Bone Marrow Transplantation (2013) 48, 383–389 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

ORIGINAL ARTICLE Efficacy of allogeneic and autologous hematopoietic SCT in patients with AML after first complete remission

Y Jing, H Li, Y Zhao, J Bo, S Wang, Q Wang, W Huang, C Gao and L Yu

The most effective post-first CR1 treatment for patients with AML, allogenic hematopoietic SCT (allo-HSCT) or autologous hematopoietic SCT (HSCT), remains to be conclusively determined. This study aimed to compare the effectiveness of treatment with allo-HSCT or auto-HSCT in patients with AML after CR1. We retrospectively reviewed medical records of 127 patients with AML who received allo- (n ¼ 52) or auto-HSCT (n ¼ 75) after achieving CR1 at a single medical center. The disease-free and overall survival rates and complications were analyzed. During a median follow-up of 1215 days, all patients (100%) in allo-HSCT group and 94.7% of patients in the auto-HSCT group had successful outcomes. The disease-free survival rates were 65.3% and 50.6% for allo- and auto-HSCT groups, respectively (P ¼ 0.158), while the overall survival rates were 65.3% and 54.9%, respectively (P ¼ 0.486). The recurrence rate was higher with auto-HSCT, whereas the GVHD only happened with allo-HSCT. In conclusion, auto-HSCT was as effective as allo-HSCT for the treatment of patients with AML after CR1. This is encouraging given that allo-HSCT is not always feasible in China because of a lack of matching donors.

Bone Marrow Transplantation (2013) 48, 383–389; doi:10.1038/bmt.2012.154; published online 24 September 2012 Keywords: AML; allogenic; autologous; CR; hematopoietic SCT; survival

INTRODUCTION in Chinese PLA General Hospital. All patients were continuously treated at Patients with AML who achieve CR1 typically receive subsequent the same institution without exclusion. This study was approved by the Institutional Review Board of Chinese PLA General Hospital. consolidation chemotherapy or hematopoietic SCT (HSCT), either allogeneic (allo-HSCT) or autologous (auto-HSCT), depending on donor availability. The National Comprehensive Cancer Network Conditioning regimen (http://www.nccn.org) recommends consolidation chemotherapy All patients received a conditioning regimen before transplantation. for patients with good risk AML and allo-HSCT for patients with Patients received one of the following conditioning regimens: modified BuCy (Bu, 1 mg/kg/6 h for 3 days; Cy, 50 mg/kg/day for 2 days);9 etoposide/ poor risk AML. In support of these recommendations, findings 2 from a recent meta-analysis suggest that allo-HSCT increases TBI/Cy (E-TBICy: E, 150 mg/m for 1 day; TBI, total 800–1000 cGy over one or two doses; Cy, 50 mg/kg/day for 2 days); (BuACy: Bu, 1 mg/kg/6 h for disease-free and overall survival compared with nonallogeneic 2 days; A, 3.0 g/day for 1 days; Cy, 50 mg/kg/day for 2 days). Patients HSCT therapies (consolidated chemotherapy, auto-HSCT) in 1 also received 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea patients with intermediate to poor risk AML. There is also (250 mg/m2). For patients receiving unrelated HSCT, antithymocyte evidence to suggest that auto-HSCT may improve various globulin was given at 3 mg/kg/day for 4 days from day 4 to day 1. measures of survival compared with consolidated chemo- 2–6 therapy. Nevertheless, the most effective post-CR1 treatment Bone marrow transplantation for patients with AML remains to be conclusively determined.7,8 In the present study, we reviewed the medical records of Under continuous epidural anesthesia, 1000–1500 mL of heparin anti- coagulated BM was collected from the iliac crest and mixed in RPMI 1640 patients with AML who received allo- or auto-HSCT, after medium. The median (range) number of mononuclear cells (MNCs) for achieving CR1 at a single medical center, to determine the most transplantation was 2.62(0.37–4.9) Â 108/kg. For patients with matching effective treatment strategy. The main aim of our study was to blood types in allo-BMT, BM was directly transfused. For patients with compare disease-free and overall survival rates between patients major blood type incompatibilities, RBCs were removed from BM before with AML who received allo- or auto-HSCT. Secondary aims transplantation, whereas for patients with minor blood type incompat- included identifying risk factors for recurrence and mortality, ibilities, plasma was removed before transplantation. During transplanta- and comparing disease-free and overall survival rates between tion, protamine sulfate was administered according to the amount of patients who received BMT and those receiving peripheral heparin used. For auto-BMT, the cells were kept at 4 1C (with heparin as an blood HSCT. anticoagulant) and then transfused (within 72 h) back into patients after pretreatment.

Allogeneic peripheral blood hematopoietic SCT MATERIALS AND METHODS All donors were human leukocyte Ag 10 of the 10 matches with recipients. Patients Donors received 5 days of treatment with s.c. recombinant human G-CSF We reviewed the medical records of patients with AML who achieved CR1 (10 mg/kg/day) before stem cells were collected. MNCs were isolated and received subsequent auto- or allo-HSCT from April 1985 to March 2008 using a Cobe Spectra separator (Lakewood, CO, USA). The extracorporeal

Department of Hematology, Chinese PLA General Hospital, Beijing, PR China. Correspondence: Dr L Yu, Department of Hematology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, PR China. E-mail: [email protected] Received 31 January 2012; revised 5 July 2012; accepted 5 July 2012; published online 24 September 2012 Allogeneic vs autologous HSCT for AML Y Jing et al 384 volume was two times the whole blood volume (8 000–12 000 mL). Hematopoietic stem cells were collected when the WBC count was The final volume of the collected stem cell suspension was 100–200 mL. 45.0 Â 109/L. Peripheral blood MNCs were isolated using a Baxter CS-3000 The number of CD34 þ cells transfused was 2.3–9.8 Â 106/kg, whereas the Plus or a COBE spectra, cryopreserved at À 80 1C, and subsequently number of colony-forming unit-granulocytes/monocytes transfused was transfused into the patient within 6 months. The median number of MNCs 1.8–6.7 Â 105/kg. The collected stem cell suspension was directly transfused was 4.03(1.23–7.38) Â 108 cells/kg (X2 Â 106 CD34 þ cells/kg). transfused to the recipient. For patients with major or mixed blood type incompatibilities, dexamethasone (5 mg) was administered before trans- plantation. After transplantation, patients were hydrated, monitored for Supportive therapy and prevention of infection renal function, and treated with sodium bicarbonate and diuretics until the Patients were treated in a class 100 laminar flow ward. Three to five days urine became clear. before entering the laminar flow ward, oral norfloxacin, sulfamethoxazole and fluconazole or ketoconazole were given. For patients who were treated with imipenem/cilastatin or third-generation cephalosporins, i.v. Autologous peripheral blood HSCT ciprofloxacin was given if fever occurred. Patients treated from 1997 Once WBC counts began to increase to 1.0 Â 109/L after combined onwards received ganciclovir for 7–10 days before conditioning. At chemotherapy, G-CSF (5–10 mg/kg/day) was administered subcutaneously. þ 3 days after transplantation, recombinant human G-CSF and human

Table 1. Summary of demographic and clinical characteristics for patients who received allogeneic or autologous hematopoietic SCT

Auto-HSCT (n ¼ 75) Allo-HSCT (n ¼ 52)P-value

Age (years) 29.0 (22.0, 35.0) 33.5 (25.0, 39.5) 0.018* Gender Female 32 (42.7%) 19 (36.5%) 0.582 Male 43 (57.3%) 33 (63.5%) FAB classification M1 5 (6.7%) 4 (7.7%) 0.004* M2 26 (34.7%) 14 (26.9%) M3 12 (16.0%) 0 (0.0%) M4 18 (24.0%) 13 (25.0%) M5 11 (14.7%) 15 (28.8%) M6 1 (1.3%) 5 (9.6%) Othera 2 (2.7%) 1 (1.9%) Symptoms (n) Fever 40 (53.3%) 30 (57.7%) 0.717 Anemia 44 (58.7%) 22 (42.3%) 0.075 Hemorrhage 34 (45.3%) 16 (30.8%) 0.139 Enlarged lymph nodes or hepatosplenomegaly 9 (12.0%) 15 (28.8%) 0.022* Time from presence symptoms to diagnosis (days) 9.0 (3.0, 38.0) 9.5 (0.0, 28.5) 0.452

Time from diagnosis to HSCT (days) 295.0 (246.0, 376.0) 203.5 (158.5, 280.5) o0.001* WBC at diagnosis (109/L) 10.7 (3.3, 30.1) 10.1 (3.3, 40.6) 0.969 Hb at diagnosis (g/L) 83.0 (66.5, 99.0) 85.0 (71.0, 97.0) 0.967 PLT at diagnosis (109/L) 68.0 (45.0, 92.0) 48.0 (28.0, 85.0) 0.069 Proportion BM primitive cells (%) 70.0 (50.8, 84.0) 60.8 (47.5, 84.0) 0.598 Clinical characteristics and treatment before HSCT (n) CNS-L before transplantation 4 (5.4%) 3 (5.8%) 1.000 Lumber puncture before transplantation 3.0 (2.0, 4.0) 2.0 (2.0, 4.0) 0.375 Chemotherapy induction courses to obtain CR 2.0 (1.0, 3.0) 1.0 (1.0, 2.0) 0.013* Consolidation chemotherapy cycles from CR to HSCT 5.0 (4.0, 6.0) 3.0 (2.0, 4.0) o0.001* Radiotherapy dose (Gy) 7.0 (7.0, 8.0) 8.0 (0.0, 9.0) 0.121 Consolidation therapy cycles 4.0 (3.0, 5.0) 3.0 (1.0, 4.0) o0.001* Intensive treatment 0 53 (70.7%) 30 (57.7%) 0.060 1 11 (14.7%) 17 (32.7%) 2–5 11 (14.7%) 5 (9.6%) Conditioning regimen TBI/Cy 63 (84.0%) 36 (69.2%) 0.041* Bu/Cy 9 (12.0%) 14 (26.9%) MAC þ F 0 (0.0%) 1 (1.9%) MAC 1 (1.3%) 0 (0.0%) F þ BU 0 (0.0%) 1 (1.9%) DEAC 1 (1.3%) 0 (0.0%) CDE 1 (1.3%) 0 (0.0%)

Abbreviations: CDE ¼ cyclophosphamide, daunorubicin, etoposide; CNS-L ¼ central nervous system leukemia; DEAC ¼ daunorubicin, etoposide, cytarabine, cyclophosphamide; FAB ¼ Franch–American–British; HSCT ¼ hematopoietic SCT; MAC ¼ semustine, cytarabine, cyclophosphamide. Data are expressed as median (interquartile range) or count (percentage). *Indicates a statistically significant between-group difference (Po0.05). aIncluded one patient with basophilic leukemia and one unclassified patient in the autologous HSCT group, and one patient with MDS-M2 in the allogeneic HSCT group.

Bone Marrow Transplantation (2013) 383 – 389 & 2013 Macmillan Publishers Limited Allogeneic vs autologous HSCT for AML Y Jing et al 385 g-globulin were infused for 5–10 days. Blood transfusion was carried out to hepatosplenomegaly in the allo-HSCT group compared with maintain hemoglobin X80 g/L in the absence of evidence of bleeding. auto-HSCT group (28.8 vs 12.0%, P ¼ 0.022). The time between diagnosis and HSCT was significantly longer in the auto-HSCT Prevention of GVHD in allo-HSCT group compared with the allo-HSCT group (295.0 days vs 203.5 CsA (2–3 mg/kg/day) was intravenously infused for 2–3 weeks after days, Po0.001). There were significantly more chemotherapy transplantation and was given orally once patients had started eating. induction courses to obtain CR and consolidation chemotherapy Blood CsA concentrations were maintained between 200 and 400 mg/L. cycles from CR to HSCT in the auto-HSCT group compared with MTX (15 mg/m2) was intravenously infused on day þ 1, 10 mg/m2 on days the allo-HSCT group (median number of induction courses to þ 3, þ 6 and þ 11. Oral mycophenolate mofetil was given from the day CR ¼ 2.0 vs 1.0, P ¼ 0.013; median number of cycles from CR to before transplantation for 28 days. For patients with unrelated hemato- HSCT ¼ 5.0 vs 3.0, Po0.001). Patients in the auto-HSCT group poietic SCT, CD25 Ab was given one to two times on day 0 or on days 0 received significantly more consolidation therapy cycles than and þ 4. All blood products (except for donor hematopoietic stem cells) patients in the allo-HSCT group (4.0 vs 3.0, P 0.001). In terms of were irradiated at 2500 cGy before transplantation. o conditioning regimens, 84% patients in the auto-HSCT group received the TBI/Cy regimen, whereas only 69.2% of patients in Prevention and treatment of hepatic veno-occlusive disease the allo-HSCT group received this regimen; 12.0% patients in auto- For all patients, compound Danshen (20 mL/day) and low MW dextran HSCT group received Bu/Cy and 26.9% in allo-HSCT group (500 mL/day) were intravenously infused from the beginning of condition- (P ¼ 0.041). ing until the platelet count was 30 Â 109/L or coagulation deficiency was apparent.

End points measures HSCT outcome and complications The primary end points of interest were disease-free survival and overall The median follow-up was 1215 days (range: 14–8286 days). HSCT survival. Disease-free survival was the time from CR to relapse or death of was successful in all patients (100%) treated with allo-HSCT and any cause. 94.7% of patients treated with auto-HSCT (Table 2, P ¼ 0.144). Other end points of interest included engraftment success rate, Aphthous ulcer, erythra and upper respiratory tract infection recurrence and mortality. Engraftment success was indicated by granulo- occurred more frequently in the allo-HSCT group compared with 9 cyte counts 40.5 Â 10 /L for 3 consecutive days or platelet counts the auto-HSCT group (aphthous ulcer: 59.6 vs 14.7%, Po0.001; 420 Â 109/L in the absence of platelet transfusion. Transplantation failure 9 erythra: 19.2 vs 2.7%, P ¼ 0.003; upper respiratory tract infection: was indicated by a granulocyte count o0.5 Â 10 /L, or the absence of 9.6% vs 1.3%, P ¼ 0.042). The rates of acute and chronic GVHD donor cells as shown by variable copy numbers of tandem repeats analysis were 42.3 and 13.5%, respectively, in the allo-HSCT group, at day þ 28. Recurrence was indicated by a greater than 5% proportion of primitive cells in the BM, development of disease, or extramedullary whereas there were no instances of GVHD in the auto-HSCT relapse following CR. group (Table 2). The disease-free survival rates in auto-HSCT group and allo-HSCT group were 50.6 and 65.3%, respectively (Figure 1a, P 0.158), whereas the overall survival rates in auto-HSCT group Statistical analysis ¼ and allo-HSCT group were 54.9 and 65.3%, respectively (Figure 1b, Continuous data are expressed as median (interquartile range) and were P ¼ 0.486). compared between groups by Mann–Whitney U test. Categorical data are expressed as count (percentage) and were compared between groups by Fisher’s exact test. Disease-free and overall survival curves were constructed using the Kaplan–Meier method and were compared between groups (allogeneic vs autologous; BMT vs peripheral blood HSCT) by log-rank test. Cox proportional hazard models were used to identify Table 2. Complications before and after allogeneic or autologous independent risk factors for recurrence and mortality. Significant factors hematopoietic SCT identified by univariable Cox proportional hazard models were selected for inclusion in the final multivariable Cox proportional hazard model using Auto-HSCT Allo-HSCT P-value the forward conditional method. All analyses were evaluated at the 0.05 (n ¼ 75) (n ¼ 52) level of statistical significance. Statistical analyses were performed using SPSS 15.0 statistical software (SPSS Inc., Chicago, IL, USA). HSCT success 71 (94.7%) 52 (100.0%) 0.144 Complications during 50 (66.7%) 43 (82.7%) 0.066 HSCT RESULTS Aphthous ulcer 11 (14.7%) 31 (59.6%) o0.001* Demographic and clinical characteristics Erythra 2 (2.7%) 10 (19.2%) 0.003* Hemorrhagic cystitis 5 (6.7%) 4 (7.7%) 1.000 A total of 127 patients with AML were included in the study; Upper respiratory 1 (1.3%) 5 (9.6%) 0.042* 76 males and 51 females, with a median age of 31 years. Among tract infection these patients, 75 (59.1%) were treated with auto-HSCT; 38 Perianal infection 7 (9.3%) 2 (3.8%) 0.307 received auto-BMT, 35 received peripheral blood HSCT, and 2 Pseudomonas 3 (4.0%) 0 (0.0%) 0.269 patients received both auto-BMT and auto-peripheral blood HSCT. Aeruginosa Infection The remaining 52 (40.9%) patients were treated with allo-HSCT; 12 Fever 10 (13.3%) 10 (19.2%) 0.459 patients received allo-BMT; 39 patients received allo-peripheral Fatigue 2 (2.7%) 2 (3.8%) 1.000 blood HSCT; and 1 patient received both allo-BMT and allo- Pulmonary infection 3 (4.0%) 3 (5.8%) 0.688 peripheral blood HSCT from the same donor. The distribution of Diarrhea 5 (6.7%) 2 (3.8%) 0.699 Pruritus 0 (0.0%) 2 (3.8%) 0.166 FAB types included: 9 (7.1%) AML-M1; 40 (31.5%) AML-M2; 12 Cerebral hemorrhage 2 (2.7%) 1 (1.9%) 1.000 (9.4%) AML-M3; 31 (24.4%) AML-M4; 26 (20.5%) AML-M5; and 6 (4.7%) AML-M6. Of the remaining 3 patients, one had basophilic Complications after HSCT leukemia, one had obvious MDS history and then transformed to Acute GVHD — 22 (42.3%) — AML-M2, and one was unclassified AML. Chronic GVHD — 7 (13.5%) — Patients in the allo-HSCT group were significantly older than Abbreviation: HSCT ¼ hematopoietic SCT. *Indicates a statistically signifi- those in the auto-HSCT group (Table 1, P ¼ 0.018). All 12 patients cant between-group difference (Po0.05). Data are expressed by count and with AML-M3 were in the auto-HSCT group. There were percentage. significantly more patients with enlarged lymph nodes or

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 383 – 389 Allogeneic vs autologous HSCT for AML Y Jing et al 386

1.0 Auto-HSCT group 1.0 Auto-HSCT Allo-HSCT group Allo-HSCT Censoring Censoring 0.8 P -value = 0.158 by the 0.8 P -value = 0.486 by the log-rank test 0.653 log-rank test 0.653 0.6 0.6 0.506 0.549 0.4 0.4

0.2 Cumulative survival rate 0.2 Cumulative disease-free rate

0.0 0.0

0 2468 10 12 14 16 18 20 02468 10 12 14 16 18 20 Disease free survival (year) Overall survival (year) Figure 1. Kaplan–Meier curves of disease-free (a) and overall (b) survival for the auto-HSCT (n ¼ 75) and allo-HSCT (n ¼ 52) groups.

Table 3. Univariable and multivariable Cox proportional hazard model for predicting disease-free survival

Univariable Multivariable

HR (95% CI) P-value HR (95% CI) P-value

Age (years) 0.998 (0.969, 1.027) 0.868 Gender Female Reference Male 0.614 (0.365, 1.033) 0.066 FAB classification M1 Reference 0.480 M2 1.007 (0.378, 2.685) 0.988 M3 0.272 (0.053, 1.403) 0.120 M4 1.189 (0.435, 3.249) 0.735 M5 0.656 (0.224, 1.921) 0.442 M6 0.712 (0.138, 3.674) 0.685 Other 1.044 (0.202, 5.390) 0.959 Symptoms Fever 0.537 (0.318, 0.907) 0.020* 0.439 (0.254, 0.757) 0.003* Anemia 1.599 (0.938, 2.727) 0.084 Hemorrhage 0.774 (0.449, 1.333) 0.355 Enlarged lymph nodes or hepatosplenomegaly 1.102 (0.571, 2.128) 0.773 Time from presence to diagnosis 1.001 (0.997, 1.006) 0.545 Time from diagnosis to HSCT 1.001 (0.998, 1.003) 0.618 WBC at diagnosis 1.001 (0.998, 1.004) 0.391 Hb at diagnosis 0.996 (0.983, 1.008) 0.501 PLT at diagnosis 1.001 (0.994, 1.007) 0.836 Proportion BM primitive cells 0.986 (0.973, 0.999) 0.042* 0.984 (0.971, 0.996) 0.012* Clinical characteristics and treatment before HSCT Leukemic meningitis 1.888 (0.681, 5.230) 0.222 Lumbar puncture 1.031 (0.919, 1.155) 0.605 Chemotherapy induction courses to obtain CR 1.124 (0.984, 1.282) 0.084 Chemotherapy cycles between CR and HSCTa 1.011 (0.889, 1.150) 0.867 Radiotherapy dose 1.094 (1.007, 1.189) 0.033* Consolidation therapy cycles 1.079 (0.960, 1.211) 0.201 Intensive treatments 0 Reference 0.098 1 0.761 (0.400, 1.445) 0.403 2–5 0.290 (0.090, 0.935) 0.038* Conditioning regimens Bu/Cy Reference Reference TBI/Cy 4.923 (1.535, 15.792) 0.007* 5.587 (1.731, 18.028) 0.004* Other (MAC þ F, MAC, F þ BU, DEAC, CDE) 8.527 (1.716, 42.384) 0.009* 8.529 (1.710, 42.538) 0.009* ATG use 0.327 (0.080, 1.341) 0.121 Group (allo-HSCT vs auto-HSCT) 0.677 (0.393, 1.168) 0.161

Abbreviations: ATG ¼ antithymocyte globulin; CDE ¼ cyclophosphamide, daunorubicin, etoposide; CI ¼ confidence interval; DEAC ¼ daunorubicin, etoposide, cytarabine, cyclophosphamide; FAB ¼ Franch–American–British; HR ¼ hazard ratio; HSCT ¼ hematopoietic SCT; MAC ¼ semustine, cytarabine, cyclophosphamide. *Indicates that the variable has a significant impact on disease-free survival (Po0.05). aIncludes consolidation chemotherapy and intensive treatment cycles.

Bone Marrow Transplantation (2013) 383 – 389 & 2013 Macmillan Publishers Limited Allogeneic vs autologous HSCT for AML Y Jing et al 387 Predictors of recurrence that the symptom of fever, the proportion of BM primitive cells Univariable analysis revealed that the symptom of fever, the and the type of conditioning regimen were the independent proportion of BM primitive cells (blast tumor cells), radiotherapy significant predictors of mortality. When controlling for factors of dose, the number of intensive treatments, and the type of proportion BM primitive cells and conditioning regimens, patients conditioning regimen were significant predictors of recurrence with the symptom of fever were found to have a significantly (Table 3). Fever (39–40 1C) typically occurred 4 days after HSCT and lower risk of mortality (HR ¼ 0.417, P ¼ 0.003); the risk of mortality persisted until the causative infection was controlled. There was decreased with every percentage increase in the proportion of no significant difference in the risk of recurrence between the allo- BM primitive cells (HR ¼ 0.984, P ¼ 0.018). Patients treated with the HSCT and auto-HSCT groups (P ¼ 0.161). The three independent Bu/Cy conditioning regimen had a significantly lower risk of significant predictors (fever, proportion BM primitive cells, and mortality than patients who were treated with the other conditioning regimens) of recurrence were entered into the conditioning regimens (TBI/Cy vs Bu/Cy: HR ¼ 4.952, P ¼ 0.008; multivariable regression analyses. When controlling for factors of other regimens vs Bu/Cy: HR ¼ 8.388, P ¼ 0.009). proportion BM primitive cells and conditioning regimens, patients with the symptom of fever were found to have a significantly lower risk of recurrence (HR ¼ 0.439, P ¼ 0.003); the risk of BMT vs peripheral blood HSCT recurrence was decreased with every percentage increase in the A total of 50 patients received BMT, whereas 74 patients received proportion of BM primitive cells (HR ¼ 0.986, P ¼ 0.042). Patients peripheral blood HSCT. The other three patients received both treated with the Bu/Cy conditioning regimen had a significantly BMT and peripheral blood HSCT. Figure 2 shows the disease-free lower risk of recurrence than patients treated with the other and overall survival rates for patients who received BMT and those conditioning regimens (TBI/Cy vs Bu/Cy: HR ¼ 5.587, P ¼ 0.004; who received peripheral blood HSCT, stratified by the source of other regimens (MAC þ F, MAC, F þ BU, DEAC, CDE) vs Bu/Cy: HSCTs (autologous or allogeneic). For both the auto- and allo- HR ¼ 8.529, P ¼ 0.009). HSCT groups, disease-free survival rates were lower (but not significantly so) for patients who received BMT compared with patients who received peripheral blood HSCTs (the 3-year Predictors of mortality survival rate for auto-HSCT: BMC ¼ 43.0% vs peripheral blood Univariable analysis revealed that gender, the symptom of fever, HSCT ¼ 58.9%; the 3-year survival rate for allo-HSCT: BMC ¼ 48.6% the proportion of BM primitive cells, radiotherapy dose and the vs peripheral blood HSCT ¼ 69.2%). Similarly, for both the auto- type of conditioning regimen were significant predictors of and allo-HSCT groups, overall survival rates were lower (but not mortality (Table 4). Subsequent multivariable analyses revealed significantly so) for patients who received BMT compared with

Auto-HSCT Allo-HSCT

1.0 BMT 1.0 BMT Peripheral blood HSCT Peripheral blood HSCT Censored case Censored case 0.8 P -value = 0.093 by 0.8 P -value = 0.123 by the the log-rank test 0.692 log-rank test 0.589 0.6 0.6 0.486 0.430 0.4 0.4

0.2 0.2 Cumulative disease-free rate Cumulative disease-free rate

0.0 0.0

024681012 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Disease free survival (year) Disease free survival (year)

Auto-HSCT Allo-HSCT 1.0 BMT 1.0 BMT Peripheral blood HSCT Peripheral blood HSCT Censored case Censored case 0.8 P -value = 0.305 by 0.8 P -value = 0.127 by the log-rank test 0.692 the log-rank test 0.589 0.6 0.6 0.486 0.521 0.4 0.4 Cumulative survival rate 0.2 Cumulative survival rate 0.2

0.0 0.0

024681012 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Overall survival (year) Overall survival (year) Figure 2. Kaplan–Meier curves of disease-free (a, b) and overall (c, d) survival for patients who received BMT and peripheral blood HSCT transplantation stratified by auto-HSCT (38 BMT vs 35 peripheral blood HSCT) and allo-HSCT (BMT n ¼ 12 vs peripheral blood HSCT n ¼ 39). Note: three patients who had both BMT and peripheral blood HSCT were excluded from these analyses.

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 383 – 389 Allogeneic vs autologous HSCT for AML Y Jing et al 388 Table 4. Univariable and multivariable Cox proportional hazard models for predicting overall survival

Univariable Multivariable

HR (95% CI) P-value HR (95% CI) P-value

Age (years) 0.999 (0.969, 1.030) 0.949 Gender Female Reference Male 0.568 (0.331, 0.974) 0.040* FAB classification M1 Reference 0.549 M2 1.157 (0.393, 3.406) 0.791 M3 0.330 (0.060, 1.809) 0.201 M4 1.337 (0.443, 4.037) 0.607 M5 0.738 (0.227, 2.398) 0.614 M6 0.905 (0.166, 4.943) 0.908 Othera 1.258 (0.230, 6.878) 0.791 Symptoms Fever 0.493 (0.285, 0.852) 0.011* 0.417 (0.236, 0.736) 0.003* Anemia 1.474 (0.850, 2.558) 0.167 Hemorrhage 0.722 (0.408, 1.276) 0.262 Enlarged lymph nodes or hepatosplenomegaly 1.254 (0.644, 2.441) 0.505 Time from presence to diagnosis 1.002 (0.997, 1.007) 0.447 Time from diagnosis to HSCT 1.001 (0.998, 1.003) 0.682 WBC at diagnosis 1.001 (0.999, 1.004) 0.287 Hb at diagnosis 0.995 (0.982, 1.008) 0.416 PLT at diagnosis 1.001 (0.994, 1.007) 0.873 Proportion BM primitive cells 0.986 (0.973, 1.000) 0.047* 0.984 (0.971, 0.997) 0.018* Clinical characteristics and treatment before HSCT Leukemic meningitis 1.514 (0.470, 4.870) 0.487 Lumbar puncture 0.998 (0.879, 1.134) 0.977 Chemotherapy induction courses to obtain CR 1.106 (0.956, 1.278) 0.174 Chemotherapy cycles between CR and HSCTa 1.017 (0.889, 1.164) 0.802 Radiotherapy dose 1.096 (1.004, 1.196) 0.040* Consolidation therapy cycles 1.082 (0.958, 1.221) 0.203 Intensive treatments 0 Reference 0.141 1 0.761 (0.389, 1.489) 0.425 2–5 0.320 (0.099, 1.037) 0.058 Conditioning regimen Bu/Cy Reference Reference TBI/Cy 4.410 (1.370, 14.196) 0.013* 4.952 (1.529, 16.035) Other (MAC þ F, MAC, F þ BU, DEAC, CDE) 8.368 (1.682, 41.617) 0.009* 8.388 (1.682, 41.838)

ATG use 0.365 (0.089, 1.500) 0.162 Group (allo-HSCT vs auto-HSCT) 0.820 (0.469, 1.435) 0.488

Abbreviations: ATG ¼ antithymocyte globulin; CDE ¼ cyclophosphamide, daunorubicin, etoposide; CI ¼ confidence interval; DEAC ¼ daunorubicin, etoposide, cytarabine, cyclophosphamide; FAB ¼ Franch–American–British; HR ¼ hazard ratio; HSCT ¼ hematopoietic SCT; MAC ¼ semustine, cytarabine, cyclophosphamide. *Indicates that the variable has a significant impact on overall survival (Po0.05). aIncludes consolidation chemotherapy and intensive treatment cycles.

patients who received peripheral blood HSCTs (auto-HSCT: disease-free or overall survival between patients who received BMC ¼ 52.1% vs peripheral blood HSCT ¼ 58.9%; allo-HSCT: BMC ¼ allo-HSCT and auto-HSCT are consistent with those from a small- 48.6% vs peripheral blood HSCT ¼ 69.2%). scale study (N ¼ 99) reporting 3-year survival rates for patients who received high-dose cytarabine followed by either allo-HSCT, auto-HSCT or a second dose of cytarabine.8 In contrast, the DISCUSSION findings from several larger-scale studies (N ¼ 734–831) with In this retrospective study, we examined outcomes of Chinese longer reported survival rates suggest that allo-HSCT/ BMT is patients with AML received allo- or auto-HSCT following CR1. We associated with better survival outcomes than auto-HSCT/ BMT.11–13 found that there were no significant differences in disease-free or Hsieh et al.14 also reported that allo-HSCT was associated with the overall survival rates between patients who received allogenic best disease-free survival and overall survival in comparison with HSCT and those who received auto-HSCT, although the rate of auto-HSC or chemotherapy in patients with cytogenetically survival was numerically higher in the allo-HSCT group. normal AML. If donors with all HLA matching are available, we In elderly patients with non-M3 acute myelogenous leukemia in suggest using allo-HSCT. In cases where HLA matching donors are first CR, Kurosawa et al.10 reported that allo-HCT may improve not available, auto-HSCT is a good choice. A large clinical trial also outcomes (compared with chemotherapy) in patients with AML reported that early allo-HSCT treatment led to better overall in CR1. Our finding that there were no significant differences in results than auto-HSCT, especially for younger patients or those

Bone Marrow Transplantation (2013) 383 – 389 & 2013 Macmillan Publishers Limited Allogeneic vs autologous HSCT for AML Y Jing et al 389 with bad/very bad risk cytogenetics.12 The lack of any significant REFERENCES between-group differences in our study may reflect the relatively 1 Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ et al. Allogeneic short duration of follow-up and/or the fact that all 12 patients with stem cell transplantation for acute myeloid leukemia in first complete remission: M3 FAB subtype, which is associated with the best prognosis and systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301: not suggested for HSCT in CR1, were in the auto-HSCT group. 2349–2361. Another potential explanation is that Chinese patients respond 2 Bleakley M, Lau L, Shaw PJ, Kaufman A. 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Intravenous Wang: data management; Yu Zhao and Quan-shun Wang: editorial assistance; Jian versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen Bo, Wen-rong Huang and Chun-ji Gao: continuous support; Yu Jing: writing the draft; for allogeneic hematopoietic stem cell transplantation: decreased incidence of and Li Yu: careful designing and revising the paper. This work was supported by hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100- grants from China (90919044, 30971297, 81170518 and 07MP03). day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 383 – 389