We conducted a retrospective study to evaluate the outcome of 94 consecutive patients with high-risk hematological malignancies who received allo-PBSCT, following idarubicin (IDA)-intensified BUCY2 (IDA-BUCY2) myeloablative conditioning regimens (n=53) and BUCY2 conditioning regimens (n=41). IDA 15 mg/m2 once daily was administered by continuous infusion on days −11 to −9, followed by BU, 3.2 mg/kg in divided doses daily, on days −6 to −4, and i.v. injection of CY, 1.8 g/m2 once daily on days −3 to −2 in the IDA-BUCY2 group. The relapse rate in patients in the IDA-BUCY2 and BUCY2-conditioning regimens group was 18.9 and 39%, respectively (P=0.030). There was no significant difference in terms of TRM. The cumulative probabilities of OS and disease-free survival at 2 years for patients conditioned with the IDA-BUCY2 and BUCY2 regimens were 65.3% vs 46.8% (P=0.038), and 63.5% vs 43.4% (P=0.025), respectively. Multivariate analysis showed that IDA-BUCY2 regimens and limited chronic GVHD were the only two factors resulting in improved survival and reduced relapse rate. This retrospective study suggests that IDA-intensified BUCY2 may be substituted for BUCY2 as conditioning regimen for patients with high-risk hematological malignancies.
Allo-hematopoietic SCT (allo-HSCT) is the most effective antileukemia treatment for hematological malignancies.1, 2 BUCY2 regimen has long represented the classical conditioning regimens used worldwide to prepare patients to receive allo-HSCT. Nevertheless, the relapse rate after such transplantation remains high, especially for the high-risk disease states, the relapse rate can reach up to 23–50%.3, 4, 5 Different modified conditioning regimens, including intensive chemotherapeutic blocks, using promising new agents before transplantation, have been explored to achieve and sustain MRD negativity. Some nonrandomized studies on the use of an intensified conditioning have reported better disease control for high-risk patients, but higher rates of toxicity and TRM have also been reported.6, 7, 8 The search for alternative regimens to the standard BUCY2 aimed at reducing the relapse rate and also TRM has proven to be difficult.9, 10, 11, 12
Idarubicin (IDA, 4-demethoxydaunorubicin) was first introduced as a new anthracycline and now it has been widely used to treat AML or relapsed/refractory ALL because it is more effective in multidrug-resistant cell lines and has relatively low cardiotoxicity, but a high penetration rate to central nervous system, compared with DNR or doxorubicin.13, 14 Furthermore, IDA induced a response rate as high as 43% in patients with relapsed or refractory intermediate–high-grade non-Hodgkin's lymphoma, with more than 10 months median duration of response.15 Recently, some studies have evaluated the efficacy and toxicity of a combination of i.v. BU and continuous infusion IDA as a conditioning regimen for auto-SCT in patients with AML and a better outcome was found.16, 17, 18, 19 Therefore, we investigated combinations of BU with IDA 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 IDA-intensified BUCY2 (IDA-BUCY2) myeloablative conditioning regimens in allo-PBSCT for high-risk hematological malignancies over a period of several years. The results suggest that the regimen with myeloablative IDA-BUCY2, which achieves low relapse rate and better survival without increasing the TRM, can be successfully utilized in high-risk patients.
Patients and methods
Between August 2003 and December 2009, 94 consecutive patients (n=53 and 41 for IDA-BUCY2 and BUCY2 conditioning regimen groups, respectively) with high-risk AML, ALL, hybrid acute leukemia, CML, non-Hodgkin's lymphoma, or myelodysplastic syndrome had been treated by allo-PBSCT at the Institute of Hematology (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China). We defined high-risk hematological malignancies as follows: ALL, any patient with poor-risk cytogenetics (Ph, t(4;11), t(1;19)), age >35 years, WBC >30 000/μl at diagnosis, or failure to achieve CR after the first induction course;20 AML, delayed response to chemotherapy,21 unfavorable karyotype,22, 23, 24 or a history of preceding neoplasia and/or chemotherapy;25, 26 myelodysplastic syndrome, a patient scoring 3 or more on the Spanish scoring system, and/or intermediate-1 on the International Prognostic Score System.27, 28 Besides, 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 was evaluated before and after PBSCT and all showed a value of 50% or more.
All donor–recipient pairs were typed by using high-resolution DNA techniques for HLA-A, -B, -C, -DRB1 and -DQB1. Donor and recipient pairs were considered matched when identical at HLA-A, -B, -C, -DRB1 and -DQB1 loci.
Conditioning regimen and supportive care
The conditioning regimen for IDA-BUCY2 group (n=53) consisted of three consecutive days i.v. injection of IDA (15 mg/m2 on days −11 to −9), followed by i.v. injection of BU (3.2 mg/kg in divided doses daily, on days −6 to −4) and i.v. injection of CY (1.8 g/m2 once daily on days −3 to −2). For the BUCY2 group (n=41), the conditioning regimen involved oral hydroxycarbamide (80 mg/kg on day −9), i.v. injection of cytarabine (2 g/m2 on day −8), followed by i.v. injection of BU (3.2 mg/kg in divided doses daily, on days −7 to −5), CY (1.8 g/m2 on days −4 to −3) and oral Me-CCNU (250 mg/m2 on day −2). To prevent seizures, phenytoin (100 mg) was administered orally three times daily beginning 24 h before the first dose of BU and continued until 24 h after the last dose. Antimicrobial prophylaxis consisted of ganciclovir 5 mg/kg twice daily from day −10 to −2, ciprofloxacin 500 mg twice daily and oral fluconazol from day −10 until engraftment. Patients received cotrimoxazole twice daily from the time of neutrophil recovery to 6 months.
Collection of hematopoietic cells
Donor PBSCs were collected using standard mobilization protocols. G-CSF (8–10 μg/kg once daily) was used to mobilize peripheral blood. The PBSCs were harvested on day 4 and 5 after G-CSF. The harvested cells were infused without manipulation on the same day of leukapheresis collection.
Granulocyte engraftment was defined as ANC of 0.5 × 109/L or more for 3 consecutive days and the platelet count needed to be above 20 × 109/L without transfusion for 3 days.
Chimerism was typically evaluated in recipient BM cells usually on days +30, +180 and +360 after transplantation. In sex-mismatched transplantation, we assessed heterosomes by FISH; in ABO-mismatched transplantation, we detected blood type by blood group examination. Sex-matched donor–recipient chimerism was evaluated using PCR-based analyses of polymorphic minisatellite or microsatellite regions (variable number of tandem repeats (VNTRs)).29 HLA typing was performed for patients after mismatched transplantation.30
GVHD prophylaxis and management
The acute GVHD (aGVHD) prophylaxis consisted of CsA orally or i.v. twice daily starting on the day −1 to maintain blood levels between 150 and 250 ng/mL until day +50. If no aGVHD occurred, CsA was tapered by 5% weekly and discontinued on the day +180. MTX was administered at 15 mg/m2 i.v. on the day +1 and 10 mg/m2 on days +3, +6 and +11. Mycophenolate mofetil (7.5 mg/kg, orally twice daily) and anti-CD25 MoAB (basiliximab, 20 mg, on days 0 and +4) were given to patients unrelated to their donors. aGVHD was graded according to Seattle criteria.31 Patients surviving more than 30 days were included in the analysis of aGVHD. Chronic GVHD (cGVHD) was defined according to standard criteria.32 A minimum of 100 days of follow-up was the criterion for cGVHD. aGVHD was treated with 1–2 mg/kg once daily of methylprednisolone and resumption of full-dose CsA administration. Second-line immunosuppressive therapy, such as tacrolimus (FK506), mycophenolate mofetil and CD25 MoAB or MTX were given for steroid refractory aGVHD.
Regimen-related toxicity was evaluated by common toxicity criteria, according to Bearman et al.33 Time of onset of grades III–IV toxicities was defined as occurring within 40 days after HCT. Organ damage due to GVHD and/or infectious complications was excluded.
Categorical variables between the two groups were compared by the χ2 test or Fisher's exact test and continuous variables by the Mann–Whitney U test. OS and disease-free survival (DFS) were calculated by the Kaplan–Meier method, and log-rank test was used to analyze the difference between the two groups.34 The Cox proportional hazards model35 was used in multivariate analyses for time-to-event outcomes (OS, DFS, relapse) using the same covariates as follows: recipient age, recipient sex, diagnosis, donor/recipient relationship, donor/recipient HLA type and conditioning regimens. All P-values were two sided and P value <0.05 was considered statistically significant. Statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL, USA).
Patient demographics and characteristics
The clinical and hematological characteristics of the two groups are summarized in Table 1. The two groups were comparable with respect to age, sex, diagnosis, donor–recipient relationship and nucleated cell dose. There were no significant differences between the patients in the two groups.
Safety assessment and early regimen-related toxicity
The tolerance of IDA infusion was good, and IDA-related side effects were moderate. One patient in the IDA-BUCY2 conditioning regimen group developed severe hepatic veno-occlusive disease and died 34 days after PBSCT. One patient in the BUCY2 group was observed to have mild hepatic veno-occlusive disease and was cured by therapy. More frequent oropharyngeal mucositis occurred in IDA-BUCY2 group than in BUCY2 group. Thirty-four cases (64.2%) of mild-to-moderate oropharyngeal mucositis were observed in the IDA-BUCY2 conditioning regimen group vs 16 patients (39%) in the BUCY2 group (P=0.015). Nausea/vomiting was observed in 20 patients (37.7%) in the IDA-BUCY2 group vs 14 patients (34.1%) in the BUCY2 group (P=0.719). Fourteen patients (26.4%) in the IDA-BUCY2 group developed CMV infection vs 10 patients (24.4%) in the BUCY2 group (P=0.823). CMV-associated interstitial pneumonia was not noted in either group. Pneumonia with bacteria was observed in 15 (28.3%) and 11(26.8%) from the IDA-BUCY2 and BUCY2 groups, respectively (P=0.874). One patient in the BUCY2 conditioning regimen group developed severe pulmonary infection and died on day +36. Other patients did not develop acute grade III (life threatening) or IV (fatal) regimen-related toxicity. Seven patients in the IDA-BUCY2 group were observed to have grade I–II hemorrhagic cystitis within 100 days after PBSCT vs four patients in the BUCY2 group (P=0.752). No other adverse hematological events occurred in either group. Early regimen-related cardiovascular, renal or nervous complications were not observed.
Hematopoietic recovery and hospitalization
Hematopoietic recovery was observed in all patients as expected. The median time of neutrophil recovery in the IDA-BUCY2 and BUCY2 conditioning regimens groups was 14 days (range: 9–21 days) and 14 days (range: 9–22 days), respectively (P=0.669). Platelet recovery in both groups occurred at median day 14 (range: 9–28 days) and 15 (range: 9–35 days), respectively (P=0.693). There was no significant difference with regard to the requirement for RBC transfusion in the two groups. The median length of hospitalization after PBSC infusion in laminar airflow wards in the two groups was 18 (range: 9–29 days) and 20 (range: 11–36 days), respectively (P=0.223). Analysis of chimerism indicated that all patients achieved full donor chimerism by day 30 after allo-PBSCT.
aGVHD and cGVHD
The incidence of GVHD is shown in Table 2. Fifteen patients (28.3%) in the IDA-BUCY2 group developed grade II–IV aGVHD and six of them (11.3%) were grade III–IV. In the BUCY2 group, 16 (39%) patients developed grade II–IV aGVHD and 8 (19.5%) were grade III–IV. Fifty-one patients in the IDA-BUCY2 group and 38 patients in BUCY2 group were evaluable for cGVHD. Seventeen patients (33.3%) developed limited cGVHD and eight patients (15.7%) developed extensive cGVHD in the IDA-BUCY2 group compared with 14 patients (36.8%) and 8 patients (21.1%) in the BUCY2 group. There were no significant differences of aGVHD and cGVHD between the two groups (P=0.273 and P=0.674, respectively).
The median follow-up durations after transplantation in the IDA-BUCY2 and BUCY2 groups were 376 days (range: 34–1230 days) and 328 days (range: 36–1260 days), respectively. In the IDA-BUCY2 group, 39 patients (73.6%) were alive compared with 22 patients (53.7%) in the BUCY2 group (P=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 patients died due to relapse, one underwent second transplantation followed by combination chemotherapy, the remaining one developed cGVHD when we began to taper immunosuppression and later died due to extensive cGVHD. In the BUCY2 group, relapse occurred in 16 patients (39%) at median 129 days (range: 63–300 days). Of these, 14 patients died, 1 patient received combination chemotherapy and the other received donor lymphocyte infusion. These two patients were still alive at the end of follow up. Relapse rate was significantly lower in the IDA-BUCY2 group than the BUCY2 group (P=0.030). The median day for relapse after PBSCT was delayed in the IDA-BUCY2 group compared with the BUCY2 group (P=0.042).
Kaplan–Meier survival estimates of OS and DFS were comparable for both groups, as shown in Figure 1. The probabilities of 2-year OS in the IDA-BUCY2 and the BUCY2 groups were 65.3% (95% CI, 49–81%) and 46.8% (95% CI, 30–64%), respectively (P=0.038, Figure 1a). The 2-year probabilities of DFS in the two groups were 63.5% (95% CI, 47–79.6%) and 43.4% (95% CI, 26.7–60%), respectively (P=0.025, Figure 1b). According to the outcome, the probabilities of 2-year OS and DFS were significantly higher in the IDA-BUCY2 conditioning regimen group than the BUCY2 group.
Causes of death
The single major cause of death in both groups was primary disease relapse. The TRM could be seen in six patients (11.3%) in the IDA-BUCY2 group as compared with five 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 TRM between the two groups was not statistically significant. One patient in the IDA-BUCY2 group died of hepatic veno-occlusive disease and was the only patient whose death was caused by early transplantation organ toxicity. Death resulting from early infections was only observed in one patient in BUCY2 group.
As shown in Table 3, the patients who were prepared with IDA-intensified BUCY2 conditioning regimen and experienced limited cGVHD had a lower incidence of relapse and had a better OS and DFS. Grade II–IV aGVHD was associated with poorer survival, but had no significant effect on relapse. Other factors including age, sex, the type of the disease, donor/recipient relationship and HLA type were found to be negatively associated with relapse, OS or DFS.
BUCY2 is considered the standard conditioning regimen in allo-SCT. Some pilot studies suggest that addition of IDA to the standard conditioning regimens may improve OS and DFS of patients with AML treated with ABMT.36, 37, 38 On the basis of these data, we conducted a retrospective trial comparing IDA intensified BUCY2 conditioning regimen with standard BUCY2 regimen in allo-SCT. Consistent with the results of the pilot study, the 2-year OS and DFS rates herein observed for patients undergoing transplantation for high-risk leukemia using the IDA-BUCY2 regimen were better than those using the BUCY2 regimen. The patients in the IDA-BUCY2 group had a significantly lower incidence of relapse with similar incidence of TRM. Taken together, our data demonstrate that IDA-intensified BUCY2 regimens have the capacity to deliver long-term DFS with good tolerability in a proportion of patients with high-risk hematological malignancies undergoing allo-HSCT from related or unrelated donors.
Mengarelli et al.8 reported an intensified regimen of BUCY combined with IDA 42 mg/m2 over 2 days, which was associated with a significantly worse survival and relapse rate. So, in our study, we adjusted the dosage of IDA to 15 mg/m2 over 3 days and this intensified-IDA conditioning regimen did result in a better therapeutic outcome. The probabilities of 2-year OS and DFS of 65.3% and 63.5%, respectively, were achieved in the IDA-BUCY2 group, thereby demonstrating a superior antileukemic efficacy of the protocol as compared with the BUCY2 group in which the probabilities of 2-year OS and DFS of 46.8 and 43.4%, respectively, have been observed. Other than the IDA-intensified regimen, attempts were made to improve the efficacy of standard regimens by the addition of other agents. A conditioning regimen of high-dose etoposide, CY and TBI followed by allogeneic BMT was administered to patients with resistant AML with 32% probability of DFS.39 Another study from Toubai with VP/CY/TBI as a preconditioning regimen for non-CR acute leukemia cases demonstrated 5-year DFS rates of 40.9%.9 The feasibility and effectiveness of reduced-intensity conditioning were also assessed for aged high-risk ALL, AML and myelodysplasia patients. The 2-year OS rates for these studies average 32% (median 31%, range 18–50%).40, 41 Only for patients with low disease burden at the time of transplant, either in a CR or with low WBC and % blasts, can OS and DFS at 2 years reach 61.5%.42 Compared to these studies, the effectiveness of IDA-intensified conditioning regimen in our study achieved better outcome.
HSCT has been recognized as an immunomodulatory therapy rather than a rescue for BM toxicity induced by high-dose chemoradiotherapy.43 Clinically, a significant GVL effect is induced by cGVHD rather than aGVHD, which also means obvious GVL occurs in the late phase of allo-SCT.44 Complete eradication of tumor in patients with high-risk hematological malignancies is much more difficult to achieve than in low-risk patients. This results in more frequent and earlier relapse, which sometimes occurs even before the start of the GVL effect. The objective of myeloablative preparation before transplantation is to eradicate cancer, to induce the immunosuppression that permits engraftment, and also to augment the antitumor immune response by causing a breakdown of tumor cells, which results in a flood of tumor Ags into APCs. This flooding can lead to the proliferation of T cells, which attack the surviving malignant cells.45 Therefore, intensification of standard myeloablative regimens may result in better purification of BM and thus leave more time for the onset of GVL. This notion is supported by our data that significantly less and delayed relapse was found in the IDA-BUCY2 group than in the BUCY2 group.
According to our results, the IDA-BUCY2 conditioning regimen may be substituted for BUCY2 because it improves efficacy and decrease relapse without increasing transplant-adverse effects. However, our analysis has limitations because of its retrospective-nature and small sample size. The privilege of this intensified regimen should be further confirmed on a larger number of patients and with a longer follow-up duration, and a prospective study is also needed.
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The authors declare no conflict of interest.
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