽

pp. 1919-1926 ◽

Cited By ~ 91

Author(s):

Gail J. Roboz ◽

Todd Rosenblat ◽

Martha Arellano ◽

Marco Gobbi ◽

Jessica K. Altman ◽

...

Keyword(s):

Clinical Trial ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase Iii ◽

Control Treatment ◽

High Dose ◽

Dismal Prognosis ◽

Significant Difference ◽

Acute Myeloid ◽

Refractory Aml

Purpose Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care. Patients and Methods A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS). Results There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation. Conclusion Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.

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Effect of intensification of induction II chemotherapy and liberalization of stem cell donor source on outcome for children with high risk acute myeloid leukemia: A report from the Children’s Oncology Group.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.10002 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 10002-10002 ◽

Cited By ~ 2

Author(s):

Richard Aplenc ◽

Lillian Sung ◽

Jessica Anne Pollard ◽

Lisa Brodersen ◽

Michael Loken ◽

...

Keyword(s):

Clinical Trial ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Clinical Outcomes ◽

Myeloid Leukemia ◽

Conditioning Regimen ◽

Phase Iii ◽

Donor Source ◽

Acute Myeloid

10002 Background: Patients with residual acute myeloid leukemia (AML) after induction fare poorly. The recently completed AAML1031 Phase III clinical trial intensified Induction II chemotherapy, altered the stem cell transplant (SCT) conditioning regimen, and liberalized SCT donor source criteria. We sought to test whether these practice changes improved clinical outcomes. Methods: Patients on AAML0531 and AAML1031, sequential Phase III trials for AML with shared high risk features of both > 15% residual blasts by morphology and ≥ 0.1% minimal residual disease (MRD) by flow cytometry with uninformative cytogenetics or high risk cytogenetic features (-7 or -5/5q-) were included. Gemtuzmab exposed and patients with high allelic ratio FLT3 ITD were excluded. Patients were observed from the start of Induction II through last available follow up. Induction II chemotherapy (ADE or AraC/Mito) was the exposure of interest. Disease free and overall survival (DFS, OS) were the primary outcomes. Standard descriptive statistics were used to compare patient characteristics and secondary outcomes; Kaplan Meier analyses were used to evaluate DFS/OS. Results: A total of 47 patients from AAML0531 (ADE) and 95 patients from AAML1031 (AraC/Mito) were included and did not differ in baseline characteristics. Five year DFS ±2SE was 17.5 ± 11.4 for ADE and 23.9 ± 8.8 for AraC/Mito, p = 0.528. Five year OS was 38.1 ± 14.2 for ADE and 33.3 ± 10.7 for AraC/Mito, p = 0.364. End of Induction II disease response and MRD did not differ between ADE and AraC/Mito. Patients receiving ADE had a higher probability of neutrophil recovery (74% vs 53%, p = 0.019) and recovered neutrophils a median of 7 days more quickly (27 vs 34 days), p = < 0.001. ADE patients also had fewer inpatient hospital days (28 days versus 32 days, p = 0.002). The percentage of patients receiving SCT did not differ, 34% vs 44%, p = 0.253 and post-SCT outcomes did not differ. Conclusions: The intensification of Induction II chemotherapy, change in SCT conditioning regimen, and liberalization of SCT donor source was not associated with improved clinical outcomes. Intensification of Induction II was associated with increased hematologic toxicity and length of stay. These data do not support the intensification of Induction II chemotherapy with AraC/Mitoxantrone. Clinical trial information: NCT01371981.

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