Adult acute lymphoblastic leukemia

Faderl, Stefan; O’Brien, Susan; Pui, Ching Hon; Stock, Wendy; Wetzler, Meir; Hoelzer, Dieter; Kantarjian, Hagop M.

doi:10.1002/cncr.24862

Cited by 231 publications

(191 citation statements)

References 105 publications

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“…As the success of developing effective treatments that eliminate LICs in leukemia patients relies on the ability to detect the presence of all subtypes of LICs in patient samples, specific attention should be placed on using xenograft models to detect heterogeneous human LICs where MLL mutations (MLL-AFX1 specifically) may provide a diagnostic marker. As AML patients with MLL translocations are 62% more likely to lack therapeutic response to pan-AML treatment approaches, 32 we further suggest that therapeutic approaches that combat lymphoid leukemias 33 have remission-induction potential in AML patients with MLL-AFX mutations.…”

Section: Discussionmentioning

confidence: 84%

Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

Risueño

Campbell²,

Dingwall³

et al. 2011

Blood

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Xenotransplantation of acute myeloid leukemia (AML) into immunodeficient mice has been critical for understanding leukemogenesis in vivo and defining selfrenewing leukemia-initiating cell subfractions (LICs). Although AML-engraftment capacity is considered an inherent property of LICs, substrains of NOD/SCID mice that possess additional deletions such as the IL2R␥c null (NSG) have been described as a more sensitive recipient to assay human LIC function. Using 23 AML-patient samples, 39% demonstrated no detectable engraftment in NOD/SCID and were categorized as AMLs devoid of LICs. However, 33% of AML patients lacking AML-LICs were capable of engrafting NSG recipients, but produced a monoclonal T-cell proliferative disorder similar to T-ALL. These grafts demonstrated selfrenewal capacity as measured by in vivo serial passage and were restricted to CD34-positive fraction, and were defined as LICs. IntroductionOne of the most provocative observations in the field of human cancer biology has been the demonstration that some types of cancer are initiated and sustained by a rare population of cells that possess stem cell characteristics. 1,2 These cells, termed cancer stem cells (CSCs), are best described in human acute myeloid leukemia (AML), representing an aggressive hematopoietic malignancy where an impaired differentiation program results in the accumulation of immature myeloid blasts. 3,4 The identification of a rare self-renewing cell population termed leukemia-initiating cells (LICs) capable of initiating and sustaining growth of human leukemia was based on transplantation of primary AML cells into immunodeficient NOD/SCID mice. 3,4 LICs can be prospectively isolated based on surface-marker expression in the BM and peripheral blood of AML patients. 4,5 Because of their characteristics that include self-renewal and disease initiation, it has been proposed that these cells possess "stem cell-like" properties and are responsible for the occurrence of minimal residual disease (MRD) and related leukemia relapse. 6-9 As such, characterization of the LICs in human leukemia has become an important pursuit for understanding the human leukemogenic process to design new therapies capable of targeting LICs with the overarching goal of eradicating the disease.Although, AML-derived LICs are defined functionally in xenotransplantation models, different strains of immunodeficient mice have been studied to detect human AML-LICs. Initially SCID recipients 3 and subsequently NOD/SCID mice 4 have been widely used to model human leukemia and define the LIC fraction that is restricted to the CD34 ϩ population. 3,4 Further modification of the NOD/SCID, especially the absence of ␤2 microglobulin in NOD/SCID ␤2 Ϫ/Ϫ mice lacking the expression of MHC class I, diminishes host innate response and permits enhanced human leukemia engraftment. 10 More recently, IL2R␥c (CD132) deficient NOD/SCID mice have impaired signaling through multiple cytokine receptors, resulting in blocked NK-cell development and severely decreased immune response, ...

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Section: Discussionmentioning

confidence: 84%

Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

Risueño

Campbell²,

Dingwall³

et al. 2011

Blood

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“…By alternating and intensifying conventional chemotherapeutic drugs, the event-free survival (EFS) in children has dramatically improved from 71 to 83% in the 1990s to more than 90% nowadays. [1][2][3][4] In contrast, treatment results in adult patients with ALL have only marginally improved during the last decades. Large multicenter studies in adult patients reported 5-year EFS of only 30-50%, despite complete remission (CR) rates between 70-90%.…”

Section: Introductionmentioning

confidence: 99%

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40

et al. 2011

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Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is 480%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

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“…Published data show a disappointing longterm survival of 20% or less with chemotherapy alone (Dombret et al, 2002;Faderl et al, 2010). The combination of BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs), most commonly imatinib, with multi-agent chemotherapy regimens has improved outcomes, with complete response rates of 80-90%, and 5-year survivals in the 35-50% range (Thomas et al, 2004;Yanada et al, 2006;de Labarthe et al, 2007;Bassan et al, 2010;Fielding, 2010).…”

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confidence: 99%

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

Thyagu¹,

Minden²,

Gupta³

et al. 2012

Br J Haematol

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SummaryAlthough the combination of tyrosine kinase inhibitors with chemotherapy is widely used for young adults with Philadelphia chromosome positiveacute lymphoblastic leukaemia (Ph+ ALL), the outcome and safety of this combination using intensive paediatric-based protocols has not been well described. The clinical course of 32 adults age 18-60 years with Ph+ ALL treated with a paediatric-based protocol plus imatinib was evaluated. The complete response rate was 94%. Grade 3-4 infections, neuropathy, myopathy and liver function abnormalities were common, resulting in major treatment delays and dose reductions, and declines in performance status (physical deconditioning), particularly in patients aged 41-60 years. Median and 3-year overall survival (OS) was 40·7 months and 53%, respectively, and median and 3-year even-free survival (EFS) was 30·1 months and 50%, respectively. OS and EFS were inferior in deconditioned patients. Of 16 patients who underwent haematopoietic stem cell transplantation (HSCT) in first complete remission, six died of non-relapse complications. There was no significant difference in OS and EFS between transplanted and nontransplanted patients, based on an intention-to-treat and time-to-donor identification analysis. The combination of imatinib with a paediatric-based regimen in adults produced high response rates, but was associated with considerable toxicity and high non-relapse mortality post-HSCT.Keywords: leukaemia, chemotherapy, haematopoietic stem cell transplantation, acute lymphoblastic leukaemia, tyrosine kinase inhibitors.Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) has long been recognized as a high-risk subset of ALL. Published data show a disappointing longterm survival of 20% or less with chemotherapy alone (Dombret et al, 2002;Faderl et al, 2010). The combination of BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs), most commonly imatinib, with multi-agent chemotherapy regimens has improved outcomes, with complete response rates of 80-90%, and 5-year survivals in the 35-50% range (Thomas et al, 2004;Yanada et al, 2006; de Labarthe et al, 2007;Bassan et al, 2010;Fielding, 2010). Nevertheless, Ph+ disease remains a poor prognosis subgroup with unacceptably high relapse rates.Allogeneic haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) remains the standard of care in most centres, and is the only treatment demonstrated to cure a significant proportion of patients. Consequently, the goal of most approaches is to optimize complete response rates and prolong remission duration, thereby permitting a larger proportion of patients to proceed to HSCT in CR1. The outcome of HSCT is largely influenced by transplant-related mortality (TRM) and post-transplant relapse. Early TRM is influenced by various factors, including pretransplant patient-related issues, toxicity of the conditioning regimen, and graft-versus-host disease (GVHD) (Sorror et al, 2005;Artz et al, 2006).For Ph-negative ALL, a number of studies in adolescents ...

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Adult acute lymphoblastic leukemia

Cited by 231 publications

References 105 publications

Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

Identification of T-lymphocytic leukemia–initiating stem cells residing in a small subset of patients with acute myeloid leukemic disease

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

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