Authors:Hanny Al-Samkari; Elizabeth M. Van Cott; David J. Kuter Pages: 581 - 588 Abstract: The thrombopoietin receptor agonist romiplostim is used for the long-term treatment of chronic immune thrombocytopenia (ITP). ITP patients have an increased thrombotic risk, which could be exacerbated if romiplostim increased platelet hyperreactivity or caused spontaneous platelet aggregation. To investigate this possibility, this study examined platelet function in romiplostim-treated ITP patients and healthy subjects. Light transmission platelet aggregometry utilizing arachidonic acid, collagen, epinephrine, ristocetin, ADP, and saline (to assess spontaneous aggregation) was performed for each subject. In addition, the ADP AC50 (ADP concentration that induced half-maximal aggregation) was determined for each patient as a sensitive measurement of altered platelet reactivity. Fifteen ITP patients and 7 healthy subjects entered the study. All ITP patients had active disease and were receiving weekly romiplostim as the sole ITP-directed therapy. Platelet aggregation in response to the strong agonists arachidonic acid, collagen, and ristocetin was not significantly different between ITP patients and healthy subjects (P = 0.2442, P = 0.0548, and P = 0.0879, respectively). Platelet aggregation in response to weak agonists was significantly reduced in ITP patients compared with that in healthy subjects: median (range) aggregation to ADP, 45% (15–84%) versus 89% (70–95%) (P = 0.0010), and epinephrine, 21% (1.6–90%) versus 88% (79–94%) (P = 0.0085). The median AC50 of ADP was threefold higher in ITP patients versus that in healthy subjects (6.3 μM vs 2.1 μM) (P = 0.0049). Significant spontaneous aggregation was not observed in any patient. Platelets from romiplostim-treated ITP patients do not show evidence for spontaneous aggregation or hyperreactivity, but instead have a modestly reduced aggregation response to ADP and epinephrine. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3556-6 Issue No:Vol. 98, No. 3 (2019)
Authors:Sandra De Barros; Flora Vayr; Fabien Despas; Mathilde Strumia; Clémentine Podevin; Martin Gauthier; Eric Delabesse; Jean-Marc Soulat; Guy Laurent; Françoise Huguet; Fabrice Herin Pages: 615 - 623 Abstract: Patients with chronic myeloid leukemia treated with breakpoint cluster region-Abelson tyrosine kinase inhibitors are likely to survive in excess of 20 years after diagnosis. New challenges appear as we consider life after the disease, including professional challenges and the social reintegration of patients. The purpose of this study was to determine the impact of chronic myeloid leukemia on employment within 2 years after diagnosis. This prospective, observational study included patients diagnosed with chronic myeloid leukemia and treated with a tyrosine kinase inhibitor. Two populations were defined as patients who reported modifications in their professional activity during the study (Acti-Pro+) and patients who did not report a modification (Acti-Pro−). Cancer survivors received a self-assessment questionnaire. The primary endpoint was to determine the professional status of patients. One hundred patients completed the questionnaire. Sixty-six patients out of 100 reported professional activity within 2 years after their diagnosis. During the 2 years after the diagnosis, 65.2% (95% confidence interval (CI), 53.7–76.7) of patients faced modifications in their professional activity due to chronic myeloid leukemia or adverse effects of drug treatments (group Acti-Pro+); in contrast, 34.8% of patients did not report any impact on their occupational activity (group Acti-Pro−). Among modifications to work organization, a change in the number of working hours was the most represented. Other modifications comprised changes in status or work pace. A majority of chronic myeloid leukemia patients face professional consequences of their disease and treatments. Our findings suggest that adverse drug reactions are a major factor affecting the occurrence of work modifications in this context. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3549-5 Issue No:Vol. 98, No. 3 (2019)
Authors:R. Borrows; A. Scheer; P. Cockwell; F. Braun; I. Anagnostopoulos; H. Riess; H. Zimmermann; R. U. Trappe Pages: 625 - 632 Abstract: Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-03591-w Issue No:Vol. 98, No. 3 (2019)
Authors:Hisashi Ishida; Akihiro Iguchi; Michinori Aoe; Takahide Takahashi; Kosuke Tamefusa; Kiichiro Kanamitsu; Kaori Fujiwara; Kana Washio; Takehiro Matsubara; Hirokazu Tsukahara; Masashi Sanada; Akira Shimada Pages: 657 - 668 Abstract: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3554-8 Issue No:Vol. 98, No. 3 (2019)
Authors:Eric Sanchez; Mingjie Li; Saurabh Patil; Camilia M. Soof; Jason D. Nosrati; Remy E. Schlossberg; Aleksandra Vidisheva; Edward J. Tanenbaum; Tara Hekmati; Brian Zahab; Cathy Wang; George Tang; Haiming Chen; James R. Berenson Pages: 691 - 703 Abstract: The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients. PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03595-0 Issue No:Vol. 98, No. 3 (2019)
Authors:Alicia Senín; Francesc García-Pallarols; Randa Ben Azaiz; Laia Martínez-Serra; Sara Montesdeoca; David Román; Mariana Ferraro; Ivonne Párraga; Carlos Besses; Eugenia Abella Pages: 705 - 711 Abstract: The availability of new agents for the treatment of multiple myeloma has allowed the use of multiple lines of treatment, but a percentage of patients do not reach to receive this combination because of toxicity and early death. In this regard, a cross-sectional European study evaluated the management of different lines and discontinuation of treatment in 7635 patients from seven countries in routine clinical practice, finding that 39% of European patients do not receive a second line and that only 4% of patients reach third line in Spain, a figure that is striking when comparing with the rest of the countries. We analyze the frequency and causes of treatment discontinuation in a series of 108 patients from a Spanish University hospital showing that the main reason for permanent treatment discontinuation after finishing first line was to have a response, while death due to disease progression accounted for the main reason in subsequent lines of therapy, with its frequency increasing according to the number of lines received. Additionally, in our longitudinal study, we estimated, using a competitive risk analysis, that 22% of patients would not receive a second line of therapy at 60 months and 47% would not reach third line, also at 60 months, showing a marked discrepancy with the results reported in the cross-sectional European study. Although based on limited data, our results suggest the convenience of validating the findings of cross-sectional studies conducted in large cohorts. PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03601-5 Issue No:Vol. 98, No. 3 (2019)
Authors:Annamaria Brioli; Maximilian Klaus; Herbert Sayer; Sebastian Scholl; Thomas Ernst; Inken Hilgendorf; André Scherag; Olaposi Yomade; Kristina Schilling; Andreas Hochhaus; Lars-Olof Mügge; Marie von Lilienfeld-Toal Pages: 713 - 722 Abstract: Infections represent a major cause of morbidity and mortality in multiple myeloma and are linked to both therapy- and disease-related factors. Although it has been suggested that the rate of infections increased since the introduction of novel agents, controversies still exist. To better assess the risk factors associated with infections in the era of novel agents, we conducted a large retrospective analysis of 479 myeloma patients treated at Jena University Hospital over a period of 12 years. During their disease history, 65% of patients developed at least one infection, and 37% of therapies were associated with at least one infectious episode. The rate of infections was constant over the years, with no increase in infectious complications after the routine implementation of novel agents. Infections were mainly bacterial and strongly associated with high disease burden, relapsed disease, and treatment with high-dose chemotherapy. Varicella zoster virus (VZV) reactivations occurred late during treatment (median time between high-dose chemotherapy and VZV reactivation 6 months, range 0–44 months), and fewer patients developed a VZV reactivation after 2009 (p = 0.001). Infections are still one of the major causes of morbidity in myeloma patients, and prophylactic measures are urgently needed to reduce this potentially lethal complication. PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03621-1 Issue No:Vol. 98, No. 3 (2019)
Authors:Seiichi Okabe; Yuko Tanaka; Tetsuzo Tauchi; Kazuma Ohyashiki Pages: 723 - 733 Abstract: Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kα and δ inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110α and δ catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3547-7 Issue No:Vol. 98, No. 3 (2019)
Authors:Chien-Chang Lee; Hsiu-Hao Chang; Meng-Yao Lu; Yung-Li Yang; Shu-Wei Chou; Dong-Tsamn Lin; Shiann-Tarng Jou; Ming Yao; Chi-Cheng Li; Su-Peng Yeh; Mei-Hui Chen; Jyh-Pyng Gau; Sin-Syue Li; Po-Nan Wang; Yi-Chang Liu; Tso-Fu Wang; Tran-Der Tan; Ming-Yang Lee; Ming-Sun Yu; Chuan-Cheng Wang; Shih-Chiang Lin; Yeu-Chin Chen; Yung-Cheng Su; Ko-Ying Su; Kai-Hsin Lin Pages: 745 - 752 Abstract: Hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). We conducted this study to investigate the incidence and risk factors of hepatic VOD for patients receiving HSCT in Taiwan. We retrospectively analyzed the data from a nationwide registry for patients receiving HSCT, which was collected by the Taiwan Society of Blood and Marrow Transplantation. The data collection period was from 2009 to 2014. A total 2345 patients were reviewed and 39 patients among them were diagnosed as having hepatic VOD. The cumulative incidence of hepatic VOD in the whole cohort of 2345 patients was 1.66%. In multivariate analysis, disease diagnosis of myelodysplastic syndrome, chronic HCV infection, condition regimens of bulsulfan intravenously administered, and antithymocyte immunoglobulin were independent factors to predict higher risk of hepatic VOD. The overall mortality rate for patients with hepatic VOD was 79%. Patients with hepatic VOD had significant worse survival outcomes when compared with those without hepatic VOD (P = 0.00063). In conclusion, although the incidence is low, hepatic VOD remains a serious complication after HSCT in Taiwan. The findings of this study could be the basis for developing prophylactic or early treatment strategies for hepatic VOD. PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03604-2 Issue No:Vol. 98, No. 3 (2019)
Authors:Sarah Weber; Michael Hogardt; Claudia Reinheimer; Thomas A. Wichelhaus; Volkhard A. J. Kempf; Johanna Kessel; Sebastian Wolf; Hubert Serve; Björn Steffen; Sebastian Scheich Pages: 763 - 773 Abstract: Enterococcus species are commensals of the human gastrointestinal tract with the ability to cause invasive infections. For patients with hematological diseases, enterococcal bloodstream infections (BSI) constitute a serious clinical complication which may even be aggravated if the pathogen is vancomycin-resistant. Therefore, we analyzed the course of BSI due to vancomycin-susceptible enterococci (VSE) in comparison to vancomycin-resistant enterococci (VRE) on patient survival. In this retrospective single-center study, BSI were caused by VRE in 47 patients and by VSE in 43 patients. Baseline patient characteristics were similar in both groups. Concerning infection-related characteristics, an increased CRP value and an increased rate of prior colonization with multidrug-resistant organisms were detected in the VRE BSI group. More enterococcal invasive infections were found in the VSE group. The primary endpoint, overall survival (OS) at 30 days after BSI, was significantly lower in patients with VRE BSI compared to patients with VSE BSI (74.5% vs. 90.7%, p = 0.039). In a multivariate regression analysis, VRE BSI and a Charlson comorbidity index higher than 4 were independent factors associated with 30-day mortality. Moreover, we found that VRE with an additional teicoplanin resistance showed a trend towards an even lower OS. PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03607-z Issue No:Vol. 98, No. 3 (2019)
Authors:João Tadeu Damian Souto Filho; Marcelo Montebello Lemos; João Carlos Borromeu Piraciaba; Ana Laura Oliveira Silveira; Arthur Pires Lacerda; Arthur Zopé Pires; Luiza Reis de Sales; Yasmim Passos Dias Pages: 781 - 782 PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03597-y Issue No:Vol. 98, No. 3 (2019)
Authors:O. Al-Sawaf; P. Köhler; D. A. Eichenauer; B. Böll; M. Kochanek; A. Shimabukuro-Vornhagen Pages: 789 - 791 PubDate: 2019-03-01 DOI: 10.1007/s00277-019-03596-z Issue No:Vol. 98, No. 3 (2019)
Authors:M. Rinelli; E. Bellacchio; F. Berardinelli; G. Pascolini; P. Grammatico; A. Sgura; A. P. Iori; L. Quattrocchi; A. Novelli; S. Majore; E. Agolini Pages: 805 - 807 PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3415-5 Issue No:Vol. 98, No. 3 (2019)
Authors:M. Rinelli; E. Bellacchio; F. Berardinelli; G. Pascolini; P. Grammatico; A. Sgura; A. P. Iori; L. Quattrocchi; A. Novelli; S. Majore; E. Agolini Pages: 809 - 809 Abstract: The original version of this article contained a mistake in the affiliation of E. Bellacchio. Correct affiliation is presented here. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3581-5 Issue No:Vol. 98, No. 3 (2019)
Authors:Amin T. Turki; Wolfgang Lamm; Christoph Schmitt; Evren Bayraktar; Ferras Alashkar; Martin Metzenmacher; Philipp Wohlfarth; Dietrich W. Beelen; Tobias Liebregts Pages: 811 - 811 Abstract: The author name Philipp Wohlfarth was incorrectly spelled as Philipp Wohlfahrth in the original version of this article. PubDate: 2019-03-01 DOI: 10.1007/s00277-018-3580-6 Issue No:Vol. 98, No. 3 (2019)
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