SEARCH

SEARCH BY CITATION

Keywords:

  • acute myeloid leukaemia;
  • haematopoietic stem cell transplantation;
  • myeloablative conditioning;
  • randomized trial;
  • reduced-intensity conditioning;
  • toxicity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

Background

To our knowledge, no randomized toxicity studies have been conducted to compare myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in allogeneic haematopoietic stem cell transplantation (HSCT).

Methods

Adult patients ≤60 years of age with myeloid leukaemia were randomly assigned (1 : 1) to treatment with RIC (= 18) or MAC (= 19) in this Phase II single-centre toxicity study.

Results

There was a maximum median mucositis grade of 1 in the RIC group compared with 4 in the MAC group (< 0.001). Haemorrhagic cystitis occurred in eight of the patients in the MAC group and none in the RIC group (< 0.01). Results of renal and hepatic tests did not differ significantly between the two groups. RIC-treated patients had faster platelet engraftment (< 0.01) and required fewer erythrocyte and platelet transfusions (< 0.001) and less total parenteral nutrition (TPN) than those treated with MAC (< 0.01). Cytomegalovirus (CMV) infection was more common in the MAC group (14/19) than in the RIC group (6/18) (= 0.02). Donor chimerism was similar in the two groups with regard to CD19 and CD33, but was delayed for CD3 in the RIC group. Five-year transplant-related mortality (TRM) was approximately 11% in both groups, and rates of relapse and survival were not significantly different. Patients in the MAC group with intermediate cytogenetic acute myeloid leukaemia had a 3-year survival of 73%, compared with 90% among those in the RIC group.

Conclusion

Reduced-intensity conditioning had several advantages compared with MAC, including less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections. Both regimens were tolerated and TRM was low.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

Reduced-intensity conditioning (RIC) was developed to reduce transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and to allow transplantation in patients who would not be eligible otherwise for transplantation due to comorbidities or old age [1, 2]. Due to the fact that it is less toxic than the established myeloablative conditioning (MAC), the use of RIC has increased [3-6]. The rationale behind RIC was to provide a regimen that would be sufficiently immunosuppressive to achieve donor engraftment, allow haematopoietic recovery of donor cells and induce a graft-versus-leukaemia effect [7, 8]. Peripheral blood stem cells (PBSCs) were used preferentially to obtain a high dose of stem cells and to allow fast engraftment. Donor lymphocyte infusions (DLIs) could also be used to enhance the antileukemic effect and donor haematopoietic engraftment [9]. Despite the fact that RIC has been used for more than a decade, to our knowledge there have been no reported prospective randomized studies to compare RIC and MAC, although several retrospective studies have compared these two conditioning protocols in patients with leukaemia [3, 4, 6]. The aim of the present study was to assess the safety and toxicity of RIC instead of MAC in HSCT patients with myeloid leukaemia.

Design and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

Study design and patients

In this prospective, randomized study, we included adult patients ≤60 years of age with acute myeloid leukaemia (AML) in first or second complete remission or with chronic myeloid leukaemia (CML) in chronic phase, who had a human leukocyte antigen HLA-identical sibling donor or an HLA-A-, HLA-B- or HLA-DRB1-identical matched unrelated donor (MUD). We excluded patients who would not be expected to tolerate MAC, had advanced disease, had HLA-mismatched grafts or had previously undergone transplantation. The primary end-point of the study was toxicity. Secondary end-points included engraftment, chimerism, need for transfusions, infections, TRM, graft-versus-host disease (GVHD), relapse and survival.

Randomization

Patients who fulfilled the inclusion criteria were asked to participate in the trial and were then randomly assigned (1 : 1) to MAC or RIC. Stratification was performed according to diagnosis (AML versus CML), donor (HLA-identical sibling versus MUD) and early disease (first complete remission or first chronic phase versus second complete remission or second chronic phase). All centres in the Nordic Bone Marrow Transplantation Group were invited to participate in the study. Most centres favoured either RIC or MAC, and we therefore performed a single-centre toxicity study to avoid a bias. During the same period, 47 patients with AML at our centre were selected for RIC due to comorbidities or advanced age. Because of a high risk of recurrent disease, 44 patients with AML were selected for MAC and two patients did not want to participate in the trial. Altogether, 37 patients were randomly assigned to treatment and the characteristics of these patients are shown in Table 1. Diagnosis, disease stage, age, donor type, stem cell source, cytomegalovirus (CMV) serology in donors and recipients and cell dose were all comparable in the two treatment groups. The study was approved by the Ethics Committee at the Karolinska Institutet.

Table 1. Characteristics of patients randomly assigned to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC)
CharacteristicsMAC (= 19)RIC (= 18)
  1. AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; CP1, first chronic phase; CR1, complete remission; M, male; F, female; MUD, matched unrelated donor; BM, bone marrow; PBSC, peripheral blood stem cell; NC, nucleated cell; CsA, cyclosporine; MTX, methotrexate; MMF, mycophenolate mofetil; TBI, total body irradiation; CMV, cytomegalovirus; ATG, antithymocyte globulin.

Diagnosis
AML1514
Intermediate/adverse cytogenetics12/311/3
CML CP144
Disease stage (CR1/>CR1)16/318/0
Sex (M/F)12/710/8
Age, median years (range)45 (22–58)46 (26–61)
Donor
Sibling77
MUD1211
Donor sex (M/F)11/89/9
Age of donor, median years (range)38 (19–56)43 (18–63)
F donor to M recipient42
Stem cell source (BM/PBSCs)3/161/17
NC dose (×108 kg−1)10.6 (2.1–25.5)11.7 (1.6–24.1)
CD34 dose (×106 kg−1)7.8 (1.6–33.5)7.5 (2.1–18.1)
GVHD prophylaxis
CsA + MTX1914
CsA + MMF02
Tacrolimus + sirolimus02
Conditioning
Busulphan-based1916
TBI-based, 2 Gy02
+ATG1215
CMV serology (recipient/donor)
−/− 22
−/+ 02
+/− 64
+/+ 1110
Home care65
Follow-up, median years (range)5.2 (1.2–9.3)3.4 (0.5–8.7)

Conditioning

Myeloablative conditioning consisted of busulfan 4 mg kg−1 day−1 administered in four doses for 4 days, combined with cyclophosphamide 120 mg kg−1 [10]. Busulfan doses were adjusted depending on pharmacokinetics. RIC consisted of fludarabine 30 mg m−2 day−1 for 6 days, combined with busulfan 4 mg kg−1 day−1 for 2 days in patients with AML and in two patients with CML [2]. Further two patients with CML received fludarabine 30 mg m−2 day−1 for 3 days combined with 2 Gy total body irradiation (TBI) [1].

Donors

Seven patients in each group had HLA-identical sibling donors. The remaining patients received grafts from MUDs, following high-resolution typing [11]. PBSCs were favoured as the source of stem cells, but bone marrow was also accepted.

Prophylaxis and treatment of GVHD

Most patients received cyclosporine (CsA) combined with four doses of methotrexate. CsA was administered intravenously (i.v.) on day 1 and on day 0, followed by oral CsA at a dose ranging between 3 and 12 mg kg−1. We aimed to achieve a trough level of 100 ng mL−1 in HLA-identical sibling transplantation for malignancies. CsA trough target levels were between 200 and 300 ng mL−1 in patients with a nonmalignant disorder and a sibling donor, and in all patients with MUDs [12]. In two patients who were given fludarabine and 2 Gy TBI, CsA was combined with mycophenolate mofetil [1]. Two patients in the RIC group were treated with tacrolimus (0.1 mg kg−1 day−1 orally), aiming at trough levels between 5 and 15 ng mL−1, in combination with sirolimus (3–6 mg) to achieve a trough level of 5–10 ng mL−1. Anti-thymocyte globulin (Thymoglobulin; Genzyme, Cambridge, MA, USA) at a dose of 6–8 mg kg−1 was given to all recipients of unrelated grafts and to four patients conditioned with RIC.

Supportive care

Prophylaxis against haemorrhagic cystitis included forced diuresis, urine alkalization and uromitexane (12 mg kg−1 dose−1) at 0, 1, 3, 6, 9 and 12 h after administration of cyclophosphamide. Allopurinol was used during conditioning. Patients were treated in hospital in reverse isolation or at home [13]. CMV infection was diagnosed with polymerase chain reaction (PCR) to detect viral DNA in blood. In the case of 1000–2000 copies of CMV DNA in blood, ganciclovir [5 mg kg−1 i.v. twice daily (bid)], foscarnet (90 mg kg−1 i.v. bid) or oral valganciclovir (450–900 mg bid) was administered for 2 weeks in pre-emptive therapy, or longer if the PCR test remained positive. Further details regarding supportive care have been published previously [12, 13].

Definitions

Cytogenetic abnormalities in AML were classified as either good [including t(8;21), t(15;17) and inv or del (16)] poor (including 11q23 abnormalities, complex karyotype ≥3 and abnormalities of chromosomes 5 and 7) [14] or intermediate (including trisomies).

Toxicity grading of the oral mucosa was performed according to the World Health Organization (WHO) [15]: grade 0, no erythema; grade 1, soreness/erythema; grade 2, erythema/ulcers but ability to eat solid food; grade 3, ulcers and only able to eat a liquid diet; grade 4, severe mucositis and requirement for total parenteral nutrition (TPN). Routine laboratory tests were performed according to the standards at the centre. For instance, serum creatinine was measured daily and bilirubin, serum aspartate aminotransferase (S-ASAT) and alanine aminotransferase (S-ALAT) were measured twice weekly, but more frequently when elevated.

Bacterial septicaemia was defined as the first positive blood culture related to a febrile episode (≥38.5 °C). Haemorrhagic cystitis was defined as painful haematuria with a negative urine culture and without any obvious cause. Haemorrhagic cystitis was graded from 1 to 5 according to National Cancer Institute criteria [16, 17]: grade 1 (mild), minimal haematuria; grade 2, gross bleeding, medical intervention or urinary tract irrigation indicated; grade 3 (severe), transfusion or endoscopic intervention indicated; grade 4–5, life-threatening. Haemorrhagic cystitis was treated with adequate fluid intake, analgesics, forced diuresis and mesenchymal stromal cells [16, 18]. CMV infection was defined as positive CMV PCR, and CMV disease was defined as symptomatic organ involvement in addition to positive CMV PCR. Acute and chronic GVHD were diagnosed using established criteria and grading [5, 12].

Acute myeloid leukaemia relapse was defined as >20% blasts in the bone marrow, or leukaemia in extramedullary organs. The value of >20% blasts was chosen for several reasons: (i) this is the definition for diagnosis of leukaemia according to the WHO, (ii) after HSCT, there are many reactive blasts in the bone marrow that may not be malignant, and (iii) patients who relapse after HSCT will eventually have more than 20% blasts in the bone marrow. Relapse of CML was determined as positive bcr/abl with PCR.

Chimerism and DLIs

Chimerism was analysed at 1, 3, 6, 9 and 12 months after transplantation. PCR amplification of a variable number of tandem repeats was used to evaluate the degree of donor and recipient chimerism in CD19+, CD3+ and CD33+ cells enriched from blood using magnetic beads (Dynal, Oslo, Norway) as previously described [19]. Donor chimerism (DC) was defined as <5% recipient cells. Until April 2005, the method of analysing DC was based on mini-satellites. Thereafter, we used a real-time PCR method based on single nucleotide polymorphisms [20]. DLIs in escalating doses were administered to eight patients in the RIC group and to five in the MAC group [21]. Multiple doses were given to three and four patients in the two groups, respectively.

Statistical analysis

Comparisons between groups were made using the Fisher's exact, chi-squared or Mann–Whitney U-tests. Probability of leukaemia-free survival (LFS) and survival rates were estimated using the Kaplan–Meier method and compared using the log-rank test (Mantel–Haenszel). TRM, GVHD and relapse rates were estimated using cumulative incidence curves, taking competing events into consideration. Statistical analyses were performed using three software packages: cmprsk (developed by Gray, June 2001), Splus 6.2 (Insightful, Seattle, WA, USA) and Statistica (StatSoft, Tulsa, OK, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

Toxicity

Maximum mucositis during the first 3 weeks after HSCT in patients in the MAC/RIC groups was grade 0, 2/7; grade 1, 2/3; grade 2, 0/5; grade 3, 4/2; and grade 4, 11/1. Median maximum mucositis WHO score was 1 in the RIC group, compared with 4 in the MAC group (< 0.001; Table 2). There were no statistically significant differences in maximum creatinine, bilirubin, S-ASAT or S-ALAT in the two patient groups (Table 2). No patients in either group developed signs of cardiac insufficiency or sinusoidal obstructive syndrome of the liver or required dialysis. Haemorrhagic cystitis was diagnosed in eight MAC patients, but in none of the RIC patients (< 0.01; Table 2). Grade 3 cystitis resolved in two patients after infusion of mesenchymal stromal cells [18].

Table 2. Values of key measures in patients who underwent reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC)
MeasureRIC (= 18)MAC (= 19)P-value
  1. Values are presented as numbers of patients or median (range).

  2. ANC, absolute neutrophil count; TPN, total parenteral nutrition.

  3. a

    Units during the first 30 days after transplantation.

Maximum mucositis grade1 (0–4)4 (0–4)<0.001
Haemorrhagic cystitis grades (1/2/3)08 (2/4/2)<0.01
Max. serum creatinine, mmol L−190 (64–214)90 (59–162)0.72
Max. bilirubin, mmol L−120 (11–76)21 (8–76)0.97
Max. S-ASAT, μkat L−10.81 (0.30–100.2)0.70 (0.46–5.05)0.88
Max. S-ALAT, μkat L−11.62 (0.25–60.69)1.17 (0.60–4.69)0.56
Time to ANC >0.5 × 109 L−118 (0–24)15 (10–26)0.9

Time to platelet counts

>30 × 109 L−1, days

12 (0–46)14 (10–115)<0.01
Erythrocyte transfusionsa2 (0–6)4 (2–18)<0.001
Platelet transfusionsa0 (0–9)4 (0–26)<0.001
TPN, days0 (0–7)13 (0–24)<0.001
Days to hospital discharge19 (14–42)20 (14–107)0.26
Cytomegalovirus infection6140.02

Engraftment, transfusions, nutrition and discharge

Two patients with CML in the RIC group had graft failure, and both had been conditioned with fludarabine and 2 Gy TBI. Therefore, this regimen was subsequently abandoned. Engraftment occurred in all other patients. One patient in each group was successfully treated with DLI for graft failure. Time to an absolute neutrophil count (ANC) of >0.5 × 109 L−1 was similar in the two groups (= 0.9; Table 2, Fig. 1a). Time to a platelet count of >30 × 109 L−1 was longer in the MAC than in the RIC group (< 0.01; Table 2, Fig. 1b).

image

Figure 1. Time to and cumulative incidences of absolute neutrophil count (ANC) of >0.5 × 109 L−1 (a) and platelet count >30 × 109 L−1 (b) in patients randomly assigned to myeloablative conditioning (MAC, solid blue line) or reduced-intensity conditioning (RIC, dashed red line). (a) = 0.9; (b) < 0.01.

Download figure to PowerPoint

Patients in the RIC group required fewer transfusions of erythrocytes and platelets than those in the MAC group (< 0.001; Table 2). TPN was required more often in patients conditioned with MAC (< 0.001; Table 2). Time to hospital discharge was not significantly different between the two groups (= 0.26; Table 2).

Infections

Bacteraemia was diagnosed in five and three patients in the MAC and RIC groups, respectively. Herpes simplex virus infection was also diagnosed in five and three patients in the two groups, respectively (no significant difference). CMV infection was diagnosed by positive PCR in 14 patients in the MAC group and six patients in the RIC group (= 0.02; Table 2). CMV disease was diagnosed in one of the MAC-treated patients, but none of the RIC-treated patients.

Chimerism

There were no significant differences in the development of DC of CD19 and CD33 in the RIC and MAC groups (Table 3). However, DC of CD3 was significantly reduced during the first 3 months in the RIC group. At 1 year, there was no significant difference in DC between the two groups. DLI was given for persistent recipient chimerism with 83% (5/6) response (i.e. no GVHD) in the RIC group and 100% (3/3) response in the MAC group (one grade I and one grade II acute GVHD).

Table 3. Donor chimerism of CD19, CD3 and CD33 after haematopoietic stem cell transplantation in patients who underwent reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC)
 1 month3 months6 months9 months1 year
  1. Data are presented as number of patients with donor chimerism/total patients examined the number of occasions with donor chimerism (<5% recipient cells).

  2. ns, not significant.

CD 19
RIC11/1614/1614/1515/1515/15
MAC13/1413/1616/1615/1515/15
CD 3
RIC2/144/156/1413/1511/14
MAC13/1412/1612/1512/1414/14
P-value<0.0010.010.06nsns
CD 33
RIC8/1410/1510/1412/1313/14
MAC13/1412/1512/1514/1515/15

GVHD and TRM

The cumulative incidence of acute GVHD of grades II–IV was 32% in the MAC group and 17% in the RIC group (= 0.29; Fig. 2a). Four patients in the MAC group had grades III–IV acute GVHD compared with none in the RIC group. The cumulative incidence of chronic GVHD was 53% and 28% among patients in the RIC and MAC groups, respectively (= 0.10; Fig. 2b).

image

Figure 2. Time to and cumulative incidences of grades II–IV acute (a) and chronic (b) graft-versus-host disease, transplant-related mortality (TRM) (c) and haematological relapse (d) in patients randomly assigned to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC). (a) = 0.29; (b) = 0.10; (d) = 0.17.

Download figure to PowerPoint

Two patients in the MAC group died from acute GVHD. In the RIC group, one died due to haemorrhage. Another patient with graft failure underwent re-transplantation twice and died as a result of Epstein–Barr virus lymphoma. The cumulative incidence of TRM 5 years after transplantation was 10.5% and 11.5% among patients in the MAC and RIC groups, respectively (Fig. 2c).

Relapse, survival and LFS

The cumulative probability of relapse was 35% among patients in the MAC group and 12% among those in the RIC group (= 0.17; Fig. 2d). DLI was given for relapse to one patient in each group; the patient treated with MAC went into remission and the RIC-treated patient died due to relapse. Death from relapse occurred in five patients in the MAC group and two in the RIC group. Five-year survival was 62% in patients conditioned with MAC and 76% in those conditioned with RIC (= 0.30; Fig. 3a). The corresponding figures for patients with AML were 58% and 83%, respectively (= 0.11). Among patients with AML, cytogenetics was most important for outcome (= 0.01; Fig. 3b); for those treated with MAC and with intermediate cytogenetics, 3-year LFS was 75%, compared with 90% in the RIC group.

image

Figure 3. (a) Probability of survival in patients randomly assigned to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) (= 0.30). One-year survival was 74% in the MAC group and 94% in the RIC group. Three-year survival probabilities are shown on the graph. (b) Probability of relapse-free survival in patients with acute myeloid leukaemia (AML) randomly assigned to MAC or RIC and grouped according to intermediate (IM) and adverse cytogenetics (Adv). There was a statistically significant difference overall between the four groups (= 0.01).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

The most common toxicity after HSCT is oral mucositis. We found that MAC patients had significantly more mucositis, median WHO grade 4, as opposed to median WHO grade 1 for the RIC group (< 0.001). This is consistent with the findings of a previous retrospective study in which patients treated with MAC had more mucositis than those treated with RIC [22]. As a result of this, patients in the MAC group required significantly more days with TPN than those in the RIC group (< 0.001; Table 2). The fact that haemorrhagic cystitis was more common in MAC-treated patients than in those treated with RIC was not unexpected. In a previous study, we also found that MAC (compared with RIC) was a risk factor for haemorrhagic cystitis [16]. Maximum serum creatinine, bilirubin, S-ALAT and S-ASAT did not differ significantly between the two groups. However, the possibility that with many more patients, there may have been a difference in kidney and liver toxicity cannot be excluded. Nevertheless, the findings of this study suggest that there is no major difference in renal, hepatic or cardiac toxicity between MAC and RIC.

There were several advantages of RIC treatment. First, platelet engraftment was faster with RIC than MAC, which has not been reported previously (Fig. 1b). In addition, fewer transfusions of platelets and erythrocytes were required in the RIC group (Table 2). We did not find an increase in the speed of engraftment of ANC, which may have been due to the small number of patients. Faster engraftment of ANC using RIC as compared to MAC was previously reported in a retrospective analysis of patients with AML [6]. The time of discharge from hospital was similar between the two groups, which was probably due to the fact that there was no significant difference in the time to reach an ANC of >0.5 × 109 L−1.

Cytomegalovirus reactivation was more common in the MAC group, which may have been due to the fact that immune recovery is better with RIC. CMV infection has been reported to be associated with delayed immune reconstitution and an increased risk of bacterial and fungal infection [23]. In the present study, there was no difference in the rate of bacteraemia between the two groups. The increased risk of CMV infection in the MAC group may also have contributed to the increased risk of haemorrhagic cystitis in these patients, as CMV infection was previously found to be a risk factor for haemorrhagic cystitis [16].

Using RIC rather than MAC, it is likely that DC would be delayed. No significant difference in DC was seen for CD19+ or CD33+ cells 1 month after HSCT. However, DC of CD3+ cells was delayed until 9 months after HSCT. It is possible that T cells in the circulation are less sensitive to chemotherapy than other cells. Most importantly, after 1 year, DC of all three lineages was similar in the two groups.

There was no significant difference in acute and chronic GVHD in the two groups of patients. Stronger chemotherapy may cause tissue damage, which may result in GVHD [24]. Although we found no significant differences in acute or chronic GVHD, four patients in the MAC group developed severe acute GVHD and two patients died, compared with none in the RIC group. It was previously shown in two studies that GVHD is more common with MAC than with RIC, supporting the idea that MAC may cause tissue toxicity, leading to GVHD [3, 25].

There is selection bias in retrospective multicentre analyses [3-6], which is avoided in randomized studies. However, the advantage of large multicentre retrospective analyses is that a large number of patients can be included. The present analysis was not powered to detect differences in TRM, relapse, survival or LFS. However, our findings complement those of the large multicentre retrospective analyses, which have not addressed the issue of toxicity.

Transplant-related mortality was the same in the two groups, at around 11%. This shows that both regimens are well tolerated in patients <61 years of age. A retrospective study of transplants from MUDs showed that, in patients <50 years of age, TRM was the same irrespective of whether RIC or MAC was used [6]. In patients over 50 years of age, TRM was reported to be increased in HLA-identical sibling transplants and MUDs using MAC compared with RIC [3, 6]. These findings are in contrast to those of the present study, probably because of the low overall TRM rate in both groups and because there were too few patients over 50 years of age to be able to conduct a separate analysis based on age.

There was no statistically significant difference in relapse probability between patients conditioned with MAC and those conditioned with RIC. There was a trend for fewer relapses in the RIC group (Fig. 2d, P = 0.17). However, this is most probably due to chance as there were too few patients in the study for a powerful statistical analysis. With more intensified chemoradiotherapy, relapse has been found to be reduced in patients with AML [26]. In retrospective studies, an increased risk of relapse has also been reported in patients with AML treated with RIC compared with those treated with MAC [3, 6]. Of note, Martino et al. [27] reported an increased risk of relapse in patients with myelodysplastic syndrome or secondary AML who had received RIC instead of MAC for sibling transplant.

Overall survival and LFS were not significantly different in the RIC and MAC groups. The main predictor of survival in patients with AML was cytogenetics (Fig. 3b), in line with the well-established finding that cytogenetics is extremely important for outcome in these patients after HSCT [28]. Similar overall survival and LFS has also been reported in retrospective analyses comparing RIC and MAC [3, 4, 6].

In conclusion, the findings of three large retrospective studies suggest that survival and LFS are not decreased by RIC compared with MAC in patients with AML [3, 4, 6]. Therefore, RIC may be favoured in standard-risk patients because of an association with less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections, as demonstrated in the present study.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

We thank Inger Holmström for excellent manuscript preparation, Ann Fransson for performing the randomizations, Charlotta Hausmann for data collection and Hugh Kidd for checking the language. We acknowledge the compassionate and competent care of the patients by the staff at the Centre for Allogeneic Stem Cell Transplantation and at the Outpatient Clinic of the Hematology Centre. This study was supported by grants from the Swedish Cancer Society (CAN 2008/562, 10 0333), the Children's Cancer Foundation (PROJ09/093, PROJ 09/014), the Swedish Research Council (K2008-64X-05971-28-3), the Cancer Society in Stockholm and Karolinska Institutet.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References

OR and JA were responsible for the study design, and OR, TE and MR for data analysis and interpretation. OR wrote the first draft of this article, and all the authors were responsible for critical revision.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Design and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. Acknowledgements
  9. Author contributions
  10. References
  • 1
    Niederwieser D, Maris M, Shizuru JA et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 16209.
  • 2
    Slavin S, Nagler A, Naparstek 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 hematologic diseases. Blood 1998; 91: 75663.
  • 3
    Aoudjhane M, Labopin M, Gorin NC et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 2005; 19: 230412.
  • 4
    Luger SM, Ringden O, Zhang MJ et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2012; 47: 20311.
  • 5
    Mohty M, Bay JO, Faucher C et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003; 102: 4706.
  • 6
    Ringden O, Labopin M, Ehninger G et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 45707.
  • 7
    Martino R, Caballero MD, Perez-Simon JA et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100: 22435.
  • 8
    Tauro S, Craddock C, Peggs K et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 938793.
  • 9
    Kolb HJ, Mittermuller J, Clemm C et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 24625.
  • 10
    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: 272330.
  • 11
    Schaffer M, Aldener-Cannava A, Remberger M, Ringden O, Olerup O. Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003; 62: 24350.
  • 12
    Ringden O, Remberger M, Persson U et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15: 61925.
  • 13
    Svahn BM, Remberger M, Myrback KE et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002; 100: 431724.
  • 14
    Suciu S, Mandelli F, de Witte T et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102: 123240.
  • 15
    WHO. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization, 1979.
  • 16
    Hassan Z, Remberger M, Svenberg P et al. Hemorrhagic cystitis: a retrospective single-center survey. Clin Transplant 2007; 21: 65967.
  • 17
    NCI. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Cancer Therapy Evaluation Program. March 31, 2003. (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). [accessed 14 March 2013].
  • 18
    Ringden O, Uzunel M, Sundberg B et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007; 21: 22716.
  • 19
    Mattsson J, Uzunel M, Tammik L, Aschan J, Ringden O. Leukemia lineage-specific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation. Leukemia 2001; 15: 197685.
  • 20
    Ringden O, Okas M, Uhlin M, Uzunel M, Remberger M, Mattsson J. Unrelated cord blood and mismatched unrelated volunteer donor transplants, two alternatives in patients who lack an HLA-identical donor. Bone Marrow Transplant 2008; 42: 6438.
  • 21
    Dazzi F, Szydlo RM, Craddock C et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 2000; 95: 6771.
  • 22
    Garming-Legert K. Conditioning associated effects on oral mucosa and salivary function in allogeneic hematopoietic stem cell recipients. Thesis, Karolinska Institutet, Stockholm, Sweden, 2011.
  • 23
    Paulin T, Ringden O, Lonnqvist B. Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection. Transplantation 1985; 39: 37784.
  • 24
    Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 1999; 5: 34756.
  • 25
    Couriel DR, Saliba RM, Giralt S et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004; 10: 17885.
  • 26
    Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood 1991; 77: 16605.
  • 27
    Martino R, Iacobelli S, Brand R et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108: 83646.
  • 28
    Burnett AK, Wheatley K, Goldstone AH et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 2002; 118: 385400.