Neutropenia and anaemia associated with T‐cell large granular lymphocyte leukaemia responds to fludarabine with minimal toxicity

Sternberg, Alexander; Eagleton, Helen; Pillai, Nithiya; Leyden, Kevin; Turner, Sue; Pearson, Danita M.; Littlewood, Timothy; Hatton, Chris

doi:10.1046/j.1365-2141.2003.04148.x

Cited by 37 publications

(34 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sternberg et al reported the reversal of severe neutropenia and/or anemia in four patients treated with fludarabine [93], although the malignant clone persisted. Similar success has been reported in case reports using pentostatin [94,95].…”

Section: Natural History Prognosis and Therapy Of Lgl Leukemiamentioning

confidence: 99%

T-Cell Large Granular Lymphocyte Leukemia and Related Disorders

2004

View full text Add to dashboard Cite

Section: Natural History Prognosis and Therapy Of Lgl Leukemiamentioning

confidence: 99%

T-Cell Large Granular Lymphocyte Leukemia and Related Disorders

2004

View full text Add to dashboard Cite

“…These agents should be offered to young patients, particularly when relevant bone marrow infiltration is demonstrated. Successful responses to purine analogs have been reported in the majority of patients treated with pentostatin, fludarabine and 2-chlorodeoxyadenosine, [42][43][44] but the numbers of patients treated in this way are still very low. In selected cases, mainly refractory/relapsed patients with NK disorders, more aggressive strategies might be tried, with the use of L-asparaginase-containing regimens.…”

mentioning

confidence: 99%

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

View full text Add to dashboard Cite

F e r r a t a S t o r t i F o u n d a t i o nhaplotype with a higher frequency than the normal population, as occurs in patients with rheumatoid arthritis. In recent years progress has been made in understanding the mechanisms sustaining T-LGL leukemia and CLPD-NK. It is now becoming evident that the phenotype of T-cell LGL leukemia is consistent with that of fully differentiated cytotoxic T lymphocytes. The hallmark of T-LGL leukemia lymphocytes is the failure to undergo activation-induced cell death (AICD), this event being consequent to a critical impairment of apoptotic pathways. T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis. Like normal activated CTL, leukemic T-LGL cells exhibit activation of multiple survival signaling pathways. 6 However, unlike normal activated CTL, leukemic T-LGL cells are not sensitive to Fas-induced apoptosis, 20 a process that is essential for AICD. 21 Fas resistance can occur in cells with overexpression of the DISC inhibitory protein c-FLIP. This latter is constitutively expressed in leukemic LGL and prevents DISC formation and Fas-mediated apoptosis. 22 Several genes are likely to be involved in the above mentioned processes and gene expression profiling has revealed that leukemic LGL are characterized by the expression of genes affecting apoptosis, regulation of TCR signaling and immune response. 23 This supports the view that an uncoupling of activation and apoptotic pathways is responsible for the failure of AICD. In fact, genes that are up-regulated in leukemic LGL have antiapoptotic functions whereas those that are down-regulated are pro-apoptotic. Pathway-based microarray analysis also indicated that the balance of pro-apoptotic (ceramide and its analogs) and anti-apoptotic (sphingosine-1-phosphate, S1P) sphingolipid-mediated signaling is deregulated in leukemic LGL in favor of S1P. 23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1. Genes belonging to the BCL-2 family, such as the BCL-2 related X gene (BAX) are down-regulated, while the myeloid cell factor (MCL-1) is up-regulated. In primary leukemic LGL, Bid (which is down-regulated by interleukin-15) levels are low but are reversed following bortezomib treatment, with subsequent increases in LGL apoptosis. These data provide a novel molecular mechanism for interleukin-15 control of Bid whi...

show abstract

“…Since only few patients with LIGIV deficiency have been described, it is still unknown whether this syndrome, like NBS and ataxia teleangiectatica, is also associated with an increased cancer risk. However, the first patient with a known defect in NHEJ who was homozygous for a missense mutation in LIGIV developed an ALL at the age of 14 years (reviewed in O'Driscoll et al 4 and Girard et al 5 ). From the evidence presented above, LIGIV involved in NHEJ is a plausible candidate gene for a cancer predisposition syndrome.…”

mentioning

confidence: 99%

“…Also, fludarabine had been reported to ameliorate the cytopenias associated with T-LGL leukemia, without eradicating the leukemic clone. 4 Furthermore, fludarabine alone or combined with cyclophosphamide was reported to induce only partial remissions in T-LGL leukemia. 5 Patient 1 in our study achieved a durable remission without mitoxantrone, a response indistinguishable from cases 2 and 3 achieving CR with FND.…”

mentioning

confidence: 99%