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T-ALL infiltration in the bone marrow: the banality of evil Gene therapy: the next generation? Live and let (tumor cells) die Hellenic Society of Haematology EU project for training early-stage researchers in personalized medicine Saskia Middeldorp: Inherited thrombophilia, a double-edged sword

The official newsletter for members of EHA

WINTER 2017

WINTER 2017 | HEMATOPICS | EHA

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COVER DIGITAL ILLUSTRATION OF BLOOD CELLS

T-ALL infiltration in the bone marrow: the banality of evil Live and let die (tumor cells) Gene therapy: the next generation? Hellenic Society of Haematology EU Project for training early-stage researchers in personalized medicine Saskia Middeldorp: Inherited thrombophilia: a double-edged sword

The official newsletter for members of EHA

WINTER 2017

WINTER 2016 | HEMATOPICS | EHA

3

Hematopics is published three times per year by the European Hematology Association. Membership of the European Hematology Association includes subscription to Hematopics. Co-Editors-in-Chief Elizabeth Macintyre, Stefan Fröhling Editors Lars Bullinger, Simon Hallam, Michael Milsom, Melania Tesio Text editor Cait Kennedy Editorial coordination Ineke van der Beek, Jon Tarifa, Chared Verschuur-Ballo Contributing writers Barbara Bain, Ineke van der Beek, Lars Bullinger, Jan Cools, Michael Milsom, Helen Papadaki, Rob Stepney, Melania Tesio, Chared Verschuur Photography, illustrations Shutterstock, Stefan Zeitz, Bart Versteeg, David Kent, Hellenic Society of Haematology, Haematologica Graphic design Niels Eijsbroek, Biltvorming

10 Gene therapy: the next generation?

6 T-ALL infiltration in the bone marrow: the banality of evil

Copyright Copyright © 2017 European Hematology Association. All rights reserved. A note to the readers The views expressed in articles are the author’s and not necessarily those of EHA. Contact editors For remarks, questions and sugges­tions, e-mail: communication@ehaweb.org

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8 Live and let (tumor cells) die


Contents

14 Report of EHA Scientific Conference on Bleeding Disorders

16

18

26

Hellenic Society of Haematology

An update on Haematologica

David Kent: The trials and triumphs of a young researcher

20 Let us now praise SI units and those who begat them

RECOMMENDED RECOMMENDEDTERMINOLOGY TERM INOL OGY abbreviations, units and unit symbols abbreviations, units and

unitvariables symbols used describing hematological usedfor for describing hematological variables Variable Variable Full blood count Full blood count White blood cell count White blood cell count Red blood cell count Red blood cell count Hemoglobin concentration Hemoglobin concentration Hematocrit Hematocrit Packed cell volume Packed cell volume Mean cell volume Mean cell volume Mean cell hemoglobin Mean cell hemoglobin Mean cell hemoglobin Mean cell hemoglobin concentration concentration Red cell distribution width Red cell distribution width

Abbreviation Unit Abbreviatio n Unit FBC FBC WBC number × 109/l WBC number× ×101012/l9/l RBC number RBC number × 1012/l Hb grams/litre Hb ** grams/litre Hct litre/litre Hct litre/litre**** PCV litre/litre PCV litre/litre** MCV femtolitre MCV femtolitre MCH picograms MCH picograms MCHC grams/litre MCHC grams/litre RDW usually RDW usuallyas CV expressed expressed /l Platelet count Plt number × as 109CV Platelet count Plt number × 109/l Mean platelet volume MPV femtolitre Mean platelet volume MPV femtolitre Plateletcrit Pct litre/litre Plateletcrit Pct litre/litre Reticulocyte count Retic number × 109/l Reticulocyte count Retic number × 1091h /l Erythrocyte sedimentation rate ESR millimetres, Erythrocyte ESR millimetres, 1h (Westergren,sedimentati 1 hour) on rate (Westergren, 1 hour) * * ** **

Unit symbol* Unit symbol*

g/l ** l/lg/l l/ll/l**** l/l fl ** pgfl pg g/l g/l % % fl fl l/l l/l mm, 1h mm, 1h

L is acceptable as an alternative to l. LOris with acceptable an alternative to l.expressed as a decimal no unit,asbeing a proportion Or with no unit, being a proportion expressed as a decimal

22

24

EU Project for training early-stage researchers in personalized medicine

EHA’s new training and mentoring program helps early career researchers design and run clinical trials

28 Saskia Middeldorp: Inherited thrombophilia, a double-edged sword

30 Remembering Professors Niels Borregaard and David Grimwade

31 Save the date WINTER 2017 | HEMATOPICS | EHA

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President’s Message

opportunity to visit the Annual Congress in Copenhagen in June. Keynote speakers presented on various topics based on original data from the previous congress. After this event, all partners were convinced that a sequel would be much welcomed next year. By providing input for and participating in stakeholder meetings in Brussels, members of the European Affairs Committee advocate for more funding opportunities for hematology research and increased awareness of hematologists’ unmet clinical and scientific needs. As an EHA member, you will have received a questionnaire on Horizon 2020, aimed at collecting experiences and opinions regarding the EU’s research and innovation funding program. The results will be used to provide input on behalf of the hematology community for the European Commission’s upcoming interim evaluation of Horizon 2020. EHA is a prominent member of the BioMed Alliance, which calls upon European decision makers to stand up for a sound research environment, fight for proper funding and put biomedical research on top of the political agenda. The EHA representative on the board of the BioMed Alliance, Ulrich Jäger, addressed the importance of biomedical research funding at the European Parliament recently. Furthermore, EHA has successfully reached out to various Dear reader,

stakeholders in order to make sure hematologists are involved in discussions with the European Commission, Member States and

Welcome to another issue of Hematopics – and my thanks to

experts on the application of EU legislation on human blood and

the Editorial team for all their hard work. We start off with three

blood components.

hot-topic contributions from the Editorial Board who reviewed articles from high impact publications and continue on to

Finally, in this winter issue of Hematopics, we pay tribute to Niels

interviews with researchers like Saskia Middeldorp and David

Borregaard and David Grimwade who passed away recently.

Kent. In these interviews, they reveal themselves as passionate

Both David and Niels will be sadly missed and you will find their

researchers as they talk about what inspires their work.

obituaries on page 30 of this issue.

EHA continues to be active in multiple areas. We staged our first

While we are at the start of 2017, we look forward to the

Clinical Research Training in Hematology (CRTH) workshop in Milan.

opportunities ahead of us. These include Version 3 of the

From November 9-12, 17 young clinical researchers worked with16

Hematology Curriculum which will be launched in the first quarter

faculty members to learn how to design and conduct clinical trials

of the year. The curriculum was last updated in 2012. It has been

effectively. The aim of the CRTH is to foster the next generation of

reviewed and revised to match recommended competence levels

leaders in clinical research in hematology.

and current education requirements. Also, the EHA website will be given a new look in 2017 and these are only a few of the many

Two other successful meetings took place in Barcelona and Dubai,

exciting things that lie ahead this year.

recently. The EHA Scientific Conference on Bleeding Disorders, under the guidance of Carlo Balduini, Anna Falanga, Francesco Rodghiero, Ingrid Pabinger and Michael Makris, included the discussion of basic science, pathogenesis, diagnosis and treatment

With best wishes,

of inherited and acquired bleeding disorders. In Dubai, the Highlights of Past EHA (HOPE) was organized with regional partners,

Tony Green

especially for colleagues in the Middle-East who did not have the

EHA President

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EHA | HEMATOPICS | WINTER 2017


Message from the Editors-in-Chief Dear reader, Welcome to the winter issue of Hematopics!

In this issue, we are also launching a new, ad hoc, section:

In this issue, you will find familiar features such as our popular “hot

‘Guidelines’. The first contribution by Barbara Bain is on SI Units

topics” in basic, translational and clinical hematology, and also

(Système International d’Unités) which describes the history and

some innovations.

importance of international standard units. You will find an SI reference card enclosed with this issue.

In his contribution “Gene therapy: the next generation?”, Michael Milsom comments on an article in Nature describing modifications

EHA is a partner of the Marie Skłodowska-Curie Innovative Training

to CRISPR/Cas9 gene editing which address technical issues and

Network PROFILE Horizon 2020 project. In a report written by

demonstrate the effectiveness of this approach in hematopoietic

Karen van Hoorelbeke, you will learn about the goals and activities

stem cells from sickle cell disease patients. In “T-ALL infiltration

of this group.

in the bone marrow: the banality of evil”, Melania Tesio reports on a recent article in Nature on how to identify the microenviron-

As if this wasn’t enough, you will also find two with successful re-

mental components involved in the initiation and progression of

searchers. One with Saskia Middeldorp, who was awarded the

T-cell acute lymphoblastic leukemia. This important publication

Ham-Wassermann Lecture at the 2016 American Society of Hema-

was written by the 2012 EHA Research Fellowship winner, Edwin

tology Annual Meeting. The other interview is with David Kent, an

Hawkins et al. while working in London’s Imperial and the Fran-

EHA Research Fellowship winner and TRTH trainee, who recently

cis Crick Institute. In “Live and let (tumor cells) die”, Lars Bullinger

won a prestigious European Research Council grant. In this inter-

describes the results of a study published in Nature on the concept

view, David explains how the EHA awards helped him in his career.

of targeting apoptosis deregulation, which plays a major role in the development of cancer.

These are only the highlights of this jam-packed issue. We promise that there are other, equally fascinating ones.

We thank Helen Papadaki, who recently joined the EHA Board, for her contribution to the ‘National society in focus’, which features the

Sit back, relax and enjoy reading this issue of Hematopics!

Hellenic Society of Haematology. The society held its 27th Annual Meeting in November in Thessaloniki, Greece.

Elizabeth & Stefan

From left to right: Simon Hallam, Melania Tesio, Lars Bullinger, Elizabeth Macintyre, Stefan Fröhling and Michael Milsom.


Focus on basic malignant hematology

T-ALL infiltration in the bone marrow:

the banality of evil According to a new study, T-ALL development

cellular constituents provide support for hematopoietic stem

does not rely on specific bone marrow niches,

microenvironmental components implicated in the initiation and

cells, more work still has to be done to precisely identify the

but rather on multiple stochastic interactions

progression of hematological malignancies.

between leukemic cells and the bone marrow

In a recent Nature issue, Edwin D. Hawkins (2012 EHA Research

microenvironment.

Fellowship winner) and colleagues investigated these issues in the context of T-cell acute lymphoblastic leukemia (T-ALL) development1. Using intravital photon microscopy, the authors

Over the past years, mouse genetics and imaging techniques

imaged the seeding of NOTCH mutant murine blasts into the

enriched our knowledge of the bone marrow microenvironment.

calvaria (skull) bone marrow. Surprisingly, T-ALL seeding seemed

Whereas it is now clear that numerous and heterogeneous

to occur in a rather stochastic manner: at very early stages of

Intravital photon microscopy of mouse calvaria revealed that NOTCH mutant T-ALL blasts engage stochastic and promiscuous interactions with vasculature, osteoblasts and nestin-GFP+ perivascular stromal cells.

6

EHA | HEMATOPICS | WINTER 2017


Focus on basic malignant hematology T-ALL development, blast cells randomly localized in proximity to

genetics and a similar activated NOTCH model of T-ALL, Pitt et al.

nestin-GFP+ perivascular stromal cells, endosteal cells or vascular

previously showed that VE-cadherin+ vascular cells expressing

cells, without preferential association to any of these three bone

CXCL-12 specifically support T-ALL development3. Genetic deletion

marrow components. Time-lapse imagining at later stages of

of CXCL-12 in these cells, but not in other cellular components of

disease development confirmed these results, showing that BM

the bone marrow, halted T-ALL development, thus demonstrating

colonization does not depend on specific BM compartments either.

that during leukemia progression T-ALL cells preferentially localize

As specific niches may contribute to mechanisms of drug resistance,

in vascular niches. These data found support in a second study,

the authors next imaged the calvaria of leukemic mice receiving

showing that the CXCL-12 receptor CXCR4 sustains the self-

dexamethasone treatment, a first-line drug in T-ALL chemotherapy

renewal of leukemia-initiating cells4. Given these prior data, why

regimens. Time-lapse imaging before and after treatment did not

do blast cells in the study from Hawkins and colleagues engage

reveal the existence of specific bone marrow niches sheltering

only in a stochastic manner, with non-specific interactions with

dexamethasone-resistant clones. In line with these data, gene

vascular cells? The use of calvaria bones as a micro environmental

expression profiles identified only 79 differentially expressed genes

model for T-ALL infiltration/development may, at least in part, be

following dexamethasone treatment. Astonishingly, resistant cells

a reason. Calvaria present structural and functional differences

were instead found to be more motile and more proliferative when

with long bones, more commonly analyzed in experimental

compared to blasts seeding the bone marrow at earlier stages of

hematology. Importantly, these differences were shown to impact

the disease.

hematopoietic reconstitution following transplantation of normal hematopoietic stem cells5 and they may impact T-ALL infiltration/

Not surprisingly, moreover, in heavy-disease-burden mice, the

colonization as well. Further studies will therefore be necessary

authors observed osteoblasts undergoing remodeling processes,

to fully validate these aspects and shed light on the controversies

which ultimately led to complete loss of this cell type by apoptosis.

raised by Hawkins and colleagues. 

Whereas these data confirm previous studies showing that leukemia infiltration alters the bone marrow microenvironment2, they do not clarify the molecular mechanisms involved in this process, nor do they elucidate its biological significance. Since osteoblasts do not constitute preferential niches for leukemic blasts, and given that their role during normal hematopoiesis remains controversial, is their loss really expected to affect normal hematopoietic stem cells

AUTHOR: MELANIA TESIO

or to have a specific functional role during T-ALL development?

INSTITUT NECKER-ENFANTS MALADES (INEM),

Surprisingly, the authors do not provide experimental answers

INSTITUT NATIONAL DE RECHERCHE MÉDICALE (INSERM)

to these questions, nor do they comment on the discrepancies

U1151, PARIS, FRANCE

between their study and recent publications3,4. By using mouse

References 1.

T-cell acute leukaemia exhibits dynamic interactions with bone

Endothelial Niches Control Acute T Cell Leukemia Maintenance.

marrow microenvironments. Nature. 2016 Oct 17;538(7626):518-

Cancer Cell. 2015 Jun 8;27(6):755-68.

522. doi: 10.1038/nature19801. 2.

Passaro D, Irigoyen M, Catherinet C, Gachet S, Da Costa De Jesus C, Lasgi C, Tran Quang C, Ghysdael J. CXCR4 Is Required for Leukemia-

DA. Leukemic cells create bone marrow niches that disrupt the

Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia.

behavior of normal hematopoietic progenitor cells. Science. 2008

Cancer Cell. 2015 Jun 8;27(6):769-79.

Dec 19;322(5909):1861-5. 3.

4.

Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins

5.

Lassailly F, Foster K, Lopez-Onieva L, Currie E, Bonnet D. Multimodal

Pitt LA, Tikhonova AN, Hu H, Trimarchi T, King B, Gong Y, Sanchez-

imaging reveals structural and functional heterogeneity in

Martin M, Tsirigos A, Littman DR, Ferrando AA, Morrison SJ,

different bone marrow compartments: functional implications on

Fooksman DR, Aifantis I, Schwab SR. CXCL12-Producing Vascular

hematopoietic stem cells. Blood. 2013 Sep 5;122(10):1730-40.

WINTER 2017 | HEMATOPICS | EHA

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Focus on translational malignant hematology

Live and let die (tumor cells)

Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is

need for MCL1‑specific BH3‑mimetic compounds, and first

tolerable and effective in diverse cancer models. Nature. 2016 Oct

attempts to target MCL1 with a selective BH3 mimetic A-1210477

19;538(7626):477-482.

showed great promise3.

Apoptosis is a cell death program that plays a crucial role not

In the current study, Kotschy and colleagues now report on the

only in regulating cell numbers during embryonic development

mechanism of action of S63845, a novel small molecule that

and tissue homeostasis, but also in eliminating damaged cells

specifically binds with high affinity to the BH3-binding groove

that could cause cancer. Thus, evasion of apoptosis is one of the

of MCL1 1. The authors could demonstrate that S63845 potently

hallmarks of cancers, which is also frequently associated with

kills MCL1-dependent cancer cells, including multiple myeloma

resistance to therapy. While apoptosis can be triggered via “death

(MM), leukemia and lymphoma cells, by activating the BAX/BAK-

receptors” of the tumor necrosis factor receptor family on the cell

dependent mitochondrial apoptotic pathway. Furthermore, by in

surface, evasion of cell death also often occurs via intracellular

vivo mouse studies, the authors demonstrated that S63845 does

signals acting through BCL2 protein family members, which control

not only have a potent anti-tumor activity, but also possesses

the integrity of the mitochondrial outer membrane. Both pathways

an acceptable safety profile, indicating a potential therapeutic

lead to the activation of caspases, i.e. dedicated proteases that

window for MCL1 inhibition in humans1.

execute the cell death program . 2

Over the last decades, many researchers have focused on the BCL2-

Notably, S63845 potently killed MCL1-dependent H929 multiple

regulated apoptotic pathway with aim of restoring pro-apoptotic

myeloma cells, whereas the BCL2-specific BH3-mimetic ABT-

mechanisms. Recently, these efforts have led to the development

199 had only a minimal impact. Furthermore, S63845 was

of “BH3-mimetics”, novel small-molecule compounds that directly

approximately 1000-fold more potent in killing H929 cells than the

activate apoptosis of malignant cells via the inhibition of pro-

previously described MCL1 inhibitor A-1210477, probably due to

survival BCL2 proteins . For example, for the treatment of chronic

a higher affinity for MCL1 and a higher bioavailability of S63845.

lymphocytic leukemia (CLL) the BCL2-specific BH3-mimetic ABT-

Finally, the authors could also convincingly show that S63845 does

199 (also known as venetoclax) has proved highly efficacious in

kill cancer cells through on-target activity, i.e. activation of the

early phase clinical trials, and it has rapidly advanced into phase

BAX/BAK-dependent mitochondrial apoptotic pathway by direct

III trials for the treatment of patients with relapsed or refractory

inhibition of MCL11.

4

disease. Similar to BCL2, the pro-survival BCL2 family member Myeloid Cell

AUTHOR: LARS BULLINGER

Leukemia 1 (MCL1) is genomically amplified and overexpressed

ULM UNIVERSITY, DEPARTMENT OF INTERNAL MEDICINE III,

in many solid and hematological cancers, such as acute myeloid

ULM, GERMANY

leukemia (AML), in which it has been proved crucial for sustained survival and growth5. In accordance with this, there is an unmet

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EHA | HEMATOPICS | WINTER 2017


Venetoclax Navitoclax A-1210477

Figure 1: Selective inhibition of pro-survival BCL-2 family proteins by BH3-mietics in cancer. Pro-survival BCL2 family proteins (highlighted in red) inhibit pro-

Pro-survival BCL2 family members: BCL2 BCL2L1 (BCL-XL) BCL2L2 (BCL-W) MCL1

S63845 Highly selective MCL1 inhibition

Pro-apoptotic e ectors: BAX BAK

apoptotic effectors BAX and BAK (highlighted in blue), thereby preventing apoptosis. BH3-mimetics (highlighted in green) antagonize the pro-survival protein activity of BCL2 family proteins,

Caspase activation

which results in the release and activation of BAX and BAK and subsequently in apoptosis via caspase activation (modified from

Apoptosis

Besbes et al. 2016).

With regard to the spectrum of tumors that might benefit from

breakthrough for cancer patients with high MCL1 and low BCL-XL

MCL1 inhibition, Kotschy and colleagues provided evidence for

expression, additional studies confirming the therapeutic window

MM with 17/25 cell lines tested being highly sensitive to S63845

and feasibility of MCL1 inhibition are warranted. Ultimately,

(IC50 < 0.1 Îź M). In addition, 5/11 lymphoma and chronic myeloid

this approach may turn out to be effective in cases refractory

leukemia cell lines, 7/7 Burkitt lymphoma cell lines, and a panel

to standard-care agents and will let patients live and let tumor

of 8/8 AML cell lines were sensitive to S63845. Investigating the

cells die.

effects of S63845 in 25 primary AML patient derived samples displayed a wide range of responses. Sensitive cases required 100to 1000-fold lower S63845 dose levels for effective killing than resistant AML cases or normal CD34+ hematopoietic progenitor cells, which further supports the hope that there might be a realistic therapeutic window for MCL1 inhibition in man.

References

In contrast to hematological malignancies, testing the activity of S63845 as a single agent in solid tumors revealed only few sensitive

1.

cell lines (3/20 non-small cell lung cancer, 3/9 breast cancers and 3/12 malignant melanoma cell lines). However, in these cases,

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al.

2.

Strasser A1, Cory S, Adams JM. Deciphering the rules of

sensitivity to the MCL1 inhibitor was also inversely correlated with

programmed cell death to improve therapy of cancer and other

BCL-XL mRNA expression levels, and the combination of S63845

diseases. EMBO J. 2011 Aug 23;30(18):3667-83.

with kinase inhibitors (such as lapatinib, erlotinib, etc.) could

3.

potently sensitize solid tumor cells to BH3-targeting1.

Besbes S, Pocard M, Mirshahi M, Billard C. The first MCL-1selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia. Crit Rev Oncol Hematol.

In summary, the work by Kotschy and colleagues further supports the concept of targeting apoptosis deregulation, which plays

2016 Apr;100:32-6. 4.

a major role in the development of cancer. As novel agents

translating cell death discoveries into novel cancer therapies. Nat

targeting BCL-2, BCL-XL and BCL-W (navitoclax, ABT-263) or BCL-2 alone (venetoclax, ABT-199) have started to enter the

Delbridge AR, Grabow S, Strasser A, Vaux DL. Thirty years of BCL-2: Rev Cancer. 2016 Feb;16(2):99-109.

5.

Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, Izon DJ,

clinic (Figure 1), MCL1 inhibition now adds additional promise,

et al. Anti-apoptotic Mcl-1 is essential for the development and

especially for MCL1 driven tumors such as AML, in which during

sustained growth of acute myeloid leukemia. Genes Dev. 2012

recent years, only few novel drugs have been proven effective.

Jan 15;26(2):120-5.

While small BH3-molecule inhibitors may provide a therapeutic

WINTER 2017 | HEMATOPICS | EHA

9


Focus on translational non-malignant hematology

Gene therapy: the next generation? The efficient editing of disease causing mutations within

disorders using retroviral transduction of HSCs, including diseases

hematopoietic stem cells (HSCs) would theoretically facilitate

such as X-linked and adenosine deaminase deficiency severe

the treatment of a wide range of inherited diseases using

combined immune deficiencies, Wiskott-Aldrich syndrome,

autologous transplantation. As gene-editing tools have

chronic granulomatous disease and β-thalassemia, as well as

developed and improved, this application should be closer

the non-hematologic disease, X-linked adrenoleukodystrophy.

to realization. However, human HSCs appear to be somewhat

These pioneering proof of concept clinical studies, largely driven

refractory to standard gene editing technology and the

by the academic community, have attracted increasing levels of

prospective identification and isolation of clones that have

commercial interest from the biotechnology and pharmaceutical

undergone successful homology-directed repair is extremely

industry. In fact, the first commercial ex vivo gene therapy

challenging. Dever and colleagues have recently described

product, Strimvelis, received approval for use in Europe this

modifications to CRISPR/Cas9 gene editing which address

year. However, there have also been significant setbacks in the

these technical issues and demonstrate the effectiveness

process of bringing hematopoietic gene therapy to the clinic.

of their approach in HSCs from human sickle cell disease

Most notably, myelodysplasia and leukemia were observed

patients .

in several of these trials and were found to be caused by the

1

phenomenon of insertional mutagenesis. Powerful enhancer Ever since the first successful genetic modification of murine HSCs

elements located in the long terminal repeats of the retroviral

using gamma retroviral vectors in the early 1980â&#x20AC;&#x2122;s, an enormous

vectors, were able to activate expression of cellular proto-

amount of effort has focused on harnessing this technology

oncogenes in the vicinity of the proviral integration site, acting

towards the development of clinical therapies for inherited

as an initiation event for cellular transformation2-4. In the wake of

hematologic disorders, based on the transplantation of corrected

these serious adverse events, numerous modifications have been

autologous HSCs. During the intervening years, the work of

made to the architecture of next generation gammaretroviral and

many groups in the gene therapy field has led to clinical trials

lentiviral vectors in order to reduce the likelihood of insertional

demonstrating success in treating life-threatening hematologic

mutagenesis. Nonetheless, it would be ideal if one could

10

EHA | HEMATOPICS | WINTER 2017


Focus on translational non-malignant hematology completely avoid the introduction of exogenous vector DNA into

AUTHOR: MICHAEL MILSOM

the genome of HSCs in order to correct them. This is the major

HI-STEMA HEIDELBERG INSTITUTE FOR STEM CELL

driving force behind the attempts to develop gene-editing tools

TECHNOLOGY AND EXPERIMENTAL MEDICINE,

that could facilitate the directed repair of a disease-causing allele.

HEIDELBERG, GERMANY

Gene editing of a specific genomic locus involves the induction of a DNA double strand break, using a directed endonuclease, followed by the replacement of the disease-associated allele

insertion or deletion resulting from repair via non-homologous

with a normal DNA template via homology directed DNA repair.

end joining, therefore successfully corrected HSC clones comprise

The key to increasing the efficiency of homology directed repair

a minor subpopulation of all HSCs undergoing the gene editing

at a given site is the specificity with which one can induce the

procedure.

DNA double strand break. A number of methodologies for inducing sequence-specific double strand breaks have been

Dever et al. have addressed the challenge of gene editing in

explored, including zinc finger nucleases, meganucleases and Tal1

HSCs by adapting the standard CRISPR/Cas9 methodology,

nucleases. However, the more recent development of the CRISPR/

with the aim of correcting the Glu6Val mutation in the β-globin

Cas9 system has caused an explosion in the number of groups

gene which gives rise to sickle cell anemia. Firstly, the authors

working on gene editing, predominantly due to the relative ease

were able to show that the delivery of the guide RNAs and

with which it is possible to design guide RNAs to target a given

Cas9 as a ribonuclear protein complex, as opposed to using a

locus in the genome. Despite the broadly successful application

Cas9-encoding mRNA, improved the efficiency with which they

of the CRISPR/Cas9 system in the gene editing of multiple cell

could target the β-globin gene in HSCs. More importantly, by

types, there are limited reports of successful gene editing of

employing a GFP reporter construct flanked with homology arms

primary HSCs. Firstly, it appears that HSCs are extremely difficult

targeting the first exon of the β-globin gene, they could observe

to transfect with exogenous DNA or RNA while retaining cellular

that HSCs that had undergone homology directed repair could be

viability. Secondly, homology-directed repair of a cleaved locus is

prospectively identified and isolated by their very high expression

normally a relatively rare event compared to the induction of an

of GFP four days after electroporation with the reporter construct.

Figure 1. Schematic representation of modified CRISPR/Cas9 strategy developed to improve derivation and subsequent isolation of HSCs which have been gene edited at the β-Globin locus. LHA and RHA= Left or right homology arm, respectively.

WINTER 2017 | HEMATOPICS | EHA

11


Focus on translational non-malignant hematology Since GFP could not be used in a clinical setting, this reporter was

applications. However, one must note that the inclusion of the

substituted with a truncated version of the human nerve growth

tNGFR reporter also requires the insertion of an exogenous

factor receptor (tNGFR), which facilitated antibody-mediated

promoter/enhancer into the host genome, albeit at a defined

isolation of repaired HSCs via either flow sorting, or clinically-

location where the risk of mutagenesis can be readily assessed. 

approved microbead-based enrichment. Using this reporter in a large scale editing procedure on mobilized peripheral blood CD34+ cells and then transplanting the manipulated cells into immune-deficient mice, the authors could demonstrate accurate editing of more than 7% of human blood cells in the reconstituted mice when bulk cells were transplanted in the absence of pre-

References

selection. While this already compares very favorably with previous reports, the enrichment of edited cells using micro-

1.

Dever, D. P. et al. CRISPR/Cas9 beta-globin gene targeting

beads resulted in cell-editing frequencies of between 10-75%

in human haematopoietic stem cells. Nature, doi:10.1038/

in human cells reconstituting the mice. Importantly, when the

nature20134 (2016).

tNGFR reporter was modified to include an upstream anti-sickling

2.

β-globin cDNA (Figure 1), this construct effectively integrated

long-term efficacy and genotoxicity. Sci Transl Med 6, 227ra233,

into 11% of CD34+ cells isolated from sickle cell disease patients, and the relative expression of the corrective cDNA was found to

Braun, C. J. et al. Gene therapy for Wiskott-Aldrich syndrome-doi:10.1126/scitranslmed.3007280 (2014).

3.

Hacein-Bey-Abina, S. et al. A serious adverse event after

comprise 70% of the total adult β-globin transcribed in erythroid

successful gene therapy for X-linked severe combined

cells derived from tNGFR-enriched CD34+ cells.

immunodeficiency. N Engl J Med 348, 255-256, doi:10.1056/ NEJM200301163480314 (2003).

Taken together, this new approach has the potential to

4.

Stein, S. et al. Genomic instability and myelodysplasia with

dramatically increase the efficiency with which functional gene

monosomy 7 consequent to EVI1 activation after gene therapy

edited HSCs can be identified and prospectively isolated prior to

for chronic granulomatous disease. Nat Med 16, 198-204,

transplantation. This could impact on both the eventual clinical

doi:10.1038/nm.2088 (2010).

translation of gene editing and also on more basic research

12

EHA | HEMATOPICS | WINTER 2017


PROFILE YOUR WORK

SUBMIT AN ABSTRACT SUBMISSION DEADLINE: MARCH 1, 23:59 (CET)

Why submit an abstract to EHA? 1

You will have an estimated audience of 10000+ researchers and clinicians, as well as an online audience which generated over 36.000 abstract views for the last Congress on the EHA Learning Center.

2

The meeting will be the premier scientific exchange and networking opportunity for hematologists in Europe and beyond.

3

The program of the 22ND Congress depends on your input, because your abstracts form the basis of a large section of the scientific program.

4

Submitting an abstract is free of charge.

5

A substantial amount of travel grants are available for junior members of EHA from around the world.

6

Learn, share and network with EHA!

Abstract submission guidelines are available on ehaweb.org

ehaweb.org

WINTER 2017 | HEMATOPICS | EHA

13


Scientific report

Report of EHA Scientific Conference on Bleeding Disorders September 14-17, 2016, Barcelona, Spain The Scientific Program Committee chaired by

Conference on Bleeding Disorders, with

C Balduini and A Falanga and supported by

interesting scientific outcomes. The variety of

M Makris, I Pabinger and F Rodeghiero,

backgrounds of the faculty and delegates

organized a successful EHA Scientific

contributed to lively discussions.

14

EHA | HEMATOPICS | WINTER 2017


Scientific report The conference was attended by 130 participants from 35

selected from submitted abstracts, in which they could discuss

countries and 6 continents, and was targeted at clinicians, basic

their research or clinical cases with the faculty and audience.

researchers, biologists and students interested in bleeding disorders. They highly appreciated the conference, as 88% of

Professor Balduini and Professor Falanga summarized the

the delegates would recommend it to their colleagues, and the

following scientific higlights of the meeting:

same percentage indicated that their objectives were achieved. The conference was assessed by delegates with an average

The prognosis and quality of life of people with coagulation

score of 8,5 (out of 10).

defects greatly improved in recent years and further advances are expected shortly thanks to the availability of

Program

new therapeutic agents. Todayâ&#x20AC;&#x2122;s challenges are to further

The program covered a wide range of topics in the field of

reduce the side effects of treatment and to extend the

bleeding disorders and included the discussion of basic

benefit to patients of less resourced countries.

science, pathogenesis, diagnosis and treatment of inherited

Despite impressive improvement of knowledge in the field

and acquired bleeding disorders, including rare coagulation

of inherited and acquired platelet defects, many aspects of

defects, thrombocytopenias and hemophilia. Moreover the

these disorders remain poorly defined. Further research is

program covered the following learning goals, which enabled

required to identify more simple and reliable diagnostic

participants to:

techniques and to offer patients personalized treatments. The training of medical and nursing staff for the care of

Identify the etiology and pathogenesis of bleeding

patients with bleeding disorders is still poorly defined in

tendency in each patient

many countries. The identification of the skills required to

Use laboratory investigations appropriately to reach

become an â&#x20AC;&#x2DC;expert in hemostasisâ&#x20AC;&#x2122; and how to acquire them

diagnostic certainty

is central for improving patient care in this area.

M anage patients at risk of hemorrhage Define how to stop bleeding once it occurs

The meeting has been organized with the main support of EHA

Consider the cost-benefit ratio in the choice of treatment

and unrestricted educational grants provided by BPL, Novartis,

of bleeding disorders

Daiichi-Sankyo and Pfizer. Moreover the meeting was endorsed by the International Society on Thrombosis and Haemostasis.

Delegates were encouraged to play an active role in the program. All sessions in the program, especially the round table

EHA would like to thank the chairs, the scientific program

discussions and the interactive case sessions (use of a voting

committee, the faculty and the oral and poster presenters, and

box system), offered the possibility to discuss and ask

sponsors for their invaluable contribution to this excellent

questions. Delegates also gave oral and poster presentations,

meeting. 

WINTER 2017 | HEMATOPICS | EHA

15


National society in focus

Hellenic Society of Haematology National society in focus

Career development

The Hellenic Society of Haematology

HSH strives to promote the career

(HSH) (President Dr Dimitrios Karakasis)

development of junior scientists

was established in 1961 and presently

in the field of hematology. HSH, in

comprises 1144 active members. The

association with the HSH Institution,

mission of HSH is to promote excellence

funds two fellowships for a two-year

in patient care, education and research

training program every year in the

in hematology by supporting (a) the

field of malignant and non-malignant

advancement of knowledge and

hematology in national Centers and

professional competence, (b) the

two fellowships for one-year research

harmonization of hematology training

in international Hematology Centers.

with the standards set by EHA, (c) the

HSH also organizes annual (live and

organization of the Annual Conference

webcast) educational program including

and the educational activities of the

courses with “hands-on” experience

Scientific Working Groups, (d) multicenter

in molecular biology techniques. The

trials, epidemiological studies and patient

society supports annual two-day tutorial

registration organized by the Scientific

courses in Alexandroupolis/Thrace

Working Groups, (e) the professional

(School of Haematology) and Heraklion/

support of its members through

Crete (clinical-laboratory

active participation in

education in hematology

the national policy

with emphasis

making bodies.

in morphology/

Since 1998, the HSH

microscopy) in May

has been organizing the External Quality Control

and September, and provides online access to top

and Accreditation of the Hematology

hematology journals. HSH organizes and

Laboratories. The official journal of

promotes volunteering across Greece for

HSH is “HAEMA”, initially published

blood, marrow and umbilical cord blood

in 1998. There are eight Scientific

donation.

Working Groups under the umbrella of namely Blood Banking & Apheresis,

Collaboration between HSH and EHA

Hemostasis, Laboratory Hematology

Since 2000, HSH has been involved in the

and Quality Control, RBC disorders,

establishment of EHA Curriculum and

Lymphoproliferative disorders,

has endorsed the EHA CV passport. HSH

Transplantation, MDS and BM Failure,

encourages its members to participate

Acute Leukemia and Myeloproliferative

in all EHA activities including the EHA

Neoplasms.

Annual Congress and has supported

HSH covering all areas of hematology,

16

EHA | HEMATOPICS | WINTER 2017


National society in focus

the election of Professor HΑ Papadaki as

trainee in hematology, was promoting

councilor to the EHA Board (2016-2020).

EHA material and a lecture on the “EHA

HSH/EHA members are actively involved

activities and the potential benefits of the

in the EHA Scientific Working Groups

Greek Hematologists as EHA members”

and EHA committees. This year, Dr E

was given by the EHA Board member

Chatzimichail was selected for a Clinical

Professor HΑ Papadaki.

Research Training in Hematology. The 27th HSH conference, which took place in Thessaloniki on November 3-6 2016, was a great success. The Molecular Hematology Workshop was introduced for the first time and was chaired by Drs

Conference details:

HA Papadaki and K Stamatopoulos. There

There were 1072 participants

were six awards for the best abstracts

(376 hematologists, 69 trainees in

presented in the plenary session, three

hematology, 236 scientists, 302

awards for the best posters and the

nurses/technicians, 89 students),

“Arkagathos Goutas award” for the best

198 abstracts (61 oral, 113 posters,

research paper.

21 publication only) and 15 distinguished international invited

At this meeting was an EHA stand where

speakers.

the HSH/EHA member Dr Maria Velegraki,

WINTER 2017 | HEMATOPICS | EHA

17


Best of Haematologica

Updates from Haematologica The number of articles that are published every year continuously

lar updates on our publications. Below are some examples of the

increases. This is a result of the large amount of new open access

graphical abstracts designed for articles of the September, Octo-

journals launched in the past few years and is further enhanced by

ber and December issues of Haematologica.

the fast online publication process. Along with the increasing number of research articles that are being published, young scientists

September

have increasing difficulty keeping up with reading all the relevant

DNA methylation (methylation of cytosines in CpG dinucleotides

literature for their research topic and beyond. This is a worrying

in the genome) is frequently altered in acute myeloid leukemia

observation, since a good knowledge of the published literature is

(AML), in part by the accumulation of mutations in genes that

required for the formulation of new hypotheses and research ques-

result in DNA methylation defects, including IDH1, IDH2, DNMT3A

tions and for correct interpretation of experimental data.

and TET2. These methylation changes can have dramatic effects on gene expression and could thus have prognostic value.

Our Hematopics newsletter provides concise summaries of impor-

Ryotokuji and colleagues observed mutations in DNA-methylation

tant work that was recently published, which is one way to help

regulatory genes in 135 of 308 AML cases (43.8%) and showed that

with the digestion of all the new publications. At Haematologica,

these mutations were more frequent in older patients (P<0.0001)

we are providing graphical abstracts to summarize the important

and in patients with intermediate cytogenetic risk (P<0.0001) and

findings of the articles. These structured images show the impor-

provided an unfavorable prognostic factor for overall survival

tant data and the conclusions for each article, and should be easier

in the whole cohort (P=0.0018).1 Among the patients with

to read than the classical text abstract. Follow Haematologica on

DNA-methylation regulatory gene mutations, 26.7% were found

Facebook and you will get to see these graphical abstracts as regu-

to have two or more such mutations and prognosis worsened with increasing number of mutations. This study demonstrates that the presence of mutations in DNA-methylation regulatory genes

is

an

important

unfavorable

prognostic factor in AML.

October Gain of chromosome 8 is a common feature of AML, including acute promyelocytic leukemia caused by the PML-RARA fusion gene.2 Scott Kogan and co-workers had previously demonstrated that the MYC gene, which is located on chromosome 8, is one of the genes that is contributing to the oncogenic effects of trisomy 8 in AML. In a new study, Keeshan and colleagues now demonstrate that TRIB1, another gene on chromosome 8, can cooperate with MYC to drive leukemia development in a mouse AML model.3 Surprisingly, while TRIB1 did contribute to MYC-induced leukemia, it

18

EHA | HEMATOPICS | WINTER 2017


Best of Haematologica

haematologica Periodico – Sped. Abb. Post. – 45% art. 2, comma 20B, Legge 662/96 - Filiale di Pavia. Il mittente chiede la restituzione dei fascicoli non consegnati impegnandosi a pagare le tasse dovute

Journal of the European Hematology Association Published by the Ferrata Storti Foundation

haematologica Periodico – Sped. Abb. Post. – 45% art. 2, comma 20B, Legge 662/96 - Filiale di Pavia. Il mittente chiede la restituzione dei fascicoli non consegnati impegnandosi a pagare le tasse dovute

Journal of the European Hematology Association Published by the Ferrata Storti Foundation

ISSN 0390-6078

haematologica

Volume 101

www.haematologica.org

OCTOBER

Periodico – Sped. Abb. Post. – 45% art. 2, comma 20B, Legge 662/96 - Filiale di Pavia. Il mittente chiede la restituzione dei fascicoli non consegnati impegnandosi a pagare le tasse dovute

2016|10

Journal of the European Hematology Association Published by the Ferrata Storti Foundation

ISSN 0390-6078

Volume 101 SEPTEMBER

2016|9

www.haematologica.org

ISSN 0390-6078

Volume 101 DECEMBER

2016|12

www.haematologica.org

did not contribute to PML-RARA-induced leukemia development.

induces a balanced activation of AKT and ERK1/2 signaling, while

Further studies documented that both TRIB1 and PML-RARA

romiplostim causes an unbalanced activation of these pathways,

targeted the myeloid transcription factor CEBPA, indicating the

resulting in a markedly different response of the cells.

critical role for CEBPA in AML pathogenesis, and explaining why the combination of PML-RARA and TRIB1 does not result in strong cooperation, as both genes have similar effects. These data suggest that both MYC and TRIB1 contribute to the pressure for AML cells to undergo trisomy 8.

References

December

1. Ryotokuji T, Yamaguchi H, Ueki T, Usuki K, Kurosawa S,

The major cytokine regulating megakaryopoiesis is thrombopoietin

Kobayashi Y, et al. Clinical characteristics and prognosis of

(TPO), which binds to its receptor MPL, and results in the activation

acute myeloid leukemia associated with DNA-methylation

of the JAK2 kinase and downstream signaling pathways. Defects

regulatory gene mutations. Haematologica. 2016;101:1074-81.

in the TPO/MPL/JAK2 signaling complex, viral infections or

2. Velasco G. The complex relationship of Tribbles pseudokinase

autoimmune diseases can all lead to thrombocytopenia.4 Di Buduo and colleagues studied and compared the actions of eltrombopag

1, PML/RARA and C/EBPα in leukemia: two possible couples but not a trio. Haematologica. 2016;101: 1129-1130.

and romiplostim, two different agents that can bind and activate

3. Keeshan K, Vieugué P, Chaudhury S, Rishi L, Gaillard C, Liang

MPL and result in increased platelet counts.5 The exact mechanisms

L, Garcia E, Nakamura T, Omidvar N, Kogan SC. Co-operative

governing eltrombopag’s impact on human hematopoiesis

leukemogenesis in acute myeloid leukemia and acute

remained largely unknown. Di Buduo et al. used an elegant in vitro

promyelocytic leukemia reveals C/EBPα as a common target of

model for studying human hematopoietic stem cell differentiation

TRIB1 and PML/RARA. Haematologica. 2016;101:1228-1236.

combined with a three-dimensional silk-based bone marrow tissue model. The key finding of their study is that eltrombopag

4. Raslova H, Vainchenker W, Plo I. Eltrombopag, a potent stimulator of megakaryopoiesis. Haematologica. 2016;101:1443-1445. 5. Di Buduo CA, Currao M, Pecci A, Kaplan DL, Balduini CL,

AUTHOR: JAN COOLS

Balduini A. Revealing Eltrombopag’s promotion of human

EDITOR-IN-CHIEF HAEMATOLOGICA

megakaryopoiesis through AKT/ERK-dependent pathway activation. Haematologica. 2016;101:1479-1488.

WINTER 2017 | HEMATOPICS | EHA

19


Guidelines

Let us now praise SI units and those who begat them “Let us now praise famous men and our fathers who begat them.” Ecclesiasticus, Chapter 44, verse 1.

SI units

derived units have their own names and symbols, and are related

The creation of the European Hematology Association (EHA)

to the basic units by 103, 10-3 or multiples thereof (see Table 1).2 In

led to extensive cooperation between hematologists in various

addition to the base units, derived units of relevance to medicine

European countries to the benefit of us all. A further development

are the gray and the becquerel. Furthermore, the degree Celsius

that would enhance European hematology would be the universal

(°C), used in medicine, is exactly equivalent to the kelvin. There are

adoption of the Système International d’Unités (SI units). This is

also a number of non-SI units that are accepted for use with the

an internationally agreed system of units and symbols, which

Système International, specifically the minute (min), the hour (h),

has been adopted in some but not all European countries. The

the day (d), the liter (l) and the dalton (Da). Unit’s symbols generally

incomplete adoption of the system means that presentations at

take the lower case unless, like the ampere (A) or the kelvin (K), they

meetings and scientific publications sometimes use outdated units (e.g. cells/mm3 for the white cell count) or completely erroneous units (e.g. G/l for the white cell count). Errors are

Table 1 Système International (SI) prefixes and symbols

likely to occur if hematologists use outdated or incorrect units in their own laboratories but seek to use SI units in publications

No

Prefix

publications, e.g. it is incorrect to say that a patient’s blood count

10-18

atto

a

attogram (ag) or attoliter (al)

showed a ‘raised white blood cell count’ of 1.3 × 109/l; similarly, a

10-15

femto

f

femtogram (fg) or femtoliter (fl)

In these sentences, either the count or the descriptive term is

10-12

pico

p

picogram (pg) or picoliter (pl)

wrong. Clinical staff may be resistant to change but they can be

10-9

nano

n

nanogram (ng) or nanoliter (nl)

10-6

micro

µ

microgram (µg) or microliter (µl)

10-3

milli

m

milligram (mg) or milleliter (ml)

10-2

centi

c

centigram (cg) or centiliter (cl)

10-1

deci

d

decigram (dg) or deciliter (dl)

10

deca

da

gram (g)

103

kilo

k

kilogram (kg), kilodalton (kD)

106

mega

M

megabyte

109

giga

G

gigabyte

1012

tera

T

1015

peta

P

1018

exa

E

or presentations. This has led to erroneous and confusing data in

patient does not have ‘thrombocytosis (platelet count 71 × 10 /l)’. 9

1

gradually educated to use SI units, as has been demonstrated in the United Kingdom. The modern metric system of units has its origins in France at the time of the Revolution when, on June 22, 1799, two platinum standards representing the meter and the kilogram were placed in the Archives de la République in Paris. Further developments occurred throughout the 19th century, with the Convention du Mètre being signed in Paris in 1875 by representatives of seventeen nations under the auspices of the Conférence Générale des Poids et Mesures (General Conference on Weights and Measures). Development continued throughout the 20th century, culminating in the establishment of the Système International d’Unités at the 11th General Conference on Weights and Measures in 1960. The Système International has base units, which include the meter, the kilogram, the second and the mole, and derived units; the

20

EHA | HEMATOPICS | WINTER 2017

Abbreviation Examples


Guidelines are derived from a proper name. Recently, the use of upper case ‘L’

AUTHOR: BARBARA J. BAIN

has been permitted as an abbreviation of ‘liter’ since this avoids the

PROFESSOR OF DIAGNOSTIC HAEMATOLOGY, CENTRE

potential confusion between the letter ‘l’ and the number ‘1’, which

FOR HAEMATOLOGY, IMPERIAL COLLEGE LONDON AND

is possible with some fonts. However, this does lead to inelegant

ST MARY’S HOSPITAL, LONDON.

abbreviation such as fL for the femtoliter; in hematology confusion is unlikely and there is no reason to avoid the abbreviation ‘l’ unless national policies (perhaps dictated by biochemists) require the use

to express hemoglobin concentration in either g/l or mmol/l.

of ‘L’.

However, it is important to note that not only clinicians but also

It should be noted that it is erroneous to use a prefix as a unit. The

hematologists are more likely to be able to adapt to a hemoglobin

‘G’ is thus an abbreviation for giga, as in ‘gigabyte’. It is erroneous

concentration expressed, for example, as 112 g/l than one

to represent a white cell count of, for example, 3.4 × 10 /l as 3.4

expressed as 6.95 mmol/l. For this reason, it is very reasonable to

G/l or G/L. It is also erroneous to fail to use a superscript when

prefer g/l to mmol/l.

9

necessary; 3.4 × 10 9/l is not an acceptable alternative to 3.4 ×

If scientific journals choose to retain non-SI units, it is important,

109/l. It should also be noted that although a decimal comma is

in the interests of clarity, to also provide SI units, as is done, for

not erroneous when using SI units, a decimal point is always used

example by the New England Journal of Medicine.

^

in English language publications. Since English is the language of communication adopted by the EHA, a decimal point should be

Beyond SI units

used. When a number is between −1 and +1 the decimal point

To improve communication between European hematologists,

should be preceded by a zero (e.g. 0.23).

there are other international conventions that should be followed.

It is important when seeking to introduce uniform units within and

1. The International Committee (now Council) for Standardization

between countries to try to avoid changes that may impinge on

in Haematology advised standardized abbreviations for

patient safety. Thus it is quite correct, in the Système International,

the components of the full blood count (Table 2). Note that ‘hematocrit’ is preferred to ‘packed cell volume’ for the automated measurement. 2. Standardized gene names, as advised by the Gene Nomenclature Committee of the Human Genome Project should be used and should be up to date, e.g. ABL1 not ABL or

INOLOGY TERM MME RECO RECO MMNDED ENDED TERM LOols GY symb unitINO

and viatio abbre abbrev iatins, onsunits , units and unit symbols

abl, MYC not c-MYC, RUNX1 not AML1, KMT2A not MLL. 3. When genus and species is given, the format is Streptococcus pyogenes whereas when only genus is given it is streptococci.

ological variables hemat binging descri used usefor d for describ hematological variables

4. Generic names of drugs (the international non-proprietary

Unit symbol* Unit n Abbreviatio Abbreviatio n Unit Unit symbol* FBCFBC 9 × r10× /l109/l number WBCWBC numbe number numbe× r10×1210/l 12/l RBCRBC grams/liter OR g/lg/l or grams/liter HbHb millimoles **per liter ** l l/lmmol/ liter/liter HctHct no unit**OR ** no unit or l/l liter/liter PCV ** liter/liter** l/l PCV femtoliter MCV no unit OR noflunit or ** liter/liter pgl/l** picograms MCH MCV femtol iter fl g/l grams/liter MCHC MCH picograms OR pg or femtomoles %fm usually RDW MCHC grams /liter g/l or as CV expressed millim oles per liter mmol/l × 109/l RDW number Plt usually % expres sed as CV fl femtoliter MPV Mean Plateleplatelet t countvolume 9 Plt numbe r × 10 /l l/l liter/liter Pct Mean platelet volume Plateletcrit MPV femtoliter 9 fl /l 10 × Platele number tcrit Retic Reticulocyte count Pct liter/liter l/l 1h Reticu locytesedimentatio mm, 1h count millimeters, ESR n rate 9 Retic Erythrocyte number × 10 /l Erythro cyte sedime ntation rate 1 hour) (Westergren, ESR millimeters, 1h mm, 1h (Westergren, 1 hour)

needed for clarity or precision, it should be given in brackets

Variable Variable blood count count blood FullFull White blood cell count White blood cell count Red blood cell count blood cell count RedHemog lobin concentration Hemoglobin concentration Hematocrit Hematocrit Packed cell volume Packed cell volume Mean cell volume Mean Meancell cellhemoglobin volume Meancell cellhemoglobin hemoglobin Mean concentration Mean hemoglobin width distribution cellcell Red concentration Red cell distribution width Platelet count

name) should be used, not trade names. If the trade name is after the generic name.

Conclusions EHA has been important in facilitating cooperation and collaboration between hematologists in Europe, and beyond. Clarity of communication could be further improved by the universal adoption of SI units and recommended terminology for hematological variables, gene names and drugs. Educational programs should be developed in European countries that are not yet consistently using SI units in order to introduce these units into medical practice within countries. Other countries with links to European hematology might well do the same.

acceptable as an alternative to l. ** LLisisaccept able as an alternative to l. being a proportion expressed as a decimal no unit, Or with **** Often expres sed as l/l but no unit is needed as it is a dimensionless fraction expressed as a decimal.

WINTER 2017 | HEMATOPICS | EHA

21


Hematopolitics

EU project for training early-stage researchers in personalized medicine PROFILE

innovative

training

network: ‘Immunoprofile-

directed stratification of patients with the autoimmune disorder

directed stratification of patients with the autoimmune

thrombotic thrombocytopenic purpura (TTP)’. In line with the

disorder thrombotic thrombocytopenic purpura (TTP)’

Marie Skłodowska-Curie ITN objectives, PROFILE aims at training a new generation of creative, entrepreneurial and innovative

The Marie Skłodowska-Curie Innovative Training Network (ITN)

PhD students or early-stage researchers (ESRs) who are able to

with the acronym PROFILE is a Horizon 2020 project launched

deal with current and future challenges and who can convert

in October 2015. The PROFILE project is titled ‘Immunoprofile-

knowledge and ideas into products and services for economic and

The PROFILE consortium visiting partner AP-HP for a workshop in Paris, France in May 2016


Hematopolitics social benefit. To reach this goal, PROFILE merges the expertise of 10 partners in Europe, from both academia and industry (Figures 1 and 2), that will provide adequate and unique training of the ESRs. The PROFILE training network will develop novel immunoprofiling technologies and treatment approaches for stratification and treatment of patients with acquired TTP. The project involves integrated and focused efforts of the six ESRs to decipher the pathophysiology of acquired TTP, to discover and validate novel biomarkers, and to develop novel personalized therapeutic modalities for patients suffering from this disorder. Importantly, the strategies developed in the PROFILE project for TTP will be applicable to many other autoimmune disorders. At the core of the training program for the six ESRs is the integrative approach to conceptualizing, developing, validating and exploiting novel therapeutic and diagnostic solutions for

the increasing prevalence of autoimmune diseases in Europe

(orphan) autoimmune diseases. ESRs will be trained in (i) the

(estimated at 4-8%), the expertise and ‘human capital’ delivered by

clinical, biotechnological and technical aspects of diagnostics and

the PROFILE training network is expected to have a huge impact

therapeutics for autoimmune diseases such as TTP, (ii) the ethical,

on the quality of life and healthcare costs in Europe.

administrative, regulatory and legal aspects, (iii) development and implementation of diagnostics and therapeutics for such

On September 13-14, 2016, the PROFILE consortium organized its

autoimmune diseases, in particular in an orphan disease setting,

second workshop in Barcelona, Spain. The workshop was hosted

(iv) innovation management of diagnostics and therapeutics for

by Dr Marta Palicio and Dr Pau Bruguera from Biokit, the Werfen

autoimmune diseases and (v) a broad set of soft skills including

Group, Barcelona. During the first day of the workshop, scientific

communication skills (verbal and written), management skills and

results were discussed by the six early-stage researchers in the

entrepreneurial and productive development skills.

consortium, a report of their clinical training at AP-HP in Paris was evaluated, the outreach, communication and dissemination

Responsible for the high-level training and supervision of these

strategy was discussed and the supervisory board meeting was

ESRs will be highly skilled and specialized immunoprofiling experts

held. All consortium members joined a guided tour at Biokit and

from small and medium-sized enterprises (Icosagen, Protobios,

learned a lot about the organization and company spirit of Biokit.

Immudex, Biokit) as well as world-leading experts on acquired

During the second day of the workshop, PROFILE organized an

TTP from academia (KU Leuven, Sanquin, Assistance

educational session on ‘Reference technologies

Publique-Hospitaux de Paris/AP-HP). Translational

in diagnostics and state of the art in therapeutic

aspects are well-covered by the inclusion of expert

scaffolds’. This training session was organized

clinicians (AP-HP) as well as representatives from

together with EHA as a pre-conference workshop of

patient groups (TTP Contact Group). Additional

the EHA Scientific Conference on Bleeding Disorders.

high-level training of the ESRs by PROFILE will occur

Topics that were covered in this training session

every six months during network-wide events.

include intellectual property, the design process of

These trainings will not only be accessible for PROFILE ESRs but

a diagnostic assay, diagnostic microfluidics and new scaffolds for

will be open for PhD students and scientists from outside the

drug screening. Besides 24 PROFILE members, nine conference

consortium as well. All trainings will be announced via the website

attendees registered for the pre-conference workshop. Feedback

(www.itn-profile.eu). Dissemination of results emanating from

showed that the lectures were educational and well received.

the PROFILE consortium to patients, clinicians and other societal interest-groups is ensured by the inclusion of the European

For more information on PROFILE, please visit www.itn-profile.eu

Hematology Association (EHA) as partner.

or contact karen.vanhoorelbeke@kuleuven.be.

It is the goal of the PROFILE training network to deliver highly skilled and broadly trained experts in the rapidly expanding area of personalized medicine for autoimmune disorders. In view of

WINTER 2017 | HEMATOPICS | EHA

23


Hematopolitics

CRTH helps young clinical researchers to design and conduct clinical trials effectively The first workshop of the Clinical Research Training in Hematology

d  eveloping strategies for effective collaboration with various

(CRTH) kicked off in Milan, Italy on November 9. During the four-

stakeholders in clinical trials

day workshop, 17 early career clinical researchers fine-tuned their

u  sing statistics effectively

skills and acquired new knowledge required to successfully design,

g  etting funding for their trials

conduct and complete clinical trials. The CRTH faculty consists of

p  ublishing their data

16 experts in various disciplines, ranging from medical ethics to

p  resenting their project to diverse audiences

statistics as well as legal and regulatory affairs. The second workshop is scheduled on February 10-11, 2017. The The CRTH program is a nine-month long unique training and

third and final meeting for this course will take place in the summer

mentoring experience focused on clinical research in Europe. Its

during the 22nd Congress of EHA in Madrid, Spain.

aim is to foster the next generation of leaders in clinical hematology research. After attending this program, participants are expected

If you would like to receive an email notification once the new call

to be adept in:

for application opens, please send an email to training@ehaweb.org.

Participants of the CRTH program 2016-2017 Annamaria Brioli Germany Annemiek Broijl

The Netherlands

Adomas Bukauskas Lithuania Monica Cabrero Spain Lucia Lopez-Anglada Fernandez

Spain

Verena Gaidzik

Germany

Karin van Galen

The Netherlands

Morag Griffin

United Kingdom

Eleftheria Hatzimichael

Greece

Janusz Krawczyk

Ireland

Caroline Mcnamara

Canada

Klaus Metzeler

Germany

Lydia Scarfò

Italy

Faculty of the first workshop of the Clinical Research Training in

Felicitas Thol

Germany

Hematology (CRTH).

Magnus Tobiasson

Sweden

Ciprian Tomuleasa

Romania

Candida Vitale

Italy

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EHA | HEMATOPICS | WINTER 2017


Hematopolitics

The participants and faculty of CRTH program 2016-2017

Faculty of the CRTH program 2016-2017 Felicia Barbieri

Martin Hutchings

Richard Schlenk

Financial expert

Clinical Oncologist

Professor of Internal Medicine and

HOVON Foundation, The Netherlands

Rigshospitalet, Copenhagen University

Hematology and Oncology

Hospital, Denmark

National Center for tumor Diseases

Peter Borchmann

Heidelberg, Germany

Assistant Medical Director

Sarah Lonergan

Department of Haematology and,

Program Manager Research

Pieter Sonneveld

Oncology

Hematology Department

Professor of Hematology

University Hospital of Cologne, Germany

Erasmus MC Rotterdam, The Netherlands

Head of the Department of Hematology

Andreas Engert

Jorge Martinalbo

Professor of Internal Medicine,

Scientific Advisor

Hematology, and Oncology

European Medicines Agency (EMEA),

Helgi Van De Velde

Coordinating Editor, Cochrane

London, United Kingdom

Vice President Oncology Clinical

Erasmus MC Cancer Institute Erasmus

Hematological Malignancies Group

University of Rotterdam, The Netherlands

Research

Vice Director, Department for

Mihaela Matei

Takeda Pharmaceuticals International Co.

Hematology and Oncology

Legal & Regulatory Officer

Antwerp, Belgium

University Hospital, Cologne, Germany

European Clinical Research Infrastructure Network (ECRIN), Paris, France

Anton Hagenbeek

Ghislaine Van Thiel Assistant Professor Medical Ethics

Professor of Hematology

MarĂ­a-Victoria Mateos

University Medical Center Utrecht,

Academic Medical Center

Associate Professor of Medicine

The Netherlands

University of Amsterdam,

and Consultant Physician

The Netherlands

Coordinator Clinical Trials Unit

Bastian Von Tresckow

University of Salamanca, Spain

Doctor of Internal Medicine

Robert Hills

Medical Head, Clinical Trial Unit

Professor of Translational Statistics

Department of Internal Medicine

CTR Lead for Clinical Cancer Research

Cologne University Hospital, Germany

Methodology Portfolio Lead for Haematological

Sonja Zweegman

Oncology

Professor of Hematology

Centre for Trials Research / College of

Head, Department of Hematology

Biomedical & Life Sciences

VU Medical Center, Amsterdam,

Cardiff University, United Kingdom

The Netherlands

WINTER 2017 | HEMATOPICS | EHA

25


Career development

DAVID KENT

The trials and triumphs of a young researcher David Kent, a two-time EHA grant winner and recent ERC

What should a first-time grant applicant consider before

grantee, talks about his trials and triumphs as a beginning

applying?

researcher, gives tips to the younger generation of researchers

The first thing that you need to have is the inclination to become

on how to get a prestigious grant and proudly shares with

a group leader. If you don’t have that, don’t apply for a grant. You

Hematopics the reason why he chose his research topic.

need to want to run your own research group. Once you decide that you want to do that, you need to have an idea what you want

Congratulations on your European Research Council (ERC)

to run your research group on. What distinguishes you from your

grant! Can you tell us about all the grants you have received?

current post-doctoral fellowship mentor and your PhD mentor?

EHA was the first opportunity that really started to give me

What unique aspects do you have and can you bring to the

independence. In 2014, I participated in the Translational Research

field? How are you going to set yourself apart from the training

Training Hematology (TRTH) program, which is co-funded by EHA

environments from which you came? I think those are the things

and the American Society of Hematology. In 2015, I was awarded

that you philosophically need to decide on before applying. What

the EHA Advanced Non-Clinical Fellowship. Subsequent to that, I

are you bringing that’s new and unique and exciting? It’s the big

have been awarded a million pounds by Bloodwise UK and now,

question that junior researchers need to be able to answer.

I got a grant from the European Research Council to go forward for the next five years. Those three together (TRTH is a coaching

So these two factors you mentioned: leadership and

program – ed.) represent my current lab’s funding, which is great

uniqueness, would you say that these are the same factors

and I am very happy about that.

that got you an ERC grant?

David Kent finished his doctorate degree in genetics at the University of British Columbia in Vancouver, Canada. He is currently group leader at the University of Cambridge Stem Cell Institute. His laboratory’s research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole blog in 2009.

26

EHA | HEMATOPICS | WINTER 2017


Career development Absolutely. My ERC grant is very much into disciplinary sciences. It’s on the physical biology of stem cells, so it explores stem cells and what impact it has on them in terms of whether or not they make decisions to become one cell type or another. It’s very interdisciplinary and very unique. We have physicists involved in it and mathematicians who are doing theoretical modeling. It’s the only research environment in Cambridge where those people sit down together because they’re all in the “same postcode”. What makes for an outstanding ERC Grant? Novelty and uniqueness. People underestimate the power of a well-written application. If you can tell a story that has a logical beginning, middle and end, it helps your reviewer. You don’t want spelling mistakes. You don’t want to have graphs that look terrible. You need to look and read like a thing of beauty because that is going to make people understand. The worst thing that can happen is that you have a brilliant idea that’s poorly communicated.

David Kent’s research team. Back row: Jiangbing Li and Nina Friesgaard-Oebro.

Having said all of that, the biggest thing you need is good science

Front row: Caroline Oedekoven, David Kent, Mairi Shepherd.

and that’s what the ERC really funds. You need to have a really good scientific idea and within that, it needs to be novel, unique and

that it is taking the idea you have for a grant and beating it into

well-prepared.

shape so that it stands the test of going through a grant procedure. As everybody’s first grant is not as good as it could be, that

Can you tell us about the trials that you faced before getting

dedication of the senior faculty members to the idea that you want

these grants?

to put forward, exposes all of the holes and really gives you that set

Every scientist who’s in the post-doctoral stage will appreciate that

of advice that helps you write a better grant. Even more critically,

careers in academic science are incredibly rare. We’re talking of

you physically meet 15 faculty members that go to TRTH and 20

15-20% success rate for post-docs to get an academic tenure track

peers. So you have that group of people whom you can share your

position. That’s quite competitive because you’re amongst a class

experiences with. That network and opportunity really helps you

of incredibly bright people, incredibly motivated people and how

get used to the people who are going to be evaluating the grants

do you stand out from amongst that crowd? Typically, it’s done by a

and hones your “grantsmanship” skills. The mentorship aspect of

publication, so there’s this stress on these early-career researchers

TRTH is incredibly powerful.

to produce high-quality, high-impact publications so that’s a trial enough in itself. It’s the trial to navigate those waters of getting

What is the difference between EHA grants and other grants?

that information out there, in that high-impact journal.

It is smaller, shorter and incredibly flexible. The EHA grant I had is more about launching a career. It’s hard to find money as a young

Can awards like what you’ve had change that?

researcher. The EHA grant allows you to be flexible in how you

There’s enormous pressure on young students and young post-

direct resources. It’s been an incredible tool to help launch my

docs and that’s where these awards really can come in. They can

career but also to make day-to-day life easier as a young researcher.

give that sort of fresh start to somebody to be able to produce the data, to have a little cushion where they can get that paper out

How will your research change the future?

so that they can launch their independent career. I think that is a

We want to apply basic biology of stem cells to understand how

unique aspect of these awards because these awards are meant

they go wrong on people with the hope that you can dial back

to give you enough resource, flexibility and ability to get that

leukemia to something that is less lethal. Some people, if they get

start where you can then turn it into another award or turn it into

this disease, die very quickly. If we can understand how they got to

another tenure track position.

that situation and how the people who are closest to them in terms of disease similarity didn’t go there, then we can perhaps, as soon

If you were to do it all over again, would you apply for the

as we see the signs of leukemia, pull that stem cell back and either

TRTH first or the EHA research grants?

selectively kill them all or selectively change the cell types that it

TRTH. It is a wonderful program for people trying to make the

makes so it doesn’t cause a leukemia. That’s where our window

transition so I would definitely do it. The benefit of the TRTH was

really is for affecting change.

WINTER 2017 | HEMATOPICS | EHA

27


Research and science Saskia Middeldorp qualified as an MD at the University of Amsterdam in 1992. She trained in internal medicine at the Academic Medical Center (AMC) and wrote a thesis on Clinical and Laboratory Studies in Hereditary and Acquired Prothrombotic States in 2000. After a period at Leiden University Medical Center, she returned to the AMC in 2010 to co-chair the Department of Vascular Medicine. Her research focuses on hereditary and acquired thrombophilia, women’s issues in thrombosis and hemostasis, and the evaluation of new anticoagulants. Saskia Middeldorp was recently invited by the American Society of Hematology to give the 2016 HamWassermann lecture on her work on inherited thrombophilia. What brought you into medicine and what interested you in thrombophilia specifically? My mother was a nurse, and at the age of five, I remember being fascinated by the needles and bandages they used. But my mother told me that I could also be a doctor! At high school, I wasn’t that good at chemistry and physics, but I needed them for medicine, and so I took these subjects. It was a decision with a purpose. At medical school, I decided to go into internal medicine. I wasn’t particularly interested in research, which I associated with labs and animal work rather than with directly relevant clinical questions. But, as a second-year resident, we had to write a scientific paper. As far as I was concerned, it would be one research paper, and that

major risk factor, it was highly prevalent. Five percent of people

was it. But the project proved a game changer.

in unselected populations had the mutation. That meant one in twenty people getting on the train. The prevalence is such that it

My first approach was to a gastroenterologist, who suggested

should be considered a variant rather than an abnormality.

work on interleukins and cytokines. For me, that was too much like basic research, and this was not why I had become a doctor. Then I

The discovery of Factor V Leiden, and shortly thereafter the

met Harry Büller, an open-minded and encouraging man who led

prothrombin mutation, came after a period in which the role

vascular medicine research at the AMC, and he became my mentor.

of three other congenital thrombophilia risk factors had been

I realized that if you ask a clinical question, you can get an answer

established: antithrombin, protein C and protein S deficiencies.

that is clinically highly relevant. Clotting and clotting tendencies

And we soon became adept at testing for the full panel. In an

represent a massively important area.

unselected population, around 10% of people have some form of thrombophilia. Not bleeding to death may have some evolutionary

What was happening in thrombosis research at the time?

advantage!

Well, it was exciting. Thanks to serendipity, I had found an area in which knowledge could be translated immediately into clinical

You use the term “a double-edged sword” in your Ham

practice. Factor V Leiden had just been discovered, and it turned

Wasserman Lecture at ASH. Does this imply that screening for

out that 20% of patients with venous thromboembolism (VTE)

inherited thrombophilia is not always a good idea?

were positive. We started to collect large series of families to try

Over the last few decades, we moved from regarding thrombophilia

and understand the implications for patients and their relatives, so

as a rare genetic disorder to seeing it as a highly prevalent trait. And

we would know how to counsel them. We were aided by the fact

there was undoubtedly a tendency to diagnose it too frequently

that efficient collaboration is easy in a small country.

– given that the implications of the diagnosis for management are not clear and that screening for any hereditary disorder has

The presence of Factor V Leiden conferred a five times higher risk

implications that are practical as well as clinical: it may make it

of thrombosis. And for a woman on the contraceptive pill, the

difficult to obtain insurance, for example.

increased risk was thirty times. Factor V Leiden was not only a

“Choose wisely who you test” should be our motto, and this is

28

EHA | HEMATOPICS | WINTER 2017


Research and science

SASKIA MIDDELDORP

Inherited thrombophilia: a double-edged sword whether aspirin and low molecular weight heparin (LMWH) should be given to women with recurrent pregnancy problems. The bottom line is “No”. There might have been more satisfaction in a positive answer. But it is also rewarding to enable women to avoid the expense and burden of eight months of subcutaneous injections, as well as the false hope that it will help them bring a baby successfully to term. We knew that inherited thrombophilia increased the risk of recurrent miscarriage and conditions such as pre-eclampsia. There was a parallel with acquired thrombophilia such as the antiphospholipid syndrome, where there was some suggestion of anticoagulant efficacy, though only from few or poorly designed now widely accepted. Sometimes you can easily justify testing

trials. Even so – in the absence of good evidence - people started

– but only when you know what to do with the answer. In terms

to widely prescribe aspirin or LMWH for women who had had

of prevention, anticoagulants carry a risk of bleeding that is high

problems in pregnancy.

relative to the risk of having a clot. That said, knowing if someone has inherited thrombophilia may suggest certain measures in

That led us to design the ALIFE study, a randomised controlled trial

relation to pregnancy, or guide choice of contraception.

(RCT) of aspirin and heparin in women with unexplained recurrent miscarriage, which included some patients with inherited

Understanding absolute risk is key in any discussion with a patient

thrombophilias. This was published in the New England Journal of

or family member. Take for example a man who has had a VTE and

Medicine in 2010 and proved entirely negative. Similar studies in

his 16-year-old daughter who wants to start taking “the pill”. We

Scotland, Germany and France have come to the same conclusion.

now have the data that allow us to quantify risk. In general, the

We are now conducting a trial (ALIFE2) confined to women with

chance of a 16-year-old developing a clot is 1 per 10,000 per year.

hereditary thrombophilia. If that too is negative, the matter is well

Given that the girl’s father has had a VTE, that risk is doubled. If she

and truly settled.

starts on the pill it increases a further 4-5 times. We have also started a large RCT in pregnant women to compare But the absolute risk is still only 10 per 10,000 per year. Given

the efficacy and safety of two widely used doses of LMWH for

the consequences of unwanted pregnancy at the age of 16, that

the prevention of recurrent VTE (Highlow). Highly pragmatic and

slightly increased risk of thrombosis may be a price worth paying

successfully recruiting in five countries, this will answer important

for a highly reliable and convenient form of birth control. And if the

questions asked by young women who want to have a baby after

man with the VTE had only sons, there would certainly be no case

having had VTE.

for testing them. My aim has been to make a difference. Sometimes, as with the The research of which you are most proud relates to

work just described, this can require a great deal of patience and

anticoagulants in pregnancy...

persistence, approaching twenty years in all. But – if you really have

This is where I really found my niche – in answering the question

a passion – go for it. 

WINTER 2017 | HEMATOPICS | EHA

29


Obituary

REMEMBERING TWO GREAT HEMATOLOGISTS In the past winter months, the hematology community lost two

Nielsâ&#x20AC;&#x2122; scientific interests were focused on the innate immune

great members at too young an age. David Grimwade (UK) died

system. He was an authority in the research of neutrophil

at 53 and Niels Borregaard (Denmark) passed away at 65.

granulocytes. He established a method for subcellular fractionation.

Both researchers are renowned for their expertise. They have contributed generously to EHA with their involvement in various

Their untimely parting is a big blow to the community. The legacy

activities.

of their important work will live on. David and Niels will be missed dearly.

David had a substantial international reputation for his translational research, particularly in the field of acute promyelocytic leukemia.

David Grimwade

30

EHA | HEMATOPICS | WINTER 2017

Niels Borregaard


Save the date

2017 February 23-24

EHA-SLCH Tutorial on Lymphoid Malignancies, Multiple Myeloma and Bone Marrow Failure Syndromes

March 10-12

EHA-SWG Scientific Meeting on Rare Lymphomas

March 17-18

EHA-PTHiT Tutorial on Lymphoid Malignancies

April 5-8

Pediatric Course 2017 (endorsed by EHA)

April 7-8

EHA-TSH Tutorial on Laboratory Hematology

June 22-25

22nd Congress of EHA

Colombo, Sri Lanka

Barcelona, Spain Warsaw, Poland Sorrento, Italy Ă&#x2021;anakkale, Turkey Madrid, Spain

Madrid, Spain

October 12-14

EHA-SWG Scientific Meeting on Challenges in the Diagnosis and Management of Myeloproliferative Neoplasms

October 20-22

EHA Hematology Tutorial on Biology and Management of Myeloid Malignancies

November 23-25

EHA-SWG Scientific Meeting on Shaping the Future of Mesenchymal Stromal Cells Therapy

TBA

Yerevan, Armenia

TBA

FOR INFORMATION AND REGISTRATION, PLEASE VISIT: EHAWEB.ORG

WINTER 2017 | HEMATOPICS | EHA

31


EHA CORPORATE SPONSORS 2017 The European Hematology Association wishes to express its gratitude to the following sponsors

PLATINUM

GOLD

SILVER

BRONZE

CONTRIBUTOR

EHA Hematopics Winter 2017  

EHA Hematopics Winter 2017

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