the hematologist - final pdf of september october 2010[1]

8/8/2019 The Hematologist - Final PDF of September October 2010[1]

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As ASH expands its goba presence, the

Societys members find greater opportunities

to contribute to the hematoogy community.

Through a partnership with Heath Vounteers

Overseas (HVO), a nonprofit organization

dedicated to improving goba heath through education, ASH

members can share their hematoogy expertise by teaching

cinicians and aboratory scientists in Uganda, Peru, and

Cambodia. ASH member HVO vounteers provide education

through day-to-day training, making a sustainabe difference at

the hospitas where they serve.

D E P A R T M E N T S

2 Presidents Column

3 news and rePorts

67 the hematologist advoCate

8 diusion

13 CliniCal trials Corner

14 the early-Career hematologist

16 mark your Calendar

F E A T u R E S

ASH NEWS AND REPORTS SEPTEMBER/OCTOBER 2010 VOlUME 7 ISSUE 5

2oP-ed: enhanCingCliniCal trials aCCrualrequires Changes in the

governmental ConerenCeroom and exam room

Dr. George Weiner discusses the

challenges surrounding enhancing

clinical trial accrual.

4raming the researChagenda or siCkle Celltrait Dr. Nigel Key recounts

the NHLBI workshop held at the NIH

campus in Bethesda, MD, on June 4

and 5.

5mini review: mcrnas

in hematologiCmalignanCy Drs. Ramiro

Garzon and Carlo M. Croce discuss

microRNA activity in the initiation

and progression o cancer, including

hematologic malignancies.

7uPdate on healthreorm initialimPlementation and

imPaCt ASHs Director oGovernment Relations and Practice Mila

Becker, Esq., details the current phase

o the Patient Protection and Aordable

Care Act.

142010 mmsaPPartiCiPants Fourreturning and 10 irst-time

medical students rom the 2010 Minority

Medical Student Award Program are

eatured.

15Proiles inhematology: the

aCCident thatChanged my lie Dr. Mohandas

Narla describes his entrance into the

ield o hematology.

ash v rc r epc o

(Cnt. n Pag 4)

d i u s i o n

JaideeP shenoi, md, and miChael linenberger, mdd. s l c cc .

op d Ppcc P t: w Plado sp t Pcc?

Slichter SJ, Kafman RM, Assmann SF, et al. Dose of prophylactic platelet transfsions and prevention of hemorrhage.

N Engl J Med. 2010;362:600-613.

The ear o catastrophic hemorrhage during severe hypo-prolierative thrombocytopenia compels physicians toact preemptively with prophylactic platelet transusions.

Without additional risk actors, spontaneous bleeding increasessignicantly at platelet counts < 5 x 10 9/L. The current acceptedprophylactic platelet transusion trigger o 10 x 109/L derivesrom multiple randomized, prospective platelet transusion trialsand refects the use o standardized platelet concentrate doses(3 x 1011 to 6 x 1011 platelets or adults).1 To meet the increas-ing demand or donor platelets in an era o dwindling supply,there is great interest in dening a minimum, sae prophylacticplatelet dose that is also cost-eective. One recent study todetermine whether low-dose products might provide equivalentsaety as standard-dose products (the SToP trial) was prema-turely closed ater enrolling only 130 patients when > 5 percentabsolute dierence in WHO grade 4 bleeds occurred in thelower-dose arm.2

The platelet dose (PLADO) trial reported by Slichter et al. orthe Transusion Medicine/Hemostasis Clinical Trials Networkprospectively evaluated 1,351 pediatric and adult patients (bodyweights 10-135 kg) with chemotherapy-induced hypoproliera-tive thrombocytopenia. Patients were randomized to receivelow-, medium-, or high-dose products (1.1 x 1011, 2.2 x 1011, or4.4 x 1011 platelets/M2 BSA, respectively) when their morningplatelet count was 10 x 109/L. Among the 1,272 evaluablepatients, the primary endpoint o WHO grade 2 or higher bleed-ing was not signicantly dierent between the three groups (71percent, 69 percent, and 70 percent, respectively), nor werethere dierences or the highest grade o bleeding. However,the total number o platelets transused (9.25 x 1011, 11.25 x1011, and 19.63 x 1011, respectively) and the median numbero transusion events (ve in the low-dose group and three inthe other two) were signicantly dierent. The median post-transusion platelet counts were 22 x 10 9/L, 34 x 109/L, and 50

x 109/L, respectively, while the median number o days until the

next transusion were 1.1, 1.9, and 2.9, respectively. Physician-initiated change to higher-dose product occurred more commonlyin low-dose patients.

What are the key fndings o the PLADO trial, and should these re-sults change transusion practice? This large and careully perormedstudy reutes the saety concerns raised by the SToP trial and sug-gests that relatively ew transused platelets can maintain vascularhemostatic integrity and prevent clinically relevant bleeding. From aclinical and resource perspective, lower overall platelet requirementsshould translate into less donor exposures (when pooled productsare used) and increased platelet inventories. However, cost-beneftanalyses are eagerly awaited, since gains in product availability maybe oset by greater administration and nursing costs, as suggestedby an economic study o a smaller platelet dosing trial.Moreover,providing customized, body surace area-based platelet products willpresent technical challenges. Thus, implementation o a low-dose

transusion policy must be guided by urther economic and logisti-cal review o the PLADO data. Concurrent with these eorts, anongoing, randomized controlled trial o prophylactic versus no-pro-phylactic platelet transusions (the TOPPS trial) should yield valuableinsights into whether therapeutic, rather than prophylactic, transu-sions can be a sae and efcient practice or some patients.1

1. Blajchman MA, Slichter SJ, Heddle NM, et al. New strategies

or the optimal use o platelet transusions. Hematology. (ASHEducation Program Book). 2008:198-204.

2. Heddle NM, Cook RJ, Tinmouth A, et al. A randomized con-trolled trial comparing standard- and low-dose strategies ortransusion o platelets (SToP) to patients with thrombocytope-nia. Blood. 2009;113:1564-1573.

3. Ackerman SJ, Klumpp TR, Guzman GI, et al. Economic con-sequences o alterations in platelet transusion dose: analysiso a prospective, randomized, double-blind trial. Transusion.

2000;40:1457-1462.

Dr. Troy Lund, ASH member and HVO volunteer, treats patients at the MulagoHospital ater the July 11 bombings in the capital o Kampala, Uganda.

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Presidents Column

Joint Society Symposia

One of the privieges of being ASH president is the opportunity to rep-

resent our Society at other organizations meetings where we have

the opportunity to bring a taste of ASH to researchers and cini-

cians in reated discipines. Whenever I attend these meetings, I am struck by

the scientific and cinica diversity of our membership, the breadth of impact

that hematoogists have in reated fieds, and the respect that ASH and its

members engender a around the word. Our goba reach has grown signifi-

canty during this past year; we have a number of joint and ongoing efforts

with the European Hematoogy Association (EHA), and we have extended our

renowned Highights of ASH programs internationay.

As I reported in the ast issue of The Hematologist, our Society hed its sec-

ond Highights of ASH in latin America in Rio de Janeiro in May. We are now

panning a third Highights of ASH in latin America, which wi be hed in

Punta de Este, Uruguay, on Apri 29-30, 2011. Drs. Rau Gabus and Sebastian

Gaeano of the Sociedad de Hematooga de Uruguay are working with ASH

Co-Chairs Drs. Bradford Schwartz and Joseph Mikhae to organize what I

know wi be an exceent scientific program.

Ive aso had the peasure of meeting with Dr. Changgeng Ruan, president

of the Chinese Society of Hematoogy (CSH), and Dr. Kaiyan liu, secretary

of CSH, who wi serve as co-chairs of the first Highights of ASH that wi be

hed in Beijing, China, Apri 1-3, 2011. We are panning scientific presenta-

tions featuring not ony the highights from the ASH meeting, but aso topics

of specia interest to Chinese hematoogists.

On June 4, I had the opportunity to co-chair the American Society of Cinica

Oncoogy (ASCO)/ASH Joint Session at ASCOs annua meeting in Chicago

with ASCO President Dr. Dougas Bayney. This was put together from

presentations at the ast ASH annua meeting in New Oreans that we fet

ASCO members woud find of interest. Dr. Mark levis, from Johns Hopkins

University, presented resuts from a randomized tria of savage chemo-

therapy foowed by estaurtinib for Ft3 mutant AMl patients in first reapse,

Dr. Noopur Raje, from Massachusetts Genera Hospita Cancer Center, spoke

about a phase III study to determine efficacy and safety of enaidomide in

combination with mephaan and prednisone (MPR) in edery patients with

newy diagnosed mutipe myeoma, Dr. Mathias J. Rumme, of Hospita of

Justus-liebig University, touched on the fina resuts of a randomized phase

III study of the Study Group Indoent lymphomas, Germany (Stil), and Dr.

Peter Borchmann, of University Hospita of Coogne, presented the fina

anaysis of the randomized German Hodgkin Study Group (GHSG) High-Dose

Therapy (HDT) tria examining optima treatment of eary-stage disease. I

anticipate an exciting ASH/ASCO Symposium at our upcoming annua meet-

ing in Orando, and I ook forward to working with new ASCO President, Dr.

George Sedge, a coeague at Indiana University.

On June 12, at the EHA meeting in Barceona, EHA and ASH coordinated a

joint symposium: Chaenges and Opportunities in Hematoogy and Oncoogy

in Deveoping Countries. This was co-chaired with ong-time friend Dr.

Robin Fo, EHA president. The tak was given by Dr. Ian Magrath, president

of the Internationa Network for Cancer Treatment and Research (INCTR)

in Brusses. I received positive feedback regarding his presentation from anumber of EHA members who fet, as we do, that more needs to be done to

hep those in deveoping countries attain access to better heath care.

This September, ASH wi participate in the 72nd Japanese Society of

Hematoogy (JSH) Annua Meeting. With Dr. Keiya Ozawa, I wi co-chair

a joint symposium on Comprehensive Genomic Anayses of lymphoid

Maignancies: Future Cinica Appications. This wi be the first JSH/ASH joint

symposium; Drs. louis Staudt of the Nationa Cancer Institute and Margaret

Shipp from the Dana-Farber Cancer Institute wi join me in representing ASH

in this exciting program.

I ook forward to continuing the partnerships we are buiding through sym-

posia and other joint initiatives, as we continue to extend our reach as an

organization and coaborate with hematoogists both here and abroad.

Ha E. Broxmeyer, PhD

ec Cc t accr C gCc r e rgeorge weiner, md

P i mc dc h Cp Cc C u i

C, ash C g a

Cinica research in hematoogy has never been more important, yet cinica

investigators are facing unprecedented chaenges. Constanty changing (and

at times inconsistent) reguations, chaotic reimbursement poicies, increasing

demands on physician time, and scientific advances demonstrating the

compex differences among individua patients a compicate hematoogy

cinica research.

The opportunities and obstaces are not unique to hematoogy and incude probems with

how we organize, support, and conduct cinica research. These are starting to receive con-

siderabe attention. The Institute of Medicine (IOM) recenty reeased a report that cas for

an overhau of the Nationa Cancer Institutes (NCI) Cooperative Group Program. The report1

identifies four overarching goas:

Improvingthespeedandefficiencyofthedesign,launch,andconductofclinicaltrials

Makingoptimaluseofscientificinnovations

Improvingselection,prioritization,support,andcompletionofclinicaltrials

Fosteringexpandedparticipationofbothphysiciansandpatientsinclinicalresearch

These are a vita issues, and addressing these goas is important for a aspects of cinica

hematoogy research, not just those studies that are part of the NCI cooperative groups.

An exceent summary of this report was recenty pubished in theNew England Journal of

Medicine by Robert Young.2

The issue of cinica trias for both maignant and non-maignant hematoogic diseases and

conditions is a priority for the Society. ASH has consistenty advocated for Medicare and pri-

vate insurer coverage of routine patient costs associated with cinica tria participation. Most

recenty, ASH supported a provision incuded in heath reform that requires coverage of routinepatient costs associated with cinica tria participation and prohibits insurers from dropping

coverage because an individua chooses to participate in a cinica tria. ASH has aso advo-

cated for egisative anguage that encourages the Department of Heath and Human Services to

determine if changes coud be made to better harmonize the federa poicies and reguations on

cinica tria operations that currenty exists at various federa agencies, which has the potentia

to expedite the initiation of new trias and access to promising treatments for patients.

At the same time, ets not forget that at the heart of cinica research is the interaction

between the physician and patient. We need to take a ong, carefu ook at what we can do to

improve the efficiency of the aspect of the cinica research process that takes pace in the

exam rooms of hematoogists and other cinica investigators across the country.

An idea came to mind recenty, when I came across a 30-year-od informed consent docu-

ment. It was cear, concise, and short in marked contrast to informed consent documents

we use today. Our current consents have mutipe pages of text to protect the institution and

the sponsor, not the subject. Indeed, physicians invoved in cinica research know how dif-

ficut it is to convince potentia subjects to read and understand ong and compex informed

consent documents. Cearer, shorter, simper informed consent documents woud be easier

for cinica investigators to present to potentia subjects, easier for those potentia subjects

to understand, and better at protecting the rights of the subjects. They woud resut in

enhanced accrua to cinica trias.

The IOM is to be commended for their thoughtfu and forward-ooking approach to how our

nations cinica research eaders seect, prioritize, and support cinica trias. However, chang-

ing how we organize cinica research in the governmenta conference rooms is not enough. We

aso need to consider how we can improve the vita part of cinica research that takes pace in

the exam room. It is time to consider ways we can revise the informed consent process to make

documents simper and more efficient. This wi be a difficut and compex discussion, but with

carefu thought we can improve the efficiency of the informed consent process, enhance accrua,

and at the same time do a better job protecting the rights of patients.

1. A nationa cancer cinica trias system for the 21st century: reinvigorating the NCI coop-

erative group program. Report. Institute of Medicine. Apri 15, 2010.

2. Young RC. Cancer cinica trias a chronic but curabe crisis. N Eng J Med.

2010;363:306-309.

2 The Hematologist: ASH NewS ANd RepoRTS

o P - e d

Th matrials cmprising th op-es fr The Hematologist: ASH News and Reportsar

prvi n an as-is, as-availabl basis fr infrmatinal purpss nly. Ths matrials

nt ncssarily rprsnt th pinins, blifs, r psitins f The Hematologist, which is nt

rspnsibl fr any rrrs r missins in th matrials. The Hematologistwlcms op-e

pics r lttrs t th itr n any subjct.


3/16

Editor-in-Chief:

r l. s, mdC Cc C, ohCoordinating Editor,

Clinical Trials Corner:C P, mdu us l C, ut

Contributing Editors:

k C. a, mdd- Cc ib, maJ b, mdt o s uC, ohn J. C, md, mbad u mc Cd, nCr , md, Pdh mc scb, ma

J r. g, md, mss Cc Cs, Cas g, mdv C urc, vaP J, mdCc rc uksp, u kd k, md, Pdy s C Cn h, Ctmc l. l, mds Cc C acs, waP l, mde C Ca, ga

C P, mdu us l C, utJ rc, mdf huc Cc rc Cs, wag m. vc, mdu mmp, mn

Managing Editor

Karn Larnr

Graphic Designer

grayHus sign

Amrican Scity f Hmatlgy

2021 L Strt, NW, Suit 900

Washingtn, dC 20036

[email protected]

2010 by the American Society of Hematology.

All materials contained in this newsletter

are protected by copyright laws and may

not be used, reproduced, or otherwise

exploited in any manner without the express

prior written permission of The Hematologist:

ASH News and Reports. Any third-party ma-

terials communicated to The Hematologist

become its copyrighted property and may be

used, reproduced, or otherwise exploited by

The Hematologist.

Contributing authors have declared any

financial interest in a product or in potentially

competing products, regardless of the dollar

amount. Any such financial interest is noted at

the bottom of the article.

HematoogistASH NEWS AND REPORTSISSN 1551-8779

THE

The Hematologist: ASH NewS ANd RepoRTS 3

n e w s a n d r e P o r t s

Register for ASH Webinar Series onThrombosis

ASH will present a series o three webinars on thrombo-

sis issues practicing hematologists requentl conront.

The sessions, moderated b Dr. Mark Crowther, o

Aberdeen Roal Infrmar, United Kingdom, will eature

presentations b experts in the feld, provide time or

questions and answers, and cover the most current

inormation on how to best diagnose and care or pa-

tients. All webinars will be one hour in length and occur

at 8:00 p.m. (EST).

September 14 Heparin-Induced Thromboctopenia

(HIT)

Speakers include: Andreas Greinacher, MD; Ted

Warkentin, MD; and Adam Cuker, MD

October 20 Coagulation Management in Cancer

Speakers include: Kenneth Mann, PhD; Ken Bauer, MD;

and David Garcia, MD

November 17 Non-Hemophilia-Associated ConditionsAssociated With Bleeding

Speakers include: Catherine Haward, MD, PhD; and

Sarah OBrien, MD

For more inormation or to register or these compli-

mentar webinars, please visit www.hematology.org/

webinars.

ASH Acknowledges National SickleCell Awareness Month and the 100th

Anniversary of the Description of theSickle Cell Trait

Congress has designated September as National Sickle

Cell Awareness Month to help ocus attention on the

need or more research and improvements in the treat-

ment o sickle cell disease.

Also marking an important date related to sickle cell

disease, the National Institutes o Health (NIH) is host-

ing the James B. Herrick Smposium Sickle Cell

Disease Care and Research: Past, Present, and Future

in commemoration o the 100th anniversar o Dr. James

Herricks initial description o sickle cell anemia. It will

be held November 16-17, 2010, on the NIH campus in

Bethesda, MD. This smposium will convene leading

sickle cell experts to celebrate research advances and

explore promising new scientifc opportunities. A number

o ASH members will be speakers. Look or a summaro the event in the Januar/Februar 2011 edition o The

Hematologist.

ASH continues to work with Congress, the NIH, the

Centers or Disease Control and Prevention (CDC), and

other ederal agencies to increase sickle cell research,

treatment options, and access to care or patients with

sickle cell disease. ASH has developed a sickle cell work-

ing group to help identi was the Societ can support

ederal programs and enhance the Societs advocac

eorts to improve research and treatment.

Inormation about NHLBIs recent workshop on Framing

the Research Agenda or Sickle Cell Trait can be ound

on page 4 o this issue. To register or the Herrick

Smposium, visit the smposium website at www.nhlbi.

nih.gov/meetings/James-Herrick-Sicklecell.

TheAmerican Society of Hematology Self-Assessment Program

(ASH-SAP) is an educational resource that brings together the latest

advances in the ever-evolving disciplines o adult and pediatric he-

matolog. This comprehensive publication, created or hematologists

and others working in hematolog-related felds, eatures inormative

content, thorough board and recertifcation preparation, and AMA PRA

Category 1 Credits.

Included with the purchase price o the print edition is access to the

ASH-SAPwebsite (www.ash-sap.org). In addition to the ull content

o the book, the electronic version oers interactive multiple-choice

questions and hperlinks to other educational resources, including

Hematology, the Societs annual meeting Education Program Book,

and the ASH Image Bank.

Two versions o the ourth edition o theASH-SAPare avail-

able or purchase: one oeringAMA PRA Category 1

Credits and the other oering bothAMA PRA Category

1 Credits and American Board o Internal Medicine

(ABIM) Maintenance o Certifcation Credits. Both ver-

sions are the same price and can be purchased as a print

and online package or as an online-onl version.

Print and OnlineOnline Access Access Onl

Members $335 $260

Non-Members $435 $360

Associates/Trainees $240 $165

ASH-SAP4th Edition Now Available for Purchase

Election Ballots Due September 30

Active members in good standing (i.e., dues paid)

should have received election materials or this

ears ASH leadership election or Vice President,

Treasurer, and Councillors. The results o the elec-

tion will be announced in the November/December

issue o The Hematologist.


4/16


A typica day for Dr. Troy lund whie in Kampaa, Uganda, is teaching pediatric residents

and caring for chidren at the Muago Hospita, which is part of the HVO program. Dr. lund,

an ASH member and a pediatric hematoogist/oncoogist at the University of Minnesota

Medica Center, Fairview, has been traveing to Uganda for years, ong before ASH and HVO

had a program; hes been seven times. However, the day of the bombings was certainy

unique. Two exposions struck two estabishments in Ugandas capita on Sunday, Juy 11,

in an apparent terrorist attack targeting crowds that gathered to watch the fina Word

Cup soccer match. Dr. lund himsef was nearby watching the game. At haf-time, he went

to check on the chidren in the hospita and received a text message about the attack. He

waited in the pediatric acute care unit thinking there woud be chidren coming in, but

there was not much activity. A resident then grabbed him, and they trucked down the hi

to the main hospitas intake ward.

It was ike a scene from a movie wa-to-wa peope, at east 100 peope down there

with head injuries and various traumatic wounds from the exposions, Dr. lund

recounted. He spent the rest of the night treating head injuries, stopping beeding, and

cosing wounds. He focused on stabiizing patients unti 7:00 the next morning.

Dr. lund expained, This was a unique experience, and I had to revert back to my origina

training in med schoo. They ost seven individuas that night. More than 60 peope died as

a resut of the basts.

After the bombings occurred in Kampaa, Dr. lund sti had another week eft before

heading back to the states. He said that no one eft eary from the group he had taken

over there; everyone continued on with their work. His stays typicay range from two

weeks to two months.

Dr. lund said he enjoys his work in pediatric hematoogy and working with the facuty at

Muago Hospita, and he ooks forward to returning. His next visit is tentativey panned

for this September.

Whie Dr. lund spends time in Uganda, Dr. lynn Bemier recenty spent time voun-

teering in Peru. This was an outstanding experience for me, both professionay and

cuturay, said Dr. Bemier. Whie in Peru, Dr. Bemier traveed to hospitas in two cit-

ies. In lima, Rebagiati Hospita serves as the main referra hospita in the country. Dr.

Bemier ectured staff and trainees on the diagnosis and management of thrombophiia

and thrombosis. She aso gave a tak on bood component therapy at a symposium pre-

sented by the hospitas hemophiia department.

Framing the Research Agenda for Sicke Ce TraitNHLBI Workshop Focuses on Current Scientific Understanding of the Health Implications for Individuals With SCT

nigel s. key, mbCb

h r. r d P dc hp t C u n C sc mc

(Cnt. frm pag 1)

ash v

n e w s a n d r e P o r t s

I spent time reviewing the hospitas capabiities and procedures for coaguation and

coaguopathy testing. Based on its current practices, I worked with the director of the

hematoogy aboratory to design a standard format for thrombophiia testing. This coud

be expanded into a standardized order set for testing and inpatient anticoaguation, Dr.

Bemier expained.

In Arequipa, a UNESCO Word Heritage Site, Hospita Escobedo serves as the teaching

site for two medica schoos in the region. Dr. Bemier participated in bedside teach-

ing by discussing inpatient cases with residents and staff. She presented daiy ectures

on thrombosis, thrombophiia, transfusion medicine, and hematoogic compications of

pregnancy and aso participated in a case-management conference on thrombocytopenia.

The vounteer experience extends to more subte interactions than just cinica care, as

Dr. Bemier described: For me, the most gratifying part of the experience was the recog-

nition that medicine is a universa anguage, jokes and a, and that a of us in medicine

have much more in common than we may think. Compassion is, ikewise, independent

of cuture and anguage. We had two seriousy i patients that I wi not forget. One was

a young gir dying incrediby bravey of reapsed eukemia, the other, an oder Native

American man who spoke a anguage neither my hosts nor I coud speak. We conveyed

understanding by touch and eye contact, which was enough.

Doctors and aboratory scientists interested in vounteering through HVO must be mem-

bers of ASH and become members of HVO. There is no restriction on nationaity to appy;

HVO accepts hematoogy vounteers from around the word for both adut and pediatric

hematoogy. Some program sites offer opportunities for feows. The first step in appying

is to submit the Vounteer Profie Form, which is avaiabe on the HVO website at www.

hvousa.org. An HVO vounteer coordinator wi contact the appicant to discuss expecta-

tions and identify an appropriate country site. The appicant wi then work cosey withthe sites program director, an ASH member who has been to the site and works cosey

with the staff to meet the sites educationa needs. To earn more about vounteering,

visit the ASH website at www.hematology.org/hvo, or visit the HVO booth in the exhibit

ha at the upcoming annua meeting in Orando this December.

On June 4 and 5, the Nationa Heart, lung,

and Bood Institute (NHlBI) hosted a

workshop at the NIH campus in Bethesda,

MD, tited Framing the Research Agenda

for Sicke Ce Trait. The purpose of the

meeting was to review the current scientific understand-

ing of the heath impications for individuas with sicke

ce trait. In particuar, the stated purpose was to focus

on sudden death in young aduts, organ system com-

pications, and ethica, ega, socia, and pubic heathimpacts. The impetus for this workshop was the Nationa

Coegiate Athetic Associations (NCAA) 2009 decision to

recommend screening of a coege athetes for sicke ce

trait (SCT). This recommendation, constituting part of a

ega settement, was precipitated by the death of Dae

loyd Jr., a footba payer with SCT who died in practice

at Rice University in 2006. In addition to NHlBI staff and

members of the academic hematoogy community, a num-

ber of other stakehoders were represented by deegates

and speakers, incuding CDCs Division of Hereditary

Bood Disorders, HRSAs Materna and Chid Heath

Bureau, the Uniformed Services University of the Heath

Sciences, and severa eading organizations, such as the

Sicke Ce Disease Association of America.

The agenda on the first day focused on the exercise-

reated compications that have been described in

subjects with SCT and exertiona heat iness. These

compications have incuded exertiona rhabdomyoysis

with or without sudden or sub-acute death. Dr. John Kark

from Thomas Jefferson University presented an update

of the miitary experience that he originay described in

a andmark paper in theNew England Journal of Medicine

in 1987. By studying records and autopsy reports of a

sudden deaths among approximatey 2 miion Armed

Forces recruits from 1977 to 1981, he demonstrated that,

compared to African-American miitary recruits without

SCT, subjects with the sicke trait had approximatey a

30-fod risk of exercise-reated death. About haf of thedescribed cases suffered exertiona heat iness (rhab-

domyoysis, heat stroke, and/or acute rena faiure), whie

the remainder suffered idiopathic sudden death from

cardio-pumonary arrest. During the ensuing decade, dri

instructors were trained to adjust workouts according to

daiy ambient temperature, to increase rest cyces and

hydration, and to measure affected subjects core tem-

perature in the case of suspicious eary symptoms. These

simpe measures, appied across the board for a recruits

(universa precautions), resuted in an enormous reduc-

tion in the rate of death reated to sicke trait.

Dr. E. Randy Eichner reviewed the cinica detais of the

18 cases of NCAA Division I footba payers who died

since 1974. SCT, present in just 3 to 4 percent of Division

I payers, has been inked to 63 percent of reported

non-traumatic deaths in the past decade. A discussion

of the ethica and practica concerns surrounding the

NCAAs approach to the probem highighted the history

of community screening for SCT, which has been fraught

by a number of exampes of poory conceived programs

resuting in stigmatization and/or discrimination. The

overa consensus seemed to be that, whie it seems a

reasonabe priority to support studies that wi resut in a

better understanding of the pathophysioogic mechanisms

and associated (exogenous and endogenous) risk factors

underying exertion-reated compications, the miitary

experience suggests that prevention of compications in

coege athetes shoud be possibe by appying universaprecautions without the need to singe out affected indi-

viduas for specia treatment.

The second day of the workshop focused on some of the

organ-specific compications of SCT. For severa decades,

numerous case series have reported a variety of adverse

medica outcomes in individuas with SCT, and this seg-

ment was an effort to sift through those areas in which

there exist not ony higher quaity cinica studies, but aso

some bioogic rationae for the association. After hearing

the evidence, the deegates were chaenged to prioritize

the areas in which further study appears warranted. By

consensus, rena compications and thrombosis were

thought to be the highest priority areas. Given that SCT

affects approximatey 3 miion individuas in the United

States, this may be an issue of genuine pubic heath con-

cern. It is very cear, however, that better data are needed

before proceeding to mass screening, with a of its poten-

tia for undesirabe stigmatization.

C o v e r s t o r y


5/16

MicroRNAs (miRNAs) are sma non-coding RNAs of about

18 to 24 nuceotides in ength that reguate gene expression

and thus infuence such processes as deveopment, differ-

entiation, proiferation, and apoptosis.1 MiRNAs exert their

bioogica effects by binding in a sequence-specific manner

for the most part to the 3 untransated region (3 UTR) of the target mRNA, causing pro-

tein transation inhibition and/or mRNA degradation. It has been estimated that miRNAs

reguate about 30 percent of human genes.1 Findings over the past eight years strongy

support a roe for dereguated miRNA activity in the initiation and progression of cancer,

incuding hematoogic maignancies (HM).1 We wi briefy summarize the state of the

fied and discuss future directions.

ep-p cc/Foowing our initia demonstration of deetion/down-reguation ofmiR-15a/miR-16-1 in B

ces of patients with chronic ymphocytic eukemia (Cll), additiona studies estabished

that maignant hematopoietic ces exhibited distinctive miRNA expression signatures

compared to their norma counterparts. The advent of high-throughput miRNA profi-

ing estabished that such miRNA expression signatures aowed discrimination with high

accuracy among different cytogenetic and moecuar subtypes of eukemias/ymphomas

and mutipe myeomas.2

Athough there were simiarities in miRNA signatures among thedisease-specific miRNA profiing studies pubished in the iterature, substantia differences

were aso noted. This coud be expained by the use of different patforms to interrogate

miRNA expression, heterogeneity in the sampe popuation, or contro ces used (CD34+

seected vs. tota bone marrow).2 Nove patforms are now increasingy avaiabe, incud-

ing next generation sequencing, which may improve sensitivity and accuracy of miRNA

detection and, in addition, may enabe discovery of nove miRNAs and mutations/poymor-

phisms. The presence of circuating miRNAs within microvesices in the periphera bood

is intriguing; however, the functiona significance remains to be fuy understood.

c Gain- and oss-of-function experiments, incuding anima modes in combination with tar-

get prediction anayses have provided insights into the roe of miRNAs in eukemogenesis.

In AMl, miR-29b is emerging as an important tumor suppressor.3-4 We have reported that

miR-29b moduates DNA methyation by targeting DNA methytransferases (DNMT)-1, 3A,

and 3B. Restoring miR-29b expression in AMl ce and primary sampes resuted in goba

DNA hypomethyation and gene re-expression of methyated and sienced tumor sup-

pressor genes.3 Furthermore, miR-29b overexpression suppresses ce proiferation and

induces ce death by directy targeting the ce-cyce reguator CDK6 and the anti-apop-

toticMCL-1. The antitumor effects were vaidated in murine xenograft modes.4

Recenty, we estabished the centra roe of miR-29b in a transcriptiona network that

reguates KIT transcription in AMl ces.5 loss of miR-29b unbocks expression of the

transcription factor Sp1 that in combination with NF-B binds to theKITpromoter and

activates its transcription. We further showed thatKIToverexpression is prognostic

in AMl and is invoved in eukemogenesis promoting ce proiferation.5 In CMl, our

group identified that upon disease progression to bast crisis there is oss of miR-328,

which directy interferes with the activity of hnRNP-E2, a poy(rC)-binding protein that

suppresses neutrophi maturation in bast-crisis CMl through transationa inhibition

of C/EBP expression.6 In contrast to the cassica miRNA effector pathways, the C-rich

mature miR-328interacts in a non-sequence-specific manner with hnRNP-E2 and prevents

its binding to the CEBPA intercistronic region (decoy activity), thus aowing C/EBP

expression, which directy enhances miR-328transcription.6

lasty, miR-15-a/miR-16-1, which is ost in Cll patients by genomic deetion and muta-

tions, directy targetsBCL-2, a known anti-apoptotic gene that is up-reguated in a subset

of Cll patients. A negative correation was found between miR-15-a/miR-16-1 and Bc-2

protein expression in Cll patients, and ectopic overexpression resuted in apoptosis in

eukemic ces. It was recenty reported that miR-15-a/miR-16-1 knockout mice deveoped

a Cll-ike disease and ymphomas, further supporting a tumor suppressor roe in Cll.

These are some exampes of functiona impications of miRNAs in HM, thereby sup-

porting a critica pathogenic roe of miRNAs. The chaenge for the future is to integrate

miRNAs into the context of oncogenic pathways in HM and deveop more anima modes

with gain or oss of function of miRNAs.

mrna In AMl, two studies reported miRNA signatures associated with outcome. In high-risk,

cytogeneticay norma, young patients (< 60 years od), defined by the presence of FlT3-

ITD mutations or wid-type nuceophosmin or the combination of both genotypes, high

eves of miR-181 famiy members were associated with better event-free surviva.7 In a

different subset of AMl patients (oder with intermediate and poor-risk cytogenetics),

high eves of miR-199a and miR-191 were associated with ower overa and disease-free

surviva.8 It has been reported that ower eves of miR-29b are associated with worse


m i n i r e v i e w

mcrna hc mcramiro garzon, md,1 and Carlo m. CroCe, md2

1. a P mc, d h, dp i mc, t o s u Cp Cc C

2. J w. w C h Cc gc; P C, dp mc v, i mc gc; dc, i gc, t o su Cp Cc C

outcome in mante ce ymphoma. In Cll, an miRNA signature, incuding high eves of

miR-155 and miR-146, was associated with disease progression.9 Concerning miRNAs as

predictor for treatment response, our group recenty reported that higher pre-treatment

eves of miR-29b were associated with achievement of cinica response to singe-agent

decitabine (20 mg/m2 for 10 days) in edery AMl patients.10 Future directions incude

standardization of assays to measure miRNAs in a reiabe and reproducibe way to test

further their biomarker potentia in cinica trias.

t rna c cOne of the most appeaing properties of miRNAs as therapeutic agents is their abiity

to target mutipes genes, frequenty within the context of a network, making them very

efficient in reguating distinct bioogica ce processes reevant to norma and maignant

ce homeostasis. One can envision that there is potentia to use strategies to moduate

miRNA expression in specific diseases. In Cll, restoring miR-15a/miR-16-1 may bock

BCL-2expression and induce apoptosis, whie in AMl over-expressing miR-29b may bock

apoptosis pathways(MCL-1), proiferation (CDK6), methyation (DNMT1, 3a, and 3b), and

kinome aterations (c-KIT). These strategies may incude the use of mimic or antisense

oigonuceotides, drugs or sma moecue compounds that affect miRNA transcription.

Current chaenges incude deivery of synthetic oigonuceotides, stabiity, and safety.11

In summary, miRNA dereguation is invoved in the initiation and progression of HM,

and there is potentia to use miRNAs to improve disease moecuar cassification and to

estabish nove biomarkers to predict outcome and treatment response and deveop nove

miRNA-based therapeutic strategies (Figure).

1. Cain GA, Croce CM. Nat Rev Cancer. 2006;6:857-866.

2. Garzon R, Croce CM. Curr Opin Hemato. 2008;15:352-358.

3. Garzon R, liu S, Fabbri M, et a. Bood. 2009;113:6411-6418.

4. Garzon R, Heaphy CE, Haveange V, et a. Bood. 2009;114:5331-5341.

5. liu S, Wu lC, Pang J, et a. Cancer Ce. 2010;17:333-347.

6. Eiring AM, Harb JG, Neviani P, et a. Ce. 2010;140:652-665.

7. Marcucci G, Radmacher MD, Maharry K, et a. N Eng J Med. 2008;358:1919-1928.

8. Garzon R, Voinia S, liu CG, et a. Bood. 2008;111:3183-3189.

9. Cain GA, Ferracin M, Cimmino A, et a. N Eng J Med. 2005;353:1793-1801.

10. Bum W, Garzon R, Kisovic RB, et a. Proc Nat Acad Sci USA. 2010;107:7473-7478.

11. Garzon R, Marcucci G, Croce CM. Nature Reviews Drug Discovery. 2010. (In press).

Drs. Garzon and Croce indicated no conficts of interest.

From the bench to the clinic: potential clinical application of

microRNAs in hematologic malignancy

D I S C O V E R Y

d

mc cfc

VAL ID AT ION

Inpnntchrts

mcrna- tpcdrugs/synthtic lignucltis

VAL ID AT ION

Clinical trials

Prclinicalstuis Phas 1 Clinical trials

D I S C O V E R Y

oc pc

t p pc

microRNAs

Figur

In this schema, we outline the potential clinical applications o microRNAs in hematologicmalignancies. Translation o molecular and prognostic biomarker discoveries to the clinic willrequire extensive validation in independent cohorts o patients using validated and reliableplatorms or miRNA detection. These results should then be tested prospectively in clinicaltrials. Targeting microRNAs expression in hematologic malignancy requires identifcationo the candidate microRNAs, evaluation o the dierent strategies to achieve expressionmodulation (drugs, antisense, or oligonucleotide mimics), and validation in preclinical animalmodels. Successul candidates then can be moved orward to phase I clinical trials or toxicityevaluation and pharmacokinetics/pharmacodynamics studies.


6/16


t h e h e m a t o l o g i s t a d v o C a t e

H E A D L I N E S F R O MWashington

HHS Announces Final Rules to Expand Use of ElectronicHealth Records

The U.S. Department of Heath and Human Services (HHS) recenty announced finarues aimed at increasing safety and reducing heath-care costs through expanded useof eectronic heath records (EHRs). Under a provision incuded in the American Recovery

and Reinvestment Act of 2009 (ARRA), eigibe heath-care professionas and hospitas

can quaify for Medicare and Medicaid incentive payments when they adopt certified EHR

technoogy and use it to achieve specified objectives. A fina rue issued on Juy 13 by the

Centers for Medicare and Medicaid Services (CMS) defines the minimum requirements (or

meaningfu use objectives) that providers must meet through their use of certified EHR

technoogy in order to quaify for incentive payments.

CMS anticipates that enroment in the EHR incentives program wi begin in January 2011,

with the first payments to eigibe professionas and hospitas expected around May 2011.

For more information, pease read Dr. larry Sobergs artice on page 14 in the Juy/August

issue of The Hematologist.

CMS Releases Proposed 2010 Regulations AffectingPhysician Payment

Earier this summer, the Centers for Medicare and Medicaid Services (CMS) reeased pro-posed rues for the Medicare Physician Fee Schedue (MPFS) and the Hospita OutpatientProspective Payment System (OPPS). The proposed MPFS woud provide a 6.1 percent cut

for physician payment in 2011 based on the sustainabe growth rate (SGR). This reduction

woud be in addition to the 23 percent reduction that wi occur on December 1, 2010, if not

prevented by new egisation. The proposed rue woud cut physician payments further

by some rescaing of the fee schedue. ASH strongy opposes these proposed cuts and wi

continue to advocate to Congress and CMS the need to provide appropriate physician reim-

bursement and find a ong-term soution to the fawed payment formua.

The OPPS proposed rue wi update poicies and payment rates for the more than 4,000

hospitas that provide hospita outpatient services to Medicare beneficiaries and for the

approximatey 5,000 Medicare-participating Ambuatory Surgery Centers. In addition, OPPS

wi impement provisions of the Patient Protection and Affordabe Care Act (PPACA). CMS

is proposing a 2.15 percent increase for hospitas that successfuy reported CMS desig-

nated quaity measures in 2010. Detaied anayses of these proposed rues may be found at

www.hematology.org/Practice.

FY 2011 NIH Funding Process Moves Forward

The Senate Appropriations Committee approved its draft fisca year (FY) 2011 labor, Heathand Human Services (HHS), Education and Reated Agencies Appropriations bi on Juy 29.The Committee-approved bi, which must sti be voted on by the fu Senate, recommends just

over $32 biion for NIH approximatey $1 biion (3.2 percent) over the fina FY 2010 funding

eves that were enacted in December of ast year. This fas short of the $35 biion in funding

ASH and the biomedica research community have advocated for NIH in FY 2011.

Meanwhie, the House labor-HHS Appropriations Subcommittee approved its version of

the FY 2011 labor-HHS bi on Juy 15. As with the Senate bi, the House Subcommittee

bi recommends that NIH be funded at just over $32 biion. However, neither the House

Appropriations Committee nor the fu U.S. House of Representatives were abe to consider

the bi prior to adjourning for the month-ong August district work period.

With both the Senate and House adjourned unti the week of September 13, it remains

unikey that the appropriations process wi be competed by the start of the new fisca

year on October 1. As a resut, Congress woud have to impement what is known as a

continuing resoution that woud simpy fund the government at current eves to avoid a

government shut-down.

ASH wi continue its advocacy efforts supporting increases for NIH on Capito Hi through-

out the remainder of the FY 2011 budget debate. The Society encourages a members to

visit the ASH Advocacy Center at www.hematology.org/takeaction to take action to support

increased funding for NIH. With a very tight year expected for the entire federa budget andmany domestic programs facing cuts or minima increases, significant grassroots support

for NIH funding is critica to gain any further traction for increasing NIH funding in the bud-

get process.

FDA Announces Reorganization of the Office of OncologyDrug Products

As part of recent organizationa changes within the Food and Drug Administration(FDA), the Office of Oncoogy Drug Products (OODP) is panning a reorganizationthat is expected to take effect in 2011. The OODP, which currenty comprises three divi-

sions, wi change its name to the Office of Hematoogy and Oncoogy Products (OHOP)

and create a new structure with four divisions:

TheDivisionofHematologyProducts(DHP)

TheDivisionofHematologyOncologyToxicology(DHOT)

TheDivisionofOncologyProducts1(DOP1)

TheDivisionofOncologyProducts2(DOP2)

The Oncoogy Program, which coordinates oncoogy activities across FDA Centers and

with the Nationa Cancer Institute (NCI) and other cancer-reated organizations, wi

remain in the main Office of Hematoogy and Oncoogy Products.

As a resut of the reorganization, review of bioogic and drug products wi be integrated

within each review division; review staff within the two divisions of oncoogy products

wi speciaize in specific oncoogic diseases (e.g., breast cancer, gastrointestina cancer,

meanoma); and there wi be a distinct division, DHOT, dedicated to reviewing the non-

cinica pharmacoogy and toxicoogy of oncoogy products.

NIH Announces Availability of Educational LoanRepayment Programs

The Nationa Institutes of Heath (NIH) recenty announced the continued avaiabiityof educationa oan repayment through its extramura loan Repayment Programs(lRPs). The NIH lRPs provide promising researchers and scientists the opportunity

to pursue research careers by repaying up to $35,000 of their quaified student oan

debt each year. The appication period for new and renewa extramura appicants is

September 1 through December 1, 2010.

Appicants accepted into the programs wi engage in NIH mission-reevant research

for at east two years, during which time a minimum of 50 percent of their work hours

(not ess than 20 hours based on a 40-hour work week) must be appied toward their

NIH research activities. The NIH extramura lRPs are intended to increase the recruit-

ment and retention of research investigators in the foowing areas of research: cinica,

pediatric, heath disparities, and contraception/infertiity. Each of the lRPs has specific

eigibiity requirements and funding set-asides. Detais of the NIH lRPs may be found on

the lRP website at www.lrp.nih.gov.


7/16


t h e h e m a t o l o g i s t a d v o C a t e

Update on Heath Reform Initia Impementation and Impactmila beCker, esq.

dc, g r Pcc, ash

On March 23, President Obama signed into law the Patient Protection and Affordable Care Act, and, one week

later, he followed with modifications in a budget reconciliation bill. Soon afterThe Hematoogist included a

summary of the new law and a timeline of when the major provisions would go into effect. Below is an update

on the health reform implementation and its initial impact.

companies, hospitas, and insurers. Payments to Medicare

Advantage, the private Medicare pans, wi aso be restruc-

tured to eiminate current overpayments. A of these

efforts, however, wi not take effect for severa years.

A second goa of the new aw is to reduce heath-care

costs. One of the new cost containment toos wi be the

Independent Payment Advisory Board, which wi make

Medicare payment and waste-reduction recommendations

to Congress (hospitas are exempt through 2019). Another

is the Center for Medicare and Medicaid Innovation, which

wi aow patient-centered care modes to be tested and

introduced system-wide with more speed and fexibiity

than traditiona demonstration projects. These new insti-

tutions coud have significant impact on hematoogists byintroducing new payment and deivery systems and experi-

menting with new ways to reward care management and

coordination. ASH has been monitoring the deveopment

of these organizations, has submitted comments on initia

reguatory proposas and priorities, and has recommended

hematoogy experts to advise the new Center. Additiona

cost containment provisions incuded in the new aw are

the creation of a pathway for approva of biogenerics

(drugs derived from ive ces, incuding recombinant

proteins and monocona antibodies), steps to strengthen

the primary-care workforce, and a new Patient-Centered

Outcomes Research Institute to oversee federay spon-

sored comparative effectiveness research to determine

what drugs, devices, or procedures work best. Athough

the Institutes creation is sti in eary reguatory phases,

ASH has nominated hematoogists to work with the new

Institute and has aready weighed in on a number of earyproposas, as the Society beieves this entity coud have a

major impact on hematoogists.

The third goa of heath reform is to improve quaity of

care. Many of the aws provisions are modest steps or

piots, focused on government-run programs ike Medicare

and Medicaid, and it is not cear how quicky or effectivey

they wi rippe through the whoe heath-care system.The aw, however, requires a nationa quaity improve-

ment strategy, which incudes weness and popuation

heath, as we as a new effort to document and address

heath-care disparities. Among the initiatives aimed at

creating a high-performing heath system that ASH is

monitoring are: encouraging the creation of Accountabe

Care Organizations (groups of providers who can jointy

be hed accountabe for the quaity and cost of care for

a defined popuation) that woud use a more integrated

and evidence-based approach to care by meeting quaity

benchmarks; providing financia incentives for hospitas to

reduce unnecessary re-admissions and bring down rates

of hospita-acquired infections and reated conditions;

estabishing payment bunding programs that woud pay

a team of providers for one episode of care across severa

heath-care settings in a way that woud regard quaity,coordination of care among providers, and outcomes; and

providing funding to assist and incentivize meaningfu

use of heath information technoogy.

As President Obama noted at the aws signing, passage of

heath reform was a remarkabe and improbabe achieve-

ment. Yet, in the countrys current poarized and partisan

environment, it remains fraught with poitica and poicy

uncertainties that coud shadow impementation in the

years to come. The aw and its impementation is a work

in progress. The 2010 egisation wi need tweaks, adjust-

ments, and, possiby over time, major amendments. States

wi aso continue to experiment on their own. Some insur-

ers and heath pans may resist change. ASH wi continue

to be activey invoved and represent members interests

and concerns as impementation moves forward.

Heath reform is now the aw of the and. A major focus

of the egisation was to expand insurance coverage, and

it is estimated that the new aw wi resut in 32 miion

uninsured Americans and ega immigrants obtaining

coverage by 2019. One of the first provisions to go into

effect is a program designed to provide access to high-risk

insurance poos for peope who have been uninsured for

at east six months and have been unabe to obtain private

heath coverage because of a pre-existing heath condi-

tion. Appication detais and coverage dates vary by state,

but the Department of Heath & Human Services expects

that 200,000 individuas wi gain coverage this year

through the pre-existing condition insurance pan. Other

coverage-reated initiatives that wi be impemented this

year incude cosing the coverage gap in the Medicareprescription drug benefit by providing a $250 rebate to

beneficiaries who reach the benefit cap, expanding preven-

tive coverage in Medicaid, and covering annua physicas

and weness visits for some Medicare beneficiaries.

Aso being impemented this fa are severa private insur-

ance market reforms that were designed to address some

of the behaviors of the insurance industry that upset

consumers. This incudes barring insurers from denying

peope coverage when they get sick or denying chidren

who have pre-existing conditions, barring insurers from

imposing ifetime caps on coverage, and requiring insur-

ers to aow young aduts to stay on their parents poicies

unti age 26.

The neary $1 triion cost of expanding coverage wi

be financed in part by higher Medicare payro taxes onupper income famiies, excise taxes on so-caed Cadiac

heath insurance poicies, and fees paid by pharmaceutica

On May 24, ASH hosted the annua Patient Advocates

Reception in Bethesda, MD. This reception was

hed in conjunction with the Nationa Heart, lung,

and Bood Institutes (NHlBI) Pubic Interest

Organization Conference. As chair of the Committee on

Communications, I represented ASH, aong with sev-

era members of the ASH staff. Patient advocate groups

in attendance represented a wide swath of hemato-

ogic diseases incuding:

AmericanAutoimmuneRelatedDiseasesAssociation

AplasticAnemia&MDSInternationalFoundation

BarthSyndromeFoundation

DaniellaMariaArturiFoundation

ChurgStraussSyndromeAssociation

Hermansky-PudlakSyndromeNetwork

NationalBloodClotAlliance

NationalHemophiliaFoundation

PlateletDisorderSupportAssociation

PulmonaryHypertensionAssociation

VasculitisFoundation

These attendees were informed about the mis-

sion and background of ASH, the numerous ASH

resources and services avaiabe to their constitu-

ents, and the ways their organizations can interact

with ASH. Foowing this introduction, Dr. Keith

Hoots, director of the Division of Bood Diseases

and Resources at NHlBI, highighted NHlBIs rea-

tionships with various patient groups. A number

of other representatives from NHlBI were present

incuding the Acting Director of NHlBI, Dr. Susan

Shurin.

This reception was initiated four years ago, fo-

owing a roundtabe meeting of patient advocate

groups, during which the advocates expressed a

desire to have a venue for networking and exchang-

ing ideas. The Committee on Communications has

recenty re-affirmed that this is an exceent venue

where ASH can reach out to these patient groups

whie aso providing an informa environment for

them to interact with one another.

Peter Emanuel, MD

ASH Hosts Patient Advocates Reception


8/16


Jonathan P. butChar, Pd, and John C. byrd, md

d. bc b c cc .

t Cd20: s mc l

kenneth anderson, mdd. a C.

a sp tw s iuu du

Ito T, Ando H, Szki T, et al. Identification of a primary target ofthalidomide teratogenicity. Science. 2010;327:1345-1350.

In this study, Ito and colleagues rom the Tokyo Institute o Technology de-lineate the mechanism whereby thalidomide causes phocomelia or ameliawhen administered to pregnant women. They showed that a carboxylic

thalidomide derivative conjugated to inert beads precipitated two proteinsrom extracts o HeLa cells cereblon (CRBN) and damaged DNA bindingprotein-1 (DDB1). To show specicity o the interactions, they demonstratedthat CRBN binding was inhibited by ree thalidomide and that recombinantCRBN could bind to the thalidomide beads. They then demonstrated thatCRBN serves as a substrate receptor o E3 ubiquitin ligase cullin-4 (Cul4A)complexes containing DDB1, suggesting that DDB1 binds to thalidomidethrough its interaction with CRBN. This complex has E3 ubiquitin ligase activ-ity, evidenced by auto-ubiquitination in a Cul4A- and DDB1-dependent ashion.Importantly, this activity was inhibited by thalidomide in wild-type cells, but notin cells with mutated CRBN binding sites that prevent thalidomide binding.These ndings were conrmed in vivo in both zebrash and chicks, sincebinding o thalidomide to CRBN homologous genes during embryogenesisalso blocked ligase activity and conerred teratogenic phenotypes, again notobserved when thalidomide binding sites were mutated. Downstream targetsimplicated in mediating these processes include broblast growth actors (g)8 and 10, which are known to be responsible or limb outgrowth and whichwere reduced by thalidomide treatment. Conversely, overexpression o CRBNrestored expression o g8 and 10 and abrogated the teratogenic eects.Most importantly, these investigators mapped the thalidomide binding site to ahighly conserved C-terminal 104 amino acid region in CRBN.

Thalidomide was rst used empirically to treat multiple myeloma (MM) basedon its anti-angiogenic eects and has remarkable activity even in patients withadvanced reractory disease. It is FDA-approved or initial treatment o MMand has also prolonged progression-ree survival when used as a maintenancetherapy. In addition to anti-angiogenic activity, preclinical studies have shownthat thalidomide has modest direct MM cell cytotoxocity, abrogates binding oMM cells to bone marrow, inhibits constitutive and MM cell binding-inducedtranscription and secretion o cytokines, and augments host cytolytic T andNK cells with anti-MM activity. Which o these activities is most important interms o mediating clinical benet remains unknown. Nonetheless, next genera-tion immunomodulatory drugs lenalidamide and pomalidamide more potentlymediate these eects and have remarkable clinical activity even in thalidomide-reractory MM. However, each o these agents also causes teratogenicity inpreclinical models, and thereore elaborate systems have been set up to as-sure that pregnant women do not receive these immunomodulatory drugs.

This study is a major advance with important implications or clinical use o thisclass o immunomodulatory drugs. First, understanding thalidomide targetswill allow or urther characterization o its eects during embryogenesis.Second, it will acilitate delineation o the mechanisms o anti-tumor activ-ity o thalidomide and, specically, whether binding to CRBN is required orthe aorementioned anti-MM cellular eects. I anti-tumor activity is preservedeven in CRBN mutants that do not bind thalidomide, then the opportunity orsynthesis o novel derivatives lacking CRBN binding or preclinical testing andeventual clinical application represents a major potential therapeutic advance.Already second-generation immunomodulatory drugs lenalidomide and pomali-damide have retained potent anti-MM clinical activity but lack the somnolence,neuropathy, and constipation attendant to thalidomide use, suggesting thataltering structure to maintain potency but avorably impact adverse eects ispossible. The current study, thereore, may lay the groundwork or synthesiso potent immunomodulatory drugs that lack CRBN binding and could havemajor implications or expansion o the spectrum o diagnoses and patientseligible or treatment with these agents.

Mssner E, Brnker P, Moser S, et al. Increasing the efficacy of CD20antibody therapy throgh the engineering of a new type II anti-CD20antibody with enhanced direct- and immne effector cell-mediated B-cellcytotoxicity. Blood. 2010;115:4393-4402.

Since the approval o the rst anti-CD20 monoclonal antibody, rituximab, inDecember 1997, signicant advances have been made in moving this therapeuticmodality orward to wide use in virtually all CD20-positive B-cell malignancies, as

well as or many autoimmune diseases. While the clinical operation to advance rituximabhas been quick, understanding how CD20 monoclonal antibodies mediate their directeect and how we can improve them has been a slower process. Early work suggestedthat CD20 was neither internalized nor shed signicantly, thereby justiying pursuit o thistarget or immune-based therapy.

CD20 antibodies mediate their biologic eects against tumor cells through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and directapoptosis. Type I CD20 antibodies (rituximab, oatumumab) redistribute into lipid rats,x complement, mediate ADCC, and promote modest apoptosis only with cross link-ing. In contrast, type II CD20 antibodies (e.g., GA-101) remain outside o the rats, lacksignicant complement xation, mediate ADCC, and promote direct cell death throughhomotypic adhesion. Although type I CD20 antibodies are utilized in clinical practice, typeII antibodies are still being tested in clinical trials with promising results. The nding thattype II CD20 antibodies work well against CLL is quite exciting, as the type I antibodieshave shown less (although still signicant) ecacy.

A very promising series o studies by several dierent groups remind us that there is stillmuch to understand about CD20 antibody-based treatment. In this latest paper, Mssnerand colleagues rom a biotechnology company in Switzerland demonstrated that typeII CD20 antibodies are much more ecient than type I at depleting normal B cells in ahuman CD20 transgenic model that is dependent upon macrophages and Fc receptors.This dierence in B-cell depletion relates to the degree o CD20 internalization ollowingantibody binding. Specically, type II antibodies undergo ar less internalization and deg-radation than type I. Surprisingly, but in agreement with clinical data collected thus ar, theauthors demonstrated that internalization and degradation o type I CD20 antibodies ismost pronounced in CLL, whereas it occurs less in other types o B-cell lymphoma. Thesedata provide a rational explanation or why type II CD20 antibodies might be more eec-tive in CLL and, again, are supportive o what has been observed to date in early phase Iclinical trials o the rst type II CD20 antibody, GA-101.

The importance o this paper to B-cell immunotherapy is clear, and there are many les-sons we can take rom it. Despite the success o rituximab, and recently o atumumab,in several dierent B-cell malignancies and autoimmune diseases, our understanding othe mechanism by which this class o drug works is still very much evolving. The unique-ness o each neoplastic disease (CLL and NHL) and oten contrasting mechanisms inpathologic, but not transormed, B cells must always be considered. For example, typeII CD20 antibodies may be eective both or B-cell-dependent autoimmune diseases,where rituximab has had modest eect, and or CLL. In contrast, the benet o type IICD20 antibodies in other types o lymphoma where antibody internalization and degra-dation are not as apparent may yield less signicant improvements. Along with tailoringantibodies to specic diseases, we might also take better advantage o the antibody-cellinteractions themselves. Type I antibodies are internalized with no measurable shaving,and this may make such antibodies ideal or the delivery o conjugated cytotoxic agents.Other possibilities undoubtedly exist and are waiting to be explored. As new therapeuticagents continue to be identied, early basic and translational investigation, such as that oMssner et al. will orm the oundation or tailoring and optimizing treatments, not only toeach disease, but to each patient.

1. Senter PD. Potent antibody drug conjugates or cancer therapy. Curr Opin Chem Biol.2009;13:235-244.


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Bendle GM, Linnemann C, Hooijkaas AI, et al. Lethal graft-verss-host disease in mose models of T cell receptor genetherapy. Nat Med. 2010;16:565-570.

Amajor component or the success o allogeneic hematopoieticcell transplantation (HCT) is the grat-versus-leukemia (GVL)eect. It is a orm o adoptive immunotherapy, albeit crude, in

that the donor cells are polymorphic and heterogeneous, sometimesleading to GVL but oten to grat-versus-host disease (GVHD) withor without GVL. The ability to induce GVL without GVHD remains theHoly Grail in HCT. There has been great interest in specic adoptiveimmunotherapy. The thinking is that perhaps one could remove all thenon-specic T cells that could cause GVHD and give only those thatare targeting a particular antigen, be it a tumor antigen or an inec-tious agent such as cytomegalovirus (CMV). Tumor- (or viral-) specicT cells can be created through transer o the genes o unique T-cellreceptor (TCR) into cytotoxic T cells (CTLs). These T cells will thenexpress high levels o the transected TCRs, creating CTLs that willrecognize the targeted antigen although it will also express its originalendogenous TCR. Clinical trials that are testing these approachesare currently ongoing.

The paper rom the lab o Schumacher in Amsterdam raises a signi-cant caution to these approaches. The concern is that the exogenousTCR (composed o the and chains) could rearrange with theendogenous chains, as each chain is expressed individually andthen combined, creating a novel TCR that would be auto-reactive.Sucient auto-reactive T cells would then lead to GVHD, espe-cially in the setting o HCT, where there is a major component ohomeostatic T-cell prolieration ater lymphodepletion. The authorsdemonstrated this concern by transecting TCR chains directedagainst the model antigen ovalbumin (OVA). They then gave thesecells to mice that had been lymphodepleted by irradiation ollowedby interleukin-2 in vivo. Within two weeks, the authors noted thatthe animals developed cachexia, lymphopenia, colitis, and mar-row ailure, similar to ndings o GVHD (called TCR gene transerinduced GVHD [TI-GVHD]). This induced GVHD occurred in animalsthat expressed OVA in their tissues and in animals that did not. Theythen demonstrated that this phenomenon was directly related to theinused OVA specic T cells, which had gained specicity or un-identied host antigens through recombination with the endogenousTCR; a single or chain was sucient or this new specicity. Thecontrol T cells transduced with green fuorescent protein (GFP) didnot develop GVHD.

Perhaps it should not have been surprising that TI-GVHD occurredin these experiments since the introduction o a polyclonal populationo T cells, even with transected TCRs, would likely represent manyTCRs that could result rom cross-pairing. The use o oligoclonal ormonoclonal transgenic T cells does not result in TI-GVHD. It is notclear how relevant these observations are in humans as many othese studies are just beginning. However, these data suggest thatit is important to develop strategies that would prevent such cross-pairing o transduced and native and chains. Such approachesinclude the addition o cystine-modied transduced TCRs that allowor a new disulde bond, thus reducing the cross-pairing or use ounique chimeric antigen receptors (CARs) that utilize the variableregions o immunoglobulin that are not likely to recognize host minorantigens. Other approaches could be to simultaneously introducesuicide genes, so that i these transduced T cells cause TI-GVHD,they could be destroyed. These are indeed complex systems.

nelson J. Chao, md, mbad. C c cc .

C y h tc e

robert laumenhat, md, Pdd. c cc .

Lam CK, Yoo T, Hiner B, et al. Embols extravasation is an alternative mechanism forcerebral microvasclar recanalization. Natre. 2010;465:478-482.

Maintenance o blood fow through the cerebral microvasculature is essential to normalcerebral unction. Fibrinolysis and hemodynamic orces clear brin-rich clots rom thecerebral microcirculation rapidly and eciently. However, ragments rom atherosclerotic

plaque and complex clots not susceptible to brinolysis can also occlude the cerebral microvascu-lature. Such emboli are not eectively cleared by the brinolytic system. What is the ate o theseragments? Lam et al. rom Northwestern University in Chicago have now identied a heretooreunrecognized mechanism or maintaining patency o the microvasculature. They demonstrated thatthe endothelium is capable o clearing the microvasculature o occlusive emboli by translocation,thereby restoring blood fow.

The investigators used transcranial two-photon microscopy o the cerebral microvasculature toevaluate the ate o fuorescent brin clots, cholesterol emboli, and microspheres inused throughthe internal carotid arteries o mice. Mice expressing Tie2-green fuorescent protein were usedin these studies to visualize the endothelium ollowing inusion o fuorescent emboli. The inves-tigators ound that emboli that were not lysed within the rst ew hours ollowing inusion wereextravasated rom the vessel over a two- to seven-day period. Electron microscopy o tissuesamples rom these mice conrmed that the emboli had been extruded into the surrounding tissue.An open luminal space completely surrounded by an endothelial layer was observed next to theextravasated emboli, consistent with the observation that blood fow is restored ater translocation.Time-lapse imaging demonstrated how the endothelium generated the proto-lumen. Endothelialmembrane projections ormed around the emboli. The new endothelium grew all the way aroundthe emboli to create the proto-lumen (Figure). The original endothelium concurrently underwentretraction, enabling the extravasation o emboli into the perivascular parenchyma. Inhibitors omatrix metalloproteinases interrupted this process, suggesting that proteases participate in theremodeling o the endothelium and are required or embolic extravasation. The authors also com-pared emboli extravasation in younger mice to that o older mice. They ound that the rate o emboliextravasation is substantially slower in older mice. In addition, the older mice suered increasedsynaptic injury and death ollowing inusion o emboli.

Loss o patency within the cerebral microvasculature can result in tissue ischemia and cognitiveimpairment. The observations that microvessels are capable o clearing emboli and that this abil-ity declines with age may improve our understanding o age-related cognitive decline and strokerecovery. That similar age-related processes occur in humans will need to be demonstrated. Inaddition, the eect o impaired embolic translocation on neuronal damage will need to be moreclearly dened. Nonetheless, these studies elegantly demonstrate an unexpected unction o thecerebral microvasculature. As the innovative imaging techniques used to make these observationscome into wider use, we will likely nd out whether this unction is observed in other microvascularbeds or whether it is a unique eature o cerebral endothelium.

Flow is reestablished rapidly during the extravasation process allowing vessel survival. (a)

In arterioles > 20 m in diameter, blood fow is reestablished, at least partially, even beorecomplete embolus extravasation given that multiple rows o cells can circulate simultaneously. (b)In capillaries, blood fow is generally reestablished ollowing complete embolus translocation.

Reprinted by permission rom Macmillan Publishers Ltd: Nature (Lam CK, Yoo T, Hiner B, et al. Nature

2010;465:478-482), copyright 2010.

Extravasation of emboli from cerebral arterioles and capillariesFigur


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Jerald P. radiCh, mdd. rc c cc .

Cp d tc:i t P l rc?

Sharma SV, Lee DY, Li B, et al. A chromatin-mediatedreversible drg-tolerant state in cancer cell sbpoplations.Cell. 2010;141:69-80.

The primary imperative o a cell is to survive. This is ne when

the cell is healthy. For a cell transormed into a cancer, thisunderlying biological drive blocks our ability to bring cures

to patients. The cancer cell has many strategies to undermine ourtreatments, including drug efux, hiding in protective microenviron-ment niches, and employing genetic instability to create clones thatcan emerge during chemotherapy through natural selection. A recentmanuscript by Sharma et al. documents another ascinating andrustrating adaptation or drug resistance.

In a very simplistic ashion, one can imagine three varieties o cancer.The rst is a homogeneous population o sensitive cells, representingthose rare patients or whom chemotherapy works immediately anddramatically. The second type, made up o a homogeneous popula-tion o reractory cells, results in early therapeutic ailure. The vastmajority o cancers are those with a heterogeneous population oboth sensitive and resistant cells. Here, therapy is a continual experi-ment o Darwinian selection, with resistant clones emerging throughthe selective pressure o the chemotherapy. Sometimes in the setting

o relapse, newly emergent clones can be detected by the presenceo genetic markers not present in the original sample. Yet, sometimesthese cells appear the same as in the original disease. Even morebafing, sometimes retreatment with the original agents will yielda response. How can one explain sensitivity (however brie) in thesame cells that were previously resistant?

In this ascinating study, Sharma et al. rom Massachusetts GeneralHospital reported on the phenomenon o reversible, drug-tolerantcells emerging during exposure to chemotherapy agents. The experi-ments were perormed in cell lines, predominately the EGFR mutantnon-small cell lung cancer derived cell line, PC9. This cell line is verysensitive to EGFR tyrosine kinase inhibition (TKI). Upon exposureto TKI, a small residual population (< 1 percent) o the original cellspersisted with radically ( > 100-old) reduced sensitivity to the TKI.These drug-tolerant persisters (DTPs) could also be ound ater thePC9 cells were exposed to cisplatin. DTPs were generally quiescent,though ~20 percent resumed normal prolieration in the continuedpresence o drug, thereby becoming drug-tolerant expanded persist-ers (DTEPs).

Several lines o experiments demonstrated that tolerance was notdue to drug efux or clonal selection o a new mutation. Other keyobservations in this study were that: 1) PC9 cells plated at low den-sity, even without exposure to drug, occasionally yielded DTP cells,consistent with low-level spontaneous emergence o the resistantphenotype; 2) DTPs and DTEPs, when subsequently grown withoutdrug, would eventually revert back to the sensitive phenotype; 3)mechanistically, the tolerance exhibited by DTPs required the chroma-tin-remodeling gene histone demethylase KDM5A; treatment o DTPsand DTEPs with histone deacetylase (HDAC) inhibitors caused areversion back to the drug-sensitive state; 4) ormation o DTPs ap-peared to require IGF-R1 signaling, thus, co-treatment o PC9 cellswith a TKI (which would generally permit the emergence o DTPs),and with an IGFR inhibitor and an HDAC inhibitor virtually eliminatedthe emergence o the drug-tolerant state.

Why is this study important? First, it illuminates a new mechanismo drug tolerance a transient, ully reversible strategy o the cell toprotect itsel rom a hostile environment (think o a tortoise duckinginto its shell, only to emerge when the coast is clear). Second, it sug-gests that drug intervention to orce the cells back down a pathwayo drug sensitivity may be possible. Lastly, it may explain why in somecases resistant cells become sensitive again a potential biologicalexplanation o the phenomenon o the benet o a drug holiday.

gregory m. verCellotti, mdd. vc c cc .

t b: h s rbC C P im i

Hod EA, Zhang N, Sokol SA, et al. Transfsion of red blood cells after prolongedstorage prodces harmfl effects that are mediated by iron and inflammation. Blood.2010;115:4284-4292.

Red blood cell (RBC) transusions are liesaving procedures or severe blood loss, but

needless transusions perormed on anemic euvolemic patients may be detrimental.Clinical trials restricting transusions improved clinical outcomes in acutely ill individuals. 1

Prolonged storage o RBCs (> 14-21 days beore transusion) increases mortality, inections,infammation, and multi-organ ailure.2,3 The proposed mechanisms linking RBC storage dura-tion to adverse clinical consequences include impaired ability to deliver oxygen and stimulationo pro-infammatory pathways.4 The ormer may be attributed to storage-mediated changes inRBC metabolites (such as 2,3-DPG), ATP depletion, or hemolysis, while the latter may be due toactivation o cytokines, coagulation, or cells (including white blood cells [WBCs], platelets, andendothelial cells). Pathophysiologically, prolonged RBC storage may promote RBC microparticleormation, altered membrane phospholipids, impaired clearance, ree hemoglobin release withsubsequent scavenging o nitric oxide (NO), release o ree iron, and oxidative stress. Hod etal. rom Steven Spitalniks laboratory at Columbia College o Physicians and Surgeons in NewYork demonstrated that tired stored red cells are rapidly cleared by the monocyte/macrophagesystem and deliver an excess iron load that can activate cytokine production and enhance proli-eration o certain bacterial pathogens.

In these experiments, murine leuko-reduced RBCs, resh or stored or 14 days, were transusedinto normal recipients. Sixteen percent o the stored RBCs were rapidly (< 2 hours) cleared by

the spleen. The ate o hemoglobin iron was compared in mice inused with resh RBCs, storedRBCs, washed stored RBCs, supernatants rom stored RBCs, or RBC ghosts derived romstored RBCs. Only stored and washed stored RBCs increased plasma nontranserrin-boundiron (NTBI) two hours ater inusion. Twenty-our hours later NTBI levels returned to baseline.Macrophages in the liver and spleen were responsible or clearing the stored RBCs. Only storedRBCs, but not ghosts or hemoglobin containing RBC lysates, induced elevated plasma cytokinelevels. Transusions using stored RBCs induced an acute-phase infammatory response andexacerbated infammation induced by endotoxin. Plasma rom these animals promoted the growtho E.Coli in vitro. Remarkably, iron-chelators deseroxmine (DFO) or iron-laden eroxamine (FO)partially ameliorated the infammatory response.

Obviously, the study invokes more questions than answers. It is ascinating that something es-sential in the stored RBCs caused enhanced clearance o these cells by monocyte/macrophageswith rapid breakdown o heme iron with release into the plasma. What caused these cells tobe so rapidly eliminated? Was there oxidative damage to the RBC membrane? Was deorm-ability aected by DPG and ATP depletion? Did phospholipid vesiculation, excessive membranephosphatidylserine expression, loss o complement/cytokine clearance, enhanced senescenceantigen expression, Band-3 modications, or altered interaction with microvascular endotheliumplay a role? Why was iron so rapidly released? Was heme oxygenase-1 not ully upregulated?Was apo-erritin not available to store the iron? Were haptoglobin, hemopexin, and transerrinoverwhelmed? I NO is pivotal in the adverse outcomes o stored blood, why didnt hemoglo-bin lysate induce the cytokine response? Why did both DFO and FO modulate the cytokineresponse?

Blood is precious, and as hematologists we must not allow colleagues to inappropriately trans-use patients. But, how can we expand the blood supply by allowing sae prolonged storage?Would adding anti-oxidants or iron chelators help? Years ago an advertisement or an iron tonicpromised to be an antidote or tired blood. Today, we need prospective human studies to urtherclariy whether stored tired RBCs could be rejuvenated and not deliver toxic iron.

1. Hbert PC, McDonald BJ, Tinmouth A. Clinical consequences o anemia and red cell transu-sion in the critically ill. Crit Care Clin. 2004;20:225-235.

2. Koch CG, Li L, Sessler DI, et al. Duration o red-cell storage and complications ater cardiacsurgery. N Engl J Med. 2008;358:1229-1239.

3. Gauvin F, Spinella PC, Lacroix J, et al. Association between length o storage o transusedred blood cells and multiple organ dysunction syndrome in pediatric intensive care patients.Transusion. 2010. [Epub ahead o print]

4. Tinmouth A, Fergusson D, Yee IC, et al. Clinical consequences o red cell storage in the criti-cally ill. Transusion. 2006;46:2014-2027.


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The IRIS study1 and its companion long-term analyses2,3 established the natural history o imatinib-

treated newly diagnosed chronic-phase (CP) CML. The trial cemented the importance o achievingan early complete cytogenetic response (CCR) and major molecular remission (MMR) thera-

peutic milestones that translate into excellent long-term responses. No patients who achieved an MMRby 18 months progressed to the accelerated or blast phase. With eight years o ollow-up, 85 percento patients remain alive, the estimated event-ree survival is 81 percent, and reedom rom progressionto advanced CML is 92 percent.3 Annual rates o progression to advanced CML remain less than 0.5percent ater ve years.

Despite ushering in a revolution in the treatment o CML, these data indicate that imatinib leaves somepeople behind on the battleeld. Naturally, the rally cry has been stronger, quicker, better. Althoughhigher starting doses o imatinib in newly diagnosed patients generated more rapid and higher-qualitycytogenetic and molecular remissions, standard dosing exhibited a catch-up phase and comparablelong-term results.4 With their ability to overcome most BCR-ABL kinase domain mutations, the morepotent second-generation ABL kinase inhibitors dasatinib and nilotinib could salvage responses in a sub-stantial proportion o patients with imatinib-resistant or intolerant CML and outperorm dose-escalatedimatinib in CP patients. Thus, the stage was set or a rontline showdown.

Results rom the upront trials o standard-dose imatinib versus nilotinib (ENESTnd) and dasatinib(DASISION) are reported in the New England Journal of Medicine. In the ENESTnd trial, two doses onilotinib (300 mg and 400 mg bid) were evaluated; in the DASISION study, a dasatinib dose o 100mg daily was employed. Dasatinib and both nilotinib doses exhibited more rapid and signicantly higherrates o CCR and MMR by 12 months (Table). Dasatinibs benets over imatinib were maintained acrossall Hasord risk categories; similarly, both nilotinib doses were superior to imatinib among patients witha high Sokal risk score. Progression to accelerated or blast-crisis CML occurred in a ewer number opatients treated with nilotinib or dasatinib. The saety proles o the drugs were generally similar, with lowrates o discontinuation and several non-overlapping, manageable toxicities.

These data support the ecacy and saety o nilotinib and dasatinib in patients with newly diagnosed CPCML. The 12-month outcomes or both drugs indicate superiority o imatinib; however, longer ollow-upwill determine whether these ecacy margins are maintained and substantial dierences in progression-ree and overall survival materialize. At the time this article went to press, nilotinib (300 mg twice daily)had been approved by the FDA or rontline treatment. Dasatinib was under FDA review and bosutinibremained under trial investigation. Both physician and patient choice regarding which tyrosine kinaseinhibitor to use will depend on several actors, such as dosing schedule (daily or dasatinib and twicedaily or nilotinib) and distinct side eect proles. For patients with in-depth responses to imatinib, thereis no reason to change. In newly diagnosed patients, it may be time to pass the baton. Even so, reportso imatinibs demise are greatly exaggerated.

1. OBrien SG, Guilhot F, Larson RA, et al. Imatinib compared with intereron and low-dose cytarabineor newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.

2. Druker BJ, Guilhot F, OBrien SG, et al. Five-year ollow-up o patients receiving imatinib or chronicmyeloid leukemia. N Engl J Med. 2006;355:2408-2417.

3. Deininger M, OBrien SG, Guilhot F, et al. International randomized study o intereron vs STI571(IRIS) 8-year ollow-up: sustained survival and low risk or progression or events in patients withnewly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood.(ASH Annual Meeting Abstract). 2009;114:1126.

4. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study o daily imatinibmesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronicmyeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimizationand selectivity study. J Clin Oncol. 2010;28:424-430.

Jason gotlib, md, msd. g s C n-p (PkC412) c c n Cp Cc n g C Cml.

Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib verss imatinib for newly diagnosed chronicmyeloid lekemia. N Engl J Med. 2010; 362:2251-2259.

Kantarjian H, Shah NP, Hochhas A, et al. Dasatinib verss imatinib in newly diagnosedchronic-phase chronic myeloid lekemia. N Engl J Med. 2010; 362:2260-2270.

the hematologist - final pdf of september october 2010[1]

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