Cytarabine syndrome despite corticosteroid premedication in an adult undergoing induction treatment for acute myelogenous leukemia

2016 ◽  
Vol 22 (6) ◽  
pp. 795-800 ◽  
Author(s):  
Matthew A Jirasek ◽  
Jon D Herrington
Keyword(s):  
Adverse Event ◽  
Proinflammatory Cytokines ◽  
Myelogenous Leukemia ◽  
Induction Treatment ◽  
Proinflammatory Response ◽  
Treatment And Prevention ◽  
Immune Mediated ◽  
Intravenous Morphine ◽  
Acute Myelogenous ◽  
Induced Apoptosis

Cytarabine syndrome is a rare clinical condition characterized by fever, malaise, myalgia, arthralgia, and/or rash that occurs after receipt of cytarabine. Our patient developed fever, malaise, and diffuse body pain shortly following cytarabine initiation despite receiving prophylactic dexamethasone. The patient’s discomfort was treated with intravenous morphine and her other symptoms were controlled with a higher dose of dexamethasone. Although the exact cause is not fully understood, cytarabine syndrome is hypothesized to be an immune-mediated response following cytarabine-induced apoptosis that results in a rapid increase in proinflammatory cytokines. While there is no standard therapy for cytarabine syndrome, corticosteroids appear to play a role in the treatment and prevention of the condition by suppressing the proinflammatory response. Since our case describes the development of cytarabine syndrome despite dexamethasone, clinicians should monitor for this adverse event if patients begin exhibiting characteristics of this syndrome.

scholarly journals Mechanistic insight into WEB-2170-induced apoptosis in human acute myelogenous leukemia cells: The crucial role of PTEN

2009 ◽  
Vol 37 (10) ◽  
pp. 1176-1185.e21 ◽  
Author(s):  
Cristina Cellai ◽  
Anna Laurenzana ◽  
Elisa Bianchi ◽  
Sara Sdelci ◽  
Rossella Manfredini ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Crucial Role ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Mechanistic Insight ◽  
Acute Myelogenous ◽  
Induced Apoptosis ◽  
Insight Into

Homoharringtonine Based Triple-Drug Regimen as Induction Chemotherapy for De Novo Acute Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2002-2002
Author(s):  
Jie Jin ◽  
Wenbin Qian ◽  
Hui Liu ◽  
Daozi Jian ◽  
Wenyuan Mai ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Neutrophil Count ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Acute Myelogenous ◽  
De Novo Aml

Abstract HAA regimen, consisting of homoharringtonine (HHT), aclarubicin and cytarabine (Ara-C), is an efficacious chemotherapy regimen for induction treatment of acute myelogenous leukemia (AML). HHT, a plant alkaloid that is derived from a Chinese evergreen tree, has been shown to inhibit protein, DNA, and RNA synthesis by inhibition of chain initiation. HAA regimen consists of HHT administered at a dose of 4 mg/m2/day by continuous infusion over 4 hours or 2 mg/m2 intramuscular injection twice daily on days 1–3, aclarubicin administered at a dose of 12 mg/m2/day by continuous infusion over 2 hours on days 1–7, and cytarabine (Ara-C) given at a dose of 75 mg/m2 twice daily on days 1–7. Granulocyte colony-stimulating factor (Lenograstim) 5 μg/kg/day subcutaneously was started from the day neutrophil count <0.5×109/l, and continued until the day neutrophil count >1.0×109/l on 3 successive days. For patients with partial remission (PR) after the evaluation of the first course of the therapy, another same induction HAA regimen was administered. Between May 1999 and June 2006, 80 patients consisted of 31 male and 49 female patients were enrolled. All patients had newly diagnosed with de novo AML and had not received any induction treatments before. Out of them, 3 were M1, 44 M2, 2 M4, and 31 M5 according to FAB classification criteria. The median age was 36 (14–59) years. Of all the 76 patients with cytogenetic analysis available, 13 had favorable karyotype, 58 intermediate karyotype, and 5 unfavorable karyotype. In all, 68 (85%) patients achieved complete remission (CR), and the first single course of this induction regimen resulted in a CR rate of 75%. The CR rate of 100%, 88% and 20% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. We also found that patients with M5 achieved a CR rate of 74% (23/31), while patients with M1 or M2 94% (44/47). The toxicities associated with this regimen were no more than those expected with standard chemotherapy, and the most common non-hematological toxicity was infection. This study suggested that HAA regimen is a safe regimen and it is efficacious, well-tolerable induction therapy for newly diagnosed de novo AML, the use of G-CSF (Lenograstim) appears to be safe, with little risk of accelerating leukemic relapse. A high CR rate can be achieved with only one or two courses of this regimen. Besides, cytogenetics is an important prognostic factor.

The pp90rsk-CREB Signaling Pathway Regulates Apoptosis In Acute Myelogenous Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3801-3801
Author(s):  
Bryan Mitton ◽  
Ritika Dutta ◽  
Yu-Chiao Hsu ◽  
Rachel Ochoa ◽  
Elliot Landaw ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Apoptosis ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Expression Level ◽  
Acute Myelogenous ◽  
Targeted Inhibition ◽  
Induced Apoptosis ◽  
Pharmacologic Inhibition

Abstract CREB (cAMP Response-Element Binding Protein) is a nuclear transcription factor critical for hematopoietic cell proliferation, differentiation, and survival. We previously demonstrated that 60% of patients with Acute Myelogenous Leukemia (AML) overexpress CREB in leukemic blasts, and CREB overexpression in these patients was associated with an increased risk of relapse and decreased event-free survival. Previous studies have suggested that CREB may play an important role in the regulation of apoptosis in a wide variety of cancers. Specifically, CREB has been shown to up-regulate members the anti-apoptotic protein family such as Bcl-2, Bcl-XL and Mcl-1, leading to chemotherapy resistance in vitro. CREB-mediated resistance to apoptosis may underlie the increased rate of relapse and poor survival of AML patients with CREB overexpression. Thus, we hypothesized that targeted inhibition of CREB in AML cells would promote AML cell apoptosis. To test this hypothesis, we developed a small-molecule inhibitor of CREB function, XX-650-23. This molecule disrupts the interaction between CREB and its binding partner CBP (CREB-Binding Protein), which is required for full activation of CREB-mediated gene transcription. Treatment of primary AML patient bone marrow samples with XX-650-23 induced apoptosis and cell death at a dose of 2 uM. The degree of apoptosis varied with the expression level of CREB in primary AML cells tested. Higher CREB levels correlated with higher sensitivity to XX-650-23. In non-leukemic primary patient bone marrow samples, CREB levels were very low, and XX-650-23 did not induce apoptosis in these cells. AML cell lines (KG-1 and HL-60) also underwent apoptosis following CREB inhibition, in proportion to CREB expression level. CREB knockdown or overexpression in KG-1 cells decreased and increased susceptibility to apoptosis, respectively. Mechanistically, the onset of apoptosis in AML cells occurred simultaneously with down-regulation of Bcl-2, a validated CREB-regulated gene. Inhibition of Bcl-2 function using the specific Bcl-2 inhibitor ABT-737 (100 nM) induced apoptosis similar to XX-650-23, indicating that Bcl-2 inhibition alone is sufficient to cause apoptosis. Thus, targeted inhibition of CREB results in Bcl-2 downregulation and is sufficient to induce apoptosis in AML cells. Proteomic analysis using Mass Cytometry-Time of Flight (CyTOF) revealed that one compensatory cellular response to CREB inhibition is increased phosphorylation of CREB. This phosphorylation decreased in the presence of BI-D1870, a specific inhibitor of the pp90RSK kinase (RSK), but not by pharmacologic inhibition of the p38 or ERK kinases, using SB202190 or U0126, respectively. We therefore examined the role of pp90RSK in the regulation of apoptosis in AML cells. Pharmacologic inhibition of RSK independently lead to AML cell apoptosis (BI-D1870, IC50=3.3 uM), in part due to blockade of CREB phosphorylation. In summary, our data provide the first evidence that inhibition of CREB, or its chief activator RSK, is sufficient to induce apoptosis in AML cells. Current work focuses on defining CREB target genes mediating XX-650-23 response using chromatin-immunoprecipitation with massively parallel DNA sequencing (ChIP-Seq), and defining the RSK kinome in AML cells using 2-dimensional gel phosphoprotein profiling. These studies will more fully define the role of the RSK-CREB signaling axis in AML proliferation, survival, and apoptosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blockade of MEK signaling potentiates 5-Aza-2′-deoxycytidine-induced apoptosis and upregulation of p21waf1 in acute myelogenous leukemia cells

2009 ◽  
Vol 125 (5) ◽  
pp. 1168-1176 ◽  
Author(s):  
Chie Nishioka ◽  
Takayuki Ikezoe ◽  
Jing Yang ◽  
Naoki Komatsu ◽  
H. Phillip Koeffler ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Acute Myelogenous ◽  
Induced Apoptosis

scholarly journals T-Cell–Depleted Allogeneic Bone Marrow Transplantation as Postremission Therapy for Acute Myelogenous Leukemia: Freedom From Relapse in the Absence of Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 1083-1090 ◽  
Author(s):  
Esperanza B. Papadopoulos ◽  
Matthew H. Carabasi ◽  
Hugo Castro-Malaspina ◽  
Barrett H. Childs ◽  
Stephen Mackinnon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Complete Remission ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Acute Myelogenous ◽  
Postremission Therapy

Thirty-one consecutive patients with acute myelogenous leukemia (AML) in first complete remission and 8 with AML in second complete remission received T cell–depleted allogeneic bone marrow transplants from HLA-identical sibling donors. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, thiotepa, and cyclophosphamide. Those patients at risk for immune-mediated graft rejection received additional immune suppression with antithymocyte globulin and methylprednisolone in the early peritransplant period. Patients with AML who underwent allogeneic T-cell–depleted bone marrow transplantations (BMT) in first or second remission have achieved respective disease-free survival (DFS) probabilities of 77% (median follow-up at approximately 56 months) and 50% (median follow-up at approximately 48 months). Ten of 31 patients transplanted in first remission were ≥ 40 years old and have attained a DFS at 4 years of 70%. For patients with AML transplanted in first or second remission, the respective cause-specific probabilities of relapse were 3.2% or 12.5%, and those of nonleukemic mortality were 19.4% or 37.5%. There were no cases of immune-mediated graft rejection and no cases of grade II to IV acute graft-versus-host disease (GVHD). All survivors enjoy Karnofsky performance scores (KPS) of 100%, except 2 patients with KPS of 80% to 90%. T-cell–depleted allogeneic BMT can provide durable DFS together with an excellent performance status in the majority of patients with de novo AML. In addition, GVHD is not an obligatory correlate of the graft-versus-leukemia benefit or freedom from relapse afforded by allogeneic BMT administered as postremission therapy for AML. This study provides a basis for prospective comparison with other postremission therapies considered standard in the management of patients with this disease.

Proteasome Inhibition Sensitizes Leukemic Cells to Anthracyclin-Induced Apoptosis by Increasing the Expression of Bim and Bax Pro-Apoptotic Proteins.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2487-2487
Author(s):  
Arnaud Pigneux ◽  
François X. Mahon ◽  
François Moreau-Gaudry ◽  
Marie L. Néré ◽  
Francis Lacombe ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Low Concentration ◽  
Cord Blood Cd34 ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Apoptotic Proteins ◽  
Induced Apoptosis ◽  
Sensitizing Effect

Abstract NF-k B is constitutively activated in the majority of acute myelogenous leukemia (AML) specimens. Anthracyclines used in AML treatment can activate NF-k B and inhibit apoptosis through synthesis of IAPs upregulation. Because proteasome activity is necessary for NF-k B activation and p53 degradation, inhibitors of the proteasome have been proposed as pro-apoptotic agents to sensitize leukemic blast cells to anthracycline chemotherapy. Apoptosis was quantified in THP-1 cells, incubated with increasing concentrations of (IDA) alone or in association with a low concentration (0.25 μM) of MG132 as a proteasome inhibitor. A low apoptotic rate was found with either MG132 or IDA alone with a range of 5 to 20 ng/ml. The combination of both drugs induced a percentage of apoptotic cells which was significantly higher than the addition of the effects of both drugs separately (p&lt;0.01). A low concentration of IDA (5ng/ml) induced, in the presence of MG132 as much apoptosis as 20 ng/ml of IDA alone. Above 40 ng/ml of IDA, the sensitizing effect of MG132 was no more significant. This shows that proteasome inhibition lowers the threshold of sensititvity of THP-1 cells to IDA-induced apoptosis. Such a sensitization was not found in a MG132-resistant THP-1 derived cell line. This difference was not related to the uptake of the drug since no difference in IDA incorporation by THP-1 cells was found in the presence or the absence of MG132. Western blot analysis of I-k B phosphorylation and degradation failed to show any difference between MG132 and control-treated cells. Conversely increased expression of Bax and Bim pro-apoptotic proteins was evidenced. The increase in Bim precedes the induction of apoptosis and participates in Idarubicin-induced apoptosis. Bortezomib gave the same results for apoptosis induction and synergistic effect with IDA, increased expression of Bax and Bim pro-apoptotic proteins was also evidenced. MG132 also potentiated IDA-induced apoptosis in primary blast cells from 22 AML patients while no effect of MG132 was found on the IDA-induced apoptosis normal lymphocytes, PHA-stimulated lymphocytes, normal cord blood CD34+ cells and bone marrow normal myeloid cells. These data confirm that proteasome inhibition induces a specific sensitization of leukemic cells to IDA and suggest that an increase in the pro-apoptotic potential (Bim, Bax) are involved in the process.

Severe palmar-plantar erythrodysesthesia and aplasia in an adult undergoing re-induction treatment with high-dose cytarabine for acute myelogenous leukemia: a possible drug interaction between posaconazole and cytarabine

2016 ◽  
Vol 23 (6) ◽  
pp. 476-480 ◽  
Author(s):  
Saeed K Alzghari ◽  
Susan E Seago ◽  
Christian T Cable ◽  
Jon D Herrington
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Induction Treatment ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
P Glycoprotein ◽  
High Dose Cytarabine ◽  
Acute Myelogenous ◽  
Hands And Feet ◽  
Glycoprotein Inhibition

High-dose cytarabine is recommended for re-induction chemotherapy in patients less than 60 years of age with acute myelogenous leukemia. This case describes a patient receiving high-dose cytarabine for re-induction and subsequently developed tingling and numbness in her hands and feet followed by severe pain, swelling, and erythema consistent with a diagnosis of palmar-plantar erythrodysesthesia. Furthermore, the patient’s hemoglobin, platelets, and neutrophils did not recover after over 30 days post high-dose cytarabine. The patient was concurrently receiving posaconazole for fungal prophylaxis which was initiated after the induction therapy. We speculate that posaconazole may inhibit the cytarabine efflux through P-glycoprotein inhibition leading to the patient’s palmar-plantar erythrodysesthesia and subsequent aplasia. Future pharmacokinetic studies need to be conducted to ascertain if posaconazole does influence the pharmacokinetics of cytarabine.

scholarly journals T-Cell–Depleted Allogeneic Bone Marrow Transplantation as Postremission Therapy for Acute Myelogenous Leukemia: Freedom From Relapse in the Absence of Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 1083-1090 ◽  
Author(s):  
Esperanza B. Papadopoulos ◽  
Matthew H. Carabasi ◽  
Hugo Castro-Malaspina ◽  
Barrett H. Childs ◽  
Stephen Mackinnon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Complete Remission ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Immune Mediated ◽  
Acute Myelogenous ◽  
Postremission Therapy

Abstract Thirty-one consecutive patients with acute myelogenous leukemia (AML) in first complete remission and 8 with AML in second complete remission received T cell–depleted allogeneic bone marrow transplants from HLA-identical sibling donors. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, thiotepa, and cyclophosphamide. Those patients at risk for immune-mediated graft rejection received additional immune suppression with antithymocyte globulin and methylprednisolone in the early peritransplant period. Patients with AML who underwent allogeneic T-cell–depleted bone marrow transplantations (BMT) in first or second remission have achieved respective disease-free survival (DFS) probabilities of 77% (median follow-up at approximately 56 months) and 50% (median follow-up at approximately 48 months). Ten of 31 patients transplanted in first remission were ≥ 40 years old and have attained a DFS at 4 years of 70%. For patients with AML transplanted in first or second remission, the respective cause-specific probabilities of relapse were 3.2% or 12.5%, and those of nonleukemic mortality were 19.4% or 37.5%. There were no cases of immune-mediated graft rejection and no cases of grade II to IV acute graft-versus-host disease (GVHD). All survivors enjoy Karnofsky performance scores (KPS) of 100%, except 2 patients with KPS of 80% to 90%. T-cell–depleted allogeneic BMT can provide durable DFS together with an excellent performance status in the majority of patients with de novo AML. In addition, GVHD is not an obligatory correlate of the graft-versus-leukemia benefit or freedom from relapse afforded by allogeneic BMT administered as postremission therapy for AML. This study provides a basis for prospective comparison with other postremission therapies considered standard in the management of patients with this disease.

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