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Cytarabine

"A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)" (MeSH 2013)

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Paubelle E, Ducastelle-Leprêtre S, Labussière-Wallet H, et al.
Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant?
Ann Hematol. 2017; 96(3):363-371 [PubMed] Related Publications
Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.

Gong D, Li W, Hu LD, et al.
Comparison of Clinical Efficacy of Cytarabine with Different Regimens in Postremission Consolidation Therapy for Adult t(8;21) AML Patients: A Multicenter Retrospective Study in China.
Acta Haematol. 2016; 136(4):201-209 [PubMed] Related Publications
BACKGROUND: The survival of patients with acute myeloid leukemia (AML) with t(8;21) was reported to be shorter in China than in other countries.
PATIENTS: We analyzed the correlation between different cytarabine (Ara-c) regimens and outcome in 255 t(8;21) AML patients in China who received postremission consolidation chemotherapy only.
RESULTS: The 5-year overall survival (OS) of the high-dose Ara-c group (HDAC; 2≤ Ara-c ≤3 g/m2), intermediate-dose Ara-c group (MDAC; 1.0≤ Ara-c <2.0 g/m2), low-dose Ara-c group (LDAC; 0.2< Ara-c <1.0 g/m2) and standard-dose Ara-c group (SDAC; 0.1≤ Ara-c ≤0.2 g/m2) were 65.3, 39.4, 25.2 and 27.9%, respectively (p = 0.003). In the HDAC group, but not in the MDAC group, the 5-year OS of patients who achieved 3-4 cycles of chemotherapy was superior to those who underwent 1-2 cycles (84.4 vs. 43.6%, p < 0.05), and the 3-year OS of patients who achieved an accumulated 36 g/m2 of Ara-c was significantly higher compared to those who did not (85.3 vs. 39.2%, p < 0.05). Multivariate analysis indicated that factors such as WBC >3.5 × 109/l, PLT ≤30 × 109/l, and extramedullary infiltration were associated with a poor prognosis.
CONCLUSION: The survival of t(8;21) AML patients treated with high-dose Ara-c (≥2 g/m2) was superior to other dose levels in postremission consolidation chemotherapy. Patient survival was improved by 3-4 cycles of chemotherapy with an accumulated concentration of 36 g/m2 of Ara-c. WBC >3.5 × 109/l, PLT ≤30 × 109/l and extramedullary infiltration could be indicative of a poor clinical prognosis.

Hermine O, Hoster E, Walewski J, et al.
Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network.
Lancet. 2016; 388(10044):565-75 [PubMed] Related Publications
BACKGROUND: Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome.
METHODS: This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222.
FINDINGS: Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups.
INTERPRETATION: Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma.
FUNDING: European Commission, Lymphoma Research Foundation, and Roche.

Drenberg CD, Buaboonnam J, Orwick SJ, et al.
Evaluation of artemisinins for the treatment of acute myeloid leukemia.
Cancer Chemother Pharmacol. 2016; 77(6):1231-43 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models.
METHODS: Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models.
RESULTS: ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo.
CONCLUSIONS: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML.

Candelaria M, Corrales-Alfaro C, Gutiérrez-Hernández O, et al.
Expression Levels of Human Equilibrative Nucleoside Transporter 1 and Deoxycytidine Kinase Enzyme as Prognostic Factors in Patients with Acute Myeloid Leukemia Treated with Cytarabine.
Chemotherapy. 2016; 61(6):313-8 [PubMed] Related Publications
BACKGROUND: Cytarabine (Ara-C) is the primary drug in different treatment schemas for acute myeloid leukemia (AML) and requires the human equilibrative nucleoside transporter (hENT1) to enter cells. The deoxycytidine kinase (dCK) enzyme limits its activation rate. Therefore, decreased expression levels of these genes may influence the response rate to this drug.
METHODS: AML patients without previous treatment were enrolled. The expression of hENT1 and dCK genes was analyzed using RT-PCR. Clinical parameters were registered. All patients received Ara-C + doxorubicin as an induction regimen (7 + 3 schema). Descriptive statistics were used to analyze data. Uni- and multivariate analyses were performed to determine factors that influenced response and survival.
RESULTS: Twenty-eight patients were included from January 2011 until December 2012. Median age was 36.5 years. All patients had an adequate performance status (43% with ECOG 1 and 57% with ECOG 2). Cytogenetic risk was considered unfavorable in 54% of the patients. Complete response was achieved in 53.8%. Cox regression analysis showed that a higher hENT1 expression level was the only factor that influenced response and survival.
CONCLUSIONS: These results highly suggest that the pharmacogenetic analyses of Ara-C influx may be decisive in AML patients.

Liu N, Wang C, Wang L, et al.
Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis.
Int J Mol Med. 2016; 37(6):1686-96 [PubMed] Related Publications
Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitor cells with a poor clinical outcome. The resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating AML. Combining valproic acid (VPA) with other anti-leukemic agents has previously been noted as a useful and necessary strategy which can be used to specifically induce anticancer gene expression. In the present study, we demonstrated the synergistic antileukemic activities between VPA and cytarabine (Ara‑C) in a retrovirus-mediated murine model with MLL-AF9 leukemia, three leukemia cell lines (THP-1, K562 and HL-60) and seven primary human AML samples. Using RT-qPCR, we noted that the combination of VPA and Ara‑C significantly upregulated Bax expression and led to the arrest of leukemia cell proliferation, sub-G1 DNA accumulation and cell apoptosis, as demonstrated by flow cytometric analysis. Significantly, further experiments revealed that knockdown of Bax expression prevented VPA and Ara‑C‑induced cell apoptosis in THP-1 cells. The results of our present study demonstrated the synergistic antileukemic effect of combined VPA and Ara‑C treatment in AML, and thus we suggest that VPA be used an alternative treatment for AML.

Gurion R, Mehta N, Migliacci JC, et al.
Central nervous system involvement in T-cell lymphoma: A single center experience.
Acta Oncol. 2016; 55(5):561-6 [PubMed] Related Publications
Background We characterized the incidence of central nervous system (CNS) involvement, risk factors and outcome in a large single institution dataset of peripheral T-cell lymphoma (PTCL). Methods Retrospective review of the PTCL database at Memorial Sloan Kettering Cancer Center. We identified 231 patients with any subtype of PTCL between 1994-2011 with a minimum six months of follow-up or an event defined as relapse or death. Results Histologies included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (31.6%), angioimmunoblastic (16.9%), anaplastic large cell lymphoma (ALCL), ALK- (12.1%), ALCL, ALK + (6.1%), extranodal NK/T-cell lymphoma (7.4%), adult T-cell leukemia/lymphoma (ATLL) (7.4%), and transformed mycosis fungoides (8.7%). Seventeen patients had CNS disease (7%). Fifteen had CNS involvement with PTCL and two had diffuse large B-cell lymphoma and glioblastoma. Median time to CNS involvement was 3.44 months (0.16-103.1). CNS prophylaxis was given to 24 patients (primarily intrathecal methotrexate). Rates of CNS involvement were not different in patients who received prophylaxis. Univariate analysis identified stage III-IV, bone marrow involvement, >1 extranodal site and ATLL as risk factors for CNS disease. On multivariate analysis, >1 extranodal site and international prognostic index (IPI) ≥ 3 were predictive for CNS involvement. The median survival of patients with CNS involvement was 2.63 months (0.10-75). Conclusions Despite high relapse rates, PTCL, except ATLL, carries a low risk of CNS involvement. Prognosis with CNS involvement is poor and risk factors include: >1 extra nodal site and IPI ≥3.

González-Barca E, Canales M, Salar A, et al.
Central nervous system prophylaxis with intrathecal liposomal cytarabine in a subset of high-risk patients with diffuse large B-cell lymphoma receiving first line systemic therapy in a prospective trial.
Ann Hematol. 2016; 95(6):893-9 [PubMed] Free Access to Full Article Related Publications
The dissemination in the central nervous system (CNS) is an uncommon but fatal complication occurring in patients with diffuse large B-cell lymphoma (DLBCL). Standard prophylaxis has been demonstrated to reduce CNS relapse and improve survival rates. Intrathecal (IT) liposomal cytarabine allows maintaining elevated drug levels in the cerebrospinal fluid for an extended period of time. Data on the efficacy and safety of liposomal cytarabine as CNS prophylaxis in patients with DLBCL are still insufficient. The objective of the present study was to evaluate the effectiveness and safety of the prophylaxis with IT liposomal cytarabine in prevention of CNS relapse in high-risk patients with DLBCL who were included in a trial of first line systemic therapy with 6 cycles of dose-dense R-CHOP every 14 days. Twenty-four (18.6 %) out of 129 patients were identified to have risk factors for CNS involvement, defined as follows: >30 % bone marrow infiltration, testes infiltration, retroperitoneal mass ≥10 cm, Waldeyer ring, or bulky cervical nodes involvement. Liposomal cytarabine (50 mg) was administered by lumbar puncture the first day of the 1st, 2nd, and 6th cycle of R-CHOP14 scheme. Among 70 IT infusions, grade 3-4 adverse events reported were headache (one patient) and nausea/vomiting (one patient). With a median follow-up of 40.1 months, no CNS involvement by DLBCL was observed in any patient. In conclusion, IT liposomal cytarabine is safe, feasible, and effective for CNS prophylaxis, causing few associated risks and little discomfort to patients with DLBCL.

Cheong JW, Kim Y, Eom JI, et al.
Enhanced autophagy in cytarabine arabinoside-resistant U937 leukemia cells and its potential as a target for overcoming resistance.
Mol Med Rep. 2016; 13(4):3433-40 [PubMed] Free Access to Full Article Related Publications
Autophagy is a lysosomal degradation mechanism that is essential for cell survival, differentiation, development, and homeostasis. Autophagy protects cells from various stresses, including protecting normal cells from harmful metabolic conditions, and cancer cells from chemotherapeutics. In the current study, a cytarabine arabinoside (Ara‑C)‑sensitive U937 leukemia cell line and an Ara‑C‑resistant U937 (U937/AR) cell line were assessed for baseline autophagy activity by investigating the LC3‑I conversion to LC3‑II, performing EGFP‑LC3 puncta, an acidic autophagolysosome assay, and measuring the expression of various autophagy‑related genes. The results demonstrated significantly higher autophagic activity in the U937/AR cells compared with the U937 cells, when the cells were cultured with or without serum. Furthermore, an increase in the autophagic activity in starved U937/AR cells was demonstrated, compared with that in the starved U937 cells. Administration of an autophagy inhibitor demonstrated no change in cell death in the two cell lines when cultured with serum, however, it induced cell death regardless of the Ara‑C sensitivity when the cell lines were cultured without serum. In addition, the U937 cells demonstrated an Ara‑C resistance when cultured without serum. Co‑treatment with Ara‑C and the autophagy inhibitor significantly induced cell death in the U937/AR and Ara‑C‑sensitive U937 cells. In conclusion, autophagy serves an important role in protecting U937 cells from Ara‑C and in the development of Ara‑C resistance. Inhibition of autophagy combined with the Ara‑C treatment in the U937 cells augmented the anti‑leukemic effect of Ara‑C and overcame Ara‑C resistance, suggesting that autophagy may be an important therapeutic target to further improve the treatment outcome in patients with acute myeloid leukemia.

Shahabadi N, Falsafi M, Mansouri K
Improving antiproliferative effect of the anticancer drug cytarabine on human promyelocytic leukemia cells by coating on Fe3O4@SiO2 nanoparticles.
Colloids Surf B Biointerfaces. 2016; 141:213-22 [PubMed] Related Publications
In this study, Fe3O4@SiO2-cytarabine magnetic nanoparticles (MNPs) were prepared via chemical coprecipitation reaction and coating silica on the surface of Fe3O4 MNPs by Stöber method via sol-gel process. The surface of Fe3O4@SiO2 MNPs was modified by an anticancer drug, cytarabine. The structural properties of the samples were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Zetasizer analyzer, and transmission electron microscopy (TEM). The results indicated that the crystalline phase of iron oxide NPs was magnetite (Fe3O4) and the average sizes of Fe3O4@SiO2-cytarabine MNPs were about 23 nm. Also, the surface characterization of Fe3O4@SiO2-cytarabine MNPs by FT-IR showed that successful coating of Fe3O4 NPs with SiO2 and binding of cytarabine drug onto the surface of Fe3O4@SiO2 MNPs were through the hydroxyl groups of the drug. The in vitro cytotoxic activity of Fe3O4@SiO2-cytarabine MNPs was investigated against cancer cell line (HL60) in comparison with cytarabine using MTT colorimetric assay. The obtained results showed that the effect of Fe3O4@SiO2-cytarabine magnetic nanoparticles on the cell lines were about two orders of magnitude higher than that of cytarabine. Furthermore, in vitro DNA binding studies were investigated by UV-vis, circular dichroism, and fluorescence spectroscopy. The results for DNA binding illustrated that DNA aggregated on Fe3O4@SiO2-cytarabine MNPs via groove binding.

Elmoneim AA, Heuston E, Wai DH, et al.
Synergisitic and Antagonistic AML Cell Type-specific Responses to 5-Aza-2-deoxycitidine and 1-h-D-Arabinofuranoside.
Anticancer Res. 2016; 36(2):691-6 [PubMed] Related Publications
BACKGROUND: The search for synergistic drug combinations is critical to the treatment of drug-resistant cancer, such as acute myeloid leukemia (AML). Characterizing RNA expression associated with 5-aza-2'-deoxycytidine (DAC) and 1-h-D-arabinofuranosylcytosine (Ara-C) is a critical step to increase the efficacy of their combinatorial therapies.
MATERIALS AND METHODS: After 72 h of single-dose treatments of AML cells with DAC or Ara-C, the half-maximal effective concentration of DAC and Ara-C and the drug combination index were assessed.
RESULTS: Pre-treatment with DAC restores cellular sensitivity in Ara-C-resistant AML cells. In contrast, DAC/Ara-C combinations are antagonistic in other Ara-C-sensitive AML cells.
CONCLUSION: Our results provide an alternative approach for predicting what combinations, dosing and scheduling of drug delivery should be used to better individualize therapy of AML.

Drenberg CD, Hu S, Li L, et al.
ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression.
Clin Transl Sci. 2016; 9(1):51-9 [PubMed] Free Access to Full Article Related Publications
Resistance to cytarabine remains a major challenge in the treatment of acute myeloid leukemia (AML). Based on previous studies implicating ABCC4/MRP4 in the transport of nucleosides, we hypothesized that cytarabine is sensitive to ABCC4-mediated efflux, thereby decreasing its cytotoxic response against AML blasts. The uptake of cytarabine and its monophosphate metabolite was found to be facilitated in ABCC4-expressing vesicles and intracellular retention was significantly impaired by overexpression of human ABCC4 or mouse Abcc4 (P < 0.05). ABCC4 was expressed highly in AML primary blasts and cell lines, and cytotoxicity of cytarabine in cells was increased in the presence of the ABCC4 inhibitors MK571 or sorafenib, as well as after ABCC4 siRNA. In Abcc4-null mice, cytarabine-induced hematological toxicity was enhanced and ex vivo colony-forming assays showed that Abcc4-deficiency sensitized myeloid progenitors to cytarabine. Collectively, these studies demonstrate that ABCC4 plays a protective role against cytarabine-mediated insults in leukemic and host myeloid cells.

Mack F, Baumert BG, Schäfer N, et al.
Therapy of leptomeningeal metastasis in solid tumors.
Cancer Treat Rev. 2016; 43:83-91 [PubMed] Related Publications
Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

Wang L, Hu J, Sun Y, et al.
Does High-Dose Cytarabine Cause More Fungal Infection in Patients With Acute Myeloid Leukemia Undergoing Consolidation Therapy: A Multicenter, Prospective, Observational Study in China.
Medicine (Baltimore). 2016; 95(4):e2560 [PubMed] Free Access to Full Article Related Publications
Invasive fungal infection (IFI) remains as a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML). Here, we report the subgroup analysis of China Assessment of Antifungal Therapy in Haematological Disease (CAESAR) study to evaluate the risk of IFI in patients with AML in 1st remission receiving high-dose cytarabine (HiDAC) as consolidation. A total of 638 patients with AML in 1st complete remission were selected from the database. Among them, 130 patients received HiDAC alone with total dose of 2-3 g/m(2) × 6 while 508 patients received multiple-agent combination chemotherapy (multiagent chemo group). The patients' characteristics were generally not different but more patients in HiDAC group had peripherally inserted central catheter (61.5% vs 44.5%, P = 0.002). The median duration of neutropenia was 8.0 days in both HiDAC (2-20) and multiagent chemo group (2-28). Number of patients with prolonged neutropenia (>14 days) tended to be more in multiagent chemo group but not significant different (16.3% vs 8.8%, respectively). There was no significant difference between 2 groups in persistent neutropenic fever (40.8% vs 33.1%), antifungal treatment (11.5% vs 11.4%), and incidence of proven/probable IFI (4 probable in HiDAC vs 1 proven/4 probable in multiagent chemo, P = 0.35) or possible IFI. As to the clinical outcome in terms of duration of hospitalization and death in remission, there was a trend of shorter duration of hospitalization in HiDAC (19 days, 3-70) compare to multiagent chemo group (21 days, 1-367, P = 0.057) while no death documented in HiDAC group and only 2 patients died in the multiagent chemo group (0.4%). As to risk factors associated with IFI in all 638 patients, there was a trend of more IFI in patients with severe neutropenia (3.0%, P = 0.089) and previous history of IFI (3.85%, P = 0.086) while the antifungal prophylaxis was not associated significantly reduced IFI. Overall, our data support the perception that HiDAC alone as consolidation in first remission AML patients was well tolerated and not associated with increased hematological toxicity and IFI than conventional combination chemotherapy. Antifungal prophylaxis may not necessary except for patients with previous history of IFI.

Subari S, Baidoun F, Hreh M, et al.
Prior hypomethylating agent use lacks impact on clinical outcome in patients with secondary acute myeloid leukemia arising from myelodysplastic syndromes treated with standard induction chemotherapy.
Int J Hematol. 2016; 103(4):409-15 [PubMed] Related Publications
Patients with secondary acute myeloid leukemia (sAML) arising from prior myelodysplastic syndromes have poor prognosis. Anthracycline plus cytarabine (7 + 3) is a standard treatment option for patients who are fit for intensive therapy. In the present study, 22 of 96 sAML patients (23 %) were treated with 7 + 3 and achieved median overall survival (OS) of 9.8 months. Hypomethylating agents (HMA) were given for MDS in 6/22 (28 %) of the patients. When evaluating the prior HMA group, CR/CRi was 50 % for those with prior HMA exposure and 63 % for those without HMA exposure (P = 0.6). Median OS was 14 months for prior HMA exposure vs 10 months for no prior HMA (P = 0.9). The outcome of sAML patients who were treated with 7 + 3 continues to be poor. No statistical significant difference was found between response rates and mOS between prior HMA exposure or not. Additional larger studies are needed to confirm our results.

Wendel T, Zhen Y, Suo Z, et al.
The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo.
Exp Cell Res. 2016; 340(2):220-6 [PubMed] Related Publications
HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCγ were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment.

Khattry N, Gupta A, Jain R, et al.
LACE versus BEAM conditioning in relapsed and refractory lymphoma transplant: retrospective multicenter analysis of toxicity and efficacy.
Int J Hematol. 2016; 103(3):292-8 [PubMed] Related Publications
We compared the lomustine, cytarabine, cyclophosphamide and etoposide (LACE) and BCNU, etoposide, cytarabine, melphalan (BEAM) conditioning regimens for toxicity, engraftment kinetics, and efficacy in 139 patients undergoing autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma. Ninety-two patients with Hodgkin lymphoma and 47 with non-Hodgkin lymphoma were enrolled. Seventy-five patients received LACE while 64 received BEAM. The incidence of grade 3-4 oral mucositis (9 vs 38%; P < 0.001) and parenteral nutrition requirement (32 vs 69%; P < 0.001) were significantly lower in the LACE cohort. The median days to myeloid (10 vs 11; P = 0.007) and platelet engraftment (13 vs 15; P = 0.026) were shorter for the LACE cohort. Transplant-related mortality in the LACE group was 9% compared to 13% in patients treated with BEAM (P = NS). The probability of overall survival (OS) and progression-free survival (PFS) at 5 years for entire cohort was 46 and 41%, respectively. Probability of OS (LACE 46% vs BEAM 47%; P = NS) and PFS (LACE 37% vs BEAM 47%; P = NS) at 5 years was comparable between two groups. We conclude that LACE has better toxicity profile compared to BEAM and results in similar long-term survival in primary refractory or relapsed lymphoma transplant.

Spagnuolo P
Interactions Between Nutraceutical Supplements and Standard Acute Myeloid Leukemia Chemotherapeutics.
J Pharm Pharm Sci. 2015; 18(4):339-43 [PubMed] Related Publications
PURPOSE: Concomitant use of nutraceuticals with chemotherapy is very common. Cancer patients self-medicate to relieve the side effects associated with chemotherapy, improve disease outcome and to regain control of their medical care. However, there is limited empirical evidence on potential drug-nutraceutical interactions and their resulting effect on chemotherapy efficacy.
METHOD: To investigate drug-nutraceutical interactions we created and screened a library of commonly used nutraceuticals for their modulatory effects on the activity of cytarabine and daunorubicin, two primary chemotherapeutics used to treat acute myeloid leukemia (AML). Combination screening was performed in 3 AML cell lines (OCI-AML2, KG1a and U937) using the MTS viability assay. Lead compounds were validated using with the Annexin V/ Propidium iodide assay and CalcuSyn drug combination software.
RESULTS: We identified zinc as a nutraceutical that enhanced AML chemotherapy efficacy with combination index (CI) values of 0.649, 0.632 and 0.615 at EC 25, 50 and 75, respectively; CI values <0.9, >1.1 or between 0.9-1.1 denote statistical synergy, antagonism or additivity, respectively. In contrast, we show that echinacea hindered AML chemotherapy efficacy by significantly reducing the ability of cytarabine to induce cell death.
CONCLUSION: Given the positive and negative effects of nutraceuticals, patients undergoing chemotherapy must consult with their oncologist before consuming over-the-counter supplements. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Degwert N, Latuske E, Vohwinkel G, et al.
Deoxycytidine kinase is downregulated under hypoxic conditions and confers resistance against cytarabine in acute myeloid leukaemia.
Eur J Haematol. 2016; 97(3):239-44 [PubMed] Related Publications
OBJECTIVES: Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 α in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML).
METHODS AND RESULTS: In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia-inducible factor 1 α as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions.
CONCLUSIONS: In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia.

Montano G, Ullmark T, Jernmark-Nilsson H, et al.
The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.
Leuk Res. 2016; 40:60-7 [PubMed] Related Publications
The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter.

Chamberlain MC
High-dose cytarabine salvage therapy for recurrent primary CNS lymphoma.
J Neurooncol. 2016; 126(3):545-50 [PubMed] Related Publications
Treatment of recurrent primary CNS lymphoma (PCNSL) though not standardized most often utilizes whole brain radiotherapy, re-challenge with high-dose methotrexate, or administration of an alkylating chemotherapy. High-dose cytarabine (HD-araC) has been advocated as an active agent in PCNSL but limited information exists regarding single agent activity in the recurrent setting. A retrospective review of 14 patients (10 males, 4 females: median age 60 years) with recurrent PCNSL treated at second recurrence with single agent HD-araC. HD-araC was administered at 3gm/m(2) over a 3-h infusion every 12 h for a total of 4 doses (defined as a cycle of therapy). GM-CSF was administered at conclusion of HD-araC. Patients were clinically and radiographically evaluated every 4-weeks. Common toxicity criteria Grade 3 or 4 toxicity included thrombocytopenia (11 patients; 79%), anemia (10; 71%), fatigue (8; 57%), mucositis (8; 57%), neutropenia (8; 57%) and neutropenic fever (5; 36%). No patient discontinued therapy due to toxicity nor were there any treatment-related deaths. Best response to HD-araC was stable disease in 6 patients (43%), partial response in 5 (36%) and progressive disease in 3 (21%). Median progression free survival 3 months (range 2-5 months; 95% CI 2-4 months) and progression free survival was 0% at 6-months. Median survival after onset of HD-araC was 12 months (range 3-18+ months; 95% CI 3-15 months). Single agent HD-araC has limited activity in recurrent PCNSL and is associated with significant toxicity in this small retrospective study.

Shen Y, Chen J, Liu Y, Wu D
Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison.
Chemotherapy. 2014; 60(5-6):368-74 [PubMed] Related Publications
OBJECTIVES: The aims of this study were to evaluate a novel induction regimen composed of idarubicin (IDA), cytarabine (Ara-C) and cladribine (IAC regimen) for acute myeloid leukemia (AML) patients, and to identify the prognostic factors affecting treatment outcomes.
METHODS: The clinical data of 27 untreated AML patients who received the IAC regimen as primary induction therapy in our hospital between April and November 2014 were analyzed retrospectively. The treatment outcomes of the IAC regimen were compared with two IA (IDA + Ara-C) regimens (IDA 10 mg/m² and IDA 12 mg/m²) in a pair-matched analysis.
RESULTS: The complete remission (CR) rate in the IAC arm was higher compared to the IA(L) arm (p = 0.002) as was the overall efficacy rate (p = 0.017). There was no significant difference in outcomes between the IAC and IA(H) (Ara-C with high-dose IDA) arms. The IAC arm contained significantly higher CR rates than the IA(L) (Ara-C with low-dose IDA) arm in both the intermediate group (p = 0.050) and the unfavorable group (p = 0.013). Toxicity did not differ between the IAC group and the other two arms. High WBC at diagnosis (p = 0.022) and an unfavorable karyotype (p = 0.026) were related to a poorer response. The IAC regimen (p = 0.013) had greater superiority over the IAL regimen on efficacy than over the IA(H) regimen (p = 0.041).
CONCLUSIONS: The IAC regimen achieved a more significant advantage over the IA(L) regimen without increasing the risk of adverse events. The efficacy of induction therapy is associated with WBC at diagnosis, karyotype and induction regimen.

Damdinsuren A, Matsushita H, Ito M, et al.
FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3.
Leuk Res. 2015; 39(12):1405-13 [PubMed] Related Publications
Internal tandem duplication (ITD) mutations of the FLT3 gene (FLT3-ITD) are well known to correlate with a poor prognosis in acute myeloid leukemia (AML). We previously reported that FLT3-ITD confers resistance to cytosine arabinoside (Ara-C), a key cytotoxic agent in AML treatments. In order to elucidate the detailed molecular mechanisms underlying the Ara-C resistance induced by FLT3-ITD, we performed a microarray gene expression analysis of the human leukemic cell line K562 transduced with FLT3-ITD (K562/FLT3-ITD) and identified RUNX3 as a downstream target of FLT3-ITD. The transcriptional induction of the RUNX3 expression by FLT3-ITD was noted on a Luciferase assay. The knockdown of the RUNX3 expression in the K562/FLT3-ITD cells increased the sensitivity to Ara-C, and the exogenous expression of RUNX3 per se resulted in the enhancement of Ara-C resistance in the K562 cells. A relationship between the FLT3-ITD-induced RUNX3 expression and Ara-C resistance was also observed in AML cells with an endogenous FLT3-ITD expression. Collectively, these findings demonstrate that RUNX3 is a prerequisite for Ara-C resistance via FLT3-ITD signaling.

Fan D, Li W, Yang Y, et al.
Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells.
J Hematol Oncol. 2015; 8:108 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: B-acute lymphoblastic leukemia (B-ALL) is derived from B cell progenitors. Recently, the development of appropriate combinations of chemotherapy and immunotherapy represents a promising approach for eliminating cancer. We previously constructed an anti-CD3 × anti-CD19 bi-specific antibody in a diabody configuration and its disulfide-stabilized format (ds-diabody). The combination of the diabody or ds-diabody and Ara-C was highly effective in enhancing the cytotoxicity of T cells against the CD19+ human leukemia cell-line, Nalm-6, both in vitro and in vivo. This study verified whether B-ALL patient-derived cells were sensitive to the diabody or ds-diabody and low-dosage Ara-C combination.
METHODS: This study aimed to detect the B7 family members B7.1 (CD80) and B7.2 (CD86) that were expressed in B-ALL patient-derived cells pre-treated by Ara-C (0.25 μM) and to determine the targeted killing ability of T cell subtypes induced by the diabody or ds-diabody combination with Ara-C both in vitro and in vivo. We also determined the levels of the cytokines that were released by activated CD4+ or CD8+ T cells during therapy.
RESULT: Low-dose Ara-C enhanced CD80 and CD86 expression in nearly 50 % of specimens of B-ALL patient-derived cells. A combination of diabody or ds-diabody and Ara-C enhanced T cell against B-ALL cells in vitro and in vivo. Both CD8+ and CD4+ T cells were potently activated. Expression of CD25 and CD69 was augmented equally by CD4+ or CD8+ T cells. However, CD8+ T cells made the major contribution by redirecting target cell lysis in a granzyme B and perforin-dependent mechanism. CD4+ T cells played an important immunomodulatory role by secreting IL2. Consequently, IL3, IL6, TNFα, and IFNγ were also released by CD4+ or CD8+ T cells following diabody-mediated T cell activation.
CONCLUSION: T cell therapy induced by diabody or ds-diabody combined with low dose of Ara-C was effective against cancer cell-lines and in clinical trials. In vivo, the ds-diabody was more efficient than its parent diabody due to its enhanced stability.

Li N, Jia X, Wang J, et al.
Knockdown of homeobox A5 by small hairpin RNA inhibits proliferation and enhances cytarabine chemosensitivity of acute myeloid leukemia cells.
Mol Med Rep. 2015; 12(5):6861-6 [PubMed] Related Publications
Homeobox genes encode transcription factors that are essential for embryonic morphogenesis and differentiation. Transcription factors containing the highly conserved homeobox motif show considerable promise as potential regulators of hematopoietic maturation events. Previous studies have suggested that the increased expression levels of homeobox (HOX)A genes was correlated with the cytogenetic findings associated with poor prognosis in acute myeloid leukemia and mixed lineage leukemia. The aim of the present study was to investigate the role of HOXA5 in leukemia. The U937 human leukemia cell line was transfected with a HOXA5‑targeted short hairpin RNA (shRNA) to determine the effects of downregulation of the HOXA5 on proliferation, apoptosis, cell cycle distribution and chemoresistance in leukemia cells. Reverse transcription‑quantitative polymerase chain reaction and western blot analyses demonstrated that the mRNA and protein expression levels of HOXA5 were markedly suppressed following transfection with an shRNA‑containing vector. Knockdown of HOXA5 significantly inhibited cell proliferation, as determined by Cell Counting kit‑8 assay. Flow cytometry revealed that reduced HOXA5 expression levels resulted in cell cycle arrest at the G1 phase, and induced apoptosis. In addition, western blot analysis demonstrated that HOXA5 knockdown increased the expression levels of caspase‑3, and reduced the expression levels of survivin in the U937 cells. Furthermore, knockdown of HOXA5 in the U937 cells enhanced their chemosensitivity to cytarabine. The results of the present study suggested that downregulation of HOXA5 by shRNA may trigger apoptosis and overcome drug resistance in leukemia cells. Therefore, HOXA5 may serve as a potential target for developing novel therapeutic strategies for leukemia.

Lamba JK, Pounds S, Cao X, et al.
Clinical significance of in vivo cytarabine-induced gene expression signature in AML.
Leuk Lymphoma. 2016; 57(4):909-20 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Despite initial remission, ∼60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML; however, the extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy, can trigger adaptive response by influencing leukemic cell transcriptome and, hence, development of resistance or refractory disease. It is, however, challenging to perform such a study due to lack of availability of specimens post-drug treatment. The primary objective of this study was to identify in vivo cytarabine-induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. The results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.

Hyo Kim L, Sub Cheong H, Koh Y, et al.
Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML.
J Hum Genet. 2015; 60(12):749-54 [PubMed] Related Publications
The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

Yingchun L, Rong Z, Kun Y, et al.
Bone Marrow MicroRNA-335 Level Predicts the Chemotherapy Response and Prognosis of Adult Acute Myeloid Leukemia.
Medicine (Baltimore). 2015; 94(33):e0986 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The aim of this study was to investigate the role of microRNA-335 (miR-335) in determining the treatment response and prognosis in adult acute myeloid leukemia (AML) patients receiving the cytarabine (Ara-C)-based chemotherapy.A total of 204 adult AML patients were collected. The miR-335 levels in serum and bone marrow samples from these patients were determined. All patients received Ara-C-based standard induction chemotherapy regimens. The treatment response to Ara-C-based chemotherapy was evaluated. All patients were followed for prognostic analyses.The levels of miR-335 in bone marrow and serum samples from adult AML patients achieving complete response were significantly higher than those without. The serum miR-335 level was not associated with the chemotherapy response and prognosis in these AML patients. In contrast, high bone marrow miR-335 level was significantly associated with a poor treatment response and also predicted a worse prognosis indicated by the relapse-free survival and overall survival periods in adult AML patients receiving Ara-C-based chemotherapy.Our finding suggests that bone marrow miR-335 level may be used as a marker to predict the chemotherapy response and prognosis in adult AML patients.

Segot A, Raffoux E, Lengline E, et al.
Liposomal cytarabine in prophylaxis or curative treatment of central nervous system involvement in Burkitt leukemia/lymphoma.
Ann Hematol. 2015; 94(11):1859-63 [PubMed] Related Publications
In recent years, the outcome of Burkitt leukemia/lymphoma (BL) has improved significantly. Central nervous system (CNS) involvement continues to be a poor prognostic indicator. High doses of intravenous polychemotherapy, intrathecal chemotherapy, and cranio-spinal radiation therapy are used by numerous groups. Majority of patients are cured after this strategy. The next challenge is to decrease toxicities of treatment, including long-term toxicities secondary to cranio-spinal radiation therapy observed in these cured patients. Liposomal cytarabine could be a good alternative to cranio-spinal radiation therapy as already reported in acute lymphoblastic leukemia. We report here eleven patients treated in our center for BL, with liposomal cytarabine instead of cranio-spinal radiation therapy as prophylactic or curative treatment for CNS involvement. Treatment was safe with no short-term grade >3 adverse events. Moreover, no long-term side effects and no impact on outcome were observed. We conclude that LC could be a good option to decrease short/long-term side effects of cranio-spinal radiation therapy in BL and could be evaluated in a future clinical trial.

Heisig M, Maj J, Szepietowski JC, Reich A
Durable remission of folliculotropic mycosis fungoides achieved with a combined topical treatment with cytarabine and carmustine.
Dermatol Ther. 2016 Jan-Feb; 29(1):15-8 [PubMed] Related Publications
Folliculotropic mycosis fungoides (MF) is an uncommon subtype of MF which has a more aggressive natural history and is more resistant to treatment than other forms of MF. In this article, an innovative method of treatment is presented. We describe a successful use of topical cytarabine combined with topical carmustine in a patient with a folliculotropic MF. Based on our patient history we suggest this method as an effective therapy option for patients with folliculotropic MF unresponsive to other forms of treatment.

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