Haploidentical hematopoietic stem cell transplantation for pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia in the imatinib era

doi:10.1016/j.leukres.2017.05.021

Leukemia Research

Volume 59, August 2017, Pages 136-141

https://doi.org/10.1016/j.leukres.2017.05.021 Get rights and content

Highlights

•
Allo-HSCT remains an important curative option for children with Ph+ ALL.
•
The role of HID HSCT in pediatric patients with Ph+ ALL has not been reported.
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The 5-year EFS and OS were 61.0% and 70.0% in HID HSCT for children with Ph+ ALL.
•
The 3-year incidence of relapse and non-relapse mortality were 22.7% and 16.4%.
•
BCR-ABL positivity on +30 day post-HSCT was a significant factor for relapse.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important curative option for children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have a poor response to chemotherapy plus imatinib. For such children, if there are no matched related or unrelated donors, alternative donor transplantation may be a choice. The role of haploidentical donor (HID) HSCT in pediatric patients with Ph+ ALL has not been reported. The study population included pediatric patients with Ph+ ALL who underwent HID-HSCT. BCR-ABL transcript levels were analyzed using real-time quantitative reverse transcription polymerase chain reaction. At a median follow-up of 34 months, the 5-year probabilities of event-free survival (EFS) and overall survival (OS) were 61.0% and 70.0%, respectively in HID HSCT. The 3-year incidence of relapse and non-relapse mortality was 22.7% and 16.4%. Multivariate analysis showed that the post-HSCT BCR-ABL transcript level on +30 day was a significant factor affecting relapse rate. HID HSCT for the treatment of pediatric patients with Ph+ ALL yielded promising long-term survival. Post-HSCT BCR-ABL transcript positivity was a significant factor for clinical relapse after allo-HSCT in the imatinib era.

Introduction

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in children was associated with a very poor prognosis despite the use of intensive chemotherapy, compared with Ph (−) ALL in children, before the advent of tyrosine kinase inhibitors (TKI). Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was the best curative therapy for children with Ph+ ALL [1], [2], [3]. Although chemotherapy combined with imatinib has greatly increased complete remission rate and remission duration in patients with Ph+ ALL, allo-HSCT is considered as an important curative treatment in younger adults with Ph+ ALL in many reports [4], [5], [6].

Recent studies showed that children and adolescents with Ph+ ALL treated with intensive chemotherapy plus intensive imatinib achieved an excellent long-term survival (70%), and allo-HSCT did not show an advantage [7]. In another key study (EsPhALL study), outcomes for pediatric patients with Ph+ ALL group who did not undergo HSCT appeared inferior to that observed in the transplanted cohort if they had available donors, but the number of patients who didn’t receive transplant was relative small [8]. Although allo-HSCT in first remission is not routinely recommended for all pediatric patients with Ph+ ALL, it may still be an important treatment option for children with Ph+ ALL, especially for those patients with poor response to chemotherapy plus TKI who have available donors.

Many studies showed that the addition of imatinib to chemotherapy in pediatric Ph+ ALL followed by allo-HSCT achieved a superior outcome compared with that of historical controls and results reported before the imatinib era [9], [10]. In almost all of these studies, matched related and matched unrelated donors were used for transplantation. We have had several reports from our center regarding haploidentical HSCT without in vitro T cell depletion that achieved promising long-term survival for patients, including both Ph+ ALL and Ph- ALL [11], [12]. However, no studies have documented the use of allo-HSCT with HID specifically for the treatment of children and adolescents with Ph+ ALL.

Therefore, in this study we aimed to explore the role of haploidentical HSCT for the treatment of pediatric patients with Ph+ ALL and investigated factors affecting the relapse rate and long-term survival of these children.

Section snippets

Patient eligibility

Pediatric patients between 1 and 18 years of age with Ph+ ALL who underwent haploidentical HSCT were consecutively enrolled. The diagnosis of Ph+ ALL was based on the World Health Organization diagnosis criteria [13]. All patients with ALL were screened for the diagnosis of Ph+ ALL using reverse transcription polymerase chain reaction (RT-PCR). The presence of the Philadelphia chromosome was also tested by standard karyotyping and/or FISH analysis for the BCR–ABL fusion gene. This study was

Enrollment

From December 2006 to March 2015, 58 consecutive pediatric patients with Ph+ ALL received allo-HSCT. Among these patients, 50 received HID transplant, and their median age was 13 years (range, 4–18 years). They received a median of six cycles of chemotherapy before HSCT (range, 3–14 cycles), and the median time from diagnosis to transplant was 180 days (range, 118–888 days). The demographic characteristics and relevant transplantation data of pediatric patients with Ph+ ALL undergoing HID

Discussion

In the imatinib era, the role of allo-HSCT for the treatment of pediatric patients with Ph+ ALL has been changing, largely because of results of the COG AALL003 study, which reported that allo-HSCT did not improve survival compared with intensive chemotherapy plus intensive imatinib therapy [7]. However, outcomes for pediatric patients who underwent HSCT in the EsPhALL study appeared superior to those in the non-transplant cohort, but limited by small number of patient without receiving

Conclusion

We conclude that HID HSCT could achieve promising long-term survival for pediatric patients with Ph+ ALL. BCR/ABL positivity post-transplant on +30 day was associated with increased risk for relapse after allo-HSCT in the imatinib era. There was some limitation in the current study including patients’ number. Carefully designed controlled study is needed to investigate whether HID transplant is preferable to children with BCR/ABL transcript positivity before transplant compared with intensive

Author contributions

H.C. designed the research, interpreted the data, and wrote the manuscript. K.-Y.L., P.-L.X., Y.-H.C., X.-H.Z., Y.W. performed the study and contributed to writing the manuscript. Y.-Z.Q. and Y.-R.L. performed the BCR-ABL RT-PCR and flow cytometry assays. Y.-Y. L. performed Karyotyping and FISH analysis. X.-J.H., the principal investigator, designed the research, interpreted the data, and wrote the manuscript. All authors read and approved the final manuscript.

Conflict of interest

There are no conflicts of interest to report.

Funding

This work was supported by grants from The Key Program of National Natural Science Foundation of China (No. 81230013) and from Scientific Research Foundation for Capital Medicine Development (No. CD 2016-1-4082).

Acknowledgement

We are grateful to Editage Group China for revisingand finalizing the manuscript.

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Studies using third-generation tyrosine kinase inhibitor (TKI) as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) harboring the T315I mutation remain scarce. We conducted a cohort study to evaluate the safety and outcomes of ponatinib maintenance therapy after HCT in Ph+ALL patients with T315I mutation. BCR-ABL kinase domain mutations were assessed using direct sequencing. Twenty-six Ph+ALL patients with T315I mutation who received allogeneic HCT were enrolled. After HCT, ponatinib was administered as a prophylactic regimen (n = 12) or a preemptive therapy (n = 7). Seven patients did not receive maintenance therapy. Adverse events (AEs) occurred in 69.4 % of patients with ponatinib maintenance, but most presented with mild toxicities. Serious non-hematological AEs were not observed. The 5-year disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse in patients receiving prophylactic ponatinib were 81.5 %, 91.7 %, and 18.5 %, respectively, whereas they were 39.8 %, 46.0 %, and 48.4 % in the total cohort, respectively. The measurable BCR-ABL transcripts in the first three months after HCT was associated with poor DFS and OS, even with ponatinib therapy. We concluded that maintenance therapy with ponatinib is safe after HCT. Patients with T315I mutation who received prophylactic regimen showed promising results with an acceptable relapse rate and encouraging survival. However, patients with measurable BCR-ABL transcripts early post-transplant had poor outcomes.
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The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.
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Research paperHaploidentical hematopoietic stem cell transplantation for pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia in the imatinib era

Highlights

Abstract

Introduction

Section snippets

Patient eligibility

Enrollment

Discussion

Conclusion

Author contributions

Conflict of interest

Funding

Acknowledgement

Blood

Lancet Oncol.

Biol. Blood Marrow Transplant.

Biol. Blood Marrow Transplant.

Biol. Blood Marrow Transplant.

Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005

J. Clin. Oncol.

Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995

Leukemia

Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia

N. Engl. J. Med.

Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

Leukemia

Pre-transplant imatinib based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia

Leukemia

Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0031

Leukemia

Clinical outcome of children with newly diagnosed Philadelphia chromosome- positive acute lymphoblastic leukemia treated between 1995 and 2005

J. Clin. Oncol.

Br. J. Haematol.

Research paper
Haploidentical hematopoietic stem cell transplantation for pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia in the imatinib era