Autografting

An auto-SCT-based total therapy resulted in encouraging outcomes in adolescents and young adults with acute lymphoblastic leukemia: report from a single center of China

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Abstract

Application of auto-SCT in the post-remission therapy for adolescents and young adults (AYAs) with ALL is controversial. We analyzed the outcomes of 79 AYAs (15–24 years) with ALL who received our designed total therapy protocol with auto-SCT in first CR from 1990 to 2009. The estimated OS and EFS at 5 years for the cohort were 62.8±5.9 and 61.5±5.7%. The cumulative non-relapse mortality and relapse rate at 5 years for the cohort were 7.2±3.1 and 33.6±5.8%. Time to CR >4 weeks was the only independent unfavorable factor associated with OS, EFS and relapse in multivariate analysis. Patients in standard risk (SR) group and high risk (HR) group had better OS (78.3±7.4, 63.8±10.2 vs 38.1±11.6%) and EFS (78.0±7.4, 63.4±9.4 vs 32.4±11.3%), and lower relapse rate (15.9±6.5, 31.5±9.5 vs 65.7±11.8%) compared with patients in very high risk (VHR) group. Our data confirmed that auto-SCT-based total therapy might be an optional treatment strategy for AYAs with ALL in SR. Patients in HR also could get benefit from such schedule. But for those in VHR, allogenetic SCT is still the prior recommendation for the frequent recurrence after auto-SCT.

Introduction

ALL has a bimodal age distribution, with the main peak in children between age 2–5 years and another peak in adults aged 40 years.1 With current treatment regimens, the most favorable outcome is achieved in children aged 1–9 years, in which the 5-year EFS is in an excess of 80%.2 The long-term survival decreases to approximately 50–60% in adolescents aged 15–18 years-old and decreases further to 40% in adults.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Older adolescents and young adults (AYAs) with ALL defined as a special subgroup displays intermediate disease biological features and intermediate outcomes, which have caught attention of both pediatric and adult hematologists. Some retrospective studies suggested that AYAs benefit from pediatric ALL protocol rather than adult regimen,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 which inspired hematologists to prospectively test pediatric protocol in adult patients up to the age of 50 years.16, 17 These results need long-term follow-up to confirm, and a debate of more toxicity from pediatric-based approach may counterbalance its value.

Retrospective studies in the early 1990s revealed encouraging results that ALL patients could get benefits from auto-SCT applied in first CR (CR1). The 3-year disease-free survival (DFS) achieved about 40–60%.18, 19 However, many patients involved in these studies were children. Most large series prospective trials demonstrated that auto-SCT had no better efficacy or even inferior outcome compared with conventional chemotherapy for adult patients.5, 7, 8, 9, 11 But an updated results from the French LALA group revealed that with a 10-year follow-up, auto-SCT was associated with a lower incidence of relapse than conventional chemotherapy arm indicating its benefit value.12 In ECOG 2993/UK MRC ALL XII study, adults ALL with minimal residual disease (MRD) 10−4 before auto-SCT achieved an improved survival with a 77% of 5-year relapse-free survival.20 Up to date, auto-SCT as a post-remission alternative for adult patients with ALL is still controversial.

There were very limited data concerning auto-SCT for AYAs with ALL. From the beginning of 1990s, we designed an auto-SCT-based complete therapeutic schedule for AYAs with ALL. Our total therapy strategy is using effective induction regimen to yield a high remission rate, followed by early intensive consolidation to further improve the quality of remission and to get ‘in vivo purging’ before stem cell collection. Then the patients received superintensive myeloablative therapy supported by auto-SCT in CR1 and followed by myelosuppressive maintenance therapy to further eradicate MRD to decrease relapse. Here, we report our results of 79 cases cohort indicating our designed auto-SCT-based total therapy have led to very encouraging outcomes.

Patients and methods

Patients

The eligible selection criteria of this study were as follows: (1) age 15 years and <25 years. The definition of AYAs varies among different published clinical trials, but usually ranges between 15 and 18 years for the lower age group, and 20 and 25 years for the upper age group. The operational definition of 15–24 years of age was used to define our study population of AYAs; (2) absence of other active malignancy including CML and myelodysplastic syndromes; (3) ALL-L3 (Burkitt lymphoma) by French-American-British subtype was excluded. The study was approved by the Ethics Committee, Blood Disease Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College (Tianjin, China). Consent was assigned by patients or patients’ parents if they were younger than 18 years. From 1 January 1990 to 31 December 2009, there were 79 consecutive AYAs with newly diagnosed ALL that were enrolled in our designed auto-SCT-based total therapy study.

Diagnostic procedures

The diagnosis of ALL was based on standard morphological, immunological, cytogenetic and/or molecular analysis. Morphological analysis of marrow aspirates and biopsies were according to the French-American-British classification,21 complemented by the cytochemical staining. Immunophenotyping was performed by routine flow cytometry using a panel of MoAbs reactive with B-cell (CD79a, CD10, CD19, CD22, sIg and cIg), T-cell (CD1a, CD2, CD3, CD4, CD5, CD7 and CD8), myeloid (CD13, CD14, CD33, CD15 and cMPO) and precursor cell (TdT, HLA-DR and CD34) associated antigens. Chromosomal analysis of BM and/or blood samples were performed at diagnosis, and the criteria of the International System for Human Cytogenetic Nomenclature 1995 were employed to describe a cytogenetic clone and for the karyotype descriptions.22 Reverse transcriptase/RQ-PCR and/or FISH specific for BCR-ABL, MLL-AF4, E2A-PBX1 and TEL-AML1 transcripts were performed on BM samples at baseline and during the follow up. MRD was evaluated in BM sample with the use of four-colour multiparametric flow cytometry approach.

Treatment protocols

Induction and early consolidation/intensification

All patients received standard induction and early intensive chemotherapy designed for the treatment of AYAs with ALL. A total of 16 patients enrolled in 1990s received the protocol BDHALL1990 from 1990 to 1999, whereas 63 patients were treated with the protocol BDHALL2000 from 2000 to 2009. The dosage of treatment agents and administration schedules are detailed in Table 1. All of patients were administered with a standard 4 or 5-drugs induction regimen (VDCP±L) for 28 days, including: VCR, doxorubicin, CY and prednisone, with or without L-asparaginase (patients treated without L-asparaginase were those either allergic to L-asparaginase or with severe liver damage). Patients who reached CR were treated with four courses of early intensive chemotherapy, which generally contained high-dose MTX, intermediate/high-dose cytarabine and/or high-dose/high-fraction CY.

Table 1 Chemotherapy regimen for adult ALL patients received auto-SCT in the study

Central nervous system prophylaxis

Patients without central nervous system disease received 8–10 injections of triple intrathecal agents with MTX (10 mg), AraC (50 mg) and DXM (10 mg) during the induction and consolidation courses. Patients with central nervous system leukemia received intrathecal treatment therapy thrice weekly until cerebrospinal fluid study findings were negative, and then treated according to the routine protocol. The protocol permitted the addition of 20–24 Gy cranial irradiation at the discretion of the treating physician.

Stem cell collection

BM stem cell harvest was performed after completion of the designed four courses intensive consolidation chemotherapy in patients (n=17) before 2000. PBSC mobilization was performed during hematopoietic recovering from the fourth course of intensive chemotherapy with modified MA (high-dose MTX plus HD-AraC) regimen combined with recombinant G-CSF in patients (n=62) treated with BDHALL2000 protocol. Patients who failed initial mobilization (defined as <1 × 106 CD34+ cells/kg obtained within 2 apheresis days) were remobilized after 10–30 days when hematopoietic recovering from myelosuppression or collected from BM.

Conditioning regimen and autografting

All patients received a myeloablative conditioning regimen before auto-SCT. Most of the present patients (73/79) received single TBI (8–10 Gy) followed by high-dose melphalan, (140 mg/m2 per day for 1 day) or CY (60 mg/kg per day for 2 days), additional HD-AraC (2000 mg/m2 per day for 3 days) or high dose of etoposide-16 (1000 mg/m2 per day for 1 day) were given to patients who received single TBI <9 Gy. Only six patients received standard BU-Mel (BU, 3.2 mg/kg per day for 4 days; Mel, 180 mg/m2) as their conditioning regimen. On day 0, the cryopreserved PBSC and/or BM stem cells were infused through a central venous catheter without filtration over 5–10 min.

Complication prevention and supportive care

All patients were protected in private class 100 laminar flow wards. Three prophylactic antibiotic drugs (fluconazole, trimethoprim-sulfamethoxazole and ganciclovir) were administered orally. Compound Danshen (a Chinese traditional medicine) and/or low-dose heparin were given for prophylaxis of hepatic veno occlusive disease and mesna was administered to patients for prevention of hemorrhagic cystitis. Episodes of febrile neutropenia were treated with broad-spectrum antibiotics according to local policy and microbiological results. Concentrated RBCs were transfused to maintain the hemoglobin level 80 g/L and platelets were transfused when platelet count was <20 × 109/L or any hemorrhage displayed. All blood products were irradiated with 25 Gy. G-CSF (5 μg/kg/d) was administered s.c. beginning on days +3 to +5 and continuing daily until absolute granulocyte count was >0.5 × 109/L on 3 consecutive days.

Maintenance therapy

After auto-SCT, maintenance chemotherapy was started when WBC reached 3 × 109/L and platelets reached 80 × 109/L, and was continued for 1–1.5 years. The maintenance therapy was based on VP regimen (VCR: 1.4 mg/m2, maximum 2 mg, i.v., weekly; prednisone: 30–40 mg per day, p.o., days 1–14). 6-mercaptopurine (60 mg/m2 p.o., days 1–14) and/or MTX (20 mg/m2 per day, p.o., day 1 and day 8) were administered according to the tolerance and the prognostic factors of each patient possessed. In addition, some patients were given IL-2 and/or IFN-γ as immunotherapy alternated with chemotherapy.

End points and statistical methods

Disease characteristics were summarized for all patients using descriptive statistics. Event free survival (EFS) was determined from the date of auto-SCT until the date of first relapse, death from any reason or last follow up. Overall survival (OS) was calculated from the date of auto-SCT to the date of death or last follow up. Cumulative incidence of relapse was determined from the date of auto-SCT to the date of relapse or last follow up. Cumulative probability of non-relapse mortality (NRM) was defined as death with no evidence of disease relapse, and was measured from the date of auto-SCT to the date of death in CR1 or last follow up. The cumulative risks of relapse and NRM over time were calculated as competing risks with actuarial methods. For patients without an event, observation was censored at the cutoff date of 31 March 2011. EFS and OS curves were plotted by the Kaplan-Meier method. Differences between survival curves within the prognostic factors were tested using the log-rank test. Simultaneous effects of multiple covariates were estimated with the Cox regression model for EFS, OS and relapse rate and tested by the likelihood-ratio test. P values were derived from 2-sided tests. P<0.05 was considered to indicate statistical significance. SPSS software version 15.0 (Chicago, IL, USA) for Windows was used for these analyses.

Results

Patients profile

Pretreatment characteristics are summarized in Table 2. The median age was 18 years. Male-to-female ratio was 2:3. Median WBC count at diagnosis was 9.6 × 109/L (range: 0.7–344 × 109/L). Immunophenotype was available for all patients: 83.5% of patients were B lineage, 16.5% had T lineage and 26.6% of patients had myeloid Ags expression. Cytogenetic and/or molecular biology evaluation was performed in all patients. The frequency of normal karyotype was 54.4% (43/79). The Ph chromosome and/or the BCR-ABL rearrangement were found in five patients, all of them only had BCR-ABL P190 transcript. t(4;11)/MLL-AF4 was found in three patients and one patient carried t(11;19), and MLL gene rearrangement was confirmed by FISH test. The frequency of hyperdioploid, diploid and hypodiploid were 17.7% (14/79), 73.4% (58/79) and 7.6% (6/79), respectively.

Table 2 Clinical and biological characteristics of 79 AYAs with ALL

Mobilization and engraftment

In all, 62 patients were mobilized by chemotherapy plus G-CSF, 52 of them received HD-AraC-based regimen whereas 10 patients received high-dose/high-fraction CY. A total of 14 patients failed initial mobilization, 8 of them received HD-AraC and 6 used high-dose/high-fraction CY. Six patients who failed mobilization collected BM stem cell as supplement while eight were remobilized when recovering from myelosuppression. The failure mobilization was significantly more often in high-dose/high-fraction CY group than in HD-Ara-C group (6/10 vs 8/52, P=0.007). Median time from the date of CR to the date of auto-SCT was 192 days (range 111–242 days). Median nucleated cell dose infused was 4.51 × 108/kg (range 1.00–12.67 × 108/kg). Median CD34+ cell dose infused was 2.59 × 106/kg (range 0.96–19.91 × 106/kg). Myeloid engraftment, defined as a neutrophil count 0.5 × 109/L in 3 continuous days, was reached at a median time of 12 days (range 8–62 days). Platelet engraftment, defined as a platelet count 20 × 109/L for 3 continuous days without platelet transfusions, was reached at a median of 16 days (range 0–92 days). Only one patient never engrafted with platelets and died of pulmonary hemoptysis on day +19.

Auto-SCT-related toxicity

Toxicity by WHO (World Health Organization) scale,23 grade III–IV was reported. All of patients in the study occurred grade IV hematologic toxicity. 64 (81.0%) patients developed documented infection and the most common locations of infection were orderly showed as below: intestinal tract (28 patients), septicemia (19 patients), lung (17 patients), crissum (17 patients) and gingival (7 patients). 10 (12.7%) patients developed fever of unknown reason. Other common complications were nausea, vomiting, hemorrhage, arrhythmia, and hepatic and renal toxicity. Most of complications were controllable except for one patient who died of pulmonary hemoptysis and two patients who died of severe pneumonia within 150 days after auto-SCT (details in Table 3).

Table 3 Major toxicity and complications during auto-SCT

Follow up and survival

By the end of 31 March 2011, there were 28 patients dead (23 from disease relapse, and 5 from NRM). The median follow-up time for the whole series and surviving patients were 31.1 months (range 0.6–252.0 months) and 41.2 months (range 14.7–252.0 months), respectively.

Both of median OS and median EFS were not reached, and the estimated 5-year OS probability and EFS probability were 62.8±5.9 and 61.5±5.7%, respectively (Figure 1).

Figure 1
figure1

Survival curves of AYAs with ALL received auto-SCT in CR1. (a) OS for all patients; (b) EFS for all patients.

Effect of maintenance chemotherapy

Maintenance chemotherapy with 6-mercaptopurine, MTX and VP (as one therapeutic agents) regimen and/or immunotherapy was administered for 1–1.5 years after auto-SCT. In all, 59 patients (74.7%) received two or three agents, 10 patients (12.7%) received only one agent or immunotherapy alone, whereas 10 patients (12.7%) did not take maintenance therapy because of early death from severe infection (for three patients), delay in hematologic reconstitution (for one patient) and noncompliance (for six patients). To evaluate the role of the maintenance therapy on EFS, OS and cumulative relapse rate, we compared patients who received two or three chemotherapeutic agents with those receiving zero or one drug or immunotherapy alone. Patients who died from NRM (except one patient who died 26 months after auto-SCT and took MM/VP regimen as maintenance therapy) were excluded from the analysis to avoid the confounding caused by poorer prognosis patients included in the no maintenance group solely because of lower disease status. There was a trend that patients might get benefit from the maintenance with two or more chemotherapeutic agents, even though there was no significant difference between this two groups in prolonging EFS (estimated 5-year EFS were 69.5±6.4 vs 54.1±13.0%, P=0.128) or OS (estimated 5-year OS were 70.4±6.5 vs 40.6±15.2%, P=0.184) or reducing relapse rate (cumulative 5-year relapse rate were 28.7±6.3 vs 51.4±12.8%, P=0.098).

NRM and relapse

Totally, five patients (6.3%) died from NRM. Three patients occurred within 150 days after auto-SCT. The reasons for NRM were respiratory failure resulting from severe pneumonia in three patients, pulmonary hemoptysis in one patient and one sudden death without defined complication. The cumulative incidence of NRM at 5 years was 7.2±3.1% (Figure 2a). At the end of follow up, a total of 23 patients relapsed, 22 patients had BM relapse and 1 relapsed in both of central nervous system and BM. The median time from auto-SCT to relapse was 242 days (54–1105 days). In all, 16 patients (69.6%) suffered disease recurrence within 1 year after auto-SCT, 21 patients (91.3%) relapsed within 2 years after auto-SCT whereas other 2 patients relapsed on day +949 and +1105. The cumulative incidence of relapse at 1 year, 2 years and 5 years were 23.7±4.9, 29.4±5.3 and 33.6±5.8%, respectively (Figure 2b).

Figure 2
figure2

Relapse on study and mortality not associated with relapse. (a) NRM for all patients; (b) Cumulative relapse rate for all patients.

Prognostic factor

Gender, age (>18 years vs 18 years), WBC count, Hb level and platelet count at presentation, ratio of blast cells in peripheral blood and BM, immunophenotype (pro-B vs others), cytogenetic abnormalities, extramedullary involvement, time to achieve CR, CR to transplantation interval (>6 months vs 6 months), stem cell source and maintenance therapy were brought into univariate analysis, and the results demonstrated that WBC >30 × 109/L in B-ALL and >100 × 109/L in T-ALL, and time to CR >4 weeks predicted poor prognosis for OS and EFS, whereas only time to CR >4 weeks adversely affected the relapse (P<0.05). Time to CR >4 weeks was the only independent unfavorable factor associated with OS, EFS and relapse in COX regression model (details in Table 4).

Table 4 Prognostic factors in univariate and multivariate analysis

Identification of MRD before auto-SCT

For MRD detection, multiparametric flow cytometry technology was applied since 2008, the MRD status before auto-SCT was identified only in 10 patients; 7 patients were MRD negative (MRD <0.01%) whereas 3 patients were MRD positive (MRD 0.01%). None of the MRD negative patients relapsed after auto-SCT. Two patients with positive MRD relapsed on day +70 and +321, respectively. The MRD status was negative persistently after auto-SCT in one patient with positive MRD pretransplant, the patient received MM/VP regimen as maintenance therapy.

Risk stratification and survival

The risk stratification was based on the criteria as follows, originally defined by GMALL protocols24: (1) high WBC count (>30 × 109/L in B-ALL and >100 × 109/L in T-ALL); (2) pro-B-cell immunophenotype; (3) cytogenetic abnormalities of t(9;22), t(4;11) or other abnormalities involving 11q23 rearrangements; (4) time to CR beyond 4 weeks. Patients were classified as high risk group (HR) if they met one of the above criteria except for (3), whereas those who met more than one risk factor or carried with cytogenetic abnormalities of t(9;22), t(4;11) or other abnormalities involving 11q23 rearrangements were defined as very high risk group (VHR). All other patients were classified as the standard risk group (SR). According to these criteria, 32 patients were assigned to SR group, 29 were in HR group and 18 were in VHR group. Survival analysis showed that both SR and HR had better survival compared with VHR. Meanwhile, comparison of incidence of relapse demonstrated that VHR had a higher incidence of relapse than SR and HR. SR had advantages compared with HR both in survival and relapse analysis, but such advantage did not reach statistical significance (details in Table 5) (Figures 3 and 4). The analysis about NRM was not performed because only five patients died from NRM.

Table 5 Results of risk stratification analysis
Figure 3
figure3

Survival curves of AYAs with ALL received auto-SCT in CR1 in SR, HR and VHR group. (a) OS for three different risk groups; (b) EFS for three risk groups.

Figure 4
figure4

Cumulative relapse rates for AYAs with ALL received auto-SCT in CR1 in SR, HR and VHR group.

Discussion

AYAs with ALL are a distinct cohort differing from pediatric and older adult patients. In general, most children are in prognostically ‘favorable’ ALL subtypes, the incidence of ‘unfavorable’ characteristics increases gradually with age.25, 26 The frequency of t(9;22) or BCR-ABL fusion gene in current series was 6.2% (5/79), which was 3% in children and 15–20% in older adults.27 A total of 4/79 (5.6%) patients were t(4; 11) or MLL gene rearrangement positive, which was more common than in children >1 year of age. Hyperdioploid, trisomy of chromosomes 4 and 17, and t(12;21) or TEL-AML1 fusion gene, which were associated with a very low risk of treatment failure,25, 28 were less frequent in our patients.

Treatment strategy specific for AYAs has not been established yet. AYAs with ALL are treated, according to loose referral patterns, either with pediatric or adult protocols. Our center designed an auto-SCT-based complete therapeutic schedule for AYAs with ALL since the 1990s and achieved satisfactory results. The most important finding in our study was the favorable survival with a 5-year OS of 62.8±5.9% and a 5-year EFS of 61.5±5.7%, which was superior to the results of most previous published clinical trials.3, 4, 5, 6, 7, 8, 9, 10, 11, 12 The development of transplant technology and supportive care might contribute to the favorable outcome. Besides, the encouraging consequence might be attributed to the following reasons. First, selection of eligible patients is the pivotal step. Risk stratification and treatment individualization is pursued as ALL is a highly heterogeneous disease comprising many entities. Age, elevated WBC count at diagnosis, adverse immunophenotypic and cytogenetic features, as well as late achievement of CR constitute the current prognostic models for adult ALL.29 The latest advances in MRD detection techniques, molecular genetics and proteomics should adjust the prognostic model and promote the use of more targeted therapies.20, 30, 31 We divided patients into three subgroups according to the GMALL protocols.30 Patients in SR/HR had superior outcome than patients in VHR (Table 5). Majority of patients enrolled in the large prospective trials, which announced auto-SCT had no superiority to conventional chemotherapy were in HR group, even included patients carrying t(9;22).7, 8 In our center, AYAs in SR were prone to undergo auto-SCT, whereas those with HR/VHR were recommended to receive allo-SCT as the first choice. Lack of HLA-identical donor forced patients in HR/VHR to turn to auto-SCT. In the present study, 2/5 patients with BCR-ABL P190-positive ALL and 1/4 patient with MLL gene rearrangement survived without disease relapse over 5 years after auto-SCT. This reminded us that although auto-SCT seemed incapable of improving the outcome of patients in VHR, our protocol might provide a chance for those without HLA-identical donor to receive myeloablative chemotherapy, which could minimize MRD and prolong survival.

Second is our ‘in vivo purging’ strategy with early sequential four courses of intensive consolidation chemotherapy prior to auto-SCT. The CR rates of adults with both of BDHALL1990 and BDHALL2000 protocols were over 90%, which were similar to most large series prospective trials.3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Recent studies have shown that AYAs who were enrolled in pediatric trials achieved better outcome than their counterparts who were enrolled in adult trials.13, 14, 15 Dose intensity and the dose density of the nonmyelosuppressive chemotherapeutic agents are greater within the pediatric protocols. M.D. Anderson cancer center explored Hyper-CVAD/HD-MA protocol, which initially was used to treat childhood Burkitt lymphoma, in adult ALL and achieved CR in excess of 90% and 5-year survival reached 40%.32 High-dose MTX, intermediate/high-dose cytarabine and HD/hyperfractionated-CY based regimens constituted the intensive consolidation courses in our center. Although MRD status in pretransplant was identified only in 10 patients, 7 patients were MRD negative. The result might show that early intensified treatment could eradicate the residual leukemia burden ‘in vivo’, and reduce the potential contamination of the hematopoietic progenitors by residual malignant cells. Also, intensive consolidation may reduce the likelihood of the development of drug resistance, achieve sufficient drug concentration in sanctuary, and thus increase the proportion of long-term disease-free survivors. The consolidation treatment before auto-SCT in most previous prospective studies was not intensive enough. Dose-intensive treatment was not applied before auto-SCT in LALA-85/87 trials.3, 11 Only one course of HD-AraC-intensive treatment was used in EROTC ALL-L3 protocol.5 Patients enrolled in ECOG 2993/UK MRC ALL XII trial and GOELAL02 trial only received high-dose MTX as intensification therapy.6, 9 This would result in high incidence of relapse because of heavy leukemia burden at auto-SCT and the potential of leukemic cell contamination in PBSC or BM stem cell.

Third is the adoption of TBI-based conditioning regimen. Although we did not perform the comparison between TBI-based conditioning and non-TBI-based conditioning because only six patients received non-TBI-based conditioning regimen, TBI conditioning might contribute to the outcomes in the present study. Results of the PETHEMA ALL-93 trial8 demonstrated that in patients submitted to auto-SCT, the 5-year relapse probabilities were lower in those conditioned by TBI-based regimens (39%) than in those who received BU chemotherapy-based schedules (60%). A meta-analysis pooled 18 trials also confirmed that for patients with ALL and AML, the TBI/CY regimen led to lower rates of leukemia relapse, lower TRM and higher DFS compared with BU/CY.33

The high incidence of recurrence is the main cause of treatment failure in adult patients with ALL. In present study, the cumulative incidence of relapse at 1 year, 2 years and 5 years were 23.7±4.9, 29.4±5.3 and 33.6±5.8%, respectively. There were 23 patients who underwent relapse, most of them occurred in the first year whereas only 2 relapsed beyond 2 years after auto-SCT. Myelosuppressive maintenance chemotherapy after auto-SCT for 1–2 years to further eradicate MRD was the forth interpretation for the favorable outcome. Although univariate analysis failed to confirm patients receiving two or three chemotherapeutic agents as posttransplantation therapy had better EFS (P=0.128) and lower relapse (P=0.098) than those receiving zero or one drug or immunotherapy alone when we excluded patients who died from NRM. There is a trend to say maintenance with combination of VCR, MTX and 6-mercaptopurine would gain better long-term survival. Maintenance with oral drugs and low dose chemotherapy will shorten the average hospital stays and increase the compliance, which is more suitable for the situation lacking of high-level community hospitals in China. A UK group reported 78/100 patients who received 6-mercaptopurine, MTX and/or VP regimen as maintenance therapy. The 7-year probabilities of DFS for patients receiving zero, one, two and three maintenance chemotherapy agents were 15%, 29%, 58% and 61%, respectively (P=0.0001).34 Only four prospective studies designed patients to receive maintenance therapy after auto-SCT,4, 6, 7, 10 and only 12–52% patients actually took maintenance therapy. This may lead to an underestimation of the real potency of auto-SCT.

Compared with allogeneic transplantation, safety and high quality life are the major advantages of auto-SCT-based post-remission treatment. Of our 79 cases, there were five patients who died from NRM, only three of them died from TRM definitely. With advances in transplant technique, supportive care and absence of GVHD, auto-SCT itself is a relatively safe procedure with low risk. Although recently, CCG-1961 trial claimed that AYAs have an excellent outcome with chemotherapy alone (5-year EFS and OS were 71.5±3.6 and 77.5±3.3%, respectively) and SCT seemed to have no role for the routine use.35 Nachman JB et al. also mentioned in Discussion that for AYAs in SR group, the 5-year EFS and OS were 72.6 and 80.3%. The estimated 5-year EFS and OS for AYAs in SR group in the present study were 78.3±7.4 and 78.3±7.4%, which was quite accordant with the outcomes of CCG-1961 trial. Compared with most of studies with long-term chemotherapy, the present results showed that our designed auto-SCT-based total treatment strategy not only effectively improved the long-term survival, but also presented with advantage over long-term chemotherapy (lasting for 2–3 years) by shortening the hospital stay, declining exposure to high-dose cytotoxic chemotherapeutic agents and improving the quality of life.

In conclusion, our designed auto-SCT-based total therapy is a reasonable and perhaps the optimal choice for AYAs without HLA-identical donor, especially for those in SR. AYAs in HR also could get benefit from such complete therapeutic schedule, but for AYAs in VHR, allo-SCT was still the prior recommendation for the high recurrence.

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Acknowledgements

This work was supported by the Key Clinical Project from the Health Ministry of China (2010–2012), the Key Projects in the National Science & Technology Pillar Program (grant no. 2008BAI61B01) and the National Public Health Research Foundation (grant no. 201002024).

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Correspondence to J-X Wang or L-G Qiu.

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The authors declare no conflict of interest.

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Keywords

  • adolescent
  • young adult
  • ALL
  • auto-SCT
  • survival

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