A New Conditioning Regimen with Clofarabine for Allogeneic Stem Cell Transplantation in Pediatric Patients with Refractory Disease.
Authors: Lang Peter J. , Mueller Ingo , Teltschik Heiko , Pfeiffer Matthias , Ebinger Martin , Feuchtinger Tobias , Handgretinger Rupert 
Published: October 2019

Abstract
We report the results of a pilot study with a clofarabine containing conditioning regimen for allogeneic stem cell transplantation. Several studies have already shown the effectivity of clofarabine in adult patients and children with acute leukemias, resistant to standard treatment protocols. Thus, we replaced fludarabine in a melphalan based myeloablative regimen by clofarabine for pediatric patients with refractory disease after standard treatment (n=7) or after previous transplantation (n=3). A total of 10 pediatric patients with acute lymphatic leukemia (non-remission (NR) 1=3, NR 2=3), acute myeloic leukemia, (NR 1=2) and metastatic rhabdomyosarcoma/neuroblastoma (partial remission (PR) =2) received clofarabine 4×50mg/m2 (day -8 to -5), thiotepa 10mg/kg (day -4), melphalan 2×70mg/m2 (day -3 to -2) and OKT3 (0, 1 mg/kg day -8 to +14; n=9) or ATG (10mg/kg; n=1), followed by infusion of full haplotype mismatched peripheral stem cells (n= 9) or bone marrow from matched unrelated donors (n=1). In mismatched family donors, depletion of T and B cells was carried out with CD3/CD19 coated magnetic microbeads and the CliniMACS® device. A median number of 16×106/kg stem cells (5.6–28) with 90 000/kg residual T cells was infused. Primary engraftment was observed in 9/10 patients. One patient experienced graft rejection but was successfully retransplanted with stem cells from a second parental donor. Thus, sustained engraftment could be obtained in all patients. Median time to ANC >500/μl with G-CSF stimulation was 10 days (9–11). Independence from platelet transfusion was reached after 9 days. Median T cell count at day 100 was 138 cells/μl (n=5). 7/10 patients are disease free with a median follow up of 100 days. Single cause of death was relapse of the underlying disease (median time to relapse: 90 days). The regimen was well tolerated without severe side effects. No TRM and no toxicity grade 4 according to NCI-CTC grading system occurred apart from mucositis. The profile of toxic side effects was as follows: gastrointestinal: diarrhea grade 0–2 (n=10), stomatitis grade 3–4 (n=10); skin: none; pulmonary: hypoxia and pneumonitis grade 3 in 2 and 1 patient, respectively; cardiac: none; hepatic: GOT/GPT or bilirubin elevation grade 1–2 in 4 patients, grade 3 in 6 patients; renal: creatinine (-clearance) grade 1 in 1 patient; neurological: none; infection: grade 2 (n=8), grade 3 (n=2).
Conclusions: clofarabine was well tolerated as part of a conditioning regimen for allogeneic transplantation. Compared to our standard regimen with fludarabine, thiotepa, melphalan, the introduction of clofarabine did not result in any unexpected toxicity. Immunosuppressive effects appeared to be similar to those of fludarabine, since primary engraftment was observed in 90%. Further studies are warranted to evaluate, whether clofarabine can contribute to reduce the risk of relapse in patients with refractory disease.