Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
From www.bloodjournal.org by guest on June 12, 2017. For personal use only. confined to B-lymphoid cells. In contrast, another subset of patients, perhaps accounting for 20% to 25%, may have a disease in which the sentinel Philadelphia chromosome and BCR-ABL1 fusion occurred in a multipotent progenitor cell. Treatment with chemotherapy and a TKI may eliminate the bulk disease in the lymphoid clone, producing an excellent MRD response when measured by conventional MRD methodologies, but leaving a reservoir of Ph1 cells in other lineages. Much more work is needed to understand these findings and particularly their clinical implications. The current study challenges us to perform these studies so that we can understand the frequency of “Ph1 ALL” subtypes that have multilineage involvement vs disease restricted to the lymphoid lineage and the clinical implications of these differences. Understanding the different potential subtypes of Ph1 ALL is particularly relevant to adults with Ph1 ALL because this subtype comprises a much higher percentage of adult than pediatric ALL, and because HSCT remains the most commonly used approach for adults with Ph1 ALL.9 As observed by the philosopher Roseanne Roseannadanna, “It just goes to show you, it’s always something—if it ain’t one thing, it’s another.” Conflict-of-interest disclosure: S.P.H. has received honoraria from Amgen, Jazz Pharmaceuticals, and Erytech and consulting fees from Novartis. n REFERENCES 1. Hovorkova L, Zaliova M, Venn NC, et al. Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology. Blood. 2017;129(20):2771-2781. 2. Chandra HS, Heisterkamp NC, Hungerford A, et al. Philadelphia Chromosome Symposium: commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genet. 2011;204(4):171-179. 3. Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016; 34(24):2851-2857. 4. Aricò M, Schrappe M, Hunger SP, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol. 2010;28(31): 4755-4761. 5. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009; 27(31):5175-5181. 6. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute 2714 lymphoblastic leukaemia (EsPhALL): a randomised, openlabel, intergroup study. Lancet Oncol. 2012;13(9):936-945. 7. Kolenova A, Maloney KW, Hunger SP. Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast crisis. J Pediatr Hematol Oncol. 2016;38(6):e193-e195. 8. Hehlmann R, Saußele S, Voskanyan A, Silver RT. Management of CML-blast crisis. Best Pract Res Clin Haematol. 2016;29(3):295-307. 9. Fielding AK. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: a broader range of options, improved outcomes, and more therapeutic dilemmas. Am Soc Clin Oncol Educ Book. 2015:e352-359. DOI 10.1182/blood-2017-04-776369 © 2017 by The American Society of Hematology l l l THROMBOSIS AND HEMOSTASIS Comment on Curtis et al, page 2793 At last: evidence rather than emotion ----------------------------------------------------------------------------------------------------Paul Monagle UNIVERSITY OF MELBOURNE Perinatal stroke is often a devastating and unexpected event for families that leads them to ask the question of “why?” The study by Curtis et al1 in this issue of Blood suggests that the answers to this question are not to be found in standard thrombophilia testing. T hrombophilia, a broad term inclusive of a variety of disorders, has variably been shown to be associated with venous thromboembolic diseases in adults, although the link to arterial disease is more tenuous. Currently, most guidelines support very limited clinical usefulness of thrombophilia testing in adult populations.2 The data supporting thrombophilia testing in neonatal or perinatal stroke is far from convincing. One could reasonably extend that statement to childhood stroke and potentially childhood thrombosis in general.3 Previous studies of dubious quality have suggested a potential association with perinatal stroke, however, none have demonstrated any impact of testing on recurrence rates, clinical outcome, or future therapy.4 Although some studies have suggested a link to neurological outcome, most would argue the recommended follow-up and interventions are unchanged by the results of thrombophilia testing.4 Yet thrombophilia testing is frequently performed in this situation. Many clinicians, in an attempt to provide some answers for desperate parents, embark on testing knowing that the interpretation of any positive results is fraught with uncertainty. Testing is often driven by parents who have been scouring the internet for answers and come asking about thrombophilia. Childbirth is supposed to be a time of great joy. An unexplained perinatal stroke that will likely have lifelong significant consequences for the infant is incredibly challenging for parents. There are issues of their fears for their child, their unfounded feelings of guilt, as well as concerns about the risks for future children. Thus, the potential impact of performing tests of unknown significance for the child’s future, and, indeed, for future children in the family, is arguably more negative than positive because it may increase unfounded fears, leading to overtreatment and inhibitions or restrictions on the child. Until now, clinicians have not had quality data to support making an argument to parents against doing such testing. Curtis et al performed a prospective, population-based, controlled, disease-specific study that suggests minimal association between perinatal stroke and thrombophilia (specifically, a broad range of thrombophilia markers). The authors make the relevant point that this does not exclude a role of disordered coagulation in the etiology of the event, but that such a role is unlikely to be found by testing standard thrombophilia assays. Such a view is entirely consistent with our knowledge of developmental hemostasis.5 The coagulation system changes rapidly in the first few days of life. In fact, the whole plasma milieu is fundamentally different when comparing neonates and adults.6 Placental-released glycosaminglycans probably contribute to the overall balance of coagulation, and yet these factors are no longer detectable after the first week of life.7 A much greater understanding the coagulation system in the placenta, fetus, and BLOOD, 18 MAY 2017 x VOLUME 129, NUMBER 20 From www.bloodjournal.org by guest on June 12, 2017. For personal use only. premature and term neonates is required. Such understanding must be an ongoing area of active research. The aim is to ultimately be able to provide families with evidence-based information to explain perinatal events, such as stroke. The reported minimal association is consistent with epidemiological data as well. The large family cohorts that defined the original thrombophilias did not report neonatal events, but rather thrombotic complications in adult life, and the conclusion is that thrombophilias interact with patient age in correlating with the risk of thrombosis and rarely cause clinical events during childhood.8 So at last we have good quality evidence. As a result, clinicians who are faced with parents full of emotion and anxiety can now say that the available data does not support thrombophilia testing in their child who has suffered a perinatal stroke, because any abnormality found occurs with the same frequency as in the general population. We do not advocate testing the general population at birth, despite the relative frequency of thrombophilias, because there is no evidence that knowing if a thrombophilia is present improves the longterm outcome for the child, and such an approach is clearly not cost effective. Certainly, being labeled unnecessarily with a diagnosis of a coagulation abnormality early in life creates much anxiety and mismanagement. Without any evidence that results would change practice, it is impossible to argue that such testing is cost effective. Thus, there is no benefit in offering this testing in children who have suffered a perinatal stroke. No answer to the question of “why” remains better than the wrong answer. In the meantime, the search for the true answers must continue. At least in regard to thrombophilia, now that we have some evidence, we can help parents deal more constructively with their emotions after perinatal stroke. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Curtis C, Mineykol A, Massicotte P, et al. Thrombophilia risk is not increased in children after perinatal stroke. Blood. 2017;129(20):2793-2800. 2. Middeldorp S. Inherited thrombophilia: a doubleedged sword. Hematology Am Soc Hematol Edu Program; 2016; 2016(1):1-9 3. Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic therapy in children: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126(3 suppl):645S-687S. BLOOD, 18 MAY 2017 x VOLUME 129, NUMBER 20 4. O’Brien SH. Perinatal thrombosis: implications for mothers and neonates. Hematology Am Soc Hematol Educ Program. 2015;2015:48-52. 7. Andrew M, Mitchell L, Berry L, et al. An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J Clin Invest. 1992;89(1):321-326. 5. Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas. Blood Rev. 2010;24(2):63-68. 8. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138(2):128-134. 6. Bjelosevic S, Pascovici D, Ping H, et al. Quantitative age-specific variability of plasma proteins in healthy neonates, children and adults [published online ahead of print 23 March 2017]. Mol Cell Proteomics. doi:10.1074/ mcp.M116.066720. DOI 10.1182/blood-2017-03-772095 © 2017 by The American Society of Hematology l l l TRANSPLANTATION Comment on Lounder et al, page 2801 Vitamin A to reduce gut leak and GVHD? ----------------------------------------------------------------------------------------------------Paul A. Carpenter FRED HUTCHINSON CANCER RESEARCH CENTER In this issue of Blood, Lounder et al report that, in children, vitamin A levels below the median at 30 days after hematopoietic stem cell transplant (HSCT) are associated with increased cumulative incidence of gastrointestinal (GI) graftversus-host disease (GVHD).1 V itamin A is an essential dietary nutrient, available to humans in 2 forms: preformed vitamin A (retinol and retinyl ester) and plantbased provitamin A carotenoids. Most of the body’s vitamin A is stored in the liver as hepatic retinyl esters. Vitamin A blood levels are homeostatically regulated to maintain a narrow range. Preformed and provitamin A must be metabolized intracellularly by gut mucosal cells to retinal and retinoic acid, the active forms that support biological functions. Lounder et al review vitamin A’s known immunological roles in the health of the intestinal mucosa; simply put, most of the existing literature supports its anti-inflammatory role in limiting chemical and infectious gut injuries (albeit some contradictory mouse data exist). Therefore, to understand their GVHD observation, Lounder et al explored associations between higher and lower vitamin A levels and measurements of retinol-binding protein 4, intestinal fatty acid–binding protein, interleukin-22 (IL-22), CCR9, and effector memory T cells (see figure). In the last few decades, our understanding of GVHD pathophysiology has expanded much beyond conditioning-mediated disruption of the intestinal mucosa and the classic interaction of donor T cells with hematopoietic antigen-presenting cells. We better appreciate how perturbation of the fecal microbiota integrates with the cellular immune system to promote inflammatory disease and diarrhea. A nonexhaustive list of important players in this regard includes: intestinal stem cells and their closely aligned Paneth cells, the protective intestinal mucous layer, intestinal fatty acids like butyrate, bacterial composition of the feces and its regulation by defensins.2,3 Antibiotic therapy and diet can further disrupt the fecal microbiota and in turn affect mucosal integrity. It is worth viewing the intriguing results of Lounder et al through the lens of this broader understanding of GVHD pathophysiology and with a shift in focus to GVHD interventions that move beyond traditional systemic immunosuppressive therapies. Recognizing the critical integration of fecal microbiota and gut immunology, our gastroenterology colleagues have also explored associations with intestinal disease. One study found that among children diagnosed with “persistent diarrhea” (.14 days) but not with inflammatory bowel disease (IBD) per se, diversity of the gut microbiota and its key bacterial phylotypes differed significantly between groups with normal or deficient vitamin A levels.4 They have also studied alternatives to systemic immunosuppressive therapy in IBD. A detailed and well-designed meta-analysis of therapy in pediatric Crohn disease examined 5 randomized clinical trials and 2 further nonrandomized trials.5 The authors concluded 2715 From www.bloodjournal.org by guest on June 12, 2017. For personal use only. 2017 129: 2714-2715 doi:10.1182/blood-2017-03-772095 At last: evidence rather than emotion Paul Monagle Updated information and services can be found at: http://www.bloodjournal.org/content/129/20/2714.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4527 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.