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We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5 mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1 mg PO daily for 10 days and then 1 mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55–81). A 10-day regimen of oral Clofarabine at 5 mg/day induced Grade IV pancytopenia. A dose of 1 mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1 mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules. [ABSTRACT FROM AUTHOR]

Clofarabine, a second-generation nucleoside analog, has clinical activity in relapsed or refractory acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndromes (MDS). However, there are few data evaluating performance of clofarabine in populations of patients not enrolled in clinical trials. We reviewed outcomes for 84 patients treated with clofarabine for relapsed or refractory AML or MDS, either with clofarabine as monotherapy ( n = 19) or in combination with cytarabine ( n = 65). Using International Working Group (IWG) response criteria, the overall response rate (ORR) of all treated patients was 21%, with a complete response rate with either complete or incomplete hematopoietic recovery (CRR = CR + CRi) of 14%. For combination therapy, ORR was 22% with CRR of 18%, and monotherapy patients had an ORR of 21% with CRR of 11%. Although limited by small numbers, subgroup analysis did not reveal variation in response rates when comparing different risk factors. The 30-day mortality was 21% and median survival was 3 months; a subset of 12 patients who were able to go to transplant had an 18-month median survival. Clofarabine's efficacy in a “real-world” setting appears to be less than has been reported in clinical trials, and treatment is associated with a high early mortality rate. [ABSTRACT FROM AUTHOR]

Abstract: We designed a phase II study evaluating the upfront combination of clofarabine and daunorubicin in acute myeloid leukemia (AML) patients≥60 years old. The median age of the 21 patients was 69 (range 60–85) years. Fourteen patients (67%) had unfavorable risk features. The principal toxicities were grade ≥3 infections and prolonged myelosuppression. Three (14%) deaths occurred from infectious complications. Six (28.6%) patients achieved complete remission including three (21.4%) of 14 patients with unfavorable AML. The median disease-free survival was 6.8 months and the median overall survival was 11.2 months. [Copyright &y& Elsevier]

Abstract: Clofarabine (CLO), a purine nucleoside analog with promising efficacy in acute myeloid leukemia (AML), inhibits the ribonucleotidereductase, p53R2. We have shown that p53R2 mRNA is up-regulated by decitabine (DEC), another drug with promising activity in AML. We developed a pharmacodynamic model to characterize the interaction between CLO and DEC on an AML cell line and down-regulated p53R2 protein to understand its role. These results confirm a role for p53R2 in both CLO and DEC mechanism of action, demonstrate synergism between these two drugs in this AML model and support the use of this combination in a future clinical trial. [Copyright &y& Elsevier]

Abstract: In this study, treatment of lymphoid tumor cells with low dose clofarabine upregulated the expression of Sp17 and SPAN-Xb. This was associated with an increase in hypomethylated CpG dinucleotides and a decrease in global DNA methylation, as demonstrated by decreases in the percent of methylated Alu repeats. The most optimal concentration of clofarabine to induce DNA hypomethylation and CT antigen expression was between 1×10−9 and 1×10−8 M. Above this, clofarabine resulted in tumor cell growth inhibition and apoptosis. Our results provide the first evidence for the CT antigen-inducing and DNA hypomethylating property of low concentration clofarabine. [Copyright &y& Elsevier]

Abstract: The nucleotide substrate specificity of yeast poly(A) polymerase (yPAP) was examined with various ATP analogues of clinical relevance. The triphosphate derivatives of cladribine (2-Cl-dATP), clofarabine (Cl-F-ara-ATP), fludarabine (F-ara-ATP), and related derivatives were incubated with yPAP and 32P-radiolabeled RNA oligonucleotide primers in the absence of ATP to assay polyadenylation. While 2-Cl-ATP resulted in primer elongation, ara-ATP and F-ara-ATP were poor substrates for yPAP. In contrast, the triphosphate derivatives of cladribine (2-Cl-dATP), clofarabine (Cl-F-ara-ATP) and its corresponding deoxyribose derivative (Cl-F-dATP) were substrates and caused chain termination in the absence of ATP. We further investigated whether analogue incorporation at the 3′-terminus of RNA primers negatively impacts polyadenylation with ATP by generating RNA oligonucleotides containing either a terminal clofarabine, Cl-F-dAdo, or cladribine residue. Incorporation of any of these analogs blocks the ability of yPAP to extend RNA past the analogue site, impeding the addition of a poly(A)-tail. To determine whether modified ATP analogues exhibit a concentration-dependent effect on polyadenylation, poly(A)-tail synthesis by yPAP with modified ATP analogues in combination with a constant level of ATP was also examined. With all the ATP analogues assayed in these studies, there was a significant reduction in poly(A)-tail length with increasing amounts of analogue triphosphate. Taken together, our results suggest that polyadenylation inhibition may be a component in the mechanism of action of adenosine analogues. [Copyright &y& Elsevier]

• The clinical outcome for older adults with ALL or ABL ineligible for multi-agent chemotherapy are poor and are a rare, unmet need. • Entinostat plus clofarabine was well tolerated but infectious and metabolic derangements were more common in the older population (vs younger). • Events of hyperglycemia and peripheral neuropathy were not appreciated with the use of Entinostat plus clofarabine. • Entinostat plus clofarabine appears to be active in older adults with de novo ALL/ABL, and further study of this combination should be considered. Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1−21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3–7) (Arm A). Adults aged 40–59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted. [ABSTRACT FROM AUTHOR]

Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu+Clo+Bu+Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation., (Published by Elsevier Ltd.)

This study uses single cell network profiling (SCNP) to characterize biological pathways associated with in vitro resistance or sensitivity to chemotherapeutics commonly used in acute myeloid leukemia (AML) (i.e. cytarabine/daunorubicin, gemtuzumab ozogamicin (GO), decitabine, azacitidine, clofarabine). Simultaneous measurements at the single cell level of changes in DNA damage, apoptosis and signaling pathway responses in AML blasts incubated in vitro with the above drugs showed distinct profiles for each sample and mechanistically different profiles between distinct classes of agents. Studies are ongoing to assess the clinical predictive value of these findings., (Copyright © 2012 Elsevier Ltd. All rights reserved.)