Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 523-536, May 2009

Busulfan in Hematopoietic Stem Cell Transplantation

  • Stefan O. Ciurea
    • ,
  • Borje S. Andersson

      Affiliations

    • Corresponding Author InformationCorrespondence and reprint requests to: Borje S. Andersson, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

University of Texas M.D. Anderson Cancer Center, Houston, Texas

Received 9 December 2008; accepted 10 December 2008. published online 13 February 2009.

Article Outline

Abstract 

The development of intravenous busulfan (Bu) and its incorporation in the preparative regimens for allogeneic stem cell transplantation has changed transplantation for myelogenous malignancies. Bypassing the oral route to achieve 100% bioavailability translated into improved control over drug administration, with increased safety and reliability of generating therapeutic Bu levels, maximizing antileukemic efficacy. Bu-nucleoside analog-based conditioning chemotherapy, thus far represented by fludarabine (Flu), is becoming the conditioning chemotherapy regimen of choice for patients with acute myelogenous leukemia (AML) at many transplant centers. The use of busulfan Bu-based conditioning is extending rapidly also to hematopoietic stem cell transplantation (HSCT) for lymphoid malignancies, genetic diseases, and umbilical cord blood transplantation.

Key Words: Busulfan, Conditioning regimens, Hematologic malignancies, Hematopoietic stem cell transplantation

 

Back to Article Outline

Introduction 

The bifunctional DNA alkylating agent Busulfan (Bu) is now widely used as an alternative to total body irradiation (TBI) in conditioning therapy for hematopoietic stem cell transplantation (HSCT). However, initially, oral Bu was used as a palliative treatment of chronic myelogenous leukemia (CML) and other myeloproliferative disorders since the 1950s [1]. Several sulfonic-acid ester derivatives had been identified as having potent antitumor activity and being inhibitory of normal hematopoiesis. One such compound, 1,4-dimethanesulphonyloxybutane, (Myleran®, Bu), showed intense suppressive properties on myelogenous cell proliferation and, “compared with X-rays, it did not appreciably depress lymphocyte formation at a dose which causes a 50% or more decrease in the number of (circulating) neutrophils” [1]. The authors perceived a relative lack of adverse effects that allowed the more widespread use of Bu in patients with myeloproliferative disorders, mainly CML 1, 2. Later on, the use of Bu was gradually replaced from palliative treatment of myeloproliferative diseases to pretransplant conditioning. This emerged from the experience of Santos and Tutschka [3], who translated to humans the potent myeloablative effect of Bu observed in their murine aplastic anemia (AA) model. These pioneer investigators combined oral Bu with cyclophosphamide (Cy), or Bu/Cy, to use it as conditioning therapy for allogeneic HSCT in patients with acute myelogenous leukemia (AML) [4]. Oral Bu/Cy was quickly recognized as an effective pretransplant regimen for a wide variety of hematologic malignancies and nonmalignant disorders, providing a desired alternative to the standard regimen of TBI and Cy (TBI/Cy). A slightly revised regimen (oral Bu/Cy2) remains a standard conditioning regimen for HSCT [5].

Lately, however, myeloablative as well as pretransplant reduced-intensity conditioning (RIC) with Bu in combination with the nuceloside analog fludarabine (Bu/Flu), is gradually replacing Bu/Cy and TBI/Cy as the preferred conditioning regimens for patients with myelogenous malignancies. Bu, in combination with melphalan (Bu/Mel), is another promising conditioning regimen for both myelogenous and lymphoid malignancies. As we look forward to the future, nucleoside analogs of later generation like clofarabine, drugs with similar immunosuppressive capabilities as Flu, but with greatly enhanced antileukemic properties, are likely to complement Flu in combination with intravenous (i.v.) Bu. Moreover, we envision an i.v. Bu-nucleoside analog platform to safely deliver other agents including chemotherapeutic drugs, immunomodulatory, and cellular therapies added pre- and/or posttransplant to further enhance the efficacy of preparative regimens and increase the benefit of HSCT.

Back to Article Outline

Clinical Experience, Therapeutic Results, and Toxicity 

It has been more then 30 years since Thomas and colleagues [6] published their results on 100 patients treated with TBI and high-dose Cy in a proof-of-principle paper, demonstrating that stem cell transplantation (SCT) is not only feasible, but may be curative for acute leukemia. Moreover, this group established the use of TBI/Cy as a conditioning regimen for such patients, using Cy at 50 mg/kg daily for 4 days in addition to 10 Gy TBI. Unfortunately, the price for this approach was a treatment-related mortality (TRM) in excess of 50%, signaling a need for improved safety of the procedure [6]. About the same time, Bleyer et al. [7] reported a successful transplant after combination chemotherapy without TBI, demonstrating that TBI is not mandatory for a successful outcome of HSCT. The use of TBI has subsequently become associated with a variety of immediate and long-term posttransplant complications, including retarded intellectual development and stunted growth in children, as well as secondary malignancies, cataracts, and endocrine dysfunction, all of which support the development of alternative conditioning regimens for HSCT 8, 9, 10.

Santos et al. [4] reported, in 1983, on the replacement of TBI with high doses of Bu. Bu, as the antileukemic agent, in combination with Cy as an immunosuppressive adjunct, proved to be an effective conditioning regimen [4]. This group treated 51 patients with AML with Bu at 1 mg/kg orally every 6 hours for 16 doses followed by Cy at 50 mg/kg i.v. daily for 4 days (Bu/Cy) [4]. An every 6-hour schedule was arbitrarily chosen because Bu tablets were highly irritating to the gastric mucosa, thus emetogenic, and patients were required to take a large number of tablets to achieve the desired Bu systemic exposure (SE). These investigators showed a clear stratification of outcomes based on disease status at transplant: 44% of the patients in first complete remission (CR1) achieved stable long-term remission, compared with 0% for patients with more advanced disease [4]. Overall, grade ii-iv acute graft-versus-host disease (aGVHD) developed in 44% of patients and chronic GVHD (cGVHD) in 22%. Clinically significant hepatic failure, veno-occlusive disease (HVOD), occurred in 3 patients [4]. These results again demonstrated that TBI can be replaced in the pretransplant conditioning for acute leukemia patients. However, a TRM rate of 73% was reported in this study. Because of this high treatment-related toxicity (including, but not limited to HVOD), Tutschka and colleagues [5] revised the preparative regimen for patients with leukemia. This group reduced the Cy dose from 200 mg/kg to 120 mg/kg (60 mg/kg daily administered over 2 days), but used the same dose of Bu (1 mg/kg every 6 hours for 16 doses) [5]. Fifty patients with leukemia (AML, acute lymphoblastic leukemia [ALL], and CML) were treated with this modified regimen with remarkable results; neutrophil engraftment was achieved in 96% of patients after a median of 13 days. No one had severe mucositis, only 1 patient developed clinically significant, but reversible, HVOD, and the actuarial 3-year overall survival (OS) was 65% [5]. A surprisingly low incidence of infectious complications, coupled with a low incidence of GVHD, was also noted [5]. This study showed that the Cy dose reduction did not compromise the antileukemic activity, but significantly reduced the toxicity of the conditioning regimen. These results compared favorably with TBI/Cy, especially for patients with CML, established a new standard in conditioning chemotherapy for HSCT for patients with leukemia, and prompted larger scale comparisons between the Bu/Cy2 regimen and the more established TBI/Cy regimen.

Investigators at the Fred Hutchinson Cancer Research Center (FHCRC) performed a study comparing oral Bu/Cy2 with TBI/Cy as conditioning for CML patients receiving allogeneic HSCT [11], and 3 other multiinstitutional, randomized studies compared Bu/Cy2 with TBI/Cy as conditioning regimen in myelogenous leukemias 12, 13, 14. In an additional single-institution study, oral Bu/Cy2 was compared with TBI-Etoposide [15]. A meta-analysis [16], and a long-term follow-up study of the first 4 studies revealed similar results; Socie et al. [17] reported the results of 488 patients, 316 with CML and 172 with AML, treated with Bu/Cy2 or TBI/Cy after a median follow-up of 7 years. All patients received either Bu 1 mg/kg by mouth every 6 hours for 4 days, or 10 Gy TBI plus the same dose of Cy, 60 mg/kg/day for 2 days. There was no difference in projected 10-year OS between patients treated with Bu/Cy2 and TBI/Cy (65% versus 63%, respectively) in CML, whereas a numeric, but statistically nonsignificant, difference in survival was noted in AML patients, whose projected 10-year OS was 51% and 63% after Bu/Cy2 and TBI/Cy, respectively. Further, there was no difference in extensive cGVHD between the 2 groups for either disease type. The frequency of HVOD was not reported. The incidence of cataracts was significantly higher in CML patients after TBI/Cy, and this complication was also associated with cGVHD. The only other difference was a slightly higher incidence of (permanent) alopecia after Bu-based therapy. The overwhelming majority of patients in these studies were adults, however, and the delayed growth and retarded intellectual development, which remain major concerns with TBI-based conditioning in children, could not be assessed. The CML study at the FHCRC showed similar outcomes as the European studies. None of these studies, unfortunately, had a long enough follow-up to address the development of secondary malignancies, which needs more than a decade of lead time after radiation therapy, and which is being increasingly recognized after the use of involved-field (mantle) radiation therapy for Hodgkin lymphoma (HL) 18, 19, 20. Moreover, a dramatic increase in the incidence of secondary solid tumors has also been observed after autologous transplant with TBI/Cy for non-Hodgkin lymphoma (NHL) [21], confirming data from the treatment of Hodgkin disease, which suggested that a combined chemotherapy-radiation program may have an increased incidence of malignancies than the chemotherapy-only approach (with alkylating agents) 8, 9, 22, 23.

Although overall there was no major difference in outcomes after TBI- and Bu-based conditioning therapy in these large studies, Bu/Cy2 slowly became accepted as a new standard conditioning regimen for myeloid leukemias and caused a shifting trend away from TBI in pretransplant therapy for most myelogenous disorders, an expected result considering its ease of administration and the lack of need for a TBI facility when using chemotherapy alone.

The toxicity from virtually any ablative preparative regimen has been associated with development of HVOD 24, 25, 26. Accordingly, HVOD and/or hepatorenal failure have been of concern with oral Bu administration in combination with Cy, and was commonly considered a “trademark” toxicity associated with high-dose Bu (both the original Bu/Cy and Bu/Cy2 regimen) 27, 28, 29, 30. Additionally, oral Bu is associated with a hepatic first-pass extraction effect that can result in locally high Bu concentrations in the portal-hepatic venous system, which conceivably may contribute to the development of HVOD [31]. However, in addition to Bu, Cy is clearly also hepatotoxic. The contributions of other alkylating agents to the emergence of HVOD, such as Cy or thiotepa (TT), have been illustrated by several investigators 32, 33, 34. Briefly, Hassan et al. [32] showed that the time interval between the last Bu dose and the first Cy dose in Bu/Cy2 is of importance for the development of HVOD. If this interval was >24 hours, the risk of HVOD was significantly lower than if it were <12 hours [32]. McDonald and coworkers [33] demonstrated a highly significant association between the blood levels of certain Cy metabolites and VOD after TBI/Cy. Finally, Przepiorka and coworkers [34] demonstrated that replacing 25% to 30% of the Bu dose in Bu/Cy2 with TT (TT-Bu/Cy) resulted in a HVOD incidence in excess of 30%, or at least as high as that reported in the literature with the standard Bu/Cy2 in patients transplanted for high-risk hematologic malignancies. Together, these data illustrate that the development of HVOD is likely multifactorial. The findings of McDonald et al. [33] suggest that interindividual differences in metabolic drug handling are of importance for development of HVOD, with Cy being a probable contributor to the overall risk. This risk should be expected to further increase with the use of 2 or more alkylating agents that utilize hepatic GSH stores for their detoxification. When such drugs are combined in close time proximity they jointly contribute to the depletion of hepatic GSH, resulting in an exacerbated risk for serious hepatic injury, HVOD, also known as sinusoidal obstruction syndrome (SOS).

In addition to HVOD, neurotoxicity was associated with Bu in animals [35]. Convulsions in a patient receiving Bu were first reported by Marcus and Goldman [36]. The incidence of neurotoxicity after Bu-based conditioning therapy was subsequently estimated to be up to 10% in adults [37], and approximately 7% in children [38]. Vassal et al. [39] reported that higher doses (>600/m2 or 16 mg/kg) were associated with an increased probability of neurotoxic manifestations. Such adverse events have been correlated with the capacity of Bu to cross the blood-brain barrier and is manifested primarily as generalized seizures. A limited degree of plasma protein binding allows Bu, unlike other lipophilic alkylating agents like Mel, to easily cross the blood-brain barrier and achieve levels in CSF that are similar to those in plasma 39, 40. An altered blood-brain barrier may further increase the susceptibility to Bu-associated neurotoxicity. Seizures are more common in older patients, and appear to be dose dependent both in adults and children 38, 40, 41. In adults, seizures typically occur in the third or fourth day of Bu administration, probably as a result of drug accumulation 36, 40, 41, 42, 43, 44. Even without overt seizure activity EEG abnormalities can occur in up to 60% of patients [42]. Various anticonvulsant medications have been used for seizure prophylaxis including phenobarbital sodium, benzodiazepines (clonazepam, lorazepam), and phenytoin 41, 42, 45, 46, 47. Phenytoin has been widely used for seizure prophylaxis in patients receiving Bu as part of the conditioning regimen because of its nonsedating properties. An i.v. loading dose is commonly administered to achieve a therapeutic level (10-20 ng/mL), thereby avoiding the delay in achieving a therapeutic level, which is commonly seen with oral phenytoin. Hassan and colleagues [48] showed that phenytoin used as prophylactic anticonvulsant caused a higher clearance of oral Bu as opposed to when diazepam was used and, therefore, suggested that drugs without microsomal enzyme-inducing properties should be used for Bu seizure prophylaxis. Benzodiazepines have since been employed for prophylaxis by numerous investigators 46, 47, 48. However, despite their use, occasional patients still develop seizures with benzodiazepine prophylaxis [49]. The sedation associated with benzodiazepines may be considered less desirable by some patients, and newer anticonvulsants like leviracetam, which does not interfere with the hepatic microsomal cytochrome P450 pathway, remain to be investigated for seizure prophylaxis in this setting.

These clinical data and related concerns about oral Bu toxicity formed the basis for our hypotheses that (1) an i.v. Bu formulation might cause less stress to the liver, because parenteral administration will alleviate the unpredictable oral drug bioavailability as well as circumvent the first-pass effect of oral drug, and (2) combining Bu with an alternative immunosuppressive agent without hepatic metabolism, that is, replacing Cy with a nucleoside analog, should yield increased safety of the conditioning therapy, because only 1 of the 2 drugs is now dependent on hepatic glutathione (GSH)-stores for its detoxification.

The practical limitations in using oral Bu relate primarily to its unpredictable and erratic bioavailability because of variable intestinal absorption. This prompted the design of an i.v. Bu formulation to achieve absolute dose assurance associated with its controlled administration [50]. The pharmacokinetics of i.v. Bu was evaluated in a phase I clinical trial performed in 15 patients with hematologic malignancies [51]. The new preparation was evaluated in combination with oral Bu and Cy. An i.v. Bu dose of 0.8 mg/kg and a targeted area under the curve (AUC) of 1100-1200 μmol/L per min were identified as equivalent to oral drug at an average of 1.0 mg/kg, and therefore considered for subsequent phase II study [51]. In this study, the average bioavailability of oral Bu was 69%, ranging from <10% to virtually 100%. These results were confirmed by the papers of Hassan et al. [52], and Schuler et al. [53], who estimated the average bioavailability of oral Bu to be in the order of 70% to 80%, using different parenteral reference formulations. A phase II clinical trial was performed in 61 patients with advanced hematologic malignancies (75% with active disease at transplant) treated with i.v. Bu (0.8 mg/kg every 6 hours × 16) followed by Cy (60 mg/kg i.v. daily × 2) [54]. The regimen was very well tolerated (day 100 TRM was <10%); however, 2 patients developed fatal HVOD, 1 of whom had a prior HSCT. Eighty-six percent of the patients achieved an AUC of 800-1500 μMol-min [54].

The combination of Cy with i.v. Bu administration appeared safer compared with that of oral Bu. So far, i.v. Bu/Cy2 has been compared with oral Bu/Cy2 in 5 retrospective studies, all showing superiority of i.v. Bu/Cy2 with regard to the development of HVOD and early TRM 55, 56, 57, 58, 59. Kashyap, et al. [55] observed a significantly lower incidence of HVOD in patients with hematologic malignancies treated with i.v. compared with oral Bu (33% versus 8%) and a significantly lower day 100 TRM. In multivariate analysis, the use of the oral formulation was the strongest predictor of the development of HVOD. Similar results were noted for patients with myelogenous diseases (leukemias and myelodysplastic syndrome [MDS]) 56, 57, 58 and lymphoid malignancies (NHL) [59]. Interestingly, Aggarwal et al. [59] reported, that in 49 patients who underwent autologous stem cell transplant for intermediate and high-risk NHL with pharmacokinetic monitoring (area under the curve [AUC] 1000-1500 μMol/min), the use of i.v. Bu yielded not only a reduction in nonrelapse mortality from 28% to 3%, but a significantly improved overall and progression-free survival (PFS) were also noted with i.v. compared with oral Bu. The latter findings were supported by Dean and coworkers [60], who reported improved outcomes of NHL patients undergoing auto-HSCT using i.v. Bu/Cy2 compared with a reference group that had received the oral formulation.

The introduction of i.v. Bu with Cy appeared to improve the safety of the Bu/Cy2 regimen; however, early regimen-related toxicity was still of concern. It had become apparent through the work of McDonald and coworkers 25, 33 that Cy, used in high doses in the pretransplant setting, contributed to significant hepatotoxicity, regardless of whether Bu is incorporated in the regimen. Thus, as the metabolites of Cy (especially o-carboxyethyl-phosphoramide mustard) likely contribute to HVOD in the double alkylating Bu/Cy conditioning regimen, the risk for this untoward effect could conceivably be decreased by substituting Cy with an immunosuppressive agent from a different class without hepatotoxicity 25, 61. Fl would fulfill these criteria; Flu is an antimetabolite nucleotide inhibitor of DNA synthesis with powerful immunosuppressive properties. It potentiates radiation- and alkylator-induced cytotoxicity through inhibition of DNA damage repair 62, 63. From these studies it can be deduced that Flu most likely has a similar synergistic interaction with Bu. Flu was introduced in HSCT by Terenzi and colleagues [64], concerned about other adverse effects associated with high-dose Cy, such as hemorrhagic cystitis, interstitial pneumonia, and cardiotoxicity, rather then hepatotoxicity, as they intended to use it in combination with TBI. Flu was equally immunosuppressive to Cy in mice, and because of significantly less adverse effects, it was an excellent candidate for replacement of Cy in preparative regimens for HSCT. Slavin and colleagues [65] subsequently reported on a reduced-intensity conditioning (RIC) regimen using oral Bu and Flu (Bu/Flu) as preparative regimen for 26 patients with hematologic malignancies and nonmalignant disorders undergoing matched sibling donor HSCT. This RIC regimen was well tolerated; however, relapse remained a major cause of treatment failure [66].

Bornhauser and colleagues [67] used oral Bu in combination with Flu (Flu 30 mg/m2 i.v. once daily for 4 days followed by Bu 1 mg/kg every 6 hours for another 4 days). The Bu dose was adjusted to target steady-state plasma levels of 900 ± 100 ng/mL (approximately 1200-1500 μMol-min). Fourty-two patients with MDS and CML were treated. Engraftment was achieved in all patients with very low day 100 regimen-related mortality. Twelve patients (29%) died of relapsed disease, whereas the 1-year TRM was 24% [67].

The long half-life of Flu allows once daily administration, and in combination with i.v. Bu has been shown to have low toxicity and an impressive antineoplastic activity 68, 69. The combination of Flu with Bu was developed to achieve effective myeloablation, and optimize antileukemic activity and safety of the conditioning therapy 68, 69.

Russell and colleagues [68] initially reported on a myeloablative conditioning regimen using i.v. Bu-Flu and ATG in a convenient once-daily dosing. Seventy patients with hematologic malignancies were treated with a combination of Flu 50 mg/m2 on days −6 to −2 and i.v. Bu 3.2 mg/kg ideal body weight (IBW) daily on days −5 to −2, and all patients received antimyocyte glubulin (ATG), 4.5 mg/kg [68]. In a second, disease-specific study, performed at the M.D. Anderson Cancer Center (MDACC), Flu and i.v. Bu were given once daily, with each dose of Bu following Flu to achieve synergistic cytotoxicity and high intracellular Bu concentrations 62, 69. Ninety-six patients with AML/MDS were treated in this study with a combination of fludarabine 40 mg/m2 daily for 4 days followed immediately by i.v. Bu 130 mg/m2 daily for 4 days (−6 to −3). ATG was added only for matched unrelated donor and 1 antigen mismatched sibling donor-patients [69]. More than 97% of the patients achieved primary engraftment in these 2 studies 68, 69. Complete chimerism was recorded in 70% by day 30, increased to 100% in 84% of patients by day 100, with the rest having a stable mixed chimera with a median of 98% donor cells. The 100 day treatment-related mortality was <5%, and the incidence of serious aGVHD (grade III-IV) was <10% in both studies. cGVHD was noted in 38% and 55% of the patients, respectively 68, 69. Overall, 34% of the AML patients relapsed in the MDACC study [69], whereas the relapse rates (21% and 26%) for patients with AML treated in CR1 were similar in both reports. Disease-free survival (DFS) and OS were 74% and 75%, and 88% and 81% (at 2 years for patients in the first study and 1 year in the second study), respectively, for patients transplanted in any CR. Pharmacokinetic studies revealed that Bu was cleared in <24 hours without drug accumulation and with <20% interdose variability in clearance and AUC. The median calculated daily Bu AUC values were 4866 and 4980 uMol-min, respectively 68, 69, 70. Stomatitis was the most common toxicity (grade 2 occurring in more than 50% of patients). The majority of patients in the first study, and 18% and 9%, respectively, in the second study, also had transient elevations of alanine aminotransferase (ALT) and conjugated bilirubin within 1 to 2 weeks after transplant, without the development of HVOD. Only 3 of 166 (1.8%) patients treated in these 2 trials developed clinically significant HVOD, 1 of whom died. Neurotoxicity was also rare; 4% of patients developed a hand-foot syndrome in de Lima and colleagues study [69], and 2 patients developed seizures, 1 reported by Russell, et al [68] as having a subtherapeutic phenytoin level and 1 at 6 weeks after transplant likely related to tacrolimus. Interstitial pneumonitis was not reported in either study.

These results suggested that i.v. Bu/Flu was effective and safe. Moreover, in a Bayesian comparison with i.v. Bu/Cy, Andersson et al. [71] demonstrated that i.v. Bu/Flu has very similar antileukemic activity to i.v. Bu/Cy2 in AML/MDS. Although no head-to-head comparison with Bu/Cy2 exists, available retrospective data comparing Bu/Flu with Bu/Cy2 strongly suggest that, indeed, i.v. Bu/Flu is safe and at least as effective as Bu/Cy2 for patients with myelogenous malignancies undergoing HSCT 71, 72. Recent matched-case data appear to challenge the latter when used for a multitude of hematologic malignancies, at least when ATG is routinely included as part of the conditioning regimen to alleviate GVHD, and when given in close proximity to the transplant to more effectively remove T cells from the graft [73]. Thus, these authors confirmed the superior safety of the i.v. Bu/Flu-ATG regimen, yet claimed better antitumor activity of oral Bu/Cy2 when used without ATG [73]. The addition of ATG may have resulted in increased in vivo T cell depletion and could explain the different results between this study and the previous 2 manuscripts 71, 72, 73. A randomized comparison of i.v. Bu/Flu and Bu/Cy2 could be necessary to resolve this conflict. Regardless, the impressive safety profile is getting the reduced-toxicity i.v. Bu/Flu regimens adopted as the new “standard of care” preparative regimen for myeloid diseases by many transplant centers around the world.

Back to Article Outline

Bu Pharmacokinetics, Systemic Exposure, and Therapeutic Interval 

The extreme variability in bioavailability and pharmacokinetics (PK) of oral Bu led to important discoveries of the relationship between PK and clinical endpoints such as engraftment and toxicity 27, 28, 29, 30, 38, 39, 40, 74, 75, 76. A large (retrospective) experience with the Bu/Cy preparative regimen in adults established a Bu therapeutic window in the range of 900 to 1500 μMol/min, surrogate numbers representing the average AUC value after 1 of 16 doses in a typical every 6-hour BuCy regimen, or a total course AUC of 14,400-24,000 uMol/min 27, 28, 29, 30, 75, 76.

Consequently, very low Bu AUC levels (below 900 μMol-min) have been correlated with graft failure and disease recurrence 29, 30, whereas high Bu systemic exposure (Bu-SE) (above 1500 μMol/min) have been associated with increased toxicity, especially hepatic and neurologic toxicity 27, 28, 29, 30, 31, 32, 36, 38, 39, 40, 44, 52. In particular, several studies concluded an association between HVOD and an elevated Bu-SE, represented by an AUC above 1500 uMol-min [30]. However, not all investigators agree with this interpretation [77], and indeed, the development of HVOD appears to be multifactorial. HVOD occurs with increased frequency after previous hepatic irradiation [78], and/or the inclusion of other hepatotoxic chemotherapy (ie, alkylating agents), like Cy, whose hepatotoxic metabolites, acrolein and phosphorodiamidic mustard, have a clear etiologic role in the generation of this disease 33, 79. Furthermore, Johnson et al. [80] reported that various isoenzymes of glutathione-S-transferase affect Bu metabolism to various degrees. Carriers of GSTA1∗B had a 30% reduced Bu clearance and on average a 2.6-fold higher Bu AUC compared with noncarriers [80]. Finally, a transient (reversible) elevation of liver function tests, predominantly after methotrexate administration, has been noted in patients receiving i.v. Bu without other signs of HVOD 68, 69, suggesting that a careful clinical evaluation and use of strict, standardized diagnostic criteria for HVOD (such as Jone's criteria) are important for establishing a diagnosis of HVOD [24]. We previously reported that a significantly higher rate of aGVHD, gastrointestinal, and hepatic toxicity, is associated with excessive Bu-SE. In contrast, posttransplant mortality showed a bimodal distribution, being significantly increased with both very high and low Bu-SE, thereby confirming the presence of a therapeutic interval for i.v. Bu of approximately 950-1520 μMol/min in the prototype i.v. Bu/Cy2 regimen [81]. This therapeutic interval was the only factor predictive of survival in CML patients transplanted using the i.v. BuCy2 therapy. The availability of detailed pharmacokinetic information in clinical Bu dosing has been reported to improve patient outcome when applied with both oral and i.v. Bu, even though the erratic bioavailability of oral Bu has put the value of therapeutic dose monitoring into question [77]. A carefully controlled study at the FHCRC by Deeg and colleagues [82] reported clinical outcomes in 50 patients between the ages or 55 and 66 transplanted for MDS. The conditioning regimens included TBI/Cy, Cy-fractionated TBI, (oral) Bu/TBI and targeted (oral) Bu/Cy2. Sixteen patients received oral Bu targeted to average steady-state plasma levels of 600-900 ng/mL (approximately 900-1350 μMol/min) and Cy. The cohort receiving PK-targeted oral Bu with Cy had the lowest nonrelapse mortality (NRM) and best survival [82]. The discrepancy in opinion about the predictive value of oral Bu-derived PK parameters likely resides in the up to 3-fold variability in dose-to-dose AUC in any patient receiving oral drugs [83]. Therefore, to somewhat accurately estimate the total course AUC after oral dosing, a minimum of 4 to 5 complete plasma concentration profiles may be necessary after a typical 16-dose regimen 75, 84. This necessitates not only in-house access to PK-laboratory services with the same day turnaround PK reporting, but also requires very dedicated staff to procure and analyze all samples (an estimated 5-10 samples per dosing profile) that have to be included in the analytic profile from individual patients.

Although high variability of Bu-SE when combined with Cy has been associated with adverse outcomes in adults, such a relationship between Bu exposure and HVOD has not been clearly established in children [85]. Still, some investigators insist that targeted Bu-SE, AUC, does improve outcomes in pediatric patients, and have demonstrated a higher engraftment rate and lower incidence of HVOD with a consistently utilized therapeutic drug monitoring (TDM) strategy 85, 86, 87. Again, the application of TDM in the setting of oral drug administration is fraught with the extremely labor-intensive need for serial complete PK dosing profiles after consecutive Bu doses to provide reliable and reproducible data 75, 84. This area potentially represents the most pronounced advantage for a parenteral Bu formulation with its minimal interdose variability in PK parameters [70].

The retrospective confirmation of an association between Bu-PK and clinical outcome after HSCT formed an incentive for TDM, which was introduced to reduce the highly variable Bu-SE, thereby improving the safety of (oral) Bu-based high-dose chemotherapy. However, when accuracy of dosing and rapid onset of action is important, PK accuracy is always superior for i.v. versus orally administered drugs [88]. We postulated that a parenteral Bu formulation would in itself provide an improved tool for safe myeloablative conditioning therapy because it circumvents both unpredictable intestinal absorption and the hepatic first-pass extraction [31]. It also allows TDM to be implemented to further reduce interpatient variability because of differences in metabolic drug clearance. Subsequently, precise Bu delivery was confirmed to be even more important than previously thought, not only in relation to early regimen-related toxicity and the development of aGVHD, but also in predicting the likelihood of being alive beyond 1 year after HSCT [81]. More recently, the i.v. Bu/Flu combinations are promising to be safer overall than Bu with Cy or other alkylating agents. It is conceivable, that a therapeutic interval will exist for i.v. Bu in combination with nucleoside analogs (Flu) as well. Indeed, Geddes et al. [89] indicated that a Bu-SE/AUC in excess of 6000 μMol/min daily, or a total course AUC in excess of 24,000 μMol/min, was associated with inferior survival, but additional work will be required to establish the exact boundaries of such an i.v. Bu therapeutic interval, when delivered in combination with (a) nucleoside analog(s).

Back to Article Outline

Development of i.v. Bu and Comparison with the Oral Drug 

In (myeloablative) pretransplant chemotherapy dosing accuracy is of major importance, and it is therefore always preferable to use parenteral drug formulations [88]. The introduction of i.v. Bu allowed both optimized safety and detailed PK assessments without resorting to the extremely labor-intensive schedules that are required for realistic PK-modeling with oral Bu 75, 84. We and others proposed that parenteral Bu would improve the safety of the conditioning regimen, as the 100% dose assurance of i.v. Bu guarantees that therapeutic drug monitoring can be optimized. As is the case with all PK assaying, however, reliable PK information can only be acquired if attention is also paid to a multitude of details including the infusion (priming the tubing with drug, not saline, all the way to the patient, infusion by controlled-rate pump, and finally disconnecting all of the tubing and pump cassette at the end of infusion without the use of “saline chasers” to “clean the line from drug”). Meticulous recording of infusion and sampling times also has to be exercised. Recently published studies have confirmed that the variability in PK parameters after i.v. Bu dosing is significantly lower than that recorded with the oral formulation 54, 68, 69, 70. In contrast, the conclusion may be that use of the respective i.v. and oral Bu formulations yield the same (major) variability in PK parameters as those reported in the oral Bu literature [90].

At least 3 different Bu solvent systems have been utilized clinically 50, 53, 91, 92 by independent investigators to estimate oral drug bioavailability by comparing the systemic exposure represented by AUC, after a predetermined oral dose with that of an i.v. reference dose with 100% bioavailability, in the same patients. All arrived to a similar conclusion, namely that, in adults, the average bioavailability of oral Bu is 70% to 80%, and, collectively, these reports unequivocally established that the i.v. Bu dose equivalent of 1 mg/kg oral Bu would be 0.7-0.8 mg/kg 51, 52, 53. The 0.8 mg/kg dose has subsequently been used in several phase II studies of i.v. Bu 54, 56, 57, 58, 59, 60, 71.

Back to Article Outline

Bu-Based Conditioning Therapy in Pediatric Transplantation 

Concerns about delayed growth and retarded intellectual development have been associated with the use of TBI in children, and it influenced a gradual shift to chemotherapy-only conditioning in pediatric transplantation. Bu has frequently been included in conditioning regimens used in pediatric HSCT since the early 1980s when the Bu/Cy regimen was introduced. Significant variability in Bu clearance was demonstrated in children 38, 39, 75, 84, 86, 93. The apparent plasma clearance rates in younger children can be up to 4 to 5 times higher than in adults, significantly lower Bu-SE with oral Bu administration when the dose range used was the same as originally used in adults. Thus, the dosing regimen of 1 mg/kg every 6 hours for 4 days was associated with very few toxic adverse effects, however, it predisposed pediatric patients to an increased risk for relapse and primary graft failure 75, 84, 85. Various mechanisms have been proposed for this difference in clearance, that is, altered intestinal drug absorption, increased hepatic first pass clearance rate in younger children, and an increased volume of distribution. These mechanisms could contribute to the lower AUC values consistently noted in children 94, 95, 96, 97, 98, 99. Further, Gibbs and colleagues [100] demonstrated that children younger than 4 years appear to have a 2 to 4 times enhanced ability to metabolize Bu in comparison with adults. This higher clearance is probably (at least in part) because of an increased formation of Bu/GSH conjugate in both the liver and upper intestinal wall mucosa, which may contribute to a greatly enhanced clearance of oral Bu, as an important mechanism by which children metabolize Bu more efficiently than adults 99, 100.

Several studies suggested that dosing based on BSA may be more appropriate to obtain an AUC closer to adult values 84, 96, 97, 98, 99. Vassal and colleagues [99] proposed a dose of 600 mg/m2, to arrive at a similar Bu-SE to the AUC values seen in adults, and similar adverse effects profile as recorded with the more commonly used course dose of 16 mg/kg dose [99]. However, even with this approach, a wide interpatient variability was noted, ranging from 3500 to 13,000 ng·h/mL (approximately 850-3300 μMol/min) [99].

The original dosing schedule of Bu administered at 1 mg/kg orally every 6 hours over 4 days was gradually modified in children to improve the safety and efficacy of drug delivery in response to the particularities related to accelerated Bu clearance seen in pediatric patients. Shaw and coworkers [101] suggested that a single daily oral Bu dose (either 4 mg/kg or 600 mg/m2) would be equivalent to divided doses and showed similar pharmacokinetic data except to a predicted 4-fold higher peak concentration. They suggested that this would be more convenient without increasing the risk of serious adverse effects. The once-daily dose delivery schedule yielded Bu plasma peak concentrations reached approximately 2 hours after administration. The drug was virtually completely eliminated at 24 hours in the majority of patients. Moreover, when the AUC was used to calculate the Bu-SE, no significant differences were found between younger and older children. This contrasted with the 1 mg/kg divided dosing schedule, which was associated with a significantly lower Bu-SE in younger children 101, 102.

Oral Bu is associated with a wider inter- and intrapatient variability in children than in adults 52, 97, 100, 101, 102. Therefore, controlling Bu-SE in children became even more important to avoid the highly variable exposures that predispose to serious adverse events, that is, graft rejection and leukemic recurrence 75, 84, 93. Targeting Bu to AUC values between 900 and 1500 μMol/min optimized the chance for engraftment and reduced the risk for severe toxicity, similar to that seen in the adult population 93, 103. Accepting that there is a continuous variation in Bu clearance inversely correlated with weight in children, Vassal, et al [93] recently proposed a refined dosing schedule based on body weight for centers that do not have access to PK monitoring. This group administered i.v. Bu in combination with either Mel or Cy in 55 patients on an every 6-hour schedule for 4 days, at 5 decrementing doses for a progressively increasing body weight, on the presumption that a continuous decrease of Bu clearance requires a gradual decrease in the dose administered. Doses ranging from 1.2 mg/kg to 0.8 mg/kg were administered to children weighing from less than 9 kg to more than 34 kg. The great majority of patients (91%) achieved an AUC in the targeted range with low interpatient variability. In this context, it may also be of interest to note the retrospective comparison between TBI/Cy and oral Bu/Cy in a matched pair analysis of pediatric patients having allogeneic SCT for ALL from the IBMTR [104]. This report strongly favored TBI/Cy over oral Bu/Cy, mostly without PK-guidance, in reference to OS, DFS and TRM [104]. It is important to note that, first, the introduction of i.v. Bu and then the replacement of Cy with Flu in the i.v. Bu/Flu and i.v. Bu/Flu/ATG regimens have contributed to drastically reduced TRM and improved OS and DFS for adults with AML/MDS and ALL 68, 69, 105. Second, in pediatric SCT the i.v. Bu has made it easier to accurately utilize the TDM concept to achieve dosing accuracy with consistent systemic exposure. More recent reports also show improved OS and DFS for patients receiving i.v. Bu-based conditioning therapy when compared with historic oral Bu controls. Additionally, Worth and colleagues [106] reported excellent 10-year OS and DFS in high-risk pediatric patients with AML/MDS and ALL. In particular, their engraftment rate of >90% and a 10-year DFS of 60% in a subpopulation of patients who received a single cord blood transplant for advanced leukemia are encouraging. Finally, the data of Russell et al. [105], utilizing their modified Bu/Bu/Flu/ATG/TBI regimen in adults with ALL (see below), together with the emerging concerns about long-term sequelae of TBI in pediatric patients, suggest that it may be time to reevaluate the purported superiority of TBI/Cy with that of an i.v. Bu-based conditioning regimen when optimized within the realm of TDM for pediatric patients.

Back to Article Outline

Current State-of-the-Art and Future Developments with i.v. Bu-Based Conditioning Therapy 

Available clinical results indicate, that the i.v. Bu/Flu conditioning regimens are safe and effective, and are being adopted as “standard of care” preparative regimens for myelogenous diseases by many transplant centers. Although no head-to-head comparison with Bu/Cy2 exists, available retrospective data comparing Bu/Flu with Bu/Cy2 suggest that Bu/Flu is indeed safer and at least as cytoreductive as Bu/Cy2 for patients with hematologic malignancies undergoing HSCT. Three retrospective studies performed in the past few years compared i.v. Bu/Flu with Bu/Cy2 71, 72, 73. In 1 of them, Bredeson and colleagues [73] reported a retrospective matched-pair analysis of 120 patients treated i.v. Bu/Flu plus ATG with 215 control patients treated with oral Bu/Cy2. This analysis partly confirmed the dramatic differences in treatment-related mortality (12% versus 34%, P < .001) and grades II-IV aGVHD (15% versus 34%) in patients treated with i.v. Bu/Flu/ATG compared with those receiving Bu/Cy2. However, they found a higher relapse rate for patients receiving i.v. Bu/Flu/ATG, translating to a similar os at 5 years (58% i.v. Bu/Flu/ATG and 51% Bu/Cy2), although the 100-day-, 1-year, and 3-year survival rates were greater and reached near statistical significance in patients treated with i.v. Bu/Flu/ATG [73]. The effaced difference in outcomes between i.v. Bu/Flu/ATG and Bu/Cy2 regimens at 5 years is not entirely clear, presumably a cumulative relapse rate for indolent diseases like multiple myeloma (MM), CML, and some lymphomas may contribute, as diseases like AML or MDS are less likely to recur at 3 or more years after HSCT. It may be of importance to remember that the patients in this study had a variety of hematologic malignancies. Therefore, comparisons of different conditioning regimens may benefit from being disease-specific to address whether antitumor efficacy is the same for regimens used for patients in different diagnostic subcategories. Furthermore, the described i.v. Bu/Flu/ATG program uses ATG. including a dose delivered on the day of the graft infusion, such that this cohort may mimic the outcomes of a T cell-depleted transplant, where a higher relapse rate is commonly observed. There was no indication that ATG was used in the oral Bu/Cy2 group.

A variant of the Bu/Flu/ATG regimen was explored recently by Russell and coworkers [105]. They treated 64 adult patients with acute leukemia in first or second remission with i.v. Bu/Flu and 400 cGy TBI. This variant of their previously reported regimen added TBI at 200 cGy given twice on days −1 or day 0, to enhance the antileukemic effect of the i.v. Bu/Flu/ATG regimen. All patients engrafted with a treatment-related mortality of only 3%, similar to the data previously reported [68]. An impressive projected DFS at 3 years of 83% ± 6% for AML and 65% ± 10% for ALL was reported [105]. Although the numbers were limited, the results are encouraging, especially for ALL patients, as a recent large retrospective analysis had shown only a modest 25% OS after the TBI/Cy or (oral) Bu/Cy2 conditioning regimens [107].

Bu/Flu conditioning has also been tested in the context of unrelated umbilical cord blood transplantation (UCBT), both with the drugs given sequentially and in the standard fixed-dose i.v. Bu/Flu (Bu 130 mg/m2/day and Flu 40 mg/m2/day × 4 days) regimen, as well as with PK-guided i.v. Bu delivery [108]. These i.v. Bu/Flu variant regimens performed poorly in patients receiving an UCBT; from 8 (of 10 total) patients who were evaluable for engraftment, and who received a double cord transplant for myeloid malignancies in CR, only 2 engrafted with donor derived hematopoiesis. No ATG was administered in this study, which could have contributed to an excessive graft failure rate. These results are in agreement with (unpublished) data from MDACC, where only 6 of 11 UCB recipients conditioned with PK-guided i.v. Bu/Flu engrafted. However, the addition of a low dose of TT, to the i.v. Bu/Flu regimen as reported by Sanz and colleagues [109], demonstrates that a modified i.v. Bu/Flu regimen could successfully be used for UCBT. This group treated 73 patients with hematologic malignancies (65 with acute leukemia and MDS) with TT/Bu/Flu, and used ATG with cyclosporine (CsA) and steroids as GVHD prophylaxis. The (presumed) improved eradication of host T cells by the addition of TT dramatically improved engraftment. Only single cords were used in this study and about 90% of the patients successfully achieved engraftment [109]. The rate of grade II-IV aGVHD was only 16% and day +100 TRM was 14% [109]. Another approach was used by Russell and coworkers [105], who utilized their i.v. Bu/Flu/ATG regimen supplemented with 200 cGy TBI for 2 doses, with the radiation therapy given the day before umbilical cord blood graft infusion [105]. Using also single unrelated cord blood grafts these investigators achieved engraftment in 12 of 12 evaluable patients before transplant day 30 (J. Russell, personal communication, November, 2008).

Bu/Mel Conditioning Chemotherapy 

Another approach to avoid the toxicity of adding Cy to Bu conditioning while maintaining a high degree of myeloablation was to replace Cy with Mel, in a combination to treat (primarily) lymphoid malignancies, especially ALL, for which current conditioning regimens provide disappointing results [108]. The Bu/Mel has been evaluated both in the autologous and allogeneic stem cell transplant setting, in adults and children 110, 111, 112, 113, 114, 115. These various regimens used in single-arm phase II studies have provided promising results, and controlled studies are warranted. For instance, in an ongoing trial, Kebriaei and coworkers [115] are evaluating once-daily i.v. Bu in combination with Mel (70 mg/m2 daily for 2 doses) for ALL and advanced high-grade lymphomas. Although this combination was well tolerated, disease control in the ALL subpopulation was still too early to fully evaluate; however, in a cohort of 30 ALL patients the 1-year survival was approximately 80% (P. Kebriaei, personal communication, November, 2008). This combination regimen appears at least as good as what would be expected with TBI/Cy in a patient population with an average age of about 35 years 105, 107, 115. Furthermore, Wall and coworkers [116] reported recently on the use of Bu/Mel/ATG regimen as conditioning for unrelated UCBT in pediatric patients. Again, the regimen was well tolerated, engraftment of granulocytes was achieved in 60% of patients by day +42 following a bone marrow transplant (BMT), and a 1-year OS rate of 47%.

Bu—Alternative Nucleoside Analogs in Pretransplant Conditioning 

Clofarabine and nelarabine are newer purine analogues, which, similar to Flu, are active in various hematologic malignancies. Both drugs have been recently granted FDA approval for treatment of advanced ALL/lymphoma 117, 118. The immunosuppressive and engraftment promoting capability of these nucleoside analogs remains unconfirmed, although the molecular structure of clofarabine suggests that it is likely to be at least comparable with that of Flu. To improve the cytoreductive effect of Bu/Flu regimen, i.v. Bu is being combined with clofarabine, in ongoing early trials [119]. Twenty-five patients with advanced AML/MDS were treated at MDACC with a combination of i.v. Bu/clofarabine ± Flu. All evaluable patients engrafted uneventfully, and when assessed approximately at 1 month and 3 months posttransplant the T cell chimerism appeared to be at least as high as that achieved with the Bu/Flu combination. Although it is too early to evaluate disease control, the preliminary data demonstrate the potential of Clo to be used as an alternative to Flu in combination with Bu in pretransplant conditioning therapy.

Bu-Nucleoside Analog as a Platform for Future Conditioning Regimens 

i.v. Bu (± pharmacokinetic monitoring) allows precise drug delivery and control of systemic exposure, to minimize adverse effects and optimize the antitumor effect, and, in combination with Flu, represents a safer conditioning regimen for transplantation. The consideration of i.v. BuFlu as an emerging platform technology can be anticipated to lead into investigation of novel strategies to further improve outcomes of transplantation, as exemplified in Figure 1. First, improvement of the cytoreductive effect could be potentially accomplished by the addition of mobilizing agents, such as plerixafor, based on the hypothesis that leukemic cells are more sensitive to chemotherapy when dissociated from the marrow stroma. Second, demethylating agents are of importance for the development of drug resistance in myelogenous leukemia (MDS, AML). By adding such agents like azacitidine or decitabine to manipulate the methylation status of malignant cell DNA, an increased sensitivity of the malignant cells could be achieved. Third, the addition of other chemotherapeutic agents, such as TT or low-dose TBI, might enhance antileukemic activity for lymphoid malignancies, and as well as promote engraftment after UCBT. Fourth, the reduced toxicity of the conditioning regimen now safely allows the use of posttransplant immunomodulation (ie, Cy or pentostatin) to reduce the incidence of GVHD and allow the use cellular therapy after transplant.

In conclusion, much has been accomplished over the past 30 years in conditioning regimens for HSCT. i.v. Bu in combination with Flu for patients with myelogenous malignancies in CR1 is associated with >80% long-term survival because of improvement in safety of chemotherapy administration and decreased TRM 68, 69, 105. Available data proves that i.v. Bu/Flu (±ATG) is a safer and at least as effective preparative regimen compared with either of the Bu/Cy2 variants or TBI/Cy, although there are no head-on comparisons available. The Bu/Flu regimen represents an important step forward in conditioning for HSCT, especially for myelogenous malignancies, and can conceptually be considered as a platform for developing improved preparative regimens for lymphoid malignancies, alternative donor transplantation, as well as for other subgroups of high-risk patients for which outcomes are largely unsatisfactory using the available conditioning regimens.

Back to Article Outline

Acknowledgments 

Financial disclosure: This work was Supported by National Institutes of Health grants 2PO1 CA55164 and 2P30CA16672-26, and the Stephen L. and Lavinia P. Boyd Fund for Leukemia Research. The authors are greatly indebted to the nursing staff of the inpatient and outpatient transplant care centers, research nurses, and members of the stem cell transplant coordinator staff. B.S. Andersson is a consultant to Otsuka America, Inc.

Back to Article Outline

References 

  1. Haddow A, Timmis GM. Myleran in chronic myeloid leukemia. Chemical constitution and biological action. Lancet. 1953;31:207–208
  2. Galton GA. Myleran in chronic myeloid leukemia. Results of treatment. Lancet. 1953;31:208–213
  3. Santos GW, Tutschka PJ. Marrow transplantation in the busulfan-treated rat: preclinical model of aplastic anemia. J Natl Cancer Inst. 1974;53:1781–1785
  4. Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983;309:1347–1353
  5. Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for acute leukemia following a new busulfan and cyclophosphamide regimen. Blood. 1987;70:1382–1388
  6. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49:511–533
  7. Bleyer AW, Blaese RM, Bujak JS, Herzig GP, Graw RG. Long-term remission from acute myelogenous leukemia after bone marrow transplantation and recovery from acute graft-versus-host reaction and prolonged immunoincompetence. Blood. 1975;45:171–181
  8. Curtis RE, Rowlings PA, Deeg JH, et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336:897–904
  9. Socie G, Curtis RE, Deeg JH, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18:348–357
  10. Baker SK, DeFor TE, Burns LJ, Ramsey NKC, Neglia JP, Robinson LL. New malignancies after blood and marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21:1352–1358
  11. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulphan and cyclophosphamide. Blood. 1994;84:2036–2043
  12. Blaise D, Maraninchi D, Archimbaud E, et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79:2578–2582
  13. Ringden O, Ruutu T, Remberger M, et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood. 1994;83:2723–2730
  14. Devergie A, Blaise D, Attal M, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM). Blood. 1995;85:2263–2268
  15. Blume KG, Kopecky KJ, Henslee-Downey JP, et al. Blood. A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Blood. 1993;81:2187–2193
  16. Hartman AR, Williams S, Dillon JJ. Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis. Bone Marrow Transplant. 1998;22:439–443
  17. Socie G, Clift RA, Blaise D, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood. 2001;98:3569–3574
  18. Van Leeuwen FE, Klokman WJ, Hagenbeek A, et al. Second cancer risk following Hodgkin's disease: a 20-year follow-up study. J Clin Oncol. 1994;12:312–325
  19. Metayer C, Lynch CF, Clarke EA, et al. Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood or adolescence. J Clin Oncol. 2000;18:2435–2443
  20. Bhatia S, Yasui Y, Robinson LL, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol. 2003;21:4386–4394
  21. Brown JR, Yeckes H, Friedberg JW, et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:2208–2214
  22. Dores GM, Metayer C, Curtis R, et al. Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol. 2002;20:3484–3494
  23. Travis LB, Hill DA, Dores GM, et al. Breast cancer risk following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290:465–475
  24. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–783
  25. McDonald GB, Hinds MS, Fisher LB, et al. Venoocclusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255–267
  26. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005–3020
  27. Grochow LB, Jones RJ, Brundett RB, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1989;25:55–61
  28. Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol. 1993;20(Suppl 4):18–25
  29. Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997;89:3055–3060
  30. Dix SP, Wingard JR, Mullins RE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996;17:225–230
  31. Peters WP, Henner WD, Grochow LB, et al. Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res. 1987;47:6402–6406
  32. Hassan M, Ljungman P, Ringden O, et al. The effect of busulfan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 2000;25:915–924
  33. McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101:2043–2048
  34. Przepiorka D, Khouri I, Thall P, et al. Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia. Bone Marrow Transplant. 1999;23:977–981
  35. Deeg HJ, Schuler US, Schulman H, et al. Myeloablation by intravenous busulfan and hematopoietic reconstitution with autologous marrow in a canine model. Biol Blood Marrow Transplant. 1999;5:316–321
  36. Marcus RE, Goldman JM. Convulsions due to high-dose busulphan. Lancet. 1984;2:1463
  37. Santos GW. Busulfan (Bu) and cyclophosphamide (Cy) for marrow transplantation. Bone Marrow Transplant. 1989;4(Suppl 1):236–239
  38. Vassal G, Deroussent A, Hartmann O, et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res. 1990;50:6203–6207
  39. Vassal G, Gouyette A, Hartmann O, Pico JL, Lemerle J. Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol. 1989;24:386–390
  40. Hassan M, Oberg G, Ehrsson H, et al. Pharmacokinetic and metabolic studies of high-dose busulphan in adults. Eur J Clin Pharmacol. 1989;36:525–530
  41. Meloni G, Raucci U, Pinto RM, Spalice A, Vignetti M, Iannetti P. Pretransplant conditioning with busulfan and cyclophosphamide in acute leukemia patients: neurological and electroencephalographic prospective study. Ann Oncol. 1992;3:145–148
  42. Kobayashi R, Watanabe N, Iguchi A, et al. Electroencephalogram abnormality and high-dose busulfan in conditioning regimens for stem cell transplantation. Bone Marrow Transplant. 1998;21:217–220
  43. Martell RW, Sher C, Jacobs P, Monteagudo F. High-dose busulfan and myoclonic epilepsy. Ann Intern Med. 1987;106:173
  44. Sureda A, Perez de Oteyza J, Garcia Larana J, Odriozola J. High-dose busulfan and seizures. Ann Intern Med. 1989;111:543–544
  45. Grigg AP, Shepherd JD, Phillios GL. Busulphan and phenyoin. Ann Intern Med. 1989;111:1049–1050
  46. Meloni G, Nasta L, Pinto RM, Spalice A, Raucci U, Iannetti P. Clonazepan prophylaxis and busulfan-related myoclonic epilepsy in autografted acute leukemia patients. Haematologica. 1995;80:532–534
  47. Chan KW, Mullen CA, Worth LL, et al. Lorazepam for seizure prophylaxis during high-dose busulfan administration. Bone Marrow Transplant. 2002;29:963–965
  48. Hassan M, Oberg G, Bjorkholm M, Wallin I, Lindgren M. Influence of prophylactic anticonvulsant therapy on high-dose busulfan kinetics. Cancer Chemother Pharmacol. 1993;33:181–186
  49. De La Camara R, Tomas JF, Figuera A, Berberana M, Fernandez-Ranada JM. High-dose busulfan and seizures. Bone Marrow Transplant. 1991;7:363–364
  50. Bhagwatwar HP, Phadungpojna S, Chow DS, Andersson BS. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol. 1996;37:401–408
  51. Andersson BS, Madden T, Tran HT, et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplant conditioning therapy: a phase I study. Biol Blood Marrow Transplant. 2000;6:548–554
  52. Hassan M, Ljungman P, Bolme P, et al. Busulfan bioavailability. Blood. 1994;84:2144–2150
  53. Schuler US, Ehrsam M, Schneider A, Schmidt H, Deeg J, Ehninger G. Pharmacokinetics of intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for haematopoietic stem cell transplantation. Bone Marrow Transplant. 1998;22:241–244
  54. Andersson BS, Kashyap A, Gian V, et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8:145–154
  55. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant. 2002;8:493–500
  56. Thall PF, Champlin RE, Andersson BS. Comparisson of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant. 2004;33:1191–1199
  57. Kim SE, Lee JH, Choi SJ, Lee JH, Ryu SG, Lee KH. Morbidity and non-relapse mortality after allogeneic bone marrow transplantation in adult leukemia patients conditioned with busulfan plus cyclophosphamide: a retrospective comparison of oral versus intravenous busulfan. Haematologica. 2005;90:285–286
  58. Lee JH, Choi SJ, Lee JH, et al. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005;84:321–330
  59. Aggarwal C, Gupta S, Vaughan WP, et al. Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen. Biol Blood Marrow Transplant. 2006;12:770–777
  60. Dean R, Pohlman B, Sweetenham JW, et al. The use of intravenous compared with oral busulfan in high-dose chemotherapy and autologous stem cell transplantation (ASCT) for lymphoma is associated with improved relapse-free survival. Blood. 2006;108:868a
  61. DeLeve LD, Schulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22:27–42
  62. Ghandi V, Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet. 2002;41:93–103
  63. Li L, Liu X, Glassman AB, et al. Fludarabine triphosphate inhibits nucleotide excision repair of cisplatin-induced DNA adducts in vitro. Cancer Res. 1997;57:1487–1494
  64. Terenzi A, Aristei C, Aversa F, et al. Efficacy of fludarabine as an immunosupressor for bone marrow transplantation conditioning: preliminary results. Transplant Proc. 1996;28:3101
  65. Slavin S, Nagler A, Naperstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant diseases. Blood. 1998;91:756–763
  66. Bornhauser M, Thiede C, Plazbecker U, et al. Dose-reduced conditioning and allogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients. Clin Cancer Res. 2001;7:2254–2262
  67. Bornhauser M, Storer B, Slattery JT, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood. 2003;102:820–826
  68. Russell JA, Tran HT, Quinlan D, et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8:468–477
  69. De Lima M, Couriel Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864
  70. Madden T, de Lima M, Thapar N, et al. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007;13:56–64
  71. Andersson BS, de Lima M, Thall PF, et al. Once daily IV busulfan and fludarabine compares favorably with IV busulfan and cyclophosphamide (IV BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14:672–684
  72. Chae YS, Sohn SK, Kim JG, et al. New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Bone Marrow Transplant. 2007;40:541–547
  73. Bredeson CN, Zhang MJ, Agovi MA, et al. Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:993–1003
  74. Meresse V, Hartmann O, Vassal G, et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant. 1992;10:135–141
  75. Slattery JT, Sanders JE, Buckner CD, et al. Graft-rejection and toxicity following bone marrow transplantation in relationship to busulfan pharmacokinetics. Bone Marrow Transplant. 1995;16:31–42
  76. Ljungman P, Hassan M, Bekassy AN, Ringden O, Oberg G. High busulfan concentrations are associated with increased treatment-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant. 1997;20:909–913
  77. Schuler U, Schroer S, Kuhnle A, et al. Busulfan pharmacokinetics in bone marrow transplant patients: is drug monitoring warranted?. Bone Marrow Transplant. 1994;14:759–765
  78. Vaughan WP, Cagnoni P, Fernandez H, et al. Decreased incidence of and risk factors for hepatic veno-occlusive disease with an intravenous busulfan (BU) containing preparative regimen for hematopoietic stem cell transplantation (HSCT). Blood. 1998;92(Suppl. 1):516a
  79. De Leve L. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology. 1996;24:830–837
  80. Johnson L, Orchard PJ, Baker KS, et al. Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation. J Clin Pharmacol. 2008;48:1052–1062
  81. Andersson BS, Thall PF, Madden T, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8:477–485
  82. Deeg HJ, Shulman HM, Anderson JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood. 2000;95:1188–1194
  83. Hassan M. Busulphan. In:  Grochow LB,  Ames NM editor. A Clinician's Guide to Chemotherapy, Pharmacokinetics, and Pharmacodynamics. Baltimore, MD: Williams and Wilkins; 1997;p. 189–208
  84. Bollinger AM, Zangwill AB, Slattery JT, et al. Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2001;28:1013–1018
  85. Nguyen L, Fuller D, Lennon S, Leger F, Puozzo C. I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients. Bone Marrow Transplant. 2004;33:979–987
  86. McCune JS, Gooley T, Gibbs JP, et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30:167–173
  87. Tran H, Petropoulos D, Worth L, Mullen CA, Madden T, Andersson BS. Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies. Biol Blood Marrow Transplant. 2004;10:805–812
  88. Benet LZ, Sheiner LB. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In:  Goodman Gilman A,  Goodman LS,  Rall TW,  Murad F editor. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York, NY: Macmillan Publishing Co.; 1985;p. 3–34
  89. Geddes M, Kangarloo BS, Naveed F, et al. High busulfan exposure is associated with worse outcomes in daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14:220–228
  90. Nath CE, Earl JW, Pati N, Stephen K, Shaw PJ. Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients. Br J Clin Pharmacol. 2008;66:50–59
  91. Hassan Z, Ljungman P, Ringden O, et al. Pharmacokinetics of liposomal busulphan in man. Bone Marrow Transplant. 2001;27:479–485
  92. Hassan M, Nilsson C, Hassan Z, et al. A Phase II trial of liposomal busulphan as an intravenous myeloablative agent prior to stem cell transplantation: 500 mg/m2 as a optimal total dose for conditioning. Bone Marrow Transplant. 2002;30:833–841
  93. Vassal G, Michel G, Esperou H, et al. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring. Cancer Chemother Pharmacol. 2008;61:113–123
  94. Hobbs JR, Hugh-Jones K, Shaw PJ, Downie CJ, Williamson S. Engraftment rates related to busulphan and cyclophosphamide dosages for displacement bone marrow transplants in fifty children. Bone Marrow Transplant. 1986;1:201–208
  95. Lucarelli G, Polchi P, Galimberti M, et al. Marrow transplantation for thalassaemia following busulphan and cyclophosphamide. Lancet. 1985;1:1355–1357
  96. Grochow LB, Krivit W, Whitley CB, Blazar B. Busulfan disposition in children. Blood. 1990;75:1723–1727
  97. Yaeger AM, Wagner JE, Graham ML, Jones RJ, Santos GW, Grochow LB. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood. 1992;80:2425–2428
  98. Hassan M, Oberg G, Bekassy AN, et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology. Cancer Chemother Pharmacol. 1991;28:130–134
  99. Vassal G, Deroussent A, Challine D, et al. Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation?. Blood. 1992;79:2475–2479
  100. Gibbs JP, Liacouras CA, Baldassano RN, Slattery JT. Up-regulation of glutathione S-transferase activity in enterocytes of young children. Drug Metab Dispos. 1999;27:1466–1469
  101. Shaw PJ, Scharping CE, Brian RJ, Earl JW. Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia. Blood. 1994;84:2357–2362
  102. Vassal G, Koscielny S, Challine D, et al. Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1996;37:247–253
  103. Lindley C, Shea T, McCune J, et al. Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: assessment of a test dose and first dose strategy. Anticancer Drugs. 2004;20:909–913
  104. Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol. 2000;18:340–347
  105. Russell JA, Savoie ML, Balogh A, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant. 2007;13:814–821
  106. Worth LL, Andersson BS, Papadoupolos D, et al. Long-term follow-up of children with acute leukemia conditioned with Thiotepa, individualized busulfan, and cyclophosphamide (TBC) with allogeneic stem cell transplantation. In press.
  107. Bishop MR, Logan BR, Gandham S, et al. Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research. Bone Marrow Transplant. 2008;41:635–642
  108. Horwitz ME, Morris A, Gasparetto C, et al. Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients. Biol Blood Marrow Transplant. 2008;14:591–594
  109. Sanz J, Arcese W, Hernandez-Boluda JV, et al. Low treatment-related mortality in patients with hematologic malignancies undergoing umbilical cord blood transplantation (UCBT) with thiotepa (TT), once-daily intravenous (IV) busulfan (BU), fludarabine (FLU) and anti-thymocyte globulin (ATG). Blood. 2007;110:618a
  110. Srivastava A, Bradstock KF, Szer J, de Bortoli L, Gottlieb DJ. Busulphan and melphalan prior to autologous bone marrow transplantation. Bone Marrow Transplant. 1993;12:323–329
  111. Martino R, Badell I, Brunet S, et al. High-dose busulfan and melphalan before bone marrow transplantation for acute nonlymphoblastic leukemia. Bone Marrow Transplant. 1995;16:209–212
  112. Vey N, De Prijck B, Faucher C, et al. A pilot study of busulfan and melphalan as preparatory regimen prior to allogeneic bone marrow transplantation in refractory or relapsed hematological malignancies. Bone Marrow Transplant. 1996;18:495–499
  113. Matsuyama T, Kojima S, Kato K. Allogeneic bone marrow transplantation for childhood leukemia following a busulfan and melphalan preparative regimen. Bone Marrow Transplant. 1998;22:21–26
  114. Small TN, Young JW, Castro-Malaspina H, et al. Intravenous busulfan and melphalan, tacrolimus, and short-course methotrexate followed by unmodified HLA-matched related or unrelated hematopoietic stem cell transplantation for the treatment of advanced hematologic malignancies. Biol Blood Marrow Transplant. 2007;13:235–244
  115. Kebriaei P, Giralt S, Madden TL, et al. Toxicity and early response after intravenous (IV) busulfan (Bu) plus melphalan (Mel) conditioning for autologous stem cell transplantation (SCT) in patients (pts) with multiple myeloma (MM). Blood. 2006;108:2943a
  116. Wall DA, Carter SL, Kernan NA, et al. Busulfan/Melphalan/antithymocyte globulin followed by unrelated donor cord blood transplantation for treatment of infant leukemia and leukemia in young children: the Cord Blood Transplantation study (COBLT) experience. Biol Blood Marrow Transplant. 2005;11:637–646
  117. Pui CH, Jeha S. Clofarabine. Nat Rev Drug Discov. 2005;(Suppl):S12–S13
  118. Cohen MH, Johnson JR, Justice R, Pazdur R. FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008;13:709–714
  119. Andersson BS, de Lima M, Worth LL, et al. Clofarabine (Clo) +/- fludarabine (Flu) with IV busulfan (Bu) and allogeneic stem cell transplantation (Allo-SCT) for relapsed, refractory myeloid leukemia and MDS. Blood Submitted for publication. 2009;

 Financial disclosure: See Acknowledgments on page 532.

PII: S1083-8791(08)01100-2

doi:10.1016/j.bbmt.2008.12.489

Biology of Blood and Marrow Transplantation
Volume 15, Issue 5 , Pages 523-536, May 2009

Article Tools

* Image Usage & Resolution