Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

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Clinical Research: Alternative Donors

Haploidentical Hematopoietic Stem Cell Transplantation

without In Vitro T Cell Depletion for the Treatment of

Philadelphia ChromosomeePositive Acute Lymphoblastic

Leukemia

Huan Chen, Kai-yan Liu, Lan-ping Xu, Yu-hong Chen, Wei Han, Xiao-hui Zhang, Yu Wang,

Ya-zhen Qin, Yan-rong Liu, Xiao-jun Huang

*

Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

Article history:

Received 16 December 2014 Accepted 10 February 2015

Key Words: Haploidentical Hematopoietic stem cell transplantation Philadelphia chromosome Acute lymphoblastic leukemia Imatinib resistance

a b s t r a c t

The role of haploidentical related allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Phila-delphia chromosomeepositive acute lymphoblastic leukemia (PhþALL) is not clear. We aimed to investigate the long-term survival of PhþALL patients who underwent haploidentical donor (HID)-HSCT and to analyze the factors influencing relapse and survival after allo-HSCT. The study population included PhþALL patients

who underwent haploidentical related allo-HSCT. Additionally, Phþ ALL patients who underwent HLA-matched related donor (MRD) transplants during the same period were included to compare outcomes. BCR-ABL transcript levels were analyzed by using real-time quantitative reverse transcription PCR. Clinical data from 139 PhþALL patients who received allo-HSCT in our center were analyzed. Of these patients, 101 received HID transplants and 38 received MRD transplants. At a median follow-up of 36 months, 5-year disease-free survival (DFS) and overall survival (OS) rates in the HID transplant group were 65.8% and 74.0%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates for the HID transplant group were 20.3% and 15.6%, respectively. In addition, there were no differences in OS, DFS, CIR, and NRM between the HID and MRD groups. Multivariate analysis showed that imatinib resistance was a significant factor influencing DFS and CIR in HID transplant patients. Haploidentical HSCT for the treatment of PhþALL achieves promising long-term survival, which is comparable with that of HLA-MRD HSCT. Imatinib resistance is a negative predictor of relapse and DFS after allo-HSCT.

Ó 2015 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

INTRODUCTION

Imatinib-incorporating induction and consolidation chemotherapy has been reported to increase complete remission (CR) and to improve the long-term survival of patients with Philadelphia chromosomeepositive acute lymphoblastic leukemia (Phþ ALL), regardless of whether they underwent allogeneic hematopoietic stem cell trans-plantation (allo-HSCT)[1-4]. Although it has been reported that imatinib mesylate in combination with intensive chemotherapy resulted in outcomes similar to allo-HSCT in pediatric patients with Phþ ALL [5], it has not been

demonstrated whether imatinib combination chemotherapy achieves comparable long-term survival to allo-HSCT in adult patients. Thus, allo-HSCT is still considered the best curative approach for adult patients with PhþALL[6,7].

The roles and outcomes of matched related donor (MRD) and matched unrelated donor (MUD) allo-HSCT have been reported [8,9]. Many studies of pretransplant imatinib therapy and survival advantage included patients who underwent MRD or MUD transplants [10-13]. However, haploidentical HSCT may be the optimal treatment choice for patients without a MRD or MUD. Several reports from our center demonstrated that haploidentical HSCT without in vitro T cell depletion can achieve promising long-term survival for patients with both malignant and nonmalig-nant hematological diseases [14-16]. In our previous prospective study, which investigated maintenance therapy with imatinib post-HSCT for Phþ ALL, the donor source

Financial disclosure: See Acknowledgments on page 1115.

* Correspondence and reprint requests: Xiao-jun Huang, MD, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11, Xizhimen South Street, Xicheng, Beijing 100044, China.

E-mail address:xiaojunhuang1@126.com(X.-j. Huang).

http://dx.doi.org/10.1016/j.bbmt.2015.02.009

1083-8791/Ó 2015 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

Biology of Blood and

Marrow Transplantation

j o u r n a l h o m e p a g e : w w w . b b m t . o r g

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included MRDs, MUDs, and haploidentical related donors

[17,18]. To date, a large population study describing the outcome of haploidentical HSCT for the treatment of PhþALL and comparing the outcomes of different donor type trans-plants between HLA-matched related and haploidentical HSCT has not been performed.

In this study, we aimed to investigate the long-term sur-vival of patients who underwent haploidentical HSCT for Phþ ALL treatment and to explore risk factors associated with relapse and long-term survival in a large cohort study. In addition, we compared the outcomes of haploidentical HSCT with matched related transplants for Phþ ALL during the same period in our center.

METHODS Patient Eligibility

Allo-HSCT recipients diagnosed with PhþALL (age< 60 years) who received transplants from HLA-haploidentical donors (HIDs) were eligible for the study. In addition, HLA-MRD transplants were also included in the study for comparison with HID transplants. The diagnosis of PhþALL was based on the World Health Organization diagnosis criteria[19]. Patients who displayed hypersensitivity or were determined to be imatinib resistant before HSCT were excluded from the study. This study was reviewed and approved by the ethics committee at Peking University People’s Hospital. All patients provided written informed consent before transplantation.

Chemotherapy before Transplantation

The induction chemotherapy regimen included daunorubicin, cyclophosphamide (Cy), vincristine, prednisone (VDCP), and L-asparaginase. Consolidation chemotherapy regimen included hyper-CVAD (B) (metho-trexate and cytosine arabinoside), high-dose metho(metho-trexate with/without L-asparaginase, and the VDCP regimen, which were given in turn. After 3 to 4 courses of consolidation therapy, patients entered the HSCT program. Prophylaxis for central nervous system leukemia was given to every enrolled patient, which consisted of intrathecal chemotherapy with methotrexate, cytosine arabinoside, and dexamethasone for at least 4 doses during induction and consolidation chemotherapy.

The enrolled patients followed the treatment diagram shown inFigure 1. If neither an HLA-identical related donor nor an unrelated donor were available after induction and consolidation chemotherapy (combined with imatinib), a haploidentical family donor was an alternative. Assessments of HLA haplotype mismatched donors were performed as described previously

[14-16].

Conditioning Regimen and Graft-versus-Host Disease Prophylaxis Myeloablative transplant conditioning regimens were administered as previously described [14,16-18]. For patients receiving haploidentical transplants, the conditioning regimens were (1) total body irradiation (TBI) with 7.7 to 12.0 Gy and Cy 1.8 g$m2d1 2 days; methyl-N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea (Me-CCNU, 250 mg$kg1d1) orally once on day3 or (2) cytosine arabinoside (4 g$m2d1) i.v. on days10 and 9,

busulfan (3.2 mg$kg1d1) i.v. on days8 to 6, Cy (1.8 g$m2d1) i.v. on

days5 and 4, and Me-CCNU, 250 mg$kg1d1orally once on day3. Both

conditioning regimens were supplemented with anti-human thymocyte Diagnosis of

Ph+ ALL WHO criteria

Induction

Chemotherapy ± Imatinib (400–600 mg/d)

Consolidation

Chemotherapy ± Imatinib (400–600 mg/d)

HLA-matched MUD Haploidentical Sibling HSCT HSCT Donor HSCT

Follow-up (Maintenance therapy with imatinib)

Figure 1. Treatment diagram for patients diagnosed with PhþALL. WHO

in-dicates World Health Organization.

Table 1

Patient Characteristics with Different Donor Type: Matched Related vs. Haploidentical Transplantation Items Matched Related HSCT (n¼ 38) Haploidentical HSCT (n¼ 101) P* Sex .692 Male 23 (60) 66 (65.3) Female 15 (40) 35 (34.7) Age, yr .001 <35 16 (42.1) 75 (74.2) >35 22 (57.9) 26 (25.8) WBC count <30  109/L 21 (55.2) 46 (44.4) .505 >30  109/L 17 (45.8) 55 (55.6) Disease status CR1 30 (78.9) 90 (89.1) .164 >CR1 8 (21.1) 11 (10.9) IM therapy pre-HSCT Yes 33 (86.8) 91 (90.1) .554 No 5 (13.2) 10 (9.9) Pre-HSCT qRT-PCR 0 15 (39.5) 46 (44.4) .569 >0 23 (60.5) 55 (55.6) Conditioning Bu/Cy 37 (97.3) 99 (98.0) 1.000 TBI/Cy 1 (2.7) 2 (2) Post-HSCT qRT-PCR, 30 d 0 19 (50) 93 .000 >0 19 (50) 8 Post-HSCT IM Yes 34 (89.5) 81 (80.2) .313 No 4 (10.5) 20 (19.8) Start of post-HSCT IM <3 mo 30 (88.2) 57 (70.4) .048 >3 mo 4 (11.8) 24 (29.6) Duration of IM therapy Post-HSCT <3 mo 11 (32.7) 33 (40.7) .826 >3 mo 23 (67.6) 48 (60.3) <6 mo 16 (47.1) 40 (49.4) .834 >6 mo 18 (52.9) 41 (5.6) IM resistant Yes 13 (34.2) 15 (14.9) .017 No 25 (65.8) 86 (85.1)

Bu indicates busulfan; TBI, total body irradiation; IM, imatinib. Values are number of cases with percents in parentheses.

*The criterion for statistical significance was P < .05.

Table 2

Engraftment and GVHD in haploidentical and matched related HSCT

Items Matched Related

HSCT (n¼ 38)

Haploidentical HSCT (n¼ 101)

P*

Median ANC engraftment, days (range) 15 (10-22) 12 (7-27) .001 Median BPC engraftment, days (range) 15 (7-31) 14 (9-150) .657 Acute GVHD Grades 0-I/II-IV 32/6 69/32 .045* Chronic GVHD 0/L/E 17/15/5 36/44/20 .499

ANC indicates absolute neutrophil count; BPC, blood platelet count.

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globulin (2.5 mg$kg1d1[Sang Stat, Lyon, France]) administered i.v. for 4 consecutive days (5 to 2). All transplant recipients received cyclosporine Aebased acute graft-versus-host disease (GVHD) prophylaxis. Supportive care was administered as described previously[14-16].

MRD Assessment

The levels of BCR-ABL transcripts in the bone marrow of patients were determined using TaqMan-based, quantitative, real-time, reverse tran-scription PCR (qRT-PCR) as previously described [20,21]. A complete molecular remission 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 usingfluorescence in situ hybridi-zation,flow cytometry, and qRT-PCR was scheduled for 1, 3, 6, 9, and 12 months post-HSCT and then once every 3 months during months 12 to 24 post-HSCT. Direct sequencing was performed to identify mutations in the BCR-ABL kinase domain if patients had increasing levels of BCR-ABL during imatinib therapy[22].

Imatinib Treatment after HSCT

After allo-HSCT, imatinib treatment was initiated if (1) patient peripheral blood absolute neutrophil counts were>1.0  109/L without

granulocyte colony-stimulating factor (G-CSF) administration and the

platelet count was>50.0  109

/L, regardless of BCR-ABL transcript levels, or (2) BCR-ABL transcript levels in the bone marrow increased in 2 consecutive tests or were high (102) after the initial engraftment. Imatinib treatment

was scheduled for 3 to 12 months after HSCT or when BCR-ABL transcript levels were negative at least for 3 consecutive tests and complete molecular remission was sustained for at least 3 months, as described in our previous report [17,18]. Additional criteria for initiation of treatment included whether patients could tolerate oral imatinib therapy without developing gut GVHD or a life-threatening infection. The initial dose of imatinib was 400 mg/d for adults (age> 17 years) and 260 mg$m2

$d1for children (age< 17 years). The daily dose of imatinib was adjusted according to the National Comprehensive Cancer Network practice guidelines regarding the management of imatinib toxicity (version 2005)[23].

Definitions

Imatinib-resistance was defined as (1) an increase in BCR-ABL transcript levels in 2 consecutive tests separated by1 month or (2) detection of point mutations in the BCR-ABL kinase domain during imatinib therapy or during readministration of imatinib post-transplant. Relapse was defined as >5% bone marrow blasts, the detection of circulating blasts, or the development of extramedullary leukemia.

Figure 2. DFS at 5 years in haploidentical and matched related HSCT (65.8% versus 61.0%, respectively; P ¼ .255).

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Statistical Analysis

Parametric tests were performed using chi-square or Fisher’s exact tests. The Mann-Whitney U test was used for nonparametric tests. Univariate analysis of disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse (CIR) for enrolled patients was conducted using Kaplan-Meier analysis and the log-rank test. Multiple regression analysis for DFS, OS, and CIR was conducted using a multiple Cox regression model. The covariates that were adjusted in the multiple regression models included factors identified in the univariate analysis with P <.1. Kaplan-Meier analysis was used to estimate DFS and OS, whereas the cumulative incidence was

calculated for nonrelapse mortality (NRM), GVHD, and relapse rate. The relapse rate and incidence of GVHD were also calculated by accounting for the competing risk of death due to other complications using a Fine-Gray model. Data analysis was performed using the SPSS 16.0 (IBM, Armonk, NY) and R (Bell Labs, New Providence, NJ) software packages, and P< .05 was considered statistically significant.

RESULTS Enrollment

From May 2005 to September 2012, 145 consecutive patients received allo-HSCT and 120 patients received imatinib maintenance therapy post-transplant. Among these patients, 101 received HID transplants, 38 received MRD transplants, and 6 received MUD transplants. Clinical data of 139 Phþ ALL patients who received either HID or MRD transplantation were analyzed. The median age of patients who received haploidentical transplants was 25 years (range, 3 to 51 years), and the median age of patients who received MRD transplants was 39 years (range, 7 to 62 years). The demographic characteristics and relevant transplantation data of patients undergoing HID transplants and MRD HSCT are shown inTable 1.

Imatinib Treatment

All enrolled patients achieved hematological remission and were in complete cytogenetic remission after initial engraftment. Additionally, 120 patients received imatinib therapy at a median time of 72 days post-HSCT (range, 20 to 270), and the median duration of imatinib therapy was 180 days (range, 30 to 540). In the haploidentical HSCT group, 81 patients received imatinib therapy at a median time of 78 days post-HSCT (range, 20 to 270), and the median duration of imatinib therapy was 180 days (range, 30 to 540). Twenty-five patients did not undergo imatinib therapy because of pancytopenia (n¼ 3), severe infections (n ¼ 8), severe gut GVHD (n¼ 8), or personal decisions (n ¼ 6).

Engraftment and GVHD

All 101 haploidentical transplant patients achieved myeloid engraftment, and all patients except 1 achieved platelet engraftment after HSCT (Table 2). All 101 patients survived>28 days and were evaluated for the development of acute GVHD. The number of patients who developed acute and chronic GVHD is shown inTable 2. In the HID group at 100 days post-HSCT, the cumulative incidence of grades I to IV, II to IV, and III to IV acute GVHD was 68.3% 4.6%, 38.4%  5.7%, and 17.6% 5.2%, respectively. One hundred patients survived>100 days post-transplant and were evaluated for chronic GVHD. The cumulative incidence of chronic and extensive chronic GVHD after 5 years for haploidentical HSCT was 68.5% .3% and 19.5%  7.1%, respectively. The incidence of grades III to IV acute and chronic GVHD did not differ between the HID group and MRD group (17.8% versus 8.2%, P¼ .343; and 68.5% versus 56.8%, P ¼ .620, respectively). However, the incidence of grades II to IV acute GVHD was higher in the HID group than in the MRD group (38.4.1% 5.3% versus 16.2% 6.1%, P ¼ .005, respectively).

NRM and Relapse Rates

At the time of the last follow-up (December 31, 2013), 16 patients in the haploidentical group had a relapse. Relapse included hematological relapse (n¼ 13) and extramedullary leukemia relapse (n¼ 3) at a median time of 14 months (range, 2 to 36). No cytogenetic relapse occurred without concurrent hematological relapse. There was no difference in the 5-year CIR between the HID and MRD transplant groups

Table 3

Univariate Analysis of Significant Predictors of DFS, OS, and CIR in Hap-loidentical Transplants

Risk Factors OS DFS CIR

Gender Male, n¼ 66 75.6% 65.9% 20.2% Female, n¼ 35 71.9% 65.5% 21.0% P .628 .981 .863 Age <35 yr (n ¼ 75) 71.2% 63.6% 22.3% 35 yr (n ¼ 26) 84.1% 71.4% 16.7% P .396 .360 .435 WBC count <30  109/L (n¼ 59) 83.3% 71.2% 21.3% 30  109/L (n¼ 42) 71.0% 63.0% 17.1% P .333 .449 .926 Disease status at HSCT CR1 (n¼ 90) 76.7% 67.8% 19.0% >CR1 (n ¼ 11) 58.2% 51.9% 30.7% P .337 .350 .926 IM pre-HSCT Yes (n¼ 91) 73.7% 66.1% 20.1% No (n¼ 10) 70.0% 60.0% 22.9% P .716 .618 .722 qRT-PCR BCR-ABL pre-HSCT >0 (n ¼ 46) 87.2% 74.0% 17.8% <0 (n ¼ 55) 62.4% 59.9% 22.6% P .007 .031 .455 Conditioning TBI/Cy (n¼ 2) 50.0% 50.0% 50.0% Bu/Cy (n¼ 99) 75.1% 66.4% 19.4% P .410 .650 .277 qRT-PCR BCR-ABL post-HSCT (þ30 d) >0 (n ¼ 93) 76.4% 66.2% 19.5% <0 (n ¼ 8) 56.2% 60.0% 30.0% P .320 .584 .425 IM post-HSCT Yes¼ 81 81.5% 72.2% 17.3% No¼ 20 44.4% 39.4% 20.6% P .000 .000 .681 Start of IM post-HSCT <3 mo (n ¼ 57) 84.1% 76.8% 81.8% >3 mo (n ¼ 24) 81.0% 64.6% 76.8% P .854 .481 .654 Duration of IM <3 mo (n ¼ 32) 76.0% 73.7% 83.6% >3 mo (n ¼ 49) 87.7% 69.3% 76.7% P .201 .846 .727 <6 mo (n ¼ 40) 77.5% 69.3% 76.4% >6 mo (n ¼ 41) 88.3% 74.2% 83.1% P .215 .418 .502 Acute GVHD Grades 0-I (n¼ 69) 76.9% 68.0% 26.5% Grades II-IV (n¼ 32) 61.4% 55.5% 14.4% P .023 .123 .227 Chronic GVHD 0 (n¼ 36) 77.3% 56.7% 26.6% L (n¼ 44) 73.3% 70.8% 17.9% E (n¼ 20) 74.3% 58.9% 17.0% P .989 .718 .658 IM resistant Yes (n¼ 15) 59.3% 12.5% 81.2% No (n¼ 86) 76.7% 74.0% 10.1% P .337 .002 .000

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(18.0% 4.7% versus 30.4%  8.2%, respectively, P ¼ .060). There was also no difference in the NRM between the HID and MRD groups (15.6% 4.0% versus 9.6%  5.3%, respec-tively, P¼ .751).

OS and DFS

At a median follow-up of 36 months (range, 2.5 to 104), the estimated 5-year probabilities of DFS and OS were 65.8%  5.2% and 74.0%  5.0% (P ¼ .255), respectively, for the HID group and 61.0% 8.2% and 68.2%  9.0%, respectively, for the MRD group (P¼ .457) (Figures 2 and 3). Twenty-three patients died after HSCT. The causes of death included relapse (n¼ 9), GVHD (n ¼ 3), infection (n ¼ 7), and other (n¼ 4).

Factors Affecting Long-Term Survival and Relapse Rate For 101 haploidentical HSCT patients, univariate analysis revealed that the pre-HSCT BCR-ABL transcript level (detec-ted by qRT-PCR) was a significant factor affecting DFS and OS (P¼ .007 and .031, respectively). Imatinib resistance was a significant factor that influenced DFS and CIR (P ¼ .002 and .000, respectively) (Table 3). Based on a multivariate analysis, imatinib resistance was a significant factor for DFS and CIR in HID HSCT. Imatinib therapy after transplant was a significant factor for DFS and OS in HID transplantation (Table 4). Multivariate analysis of 38 MRD transplant patients revealed that imatinib therapy post-HSCT was a significant factor for CIR, DFS, and OS (Table 5).

Relapse and Imatinib Resistance

During the post-transplant follow-up period, 28 patients in both the HID and MRD transplant groups were determined to be imatinib resistant. Fifteen of these patients were in the HID group. Imatinib resistance occurred during either ima-tinib therapy or imaima-tinib readministration after disease recurrence. Kinase domain mutations in BCR-ABL were detected in 15 of 28 patients. Among these patients, the T315I mutation was detected in 11 patients, and other point mutations in BCR-ABL were detected in 4 patients. Twenty-four of these patients were switched to treatment with second-generation tyrosine kinase inhibitors, including dasatinib (n ¼ 21) and nilotinib (n ¼ 3), and received chemotherapy plus donor lymphocyte infusion. Of these patients, 8 did not progress to hematological relapse. Sixteen

patients eventually experienced clinical relapse, and 10 of them died because of it. Only 4 patients received chemo-therapy plus donor lymphocyte infusion or a second HSCT, and all died (3 of 4 patients died of relapse). During the median follow-up period of 27.7 months, the estimated 3-year DFS and OS rates for 28 imatinib-resistant patients were 14.8% and 52.3%, respectively. The 3-year DFS and OS rates were 12.5% and 59.3%, respectively, in 15 imatinib-resistant patients in the HID group.

DISCUSSION

In recent years, imatinib combined with intensive chemotherapy before HSCT has greatly improved DFS and OS in patients with Phþ ALL compared with control subjects

[1,3,10-13]. In these studies, transplantation included both HLA-MRDs and MUDs. However, relapse is still one of the most common treatment failures during long-term follow-up. Therefore, it is necessary to investigate other treatment modalities, including alternative donor transplants (ie, mismatched related transplants) or other conditioning regi-mens for the treatment of PhþALL. In our study, 101 patients received haploidentical HSCT, with 5-year DFS and OS rates reaching 65.8% and 74.0%, respectively. This is the largest published report to date on patients with Phþ ALL who received haploidentical HSCT. The patients who underwent haploidentical transplant achieved identical outcomes compared with matched related transplants in our center during the same period and matched sibling transplants reported by other centers, although the demographic char-acteristics of the patients were not completely comparable between the different donor type groups and the different centers. There was also no difference in the NRM between the 2 transplant groups.

Most PhþALL patients treated with allo-HSCT receive TBI/ Cy as the conditioning regimen. Laport et al.[24]reported that fractionated TBI and high-dose VP16, with or without Cy, confers long-term survival in PhALL patients. In their study, the relapse rate did not significantly differ between patients in first CR (CR1) and beyond CR1 at transplant. In our study, all patients except 3 received modified busulfan/Cy-based con-ditioning and a novel approach using G-CSFeprimed bone marrow plus G-CSFemobilized peripheral blood stem cells without in vitro T cell depletion after conditioning in the HID group[14,16-18]. We achieved an outcome consistent with the

Table 4

Multivariate Analysis of Significant Predictors for DFS, OS, and CIR in Haploidentical Transplants

Variable DFS OS CIR

HR 95% CI P* HR 95% CI P* HR 95% CI P*

BCR-ABL(þ)pre-HSCT .6 .2-1.3 .236 .2 .1-1.1 .100 .4 .1-1.5 .277

IM therapy post-HSCT .2 .1-.5 .001 .2 .1-.6 .004 .7 .2-2.1 .556

IM resistance 3.2 1.5-7.0 .002 1.6 .6-4.4 .333 8.9 3.2-24.4 .000

95% CI indicates 95% confidence interval.

*The criterion for statistical significance was P < .05.

Table 5

Multivariate Analysis of Significant Predictors of DFS, OS, and CIR in HLA-Matched Related Transplants

Variable DFS OS CIR

HR 95% CI P* HR 95% CI P* HR 95% CI P*

Status (CR1/>CR1) .3 .1-1.1 .081 .2 .06-.6 .018 .4 .1-1.5 .287

IM therapy post-HSCT 13 3.7-49 .001 .1 .02-.4 .001 22 4.3-112 .002

IM resistance 6.0 2.3-16 .002 3.1 .8-9.4 .092 16 3.8-67 .001

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reports from other centers that use TBI-based conditioning for PhþALL in the era of imatinib. Factors affecting relapse in Phþ ALL patients after transplant have been discussed in many reports; they include remission status at transplant and minimal residual disease pre- and post-transplant[25,26].

Before the development of imatinib, Stirewalt et al.[25]

reported that the BCR-ABL transcript level post-transplant was a significant predictor of clinical relapse (P ¼ .001). Many studies indicated that OS and progression-free survival were significantly better for patients with Phþ ALL who

received transplants in CR1 than in patients with advanced disease who received HSCT[9,27]. In our study, detection of BCR-ABL transcript levels post-transplant (þ30 days) and disease status (>CR1) were not significant factors for pre-dicting clinical relapse in HID transplant patients. We believe this can be partially explained by the effects of imatinib maintenance therapy after HSCT. Kebriaei et al. [26]

demonstrated that the cumulative incidence of grades II to IV acute GVHD was associated with a significantly better progression-free survival in multivariate analyses (P¼ .01) for PhþALL after allo-HSCT. Additionally, Yanada et al.[28]

demonstrated that chronic GVHD was associated with a lower risk of relapse without an increase in the risk of treatment-related mortality and that PhþALL patients had better survival (P ¼ .0217). In our study, the incidence of grades II to IV acute GVHD was higher in the HID group than in the MRD group (P¼ .03). The incidence of chronic GVHD was as high as 68.5%. A recent study performed in our center to evaluate haploidentical transplant for the treatment of Ph ALL showed no differences in DFS and OS between standard-risk and high-risk ALL patients[29]. We also found superior graft-versus-leukemia (GVL) effects associated with HID transplants compared with MRD transplants for high-risk acute leukemia [30]. Therefore, we hypothesize that the favorable leukemia-free survival of haploidentical HSCT patients beyond CR1 and of patients detected with the BCR-ABL transcript post-transplant might primarily be due to the GVL effect caused by the high HLA disparity.

Our data also showed for grades III to IV acute GVHD no difference between the 2 donor type groups, and the NRM in haploidentical transplants was 15.6%, which was not different from that of MRD transplants. These results are consistent with the beneficial effect of mild to moderate GVHD, which was associated with a lower relapse rate but not an increased NRM[31-33]. Our previous study showed that maintenance therapy with imatinib post-HSCT reduced the relapse rate[18]. The donor types in this study included MRD (n¼ 19) and HID related (n ¼ 60) and unrelated donors (n¼ 3). Here, we found that imatinib therapy post-HSCT is not a significant factor affecting relapse rate in the HID transplant group, but it was still a significant influencing relapse in the MRD transplant group. We believe this is because of the small number of patients in the HID group who did not receive imatinib post-HSCT and because of the potential GVL effect conferred by HID transplant, which may influence the relapse rate in a multivariate analysis. In the future, a carefully designed controlled study may better define this problem.

Other studies showed that age was also a predictor for worse OS and DFS [26]. Our study classified patients as younger or older than 35 years, and more patients younger than 35 years were in HID group. Therefore, the median age was younger in the HID group. This is a limitation of the present study. With more older patients receiving HID transplants, we can better demonstrate our study conclusion.

Imatinib resistance remains a problem in a substantial proportion of patients with Phþ ALL during the period of imatinib therapy, and it is frequently observed with disease recurrence. Second-generation tyrosine kinase inhibitors (ie, dasatinib and nilotinib) have demonstrated promising ef fi-cacy in the treatment of imatinib-resistant PhþALL[34,35]. However, the prognosis of patients who showed relapse after allo-HSCT is extremely poor. We described imatinib resis-tance as a negative predictor for relapse and DFS after HSCT. Although our study showed that second-generation imatinib combined with donor lymphocyte infusion might improve the OS of imatinib-resistant patients after HSCT, the long-term survival is dismal with longer follow-up. Therefore, additional studies are required to investigate new treatment modalities and further reduce the relapse rate of PhþALL patients after allo-HSCT. In our present study we showed that less patients developed imatinib resistance in the HID group after transplant, which should be another limitation of the study. We believe this may be associated with more intensive GVL effect provided by HID transplants to reduce the MRD level, which could potentially develop imatinib resistance after transplant.

We conclude that haploidentical HSCT for Phþ ALL achieves promising long-term survival compared with matched related transplants, without increasing NRM, which suggests that haploidentical HSCT is an alternative approach for PhþALL patients without HLA matched donors. Imatinib resistance is a significant factor that affects relapse and DFS after transplantation.

ACKNOWLEDGMENTS

We are grateful to Edanz Group China for revision to and perfection of the manuscript.

Financial disclosure: This work was supported by grants from the Natural Science Foundation of China (no. 81230013), Beijing Science & Technology Program (no. Z141100000214011), and the Nature Science Foundation of China (no. 81170483).

Conflict of interest statement: There are no conflicts of in-terest to report.

Authorship statement: H.C. designed the research, inter-preted the data, and wrote the manuscript. K.-Y.L., X.-L.X., Y.-H.C., X.-Y.Z., W.H., X.-H.Z., Y.W., and Y.-Y.Z. performed the study and contributed to writing the manuscript. Y.-Z.Q. and Y.-R.L. performed the BCR-ABL RT-PCR andflow cytometry assays. X.-J.H., the principal investigator, designed the research, interpreted the data, and wrote the manuscript. All authors read and approved thefinal manuscript.

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Figure

Updating...

References

  1. http://dx.doi.org/10.1016/j.bbmt.2015.02.009
  2. w w w . b b m t . o r g
  3. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added tointensive combination chemotherapy for newly diagnosed
  4. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphiachromosome-positive acute lymphocytic leukemia with hyper-CVAD
  5. 2006;24:460-466
  6. Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant imatinib basedtherapy improves the outcome of allogeneic hematopoietic stem cell
  7. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up ofimatinib
  8. Forman SJ, O’Donnell MR, Nademanee AP, et al. Bone marrow trans-plantation for patients with Philadelphia chromosomeepositive acute
  9. Chao NJ, Blume KG, Forman SJ, et al. Long-term follow-up of allogeneicbone marrow recipients for Philadelphia chromosomeepositive acute
  10. Lee HJ, Thompson JE, Wang ES, et al. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future
  11. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on267 unselected adult patients with Philadelphia chromosomeepositive
  12. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus con-current schedules of imatinib and chemotherapy as frontline therapy
  13. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combinedwith induction or consolidation chemotherapy in patients with de
  14. Ribera JM, Oriol A, Gonzalez M, et al. Concurrent intensive chemo-therapy and imatinib before and after stem cell transplantation in
  15. Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased imatinibpulses improve long-term outcome of adult patients with Philadelphia
  16. Huang XJ, Liu DH, Liu KY, et al. Haploidentical hematopoietic stem celltransplantation without in vitro T-cell depletion for the treatment of
  17. Xu LP, Liu KY, Liu DH, et al. A novel protocol for haploidentical hemato-poietic SCT without in vitro T-cell depletion in the treatment of severe
  18. Wang Y, Liu DH, Xu LP, et al. Haploidentical/mismatched hematopoi-etic stem cell transplantation without in vitro T cell depletion for T cell
  19. Chen H, Liu KY, Xu LP, et al. Administration of imatinib in thefirst 90
  20. Chen H, Liu KY, Xu LP, et al. Administration of imatinib after allogeneichematopoietic stem cell transplantation may improve disease-free
  21. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization sification of neoplastic diseases of the haematopoietic and lymphoid
  22. Qin YZ, Liu YR, Zhu HH, et al. Different kinetic patterns of BCR-ABLtranscript levels in imatinib-treated chronic myeloid leukemia
  23. Beillard E, Pallisgaard N, van der Velden VH, et al. Evaluation ofcandidate control genes for diagnosis and residual disease detection in
  24. Qin Y, Chen S, Jiang B, et al. Characteristics of BCR-ABL kinase domainpoint mutations in Chinese imatinib-resistant chronic myeloid
  25. Management of Imatinib Toxicity. National Comprehensive CancerNetwork Clinical Practice Guideline in Oncology Chronic Myelogenous
  26. Laport GG, Alvarnas JC, Palmer JM, et al. Long-term remission of Phil-adelphia chromosomepositive acute lymphoblastic leukemia after
  27. Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse andoverall survival in Philadelphia chromosome-positive acute
  28. Kebriaei P, Saliba R, Rondon G, et al. Long-term follow-up of allogeneichematopoietic stem cell transplantation for patients with Philadelphia
  29. Doki N, Ohashi K, Oshikawa G, et al. Clinical outcome of hematopoieticstem cell transplantation for Philadelphia chromosome-positive acute
  30. 2005;36:867-872.
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