Allo-SCT remains the only curative option for patients with high-risk hematologic malignancies or acute leukemia[1]. The nonmyeloablative (NMA) conditioning regimen is the least intense of the conditioning therapies and the most tolerated[2]. Reduced-intensity conditioning (RIC) regimens emerged around two decades ago with the aim of decreasing the toxicities and morbidities related to allo-SCT. The concept of RIC switched progressively to the concept of reduced-toxicity conditioning (RTC) regimens, which are currently the most used conditioning regimens worldwide. Due to lower NRM associated with RIC and RTC, such regimens allow older patients or those with co-morbidities to be transplanted. The combination of Flu, an intermediate dose of intravenous busulfan, and low dose ATG is among the most popular RIC regimen used in Europe, particularly in France. Other RIC regimens involve other drugs such as a combination of Flu, melphalan, busulfan, and ATG[3-6]. Nevertheless, relapse remains a challenge after such regimens. Therefore, attempts to intensify the RIC regimen without increasing NRM might be an attractive option to obtain better disease control while waiting for the immune graft-versus-leukemia (GVL) effect. Thus, the incorporation of new drugs with greater anti-tumor activity and acceptable toxicity merits further investigation as part of the RTC approach.
Historically, 20% of allo-SCT performed after NMA regimens resulted in graft failure and rejection; the addition of Flu to these regimens decreased the rejection rate to 3%. Flu's efficacy was proven in many studies of allo-SCT and haplo-SCT. However, disease-related mortality remained high[7].
Clofarabine (Clo) is a second-generation purine analog that requires intracellular phosphorylation to be active. Clofarabine triphosphate impedes DNA synthesis and repair by inhibiting ribonucleotide reductase and DNA polymerase. It has been documented that Clo has significant anti-leukemic activity, particularly in relapsed AML and ALL, and the drug is approved by the United States Food and Drug Administration for the treatment of pediatric ALL patients after at least two prior regimens. Hand-foot syndrome and reversible liver function abnormalities are the two main complications of the drug. Clo combines the most favorable pharmacokinetic properties of the first-generation purine analogs, namely Flu and cladribine, with superior anti-leukemic activity, due to increased resistance to deamination and phosphorolysis, conferring better drug stability[8]. Direct induction of apoptosis by activation of caspase-9, and direct interaction with the mitochondrial membrane may also play a role in this superior anti-leukemic effect[9]. Clo is also more active in non-dividing lymphocytic cells, which might give more immunosuppression and decrease engraftment failure[10]. Due to its strong anti-leukemic action and lower organ toxicity compared to Flu, it has been increasingly used in adult patients, not only as an alternative to RIC regimens but also as a RTC alternative to standard myeloablative (MA) regimens.
Thus, one can also exploit the anti-leukemic, immunosuppressive effects and Clo’s favorable toxicity profile in an RTC regimen setting before allo-SCT. Many studies have also been also carried out to evaluate the efficacy of Clo, in place of Flu to tackle the high relapse rate[10-13]. A phase 1 study of Clo 52 mg/m2 with TBI (2 Gy), published in 2017, was performed with 18 pediatric patients with hematologic malignancies in CR and considered to be at high mortality risk from MA conditioning regimens. At one-year post-transplant, the mortality rate due to disease progression was 33%, NRM was 0%, event-free survival (EFS) was 60%, and OS was 71%. It was concluded that Clo/TBI can be used for successful engraftment while maintaining a low rate of NRM in pediatric leukemia patients[10].
Another study retrospectively compared Clo versus the same regimen with Flu (FLAG or FA, retrospectively) in combination with high-dose cytarabine with or without granulocyte colony-stimulating factor (GCSF). The study included 151 patients and showed that treatment with Clo was associated with higher CR rates and longer survival even after accounting for other variables, especially in patients with unfavorable genetics or a short duration of first CR[11] . Another retrospective study of 355 AML/MDS patients who were allo-transplanted between 2009 and 2014 and received either Clo/busulfan x 2 days (CloB2ATG2) or a Flu/busulfan x 2 days with ATG x 2 days (FB2ATG2) showed that FB2ATG2 was associated with lower OS (hazard ratio [HR]=2.14, P=0.04) and higher relapse risk (HR=2.17, P=0.04)[12].
Another retrospective study in France, of 36 adult patients with myeloid malignancies, treated between 2014 and 2017 with Haplo-SCT, treated the patients with the Baltimore RIC regimen and high-dose post-transplant cyclophosphamide (PTCy). However, they replaced Flu with Clo, bone marrow (BM) with peripheral blood stem cells (PBSC), and tacrolimus with cyclosporine A (Clo-Baltimore). The Clo-Baltimore regimen showed encouraging results for patients regardless of disease activity at transplant. All the patients engrafted except for one. The rates of acute GVHD grade II-IV and chronic GVHD were 49% and 21% respectively. The two-year disease-free survival was 52% and OS was 66%. The Clo-Baltimore outcomes were superior to the classical Baltimore outcomes with EFS of 26%, and OS of 37%[13].
With all of these studies showing the efficacy of Clo, this paper is mainly focused on exploring the outcomes of using Clo together with TBI (4-8 Gy) as conditioning therapy before allo-SCT.