Mature T‐cell leukemias

Ravandi, Farhad; Kantarjian, Hagop; Jones, Dan; Dearden, Claire; Keating, Michael J.; O’Brien, Susan

doi:10.1002/cncr.21405

Cited by 26 publications

(13 citation statements)

References 214 publications

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“…Human mature T-cell leukemias/lymphomas are less frequent and occur predominantly in older patients after a long latency. 17 In clinical trials involving gene transfer into mature T cells, leukemia was never observed, despite follow-up assessments of more than 10 years. [18][19][20][21] On the other hand, in none of the T-cell trials was such a high level of gene marking achieved as in the SCID-X1 trial, and in SCID-X1 the selective advantage mediated by transgene expression may also have contributed to leukemic transformation.…”

Section: Introductionmentioning

confidence: 99%

Resistance of mature T cells to oncogene transformation

Newrzela

Cornils

et al. 2008

Blood

184

141

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Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or ⌬TrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1-deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received IntroductionGamma retroviral vectors integrate into the target cell genome, thus supporting long-term transgene expression. They are among the best-established therapeutic vector systems and have successfully been used for gene transfer to hematopoietic stem cells (HSCs) in the treatment of X-linked and adenosine deaminase-deficient severe combined immunodeficiency (SCID). A limitation of retroviral gene transfer to HSC has been the risk of insertional mutagenesis, which was reported to lead to the preferential expansion of individual hematopoietic cell clones (clonal dominance) or even overt leukemia/lymphoma. 1 At the date of submission, 4 human cases of leukemia resulting from retroviral insertional mutagenesis had been described, all after initially successful treatment of X-linked SCID. 2-4 Three of these cases were associated with the activation of the T-cell oncogene LMO2 near the retroviral integration site, and all cases manifested as T-cell lineage leukemias. 5 It has been long known that leukemias can be linked to specific chromosomal translocations that juxtapose a strong promoter/ enhancer element to a cellular oncogene, such as LMO2 or TCL1, 6,7 thus up-regulating the expression of the oncogene. For several of these oncogenes, transgenic mouse models have confirmed their transforming activity. 8,9 LMO2-transgenic mice develop T-cell leukemia of an immature phenotype, whereas TCL1 is found to induce mature T-cell malignancies. A deletion mutant of the receptor tyrosine kinase TrkA (⌬TrkA) for nerve growth factor was described that is constitutively active. ⌬TrkA was found to generate acute myeloid leukemia as well as immature T-cell leukemia after retroviral gene transfer and a very short latency period. 10 Activation of potential oncogenes by retroviral insertion alone is not thought to be sufficient for transformation. 11,12 One factor that may determine the penetrance of overt leukemia after oncogene activation is thought to be the level of cell lineage differentiation. In general, stem cells a...

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Section: Introductionmentioning

confidence: 99%

Resistance of mature T cells to oncogene transformation

Newrzela

Cornils

et al. 2008

Blood

184

141

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“…Although treatments are much more variable in mature T-cell leukemias, we noted in a series from M. D. Anderson Cancer Center that T-LGL has, despite severe symptoms, a good outcome, while Sézary leukemia is of intermediate prognosis, and T-PLL has a poor outcome [11]. Anti-viral therapy is of central prognostic importance in ATLL [13,26].…”

Section: Prognostic Models For Tcl/lmentioning

confidence: 94%

Clinical Management of Non-cutaneous T-cell and NK-cell Malignancies

Herling

2009

Neoplastic Hematopathology

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Abstract/Scope of Chapter The uncommon but heterogeneous group of peripheral T-cell lymphomas and leukemias are now recognized to be derived from various functional subsets of post-thymic (mature) T cells. Conventional multi-agent chemotherapeutic regimens, developed primarily for B-cell tumors, generally work poorly for T-cell tumors. In this chapter, we outline the current clinical approaches to staging, outcome prediction, and therapy in T-cell and NK-cell malignancies presenting in the lymph node, peripheral blood, bone marrow and at extranodal sites with the exception of cutaneous T-cell lymphomas and Sézary syndrome which are covered in Chap. 25. We describe frontline and salvage therapies, introduce prognostic models, and evaluate the role of autologous and allogeneic stem cell transplantation. Finally, an overview of novel T-cell selective therapeutic agents is presented.

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“…Alkylating agents, including chlorambucil, are usually not effective in B-PLL when used in monotherapy. A greater number of responses including some complete ones, have been obtained with the combination of cyclophosphamide, vincristine and prednisone (COP) or additionally with hydroxirubicin (CHOP) [21,41] . However, the median response duration was similar to that obtained with COP and usually not longer than 30 months.…”

Section: Medical Needmentioning

confidence: 99%

“…However, case reports have described patients with CD4 + CD8 -, CD4 + CD8 + , and CD4 -CD8 - [32] . An increase in the number of circulating LGLs greater than 2.0 × 10 9 L lasting for more than six months is the necessary criterion for diagnosis [21] . Demonstration of clonality of T-LGL is required to establish the diagnosis of these leukemias.…”

Section: T-cell Large Granular Lymphocyte Leukemiamentioning

confidence: 99%

Emerging drugs for rarer chronic lymphoid leukemias

Robak

2008

Expert Opinion on Emerging Drugs

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Mature T‐cell leukemias

Cited by 26 publications

References 214 publications

Resistance of mature T cells to oncogene transformation

Resistance of mature T cells to oncogene transformation

Clinical Management of Non-cutaneous T-cell and NK-cell Malignancies

Emerging drugs for rarer chronic lymphoid leukemias

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