clofarabine
Regulatory sources consulted
Approved indications
- Pediatric relapsed or refractory acute lymphoblastic leukemia after at least two regimens and with no other option expected to provide durable response.
Contraindications
Absolute
- Hypersensitivity; severe renal impairment; severe hepatic impairment; breastfeeding.
Clinical warnings
- Monitor blood counts before each cycle and through the nadir. Delay or modify the cycle for myelosuppression; infections and bleeding may be severe or fatal. — CIMA/AEMPS, ficha técnica 84596
- Prevent tumor lysis syndrome with hydration during all 5 days and consider allopurinol. Interrupt for clinically significant SIRS or capillary leak and monitor renal and hepatic function. — CIMA/AEMPS, ficha técnica 84596
Drug interactions
- HighNephrotoxic or hepatotoxic drugs
Mechanism: They may increase organ toxicity during clofarabine dosing days.
Recommendation: Avoid when possible during the 5 dosing days or intensify renal and hepatic monitoring.
CIMA/AEMPS, ficha técnica 84596
Pregnancy and lactation
It may cause fetal harm; perform pregnancy testing before treatment. Women must use effective contraception during treatment and for 6 months afterward; men during treatment and for 3 months afterward. Do not breastfeed during treatment or for 2 weeks after the last dose.
Recent literature (PubMed)
Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML. ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens. Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002). Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.
Clofarabine monotherapy at a dose of 52 mg/m2 per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21 years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted. A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52 mg/m2. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety. A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52 mg/m2; of them, 374 were aged < 22 years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95% CI 20, 37), respectively, in the pediatric population and 12% (95% CI 5, 21) and 21% (95% CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7 months (95% CI 0.1, 31.4), reaching 10.1 months (95% CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade 3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia. In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phase II study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.
The traditional cytotoxic induction regimen for acute myeloid leukemia (AML) is seven days of standard-dose cytarabine and three days of an anthracycline antibiotic (such as daunorubicin or idarubicin), commonly known as "7 + 3." Many studies have been conducted to find an additional agent that might improve efficacy. Data from select studies has shown, in certain populations, benefit to adding cladribine, clofarabine and lomustine to a traditional backbone. For mutation-based chemotherapy regimens, midostaurin with 7 + 3 is the current standard of care for FLT3-mutant, younger AML patients. As we learn more about the synergism of molecular agents and traditional anti-cancer treatments, we can hopefully develop novel regimens without abandoning some of the benefits of these mutation agnostic historical therapies.
Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors.
The proteasome inhibitor bortezomib and purine nucleoside analog clofarabine combination had greater than additive activity in the NCI-ALMANAC preclinical screen. We conducted a phase 1 trial (NCT02211755) to evaluate the combination's safety and efficacy in patients. We administered bortezomib subcutaneously on days 1 and 4, and clofarabine intravenously on days 1-5 of each 21-day cycle. The primary objective was to establish the safety, tolerability, and maximum tolerated dose (MTD) of bortezomib and clofarabine in patients with refractory solid tumors, lymphomas, or MDS. The secondary objective was to determine the effects of the combination on biomarkers of cell death and DNA damage response (DDR) in tumor biopsies. Of 28 patients enrolled, 11 had a best response of stable disease (median 5 cycles; range 2-10 cycles), including 5 patients (4 from the solid tumor cohort, 2 of which were at MTD) with stable disease for ≥ 6 cycles. The MTD for the solid tumor cohort was 1.3 mg/m2 bortezomib on days 1 and 4, and 1.5 mg/m2 clofarabine on days 1-5 of each cycle. The MDS cohort closed prior to MTD determination, due to low accrual. The most common study drug related adverse events were hematologic. Two out of 3 patients with evaluable biopsies had increased markers of cell death, and 1 patient also had increased DDR markers after treatment. The combination of bortezomib with clofarabine demonstrated limited antitumor effects possibly due to the inability to reach the efficacious doses achieved in preclinical models.