Idarubicin-Intensified BUCY2 Regimens May Lower Relapse Rate and Improve Survival in Patients Undergoing Allo-SCT for High-Risk

ORIGINAL ARTICLE Idarubicin-intensiﬁed BUCY2 regimens may lower relapse rate and improve survival in patients undergoing allo-SCT for high-risk hematological malignancies: a retrospective analysis

M Hong1,QWu1, C Hu, J Fang, Y You, Z Zhong, P Zou, Y Hu and L Xia

Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China

We conducted a retrospective study to evaluate the transplantation remains high, especially for the high-risk outcome of 94 consecutive patients with high-risk hema- disease states, the relapse rate can reach up to 23–50%.3–5 tological malignancies who received allo-PBSCT, follow- Different modified conditioning regimens, including intensive ing idarubicin (IDA)-intensified BUCY2 (IDA-BUCY2) chemotherapeutic blocks, using promising new agents before myeloablative conditioning regimens (n ¼ 53) and BUCY2 transplantation, have been explored to achieve and sustain conditioning regimens (n ¼ 41). IDA 15 mg/m2 once daily MRD negativity. Some nonrandomized studies on the use of was administered by continuous infusion on days À11 an intensified conditioning have reported better disease to À9, followed by BU, 3.2 mg/kg in divided doses daily, control for high-risk patients, but higher rates of toxicity on days À6toÀ4, and i.v. injection of CY, 1.8 g/m2 and TRM have also been reported.6–8 The search for alter- once daily on days À3toÀ2 in the IDA-BUCY2 group. native regimens to the standard BUCY2 aimed at reducing The relapse rate in patients in the IDA-BUCY2 and therelapserateandalsoTRMhasproventobedifficult.9–12 BUCY2-conditioning regimens group was 18.9 and 39%, Idarubicin (IDA, 4-demethoxydaunorubicin) was first respectively (P ¼ 0.030). There was no significant differ- introduced as a new anthracycline and now it has been ence in terms of TRM. The cumulative probabilities widely used to treat AML or relapsed/refractory ALL of OS and disease-free survival at 2 years for patients because it is more effective in multidrug-resistant cell lines conditioned with the IDA-BUCY2 and BUCY2 regimens and has relatively low cardiotoxicity, but a high penetration were 65.3% vs 46.8% (P ¼ 0.038), and 63.5% vs 43.4% rate to central nervous system, compared with DNR or (P ¼ 0.025), respectively. Multivariate analysis showed doxorubicin.13,14 Furthermore, IDA induced a response that IDA-BUCY2 regimens and limited chronic GVHD rate as high as 43% in patients with relapsed or refractory were the only two factors resulting in improved survival intermediate–high-grade non-Hodgkin’s lymphoma, with and reduced relapse rate. This retrospective study suggests more than 10 months median duration of response.15 that IDA-intensified BUCY2 may be substituted Recently, some studies have evaluated the efficacy and for BUCY2 as conditioning regimen for patients with toxicity of a combination of i.v. BU and continuous high-risk hematological malignancies. infusion IDA as a conditioning regimen for auto-SCT in Bone Marrow Transplantation (2012) 47, 196–202; patients with AML and a better outcome was found.16–19 doi:10.1038/bmt.2011.66; published online 28 March 2011 Therefore, we investigated combinations of BU with IDA Keywords: IDA-BUCY2; allo-SCT; high-risk leukemia instead of BUCY2 as a myeloablative conditioning regimen that may result in effective and well-tolerated myeloablative conditioning regimens. Here, we report the results obtained in our institute retrospectively by comparing standard vs Introduction IDA-intensified BUCY2 (IDA-BUCY2) myeloablative conditioning regimens in allo-PBSCT for high-risk hema- Allo-hematopoietic SCT (allo-HSCT) is the most effective tological malignancies over a period of several years. antileukemia treatment for hematological malignancies.1,2 The results suggest that the regimen with myeloablative BUCY2 regimen has long represented the classical IDA-BUCY2, which achieves low relapse rate and better conditioning regimens used worldwide to prepare patients survival without increasing the TRM, can be successfully to receive allo-HSCT. Nevertheless, the relapse rate after such utilized in high-risk patients.

Correspondence: Dr L Xia, Institute of Hematology, Union Hospital, Patients and methods Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China. Patients’ characteristics E-mail: [email protected] 1These authors contributed equally to this work Between August 2003 and December 2009, 94 consecutive Received 8 October 2010; revised 21 January 2011; accepted 13 February patients (n ¼ 53 and 41 for IDA-BUCY2 and BUCY2 2011; published online 28 March 2011 conditioning regimen groups, respectively) with high-risk Idarubicin-intensified BUCY2 for hematological malignancies M Hong et al 197 AML, ALL, hybrid acute leukemia, CML, non-Hodgkin’s needed to be above 20 Â 109/L without transfusion for lymphoma, or myelodysplastic syndrome had been treated 3 days. by allo-PBSCT at the Institute of Hematology (Union Hospital, Tongji Medical College, Huazhong University of Chimerism analyses Science and Technology, China). We defined high-risk Chimerism was typically evaluated in recipient BM cells hematological malignancies as follows: ALL, any patient usually on days þ 30, þ 180 and þ 360 after transplanta- with poor-risk cytogenetics (Ph, t(4;11), t(1;19)), age 435 tion. In sex-mismatched transplantation, we assessed years, WBC 430 000/ml at diagnosis, or failure to achieve heterosomes by FISH; in ABO-mismatched transplanta- CR after the first induction course;20 AML, delayed tion, we detected blood type by blood group examination. response to chemotherapy,21 unfavorable karyotype,22–24 Sex-matched donor–recipient chimerism was evaluated or a history of preceding neoplasia and/or chemother- using PCR-based analyses of polymorphic minisatellite or apy;25,26 myelodysplastic syndrome, a patient scoring 3 or microsatellite regions (variable number of tandem repeats more on the Spanish scoring system, and/or intermediate-1 (VNTRs)).29 HLA typing was performed for patients after on the International Prognostic Score System.27,28 Besides, mismatched transplantation.30 the high-risk patients contained accelerated phase or blastic phase of CML, progressive lymphoma, and hybrid acute leukemia. In all patients, left ventricular ejection fraction GVHD prophylaxis and management was evaluated before and after PBSCT and all showed a The acute GVHD (aGVHD) prophylaxis consisted of CsA value of 50% or more. orally or i.v. twice daily starting on the day À1 to maintain blood levels between 150 and 250 ng/mL until day þ 50. If no aGVHD occurred, CsA was tapered by 5% weekly HLA typing and discontinued on the day þ 180. MTX was adminis- All donor–recipient pairs were typed by using high- tered at 15 mg/m2 i.v. on the day þ 1 and 10 mg/m2 on days resolution DNA techniques for HLA-A, -B, -C, -DRB1 þ 3, þ 6 and þ 11. Mycophenolate mofetil (7.5 mg/kg, and -DQB1. Donor and recipient pairs were considered orally twice daily) and anti-CD25 MoAB (basiliximab, matched when identical at HLA-A, -B, -C, -DRB1 and 20 mg, on days 0 and þ 4) were given to patients unrelated -DQB1 loci. to their donors. aGVHD was graded according to Seattle criteria.31 Patients surviving more than 30 days were Conditioning regimen and supportive care included in the analysis of aGVHD. Chronic GVHD The conditioning regimen for IDA-BUCY2 group (n ¼ 53) (cGVHD) was defined according to standard criteria.32 consisted of three consecutive days i.v. injection of IDA A minimum of 100 days of follow-up was the criterion for (15 mg/m2 on days À11 to À9), followed by i.v. injection of cGVHD. aGVHD was treated with 1–2 mg/kg once daily of BU (3.2 mg/kg in divided doses daily, on days À6toÀ4) methylprednisolone and resumption of full-dose CsA and i.v. injection of CY (1.8 g/m2 once daily on days À3to administration. Second-line immunosuppressive therapy, À2). For the BUCY2 group (n ¼ 41), the conditioning such as tacrolimus (FK506), mycophenolate mofetil and regimen involved oral hydroxycarbamide (80 mg/kg on day CD25 MoAB or MTX were given for steroid refractory À9), i.v. injection of cytarabine (2 g/m2 on day À8), aGVHD. followed by i.v. injection of BU (3.2 mg/kg in divided doses daily, on days À7toÀ5), CY (1.8 g/m2 on days À4to Regimen-related toxicities À3) and oral Me-CCNU (250 mg/m2 on day À2). To Regimen-related toxicity was evaluated by common toxi- prevent seizures, phenytoin (100 mg) was administered city criteria, according to Bearman et al.33 Time of onset of orally three times daily beginning 24 h before the first dose grades III–IV toxicities was defined as occurring within of BU and continued until 24 h after the last dose. 40 days after HCT. Organ damage due to GVHD and/or Antimicrobial prophylaxis consisted of ganciclovir 5 mg/ infectious complications was excluded. kg twice daily from day À10 to À2, ciprofloxacin 500 mg twice daily and oral fluconazol from day À10 until engraftment. Patients received cotrimoxazole twice daily Statistical analysis from the time of neutrophil recovery to 6 months. Categorical variables between the two groups were compared by the w2 test or Fisher’s exact test and continuous variables by the Mann–Whitney U test. OS Collection of hematopoietic cells and disease-free survival (DFS) were calculated by the Donor PBSCs were collected using standard mobilization Kaplan–Meier method, and log-rank test was used to protocols. G-CSF (8–10 mg/kg once daily) was used to analyze the difference between the two groups.34 The Cox mobilize peripheral blood. The PBSCs were harvested on proportional hazards model35 was used in multivariate day 4 and 5 after G-CSF. The harvested cells were infused analyses for time-to-event outcomes (OS, DFS, relapse) without manipulation on the same day of leukapheresis using the same covariates as follows: recipient age, recipient collection. sex, diagnosis, donor/recipient relationship, donor/recipient HLA type and conditioning regimens. All P-values were Engraftment two sided and P value o0.05 was considered statistically Granulocyte engraftment was defined as ANC of 0.5 Â 109/ significant. Statistical analyses were performed with SPSS L or more for 3 consecutive days and the platelet count (SPSS Inc., Chicago, IL, USA).

Bone Marrow Transplantation Idarubicin-intensiﬁed BUCY2 for hematological malignancies M Hong et al 198 Results mild hepatic veno-occlusive disease and was cured by therapy. More frequent oropharyngeal mucositis occurred Patient demographics and characteristics in IDA-BUCY2 group than in BUCY2 group. Thirty-four The clinical and hematological characteristics of the two cases (64.2%) of mild-to-moderate oropharyngeal muco- groups are summarized in Table 1. The two groups were sitis were observed in the IDA-BUCY2 conditioning comparable with respect to age, sex, diagnosis, donor– regimen group vs 16 patients (39%) in the BUCY2 group recipient relationship and nucleated cell dose. There were (P ¼ 0.015). Nausea/vomiting was observed in 20 patients no signiﬁcant differences between the patients in the two (37.7%) in the IDA-BUCY2 group vs 14 patients (34.1%) groups. in the BUCY2 group (P ¼ 0.719). Fourteen patients (26.4%) in the IDA-BUCY2 group developed CMV infection vs 10 patients (24.4%) in the BUCY2 group Safety assessment and early regimen-related toxicity (P ¼ 0.823). CMV-associated interstitial pneumonia was The tolerance of IDA infusion was good, and IDA-related not noted in either group. Pneumonia with bacteria was side effects were moderate. One patient in the IDA-BUCY2 observed in 15 (28.3%) and 11(26.8%) from the IDA- conditioning regimen group developed severe hepatic BUCY2 and BUCY2 groups, respectively (P ¼ 0.874). veno-occlusive disease and died 34 days after PBSCT. One patient in the BUCY2 conditioning regimen group One patient in the BUCY2 group was observed to have developed severe pulmonary infection and died on day þ 36. Other patients did not develop acute grade III (life Table 1 The characteristics of 94 patients conditioned with IDA- threatening) or IV (fatal) regimen-related toxicity. Seven BUCY2 and BUCY2 patients in the IDA-BUCY2 group were observed to have grade I–II hemorrhagic cystitis within 100 days after IDA-BUCY2 BUCY2 P-value PBSCT vs four patients in the BUCY2 group (P ¼ 0.752). No. of patients 53 41 No other adverse hematological events occurred in either Median age (range) 27 (14–53) 29 (14–46) 0.957 group. Early regimen-related cardiovascular, renal or Sex, male/female 32/21 28/13 0.428 nervous complications were not observed.

Diagnosis 0.873 ALL 22 15 Hematopoietic recovery and hospitalization High WBC before 54 Hematopoietic recovery was observed in all patients as transplant expected. The median time of neutrophil recovery in the CNS leukemia 2 1 Ph+ 6 4 IDA-BUCY2 and BUCY2 conditioning regimens groups CR1 12 8 was 14 days (range: 9–21 days) and 14 days (range: 9–22 XCR2 4 3 days), respectively (P ¼ 0.669). Platelet recovery in both NR 6 4 groups occurred at median day 14 (range: 9–28 days) and AML 21 17 High WBC before 76 15 (range: 9–35 days), respectively (P ¼ 0.693). There was transplant no signiﬁcant difference with regard to the requirement for CNS leukemia 1 1 RBC transfusion in the two groups. The median length CR1 11 7 of hospitalization after PBSC infusion in laminar airﬂow XCR2 5 4 wards in the two groups was 18 (range: 9–29 days) and NR 5 6 HAL 2 2 20 (range: 11–36 days), respectively (P ¼ 0.223). Analysis of CML 2 3 chimerism indicated that all patients achieved full donor MDS 3 2 chimerism by day 30 after allo-PBSCT. NHL(IV) 3 2

Donor–recipient 0.864 aGVHD and cGVHD relationship The incidence of GVHD is shown in Table 2. Fifteen Related 34 27 patients (28.3%) in the IDA-BUCY2 group developed Unrelated 19 14

Donor–recipient HLA type Matched 38 28 0.720 Table 2 Comparison of acute and chronic GVHD between Mismatched 15 13 IDA-BUCY2 group and BUCY2 group

Donor–recipient ABO 0.628 IDA-BUCY2 BUCY2 P-value blood type Matched 31 26 Acute GVHD 0.273 Mismatched 22 15 0–I 38 (71.7%) 25 (61%) Nucleated cell dose ( Â 108/kg) 5.6 (3.6–26) 5.8 (3.3–10.02) 0.828 II–IV 15 (28.3%) 16 (39%) CD34+ cell dose ( Â 106/kg) 5.4 (3.2–12.8) 5.12 (2.8–13.8) 0.141 III–IV 6 (11.3%) 8 (19.5%) Median follow-up time, 376 (34–1230) 328 (36–1260) 0.151 days (range) Chronic GVHD 0.674 No 26 (51%) 16 (42.1%) Abbreviations: CNS ¼ central nervous system; CR1 ¼ the ﬁrst CR; Limit 17 (33.3%) 14 (36.8%) CR2 ¼ the second CR; HAL ¼ hybrid acute leukemia; IDA ¼ idarubicin; Extensive 8 (15.7%) 8 (21.1%) MDS ¼ myelodysplastic syndrome; NHL ¼ non-Hodgkin’s lymphoma; NR ¼ no response. Abbreviation: IDA ¼ idarubicin.

Bone Marrow Transplantation Idarubicin-intensified BUCY2 for hematological malignancies M Hong et al 199 grade II–IV aGVHD and six of them (11.3%) were grade 63.5% (95% CI, 47–79.6%) and 43.4% (95% CI, 26.7– III–IV. In the BUCY2 group, 16 (39%) patients developed 60%), respectively (P ¼ 0.025, Figure 1b). According to the grade II–IV aGVHD and 8 (19.5%) were grade III–IV. outcome, the probabilities of 2-year OS and DFS were Fifty-one patients in the IDA-BUCY2 group and 38 significantly higher in the IDA-BUCY2 conditioning regi- patients in BUCY2 group were evaluable for cGVHD. men group than the BUCY2 group. Seventeen patients (33.3%) developed limited cGVHD and eight patients (15.7%) developed extensive cGVHD in the Causes of death IDA-BUCY2 group compared with 14 patients (36.8%) The single major cause of death in both groups was primary and 8 patients (21.1%) in the BUCY2 group. There were no disease relapse. The TRM could be seen in six patients significant differences of aGVHD and cGVHD between the (11.3%) in the IDA-BUCY2 group as compared with five two groups (P 0.273 and P 0.674, respectively). ¼ ¼ patients (12.2%) in the BUCY2 group. GVHD was the second cause of death in four patients in the BUCY2 group and five patients in the IDA-BUCY2 group. Comparison of Patient outcome TRM between the two groups was not statistically The median follow-up durations after transplantation in significant. One patient in the IDA-BUCY2 group died of the IDA-BUCY2 and BUCY2 groups were 376 days hepatic veno-occlusive disease and was the only patient (range: 34–1230 days) and 328 days (range: 36–1260 days), whose death was caused by early transplantation organ respectively. In the IDA-BUCY2 group, 39 patients toxicity. Death resulting from early infections was only (73.6%) were alive compared with 22 patients (53.7%) in observed in one patient in BUCY2 group. the BUCY2 group (P ¼ 0.045). Relapse occurred in 10 patients (18.9%) at median 185 days after transplantation (range: 70–350 days) in the IDA-BUCY2 group. Eight Multivariate analysis patients died due to relapse, one underwent second As shown in Table 3, the patients who were prepared with transplantation followed by combination chemotherapy, IDA-intensified BUCY2 conditioning regimen and experi- the remaining one developed cGVHD when we began to enced limited cGVHD had a lower incidence of relapse and taper immunosuppression and later died due to extensive had a better OS and DFS. Grade II–IV aGVHD was cGVHD. In the BUCY2 group, relapse occurred in 16 associated with poorer survival, but had no significant patients (39%) at median 129 days (range: 63–300 days). Of effect on relapse. Other factors including age, sex, the type these, 14 patients died, 1 patient received combination of the disease, donor/recipient relationship and HLA type chemotherapy and the other received donor lymphocyte were found to be negatively associated with relapse, OS or infusion. These two patients were still alive at the end of DFS. follow up. Relapse rate was significantly lower in the IDA- BUCY2 group than the BUCY2 group (P ¼ 0.030). The median day for relapse after PBSCT was delayed in the Discussion IDA-BUCY2 group compared with the BUCY2 group (P ¼ 0.042). BUCY2 is considered the standard conditioning regimen in Kaplan–Meier survival estimates of OS and DFS were allo-SCT. Some pilot studies suggest that addition of IDA comparable for both groups, as shown in Figure 1. The to the standard conditioning regimens may improve OS probabilities of 2-year OS in the IDA-BUCY2 and the and DFS of patients with AML treated with ABMT.36–38 BUCY2 groups were 65.3% (95% CI, 49–81%) and 46.8% On the basis of these data, we conducted a retrospective (95% CI, 30–64%), respectively (P ¼ 0.038, Figure 1a). trial comparing IDA intensified BUCY2 conditioning The 2-year probabilities of DFS in the two groups were regimen with standard BUCY2 regimen in allo-SCT.

1.0 1.0

0.8 0.8 P = 0.038 P = 0.025 IDA-BuCy2 IDA-BuCy2 0.6 0.6 BuCy2 BuCy2 Survival Survival 0.4 0.4

0.2 0.2

0.0 0.0

0 250 500 750 1000 1250 0 250 500 750 1000 1250 Time (Days after SCT) Time (Days after SCT) Figure 1 Kaplan–Meier estimates of the cumulative probability of OS (a) and DFS (b) in 94 high-risk patients conditioned with IDA-BUCY2 (n ¼ 53) and BUCY2 (n ¼ 41) conditioning regimens.

Bone Marrow Transplantation Idarubicin-intensiﬁed BUCY2 for hematological malignancies M Hong et al 200 Table 3 Multivariate analysis for relapse, OS and DFS

Variable Relapse OS DFS

RR 95% CI P-value RR 95% CI P-value RR 95% CI P-value

Recipient age, years 435 vs p35 1.079 0.433–2.689 0.871 1.022 0.448–2.332 0.959 1.367 0.635–2.945 0.424 Recipient sex Female vs male 1.245 0.491–3.160 0.645 1.549 0.688–3.490 0.291 1.483 0.692–3.175 0.311 Diagnosis ALL 1 — — 1 — — 1 — — AML 1.598 0.651–3.921 0.306 0.918 0.413–2.040 0.833 1.025 0.482–2.178 0.949 CML 3.376 0.633–17.990 0.154 2.268 0.593–8.673 0.231 2.495 0.653–9.538 0.181 Other 0.164 0.020–1.379 0.096 0.380 0.097–1.492 0.166 0.542 0.162–1.812 0.320 Donor/recipient relationship Unrelated vs related 0.628 0.256–1.540 0.310 0.659 0.302–1.439 0.295 0.584 0.271–1.259 0.170 Donor/recipient HLA type Mismatched vs matched 0.914 0.349–2.396 0.855 1.076 0.463–2.500 0.865 0.857 0.376–1.956 0.714 Acute GVHD Grade I–IV vs Grade 0–I 2.134 0.822–5.540 0.120 2.488 1.096–5.650 0.029 2.916 1.353–6.286 0.006 Chronic GVHD No 1 — — 1 — — 1 — — Limited 0.179 0.056–0.573 0.004 0.141 0.044–0.447 0.001 0.155 0.054–0.446 0.001 Extensive 0.294 0.085–1.012 0.052 0.572 0.239–1.369 0.210 0.467 0.194–1.121 0.088 Conditioning regimens IDA-BUCY2 vs BUCY2 0.238 0.096–0.589 0.002 0.380 0.175–0.825 0.014 0.390 0.187–0.816 0.012

Abbreviations: CI ¼ condence interval; DFS ¼ disease-free survival; IDA ¼ idarubicin; RR ¼ Relative Risk.

Consistent with the results of the pilot study, the 2-year OS studies average 32% (median 31%, range 18–50%).40–41 and DFS rates herein observed for patients undergoing Only for patients with low disease burden at the time of transplantation for high-risk leukemia using the IDA- transplant, either in a CR or with low WBC and % blasts, BUCY2 regimen were better than those using the BUCY2 can OS and DFS at 2 years reach 61.5%.42 Compared regimen. The patients in the IDA-BUCY2 group had a to these studies, the effectiveness of IDA-intensified significantly lower incidence of relapse with similar conditioning regimen in our study achieved better outcome. incidence of TRM. Taken together, our data demonstrate HSCT has been recognized as an immunomodulatory that IDA-intensified BUCY2 regimens have the capacity to therapy rather than a rescue for BM toxicity induced by deliver long-term DFS with good tolerability in a propor- high-dose chemoradiotherapy.43 Clinically, a significant tion of patients with high-risk hematological malignancies GVL effect is induced by cGVHD rather than aGVHD, undergoing allo-HSCT from related or unrelated donors. which also means obvious GVL occurs in the late phase of Mengarelli et al.8 reported an intensified regimen of allo-SCT.44 Complete eradication of tumor in patients with BUCY combined with IDA 42 mg/m2 over 2 days, which high-risk hematological malignancies is much more difficult was associated with a significantly worse survival and to achieve than in low-risk patients. This results in more relapse rate. So, in our study, we adjusted the dosage of frequent and earlier relapse, which sometimes occurs IDA to 15 mg/m2 over 3 days and this intensified-IDA even before the start of the GVL effect. The objective of conditioning regimen did result in a better therapeutic myeloablative preparation before transplantation is to outcome. The probabilities of 2-year OS and DFS of 65.3% eradicate cancer, to induce the immunosuppression that and 63.5%, respectively, were achieved in the IDA-BUCY2 permits engraftment, and also to augment the antitumor group, thereby demonstrating a superior antileukemic immune response by causing a breakdown of tumor cells, efficacy of the protocol as compared with the BUCY2 which results in a flood of tumor Ags into APCs. This group in which the probabilities of 2-year OS and DFS of flooding can lead to the proliferation of T cells, which 46.8 and 43.4%, respectively, have been observed. Other attack the surviving malignant cells.45 Therefore, intensifi- than the IDA-intensified regimen, attempts were made to cation of standard myeloablative regimens may result in improve the efficacy of standard regimens by the addition better purification of BM and thus leave more time for the of other agents. A conditioning regimen of high-dose onset of GVL. This notion is supported by our data that etoposide, CY and TBI followed by allogeneic BMT was significantly less and delayed relapse was found in the IDA- administered to patients with resistant AML with 32% BUCY2 group than in the BUCY2 group. probability of DFS.39 Another study from Toubai with VP/ According to our results, the IDA-BUCY2 conditioning CY/TBI as a preconditioning regimen for non-CR acute regimen may be substituted for BUCY2 because it leukemia cases demonstrated 5-year DFS rates of 40.9%.9 improves efficacy and decrease relapse without increasing The feasibility and effectiveness of reduced-intensity con- transplant-adverse effects. However, our analysis has ditioning were also assessed for aged high-risk ALL, AML limitations because of its retrospective-nature and small and myelodysplasia patients. The 2-year OS rates for these sample size. The privilege of this intensified regimen should

Bone Marrow Transplantation Idarubicin-intensified BUCY2 for hematological malignancies M Hong et al 201 be further confirmed on a larger number of patients and 11 Shigematsu A, Kondo T, Yamamoto S, Sugita J, Onozawa M, with a longer follow-up duration, and a prospective study is Kahata K et al. Excellent outcome of allogeneic hematopoietic also needed. stem cell transplantation using a conditioning regimen with medium-dose VP-16, cyclophosphamide and total-body irradiation for adult patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2008; 14: 568–575. Conflict of interest 12 Zohren F, Czibere A, Bruns I, Fenk R, Schroeder T, Graf T et al. Fludarabine, amsacrine, high-dose cytarabine and 12 Gy The authors declare no conflict of interest. total body irradiation followed by allogeneic hematopoietic stem cell transplantation is effective in patients with relapsed or high-risk acute lymphoblastic leukemia. Bone Marrow Transplant 2009; 44: 785–792. References 13 Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G et al. Daunorubicin versus mitoxantrone versus idarubicin 1 Zittoun RA, Mandelli F, Willemze R, De Witte T, Labar B, as induction and consolidation chemotherapy for Resegotti L et al. Autologous or allogeneic bone marrow adults with acute myeloid leukemia: the EORTC and transplantation compared with intensive chemotherapy in GIMEMA Groups Study AML-10. J Clin Oncol 2009; 27: acute myelogenous leukemia: European Organization for 5397–5403. Research and Treatment of Cancer (EORTC) and the Gruppo 14 Reid JM, Pendergrass TW, Krailo MD, Hammond GD, Italiano Malattie Ematologiche Malignedell’Adulto (GIME- Ames MM. Plasma pharmacokinetics and cerebrospinal fluid MA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: concentrations of idarubicin and idarubicinol in pediatric 217–223. leukemia patients: a Children’s Cancer Study Group report. 2 Appelbaum FR. Haematopoietic cell transplantation as Cancer Res 1990; 50: 6525–6528. immunotherapy. Nature 2001; 411: 385–389. 15 Case DC, Gerber MC, Gams RA, Crawford J, Votaw ML, 3 Lee KH, Lee JH, Choi SJ, Lee JH, Kim S, Seol M et al. Higano CS et al. Phase II study of intravenous idarubicin Bone marrow vs extramedullary relapse of acute leukemia in unfavourable non-Hodgkin’s lymphoma. Leuk Lymphoma after allogeneic hematopoietic cell transplantation: risk factors 1993; 10: 73–79. and clinical course. Bone Marrow Transplant 2003; 32: 16 Ferrara F, Palmieri S, Annunziata M, Viola A, Pocali B, 835–842. Califano C et al. Continuous infusion idarubicin and oral 4 Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, busulfan as conditioning for patients with acute myeloid Kolb HJ et al. Comparative outcome of reduced intensity and leukemia aged over 60 years undergoing autologous stem myeloablative conditioning regimen in HLA identical sibling cell transplantation. Bone Marrow Transplant 2004; 34: allogeneic haematopoietic stem cell transplantation for pa- 573–576. tients older than 50 years of age with acute myeloblastic 17 Ferrara F, Palmieri S, De Simone M, Sagristani M, Viola A, leukaemia: a retrospective survey from the Acute Leukemia Pocali B et al. High-dose idarubicin and busulphan as Working Party (ALWP) of the European group for Blood conditioning to autologous stem cell transplantation in adult and Marrow Transplantation (EBMT). Leukemia 2005; 19: patients with acute myeloid leukaemia. Br J Haematol 2005; 2304–2312. 128: 234–241. 5 Valca´rcel D, Martino R, Caballero D, Martin J, Ferra C, 18 Ferrara F, Palmieri S, Pedata M, Viola A, Izzo T, Criscuolo C Nieto JB et al. Sustained remissions of high-risk acute myeloid et al. Autologous stem cell transplantation for elderly patients leukemia and myelodysplastic syndrome after reduced-inten- with acute myeloid leukaemia conditioned with continuous sity conditioning allogeneic hematopoietic transplantation: infusion idarubicin and busulphan. Hematol Oncol 2009; 27: chronic graft-versus-host disease is the strongest factor 40–45. improving survival. J Clin Oncol 2008; 26: 577–584. 19 Ferrara F, Mele G, Palmieri S, Pedata M, Copia C, Riccardi C 6 Beelen DW, Trenschel R, Casper J, Freund M, Hilger RA, et al. Continuous infusion idarubicin and intravenous Scheulen ME et al. Dose-escalated treosulphan in combination busulphan as conditioning regimen to autologous stem cell with cyclophosphamide as a new preparative regimen for transplantation for patients with acute myeloid leukaemia. allogeneic haematopoietic stem cell transplantation in patients Hematol Oncol 2009; 27: 198–202. with an increased risk for regimen-related complications. 20 Hunault M, Harousseau JL, Delain M, Truchan-Graczyk M, Bone Marrow Transplant 2005; 35: 233–241. Cahn JY, Witz F et al. Better outcome of adult acute 7 Aschan J. Risk assessment in haematopoietic stem cell lymphoblastic leukemia after early genoidentical allogeneic transplantation: conditioning. Best Pract Res Clin Haematol bone marrow transplantation (BMT) than after late high-dose 2007; 20: 295–310. therapy and autologous BMT : a GOEL-AMS trial. Blood 8 Mengarelli A, Iori AP, Guglielmi C, Romano A, Cerretti R, 2004; 104: 3028–3037. Torromeo C et al. Standard versus alternative myeloablative 21 Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, conditioning regimens in allogeneic hematopoietic stem cell Heinecke A et al. Early blast clearance by remission induction transplantation for high-risk acute leukemia. Haematologica chemotherapy is a major independent prognostic factor for 2002; 87: 52–58. both achievement of complete remission and long-term 9 Toubai T, Tanaka J, Mori A, Hashino S, Kobayashi S, Ota S outcome in acute myeloid leukemia:data from the German et al. Efficacy of etoposide, cyclophosphamide, and total AML cooperative group (AMLCG) 1992 trial. Blood 2003; body irradiation in allogeneic bone marrow transplantation for 101: 64–70. adult patients with hematological malignancies. Clin Trans- 22 Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, plant 2004; 18: 552–557. Harrison G et al. The importance of diagnostic cytogenetics on 10 Mengarelli A, Iori AP, Guglielmi C, Perrone MP, Gozzer M outcome in AML:Analysis of 1,612 patients entered into the et al. Idarubicin intensified BUCY2 regimen in allogeneic MRCAML10 trial—The Medical Research Council Adult unmanipulated transplant for high-risk hematological malig- and Children’s Leukaemia Working Parties. Blood 1998; 92: nancies. Leukemia 2000; 14: 2052–2058. 2322–2333.

Bone Marrow Transplantation Idarubicin-intensified BUCY2 for hematological malignancies M Hong et al 202 23 Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil 35 Cox DR. Regression models and life-tables. JR Stat Soc 1972; KS, Mohamed A et al. Karyotypic analysis predicts outcome 34: 187–189. of preremission and postremission therapy in adult acute 36 Ferrara F, Palmieri S, De Simone M, Sagristani M, Viola A, myeloid leukemia: a South west Oncology Group/Eastern Pocali B et al. High-dose idarubicin and busulphan as Cooperative Oncology Group Study. Blood 2000; 96: conditioning to autologous stem cell transplantation in adult 4075–4083. patients with acute myeloid leukaemia. Br J Haematol 2005; 24 Schoch C, Haferlach T, Haase D, Fonatsch C, Lo¨ffler H, 128: 234–241. Schlegelberger B et al. Patients with denovo acute myeloid 37 Ferrara F, Annunziata M, Schiavone EM, Copia C, De leukaemia and complex karyotype aberrations show a poor Simone M, Pollio F et al. High-dose idarubicin and busulphan prognosis despite intensive treatment: a study of 90 patients. as conditioning for autologous stem cell transplantation in Br J Haematol 2001; 112: 118–126. acute myeloid leukemia: a feasibility study. Hematol J 2001; 2: 25 Appelbaum FR. Who should be transplanted for AML. 214–219. Leukemia 2001; 15: 680–682. 38 Jerjis S, Roovers E, Muus P, Schaap N, De Witte T. Idarubicin 26 Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. to intensify the conditioning regimens of autologous bone Karyotype is an independent prognostic parameter in therapy- marrow transplantation for patients with acute myeloid related acute myeloid leukemia (t-AML): An analysis of 93 leukemia in first complete remission. Bone Marrow Transplant patients with t-AML in comparison to 1092 patients with 1998; 22: 13–19. de novo AML. Leukemia 2004; 18: 120–125. 39 Brown RA, Wolff SN, Fay JW, Pineiro L, Collins Jr RH, 27 Sanz GF, Sanz MA, Vallespi T, Canizo MC, Torrabadella M, Lynch JP et al. High-dose etoposide, cyclophosphamide and Garcia S et al. Two regression models and a scoring system for total body irradiation with allogeneic bone marrow transplant- predicting survival and planning treatment in myelodysplastic ation for resistant acute myeloid leukemia: a study by the syndrome: a multivariate analysis of prognostic factors in 370 North American Marrow Transplant Group. Leuk Lymphoma patients. Blood 1989; 74: 395–408. 1996; 22: 271–277. 28 Greenberg P, Cox C, Le Beau MM, Fenaux P, Morel P, 40 Hamaki T, Kami M, Kanda Y, Yuji K, Inamoto Y, Kishi Y Sanz G et al. International scoring system for evaluating et al. Reduced-intensity stem-cell transplantation for adult prognosis in myelodysplastic syndromes. Blood 1997; 89: acute lymphoblastic leukemia: a retrospective study of 33 2079–2088. patients. Bone Marrow Transplant 2005; 35: 549–556. 29 Thiede C, Florek M, Bornhaüser M, Ritter M, Mohr B, 41 Mohty M, Labopin M, Volin L, Gratwohl A, Socie´G, Esteve J Brendel C et al. Rapid quantication of mixed chimerism using et al. Reduced intensity conditioning allogeneic stem cell multiplex amplification of short tandem repeat markers transplantation for adult patients with acute lymphoblastic and uorescence detection. Bone Marrow Transplant 1999; 23: leukemia: a retrospective study from the European Group 1055–1060. for Blood and Marrow Transplantation. Haematologica 2008; 30 Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W et al. 93: 303–306. Conditioning including antithymocyte globulin followed by 42 Stein AS, Palmer JM, O’Donnell MR, Kogut NM, Spielberger unmanipulated HLA-mismatched/hapl oidentical blood and RT, Slovak ML et al. Reduced-intensity conditioning followed marrow transplantation can achieve comparable outcomes by peripheral blood stem cell transplantation for adult patients with HLA-identical sibling transplantation. Blood 2006; 107: with high-risk acute lymphoblastic leukemia. Biol Blood 3065–3073. Marrow Transplant 2009; 15: 1407–1414. 31 Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty 43 Aschan J. Allogeneic haematopoietic stem cell transplantation: P, Hows J et al. 1994 consensus conference on acute GVHD current status and future outlook. Br Med Bull 2006; 77–78: grading. Bone Marrow Transplant 1995; 15: 825–828. 23–36. 32 Sullivan KM. Graft-versus-host disease. In: Thomas ED, 44 Lee S, Cho BS, Kim SY, Choi SM, Lee DG, Eom KS et al. Blume KG, Forman SJ (eds). Hematopoietic Cell Transplanta- Allogeneic stem cell transplantation in first complete remission tion. Blackwell Scientific: London, Oxford, 1999, pp 515–536. enhances graft-versus-leukemia effect in adults with acute 33 Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, lymphoblastic leukemia: antileukemic activity of chronic Fisher LD, Clift RA et al. Regimen-related toxicity in patients graft-versus-host disease. Biol Blood Marrow Transplant undergoing bone marrow transplantation. J Clin Oncol 1988; 2007; 13: 1083–1094. 6: 1562–1568. 45 Lake RA, Robinson BW. Immunotherapy and chemo- 34 Kaplan EL, Meier P. Non parametric estimation from therapy—a practical partnership. Nat Rev Cancer 2005; 5: incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 397–405.

Bone Marrow Transplantation