Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease

Yanada, Masamitsu; Naoe, Tomoki; Iida, Hiroatsu; Sakamaki, Hisashi; Sakura, Toru; Kanamori, Heiwa; Kodera, Yoshihisa; Okamoto, Shinichiro; Kanda, Yoshinobu; Sao, Hiroshi; Asai, Osamu; Nakai, Kenta; Maruta, Atsuo; Kishi, Kenji; Furukawa, Tatsuo; Atsuta, Yoshiko; Yamamoto, Kazuhito; Tanaka, Junji; Takahashi, Satoshi

doi:10.1038/sj.bmt.1705148

Cited by 43 publications

(35 citation statements)

References 31 publications

(21 reference statements)

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“…The latter can be explained by the well-known poor GVT effect for high-risk AL, including blast crisis of CML and myeloma. 2 Such results are not completely surprising 10,[13][14][15][16][17][18][19] reflecting also the dismal response of very fast-growing hematological diseases as well as the higher toxicity of the procedure in heavily pre-treated patients. However, these data may be tempered as better outcomes may be obtained in some selected subgroups according to pre-transplant variables, as previously described by Duval et al 10 in patients with active relapsed/refractory AL after myeloablative conditioning regimens.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Chevallier

Labopin

Milpied

et al. 2013

Bone Marrow Transplant

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for the SFGM-TC Previous data suggested that allo-SCT might be an effective therapy in the setting of chemo-refractory/relapsed diseases because of the potent long-term immune-mediated tumor control. This retrospective study aimed to analyze the outcome of adult patients who received allo-SCT in a chemo-refractory/relapsed status. The series included 840 patients with active or progressive disease at the time of transplant. Median age was 50 years. With a median follow-up of 40 months, 3-year OS, disease-free survival (DFS), and non-relapse mortality rates were 29 ± 2, 23 ± 2, and 30 ± 2%, respectively. At the last follow-up, 252 patients (30%) were still alive (of whom 201 were in CR (24%). In a Cox multivariate analysis, the use of a reduced-intensity conditioning (RIC) before allo-SCT and use of an HLA-identical sibling donor remained independently associated with a better OS (hazard ratio (HR) ¼ 0.82; 95% confidence interval (CI), 0.69-0.98, P ¼ 0.03; and HR ¼ 0.79; 95% CI, 0.66-0.93, P ¼ 0.006, respectively). Also, a diagnosis of myelodysplastic syndrome/myeloproliferative disorder, Hodgkin lymphoma and non-Hodgkin lymphoma compared with acute leukemia had a favorable impact on OS (HR ¼ 0.55; 95% CI, 0.45-0.68, Po0.0001; HR ¼ 0.49; 95% CI, 0.31-0.75, P ¼ 0.001; and HR ¼ 0.47; 95% CI, 0.35-0.63, Po0.0001, respectively). In conclusion, this study suggests that allo-SCT may be of benefit in some subgroups of patients with active or progressive hematological malignancies at the time of allo-SCT.

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Section: Discussionmentioning

confidence: 99%

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Chevallier

Labopin

Milpied

et al. 2013

Bone Marrow Transplant

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“…13,[16][17][18] In a retrospective review of 197 patients with Ph + ALL who underwent allogeneic SCT, the 5-year survival rates were 34% for patients in first CR, 21% for those in second or subsequent CR, and 9% for those with active disease (P < .0001). 19 Multivariate analysis identified that younger age, CR at the time of SCT, conditioning with total body irradiation, and an HLA-identical sibling donor were factors associated with improved survival. Newer modalities such as nonmyeloablative conditioning regimens or donor cells derived from umbilical cord blood have increased the applicability of allogeneic SCT, but a significant proportion of patients remain ineligible for this potentially curative approach and are in need of novel therapy.…”

Section: Allogeneic Stem Cell Transplantation For Phmentioning

confidence: 99%

Philadelphia Chromosome–Positive Acute Lymphocytic Leukemia: A New Era of Challenges

Thomas

2007

Hematology

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IntroductionThe Philadelphia (Ph) chromosome is the most frequent karyotypic aberration in adults with acute lymphocytic leukemia (ALL). 1 It occurs in 20% to 30% of adult patieints with ALL overall, with the incidence rising to more than 50% in patients aged 50 years or older.2 The Ph chromosome results from the reciprocal translocation that fuses the BCR (breakpoint cluster region) gene from chromosome 22 to the ABL (Abelson tyrosine kinase) gene from chromosome 9.3-6 This translocation [t(9;22)(q34;q11)] ultimately results in a constitutively active tyrosine kinase protein. The location of the breakpoint within the BCR gene results in either the p190bcr-abl protein exclusively observed in Ph + ALL, or the p210bcr-abl protein common to 20% to 40% patients with Ph + ALL and nearly all patients with Ph + chronic myelogenous leukemia (CML).

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“…Thus, patients who developed extensive chronic GVHD had better survivals (P = .0217), and those who developed grade III-IV acute GVHD had worse survivals (P = .0023) than did the others. 36 Immunotherapy with donor lymphocyte infusion (DLI) and imatinib appears to be well tolerated but is rarely and in general only transiently effective. A rationale for the combined use of DLI and second-generation TKIs such as nilotinib is suggested by case reports, but prospectively collected data are as yet not available.…”

Section: Allogeneic Stem Cell Transplantation With Myeloablative Condmentioning

confidence: 99%

“…An intensified preparatory regimen consisting of SCT after fractionated total body irradiation and etoposide with or without cyclophosphamide was explored by Kröger et al 34 and Laport et al 35 TRM was mainly due to infections or GVHD, and was higher in patients with more advanced disease. 35,36 Factors affecting event-free and overall survival likewise included disease status (CR1 vs > CR1) and higher age, with a cutoff at approximately 30 years, at the time of transplantation. [32][33][34][35] Thus, while these intensified preparatory regimens confer long-term survival in a subset of patients with Ph + ALL, relapse and TRM remain important causes of treatment failure, making success unlikely in patients with more advanced disease.…”

Section: Allogeneic Stem Cell Transplantation With Myeloablative Condmentioning

confidence: 99%

Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)

Ottmann¹,

Pfeifer²

2009

Hematology

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The tyrosine kinase inhibitor (TKI) imatinib has become an integral part of front-line therapy for Ph + ALL, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Acquired resistance on TKI treatment is associated with mutations in the bcr-abl tyrosine kinase domain in the majority of patients, and may be detected at low frequency prior to TKI treatment in a subset of patients. Second generation TKIs, eg, dasatinib and nilotinib, show activity against most of the bcr-abl tyrosine kinase domain (TKD) mutations involved in acquired imatinib resistance, but clinical benefit is generally short-lived. Accordingly, SCT in first complete remission (CR) is considered to be the best curative option. Molecular monitoring of minimal residual disease levels appears to have prognostic relevance and should be used to guide treatment. International standardization and quality control efforts are ongoing to ensure comparability of results. Mutation analysis during treatment relies increasingly on highly sensitive PCR techniques or denaturing HPLC and may assist in treatment decisions, eg, in case of molecular relapse. Results from current studies of second-generation TKI as front-line treatment for Ph + ALL are promising and show high molecular response rates, but follow-up is still too short to determine their impact on remission duration and long-term survival. Strategies to improve outcome after SCT include the pre-emptive use of imatinib, which appears to reduce the relapse rate. In patients ineligible for transplantation, novel concepts for maintenance therapy are needed. These could involve novel immunotherapeutic interventions and combinations of TKI. P hiladelphia chromosome (Ph)/BCR-ABL-positive acute lympoblastic leukemia (ALL) is the largest genetically defined subtype in adult ALL, and until recently the one with the most unfavorable prognosis. Introduction of the tyrosine kinase inhibitor (TKI) imatinib in combination chemotherapy has led to a marked improvement in treatment outcome of this leukemia; survival now ranges from 40% to 50%. Remarkably, patients with Ph + ALL now have a better prognosis than patients with bcrabl-negative high-risk B-precursor ALL.1 It has become clear that these improvements are not attributable to TKI alone, but depend on the implementation of an integrated strategy incorporating chemotherapy, stem cell transplantation (SCT), second-generation TKIs and molecular monitoring to guide therapeutic decisions.2 Despite these advances, substantial obstacles remain. Ph + ALL is notorious for its ability to rapidly develop resistance to TKI, with bcr-abl tyrosine kinase domain mutations being a major, but not the only, culprit.3-5 Furthermore, the incidence of Ph + ALL increases with age, limiting the option of allogeneic SCT in a significant pro...

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Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease

Cited by 43 publications

References 31 publications

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Philadelphia Chromosome–Positive Acute Lymphocytic Leukemia: A New Era of Challenges

Management of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)

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