Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR–ABL-positive ALL

Mizuta, Shuichi; Matsuo, Keitaro; Maeda, Tomoya; Yujiri, Toshiaki; Hatta, Yoshihiro; Kimura, Yukihiko; Ueda, Yasunori; Kanamori, Heiwa; Usui, Noriko; Akiyama, Hideki; Takada, Satoru; Yokota, Akira; Takatsuka, Yuichi; Tamaki, Sigehisa; Imai, Kiyotoshi; Moriuchi, Yukiyoshi; Miyazaki, Yasushi; Ohtake, Shigeki; Ohnishi, Kazunori; Naoe, Tomoki

doi:10.1038/bcj.2012.18

Cited by 26 publications

(28 citation statements)

References 23 publications

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“…These results confirm the observations made in our previous study based on the use of dasatinib in induction, 16 and are in line with the current general knowledge on the prognostic impact of MRD. 12,19,[37][38][39][40][41][42][43] Furthermore, they strengthen the notion that MRD negativity should be regarded as a major goal in Ph + ALL treatment. Indeed, with few exceptions, 20,38 it is now well established that BCR-ABL1 transcript levels correlate with response.…”

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confidence: 60%

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

et al. 2016

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In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0-79.3 vs. 20%, 95%CI: 5.8-69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3-82.6 vs. 20%, 95%CI: 5.8-69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2-38.6 vs. 60.0%, 95%CI: 21.6-84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1 p190 patients showed a significantly faster molecular response than BCR-ABL1 p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

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confidence: 60%

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

et al. 2016

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“…In this largest sample study, we extended the established MRD experience in the MDST, MUDT, and CBT settings and showed that, in unmanipulated haplo‐SCT modality, ( a ) pre‐MRD status was associated with a higher incidence of relapse as well as lower LFS and OS; ( b ) the levels of pre‐MRD were also correlated with CIR, LFS, and OS; and ( c ) a scoring system that could be used in predicting transplant outcomes, including relapse, LFS, and OS, was effectively established based on pre‐MRD. Our study adds novel evidence, suggesting that the incorporation of MRD platforms into the monitoring of patients with ALL pretransplantation is a transformative approach in the risk stratification of cases with this clinically challenging disease.…”

Section: Discussionmentioning

confidence: 96%

“…In allo‐SCT settings, the importance of pretransplantation MRD (pre‐MRD) status is gaining appreciation based on several publications showing significantly inferior outcomes for ALL patients with positive pre‐MRD, and possibly, the clinical benefit accrued by an allo‐SCT in ALL patients with a suboptimal MRD response to initial induction chemotherapy . However, these studies, with heterogeneous conditioning regimen, stem cell source, and graft‐vs‐host disease (GVHD) prophylaxis, mainly focused on human leukocyte antigen (HLA)‐matched related (MSDT) and unrelated donor transplantation (MUDT) as well as cord blood transplantation (CBT) . With the increased use of haploidentical SCT (haplo‐SCT) in ALL patients, it is becoming increasingly imperative to determine the role of pre‐MRD studies may assume in prognostication of patients with ALL who underwent haplo‐SCT.…”

Section: Introductionmentioning

confidence: 99%

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

Zhao

Liu

et al. 2019

American J Hematol

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This study evaluated the effects of pretransplantation minimal residual disease (pre-MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical stem cell transplantation (haplo-SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T-ALL or B-ALL, patients with positive pre-MRD had a higher incidence of relapse (CIR) than those with negative pre-MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia-free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre-MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre-MRD. A risk score for CIR was developed using the variables pre-MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2-3, respectively (P < 0.001). Three-year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS.The results indicate that positive pre-MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo-SCT.

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“…As clinical trial in Japan, 60 patients received allo-HCT in CR1 in the JALSG Ph+ALL202 study (registered between September 2002 and May 2005) 20 and 43 patients received allo-HCT in CR in the Japan Adult Leukemia Study Group (JALSG) Ph+ALL208IMA study (registered between October 2008 and December 2010). 21 Additional data for the use of pre-and post-transplant TKI administration and MRD at and after allo-HCT were collected for this study.…”

Section: Patientsmentioning

confidence: 99%

Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT

Nishiwaki

Imai

Mizuta

et al. 2015

Bone Marrow Transplant

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To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(− )) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD( − ) was significantly better than that in patients transplanted in MRD(+) (MRD( − ): 67% vs MRD(+): 55% at 4 years; P = 0.001). MRD( − ) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD( − ) was significantly lower than that in patients transplanted in MRD(+) (MRD( − ): 19% vs MRD(+): 29% at 4 years; P = 0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P o0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph +ALL patients transplanted in CR1.

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Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR–ABL-positive ALL

Cited by 26 publications

References 23 publications

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT

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