Successful management with clofarabine for refractory leukaemia in a young adult with chronic renal failure
Authors: Helene Sudour, Antoine Kimmoun, Audrey Contet, Laurence Clement, Alexandra Salmon, Claudine Schmitt, Pascal Chastagner
Journal: American Journal of Hematology (2010)

Adult acute lymphoblastic leukemia (ALL) remains a difficult disease to cure. For high-risk patients, front-line protocols are often aggressive and call for allogeneic HSCT with the aim to offer prolonged leukemia-free survival. If patients relapse after transplantation, novel salvage therapies are desperately needed. However, some comorbid medical conditions post-transplantation can preclude the potential to cure. Clofarabine is a new nucleoside analog, which appears to act by inhibiting DNA polymerase, alpha ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. It has shown a significant efficacy in myeloid hematologic malignancies [1] and in patients with relapsed or refractory T-cell and B-cell lymphoblastic leukemia both in adult [2] and especially in pediatric patients [3]. Its combination with a low dose of cytarabine seems, in a phase II study, to exhibit greater antitumor activity [4]. For patients with moderate renal impairment, a reduced dose has to be chosen for a similar exposure, because the total body clearance of the principal metabolite (2-fluoro-ara-A) correlates with the creatinine clearance [5]. There are no published data on the possibility to use this chemotherapy in patient with chronic end-stage renal failure and only rare data about the effect of hemodialysis on the pharmacokinetics of clofarabine. We report the pharmacokinetics data, tolerance and efficacy of clofarabine in combination with cytarabine, realized using continuous venovenous hemodialysis (CVVHD) in a young patient treated for relapsed high-risk leukemia. A 22-year-old young adult was referred with bone marrow relapse of a high risk B-cell ALL, 20 months following an allogeneic hematopoietic stem cell transplantation (HSCT). He was diagnosed at the age of 20 with CD10 negative hyperleukocytosis B-cell ALL and complex cytogenetic karyotype. He received chemotherapy (GRALL 2005 protocol), then proceeded to HSCT (two unrelated umbilical cord blood) after a myeloablative conditioning regimen using total body irradiation 12 Gy and cyclophosphamide (120 mg/kg). Evolution was marked by a Grade II acute gastro-intestinal graft versus host disease (GI GVHDa), a chronic cutaneous GVHD, an obliterans bronchiolitis, a Grade III polyomavirus-associated hemorrhagic cystitis, and finally, an acute tubular necrosis leading to end-stage renal failure. He was placed under a dialysis program from the second month following HSCT and continued afterwards with three sessions of dialysis per week. He was in persistent complete remission (CR1) for 19 months. Then, he developed thrombopenia and the level of minimal residual disease (MRD), measured by RQ-PCR, increased. Bone marrow evaluation confirmed the bone marrow relapse. A multidisciplinary discussion between hematologists, nephrologists, and intensivists allowed the administration of a chemotherapy plan taking into account some morbidities (intolerance to L-asparaginase and Erwinia asparaginase and end-stage renal failure). He received steroid therapy, vindesine, PEG asparaginase, and intrathecal injection of liposomal cytarabine (Dépocyte®). In parallel, he was dialysed four times per week to obtain the most physiological chemotherapy clearance possible. No response occurred and two doses of doxorubicin were administered, which decreased only of 25% the bone marrow blasts. Next, he was tried on an intensified chemotherapy with the association of clofarabine (Evoltra®, 40 mg/m2/day IV daily for 5 days) and cytarabine (20 mg/m2/day SC for 7 days). Clofarabine was administered concurrently with CCVHD from day 1 to 5. Filters with the HF 1000 membrane (Prismaflex® HF1000 Set, Gambro Lundia AB, Sweden, filter surface area: 1.1 m2) were used. Hemosol BO fluid (Gambro) was used as the dialysate and replacement fluid. Blood flow was kept above 250 ml/min. The effluent flow prescribed was based on the patient's body weight and was just about 55 ml/kg/h. Considering that chemotherapy induced thrombopenia, no anticoagulation was prescribed. Thus, predilution was maximized to avoid filter clotting with a ratio 1:1 (predilution: 1,500 ml/h, postdilution 500 ml/h, and dialysate 1,000 ml/h). Fluid was reduced to 150 ml/h by decreasing the flow of the replacement fluid and of the dialysate in equal proportion. Once the patient's informed consent had been obtained, plasma and dialysate specimens were collected for determination of clofarabine levels at H0, H3, H7, and H24 as indicated in Fig. 1a. Total drug removal was assessed by measuring drug concentration in the effluent at H24. All the clofarabine concentrations were assayed using high-performance liquid chromatography. The CVVHD clofarabine clearance rate was calculated as (Ceff × Veff)/(CPH24 × time), where Ceff = clofarabine concentration in the effluent, Veff = volume of effluent collected over the time interval, CPH24 = plasma clofarabine concentration at H24, and time = duration of effluent collection (1.75 hr for one bag of effluent). The average peak of clofarabine was 2.72 ± 0.81 μM. There was no accumulation between day 1 and 5: clofarabine concentrations were 0.36 μM at 24 hr after the first dose, 0.56 μM at 24 hr after the second dose, 0.37 μM at 24 hr after the third dose, 0.30 μM, and 0.26 μM after the fourth and fifth dose. The average dialysis clearance was 1.39 ± 0.26 L/H/m2, as illustrated in Fig. 1b. (a) Plasmatic concentration of clofarabine under CVVHDF and (b) clofarabine clearance in our patient under CVVHDF: comparison with clearance in patient with normal renal function. After chemotherapy, hospitalization continued in intensive care hematology unit. The intermittent dialysis was resumed at 3 sessions per week. The patient experienced Grade III/IV toxicities (NCI Common Toxicity Criteria): febrile pancytopenia, painful hand-foot syndrome, stomatitis, colitis requiring parenteral nutrition and opioid analgesics, and cytolysis with liver transaminases to 8 N. With appropriate symptomatic treatments, he recovered from all toxicities. The neutrophil count recovered within 26 days using 6 GCS-F injections. The platelet count recovered within 35 days. Bone marrow examination following hematopoietic recovery demonstrated no residual leukemia by morphologic, flow cytometric and cytogenetic criteria. Three months after the clofarabine treatment, he was in persistent CR2 and underwent a second cord blood transplantation following a non-myeloablative conditioning regimen. Eighteen months latter, he is alive in CR2 and has undergone a renal transplant with cadaveric donor. Relapsed B-cell ALL following HSCT carries a dismal prognosis. Few chemotherapy agents have demonstrated efficiency, and most patients die despite achieving a second remission. We present a particularly challenging patient with a highly resistant disease and underlying severe renal dysfunction. Phase I [6] and phase II [3] studies showed significant activity of clofarabine in both young adult and pediatric patients with multiple relapse or refractory leukemia. It compares favorably with other salvage therapies in both ALL and AML lineages [3–7]. Our patient was offered clofarabine as a last promising salvage therapy. Clofarabine and cytarabine together may be synergistic and have been used safely in adult leukemia patients with a complete response rate of 22% and an overall response rate of 38% [4]. We decided to use classic adult dose of clofarabine (40 mg/m2) and low dose of cytarabine (20 mg/m2/dose). In humans, clofarabine is primarily excreted by the kidney, with 60% of the drug being excreted unchanged by both tubular secretion and glomerular filtration, with a half life of 4–6 hr in most cases [8]. To mimic this physiological excretion, the patient underwent CVVHDF with a closed monitoring of the clofarabine levels both in plasma and spent dialysate. Only one work reported nucleoside analog administration under continuous renal replacement therapy for acute renal impairment [9]. This is the first report about the pharmacokinetics of clofarabine during CVVHD in a patient with end-stage renal failure. Normally, the level peaks about 1 hr after the start of infusion. Under CVVHDF, the expected rise in the plasma levels with each following infusion was observed, suggesting that the rate of increase exceeded the rate of elimination. Clofarabine concentrations peaks, occurred just after the infusion and were slightly above the range of expected values (1.5 μM, range 0.42–3.2 μM) previously studied in seven patients treated for an acute leukemia [10]. However, at 40 mg/m2, the maximum clofarabine dose in adult acute leukemia, there is substantial variation in the plasma concentration of clofarabine between patients [10]. The residual plasmatic concentrations of clofarabine remained significant compared to the predicted concentration in patients with normal renal function. Moreover, important residual concentrations could be an explanation to the too overly peak concentrations following clofarabine infusions. The average dialysis clearance was 1.39 ± 0.26 L/H/m2, which is about 15% of the clearance in patients without renal failure (10.8 L/H/m2) [11]. Nevertheless, no accumulation was found over the 5 days (Fig. 1a). Two hypotheses could account for this finding: first, with continuous renal replacement therapy, samples in each effluent bag every 105 min could not be achieved for the clearance calculation. Second, clofarabine assay was not done routinely in our hospital. Thus, the rate of clofarabine metabolite clearance was probably underestimated and represented only the clearance before next clofarabine injection. Unfortunately, we did not collect a sample for the clofarabine assay at the end of the first effluent bag after clofarabine infusion, which could achieve a better clearance result. Given the extensive volume of distribution (210 L in a 40-kg individual [11], with significant tissue distribution, only a small portion of drug is contained in the plasma compartment. The protein-bound fraction is significant (47%). The small molecular weight (303.68 Dalton) suggests that the unbound drug in the plasma is able to pass through the pores of the dialysis membrane. Finally, the drug removal seems mainly due to hemofiltration. Also, substantial non-renal elimination (40%, unknown mechanism) may explain the unexpected good residual rates in our patient [8]. The most common adverse events ≥ Grade III reported with clofarabine are febrile neutropenia, anorexia, and nausea, observed in about 10% of heavily pretreated patients [3]. Our patient experienced more severe events but no unmanageable toxicity and was able to receive further chemotherapy for a second transplantation providing a new complete remission. In conclusion, this report highlights the efficacy of clofarabine in high-risk leukemia. Above all, it suggests that, if clofarabine administration in the setting of end-stage renal failure may carry significant life-threatening risks, it can be considered whether adequate removal of the drug is provided by CVVHD. The relationship between clofarabine plasma concentration and both efficacy and toxicity remains to be elucidated. Further studies on clofarabine pharmacokinetics in the setting of severe renal impairment are needed to develop appropriate guidelines in this situation. The authors thank Jeha S., MD, from the Department of Oncology at St. Jude Children's Research Hospital, for supporting this work. Helene Sudour , Antoine Kimmoun , Audrey Contet , Laurence Clement , Alexandra Salmon , Claudine Schmitt , Pascal Chastagner