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Bone Marrow Transplantation (2004) 34, 215–220 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00

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Acute myeloid leukaemia Autologous stem cell transplantation using modified TAM or combination of triple-alkylating agents conditioning regimens as one of the post-remission treatments in patients with adult acute myeloid leukemia in first complete remission H-J Kim, W-S Min, K-S Eom, S-J Park, Y-H Park, D-W Kim, J-W Lee, C-W Park and C-C Kim Division of Hematology, Department of Internal Medicine, Catholic Hemopoietic Stem Cell Transplantation Center, The Catholic University of Korea College of Medicine, Seoul, Korea

Summary: A total of 174 newly diagnosed adult acute myeloid leukaemia (AML) patients were treated in first complete remission (CR1) using modified TAM or a combination of triple-alkylating agents followed by autologous transplantation (AT). Cytogenetic risk groups were classified and most patients received mobilized peripheral blood stem/ progenitor cells (PBSCs). The infused cell dose consisted of a median of 4.172 (range, 1.2–17.1) 106/kg CD34 þ cells. With a median follow-up of 51 months (range, 5–131 months) after CR1, the estimated 5-year disease-free survival (DFS) rate was 68 (95% confidence interval (CI), 63–73%) and the event-free survival rate at 5 years was 59 (95% CI, 54–64%). AML patients other than M3 subtype, the long-term DFS rate was 76, 33% for favourable and unfavourable risk groups, respectively. In all, 40 patients had relapses (40/174, 23%) at the median 15 months after CR1 (range, 8–66 months). Overall, seven patients (4%) died in connection with AT. The infused CD34 þ cell dose (P ¼ 0.0389) was associated with survival by multivariate analysis. In conclusion, two novel conditioning regimens in AT are feasible for adults with variable risk AML followed for over a 10-year period. Bone Marrow Transplantation (2004) 34, 215–220. doi:10.1038/sj.bmt.1704556 Published online 31 May 2004 Keywords: autologous transplantation; AML; modified TAM; triple-alkylating agents; CD34 þ cells

Relapse after autologous transplantation (AT) is a common cause of treatment failure in acute myeloid leukaemia

Correspondence: Professor Dr W-S Min, Division of Hematology, Department of Internal Medicine, Catholic Hemopoietic Stem Cell Transplantation Center, The Catholic University of Korea College of Medicine, 62, Youido-dong, Youngdungpo-ku, Seoul 150-713, Korea; E-mail: [email protected] Received 5 December 2003; accepted 19 March 2004 Published online 31 May 2004

(AML) patients, including the subset with cytogenetic highrisk features. Several large series of randomised studies comparing either multiple cycles of intensive consolidation chemotherapy (IC) after first complete remission (CR1) or induction chemotherapy with subsequent stem cell transplantation (SCT) in CR have produced contradictory results.1–5 There was no consensus because the studies assessed clinically heterogeneous patient populations, examined poor molecular markers, including cytogenetics, FISH, PCR, etc, and used different chemotherapy regimens before SCT. Even with high-dose cytosine arabinoside (AraC)-based intensive induction and consolidation courses, there is no consensus on post-remission therapy in AML. With regard to the in vivo leukaemia purging effect, minimal residual disease (MRD) or contaminating cells may in part be responsible for post-AT relapses. Moreover, the correlation between clinical outcome and the many parameters involved in AT in AML is controversial, compared with other treatment modalities, such as allogeneic transplantation or IC alone. We modified the original regimen of total-body irradiation (TBI), high-dose AraC, and melphalan, the so-called TAM regimen,6 which was originally introduced for children with high-risk acute lymphoblastic leukaemias. We adopted it as a TBI-containing conditioning regimen for adults with AML in Korea. According to our review of the literature, this may be the first report of its use as a conditioning regimen in adult patients with AML. In addition, as a non-TBI conditioning regimen, we used a combination of triple-alkylating agents7 in some of the AML patients enrolled in this study. Our study indicates that AT performed as early as possible after the first CR (CR1) was beneficial in patients younger than 65 years old. Patients with intermediate or unfavourable cytogenetics showed a comparable or better outcome than did patients in other studies treated with high-dose AraC containing IC or with allogeneic transplantation, especially for the M2 and M4e subtypes of AML. We believe that a better-defined strategy for postremission adult AML is needed, and this study provides support for the use of modified TAM or triple-alkylating agents as potent novel conditioning regimens.

Modified TAM or triple-alkylating agents conditioning in AML H-J Kim et al

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Patients and methods Patients’ clinical characteristics In all, 174 newly diagnosed adult AML patients in CR1 with a median age of 34 years (range: 15–61) have undergone transplantation at the Catholic Hemopoietic Stem Cell Transplantation Center of Korea since 1993. After the second course of consolidation chemotherapy, the patients younger than 65 years of age in CR1 were assigned to receive an AT if an HLA-identical donor was not available. There were 103 male and 71 female patients. The median time to transplantation from CR was 6 months (range: 3–12). Three patients were excluded from the longterm follow-up analysis because they refused to take part in post transplant follow-up. The initial WBC count and percentage of leukaemic blasts were recorded and analysed as prognostic parameters. Details of the clinical profiles of the patients at the time of transplantation are summarised in Table 1.

Table 1 this study

Clinical and laboratory characteristics of AML patients in

Characteristics Age (years) 15–30 31–40 41–50 51–61 Male/female WBC count ( 109/l) Initial PB leukemic blasts (%) o45 X45

No. (%) 67 (38) 54 (31) 38 (22) 15 (9) 103/71 Median 25 (range, 0.7–150) Median 44 (range, 0–97) 87 87

FAB subtypes M0 M1 M2 M3 M3v M4 M5 M6 Biphenotypic

3 (2) 37 (21) 71 (41) 29 (19) 4 18 (10) 7 (4) 3 (2) 2 (1)

Cytogenetics Favourable Intermediate risk Unfavourable Unknown Not available

44 50 13 2 65

Cytogenetics and immunophenotyping The International System for Cytogenetic Nomenclature (ISCN)8 was used as a guideline for classification, and data on 109 patients (63%) were available in this study. Cytogenetic risk groups were classified using the guidelines of the SWOG trial.9 Briefly, the presence of t(15;17) or inv16/t(16;16)/del(16q) with any other abnormality, and t(8;21) without del(9q) or a complex karyotype at presentation were classified as the favourable risk group. Normal cytogenetics in addition to þ 8, Y, þ 6, and del(12p) at presentation were considered intermediate risk. A number of other specific cytogenetic abnormalities, including complex karyotypes, were deemed unfavourable. All other clonal chromosomal aberrations with fewer than three abnormalities were assigned to the unknown prognostic group. Only 66 of the patients enrolled in the study underwent immunophenotyping at initial diagnosis because we only began this routinely for all AML patients diagnosed at our centre in 2000. CD34, CD56, and other aberrantly expressed lymphoid markers were included in this study.

Induction and consolidation chemotherapy All the patients were treated according to our centre’s standard protocol, which consists of ‘3 7’ idarubicin (IDA) plus N4-behenoyl-1-b-D-arabinofuranosyl cytosine (BH-AC) induction chemotherapy.10 Briefly, IDA was administered daily at a dose of 12 mg/m2 for 30 min intravenously for 3 consecutive days, and BH-AC was administered daily at a dose of 300 mg/m2 over a period of 4 h for 7 consecutive days, as previously reported.10 For AML-M3 patients enrolled in this study, we used the same AML induction and consolidation strategy, in addition to all-trans-retinoic acid (ATRA), at a dose of 45 mg/m2/day orally for 2 months at the time of induction chemotherapy. This consolidation chemotherapy was repeated twice in all patients and consisted of either a combination of an intermediate dose of AraC (1.0 g/m2 intravenously every Bone Marrow Transplantation

Conditioning regimen Modified TAM Triple-alkylating agents BMT BMC CMT Others

(25) (29) (7) (1) (38)

129 (74) 38 (22) 23 8 7 7 (4)

TAM ¼ total body irradiation, AraC, melphalan; BMT ¼ busulphan, melphalan, thiotepa; BMC ¼ busulphan, melphalan, cyclophosphamide; CMT ¼ cyclophosphamide, melphalan, thiotepa; Others ¼ either totalbody irradiation plus cyclophosphamide or busulphan plus cyclophosphamide, and one patient received modification of total-body irradiation plus cyclophosphamide, that is, addition of AraC.

12 h for 5 days) and mitoxantrone (12 mg/m2 intravenously for 3 days), with or without etoposide (100 mg/m2 intravenously for 3 days) (n ¼ 95), or a combination of an intermediate dose of AraC (1.0 g/m2 intravenously every 12 h for 5 days) and amsacrine (100 mg/m2 intravenously for 3 days), with or without etoposide (100 mg/m2 intravenously for 3 days) (n ¼ 79).

Bone marrow and peripheral blood stem/progenitor cells (PBSCs) Overall, 15 patients received their pre-transplant bone marrow cells while they were in CR after conditioning, and 12 received pre-transplant bone marrow cells plus PBSCs because the dose of stem cells was insufficient. In total, 13 patients required extra PBSC mobilisation to produce an adequate transplantable cell dose (poor mobilisers). They received PBSCs only, but needed an additional PBSC collection using G-CSF stimulation (10 mg/kg


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subcutaneously for 7 days with the cells collected by leukapheresis on days þ 5, þ 6, and þ 7) with no further chemotherapy. The other 134 patients seen since 1998 received PBSCs only. The PBSCs were collected after administering granulocyte colony-stimulating factor (GCSF), following intermediate doses of chemotherapy. We collected PBSCs for 3 days. The median number of CD34 þ cells collected was 10.8 106/kg (range: 1.2– 49.2), and we infused a maximum of 20 106 CD34 þ cells/kg, although more than the target number of CD34 þ cells was collected in some patients. The median number of infused CD34 þ cells was 4.1 106/kg (range: 1.2–17.2). The extra cells that were not infused were stored in cryopreservation bags for up to 2 years.

Conditioning regimens for autologous PBSCT In total, 129 patients received our modified TAM, which consisted of fractionated TBI (10 Gy, five fractions in 3 days) from day –8 to –6, followed by intermediate-dose AraC (1.5 g/m2. over 3 h every 12 h for six doses) from day 5 to 3, and melphalan (100 mg/m2 over 30 min) on day 2 only. Between September 1996 and August 1998, we studied non-TBI regimens to compare various combinations of triple-alkylating agents in 38 adult patients. The regimens were as follows. In all, 23 patients received the ‘BMT’ regimen: busulphan (BU) 1 mg/kg orally every 6 h for 12 doses (total dose: 12 mg/kg) on days –8, –7, and –6, melphalan (Mel) 50 mg/m2 intravenously on days –5 and –4 (total dose: 100 mg/m2), and thiotepa (Thio) 250 mg/m2 intravenously on days –3 and –2 (total dose: 500 mg/m2). The PBSCs were thawed and infused at least 36 h after the last dose of Thio on day 0. Overall, 15 patients received ‘BMC’ or ‘CMT’ regimens. They received cyclophosphamide instead of Thio or BU at a dose of 50 mg/kg/day intravenously for 2 days. The other seven patients received AT using regimens other than the TAM or the combination of triple-alkylating agents individualised for their clinical condition, for example, gastrointestinal discomfort, following pneumonia, a previous history of radiation exposure, a history of AraC intolerance, etc.

Engraftment The time to hematopoietic recovery was measured as an absolute neutrophil count (ANC) X0.5 109/l and a platelet count X20 109/l with no platelet transfusion for 3 consecutive days. Engraftment was also assessed using routine marrow aspiration. Graft failure or aplasia was defined as the absence of haematological recovery in patients after transplantation.

þ 90 following PBSC infusion. All the patients received G-CSF beginning on day þ 5 after PBSC infusion at a dose of 5 mg/kg/day subcutaneously until the ANC 41.0 109 cell/l. All the blood components given to patients were irradiated and leukocyte-filtered before transfusion.

Statistical analysis Disease-free survival (DFS) was calculated from the date of CR until the date of the first relapse or death during the first CR. The event-free survival (EFS) was calculated from the date of CR1 until recurrence or death from any cause, or alive in CR at last follow-up. The Kaplan–Meier method was to calculate DFS, EFS, and overall survival, and the statistical significance of differences under various clinical conditions was calculated using the log-rank test. Patients still alive in CR were censored at their last follow-up. Multivariate analysis was performed with the Cox proportional hazards model to obtain the estimate, 95% confidence interval (CI), and hazard ratio (HR) of the instantaneous event rate between groups. The Cox model was also used to determine which of the independent prognostic factors were important in a univariate analysis using Po0.2. All analyses were based on a retrospective review. The last follow-up date was 30 September 2003. The SAS 8.1e statistical software for Windows (SAS Institute, Cary, NC, USA) was used.

Results Cytogenetics and immunophenotyping Of the 109 patients for whom cytogenetic data were available, 44 patients (40%) had chromosomal abnormalities leading to a favourable prognosis, 50 (46%) had an intermediate prognosis, 13 (12%) had an unfavourable prognosis, and the remaining two patients had an unknown prognosis. According to the immunophenotyping data at initial diagnosis (n ¼ 66), 46 patients (46/66, 70%) showed CD34 þ with a wide range of antigenic expression, and 20 patients were negative (30%). Of these, 17 patients had other aberrant antigenic expression, such as CD56, CD7, or CD19. In all, 10 patients also were CD56 þ .

Infused cell dose The median infused cell dose was 4.172 106/kg. CD34 þ cells (range: 1.2–17.2 106) (n ¼ 174). For patients who received bone marrow cells only, the harvested cell dose was 7.474.7 108/kg MNCs (range: 1.7–18 108).

Survival and relapse Toxicity grading and supportive care Major toxicity was assessed using the WHO criteria.11 All the patients received prophylactic antibiotics starting from day –14 until the ANC 41.5 109 cell/l. All the patients received antifungal prophylaxis with itraconazole from day 14 to þ 60 post-PBSC infusion. PCP prophylaxis with Bactrim was given throughout conditioning, discontinued 48 h before PBSC infusion, and given from day þ 21 to

The overall survival was 71% (124/174). Of the 174 patients, 131 were in continuous CR, while seven died due to nonrelapse causes. The median follow-up time from CR1 for this group of surviving patients was 51 months (range: 5–131 months) with the latest recurrence event occurring 60 months after CR1. The Kaplan–Meier estimated 5-year DFS rate was 68% (95% CI 63–73%) (Figure 1). The EFS rate at 5 years was 59% (95% CI Bone Marrow Transplantation


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Probability of survival

1.00 Favourable, 0.7234(n=36)

0.75

Intermediate, 0.5061(n=46)

0.50

Unfavourable, 0.3182 (n=13)

0.25 P = 0.1727

0.00 0

60

80

100

Figure 3 Probability of disease-free survival in the AML patients (except AML-M3) after autologous transplantation in first complete remission. Analysed according to the cytogenetic risk characteristics in 95 patients.

1.00 Triple-alkylators, 0.6176 (n=37)

0.75 Modified TAM, 0.7144 (n=89)

0.50 0.25 0.00 0


40

P = 0.6113

1.00

0.75

10

20

30

40 50 Months

60

70

80

90

Figure 4 Probability of disease-free survival analysed according to the conditioning regimens used at autologous transplantation in the 126 AML patients in first complete remission.

0.6769

0.50

0.25

0.00 0

20

40

60 80 Months

100

120

140

Figure 1

Probability of disease-free survival in the 174 AML patients after autologous transplantation.

1.00 Probability of survival

20

Months


54–64%). In total, 40 patients relapsed (40/174, 23%) at a median time of 15 months after CR1 (range: 8–66 months); of these, three of 33 AML-M3 patients relapsed at 12, 25, and 54 months, respectively. Of 38, 11 (29%) patients who received triple-alkylating agents as conditioning (non-TBI regimen) relapsed, and 27 of 129 (21%) patients who received modified-TAM (TBI-containing regimen) as conditioning relapsed (P ¼ 0.3891). The long-term DFS rate according to the cytogenetic risk characteristics was 78% (95% CI 71–85%), 61% (95% CI 50–72%), and 32% (95% CI 9–54%) for the favourable, intermediate, and unfavourable risk groups, respectively. The differences in the probability of survival were not significant (P ¼ 0.1510) (Figure 2). This might be due to the relatively small sample numbers, especially in the unfavourable group (n ¼ 13). Moreover, when we exclude AML-M3 from the analysis of DFS, there was no difference between the three cytogenetic risk groups (P ¼ 0.1727; Figure 3). However, there was a marginal survival difference when we compared the favourable and unfavourable groups (P ¼ 0.0662). With respect to the two different conditioning regimens, that is, modified TAM vs the various triple-alkylating agents, used in this study, there was no significant difference (P ¼ 0.6113; Figure 4). By contrast, the number of infused CD34 þ cells (over and under 5 106/kg

Favourable, 0.7742 (n=44)

0.75 Intermediate, 0.6070 (n=50)

0.50 Unfavourable, 0.3182 (n=13)

0.25 P = 0.1510

0.00 0

20

40

60

80

100

Months Figure 2

Probability of disease-free survival in the AML patients after autologous transplantation in first complete remission. Analysed according to the cytogenetic risk characteristics in 107 patients.

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CD34 þ cells) caused a significant (P ¼ 0.0032) difference in DFS (Figure 5). We looked for FAB subgroup-specific differences, and the most frequent subtype (AML-M2) was selected for comparison with the other subgroups. When we excluded AML-M3 from the analysis, there was no significant DFS difference between AML-M2 and the other subtypes (P ¼ 0.9515). Specifically, AML-M2 patients had similar DFS rates according to the cytogenetic risk characteristics (data not shown). Infused stem cell sources also had no marked survival differences in this analysis (P ¼ 0.0914). In the univariate analysis, sex, age, percentage of initial peripheral blood leukaemic blasts, chromosomal abnormalities, and infused CD34 þ cell dose correlated with survival to the extent of the statistical power, Po0.2 (Table 2). In the multivariate analysis, however, only the infused CD34 þ cell dose influenced survival (P ¼ 0.0389). The percentage of initial peripheral blood leukaemic blasts and chromosomal abnormalities were not significantly associated with survival (P ¼ 0.1086, 0.0734, respectively).

Regimen-related toxicity (RRT) and transplant-related mortality (TRM) The most frequent RRT was mucositis – it developed in 115 of 174 patients (66%). According to the toxicity criteria of


219 1.00 Probability of survival

< 5.0x106/kg CD34+, 0.7335 (n=120)

0.75

0.50

> 5.0x106/kg CD34+, 0.5684 (n=52)

0.25 P = 0.0032

0.00 0

20

40

60 80 Months

100

120

140

Figure 5 Probability of disease-free survival analysed according to the infused CD34 þ cell doses at autologous transplantation in the 172 AML patients in first complete remission.

Table 2 Analysis of the clinical and laboratory characteristics which influence for DFS at transplant Analysis

Parameter

P

RR

95% CI

Sex Age WBC Initial PB blasts Conditioning regimens CD34+ vs CD34 CD7/19+ vs CD7/19 CD56+ vs CD56 Cytogenetic abnormalities Infused CD34+ cells CR to transplant

0.1549 0.1557 0.9216 0.0972 0.4708 0.7862 0.9750 0.6384 0.1890 0.0294 0.6065

0.6 0.6 1.0 0.4 1.3 1.2 1.0 1.4 2.4 2.2 0.8

0.3–1.2 0.3–1.2 0.4–2.6 0.2–1.2 0.6–2.9 0.4–3.9 0.3–3.2 0.3–5.7 0.6–9.2 1.1–4.6 0.3–1.9

Initial PB blasts Cytogenetic abnormalities Infused CD34+ cells

0.1086 0.0734 0.0389

0.3 1.7 2.6

0.1–1.2 0.9–3.8 1.1–6.6

Univariate

Multivariate

the WHO, 37 of 38 patients who received triple-alkylating agents as a conditioning regimen developed severe mucositis (Xgrade III), and three (8%) of them died due to pneumonia, sepsis, and multiorgan failure, respectively. One patient had aplasia post transplant and died of sepsis within 1 month. In addition, three of 129 (2%) patients who received modified TAM agents as a conditioning regimen died; therefore, TRM occurred in seven patients overall (7/174, 4%), including four cases of pneumonia with sepsis (ARDS) and one each of fulminant hepatitis, Guillain–Barre´ Syndrome, and Vibrio infection. Nevertheless, there was no difference in TRM between modified TAM and triple-alkylating agents (P ¼ 0.5000), which might be due to the comparatively small sample in the latter group.

Discussion This study showed that autologous haematopoietic SCT (HSCT), using two conditioning regimens (either modified TAM or a combination of triple-alkylating agents),

affected the long-term continuous complete remission (CCR) in a diverse population of adult AML patients in CR1. Even after considering the possible selection bias in the transplantation strategy – many patients had adverse pre-treatment characteristics, and many would not have been eligible for allogeneic transplantation otherwise – 68% of the transplanted patients were cured of AML in this study. Larger studies have examined the superiority of transplantation over simple chemotherapy and have investigated different intensive conditioning regimens as a potent antileukaemic pre-transplant tool, especially in an autologous setting in which there is no hope of a graft-versusleukaemia (GvL) effect.1,11–14 However, the optimal postremission treatment and preparative regimen are still in dispute. More intense conditioning may lead to higher transplant-related mortality (TRM). Therefore, we modified the original TAM regimen and performed the transplantation during CR1, instead of delaying the transplant schedule or increasing the conditioning dose. Our results seem optimistic for adult AML patients in CR1, including cytogenetically intermediate and unfavourable risk groups, treated with autologous transplantation. In our study, the overall relapse rate was 23% and the actuarial DFS rate was 68% with a median follow-up time of 51 months. Most of all, TRM was only 4% (7/174). If we consider the higher relapse rate one of the major problems in patients who received AT to treat adult AML, we should, at least as part of the overall treatment procedure, consider the role of various preparative regimens. Comparisons between regimens are very difficult because patients or pre-transplant conditions are heterogeneous, and it is difficult to perform a well-designed prospective randomisation with exactly the same clinical and biological risk groups and treatment strategies. Because busulphan, melphalan, and thiotepa conditioning have been used to treat patients with various solid tumours,15–17 this combination of triple alkylating agents should help to reduce the tumour burden in leukaemias. In our study, 38 adult AML patients in CR1 received this nonTBI conditioning before autologous transplantation. As expected, almost all these patients developed moderate to severe mucositis, but most were ultimately managed successfully. Moreover, the relapse rate was 29% compared with 21% for patients who received the modified TAM regimen in the same clinical situation. We cannot clearly verify the superiority of our two conditioning methods. However, our results complement new information on the many adult AML patients who are long-term survivors (over 5 years). Therefore, we are confident of the durability of the leukaemia-free survival achieved after AT for patients with adult AML in CR1. Our results indicate that cytogenetically favourable and intermediate risk groups achieved 77 and 61% DFS rates in the respective populations, when we included AML-M3. Even after excluding AML-M3, the respective DFS rates were 76 and 54%, respectively. We have changed our treatment strategy for AML-M3 in the last few years and now use ATRA-containing chemotherapy without transplant-based post-remission intensification therapy. As in other major reports, chromosomal abnormalities also predicted the Bone Marrow Transplantation


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response to AT in this study. For patients with severe chromosomal abnormalities, more potent treatment tools, such as allogeneic transplantation or combined post transplant immunotherapy, should be considered. Interestingly, the high content of CD34 þ stem/progenitor cells in the autologous PBSCs of AML patients collected during consolidation chemotherapy was closely related to an adverse prognosis post transplant in this analysis. We analysed both the number of CD34 þ cells in the peripheral blood after G-CSF stimulation and the number of CD34 þ cells infused at transplantation in all patients, and both were associated with a higher relapse rate in this study (P ¼ 0.0392). Simply, the strong correlation between rapid CD34 þ cell recovery post-consolidation chemotherapy and the infusion of more CD34 þ cells have a poor clinical outcome, as reported elsewhere.18,19 Perhaps the higher relapse rates after autologous transplantation are due to similarly higher MRD frequencies in PBSCs collected serially after consolidation chemotherapy. Future studies must examine the roles of leukaemic cell contamination, insufficient in vivo purging pre-transplantation, uncertain genetic polymorphism related to chemosensitivity in AML patients, and other factors. In conclusion, the modified TAM and triple-alkylating agent combination are two novel conditioning regimens in AT for adults with variable-risk AML. The DFS, EFS, and overall survival in a diverse population of adult AML patients followed over a 10-year period confirm that AT using these two conditioning regimens is likely to be stable. Furthermore, the higher relapse rate associated with a higher CD34 þ content in the mobilised PBSCs and the need for more potent therapeutic plans for the unfavourable risk groups of patients with AML have again been emphasised.

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postremission treatment in patients with de novo acute myelogenous leukemia. Cancer 2003; 97: 1721–1731. Cahn JY, Souillet BG, Pico JL et al. The TAM regimen prior to allogeneic and autologous bone marrow transplantation for high-risk acute lymphoblastic leukemias: a cooperative study of 62 patients. Bone Marrow Transplant 1991; 7: 1–4. Holmberg LA, Lemirer T, Rowley S et al. High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer. Bone Marrow Transplant 1998; 22: 651–659. Mitelman F ( ed.). ISCN 1995: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: S Karger, 1995. Slovak ML, Kopecky KJ, Cassileth R et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000; 96: 4075–4083. Park HS, Kim DW, Kim CC et al. Induction chemotherapy with Idarubicin plus N4-behenoyl-1-b-D-arabinofuranosylcytosine in acute myelogenous leukemia: a newly designed induction regimen – a prospective, cooperative multicenter study. Seminar Hematol 1996; 33 (Suppl. 3): 24–29. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. Amadori S, Testi AM, Arico M et al. Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. J Clin Oncol 1993; 11: 1046–1054. Ewing JC, Robertson JD, Kell WJ et al. Autologous peripheral blood stem cell transplantation in first remission adult acute myeloid leukaemia – an intention to treat analysis and comparison of outcome using a predictive model based on the MRC AML10 cohort. Hematology 2003; 8: 83–90. Collisson EA, Lashkari A, Malone R et al. Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission. Leukemia 2003; 17: 2183–2188. Weaver CH, Bensinger WI, Appelbaum F et al. Phase I study of high-dose busulfan, melphalan, thiotepa with autologous stem cell support in patients with refractory malignancies. Bone Marrow Transplant 1994; 14: 813–819. Schiffman KS, Bensinger WI, Appelbaum FR et al. Phase II study of high-dose busulfan, melphalan and thiotepa with autologous peripheral blood stem cell support in patients with malignant disease. Bone Marrow Transplant 1996; 17: 943–950. Holmberg LA, Demirer T, Rowley S et al. High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer. Bone Marrow Transplant 1998; 22: 651–659. Keating S, Suciu S, de Witte T et al. The stem cell mobilization capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTCGIMEMA AML-10 trial. Leukemia 2003; 17: 60–67. Feller N, Schuurhuis GJ, van der Pol MA et al. High percentage of CD34-positive cells in autologous AML peripheral blood stem cell products reflects inadequate in vivo purging and low chemotherapeutic toxicity in a subgroup of patients with poor clinical outcome. Leukemia 2003; 17: 68–75.