An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m2 treosulfan and 5 × 30 mg/m2 fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III–IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II–IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.
AML is the most common indication for allo-SCT. In patients with intermediate or poor prognostic cytogenetic characteristics, allo-SCT in addition to conventional chemotherapy leads to a significant survival benefit, both for overall survival (OS) and relapse-free survival.1
Myeloablative TBI or BU-based conditioning regimens were the standard treatment for many years. However, those standard conditioning regimens are associated with substantial morbidity and mortality. In consequence, allo-SCT was restricted to younger patients with good performance status for many years.
Reduced intensity conditioning (RIC) regimens have been developed in the past two decades in order to make allogeneic hematopoietic SCT accessible to older and/or medically infirm patients. These regimens usually combine fludarabine and reduced doses of either an alkylating drug (for example, BU or melphalan) or TBI. Whereas there is increasing evidence from retrospective studies that treatment-related mortality is lower after RIC regimens than after myeloablative conditioning,2, 3 disease control seems to be less effective.4 In consequence, similar OS and disease-free survival (DFS) is observed for RIC and standard conditioning regimens.5, 6, 7
We have started to develop a new conditioning regimen based on fludarabine in combination with dose-escalated treosulfan. Treosulfan is a bifunctional alkylating drug with myelotoxic, immunosuppressive and antileukemic efficacy.8, 9, 10, 11, 12 Clinical data show that this conditioning regimen is myeloablative as indicated by profound, long-lasting and usually irreversible marrow aplasia, and is associated with a favorable safety profile.13, 14, 15, 16, 17, 18, 19 A recently published dose-escalation study revealed a dose of 3 × 14 g/m2 treosulfan in combination with 5 × 30 mg/m2 fludarabine to be safe and effective.20 In addition, excellent engraftment and low transplantation-related mortality has been reported in children even with nonmalignant diseases and at high risk of graft failure and treatment-related toxicity.21, 22, 23, 24 First disease-specific studies confirm the concept of reduced toxicity while maintaining the antileukemic activity in patients with CML or myelodysplastic syndrome.17, 18
The current prospective and multicentre phase II study was designed to investigate the safety and efficacy of treosulfan at a dose of 3 × 14 g/m2 in combination with fludarabine at a dose of 5 × 30 mg/m2, followed by allo-SCT in AML patients. Final results of the study are reported after all surviving patients had been observed for 1 year after transplantation of the last patient included.
Patients and methods
Between September 2004 and October 2006, 75 AML patients were enrolled consecutively in this prospective nonrandomized phase II study at 10 study centers in four European countries. Written informed consent on all aspects of the study was obtained from all study patients before treatment. The study was approved by the appropriate independent ethics committees and competent authorities, and was performed in accordance with the Declaration of Helsinki.
Eligibility criteria included diagnosis of AML according to the WHO (World Health Organization) classification 2001, <5% blasts in the BM, indication for allo-SCT according to institutional policy, age 18–60 years, Karnofsky performance score of ⩾80%, adequate contraception in female patients of child-bearing potential, availability of an HLA-identical sibling or matched unrelated donor.
Main exclusion criteria were therapy-related secondary AML, AML with t(8;21) (q22;q22) in CR1, acute promyelocytic leukemia with t(15;17) (q22;q12) in CR1, secondary malignancies, previous allo-SCT, severe concomitant illnesses, active infectious disease, impaired liver function (bilirubin more than upper normal limit, transaminases three times more than the upper normal limit) and impaired renal function (creatinine clearance <60 ml/min, serum creatinine >1.5 times the upper normal limit).
Outcome parameters were followed until 1 year after transplantation of the last patient included.
Donors and grafts
Either HLA-identical siblings or matched unrelated donors were allowed (eight out of eight Ags, Table 1). At least serological typing was required for class I (HLA-A/-B) and molecular typing for class II (HLA-DRB1/-DQB1) Ags.
Conditioning regimen and transplantation
All patients received fludarabine 30 mg/m2 i.v. from day −6 to day −2 (total dose: 150 mg/m2) and treosulfan (medac GmbH, Hamburg, Germany) 14 g/m2 i.v. on days −6, −5 and −4 (total dose: 42 g/m2) before allo-SCT. Allogeneic hematopoietic stem cells either from PBSC or from BM were given on day 0 (Table 1).
GVHD prophylaxis consisted of CsA (3 mg/kg per day), starting 1 day before allo-SCT in combination with short course MTX (15 mg/m2 i.v. on day +1 and 10 mg/m2 i.v. on day +3 and +6). In the case of an unrelated donor, anti-T-cell globulin (ATG-Fresenius (S), Fresenius, Fresenius Biotech, Graefelfing, Germany) was given at a dose of 10 mg/kg i.v. from day −4 to day −2. Supportive care was provided according to centre-specific guidelines. The use of GCSF was not recommended unless clinically indicated.
Engraftment, graft failure and chimerism analysis
Engraftment and graft failure were defined and described previously.20 Chimerism analysis was performed in the total BM according to established methods of the participating institutions.20 Complete chimerism was defined as ⩾95% of donor type chimerism in the total BM as quantified by dual color XY chromosome FISH in opposite sex donor-recipient pairs or by variable number of tandem repeats analysis in sex concordant donor-recipient combinations.
Adverse events including serious adverse events were evaluated from the start of conditioning to day +28. In addition, serious adverse events occurring after day +28 had to be reported if at least a possible relation to the conditioning regimen was suspected. Changes in laboratory values were not included in the adverse event analyses, but were separately documented.
Apart from hepatic veno-occlusive disease/sinusoidal obstructive syndrome, all adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, NCI, Bethesda, MD, USA, Version 3.0). Hepatic veno-occlusive disease/sinusoidal obstructive syndrome was evaluated according to standard criteria.25, 26
Statistical considerations and analyses
The aim of this study was to evaluate the efficacy and safety profile of the treosulfan-based conditioning. With a sample size of 75 patients, an expected neutrophil engraftment rate of 97% could be estimated with a precision of ±10% points, with a power of 80% using a two-sided exact Clopper-Pearson 95% confidence interval (CI). In addition, any toxicity occurring with a probability of at least 3% had a 90% chance of being seen at least once, whereas any toxicity occurring with a probability of 2.1% had an 80% chance of being seen at least once. Time to recovery of neutrophils, leukocytes and platelets was calculated from day 0 by means of conditional cumulative incidence curves. Day +28 rates were extracted from the conditional cumulative incidence curves. Estimates of chimerism, non-relapse mortality (NRM), relapse incidence, and acute and chronic GVHD were derived using cumulative incidence rates to accommodate competing risks. DFS and OS were analyzed using the Kaplan-Meier estimator.
The incidence of adverse events was calculated as the number of patients who experienced at least one adverse event of a certain CTCAE category as the percentage of the total number of patients. Incidences of selected grade III–IV adverse events reported in the setting of allo-SCT were the primary combined end point of the study.
For exploratory purposes, outcome data were stratified by type of donor (HLA-identical siblings vs matched unrelated), remission status at study entry (CR1 vs >CR1), cytogenetic risk (intermediate vs adverse karyotype), age (<50 years vs ⩾50 years) and stem cell source (BM vs PBSC). For the comparison of cumulative incidence curves, the test of Gray was applied, whereas log-rank tests were used in Kaplan-Meier analyses. All P-values were derived from two-sided testing.
The statistical analyses were performed using SAS software package V.9.1.3 (SAS Institute, Cary; NC, USA) and R Version 2.2.1 (The R Foundation for Statistical Computing, Vienna, Austria).
A total number of 75 patients with AML underwent allo-SCT according to the study protocol. Table 1 summarizes patient and disease characteristics. In all, 80% of the patients were in CR1, 17% in CR2 and 3% in CR3 at the time of transplantation.
Cytogenetic characteristics according to predefined categories were adverse in 17%, intermediate in 68% and favorable in 4% of the patients. In 9% of the patients, cytogenetics did not match the predefined categories.
Engraftment and chimerism
CTCAE grade IV neutropenia, leukocytopenia and thrombocytopenia occurred in virtually all patients. The day 28 conditional cumulative incidences of engraftment for neutrophils, leukocytes and platelets reached 93% (95% CI (85%, 100%)), 100% (95% CI (94%, 100%)) and 93% (95% CI (87%, 100%)), respectively. The median time to engraftment ranged between 14 days (range 7–31 days) for platelets and 20 days (range 12–38 days) for neutrophils. No primary and one secondary failure of engraftment were documented. The cumulative incidence of complete donor-type chimerism increased from 72% (95% CI (63%, 81%)) on day +28–88% (95% CI (77%, 99%)) on day +56 to 92% (95% CI (81%, 100%)) on day +100.
Within the observation period (start of conditioning to day 28), 65% of the patients experienced at least one episode of CTCAE grade III–IV adverse events (Table 2). Most frequently reported CTCAE categories (>5%) were infection (59%) and gastrointestinal (7%). Infections included grade III–IV febrile neutropenia (40%), and infection either with (20%) or without neutropenia (5%). Events were mostly grade III, and only three grade IV adverse events (4%) were reported. Those were infection with neutropenia, poor graft function and hemorrhagic cystitis (one case each). Incidences of selected grade III–IV adverse events frequently reported in the setting of allo-SCT had been chosen as primary end points of the study. Incidences of those events were 8% (95% CI (3%, 17%)) for hyperbilirubinemia, 5% (95% CI (1%, 13%)) for mucositis/stomatitis and 0% (95% CI (0%, 5%)) for seizures. All reported events were grade III in severity. No patient (0%, 95% CI (0%, 5%)) experienced grade II or III veno-occlusive disease/sinusoidal obstructive syndrome. Changes in laboratory values were within expected ranges (Table 3).
No serious adverse event with suspected causal relation to treosulfan occurred after day 28.
Acute and chronic GVHD
Day 100 cumulative incidences of grade I–IV, II–IV and III–IV acute GVHD were 52% (95% CI (40%, 64%)), 21% (95% CI (12%, 31%)) and 11% (95% CI (4%, 18%)). The cumulative incidence of chronic GVHD at 2 years was 48% (95% CI (35%, 61%)), whereas extensive chronic GVHD reached a cumulative incidence of 16% (95% CI (7%, 25%)).
No patient died within 28 days after transplantation. Thereafter, a total number of eight patients died without previous relapse of AML. Causes of death were infection/sepsis (four patients), infection with EBV proliferative disease (one patient), infection with chronic GVHD (two patients) and acute GVHD (one patient). Cumulative incidences of NRM were 3% (95% CI (0%, 6%)) at 100 days, 9% (95% CI (3%, 16%)) at 1 year and 11% (95% CI (4%, 18%)) at 2 years (Figure 1). Non-relapse mortality was similar among patients transplanted from sibling vs unrelated donor (7 vs 13%, P=0.3439, Gray test), among patients with adverse vs intermediate cytogenetic risk (8 vs 12%, P=0.7965, Gray test) and among patient <50 vs ⩾50 years of age (7 vs 18%, P=0.1047, Gray test). However, the 2-year cumulative incidence of NRM was significantly lower for patients transplanted in CR1 compared with those transplanted in subsequent CR (7 vs 27%, P=0.0282, Gray test), and for patients who received BM compared with PBSC (0 vs 17%, P=0.0232, Gray test).
Incidence of relapse
The 2-year cumulative incidence of relapse was 34% (95% CI (23%, 46%)) (Figure 2). Out of 26 relapsed patients, 20 died within 12–344 days after relapse whereas 6 were alive at the last date of contact (between 140 and 505 days after relapse). However, no information is available on salvage therapy. Patients <50 years of age had a significantly lower relapse incidence compared with patients ⩾50 years (25 vs 52%, P=0.0158, Gray test). The relapse incidence did not differ among patients transplanted from sibling vs unrelated donor (35 vs 33%, P=0.7669, Gray test) or among patients who received BM vs PBSC (39 vs 32%, P=0.7745, Gray test). The relapse incidence for patients with an adverse karyotype reached 62% at 2 years, but this was not significantly different when compared with the 28% cumulative relapse incidence calculated for patients with an intermediate cytogenetic risk profile (P=0.1113, Gray test). Patients transplanted in CR1 or in consecutive CR had relapse incidences of 20%, respectively 38% at 2 years (P=0.1862, Gray test).
The 2-year estimate for DFS was 55% (95% CI (43%, 67%)) (Figure 3). The 2-year DFS was significantly in favor of patients <50 years of age compared with those ⩾50 years of age (69 vs 32%, P=0.0006, log-rank test). Patients with an adverse cytogenetic risk had a 2-year DFS of 31% (95% CI (2%, 60%)) whereas patients with an intermediate karyotype had a 2-year DFS of 60% (95% CI (45%, 74%)). However, this difference was not significant (P=0.2191, log-rank test). A comparable DFS was observed for patients who received PBSC compared with patients who received BM (51 vs 62%, P=0.2029, log-rank test). No differences were observed among patients transplanted in CR1 vs >CR1 (56 vs 53%, P=0.8997, log-rank test) or transplanted from sibling vs unrelated donor (59 vs 53%, P=0.2869, log-rank test).
After a median follow-up of 715 days (range of those surviving: 378–1157 days), 47 patients (63%) were alive and 28 (37%) died. The estimated OS was 61% (95% CI (48%, 73%)) at 2 years (Figure 4). A significantly lower 2-year OS was observed for patients who received PBSC compared with those who received BM (54 vs 73%, P=0.0304, log-rank test) and for patients ⩾50 years of age compared with patients <50 years of age (40 vs 73%, P=0.003, log-rank test).
Survival estimates were similar in all other exploratory stratified analyses: sibling vs unrelated donor (66 vs 58%, P=0.1514, log-rank test); CR1 vs >CR1 (63 vs 50%, P=0.4744, log-rank test); intermediate vs adverse karyotype (62 vs 42%, P=0.3797, log-rank test).
An alternative-conditioning regimen based on fludarabine and treosulfan has recently been identified. Our prospective multinational study investigated the safety and efficacy of this new treosulfan/fludarabine-based conditioning regimen in 75 AML patients in CR.
As expected from previous studies using the same conditioning regimen,13, 22 in general, low incidences of grade III/IV toxicities were observed. Only infections as a consequence of the duration and severity of marrow aplasia occurred with a substantial incidence of 59%. Notably, severe side effects like veno-occlusive disease/sinusoidal obstructive syndrome or heart failure known for other even RIC regimens did not occur at all.30 The resulting NRM of 11% at 2 years is very promising and lower than in our previous treosulfan dose-escalation study, where a NRM of 20% at 2 years was reported.20 However, in this study, patients with compromised health status and a variety of hematological malignancies even not in CR at the time of transplantation were included.
A stratified analysis of this phase II trial revealed that patients in CR1 had a significantly lower NRM than patients transplanted in >CR1 (7 vs 27%, P=0.0282). It can be assumed that CR1 patients were pretreated less intensive and were thus at lower risk of complications. As might be expected from the literature, age-stratified analysis revealed a lower NRM for patients <50 years compared with patients ⩾50 years (7 vs 18%, not significant). Interestingly, the NRM was higher in patients who received PBSC compared with patients who received BM. As both patient groups were homogenously distributed with respect to the remission status, no reasonable explanation for this finding can be provided within this small data set. A recent multivariate analysis in high-risk AML patients in CR1 showed an increased risk of TRM for patients with BM compared with PBSC transplantation in the first 3 months after treatment, which, however, reversed 3 months after treatment.4
Registry data for AML patients <50 years of age, and conditioned with RIC regimens as well as several prospective and retrospective studies in AML and AML/myelodysplastic syndrome (MDS) patients reported NRM rates ranging between 19% and 53%.5, 31, 32, 33, 34, 35, 36, 37 NRM rates comparable to our observations were reported after RIC conditioning with low dose TBI (16%)2, 3 and after targeted IV BU/fludarabine conditioning (15% at 1 year).38
The favorable NRM following treosulfan and fludarabine conditioning, however, has obviously not been counterbalanced by an increased relapse rate. Taking into account the limitations of an historical comparison, the reported 2-year relapse incidence of 34% for all and 20% for CR1 patients only is comparable to relapse incidences reported for AML patients in CR1 after standard conditioning with BU and CY,39, 40 or for CR1 patients after targeted standard dose IV BU/fludarabine conditioning (1-year relapse incidence: 30.6%).38 In the present study, patients <50 years of age had a favorable relapse incidence compared with patients ⩾50 years (25 vs 52%, P=0.0158). This favorable outcome translated into a significantly better disease-free and OS in younger patients. It has to be kept in mind, however, that the younger patient group consisted of more patients with an intermediate karyotype and more patients in CR1.
Registry data for AML patients with matched unrelated transplantation showed a 2-year relapse rate of 30% after myeloablative conditioning and of 38% following RIC.31 Data from a prospective study with a RIC regimen resulted in a 2-year relapse incidence of 37% following fludarabine and CY conditioning in patients with AML in CR1.41
With an OS and DFS of 61 and 55% at 2 years, the survival data following treosulfan and fludarabine conditioning in AML patients are in the upper range of those previously reported. Pidala et al., (2011)38 reported a similar 2-year OS rate of 62% for patients in CR1 following targeted standard dose IV BU/fludarabine conditioning. Recent registry data showed a 2-year DFS of 37% for RIC and of 43% for myeloablative conditioning in patient <50 years compared with 69% observed in the present study. However, the registry data did contain a less favorable patient selection as approximately one third of the patients were transplanted in advanced disease status.31 As reviewed by Blaise et al. (2007),42 OS after most RIC regimens ranges between 32 and 50%, and only one study in that review showed a superior OS of 79%. However, only patients in CR1 were entered into that study after being treated with two consolidation courses, including at least one course of high dose cytarabine. In addition, more than one third of the patients received an autologous transplant before allogeneic transplantation.43
Similar results for overall and disease free survival compared with the present study were obtained after RIC with fludarabine and CY (68% and 56%, respectively).41 However, those study patients probably had more favorable disease-specific prognostic profiles and transplant characteristics; 85% of the patients had an intermediate cytogenetic risk, and all patients were in CR1 and received PBSCs from a sibling donor.
Several other studies using RIC regimens were not restricted to AML patients, but additionally included patients with MDS or other indications, which can exert a substantial influence on the outcome.37, 44, 45, 46 In a parallelly conducted study using the identical treosulfan and fludarabine conditioning regimen in 45 MDS patients, the 2-year relapse incidence reached 16%,18 which appears to be substantially lower than the overall relapse incidence in the present AML study.
From the data obtained, we conclude that the treosulfan and fludarabine conditioning regimen combines high dose intensity of a standard myeloablative conditioning regimen with low nonhematological toxicities, comparable to reduced intensity regimens resulting in a low NRM without an obvious increase of the relapse risk. We are well aware that a comparison between published, either retrospective or prospective, studies with varying patient populations have many limitations. Therefore, based on the disease-specific trials in AML and MDS patients, a multicenter, multinational randomized study including AML and MDS patients to compare the treosulfan and fludarabine conditioning regimen, with a reference reduced intensity BU and fludarabine regimen is in progress.
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We thank all patients who participated in this trial as well as the nursing staff.
This work was supported by an unrestricted grant of medac GmbH (Hamburg, Germany).
Professor Dr DW Beelen, Professor Dr J Casper and Professor Dr M Freund have received research funding by medac GmbH and they have received honoraria for speeches and presentations. Professor Dr J Casper has consulted for medac GmbH and received compensation. Dr J Baumgart, Dr HA Mylius and Dr U Pichlmeier are compensated employees of medac GmbH. All other authors declare no conflict of interest.
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Casper, J., Holowiecki, J., Trenschel, R. et al. Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. Bone Marrow Transplant 47, 1171–1177 (2012) doi:10.1038/bmt.2011.242
- allogeneic hematopoietic cell transplantation
- reduced toxicity conditioning
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