Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphobla stic leukemia
© Chen et al.; licensee BioMed Central Ltd. 2012
Received: 23 March 2012
Accepted: 8 June 2012
Published: 8 June 2012
Maintenance therapy with imatinib during the post-transplant period has been used for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL); however, its efficacy has not been demonstrated. A study was designed to investigate the safety of imatinib and its efficacy in preventing hematological relapse and improving disease-free survival (DFS) when administered after allogeneic hematopoietic stem cell transplantation (allo-HCT).
Patients with Ph + ALL that received allo-HCT were enrolled in the study. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect BCR-ABL transcript levels. Imatinib therapy was initiated if patient neutrophil counts were > 1.0 × 109/L and platelet counts were > 50.0 × 109/L, or if they displayed either elevated BCR-ABL transcript levels in two consecutive tests, or a BCR-ABL transcript level ≥ 10-2 after initial engraftment. Patients receiving imatinib after relapse were assigned to the non-imatinib group. The imatinib treatment was scheduled for 3–12 months, until BCR-ABL transcript levels were negative at least for three consecutive tests or complete molecular remission was sustained for at least 3 months.
A total of 82 patients were enrolled. Sixty-two patients initiated imatinib therapy post-HCT. Imatinib therapy was initiated at a median time of 70 days post-HCT. Grade 3–4 adverse events (AEs) occurred in 17.7% of patients. Ten patients (16.1%) terminated imatinib therapy owing to AEs. Among the patients in imatinib and non-imatinib groups, the estimated 5-year relapse rate was 10.2% and 33.1% (p = 0.016), and the 5-year probability of DFS was 81.5% and 33.5% (p = 0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4–72 months), respectively. Multivariate analysis identified imatinib maintenance therapy post-HCT as an independent prognostic factor for DFS (p = 0.000, hazard ratio [HR] =4.8) and OS (p = 0.000, HR = 6.2).
These results indicate that relapse rate can be reduced and DFS may be improved in Ph + ALL patients with imatinib maintenance therapy after HCT. BCR-ABL monitoring by qRT-PCR can guide maintenance therapy with imatinib including initiation time and treatment duration after allo-HCT.
KeywordsPhiladelphia chromosome Acute lymphoblastic leukemia Allogeneic hematopoietic cell transplantation Minimal residual disease Imatinib
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is still considered the optimal curative treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). The disease-free survival (DFS) of Ph + ALL patients after allo-HCT ranges from 21% to 57% [1–4]. The main cause of treatment failure is relapse, and approximately 30% of patients that undergo allo-HCT in first complete remission (CR1) eventually relapse. Of the patients that undergo allo-HCT beyond CR1, or for those with refractory disease, the relapse rate is even higher. The tyrosine kinase inhibitor, imatinib, has been widely used for the treatment of chronic myelogenous leukemia [5, 6], and has recently been used for treatment of Ph + ALL. Since the introduction of imatinib in the combination chemotherapy regimes for newly diagnosed Ph + ALL, more than 95% of patients can achieve CR1. Several studies have shown decreased relapse rates and improved DFS for patients with imatinib-based treatment prior to allo-HCT, compared with their historical controls [7–9]. However, the efficacy of maintenance therapy with imatinib after transplant for Ph + ALL patients is still uncertain.
Detection of minimal residual disease (MRD) after transplant is associated with an increased risk of relapse . An early study by Wassmann et al showed that MRD-triggered imatinib therapy led to complete molecular remission (CRmol) in 52% of patients expressing BCR-ABL after HCT; however, approximately 50% of patients ultimately experienced hematological relapse . In addition, it was reported that 23% of Ph + ALL patients that screened negative for BCR-ABL after allo-HCT relapsed . Thus, earlier initiation of imatinib treatment in the setting of low leukemia burden, or negative detection of MRD after HCT, may reduce the relapse rate and improve survival to an even greater extent. The feasibility and safety of early prophylactic administration of imatinib after HCT has been previously confirmed . However, imatinib toxicity is relevant when started soon after HCT.
We previously demonstrated that administration of imatinib in the first 90 days after allo-HCT, based on MRD monitoring, is feasible, and the toxicity is acceptable. Preliminary results showed that treatment outcome was significantly improved compared with our previous study . In this phase II study, we evaluated the safety and efficacy of imatinib therapy, when initiating treatment based on patient clinical conditions and BCR-ABL transcript levels after allo-HCT. We also investigated the factors that may impact relapse and survival.
Materials and methods
Allo-HCT recipients diagnosed with Ph + ALL (< 60 years of age) were eligible for the study, regardless of the source of HCT (from either HLA-matched sibling donors, unrelated donors or mismatched related donors). The diagnosis of Ph + ALL was based on the WHO diagnosis criteria. Patients were excluded from the study if they displayed hypersensitivity or were assessed as resistant to imatinib before HCT. Patients were also excluded if either hematological relapse or extramedullary leukemia involvement was diagnosed after initial engraftment, or if the life expectancy was less than 1 month post-HCT. The study was reviewed and approved by the ethics committee at Peking University People’s Hospital. All patients provided written, informed consent before transplantation.
Conditioning regimen and graft-versus-host disease (GVHD) prophylaxis
All patients received a myeloablative transplant. Conditioning regimens were as previously described [14, 15]. In matched sibling transplants, the conditionings were (1) total body irradiation (TBI) with 7.7-12.0 Gy and cyclophosphamide (Cy) 1.8 g/m2/d × 2 days or (2) hydroxyurea (40 mg/kg, q12 h) given on day −10, cytosine arabinoside (Ara-C, 2 g/m2/d) intravenously on day −9; busulfan (Bu,3.2 mg/kg per day) intravenously on days −8 to −6; Cy (1.8 g/m2/d) intravenously on days −5 and −4; Methyl-N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea (Me-CCNU, 250 mg/kg/d) orally once on day −3. Patients that underwent mismatched related and unrelated HCT were given cytosine arabinoside (2–4 g/m2/d) on days −10 and −9 in the Bu/Cy regimen (as shown above) and anti-human thymocyte globulin (ATG, 2.5 mg/kg/d,Sang Stat, Lyon, France) intravenously for 4 consecutive days from days −5 to −2.
The level of BCR-ABL transcripts in patient bone marrow was assessed by TaqMan-based real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), as previously described . The BCR-ABL primers and probe that amplify both the b3a2 and b2a2 junctions are previously published . The primers and probe that amplify the ABL and e1a2 BCR-ABL junctions are listed in the report of the Europe against Cancer Program [17, 18]. BCR-ABL transcript level was calculated as: fusion transcript copies / ABL transcript copies × 100 (%). The ABL copy number of all the samples included in this study was greater than 3 × 104. The reproducible sensitivity of qRT-PCR was five copies. A CRmol was defined as the negative expression of BCR-ABL by qRT-PCR in patient bone marrow specimens. Bone marrow aspiration for morphological and cytogenetic analysis (fluorescence in situ hybridization, FISH), flow cytometry and qRT-PCR was scheduled for 1, 3, 6, 9 and 12 months post-HCT (qRT-PCR tests were repeated at 2-week intervals if necessary), then once every 6 months between months 12 and 24 post-HCT.
Study design and treatment
Treatment with imatinib was initiated: (1) if patient peripheral blood absolute neutrophil counts (ANC) were >1.0 × 109/L without granulocyte colony-stimulating factor (G-CSF) administration, and the platelet count was >50.0 × 109/L, regardless of the level of BCR-ABL transcript; or (2) if the level of BCR-ABL transcript in the bone marrow was detectable and transcript levels increased for two consecutive tests, or if the BCR-ABL transcript level was ≥10-2 after the initial engraftment, although patients ANC or platelet count were below the above values. Other criteria for initiation of treatment included that patients could tolerate oral imatinib without gut GVHD or life-threatening infection.
Imatinib treatment was scheduled for 3–12 months after HCT, until BCR-ABL transcript levels were negative at least for 3 consecutive tests or CRmol was sustained for at least 3 months, as described in our previous report .
The initial dose of imatinib was 400 mg/d for adults (> 17 years) and 260 mg/m2/d for children (< 17 years). The daily dose of imatinib was adjusted according to the National Comprehensive Cancer Network practice guideline regarding the management of imatinib toxicity (version 2005). The dose of imatinib was reduced to 300 mg/d if the ANC was <1.0 × 109/L, despite administration of G-CSF, or if the platelet count was less than 20 × 109/L. The dose of imatinib could escalate to 600 mg/d (340 mg/m2/d in children <17 years). The minimum acceptable dose of imatinib was 300 mg/d (260 mg/m2/d for children <17 years) for at least 5 days per week.
Patients were permitted to voluntarily withdraw from the study at any time or were withdrawn if grade 3 or 4 toxicity was sustained for more than 2 weeks, despite interrupting the imatinib therapy.
Safety and efficacy
The primary study end point addressed patient safety. The toxicity of imatinib was assessed according to the Common Toxicity Criteria, version 3.0. The secondary study endpoint assessed the efficacy of imatinib therapy. The efficacy evaluation included relapse rate, DFS and overall survival (OS). A post-transplant relapse was defined as hematological relapse, extramedullary involvement of leukemia and cytogenetic relapse. DFS was defined as continuous survival without relapse or death from any cause after HCT. OS was defined as continuous survival until death from any cause after HCT. Patients who were treated with imatinib for less than 7 days were not included for the efficacy evaluation, but were included in the safety evaluation.
Parametric tests used the χ2 test or Fisher’s exact test. The Mann–Whitney U test was used for nonparametric tests. Univariate analysis for DFS and OS of all enrolled patients was conducted using Kaplan-Meier analysis with the log-rank test. The factors included in the univariate analysis were sex, age (> 30/< 30 years), disease status pre-HCT (CR1/> CR1), BCR-ABL transcript levels before and after HCT, donor type, acute and chronic GVHD, imatinib therapy versus no treatment, post-HCT. Multiple regression analysis for DFS and OS was conducted using multiple Cox regression. The covariates adjusted in the multiple regression models included factors identified as significant in the univariate analysis (p < 0.05). Kaplan-Meier analysis was used to estimate DFS and OS, while cumulative incidence was calculated for non-relapse mortality (NRM) and relapse rate. The relapse rate was also calculated by taking into account the competing risk of death due to other complications using the Fine-Gray model. The log-rank test was used to compare the survival curve and the Gray test for cumulative incidence curve between the imatinib and non-imatinib groups. Data analysis was performed using the SPSS and R software packages, and a p-value < 0.05 was considered statistically significant.
Patient enrollment and engraftment
Patient characteristics in the imatinib and non-imatinib groups
Number of patients
Age (y), median (range)
<30 / >30 y
Disease status pre-HCT
Imatinib therapy before HCT
HLA matched siblings
BMT + PBSCT
0/ I°-II°/ III-IV°
30/ 28/ 4
5/ 11/ 4
no/ L/ E-cGVHD
22/ 25/ 12
3/ 8/ 8
All 82 patients achieved myeloid engraftment after HCT. All patients, except one, achieved platelet engraftment. The engraftment time was not significantly different between the imatinib and non-imatinib groups (Table 1).
Imatinib treatment and safety
All enrolled patients achieved hematological remission and all of them were in complete cytogenetic remission (CCyR) following myeloid engraftment. Treatment with imatinib was initiated at a median time of 70 days post-HCT (range, 20–270 days), and the median duration of imatinib therapy was 90 days (range, 13–540 days).
Thirty-four adult patients tolerated imatinib at a daily dose of 400 mg. The daily dose of imatinib was decreased to 300 mg in 16 adults for 5–7 days a week. Seven out of 10 children tolerated imatinib at a daily dose of 260 mg/m2.
Number of patients with adverse events related to imatinib
No. of patients with AEs
Elevation of ALT/AST
Response to imatinib therapy and outcome after HCT
After HCT, the bcr-abl tests by qRT-PCR were negative in 48 patients prior to administration of imatinib. Within this group, hematological relapse occurred in 4 patients (1 received imatinib for less than 7 days after HCT) and extramedullary leukemia relapse occurred in one patient. These five patients received other treatment option in addition to imatinib, including chemotherapy or irradiation, followed by donor lymphocyte infusion (DLI). Of this group, two patients died from relapse and two patients died from non-relapse complications.
Prior to imatinib therapy, 14 patients tested positive for BCR-ABL expression following engraftment. Eight patients became BCR-ABL negative 1 month after imatinib therapy (range, 1–3 months). Two patients died from hematological relapse. Four patients displayed persistent BCR-ABL expression for 3 months and achieved CRmol with additional treatment such as chemotherapy plus DLI, second-generation tyrosine kinase inhibitors, or secondary allo-HCT. Four patients died from non-relapse complications, including respiratory failure (n = 2); demyelinating polyneuropathy (n = 1) or post-transplant lymphoproliferative disease (n = 1).
In the non-imatinib treated group, five patients died from hematological relapse. One patient with central nervous system relapse survived in complete remission after receiving central nervous system irradiation and imatinib therapy. The causes of non-relapse death included GVHD (n = 1), infection (n = 3) and others (n = 3).
Relapse rates and NRM
DFS and OS
Prognostic factors associated with DFS and OS
Univariate analysis revealed that post-HCT maintenance therapy with imatinib treatment, pre-HCT disease status and pre-HCT BCR-ABL transcript levels were significant factors impacting DFS and OS (p = 0.000, 0.013, 0.020, respectively).
Multivariate analysis of factors associated with DFS and OS
non-IM use post-HCT
> CR1 pre-HCT
Until now, there have been no large, controlled studies demonstrating that imatinib therapy after HCT can improve DFS. A small non-randomized, single-center study from Minnesota identified a trend toward decreased relapse rate in patients treated with imatinib in the pre- and/or post-transplant period . However, only two patients in their study were treated with imatinib maintenance therapy post-transplant. The reports from the Children’s Oncology Group recently showed that patients receiving imatinib therapy for 6 months following matched sibling donor HCT (n = 19) showed no advantage in 3-year event-free survival (EFS) compared with bone marrow transplantation (BMT) alone [21, 22].
We administered imatinib maintenance therapy for Ph + ALL patients after HCT based on patient clinical conditions and BCR-ABL transcript levels. Our study demonstrates for the first time that patients treated with imatinib maintenance therapy post-HCT have a lower relapse rate and a survival advantage in term of DFS and OS, compared with non-imatinib treated patients. The limitation to this study was that patients in our trial were not randomized to receive imatinib therapy post-HCT. In addition, more patients died from non-relapse complications in the non-imatinib group compared with the imatinib treated group, which may impact the outcome. It should be noted, however, that the demographic characteristics and certain relevant transplant data were similar between the two patient groups (except for 3 patients receiving TBI/Cy as conditioning regimen in the non-imatinib group), thus allowing for a comparison. Multivariate analysis of all enrolled patients also showed that imatinib maintenance therapy post-HCT was an independent prognostic factor for DFS. Additional carefully designed or randomized studies with large patient cohorts are required, however, to confirm the efficacy of this strategy.
The optimal time for initiating imatinib treatment post-HCT is not well established. Previous studies have shown that the ability of patients to tolerate imatinib therapy decreases in cases of poor engraftment and GVHD reactions following HCT. Early initiation of imatinib is frequently associated with grade 3 or 4 cytopenia in the first 100 days after allo-HCT . A study in which all patients were anticipated to begin imatinib treatment (400 mg/day) from the time of full hematological recovery after HCT showed that 12 of 21 patients initiated imatinib at a median time of 3.9 months post-HCT; however, treatment was interrupted in 10 patients owing to complications such as GVHD . Thus, early initiation of imatinib treatment in patients, regardless of their clinical conditions following allo-HCT, may be limited by transplant-related complications and drug toxicity. A recent multi-center, randomized trial by Pfeifer et al revealed no significant difference in OS between patients with pre-emptive imatinib therapy and those with prophylactic administration of the drug after HCT . In this study, more than half of enrolled patients discontinued imatinib therapy in both groups of patients, predominantly owing to gastrointestinal toxicities . These data suggest that there are still limitations in the initiation of imatinib therapy just based on post-HCT BCR-ABL transcript levels. Furthermore, imatinib therapy may not need to be initiated at the same time period after HCT in patients with negativity for BCR-ABL expression. This report also showed that detection of BCR-ABL transcripts within 100 days of transplant is associated with a significantly inferior EFS, despite rapid initiation of imatinib treatment . This indicates that delayed initiation of imatinib therapy after HCT may decrease the efficacy of imatinib therapy for some patients.
Our trial was designed to initiate imatinib therapy based on patient BCR-ABL transcript levels, while concurrently taking into account the clinical conditions of individual patients (including blood cell counts, GVHD). Grade 3–4 AEs and interruption of imatinib therapy due to AEs or gut GVHD were relatively low compared with other reports [23–25]. Therefore, we conclude that our treatment strategy balanced the safety and efficacy of imatinib therapy after allo-HCT.
MRD positivity pre- and post-HCT is reported to be associated with a high relapse rate after HCT [10, 12]. In our study, we found that detection of BCR-ABL expression pre-HCT had a significant adverse impact on DFS. This is in line with recent studies showing that MRD levels at different time points prior to HCT have prognostic relevance, and that lower levels of MRD prior to HCT are associated with better DFS following allo-HCT [26, 27].
To date, there is no defined period of administering imatinib therapy post-HCT that has been demonstrated to be more appropriate for reducing relapse rate and improving survival. Most studies suggest arbitrarily using imatinib therapy for 6 months to 1 year after allo-HCT, or for 1 year after the first documentation of BCR-ABL negativity post-HCT [11, 22]. However, in these studies patients still experienced molecular relapse or even hematological relapse after termination of imatinib treatment. Sustained CRmol is defined by some researchers as BCR-ABL negativity lasting for a period of at least 3 months . Our regimen was designed to use imatinib until BCR-ABL transcripts were negative at least for 3 consecutive tests or CRmol was sustained for at least 3 months. Our preliminary results showed that the relapse rate was lower and DFS was higher compared with our previous studies (DFS, 37.1%) . These data support the rationale of our strategy, which employs regular monitoring of BCR-ABL transcript levels by qRT-PCR to guide the treatment period in which imatinib therapy should be administered after HCT. Other factors such as graft-versus leukemia effect may also contribute to eradicating MRD when combined with imatinib therapy after allogeneic transplant. We are aware, however, that the patient numbers in our study are still limited, and future studies involving larger patient cohorts with a longer follow-up period are needed to accurately define the time period of imatinib therapy post-HCT.
Our study also showed that the remission status at the time of HCT significantly predicted OS. Thus, patients transplanted in CR1 had significantly higher OS rates compared with those transplanted in > CR1. These data are supported by other studies involving both matched-related and unrelated donors for both adults and children with either Ph-ALL or Ph + ALL [29–31]. Therefore, we still recommend that patients with Ph + ALL undergo allo-HCT in CR1 if they have available donors.
In summary, our study demonstrates that relapse rate can be reduced and DFS may be improved in Ph + ALL patients using imatinib maintenance therapy. BCR-ABL monitoring by qRT-PCR can well guide imatinib therapy including initiation time and duration of treatment after HCT. Even in the imatinib era, Ph + ALL patients with available donors will benefit from receiving allo-HCT in CR1.
- Ph + ALL:
Philadelphia chromosome acute lymphoblastic leukemia
Allogeneic hematopoietic cell transplantation
Quantitative reverse-transcription polymerase chain reaction
Absolute neutrophil count
Minimal residual disease
Tyrosine kinase inhibitor
First complete remission
Complete molecular remission
Total body irradiation
Granulocyte colony-stimulating factor
This work was supported by the National Natural Science Foundation of China (General Program, grant No. 30971292), National High-tech R&D Program of China (grant No.2011AA020105) and Leading Program of Clinical Faculty accredited by the Ministry of Health of China. We are grateful to Edanz Group China to revise and perfect the manuscript.
- Rdich JP: Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2001, 15: 21-36. 10.1016/S0889-8588(05)70198-2.View ArticleGoogle Scholar
- Sierra J, Radich J, Hansen JA, Martin PJ, Petersdorf EW, Bjerke J: Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 1997, 90: 1410-1414.PubMedGoogle Scholar
- Laport GG, Alvarnas JC, Palmer JM, Snyder DS, Slovak ML: Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors:a 20 year experience with the fractionted total body irradiation-etoposide regimen. Blood. 2008, 112: 903-909. 10.1182/blood-2008-03-143115.PubMed CentralView ArticlePubMedGoogle Scholar
- Xu LP, Huang XJ, Liu KY, Chen Huan, Liu DH, Zhang YC: Allogeneic hematopoietic stem cell transplantation for treatment of Philadelphia chromosome positive acute lymphoblastic leukemia. Beijing Da Xue Xue Bao. 2005, 37 (3): 231-235. ChinesePubMedGoogle Scholar
- Wei G, Rafiyath S, Liu DL: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol. 2010, 3: 47-10.1186/1756-8722-3-47.PubMed CentralView ArticlePubMedGoogle Scholar
- Karen Seiter: Update of recent studies in chronic myeloid leukemia. J Hematol Oncol. 2009, 2 (Suppl 1): A2-10.1186/1756-8722-2-S1-A2. 26 June 2009View ArticleGoogle Scholar
- Lee S, Kim YJ, Min CK, Kim HJ, Eom KS, Kim DW: The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2005, 105: 3449-3457. 10.1182/blood-2004-09-3785.View ArticlePubMedGoogle Scholar
- de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S: Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007, 109: 1408-1413. 10.1182/blood-2006-03-011908.View ArticlePubMedGoogle Scholar
- Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006, 24: 460-466. 10.1200/JCO.2005.03.2177.View ArticlePubMedGoogle Scholar
- Radich J, Gehly G, Lee A, Avery R, Bryant E, Edmands S: Detection of bcr-abl transcripts in Phyladelphia chromosome-positive acute lymphoblastic leukemia after bone marrow transplantation. Blood. 1997, 97: 2602-2609.Google Scholar
- Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Brug G, Scheuring UJ: Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia. Blood. 2005, 106: 458-463. 10.1182/blood-2004-05-1746.View ArticlePubMedGoogle Scholar
- Stirewalt DL, Guthrie KA, Beppu L, Bryant EM, Doney K, Gooley T: Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant. 2003, 9: 206-212. 10.1016/S1083-8791(03)70011-1.View ArticlePubMedGoogle Scholar
- Carpenter PA, Snyder DS, Flower ME, Sanders JE, Gooley TA, Martin PJ: Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007, 109: 2791-2793.PubMed CentralPubMedGoogle Scholar
- Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006, 38: 291-297. 10.1038/sj.bmt.1705445.View ArticlePubMedGoogle Scholar
- Huan XJ, Wang Y, Liu DH, Xu LP, Chen H, Chen YH: Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia–feasibility and safety study. J Clin Immunol. 2008, 28 (4): 390-397. 10.1007/s10875-008-9193-4.View ArticleGoogle Scholar
- Qin YZ, Liu YR, Zhu HH, Li JL, Ruan GR, Zhang y: Different kinetic patterns of BCR-ABL transcript levels in imatinib-treated chronic myeloid leukemia patients after achieving complete cytogenetic response. Int J Lab Hematol. 2008, 30: 317-323. 10.1111/j.1751-553X.2007.00962.x.View ArticlePubMedGoogle Scholar
- Beillard E, Pallisgaard N, van der Velden VH, Bi W, Dee R, van der Schoot E: Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQPCR)—a Europe against cancer program. Leukemia. 2003, 17: 2474-2486. 10.1038/sj.leu.2403136.View ArticlePubMedGoogle Scholar
- Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N: Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003, 17: 2318-2357. 10.1038/sj.leu.2403135.View ArticlePubMedGoogle Scholar
- Chen H, Liu KY, Xu LP, Liu DH, Chen YH, Shi HX: Administration of imatinib in first 90 days after allogeneic hematopoistic cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Chin Med J. 2011, 124 (2): 246-252.PubMedGoogle Scholar
- Burke MJ, Trotz B, Luo X, Baker KS, Weisdorf DL, Waqner JE: Allo-hematopoietic cell transplantation for Ph chromosome–positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant. 2009, 43 (2): 107-113. 10.1038/bmt.2008.296.View ArticlePubMedGoogle Scholar
- Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M: Improved Early Event-Free Survival With Imatinib in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study. J Clin Oncol. 2009, 27: 5175-5181. 10.1200/JCO.2008.21.2514.PubMed CentralView ArticlePubMedGoogle Scholar
- Schultz KR, Bowman WP, Slayton W, Aledo A, Devidas M, Sather H: Improved early event free survival (EFS) in children with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with intensive imatinib in combination with high dose chemotherapy: Children’s Oncology Group (COG) Study AALL0031. Blood. 2007, 110: 4-Google Scholar
- Anderlini P, Sheth S, Hicks K, Ippolili C, Giratt S, Champlin RE: Imatinib mesylate administration in the first 100 day after stem cell transplantation. Biol Blood Marrow Transplant. 2004, 10: 883-884. 10.1016/j.bbmt.2004.09.004.View ArticlePubMedGoogle Scholar
- Ribera JM, Oriol A, Gonzalez M, Brunet S, Esteve J, Del Potro E: Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010, 95 (1): 87-95. 10.3324/haematol.2009.011221.PubMed CentralView ArticlePubMedGoogle Scholar
- Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhauser M, Stadler M: Updated Long-Term Results of a Randomized Comparison of Prophylactic and Pre-Emptive Imatinib Following Allogeneic Stem Cell Transplantation for Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph + ALL)[abstract]. Blood. (ASH Annual Meeting Abstracts). 2011, 118 (21): 614.
- Lee S, Kim YJ, Chung NG, Lim J, Lee DG, Kim HJ: The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2009, 115: 561-570. 10.1002/cncr.24026.View ArticlePubMedGoogle Scholar
- Pane F, Cimino G, Izzo B, Canera A, Quintarelli C, Picardi M: Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. Leukemia. 2005, 19: 628-635.PubMedGoogle Scholar
- Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G: Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia. Blood. 2005, 106 (2): 458-463. 10.1182/blood-2004-05-1746.View ArticlePubMedGoogle Scholar
- Kiehl MG, Kraut L, Schwerdtfeger R, Hertenstein B, Remberger M, Kroeqer N: Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004, 22: 2816-2825. 10.1200/JCO.2004.07.130.View ArticlePubMedGoogle Scholar
- Munoz A, Diaz-Heredia C, Diaz MA: Allogeneic hematopoietic stem cell transplabtationfor childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: A study of the Spanish Working Party for Blood and Marrow Transplantation in Children(Getmon). Pediatr Hematol Oncol. 2008, 25 (4): 245-259. 10.1080/08880010802016557.View ArticlePubMedGoogle Scholar
- Burke MJ, Cao Q, Trotz B, Weigel BJ, Kumar A, Smith A: Allogeneic hematopoietic cell transplantation for treatment of pediatric Philadelphia chromosome-positive acute lymphiblastic leukemia(ALL). Pediatr Blood Cancer. 2009, 53: 1289-1294. 10.1002/pbc.22263.View ArticlePubMedGoogle Scholar
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