ETV6–RUNX1 ALL Reveals That NCI Risk, Rather Than Secondary Genetic Abnormalities, Is the Key Risk Factor

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ETV6–RUNX1 ALL Reveals That NCI Risk, Rather Than Secondary Genetic Abnormalities, Is the Key Risk Factor Letters to the Editor 2254 treated with vitamin E, which reduced ROS by approximately 3Abteilung Haematologie/Onkologie, Universitaetsklinikum twofold (Figure 1a).9,11 Jena, Jena, Germany and Human CD45 þ cells collected from bone marrows and spleens 4Department of Immunology, Medical University of Warsaw, of NSG mice formed colonies in vitro, and vitamin E treatment did Warsaw, Poland not affect the engraftment (Figure 1b). Imatinib-resistant clones E-mail: [email protected] carrying either E255K or T315I BCR-ABL1 kinase mutations were detected in three out of five untreated xenografts, but in none of the vitamin E-treated samples (Table 1). REFERENCES In conclusion, we postulate that anti-oxidants such as vitamin E 1 Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in may be applicable in prevention of TKI-resistance, in particular of human cancer. Nat Rev Cancer 2007; 7: 441–453. that driven by BCR-ABL1 kinase mutations. Moreover, as imatinib- 2 Eiring AM, Khorashad JS, Morley K, Deininger MW. Advances in the treatment of treated CML-CP LSCs and LPCs continue to accumulate high levels chronic myeloid leukemia. BMC Med 2011; 9:99. of ROS resulting in TKI-resistant mutations,9,10 anti-oxidant treatment 3 Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederweiser D et al. High- could be combined with TKIs to extend/improve the therapeutic sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive effects of ABL1 kinase inhibitors. This speculation is reinforced by the patients: correlation with clonal cytogenetic evolution but not response to observation that anti-oxidants vitamin E and N-acetyl-cysteine therapy. Blood 2005; 106: 2128–2137. 4 Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous reduced the percentage of the resistant clones emerging in vitro 11 leukemia: strategies to avoid and overcome resistance. Leukemia 2004; 18: from imatinib-treated BCR-ABL1–positive cells. 1321–1331. 5 Eide CA, Adrian LT, Tyner JW, MacPartlin M, Anderson DJ, Wise SC et al. The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia CONFLICT OF INTEREST mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res 2011; 71: 3189–3195. The authors declare no conflict of interest. 6 Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood 2013; 121: 489–498. ACKNOWLEDGEMENTS 7 Skorski T. BCR-ABL1 kinase: hunting an elusive target with new weapons. Chem MN-S and GH share equal contribution. This work was supported by NIH/NCI Biol 2011; 18: 1352–1353. CA123014 and CA134458 to T Skorski, N401 039037 from the Polish Ministry of 8 Gutteridge JM, Halliwell B. Free radicals and antioxidants in the year 2000. A Education and Science to G Hoser and EU program: FP7-REGPOT-2012-CT2012- historical look to the future. Ann NY Acad Sci 2000; 899: 136–147. 316254-BASTION to T Stoklosa. 9 Nieborowska-Skorska M, Kopinski PK, Ray R, Hoser G, Ngaba D, Flis K et al. Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid M Nieborowska-Skorska1, G Hoser2, A Hochhaus3, leukemia stem cells and primitive progenitors. Blood 2012; 119: 4253–4263. T Stoklosa4 and T Skorski1 10 Bolton-Gillespie E, Schemionek M, Klein HU, Flis S, Hoser G, Lange T et al. Genomic 1 instability may originate from imatinib-refractory chronic myeloid leukemia stem Department of Microbiology and Immunology, cells. Blood 2013 (in press). School of Medicine, Temple University, Philadelphia, PA, USA; 11 Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M 2 Department of Clinical Cytology, Medical Center for et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to Postgraduate Education, Warsaw, Poland; encode imatinib resistance. Blood 2006; 108: 319–327. Long-term follow-up of treatment with imatinib in eosinophilia-associated myeloid/lymphoid neoplasms with PDGFR rearrangements in blast phase Leukemia (2013) 27, 2254–2256; doi:10.1038/leu.2013.129 Thirteen patients were FIP1L1-PDGFRA-positive (myeloid BP, n ¼ 8; chloroma, n ¼ 2; lymphoid BP, n ¼ 3). In all three patients investigated, FIP1L1-PDGFRA could be identified contempora- neously in myeloid cells derived from BM and CD3-positive Several cooperative study groups and single institutions lymphoblasts in LN biopsies. Four patients (myeloid BP, n ¼ 2; have reported on high rates of rapid and durable complete lymphoid BP, n ¼ 2) were positive for a rearrangement of PDGFRB hematologic (CHR) and complete molecular remissions (CMR) (partner genes: ETV6, n ¼ 1; SART3, n ¼ 1; unknown partner gene, 10 on imatinib in eosinophilia-associated myeloid/lymphoid n ¼ 2). All patients were male, median age was 46 years (range 9 9 neoplasms (MLN-Eo) with rearrangements of PDGFR (PDGFRA 37–66). Significant eosinophilia 41.5 Â 10 /l (median 7.7 Â 10 /l, and PDGFRB) in chronic phase (CP). These responses have range 1.3–20.7) was present in 12 of 13 (92%) FIP1L1-PDGFRA- 9 translated into vastly improved progression-free and overall positive patients and 2 of 4 (50%) patients (median 1.2 Â 10 /l, survival (OS).1–9 In this report, we present data from the range 0.1–33.0) with rearrangements of PDGFRB. In addition to the ‘German Registry on Disorders of Eosinophils and Mast Cells’ on specific morphologic features of PB, BM and LN, the most long-term follow-up of 17 patients primarily diagnosed in blast common clinical characteristics included splenomegaly (17/17, phase (BP). BP was defined as (i) myeloid BP (420% blasts in 100%), involvement of lung (4/17, 24%; pleural effusion, n ¼ 4), peripheral blood (PB) and/or bone marrow (BM)), (ii) chloroma skin (4/17, 24%) and heart (2/17, 12%; endo-/myocarditis, n ¼ 1; (extramedullary tissue infiltration by myeloid blasts) or (iii) intracardial thrombus, n ¼ 1). extramedullary lymphoid BP (lymph node (LN) infiltration by Without initial knowledge of the underlying fusion gene, nine lymphoblasts of T-cell origin). patients received primary chemotherapy according to protocols Accepted article preview online 25 April 2013; advance online publication, 21 May 2013 Leukemia (2013) 2242 – 2267 & 2013 Macmillan Publishers Limited Letters to the Editor 2255 100 after SCT. Overall, only 2 of 17 (12%) patients have died after a median observation time of 65 months (range 7–106), which is not 80 different as compared to 46 patients in CP (median 51 months, range 1–103; Figure 1a and b). 60 Besides the excellent and sustained responses to imatinib in PDGFR fusion gene-positive MLN-eo in BP, our data also under- 40 score the failure of standard diagnostic work-up at initial diagnosis to identify pathogenetically relevant tyrosine kinase (TK) fusion genes, for example, PDGFRA, PDGFRB or FGFR1, in patients with Overall survival (%) Overall 20 eosinophilia and supposed ‘acute myeloid leukemia (AML)’ or ‘T-cell lymphoma’. It is noteworthy that the frequency of so called 0 1224 36 48 60 72 84 96 108 120 ‘T-cell lymphomas’ is even more frequent in patients with FGFR1 fusion genes as consequence of reciprocal translocations with imatinib (months) involvement of 8p11, particularly in t(8;13)(p11;q13) with a ZNF198-FGFR1 fusion gene.12 Careful attention should therefore 100 be paid to the potential presence of these TK fusion genes in primarily diagnosed myeloid and lymphoid malignancies through 80 distinctive clinical (for example, splenomegaly), biochemical (for example, elevated serum levels of tryptase or vitamin B12), 60 morphological (for example, leukocytosis with left-shift and dysplasia, eosinophilia, fibrosis and/or increased numbers of 40 loosely scattered mast cells in BM) and molecular genetic (for example, FIP1L1-PDGFRA, reciprocal translocations with Overall survival (%) Overall 20 involvement of 4q12-PDGFRA, 5q33-PDGFRB or 8p11-FGFR1) features of an eosinophilia-associated and TK fusion-positive 0 stem cell disorder with involvement of the myeloid and 0 1224 36 48 60 72 84 96 108 120 lymphoid lineage. Having established the presence of a fusion imatinib (months) gene, we consider that the diagnosis of these cases should be revised to ‘myeloid BP’ and ‘extramedullary lymphoid BP’ of MLN- Figure 1. (a) Overall survival of 49 patients with a FIP1L1-PDGFRA by eo, respectively, the latter reflecting the fact that these are stem FIP1L1-PDGFRA fusion gene (upper graph) and 14 patients with cell disorders in which affected TK fusion gene-positive diverse PDGFRB fusion genes (lower graph) in chronic and blast T-lymphoblasts predominantly reside in the LN.11 phase (P ¼ nonsignificant (NS)). (b) Overall survival of 63 patients (middle graph) with a FIP1L1-PDGFRA fusion gene (n ¼ 49) or diverse In conclusion, our data highlight several new aspects for PDGFRB fusion genes (n ¼ 14). Patients in chronic phase (FIP1L1- diagnosis and treatment of MLN-eo with PDGFR fusion genes: (i) PDGFRA, n ¼ 36; X-PDGFRB, n ¼ 10) are shown in the top graph while mimicking de novo AML and T-cell lymphoma, myeloid and patients in blast phase (FIP1L1-PDGFRA, n ¼ 13; X-PDGFRB, n ¼ 4; lymphoid BP of MLN-eo with an underlying imatinib-sensitive P ¼ NS) are shown in the lower graph. PDGFR fusion gene is frequently not identified, (ii) in the absence of CBF fusion genes, patients with eosinophilia-associated AML but for acute leukemia or lymphoma.11 Despite clear signs of also patients with eosinophilia-associated T-cell lymphoma should remission, for example, clearance of blasts or partial/complete be actively screened for PDGFR fusion genes by PCR, cytogenetics clinical and/or hematologic remission, eosinophilia persisted at and/or fluorescence in situ hybridization and (iii) the excellent various levels in all nine patients.
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