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"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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Web Resources: Cytarabine
Latest Research Publications

Web Resources: Cytarabine (7 links)

Latest Research Publications

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

Mayer LD, Tardi P, Louie AC
CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties.
Int J Nanomedicine. 2019; 14:3819-3830 [PubMed] Free Access to Full Article Related Publications
Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.

Nakamura Y, Tanaka Y, Tanaka M, et al.
Significance of Granulocyte Colony-Stimulating Factor-Combined High-Dose Cytarabine, Cyclophosphamide, and Total Body Irradiation in Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignant Neoplasms.
Transplant Proc. 2019; 51(3):896-900 [PubMed] Related Publications
Allogeneic hematopoietic cell transplant (HCT) is a curative procedure for myeloid malignant neoplasms, but relapse after HCT remains critical. A conditioning regimen involving granulocyte colony-stimulating factor-combined high-dose cytarabine, cyclophosphamide, and total body irradiation (G-CSF-combined high-dose cytarabine/cyclophosphamide/total-body irradiation [HDCA/CY/TBI]) was reported to improve outcomes after cord blood transplant (CBT) for myeloid malignant neoplasms, but this regimen was not previously evaluated among patients undergoing bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT).
METHODS: We retrospectively analyzed 28 patients who underwent allogeneic HCT including BMT from a related (1 patient) or unrelated donor (9 patients), PBSCT from a related donor (7 patients), or single-unit CBT from an unrelated donor (11 patients) after a G-CSF-combined HDCA/CY/TBI regimen.
RESULTS: All patients achieved neutrophil and platelet engraftment, which were significantly more rapid in the BMT/PBSCT group than in the CBT group. Eighteen patients were alive at a median follow-up of 54.3 months. The 3-year relapse and nonrelapse mortality rates were 28.6% and 7.1%, respectively, which were similar between the BMT/PBSCT and CBT groups. Overall survival and disease-free survival at 5 years after HCT were 62.6% and 64.3%, respectively, which were also similar between the BMT/PBSCT and CBT groups. Only disease status at HCT had a significant impact on overall survival and disease-free survival (86.7% with standard risk vs 38.5% with high risk and 86.7% with standard risk vs 38.5% with high risk, respectively).
CONCLUSION: A G-CSF-combined HDCA/CY/TBI regimen is a promising conditioning in patients with myeloid malignant neoplasms who undergo not only CBT but also BMT or PBSCT.

Shea LK, Uy GL
Choosing induction chemotherapy in therapy-related acute myeloid leukemia.
Best Pract Res Clin Haematol. 2019; 32(1):89-97 [PubMed] Related Publications
Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.

Ko YC, Hu CY, Liu ZH, et al.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from

Cheung E, Perissinotti AJ, Bixby DL, et al.
The leukemia strikes back: a review of pathogenesis and treatment of secondary AML.
Ann Hematol. 2019; 98(3):541-559 [PubMed] Related Publications
Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

Lowinus T, Heidel FH, Bose T, et al.
Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of K
Cell Commun Signal. 2019; 17(1):5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment of acute leukemia is challenging and long-lasting remissions are difficult to induce. Innovative therapy approaches aim to complement standard chemotherapy to improve drug efficacy and decrease toxicity. Promising new therapeutic targets in cancer therapy include voltage-gated K
METHODS: We analyzed acute lymphoid (Jurkat, CEM) and myeloid (HL-60, Molm-13, OCI-AML-3) leukemia cell lines and patients' acute leukemic blasts after treatment with either drug alone or the combination of cytarabine and memantine. Patch-clamp analysis was performed to evaluate inhibition of K
RESULTS: Our study demonstrates that memantine inhibits K
CONCLUSIONS: Our study underlines inhibition of K

Cortes JE, Heidel FH, Hellmann A, et al.
Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome.
Leukemia. 2019; 33(2):379-389 [PubMed] Free Access to Full Article Related Publications
Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39-0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit-risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Cao Y, Wu C, Song Y, et al.
Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation.
Int J Mol Med. 2019; 43(2):1011-1020 [PubMed] Related Publications
Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara‑C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara‑C‑induced apoptosis of ALL cells, and its function was blocked by the use of the anti‑Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl‑2 in Ara‑C‑treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara‑C partially via the NF‑κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF‑κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.

Wang X, Nachliely M, Harrison JS, et al.
Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen.
J Steroid Biochem Mol Biol. 2019; 187:166-173 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.

Howell G, Oliai C, Schiller G
Liposomal Cytarabine-Daunorubicin (CPX-351) Extravasation: Case Report and Literature Review.
Anticancer Res. 2018; 38(12):6927-6930 [PubMed] Related Publications
BACKGROUND: Liposomal formulation of anthracyclines provide better systemic and organ-specific tolerance, with potential for less local tissue damage during extravasation. Several small series have reported that most liposomal anthracycline extravasations are consistent with irritant injury without tissue necrosis. There have been no reports published regarding the clinical effects of extravasation of liposomal cytarabine-daunorubicin (CPX-351).
CASE REPORT: The patient received CPX-351 for relapsed acute myelogenous leukemia via a left chest wall port-a-catheter. The catheter became dislodged. Once symptoms developed, the infusion was discontinued, with observations demonstrating an 8-cm region of edema, warmth, no erythema, and no drainage. Limited supportive management was performed. Physical examination the following day demonstrated no evidence of necrosis, and erythema resolved completely without additional intervention.
CONCLUSION: CPX-351 extravasation behaving as an irritant is consistent with the reports of other liposomal anthracyclines.

Khoury H, He R, Schimmer A, et al.
Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia.
Chemotherapy. 2018; 63(4):225-237 [PubMed] Related Publications
Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50-70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi-voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

Pillozzi S, Bernini A, Spiga O, et al.
Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias.
Oncol Rep. 2019; 41(1):312-324 [PubMed] Related Publications
Notable advances in treatment have been made and increases in the cure rates of pediatric leukemia have been achieved. However, the majority of children with relapsed disease are not expected to survive, with chemotherapy resistance acting as the principal cause of treatment failure. Interaction between leukemic cells and the bone marrow microenvironment is the primary cause of relapse. It was identified that a multi‑protein membrane complex, formed by potassium voltage‑gated channel subfamily H member 2 (hERG1) channels, the β1 integrin subunit and the stromal cell‑derived factor 12 (CXCL12) receptor, C‑X‑C chemokine receptor type 4 (CXCR4), exerts a role in mesenchymal stromal cell (MSC)‑mediated chemoresistance in pediatric leukemias. hERG1 blockade was able to overcome chemoresistance in vitro and in vivo. As an alternative strategy to overcome chemoresistance, the present study evaluated the effects of novel tools targeting the CXCR4/CXCL12 axis. The analysis of CXCL12 structural dynamics was used for the selection of a peptide (4‑1‑17) and a small molecule (8673), which interact with a transient hot spot, identified by a dynamic drug design approach. The present findings indicated that peptide 4‑1‑17 and small molecule 8673 inhibited leukemia cell proliferation and induced a pro‑apoptotic effect, which was not reduced by the presence of MSCs. The combined treatment with 4‑1‑17 and 8673 had a stronger pro‑apoptotic effect, particularly on cells cultured on MSCs in normoxic and hypoxic conditions, and was able to overcome MSC‑induced resistance to cytarabine. Overall, the targeting of CXCL12 and the ensuing inhibition of the CXCR4/CXCL12 axis may be proposed as an alternative strategy to overcome chemoresistance in leukemia.

Braess J, Amler S, Kreuzer KA, et al.
Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study.
Leukemia. 2018; 32(12):2558-2571 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CR

Döhner H, Dolnik A, Tang L, et al.
Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care.
Leukemia. 2018; 32(12):2546-2557 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m

Liu R, Jiang Y, Hu X, et al.
A preclinical evaluation of cytarabine prodrug nanofibers assembled from cytarabine-lauric acid conjugate toward solid tumors.
Int J Pharm. 2018; 552(1-2):111-118 [PubMed] Related Publications
Cytarabine (Ara-C) has become cornerstones for the treatment of hatmatological malignancies for several decades; however, it still faces serious challenges in clinical applications due to its side effects such as hand foot syndrome (HFS) and stomatitis. Therefore, considerable researchers have devoted to looking for the new derivative with desirable activity and low toxicity. A new prodrug based on the conjugation of cytarabine with lauric acid (LA-Ara) was synthesized in our group, and it could self-assemble into nanofibers (NFs) in aqueous solution with high drug loading (57 wt%). The lauric acid moiety protects NH

Shen WC, Chang Liao NF, Lin TY, Wu PY
Co-existence of Langerhans cell histiocytosis and reticulohistiocytosis with initial presentation of skull lesions: A case report.
J Cutan Pathol. 2019; 46(1):62-66 [PubMed] Related Publications
Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder resulting from dysregulated clonal proliferation of Langerhans cells. Reticulohistiocytosis (RH) is another rare histiocytosis caused by the proliferation of histiocytes other than Langerhans cells. Co-existence of LCH and RH in different organs and in the same skin area has not been reported. We present the case of a 20-year-old woman who initially had co-existing bone LCH and cutaneous RH. After 1 year of chemotherapy with cytarabine, bone LCH significantly improved but cutaneous LCH developed in the same area where cutaneous RH was, resulting in hybrid LCH and RH of the skin. This unique history provides some evidence to support the theory that LCH and RH originate from the same stem cells and subsequently develop into hybrid LCH and RH of the skin in a cytokine environment influenced by chemotherapy. Repeat skin biopsies may be considered for adjusting treatment regimens in LCH patients whenever pre-existing skin lesions progress.

Ciftciler R, Demiroglu H, Buyukasık Y, et al.
Effect of postremission high dose cytarabine-based consolidation chemotherapy before allogenic stem cell transplantation in outcomes of acute myeloid leukemia patients.
Transfus Apher Sci. 2018; 57(6):752-755 [PubMed] Related Publications
BACKGROUND AND AIM: This is a retrospective study aiming to investigate the effect of the number of high dose cytarabine-based chemotherapy (HiDAC) courses in patients with acute myeloid leukemia before allogenic stem cell transplantation (ASCT).
MATERIALS AND METHODS: A total of 110 patients with acute myeloid leukemia who received ASCT between 2001 and 2018 were included in the study.
RESULTS: Of the 110 patients, 25 (23%) patients received one course of HiDAC, 42 (38%) patients received two courses of HiDAC, 34 (31%) patients received three courses of HiDAC and 9 (8%) patients received four courses of HiDAC. Median follow-up for survivors was 71 months (range 4-186) for all patients. The 3-year overall survival for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 49% and 70%, respectively (p = 0.29). The 3-year disease free survival (DFS) for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 38% and 66%, respectively (p = 0.05). There was no statistically significant difference in OS between patients who received one or more than one consolidation chemotherapy. But there was nearly a statistically significant difference between patients who received one or more than one consolidation chemotherapy in DFS.
CONCLUSION: In conclusion, the administration of more than one consolidation chemotherapy may provide longer DFS, however the number of consolidation chemotherapy is not associated with statistically significant differences in overall outcomes.

Talati C, Sweet K
Recently approved therapies in acute myeloid leukemia: A complex treatment landscape.
Leuk Res. 2018; 73:58-66 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a heterogeneous disease. Until recently, treatment for patients with AML was limited to induction chemotherapy with cytarabine and anthracycline or hypomethylating agents, and, in some instances, allogeneic hematopoietic stem cell transplant. With the recent approval of new therapies-i.e., CPX-351, enasidenib, ivosidenib, gemtuzumab ozogamicin, and midostaurin-a new era in AML treatment has emerged. Comprehensive diagnostic testing, such as cytogenetic and molecular testing, is necessary for establishing patient eligibility for these new agents and should be performed in a timely manner. However, choosing a therapy for patients who are eligible for multiple treatments may be a complex process, particularly for patients with newly diagnosed AML. This review discusses data, including associated safety profiles that supported these recent approvals, and provides insights to help clinicians navigate new therapy options for this devastating disease. Given the heterogeneity of AML, the treatment landscape will likely continue to grow and evolve as additional agents (and their combinations) are approved for the treatment of subpopulations of patients with AML. Physicians will need to remain abreast of the ever-changing treatment landscape.

Hedlund NG, Isgor Z, Zwanziger J, et al.
Drug Shortage Impacts Patient Receipt of Induction Treatment.
Health Serv Res. 2018; 53(6):5078-5105 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
OBJECTIVE: Examine the impact of the 2011 shortage of the drug cytarabine on patient receipt and timeliness of induction treatment for Acute Myeloid Leukemia (AML).
STUDY DESIGN: A retrospective cohort was utilized to examine odds of receipt of inpatient induction chemotherapy and time to first dose across major (N = 105) and moderate (N = 316) shortage time periods as compared to a nonshortage baseline (N = 1,147).
DATA COLLECTION/EXTRACTION METHODS: De-identified patient data from 2008 to 2011 Surveillance, Epidemiology, and End Results (SEER) were linked to 2007-2013 Medicare claims and 2007-2013 Hospital Characteristics.
PRINCIPAL FINDINGS: Compared to prior nonshortage time period, patients diagnosed during a major drug shortage were 47 percent less likely (p < .05) to receive inpatient chemotherapy within 14 days of diagnosis. Patients who were younger, had a lower Charlson Comorbidity score, and for whom AML was a first primary cancer were prioritized across all periods.
CONCLUSIONS: Period of major shortage of a generic oncolytic, without an equivalent therapeutic substitute, reduced timely receipt of induction chemotherapy treatment. More favorable economic and regulatory policies for generic drug suppliers might result in greater availability of essential, older generic drug products that face prolonged or chronic shortage.

Onec B, Okutan H, Albayrak M, et al.
Combination therapy with azacitidine, etoposide, and cytarabine in the treatment of elderly acute myeloid leukemia patients: A single center experience.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):1105-1111 [PubMed] Related Publications
Aims: The prognosis of acute myeloid leukemia (AML) in elderly patients is worse due to age and comorbidities. Lately, monotherapy with hypomethylating agents like azacitidine (Aza) has been used to prolong overall survival (OS) in AML patients. Herein, we present a retrospective study investigating treatment responses and OS of Aza in combination with etoposide (Eto) and cytarabine (ARA-C) in elderly.
Materials and Methods: In this study, therapies and outcomes of 37 newly diagnosed AML patients, >60 years old, and ineligible for intensive chemotherapy were investigated retrospectively. Patients were grouped according to the treatments they received as follows - Group 1: low-dose conventional therapies as hydroxyurea, low-dose ARA-C, or best supportive care (n = 11); Group 2: Aza alone (n = 6); Group 3: Aza in combination with Eto and ARA-C (Aza + Eto + ARA-C, n = 20).
Results: It was found that an Aza + Eto + ARA-C combination therapy had significantly better overall response rates (P = 0.002). Combination group had significantly better OS than Group 1 (8 months vs. 1 month, P < 0.001), the difference between combination and monotherapy was not significant. The OS was also associated with age and performance status, but the difference was still statistically significant after adjustment for these factors, especially for patients with younger age and better performance.
Conclusions: We concluded that combination therapy of Aza with Eto and ARA-C increases response rates, and prolong survival for this poor prognosed patient group. We believe that larger controlled studies investigating Aza combinations with other antileukemic drugs will contribute to the development of tolerable treatment protocols for elderly AML patients.

Tang C, Li MH, Chen YL, et al.
Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.
J Exp Clin Cancer Res. 2018; 37(1):204 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.
METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.
RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.
CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.

Guillaume C, Vegas H, Pastuszka A, et al.
Cerebrospinal fluid examination after liposomal cytarabine intrathecal injection.
Ann Biol Clin (Paris). 2018; 76(5):568-570 [PubMed] Related Publications
The patient is a 36 year old female who presented breast cancer with leptomeningeal involvement. A systematic lumbar puncture was performed and sent to the laboratory for CSF analysis. CSF examination using wet mount preparation showed a large number of round spherules. After discussion with the ordering physician, we learnt that the patient had received intrathecal liposomal cytarabine injection 19 days earlier. Cytarabine liposomes are spherules with a granular interior and range in size from 10-30 μm. It can be confused with leukocytes and lead to spurious elevation of CSF leukocytes count. Care needs to be taken in interpreting CSF results in patients who have received intrathecal liposomal cytarabine.

Scharadin TM, Malfatti MA, Haack K, et al.
Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing.
Chem Res Toxicol. 2018; 31(10):1042-1051 [PubMed] Article available free on PMC after 15/10/2019 Related Publications
Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of

Picou F, Debeissat C, Bourgeais J, et al.
n-3 Polyunsaturated fatty acids induce acute myeloid leukemia cell death associated with mitochondrial glycolytic switch and Nrf2 pathway activation.
Pharmacol Res. 2018; 136:45-55 [PubMed] Related Publications
Acute Myeloid Leukemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. n-3 polyunsaturated fatty acids (PUFAs), present in fish oil (FO) at high concentrations, have antitumoral properties in various cancer models. We investigated the effects of two n-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in AML cell lines and primary AML blasts. EPA and DHA induced a dose-dependent decrease in cell viability in five AML cell lines, which was also observed with FO, but not SO (devoid of n-3 PUFAs) in cell lines and primary leucoblasts. Mitochondrial energy metabolism shifted from oxidative respiration to glycolytic metabolism in the U937, MOLM-13, and HL-60 cell lines. This phenomenon was associated with major disorganization of the mitochondrial network and mitochondrial swelling. Transcriptomic analysis after 6 h and 24 h of exposure to FO revealed a Nrf2 activation signature, which was confirmed by evidence of Nrf2 nuclear translocation in response to oxidative stress, but insufficient to prevent cell death following prolonged exposure. Apoptosis studies showed consistent phosphatidylserine exposition among the AML cell lines tested and a reduced mitochondrial membrane potential. The cell-killing effect of FO was additive with that of cytarabine (AraC), by the Chou and Talalay method, and this combination effect could be reproduced in primary AML blasts. Altogether, our results show deleterious effects of n-3 PUFAs on mitochondrial metabolism of AML cells, associated with oxidative stress and Nrf2 response, leading to cell death. These observations support further investigation of n-3 PUFA addition to standard chemotherapy in AML.

Anderson E, Mehta P, Heywood J, et al.
CPX-351 exhibits hENT-independent uptake and can be potentiated by fludarabine in leukaemic cells lines and primary refractory AML.
Leuk Res. 2018; 74:121-129 [PubMed] Related Publications
CPX-351, a liposomal formulation co-encapsulating cytarabine and daunorubicin (DNR) in a synergistic 5:1 M ratio, has shown favourable response in newly diagnosed elderly high-risk AML. This study assessed intracellular ara-CTP levels following in vitro exposure of human immortalised leukaemic cell lines and primary AML blasts to CPX-351, and investigated fludarabine potentiation of intracellular ara-CTP formation from CPX-351. Comparison of intracellular handling of CPX-351 to cytarabine in HL-60 cells indicated slower conversion to ara-CTP for CPX-351, but equivalent cytotoxicity to cytarabine and combined DNR/cytarabine (DA) at 48 h, mostly likely reflecting the need for intracellular liposome processing to release encapsulated drugs. Further assessment demonstrated cytotoxicity of CPX-351 to be superior to DA at 48 and 72 h in cytarabine-resistant THP-1 cells (p < 0.001), and this effect could not be inhibited upon blockade of human equilibrative nucleoside transporter (hENT) function with dipyridamole. Assessment of Flu-CPX in primary blasts from presentation AML patients (n = 5) demonstrated a more rapid and pronounced potentiation of ara-CTP from CPX-351 than in immortalised cell lines, with 4/5 patients showing significant increases in ara-CTP, notably for those that went on to fail induction and relapse treatment in vivo (n = 3). This suggests a favourable impact on patient outcome from Flu-CPX.

Kadia TM, Cortes J, Ravandi F, et al.
Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial.
Lancet Haematol. 2018; 5(9):e411-e421 [PubMed] Related Publications
BACKGROUND: Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents.
METHODS: In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m
FINDINGS: Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients).
INTERPRETATION: The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population.
FUNDING: Part supported by the National Institutes of Health.

Chen Y, Gan D, Huang Q, et al.
Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo.
Cell Physiol Biochem. 2018; 48(5):2061-2073 [PubMed] Related Publications
BACKGROUND/AIMS: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor survival and a high risk of relapse, which is mainly caused by the emergence of multidrug resistance (MDR). The identification of novel agents to improve therapeutic strategies becomes important priority for AML treatment. It has been shown that emodin has therapeutic effects on many kinds of human malignant tumors. In this study, we investigated the anti-leukemia effects of emodin alone or in combination with cytarabine (Ara-C) on multidrug-resistant AML HL-60/ADR cells and in a mouse xenograft model of human highly tumorigenic AML HL-60/H3 cells. The underlying mechanism was also addressed.
METHODS: Cell viability after treatment was measured by MTT assay. The DNA fragmentation assay, Annexin V-PE/7-AAD, AO/EB staining, and electron microscopy were introduced to assess the apoptotic induction effects. Changes in protein expression in the Akt and ERK signaling pathways were determined by western blotting. In vivo antileukemia effects on HL-60/H3 xenograft model and overall mouse survival outcomes were further analyzed in this study.
RESULTS: Emodin dose-dependently induced growth inhibition and apoptotic effects in resistant HL-60/ADR cells in vitro as well as in the HL-60/H3 xenograft models in vivo. Moreover, emodin significantly enhanced chemosensitivity of AML cells to Ara-C, inhibited leukemic cell growth, and improved survival in the mouse xenograft model of AML. Dual targeting of Akt and ERK signaling pathways might contribute to the anti-leukemia effects on AML cells in vitro and in vivo.
CONCLUSION: Emodin and its combination with Ara-C may be considered a promising therapeutic approach in AML and worthy of further investigation.

Zhou JH, Lin HQ, Shen Q, et al.
Comparison of Mitoxantrone in Combination with Intermediate-dose Cytarabine versus High-dose Cytarabine as Consolidation Therapies for Young Non-APL Acute Myeloid Leukemia Patients with Favorable and Intermediate Cytogenetics.
Curr Med Sci. 2018; 38(1):51-57 [PubMed] Related Publications
In this study, we compared the efficacy of mitoxantrone in combination with intermediate-dose cytarabine (HAM) with that of high-dose cytarabine alone (HiDAC) as consolidation regimens in non-acute promyelocytic leukemia (APL) acute myeloid leukemia patients with favorable and intermediate cytogenetics. A total of 62 patients from Shenzhen People's Hospital were enrolled in this study. All patients enrolled received standard induction chemotherapy and achieved the first complete remission (CR1). In these patients, 24 received HiDAC and 38 received HAM as consolidation. The median relapse free survival (RFS) and overall survival (OS) were similar between these two consolidation regimens. Even in subgroup analysis according to risk stratification, the combination regimen conferred no benefit in longterm outcome in patients with favorable or intermediate cytogenetics. However, in patients receiving HAM regimen, the lowest neutrophil count was lower, neutropenic period longer, neutropenic fever rate higher, and more platelet transfusion support was required. HAM group also tended to have higher rate of sepsis than HiDAC group. According to our results, we suggest that combination treatment with mitoxantrone and intermediate-dose cytarabine has limited value as compared to HiDAC, even in young non-APL AML patients with favorable and intermediate cytogenetics.

Guo H, Lin SY, Ren WX, et al.
Enhanced Response of Acute Monocytic Leukemia Cells to Low-dose Cytarabine by 1,25-dihydroxyvitamin D3.
Curr Med Sci. 2018; 38(1):35-42 [PubMed] Related Publications
Low-dose cytarabine combined with differentiating or DNA hypomethylating agents, such as vitamin D compounds, is a potential regimen to treat acute myeloid leukemia (AML) patients who are unfit for high-intensity chemotherapy. The present study aimed to determine which subset of AML would be most responsive to low-dose cytarabine with the differentiating agent 1,25-dihydroxyvitamin D3 (1,25-D3). Here, firstly, cBioPortal database was used and we found out that vitamin D receptor (VDR) was highly expressed in acute monocytic leukemia (M5) and high VDR expression was associated with a poor survival of AML patients. Then, we confirmed that 1,25-D3 at clinical available concentration could induce more significant differentiation in acute monocytic leukemia cell lines (U937, MOLM-13, THP-1) and blasts from M5 patients than in non-monocytic cell lines (KGla and K562) and blasts from M2 patient. Finally, it was shown that the combination of 1,25-D3 and low-dose cytarabine further increased the differentiating rate, growth inhibition and G0/G1 arrest, while mild changes were found in the apoptosis in acute monocytic leukemia cell lines. Our study demonstrates that the enhanced response of acute monocytic leukemia cells to low-dose cytarabine by 1,25-D3 might indicate a novel therapeutic direction for patients with acute monocytic leukemia, especially for elderly and frail ones.

Chen P, Zhu KW, Zhang DY, et al.
Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.
J Transl Med. 2018; 16(1):197 [PubMed] Article available free on PMC after 15/10/2019 Related Publications
BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.
METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.
RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10
CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

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