Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.
Although the combination of fludarabine plus high-dose (140–180 mg/m2) melphalan (FLU/MEL) has been widely used as a reduced-intensity conditioning regimen for myeloid malignancies [1,2,3,4], high-dose MEL occasionally causes severe mucositis, especially in elderly patients [2, 5,6,7]. Because mucositis adversely affects clinical outcomes, particularly infection [8, 9], reduction of MEL toxicity is desirable.
To reduce the toxicity of MEL without losing its antileukemic effect, we designed a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative dosage of busulfan [BU; 4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. In this regimen, instead of reducing the dose of MEL, a non-myeloablative dosage of BU was added, because non-myeloablative dosages of BU could reduce the frequency of non-relapse mortality (NRM) without the loss of antileukemic effect in elderly patients with controlled myeloid malignancies . In this study, we retrospectively analyzed the efficacy and safety of FLU/MEL/BU in elderly patients with myeloid malignancies in stable disease status after a long period. We found promising long-term efficacy of FLU/MEL/BU, particularly FLU/MEL/iv BU, as a novel reduced-intensity conditioning regimen.
Subjects and methods
Eligibility criteria and definition
Patients who were older than 55 years of age and/or with comorbidities and/or were fragile received the FLU/MEL/BU regimen. Data for 32 patients with myeloid malignancies, who underwent FLU/MEL/BU conditioning between January 2004 and December 2012 in our institute, were retrospectively reviewed. Acute myeloid leukemia (AML) in complete hematological remission or myelodysplastic syndrome (MDS) with blasts < 10% was defined as controlled disease in this study. Our study complied with the Declaration of Helsinki, and was approved by the institutional review board of Kurashiki Central Hospital (approval number: 2844). Written informed consent was obtained from all patients analyzed in this study.
Conditioning consisted of FLU 25 mg/m2 for 5 days (125 mg/m2), MEL 50 mg/m2 administered by iv infusion for 2 days (100 mg/m2), and BU 2 mg/kg oral or 1.6 mg/kg iv for 2 days (4 mg/kg oral or 3.2 mg/kg iv). BU was administered orally between 2004 and 2006, and was administered intravenously after 2007.
Transplantation procedure and supportive care
Patients received related/unrelated bone marrow transplantation (BMT), related peripheral blood stem cell transplantation (PBSCT), or unrelated cord blood transplantation (CBT). Oral valproic acid was started the day before BU therapy and continued until the day of the final BU administration. Ursodeoxycholic acid and heparin were administered for the prevention of sinusoidal obstruction syndrome.
All patients received standard prophylaxis of graft-versus-host disease (GVHD) with iv tacrolimus (FK506; 0.03 mg/kg/day, continuous infusion, starting on day − 1) or iv cyclosporin A (CsA; 3 mg/kg/day, continuous infusion, starting on day − 1) and iv methotrexate (MTX; 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6). From 2007, iv folinic acid (15 mg/m2 on days 1 and 2, and 10 mg/m2 on days 3, 4, and 7) was administered for the prevention of MTX-related toxicities.
The time of neutrophil engraftment was considered the first of three successive days with an absolute neutrophil count ≥ 500/μL during recovery after transplantation. The time of platelet engraftment was defined as the first day on which the platelet count was ≥ 2 × 104/μL for 7 consecutive days during recovery without platelet transfusion.
The chimerism status after transplantation was determined using fluorescent in-situ hybridization of X and Y chromosomes or quantitative polymerase chain reaction analysis for microsatellite DNA markers. Complete donor chimerism was defined as the presence of more than 95% of donor cells.
Patients who achieved neutrophil engraftment were evaluable for acute GVHD according to the standard criteria . The diagnoses and the grades of chronic GVHD were based on the National Institute of Health criteria . The first-line therapy for acute (grades II–IV) and moderate–severe chronic GVHD usually comprises corticosteroids. The second-line treatment was at the discretion of treating physicians.
All patients were treated in HEPA-filtered rooms, and received fungal, herpes zoster/herpes simplex, bacterial, and Pneumocystis jirovecii prophylaxis. Cytomegalovirus (CMV) reactivation was monitored using C10/C11 antibodies at least once a week. Pre-emptive ganciclovir, valganciclovir, or foscarnet was administered to patients in case of CMV reactivation. Toxicity was scored using the Common Terminology Criteria for Adverse Events version 4.0 (NCI, Bethesda, MD).
Survival probability was estimated using the Kaplan–Meier method. The log-rank test was used to compare survival probability among subgroups of patients. The cumulative incidence of NRM was estimated by considering death due to disease relapse as a competing risk. To estimate the cumulative incidence of acute and chronic GVHD, death or relapse without GVHD was considered as a competing event. All statistical analyses were performed using EZR . P values < 0.05 indicated statistical significance.
Between January 2004 and December 2012, 32 patients underwent FLU/MEL/BU conditioning. The characteristics of these patients are shown in Table 1. The median patient age at transplantation was 59 years (range 32–66 years). Most of the patients (n = 28, 88%) were older than 55 years, except for 4 patients (32–53 years) with comorbidities and/or fragility. The first patient was a 32-year-old male AML patient with recurrent cerebral infarction and bilateral internal carotid artery occlusion, and the second was a 46-year-old male AML patient with a high hematopoietic cell transplantation—specific comorbidity index (HCT-CI) (4) due to liver dysfunction (chronic type C hepatitis) and cardiac dysfunction. The third patient was a 53-year-old female AML patient with active infection (fungal and varicella-zoster), and the fourth was a heavily treated 53-year-old female AML patient who received SCT in her third CR. The median follow-up period after allo-SCT was 8.2 years (range 3.0–13.5 years). Seventeen patients with AML and 15 patients with MDS were included, and most of the patients (n = 31, 97%) were in controlled disease status at transplantation. Approximately, two-thirds of the patients (n = 22, 68%) underwent unrelated BMT. Oral and iv BU were administered to 11 (34%) and 21 (66%) patients, respectively.
Engraftment and chimerism
The rates of neutrophil and platelet engraftment were 93.3% [95% confidence interval (CI): 74.3–98.2%] and 93.3% (95% CI 74.6–98.3%), respectively, and the median time for engraftment was 15 days (10–20 days) and 24 days (15–38 days), respectively. Primary induction failure occurred in two patients: a 57-year-old man with chemotherapy-resistant MDS (RAEB) who received CBT, and the other was a 59-year-old woman with untreated MDS (RA) who received BMT from HLA-matched unrelated donor. Among the patients whose chimerism was examined in whole blood at 1 month after transplantation (n = 26), complete donor chimerism was achieved in 25 (96%) patients.
The frequencies of grades 3–4 regimen-related toxicities occurring during the first 20 days after transplantation are listed in Table 2. The most common toxicity was febrile neutropenia. Although the incidence of severe oral/pharyngeal mucositis and diarrhea was relatively high in patients who received oral BU (oral/pharyngeal mucositis; 73%, diarrhea; 45%), it was improved by the administration of BU iv (oral/pharyngeal mucositis; 14%, diarrhea; 14%). There was no occurrence of sinusoidal obstruction syndrome.
OS, disease-free survival, NRM, and relapse rate
At the last follow-up, 21 of the 32 patients were alive. Eleven patients died because of infection (n = 4), primary disease (n = 3), chronic GVHD (n = 2), and hemorrhage (n = 2) (Table 2). The 1-year OS, disease-free survival (DFS), NRM, and relapse rate (RR) were 81.2% (95% CI 62.9–91.1%), 78.1% (95% CI 59.5–88.9%), 15.6% (95% CI 5.6–30.3%), and 6.2% (95% CI 1.1–18.4%), respectively, and the corresponding 5-year OS, DFS, NRM, and RR were 68.5% (95% CI 49.3–81.6%), 62.1% (95% CI 42.9–76.4%), 22.0% (95% CI 9.5–37.8%), and 15.9% (95% CI 5.6–30.9%) in all patients (Fig. 1a–c). Notably, the outcome of the iv BU-containing regimen (FLU/MEL/iv BU) tended to be better than that of the oral BU-containing regimen (FLU/MEL/oral BU), with a 5-year OS of 75.6% (95% CI 50.9–89.1%) vs 54.5% (95% CI 22.9–78.0%), DFS of 70.8% (95% CI 46.2–89.1%) vs 45.5% (95% CI 16.7–70.7%) (Fig. 2a), NRM of 19.3% (95% CI 5.8–38.8%) vs 27.3% (95% CI 5.8–55.2%), and RR of 9.8% (95% CI 1.5–27.5%) vs 27.3% (95% CI 5.5–55.9%). Furthermore, the tendency sustained regardless of the primary disease (Fig. 2b). Although HLA mismatch and high refined disease risk index (DRI-R) worsened the 5-year DFS (HLA match 71.8% vs mismatch 28.6%; DRI-R low 75.0%, intermediate 69.3%, high 20%), a high HCT-CI did not negatively impact DFS (HCT-CI 0–2: 69.2%, HCT-CI ≥ 3: 55.6%).
The cumulative incidences of grades II–IV and grades III–IV acute GVHD at day + 100 were 29.2% (95% CI 8.2–45.4%) and 11.4% (95% CI 0.0–22.8%), respectively. Notably, the incidences of grades II–IV and III–IV acute GVHD associated with FLU/MEL/iv BU were lower than those associated with FLU/MEL/oral BU [15.3% (95% CI 3.5–34.9%) vs 56.3% (95% CI 16.4–83.3%) and 0.0% (95% CI 0.0–0.0%) vs 41.7% (95% CI 0.0–68.7%), respectively]. The cumulative incidences of all grades, moderate-to-severe, and severe chronic GVHD were 70.4% (95% CI 48.6–84.3%), 44.5% (95% CI 25.6–61.9%), and 31.7% (95% CI 15.5–49.3%), respectively.
We designed a novel FLU/MEL/BU regimen with the aim of attenuating the toxicities of FLU/MEL without losing the antileukemic effect and engraftment for elderly patients by adding a non-myeloablative dosage of BU (4 mg/kg oral or 3.2 mg/kg iv) instead of reducing the dose of MEL from 140–180 to 100 mg/m2. We have been using this regimen in clinical practice since 2004 in our institute. In this study, we retrospectively evaluated the efficacy and safety of FLU/MEL/BU regimen in patients with myeloid malignancies. The results showed a sustained long-term antileukemic effect and low NRM incidence in patients with stable disease status, especially attributable to the FLU/MEL/iv BU regimen.
Although FLU/MEL is useful even for advanced myeloid malignancies [14, 15], the high incidence of NRM (28–40%) has been reported to be a drawback [1, 7, 16, 17], which worsens the outcome, especially of controlled diseases . One of the major causes of NRM in FLU/MEL is infection [1, 7, 18], which should be related to severe mucositis . In contrast, our regimen, especially FLU/MEL/iv BU, was associated with a low incidence of severe mucositis and life-threatening infection. Administration of folinic acid, which was introduced for the prevention of MTX-related toxicities, since 2007 in our institute, would have contributed to the amelioration of mucositis [20, 21]. Another major cause of NRM in FLU/MEL is acute GVHD [1, 7, 18]. Although severe acute GVHD is frequently observed in FLU/MEL (grades II–IV, 39–53%; grades III–IV, 15–42%) [7, 16, 18], our regimen, especially FLU/MEL/iv BU, was associated with a lower incidence of severe acute GVHD. Lower frequencies of bloodstream infection  and intestinal toxicity  associated with the iv BU-containing regimen might have contributed to the result.
Despite the reduced incidence of NRM, FLU/MEL/BU retained a long-term antileukemic effect with a 5-year DFS of 62.1%. In addition, as has been previously reported , the outcome was improved by the introduction of iv BU. This was not only due to the reduction of NRM, but also due to the decrease in relapse , which resulted in an improved 5-year DFS of 70.8%, as shown by FLU/MEL/iv BU in our study. Notably, the outcome obtained with FLU/MEL/BU, particularly FLU/MEL/iv BU, might be better than that obtained with FLU/MEL as well as other reduced-intensity conditioning (RIC) regimens conducted for elderly patients with myeloid malignances with a similar disease background and a 3-year DFS of 31–52% [4, 25]. Another advantage of FLU/MEL/BU is that it is a so-called “non-TBI” regimen, which was the other purpose for which we designed this regimen. Although low-dose TBI is often included in RIC regimens to promote engraftment, it is not necessarily required for engraftment . In fact, engraftment and donor-type chimerism were successfully achieved using FLU/MEL/BU in most patients. In contrast, the side effects of TBI, such as lung injury and cardiovascular events, would be problematic [27,28,29]. The increased risk of severe acute GVHD due to TBI should also be considered . Additionally, the demand for non-TBI regimens has increased with the growing number of allo-SCT cases, because non-TBI regimens can be conducted even in institutions or situations in which TBI cannot be applied.
In recent years, the efficacy of a combination regimen with FLU, BU, and MEL for myeloid malignancies has been examined and reported independently by several institutes. Two pediatric hematology groups demonstrated the efficacy and safety of the combination for AML in childhood or adolescence [31, 32]. In addition, two groups evaluated the effectiveness of the conditioning regimen with FLU, MEL, and myeloablative dosages of iv BU (FLU/BU4/MEL) in adult patients with advanced myeloid malignancies [33, 34]. These studies demonstrated the curative potential of the FLU/BU4/MEL regimen for myeloid malignancies with no remission. The 2-year OS after CBT was 54.9% and the 4-year OS after BMT and PBSCT was 49.4%. However, Ueda et al.  reported a disadvantage of the FLU/BU4/MEL regimen: a higher incidence of NRM, especially in patients with controlled disease status. In contrast, our regimen was associated with a lower incidence of NRM even in elderly patients. Furthermore, the lower proportions of infection, severe mucositis, and severe acute GVHD associated with FLU/MEL/BU helped reduce NRM.
One of the disadvantages of the FLU/MEL/BU regimen was the high incidence of chronic GVHD, which directly resulted in death in some cases. The frequency of chronic GVHD, including severe chronic GVHD, might be slightly higher than that reported based on other regimens [24, 35]. One of the reasons could be the older age of the recipients . Modification of GVHD prophylaxis and therapy should be considered to further improve overall outcomes. Another disadvantage of FLU/MEL/BU is the insufficient antileukemic effect for high-risk and advanced disease. Although patients with low or intermediate DRI-R exhibited sufficient DFS, the outcome was poor in those with a high DRI-R. In addition, although we intensified the FLU/MEL/BU regimen by adding cytarabine or etoposide for advanced cases, most of the patients relapsed and the outcomes were extremely poor (data not shown). Because FLU/BU4/MEL has curative potential for advanced myeloid malignancies [33, 34], dose escalation of BU should be considered for such cases.
There are certain limitations of this study. First, this is a retrospective, small-scale, single-arm cohort study, and therefore, the impact of the FLU/MEL/BU regimen was not statistically determined. Although our study indicated higher efficacy of FLU/MEL/BU than that of other RIC regimens, a large-scale, prospective, randomized study comparing FLU/MEL/BU and other regimens, particularly FLU/MEL, would be required to address this issue. Second, we lack information on molecular aberrations of leukemic cells, such as NPM1, internal tandem duplication of FLT3, and c-KIT, which might also affect the outcome [37,38,39].
In conclusion, the FLU/MEL/BU regimen, in particular FLU/MEL/iv BU, is a promising strategy with sufficient curative potential, especially for controlled myeloid malignancies, even in elderly patients. The control of chronic GVHD and the intensification of regimen for advanced cases should be further examined to improve overall outcomes.
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This study was conducted at Kurashiki Central Hospital’s Department of Hematology/Oncology. We would like to thank all clinicians, medical staffs, and patients who contributed to this research.
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Ueda, T., Jo, T., Okada, K. et al. Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy. Int J Hematol 111, 247–255 (2020). https://doi.org/10.1007/s12185-019-02763-2
- Allogeneic stem cell transplantation
- Conditioning regimen
- Myeloid malignancy