The use of higher dose clofarabine in adults with relapsed acute lymphoblastic leukemia Bradley A. McGregor, 1 Alexander W. Brown, 1 Michael B. Osswald, 1 and Michael R. Savona 1,2 * The standard dose of clofarabine is 52 mg/m 2 for pediatrics and 40 mg/m 2 in adults. Clofarabine dosed at 52 mg/m 2 was used in adult patients with refractory ALL to maximize response before allo-HSCT. All patients had a significant response to therapy. Published pharmacokinetic analysis revealed no difference in peak plasma or intracellular concentrations at clofarabine dosed above 40 mg/m 2 , yet inhibition of repli- cation in leukemia cells was only sustained over 24 hr at 55 mg/m 2 . Despite this, there have been no reports of high dose clofarabine used in this setting. Our experience implies that there may be a niche role for clofarabine in reducing disease burden before allo-HSCT for adults with relapsed ALL. Am. J. Hematol. 84:228–230, 2009. Published 2009 Wiley-Liss, Inc. y Introduction There are 4,000 new cases of acute lymphoblastic leuke- mia (ALL) in the United States annually. Approximately, one third of those cases are adults, and while long term survival rates approach 90% in children and adolescents, the 5- year overall survival for adults with ALL is less than 50%, even with the use of allogeneic hematopoietic stem cell transplant (allo-HSCT) [1]. In relapsed disease, prognosis is dismal, with 5-year disease-free survival rates of near 10% [2]. Given the curative potential of allo-HSCT, and the lack of effective alternatives, this is the preferred therapy for relapsed ALL. That said, debulking relapsed disease appears essential for success with allo-HSCT. In one study, post-transplant relapse occurred in 11/11 patients with mo- lecular evidence of disease [as detected through PCR for presence of immunoglobulin heavy chain variable-diversity- junctional (IgH V-D-J) gene rearrangements], and in only 1/5 patients with no molecular evidence of disease prior to transplant [3]. Unfortunately, achieving a second CR in relapsed ALL is difficult with available therapy, and thought to occur in less than 50% of patients [2]. Clofarabine is a second generation nucleoside purine analogue with activity against hematologic malignancies. Given successes in the pediatric population, clofarabine is FDA-approved as a salvage therapy in children with relapsed ALL [4,5]. The majority of current research in the adult population, however, has been in the setting of AML or other myeloid diseases [6,7]. In published phase I/II studies, clofarabine was only given to 25 adult patients with ALL, [6,7] and there is only one case report specifically addressed its use in the setting of refractory ALL [8]. In none of these reports was clofarabine 52 mg/m 2 given daily for 5 days. Although in the pediatric population, 52 mg/m 2 / day for 5 days is used, the established maximum tolerated dose of clofarabine in adults is 40 mg/m 2 /day for 5 days. Here, we report the use of clofarabine as a means of obtaining PR/CR for three adults with relapsed ALL prior to allo-HSCT. Cases Patient #1 is a 19-year-old male who presented with Ph 2 pre-B Cell ALL with leukocytosis (WBC >250 K), but no other poor risk factors. He reached a PR after three cycles of HyperCVAD [9] induction, and after a subsequent cycle of FLAG-IDA [10] was found to be in a morphologic CR with elimination of the clone by flow cytometry. He subse- quently underwent allo-HSCT from an HLA-matched sibling after conditioning with cytoxan and total body irradiation (Cy/TBI). His post-HSCT course was uneventful until he relapsed 5 months later. After a brief trial with mitoxantrone 1 etoposide failed, he was given clofarabine 52 mg/m 2 and was found to have an aplastic marrow without evidence of leukemia on day 14 of therapy. Patient remained pancyto- penic, and on day 16 of therapy, 8 months after his first transplant, he proceeded directly to second allo-HSCT from the same HLA-matched sibling. He engrafted with no trans- plant or chemotherapy related hepatic toxicity, and has no evidence of disease at 1 year post transplant. Patient #2 is a 39-year-old male who was initially diag- nosed with Ph 2 pre-B cell ALL. He achieved CR by mor- phology and flow cytometry after one cycle of HyperCVAD [9]. He was given three further cycles and underwent allo- HCST from an HLA-matched sibling after conditioning with Cy/TBI. The patient had an uncomplicated course until he relapsed with central nervous system involvement 10 months later. He was given Flag-Ida [10] with no response and was subsequently treated with clofarabine 52 mg/m 2 with an aplastic marrow without evidence of leukemia noted after one cycle. Immediately following a second cycle of clofarabine 52 mg/m 2 , he received a second allo-HSCT from a different HLA-matched sibling without any hepatic toxicity. Patient had delayed engraftment, but was free of disease at day 30. In the setting of continued immunosup- pression and development of an invasive fungal infection Conflict of interest: Nothing to report. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the official policy of the Department of Defense or other Departments of the US Gov- ernment. *Correspondence to: M.R. Savona, 2200 Berquist Dr Ste#1, Lackland AFB, TX 78236. E-mail: Michael.Savona@lackland.af.mil 1 Department of Medicine, Hematology–Oncology, San Antonio Military Medi- cal Center, San Antonio, Texas; 2 Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center San Antonio, Texas Received for publication 9 October 2008; Revised 7 January 2009; Accepted 8 January 2009 Am. J. Hematol. 84:228–230, 2009. Published online 20 January 2009 in Wiley InterScience (www.interscience. wiley.com). DOI: 10.1002/ajh.21365 Brief Research Report Published 2009 Wiley-Liss, Inc. y This article is a US Government work and, as such, is in the public domain in the United States of America. American Journal of Hematology 228 http://www3.interscience.wiley.com/cgi-bin/jhome/35105