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Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection.
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Long-term CD38 saturation by daratumumab interferes with diagnostic myeloma cell detection.

Haematologica. 2017 May 18;:

Authors: Oberle A, Brandt A, Alawi M, Langebrake C, Janjetovic S, Wolschke C, Schütze K, Bannas P, Kröger N, Koch-Nolte F, Bokemeyer C, Binder M

PMID: 28522580 [PubMed - as supplied by publisher]




Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier.
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Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier.

Haematologica. 2017 May 18;:

Authors: Navarro A, Clot G, Martínez-Trillos A, Pinyol M, Jares P, González-Farré B, Martínez D, Trim N, Fernández V, Villamor N, Colomer D, Costa D, Salaverria I, Martín-Garcia D, Erber W, López C, Jayne S, Siebert R, Dyer MJS, Wiestner A, Wilson WH, Aymerich M, López-Guillermo A, Sánchez À, Campo E, Matutes E, Beà S

PMID: 28522579 [PubMed - as supplied by publisher]




Mutated ASXL1 and number of somatic mutations as possible indicators of progression to chronic myelomonocytic leukemia of myelodysplastic syndromes with single or multilineage dysplasia.
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Mutated ASXL1 and number of somatic mutations as possible indicators of progression to chronic myelomonocytic leukemia of myelodysplastic syndromes with single or multilineage dysplasia.

Haematologica. 2017 May 18;:

Authors: Valencia-Martinez A, Sanna A, Masala E, Contini E, Brogi A, Gozzini A, Santini V

PMID: 28522578 [PubMed - as supplied by publisher]




Shorter leukocyte telomere length is associated with higher risk of infections: a prospective study of 75,309 individuals from the general population.
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Shorter leukocyte telomere length is associated with higher risk of infections: a prospective study of 75,309 individuals from the general population.

Haematologica. 2017 May 18;:

Authors: Helby J, Nordestgaard BG, Benfield T, Bojesen SE

Abstract
In the general population, older age is associated with short leukocyte telomere length and with high risk of infections. In a recent study of allogeneic hematopoietic cell transplantation for severe aplastic anemia, long donor leukocyte telomere length was associated with improved survival in the recipients. These findings suggest that leukocyte telomere length could possibly be a marker of immune competence. Therefore, we tested the hypothesis that shorter leukocyte telomere length is associated with higher risk of infectious disease hospitalization and infection related death. Relative peripheral blood leukocyte telomere length was measured using quantitative polymerase chain reaction in 75,309 individuals from the general population and the individuals were followed for up to 23 years. During follow-up, 9,228 individuals were hospitalized with infections and infection related death occurred in 1508 individuals. Shorter telomere length was associated with higher risk of any infection (hazard ratio 1.05 per standard deviation shorter leukocyte telomere length; 95% confidence interval 1.03-1.07) and pneumonia (1.07;1.03-1.10) after adjustment for conventional infectious disease risk factors. Corresponding hazard ratios for infection related death were 1.10 (1.04-1.16) for any infection and 1.11 (1.04-1.19) for pneumonia. Telomere length was not associated with risk of skin infection, urinary tract infection, sepsis, diarrhoeal disease, endocarditis, meningitis or other infections. In conclusion, our findings indicate that leucocyte telomere length may be a marker of immune competence. Further studies are needed to determine whether risk of infections in allogeneic hematopoietic cell transplantation recipients can be reduced by considering donor leukocyte telomere length when selecting donors.

PMID: 28522577 [PubMed - as supplied by publisher]




Natural killer cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.
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Natural killer cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

Haematologica. 2017 May 18;:

Authors: Rea D, Henry G, Khaznadar Z, Etienne G, Guilhot F, Nicolini F, Guilhot J, Rousselot P, Huguet F, Legros L, Gardembas M, Dubruille V, Guerci-Bresler A, Charbonnier A, Maloisel F, Ianotto JC, Villemagne B, Mahon FX, Moins-Teisserenc H, Dulphy N, Toubert A

Abstract
Despite leukemic stem cell persistence, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T-cells and natural killer-cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients displayed significantly higher numbers of natural killer-cells of the cytotoxic CD56dim subset than relapsing patients, while CD56bright natural killer cells, T-cells and their subsets did not significantly differ. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, natural killer cells activating receptor expression, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, natural killer-cells significantly increased and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer-cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms for natural killer-cell functional differences between patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies.(ClinicalTrial.gov Identifier NCT00478985).

PMID: 28522576 [PubMed - as supplied by publisher]




Amplification of mixed lineage leukemia gene perturbs hematopoiesis and cooperates with partial tandem duplication to induce acute myeloid leukemia.
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Amplification of mixed lineage leukemia gene perturbs hematopoiesis and cooperates with partial tandem duplication to induce acute myeloid leukemia.

Haematologica. 2017 May 18;:

Authors: Yip BH, Tsai CT, Rane JK, Vetharoy W, Anguita E, Dong S, Caligiuri MA, So CWE

PMID: 28522575 [PubMed - as supplied by publisher]




Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukaemia treated with nilotinib.
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Single cell immune profiling by mass cytometry of newly diagnosed chronic phase chronic myeloid leukaemia treated with nilotinib.

Haematologica. 2017 May 18;:

Authors: Gullaksen SE, Skavland J, Gavasso S, Tosevski V, Warzocha K, Dumrese C, Ferrant A, Gedde-Dahl T, Hellmann A, Janssen J, Labar B, Lang A, Majeed W, Mihaylov G, Stentoft J, Stenke L, Thaler J, Thielen N, Verhoef G, Voglova J, Ossenkoppele G, Hochhaus A, Hjorth-Hansen H, Mustjoki S, Sopper S, Giles F, Porkka K, Wolf D, Gjertsen BT

Abstract
Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognostication, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukaemia. Changes in phosphorylated Bcr-Abl1 and its involved signalling pathways were readily identifiable in peripheral blood single cells already within 3 hours of per oral nilotinib dosing. The signal transduction profiles of healthy donors were clearly distinct from that of the patients at diagnosis. Furthermore, using principal component analysis we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within 7 days reflected BCR-ABL1IS at 3 and 6 months. Analyses of peripheral blood cells longitudinally collected from ENEST1st clinical trial patients showed that single cell mass cytometry appears highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials.gov Identifier:NCT01061177).

PMID: 28522574 [PubMed - as supplied by publisher]




Lenalidomide/Melphalan/Dexamethasone in newly diagnosed patients with AL Amyloidosis: results of a prospective phase 2 study with long-term follow-up.
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Lenalidomide/Melphalan/Dexamethasone in newly diagnosed patients with AL Amyloidosis: results of a prospective phase 2 study with long-term follow-up.

Haematologica. 2017 May 18;:

Authors: Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO

Abstract
Chemotherapy in light chain amyloidosis aims to normalize the involved free light chain in serum, which leads to an improvement or at least stabilization of organ function in most responding patients. We performed a prospective single center phase 2 trial with 50 untreated patients not eligible for high-dose treatment. The treatment schedule comprised 6 cycles of oral lenalidomide, melphalan and dexamethasone every 4 weeks. After 6 months complete remission was achieved in 9 patients (18%), very good partial remission in 16 (32%) and partial response in 9 (18%). Overall, organ response was observed in 24 patients (48%). Hematologic and cardiac toxicities were predominant adverse events. Mortality at 3 months was low with 4% (n=2) despite inclusion of 36% of patients (n=18) with cardiac stage Mayo 3. After a median follow-up of 50 months, median overall and event-free survival were 67.5 months and 25.1 months, respectively. We conclude that the treatment of lenalidomide, melphalan and dexamethasone is very effective to achieve a hematologic remission, organ response and consecutively a long survival in transplant ineligible patients with light-chain amyloidosis. However, as toxicity and tolerability are the major problems of 3 drug regimens a strict surveillance program is necessary and sufficient to avoid severe toxicities. This study is registered at www.clinicaltrials.gov as #NCT00883623 (Eudract2008-001405-41).

PMID: 28522573 [PubMed - as supplied by publisher]




The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype.
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The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype.

Haematologica. 2017 May 18;:

Authors: Schinke C, Hoering A, Wang H, Carlton V, Thanendrarajan S, Deshpande S, Patel P, Molnar G, Susanibar S, Mohan M, Mathur P, Radhakrishnan M, Hoque S, Jo Kamimoto J, Grazziutti M, van Rhee F, Zangari M, Insuasti-Beltran G, Alapat D, Post G, Yaccoby S, Epstein J, Rasche L, Johnson S, Moorhead M, Willis T, Barlogie B, Walker B, Weinhold N, Davies FE, Morgan GJ

PMID: 28522572 [PubMed - as supplied by publisher]




FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin dependent kinase inhibitor p27Kip1 in acute myeloid leukemia.
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FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin dependent kinase inhibitor p27Kip1 in acute myeloid leukemia.

Haematologica. 2017 May 18;:

Authors: Peschel I, Podmirseg SR, Taschler M, Duyster J, Götze KS, Sill H, Nachbaur D, Jäkel H, Hengst L, Austrian Science Fund (FWF) P24031 Grant, Österreichische Krebshilfe Tirol (ÖKH-KG)

Abstract
p27Kip1 can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples. Inhibition of FLT3 kinase activity with AC220 significantly reduced p27 tyrosine 88 phosphorylation in cells isolated from FLT3 wildtype expressing acute myeloid leukemia patients. In FLT3-ITD positive acute myeloid leukema patients, p27 tyrosine 88 phosphorylation was reduced in 5 out of 9 subjects but surprisingly increased in 4 patients. This indicated that other tyrosine kinases such as Src family kinases might contribute to p27 tyrosine 88 phosphorylation in FLT3-ITD positive acute myeloid leukemia cells. In fact, incubation with the Src family kinase inhibitor dasatinib could decrease p27 tyrosine 88 phosphorylation in these patient samples, indicating that p27 phosphorylated on tyrosine 88 may be a therapeutic marker for the treatment of acute myeloid leukemia patients with tyrosine kinase inhibitors.

PMID: 28522571 [PubMed - as supplied by publisher]




Clinical and diagnostic relevance of NOTCH2 and KLF2 mutations in splenic marginal zone lymphoma.
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Clinical and diagnostic relevance of NOTCH2 and KLF2 mutations in splenic marginal zone lymphoma.

Haematologica. 2017 May 18;:

Authors: Campos-Martín Y, Martínez N, Martínez-López A, Cereceda L, Casado F, Algara P, Oscier D, Menarguez FJ, García JF, Piris MA, Mollejo M

PMID: 28522570 [PubMed - as supplied by publisher]