ASH Agenda Brochure 0221

8/13/2019 ASH Agenda Brochure 0221

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A M E R I C A N S O C I E T Y O F H E M A T O L O G Y

A G E N D A F O R H E M ATO LO GY

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Breakthrough therapies designed to treatblood disorders not only benethematology patients, but also advance thecare of patients with other diseases .


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Hematology: A Critical Field For All of Health CareThe eld of hematology has made signicant contributions to human health over the last hundred years.With the advances gained through an increasingly sophisticated understanding of how the blood systemfunctions, hematologists (both scientists and clinicians) have changed the face of medicine through theirdedication to improving the lives of patients around the world.

More than a century ago, early hematologists laid thefoundation for the eld with the rst descriptions ofleukocyte phagocytosis, the coagulation system, andthe lymphomas. In the last few decades, hematologistshave pioneered uses for gene cloning, recombinantprotein expression, and genome sequencing. Recently,leaders in hematology have applied these techniquesto dene novel treatments that have had a dramaticimpact on patient survival. And today, hematologistsare at the forefront of biomedical discovery, nding theprecise DNA alterations that can determine whether apatient responds to a given therapy or not.

Importantly, many of the new treatments for blooddisorders are applicable beyond the eld of hematologyand have already proved benecial for many patientswith other diseases. Examples of these applications areillustrated in the success stories below. Hematologyresearch has advanced health care on many fronts,and small investments in this eld have yielded largedividends for many other disciplines.

Despite impressive progress in understanding andtreating hematologic disease, signicant challengesremain, as each new discovery illustrates how muchmore we have yet to learn. The challenge now is totranslate these new discoveries into patient care thatdelivers better survival, less toxicity, and even diseaseprevention.

The American Society of Hematology (ASH) Agendafor Hematology Research describes the valuablecontributions of hematologists and illustrates thenecessity of continuing to place this specialty among

the top priorities for funding within the health-carecommunity, both today and in the future. The rstsection describes stories of success in treatinghematologic diseases, demonstrating the return oninvestment from past hematology research. The secondhalf outlines the foremost challenges still confrontingthe eld and identies the highest priority scienticthemes for the Society.


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Hematology Advances Have Saved LivesSuccess Story: Chronic MyeloidLeukemia Mortality Falls Signicantlyin a Generation

Just ve decades ago, chronic myeloid leukemia (CML)was usually fatal. Because of a better understanding ofthe precise molecular basis for this disease, the mortalityrate has decreased signicantly, and fatalities fromCML are now uncommon. This remarkable successstory started in 1960, when a team of scientists inPhiladelphia, using a simple desktop microscope, foundthat bone marrow cells from patients with CML had aunique chromosome. They called this abnormality thePhiladelphia chromosome. It was later found to be theresult of a translocation between chromosomes 9 and22. Other hematologists uncovered the fusion geneformed by the translocated chromosome, known asBCR-ABL, which caused the myeloid cell proliferationthat marks CML.

Despite that critical understanding of the diseasebiology, treatment advances for this disease took morethan two decades of meticulous work. Bone marrowtransplants were often used, but this treatment wascostly, both economically and physically. Treatmentof CML with the drug interferon could also produceremissions in some patients, but it was expensive,it had severe side effects, and the remissions wereusually not long-lasting.

Many years later, the hematology community made adiscovery that would forever change treatment andprognosis of this disease. A team of hematologistsstudying compounds that might prevent tumor cellsfrom proliferating found one compound in particularthat seemed to rapidly kill CML cells. Later studiesconrmed that the compound, today known as imatinib,was remarkably effective in the treatment of CML andhad very low toxicity.

The overall death rate from CML in the U.S.population decreased signicantly after theintroduction of imatinib.

The upper red line is elderly patients (80+ years old),the middle blue line is older patients (60-79), andthe lower green line is younger patients (under 50).

The downward inection in each of these age groupsindicates the marked decrease in death rate in thegeneral population. American Journal of Medicine,2010 Aug; 123(8):764-773.

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remains to further improve the care of these patients.For example, the same drugs that reduce death fromheart attack or stroke can inadvertently harm patientsby increasing the risk of bleeding. Funding is critical forresearch to develop even more effective anti-plateletdrugs that can block inappropriate blood clotting incoronary arteries while allowing platelets to controlbleeding elsewhere in the body.

Success Story: Multiple MyelomaSurvival Doubles in 10 Years

For many decades, multiple myeloma was an incurablebone marrow cancer with an average survival of justthree years. This poor prognosis remained unchangeduntil the past decade, when survival rates have morethan doubled, thanks to a signicantly improvedunderstanding of the disease.

This success has been the result of dedicated researchon how myeloma cells are able to grow within the bonemarrow environment. There have been three signicantadvances to achieve this remarkable success: theintroduction of autologous stem cell transplantation,bone stabilizing drugs called bisphosphonates, and thediscovery of several novel anti-myeloma drugs that areparticularly effective when used in combination.

In the 1990s, the use of autologous stem celltransplantation increased survival in myeloma patientscompared to conventional drug therapy, but the fulleffect of this procedure was not seen until the early2000s, when it was vastly improved and a wider rangeof patients was made eligible for the procedure.

The discovery of several new drugs, includingthalidomide, bortezomib, and lenalidomide, has hadan even greater impact on survival rates of multiplemyeloma. The use of these agents in both early and latestages of the disease has resulted in a paradigm shiftin treatment protocols, as documented in numerouspopulation-based databases worldwide. For example, arecent analysis of more than 250,000 myeloma patientsfound that the combination of stem cell transplantationand these new drugs has resulted in a signicantimprovement in survival. Thus, the remarkable synergyof combination treatments has resulted in even greaterimprovements in myeloma survival.

The future is even brighter, as innovative modicationsof these novel drugs are currently in clinical trials.There is a long list of therapies being developed totarget myeloma. The rapid pace of progress from basicresearch to clinical practice has not slowed, and theoutlook for myeloma patients is exciting, as this oncefatal disease becomes more and more treatable.

By combining new multiplemyeloma drugs, this previouslyincurable cancers survival ratehas doubled in just 10 years.


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Success Story: The Unlikely Cure ofAcute Promyelocytic Leukemia

The success of the treatment of acute promyelocyticleukemia (APL) has undergone some of the mostdramatic improvements, not only in the history ofhematology, but in all of medicine. This rare diseasewas historically one of the most deadly forms ofleukemia, with rapid proliferation and multiplecomplications (such as bleeding) that often killedpatients within weeks of diagnosis.

In the 1970s, a regimen of cytotoxic chemotherapyhelped cure up to one-third of APL patients, yet manypatients still died from bleeding complications beforethe chemotherapy could take effect. Then in the mid-1980s, a natural product called retinoic acid, originallyused to treat skin disorders, was found to differentiateAPL cells into nearly normal mature neutrophils thatrapidly died on their own. Retinoic acid also improved

coagulation in this disease, thereby protecting patientsfrom the hemorrhagic complications that oftenresulted in early mortality. Further research found thatwhen used alone, the effect of retinoic acid was onlytemporary, but when combined with chemotherapy,it improved cure rates by up to 70 percent. Later,investigators found that arsenic trioxide, once usedto treat syphilis, could also cure up to 70 percent ofAPL patients.

Evaluation of the mechanism of action of these twocompounds found that they both directly degrade the

oncogenic fusion protein PML-RAR

, which resultsfrom the diagnostic chromosomal translocation of APLand is responsible for this disease. Because eachof the drugs has different targets within that protein,clinical trials have demonstrated that greater than 90percent of APL patients treated with a combination ofthese two agents are cured. In fact, many patients withAPL who receive this regimen never need conventionalcytotoxic chemotherapy.

The success in APL epitomizesmany aspects of modern cancer

molecular biology, such as the roleof cloning of the translocated genes,identication of drugs that combatthe resulting fusion protein, use ofgenetically engineered mice in pre-clinical modeling of the disease, andclinical trials with active internationalcooperation, all converging togenerate a cure.

Multiple strategies developed from modern cancer molecular biology research are now used to target a once-incurable cancer , resulting in amore than 90 percent cure rate without the need of chemotherapy.

Bone marrow cells from a patient with acute promyelocytic leukemia.


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Important Unsolved Problems for the Next Eraof Hematology ResearchStem Cells and RegenerativeMedicine: Improving CurrentTechnologies to Cure Blood Disorders

The eld of stem cell biology was started byhematologists studying blood cell development.Hematologists have been studying the basic biologyof stem cells for decades, exploring their extensivepotential to repair damaged tissue, ght infections,

and reduce autoimmune diseases. The techniquesand principles used by hematologists in the bloodsystem have been applied to stem cells from manyother tissues with great success, spawning a hugestem cell research effort in many countries. Researchin hematopoietic stem cells has led to signicantclinical applications. For example, hematopoietic stemcell transplantation has been used for both geneticdiseases and patients with hematologic malignancies.Since the introduction of this clinical procedure, curerates in these diseases have steadily risen.

Future stem cell advances are highly dependent onthe ability to transplant stem cells at high efcienciesand then have them perform well once transplanted.Investigators have examined methods to amplifyhematopoietic stem cells in the bone marrow andin umbilical cord blood, and several preliminarymechanisms for stem cell amplication may help maketransplantation much more efcient.

Recently, several research teams have made signicantprogress in re-programming adult cells into anundifferentiated embryonic stem cell state. These re-programmed cells, known as induced pluripotent stem(iPS) cells, can subsequently develop into any tissueof the body. The cell re-programming is accomplishedby transducing the genes essential for embryonic stemcells, such as Oct-4 , SOX2, and Nanog, into broblastsobtained from adult skin or bone marrow.

These iPS cells may ultimately be used as atransplantable source of stem cells for any numberof diseases. They can be generated and used inpatients who have genetic blood diseases as well asother complex diseases because they have severaltheoretical advantages: they do not require accessto human eggs or embryos, they will not be attackedby a patients own immune system, they serve as acontinuous source of cells, and they are amenable togenetic manipulation. However, several barriers remainthat currently prevent the clinical translation of iPScell technology. Compared to other sources of stem

cells, iPS cells have slower growth kinetics, are moregenomically unstable, and have decreased efciencyfor differentiation. These barriers are important areasfor future research, and a federally funded Request forApplications to investigate solutions to these problemswould be an important step in bringing the promise ofiPS cells to the clinic.

Recent research has suggested that iPS cells canbe manipulated to become hematopoietic stem cells

With sustained funding, blood stem cells will be among the rst tissues to bederived from iPS cells and used clinically to treat hematologic diseases. This willset the stage for repair of other tissues and, eventually, regeneration of organs.


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and be used as a transplant source for patients whodo not have a matched donor. If recapitulating theblood system is successful, it may also be possible totransplant other organs, such as the kidney, heart, orbrain. Creating blood stem cells from iPS cells meansthe community will have a new source for blood stemcells. This will have huge medical impact, becausemore than two-thirds of patients lack a human leukocyteantigen (HLA)-matched sibling for a marrow transplant.This will also generate signicant nancial savings, asthere is a substantial morbidity to using poorly matchedsources of blood stem cells, includingbone marrow and cord blood stemcells. Closer to clinical application isthe ability to generate personalizedmegakaryocytes for unlimited, patient-specic platelet production from iPScells. Such donor platelets couldbe produced from a diverse set ofHLA serotypes for transfusion, whichwould prevent the complication of the

recipient immunologically destroyingtransfused platelets. Funding of theseprecedent-setting approaches iscrucial to the future of regenerativemedicine.

New uses for iPS cells couldbe implemented with existing

technologies, but progress is limited due to insufcientfunding. For example, iPS-generated red blood cellsfrom rare blood types could be used in blood bankingas reagents to identify allo-immunized patients andblood units suitable for transfusion. This is alreadyfeasible, as only small numbers of these red bloodcells are needed. Also, iPS cells generated fromdiseases could serve as targets to test new drugsin rare conditions. Further, use of iPS technology togenerate individual cancer stem cells for drug testingmay be extremely valuable, since most relapse occursfrom the small stem cell population within a malignancy.Additional funding from national blood bankingorganizations and the pharmaceutical industry couldaccelerate these important efforts.

Studies with iPS cells have also provided new insightsinto how normal stem cells differentiate into maturelineages. Extensive studies of how hematopoietic stemcells regulate daughter cell fates have demonstratedthat key transcription factor proteins in the nucleus ofa cell can turn on an entire gene expression program.The hematology community is now keenly focusedon understanding how these few key transcriptionfactors alter a cells function and how they can modifythe expression patterns of gene families. For example,recent research has found that regulating a single

transcription factor can re-activate fetal hemoglobin

Fluorescence representing the expression of fetal globin indifferentiating human iPS-derived erythroid cells. Courtesy of Thalia

Papayannopoulou, MD, DrSci

Ultimate goal: stem cell therapy


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in adult erythroid cells. This is a promising goal fortherapy of sickle cell anemia. Results from thesestudies will also help to resolve other blood disorderslike thalassemia, which carry a signicant burdenworldwide. Funding is absolutely critical to makeprogress in the discovery of compounds that targetthese regulatory transcription factors, particularlyfor chemical screening for modiers of globinswitching. This would provide a meaningful advancefor the millions of people with sickle cell anemia andthalassemia around the world.

Myelodysplastic Syndrome and

Acute Myeloid Leukemia: Findingan Effective and PersonalizedTreatment for the Elderly

More than 12,000 Americans of all ages arediagnosed with acute myeloid leukemia (AML) every

year. If left untreated, this aggressive disease can leadto death within a matter of weeks. Fortunately, thanksto advances in hematology research, this diseasecan now be cured in up to 40 percent of patients.A related condition, myelodysplastic syndrome (MDS),affects an additional 10,000 Americans annually, andalthough less aggressive than AML, it is ultimatelyfatal in the vast majority of patients as a result of bonemarrow failure, immune deciency, and, in some cases,transformation to AML. MDS can also be extremelydifcult to diagnose; thus, the true incidence of MDSlikely far exceeds current estimates.

Research successes have resulted in strikingimprovements in outcomes for younger patients withAML and MDS, but very few older patientshave beneted from these improvements. Theseolder patients have more frequent drug resistance,more co-morbidities that limit their tolerance ofeffective therapies or transplantation, and morefrequent DNA mutations.

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Modied from Farag et al., 2006; Ma et al., 2007.


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New treatment strategies are desperately neededfor older patients with AML or MDS, but developingsolutions will require a multi-faceted approach thatincludes basic, translational, clinical, and public healthresearch across three primary areas:

1. First and foremost is the development of agentsthat specically target common genetic mutationsin older MDS or AML patients. Such agentswill have to be derived from basic research intothe mechanisms of this disease. Support is alsoneeded for high-throughput screening, which hasled to therapeutic advances in other cancers andshould be applied to study MDS and AML in theelderly. Re-purposing existing drugs could be aninexpensive and effective method of nding lesstoxic and more effective agents. Further, usingnewly gained information about mutations inDNA methyltransferases,Tet genes, and splicingmechanisms will help focus study on the righttargets for MDS and AML in the elderly.

2. Second, funding is critical for dened clinical trialsstudying specic groups of patients based on thebiology of their disease. Identifying genetic or otherbiologic markers that predict a patients responseto treatment will help facilitate more focused andless expensive clinical trials. Ancillary studiescan help identify reasons why certain drugs fail,explain why leukemia cells become resistant todrugs, or describe tumor-host interactions thatallow leukemia cells to survive therapy. Additionally,racial, ethnic, and socio-economic diversity isnot sufciently captured in most clinical trials,so support for more extensive, comprehensivepatient inclusion (through cooperative groups, forexample) will help ensure that the results can beapplied to broader patient segments.

3. The third important priority is the developmentof a personalized approach to treatment basedon the specic DNA mutations found in eachpatient. Genetic and clinical markers must

be identied to help better inform treatmentselection for each patient. Based on the personalleukemia DNA sequence or other biomarkerspresent, the individuals treatment regimen mayinclude a customized combination of intensivestandard chemotherapy, stem cell transplantation,investigational drugs, or supportive care alone,tailored specically to optimize patient outcomes.More research should also be invested in shareddecision-making, in order to better understand howolder individuals with MDS and AML choose theirtreatment. Identifying situations when treatmentintervention may improve quality of life or prolongsurvival (or when it may not) is critical in choosingthe right course of treatment.

Through these three dened approaches, older AMLor MDS patients may achieve outcomes comparableto those of younger patients. This subject shouldbe especially of interest to funding agencies orfoundations focused on aging, and their participationin supporting these research efforts would beencouraged and valued.

Leukemic blasts and dysplastic blood precursors from an elderly patient who had prior MDS. These leukemia cells are more resistantto therapy than cells from younger patients, even if they carry similar

genetic abnormalities. It remains unclear why this is the case.


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Hematopoietic Stem CellTransplantation: Increasing SuccessRates by Improving Management ofGraft vs. Host Disease

For patients with hematologic malignancies, allogeneicbone marrow or blood stem cell transplantation(SCT) is an effective treatment, and the frequencyof transplants continues to increase worldwide.Unfortunately, almost half of all SCT patients developgraft-versus-host disease (GVHD), a condition in whichthe donors immune cells attack the patients skin,liver, or intestines. This is the single most importantbarrier to improving the success of this procedure, asabout a quarter of these patients die from GVHD or itsrelated complications. GVHD occurs more frequentlyfollowing SCT from unrelated volunteer donors, a trendthat has increased dramatically in the last 10 years

as more transplants are conducted from unrelateddonors. GVHD is also seen more commonly in olderpatients, and since older patients are more frequentlyundergoing SCT, there are now more patients withGVHD than ever before.

GVHD can occur soon after transplantation, whichis termed acute GVHD, or more than three monthslater, which is called chronic GVHD. ChronicGVHD is an especially complex challenge. For manyreasons, the hematology community has a limitedunderstanding of the natural history of chronic GVHD.It normally occurs after patients have returned homeand are no longer being closely followed at thetransplant center. The onset can be so gradual thatmany patients do not even notice the subtle changes,and, by the time a denitive diagnosis is established,some effects may be irreversible. The few treatmentoptions for chronic GVHD usually involve additionalimmunosuppression for patients who are already

Stem Cell Transplant Activity Worldwide 1980-2009

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deeply immunosuppressed, which increases the rateof infections in patients who are poorly equipped toght them. Unfortunately, denitive clinical trials arelacking due to complicated logistics and a dearthof new drugs to treat GVHD.

The biology of chronic GVHD is also poorlyunderstood, further challenging treatment.Few experimental models have been developed,in part because the chronic nature of the diseasemakes such experiments lengthy, labor-intensive,and prohibitively expensive. The biology of acuteGVHD is better understood, not only because themodels are better, but also because the diseaseoccurs sooner after transplant, while a patient is stillunder the care of experienced transplant physicians.But even in the acute setting, progress has beenagonizingly slow, and early studies have not yettranslated into major clinical breakthroughs.

To accelerate progress and capitalize on relevantscientic advances, four broad areas should betargeted for additional funding. First, recent progressin cellular and molecular biology of GVHD targettissues offer opportunities to fund the identicationof new treatments. Second, the interaction betweenthe innate and adaptive immune systems is importantin GVHD and will benet from the study of newapproaches in models and trials. Third, gradingsystems focusing on the severity of GVHD have notchanged in 40 years and may not be as relevant aspreviously thought. Recently identied biomarkersshould be more widely validated and incorporatedinto new grading systems to risk-stratify patients andbetter customize treatment. This would be particularlyvaluable for chronic GVHD, whose current consensuscriteria are labor-intensive and still not validated

prospectively. Finally, the percentage of SCT patientsenrolled in trials remains small due to the substantialregulatory burdens and the prohibitive costs of clinicalresearch, so the extension of the Bone MarrowTransplantation Clinical Trials Network should be atop priority for funding.

The technology available today could markedlyincrease the success of SCT, if it could be uniformlyapplied to GVHD research. Thus, support is neededtoday to translate this technology into new treatmentoptions for GVHD in the near future, as it remains themajor barrier to the success of SCT. Since GVHDresearch spans many disciplines, from hematology andpathology to immunology and blood banking, multi-investigator grants combining distinct approaches tocombat this problem may be the most effective avenuethrough which progress can be achieved.

An increasing number of stem cell transplants have been performedeach year worldwide for the last 40 years to treat and sometimes curehematological diseases. However, chronic graft-versus-host diseaseremains a challenge that spans many disciplines , from hematologyand pathology to immunology and blood banking.


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Sickle Cell Disease: Reducing theBarriers to Care, Burden of Pain, End-Organ Injury, and Premature Death

Sickle cell disease (SCD) is the most commoninherited red blood cell disorder in the United States,affecting 70,000-90,000 Americans. Although the

molecular basis of SCD was established severaldecades ago, it has been challenging to translate thisknowledge into the development of novel targetedtherapies. Nevertheless, enormous advances havebeen made. As recently as the 1960s, this disease wasdescribed as a disorder of childhood, because patientsrarely survived their teenage years. Today, most sicklecell anemia patients can expect to live into adulthood,but the cost of care and the burden of pain, end-organinjury, and premature death remain high.

New approaches in managing this disease have

improved diagnosis and disease maintenance overthe last few decades, but many patients still havesevere complications that have yet to be overcome.For example, the introduction of newborn screeninghas improved early management of the disease, andnovel treatments have measurably reduced the diseaseburden. Oral penicillin prophylaxis, the impact of which

was rst seen thirty years ago, remains the primarymethod to prevent infection-related deaths duringchildhood, which are now rare. In addition, hydroxyurea,the only FDA-approved drug with a specic indicationfor SCD, has been shown to reduce hospitalizationsfor sickle cell pain and acute chest syndrome in adultsand children. However, the drug is underused outsideof academic centers, so understanding barriers to its

use is an important area for health outcomes research.Blood transfusions have also offered signicantbenets for the prevention of stroke and othercomplications in SCD, and stem cell transplantefforts have led to cures in some children and adults.For patients who have matched donors, stem celltransplantation is likely underutilized and may improvequality of life, but since many patients lack HLA-matched stem cell donors, its use is still limited.

Adding to these clinical challenges is the worry that

federal NIH funding will signicantly decrease incoming years, resulting in fewer research initiatives,loss of infrastructure support, and fewer clinical trials.Research on the effect of psychosocial variableson SCD outcomes may be one of the rst areasto be cut, even though it may signicantly improvethe health of this underserved patient population.

The future of care for SCD patients will be dependenton advanced and highly targeted approaches toresearch, discovery, and implementation of newinterventions. Clinical research can make a dramatic

difference in the SCD treatment paradigm with specicpriority areas of focus. For example, in genetics, studiesare needed to identify and validate genetic markersthat predict disease severity, as SCD manifestationsvary greatly among patients due to modied genes.There is an emerging body of evidence suggestingthat some people with sickle cell trait are at increasedrisk for life-threatening medical conditions, such as

The future of care for SCD patientswill be dependent on advanced andhighly targeted approaches to research,discovery, and implementation ofnew interventions.


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renal failure, so further studies are essential to identifythe association between sickle cell trait and theseconditions. Additional research is also needed to helpidentify markers of early progression in SCD, such asacute chest syndrome or sickle lung disease. Finally,studies to better understand the neurocognitive effectsof SCD are critical, since neurocognitive defects (other

than stroke-related disabilities) are not well understoodand are difcult to prevent or treat.

New treatments for sickle cell disease to preventpain, reduce severe anemia, and control inammationare desperately needed. Studying pain in SCD mayprovide opportunities for hematologists to partnerwith investigators in the neurosciences to examine theneurobiology of pain and to consider more innovativeand evidence-based approachesto pain management.

In addition, further research isneeded concerning barriersto health care. For example,applying care models like thepatient-centered medical hometo SCD needs further study, aswell as assessments of otherinnovative team systems thatcan ensure the availability ofcoordinated, comprehensivecare to SCD patients. Thisissue is not unique to the United

States: hemoglobin disordersshould be high priorities forglobal health initiatives, as theyrepresent opportunities forinternational collaborations thatcan improve sickle cell diseasecare worldwide.

Deep-Vein Thrombosis and VenousThromboembolism: Understandingthe Risk Factors and DevelopingTargeted Therapies

Venous thromboembolism (VTE) comprisestwo related conditions, deep vein thrombosis andpulmonary embolism. This common disease, which isoften preventable, has become a public health crisis inthe United States, costing-health care providers morethan $2 billion annually. Even though between one-thirdand one-half of surviving patients develop recurrentthrombosis or long-term morbidity, the burden of VTEon society remains largely under-reported and under-

Venous thromboembolism (VTE) is common disease and is often preventable.Yet, it has become a public health crisis in the United States, costing health-care providers more than $2 billion annually. Understanding molecularmechanisms and identifying risk factors for VTE will lead todevelopment of new targeted treatments.

Vessel Wall

Photomicrograph of a venous thrombus

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Endothelium

Photo courtesy of Thomas Wakeeld, MD


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studied. Further, the disease impact increasesdramatically with age, indicating that the societalburden will continue to increase in future years as theU.S. population ages. Signicant research has beenconducted in this area during the last decade, asstudies have identied risk factors for a rst orrecurrent VTE. Tests have been developed to identifyrisk factors after an initial event, and physicians havebeen able to use this information to better manage themortality and morbidity associated with the disease.Traditional therapies, such as warfarin, unfractionatedheparin, and low-molecular-weight heparin, are beingreplaced by new oral clotting inhibitors, such as directthrombin or factor Xa inhibitors, which reduce the needfor constant monitoring of a patients coagulation

function. While new options are in development,research is required to dene who needs to be treatedwith a traditional or newer agent.

Despite these advances, substantial epidemiological,clinical, and basic science studies remain to becompleted. Studies show that about one-third ofpatients will develop a recurrent VTE and may die iftheir anticoagulation therapies are interrupted. Yet itremains difcult to distinguish between patients whoseclotting will recur and need prolonged anticoagulationtherapy and those patients who will not have another

blood clot and therefore should not be exposed tothe hemorrhagic risk of prolonged anticoagulation

therapy. Since the cause of at least half of VTE eventscannot be determined through currently availabletesting, it is critical to understand the risk factors thatcontribute to the disease and its recurrence. This willrequire a number of investigative priorities, includingnew methods for identifying risk factors, better clarityabout the molecular events that lead to venous thrombi,and dening the effects of VTE on systemic plateletfunction and clotting mechanisms.

With these insights, advanced modeling combinedwith in vitro and in vivo studies may eventually providea more complete understanding of the mechanismsthat cause thrombosis in order to develop andtest targeted therapies. Collaborations betweenhematologists and scientists in other elds, such asepidemiologists, computer scientists, biomedicalengineers, and behavioral psychologists, will also beessential in order to make advances toward reducingthis signicant public health problem. Progress intreating VTE will necessitate a number of importantstrategies that include:

1. Large clinical studies designed around treatmentstrategies, especially for patients who havesuffered a single event. Essentially, who needstreatment and for how long?

2. Prediction models dening individuals who are athigh risk for both initial and recurrent events.

Collaborations between hematologists and scientists in otherelds , such as epidemiologists, computer scientists, biomedical engineers,and behavioral psychologists,will also be essential in order to makeadvances toward reducing this signicant public health problem.


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3. Studies of the new oral anticoagulants to deneappropriate clinical settings for use, to developeffective methods to monitor efcacy, and tounderstand when and how to treat bleedingcomplications.

4. Inclusion of elderly and minority populations inclinical studies to expand the utility of the results.

5. Investigation of emerging ndings that re-purposing known drugs may prevent VTE. Forexample, several studies have suggested thestatins may prevent VTE, and further researchshould identify the patient populations that aremost likely to benet from this intervention.

6. Study of thrombosis and stroke in children,as children suffer from the morbidity for theseconditions substantially longer than adults.

This framework for future research will help thehematology community meet its goals of minimizingthe burden of this disease and ultimately preventingVTE entirely. This disease represents a challenge thatextends well beyond the hematology community, andfullling the research strategies above will require closecollaboration with many other disciplines.

Childhood Leukemia: Improving CureRates by Performing CoordinatedResearch on Novel Targeted Therapies

Relapsed B-lineage acute lymphocytic leukemia (ALL)is a leading cause of cancer death in children. Recentgenomic analyses have identied a unique subtype ofhigh-risk ALL that has high rates of relapse. This typeof ALL has mutations in theCRLF2, IKZF1, and/orJAK genes. Proteins coded by these genes function inthe same pathway, which is associated with increased


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survival and proliferation of B-lymphoid cells. Strategiesto block this signaling pathway are needed to preventrelapse and enhance patient survival where currenttherapies are insufcient.

Acute leukemia in infants is another type of childhoodleukemia that is prone to frequent relapse. One of themost common forms of infant leukemia, characterizedby a rearrangement of the MLLgene, still hasparticularly poor outcomes. Research has identiedseveral factors that may predispose some infants toMLL leukemogenesis even before birth. Genomicinvestigation has also dened molecular abnormalitiesthat are associated with more aggressive disease,pinpointing several molecular causes for infantleukemia and offering important insight into the biologyof the disease. In addition, insights gained from geneexpression proling have identied possible therapeutictargets, and drugs for those targets are now underdevelopment. Yet one of the primary challenges todayis to effectively integrate this genomic information intonovel treatment strategies.

Several ongoing clinical trials will soon answer criticalquestions about infant leukemia. One importantadvance occurred in 2008, when the kinase inhibitordrug lestaurtinib was added to an ongoing infantleukemia clinical trial, making it the rst trial to evaluatea targeted agent in this young population. Then in2009, a phase I trial was initiated to test a targetedtherapy for relapsed pediatric cancers and infantleukemia called obatoclax, which inhibits the proteinsthat prevent leukemia cell death. Despite theseadvances, leukemia in infants remains a formidable

challenge, with the youngest patients suffering theworst survival rates, so there remains a dire needfor more effective and safer treatments.

In order to prevent relapse in all types of pediatricacute leukemia, coordinated research that addressesdiscovery of targets, preclinical testing, and clinicaltrials of novel targeted agents would be an efcientstrategy to achieve measurable progress in thisdisease. It is critical that research programs areinterdependent and multi-disciplinary in order toovercome drug resistance and further reduce toxicity.For example, program project grants may be especiallyeffective to integrate biological advances into therapy,as the insights gained will likely translate into otherareas of cancer research and treatment, especiallyfor infant cancers.

Preclinical work is also desperately needed tomeet new regulatory standards requiring thattargeted agent combinations must inhibit specictargets and overcome resistance mechanisms.Furthermore, funding is essential to improveclinical trial designs in order to gain informationon adult and pediatric leukemias that share similarunderlying molecular abnormalities. It may bepossible to leverage information between adults andchildren to help streamline research progress andaccelerate introduction of new drugs into the clinic.Pharmaceutical industry partners should be soughtto assist in achieving this goal.

Infant leukemia remains a signicant challenge to manage, and largelyremains incurable. Hope for these patients depends on coordinated researchthat addresses discovery of new targets, preclinical testing, and clinical trials ofnovel targeted therapies.


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Translating Laboratory Advances intothe Clinic: Using Novel GenomicTechnologies to Improve Treatmentof Hematologic Diseases

Dedicated laboratory and epidemiologic research in anarray of hematologic disorders has led to the discoveryof important new genetic and biologic markers thatdene disease susceptibility, etiology, and treatmentresponsiveness. However, there has been limitedsuccess in translating these discoveries into improvedpatient care, and there is now an urgent need toclinically apply these ndings.

While many treatments used for malignant andnon-malignant hematologic diseases are fairly effective,they are commonly based on empiric discoveries, withlimited knowledge of the basic biology of the disease.

Unfortunately, many hematologic diseases still lackeffective therapy, and the resulting patient burden isgreat, so novel therapies directed against therapeutictargets are urgently needed. Recently it has beenshown that a patients responsiveness to differenttreatments and susceptibility to adverse treatmentreactions are heavily inuenced by both the genetics ofthe disease and the inherited genetics of the patient.Thus, new research priorities addressing these specicinsights should be implemented to ensure that patientsreceive the right treatment protocols to maximize theiropportunities for successful outcomes.

Many recent advances have stemmed from the useof advanced DNA sequencing technologies, includingsequencing of entire cancer genomes. This hashelped explain the changes in diseased cells, howthese sequences relate to cells in other tissues inthe body, and how they may help identify targets fornew therapies to improve patients responsiveness.


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Research teams are working to determine the bestmechanism to use these technologies to inuencethe course of hematologic diseases. Genome studiesare still in their infancy, and additional studies areneeded in large cohorts of patients before widespreadindividual genetic testing can be implemented in theclinical setting.

Some challenges remain in the proper identicationof the genetic alterations through these technologies,such as the distinction between changes specicallyacquired by a malignancy or those that are simplyinherited by the patient. These obstacles must beresolved before the genomic technologies can be usedcondently and broadly. Thus, investment is required tocomprehensively identify acquired molecular alterationsunderlying disease biology and inherited geneticalterations that predispose to cancer or inuencetoxicity and efcacy of therapy. Such an investmentwould improve the applicability of sequencingtechnology to the diagnosis and treatment of patients.

To shift this early success in genomic research intoroutine diagnostic testing, ve specic challenges mustbe addressed:

1. Identify all important inherited and acquired geneticalterations that contribute to the developmentof hematologic disease.

2. Determine whether patients will be best served bytesting limited numbers of genes or whole-genomeapproaches. While single-gene testing is already

underway and is much more rapid, whole-genomesequencing will likely eventually become routine.Associated standards of quality control, andFDA or CLIA accreditation are issues that have notyet been addressed for many genomicproling approaches.

3. Work to ensure that whole-genome sequence dataor data subsets are not exploited by third partiesto the detriment of patients, such as by denyinghealth insurance. Some protections are in place incurrent federal policies, but additional measureswill be required to fully protect patient rights.

4. Agree on the management of the unprecedentedlarge amounts of data that are generated bywhole-genome sequencing. Unlike single-genetests, genome-wide sequencing produces massiveamounts of data that will need novel informaticsapproaches for rapid analysis, and the data willneed to be stored for a currently undeterminedperiod of time. This may lead to better patientstratication and new drugs targeted to specicnew disease targets.

5. Rationally prioritize these data for developmentof targeted drugs. There is already a ood ofinformation based on limited years of study, andselecting the best targets in an era of limitedresources will be essential for translation intoclinical relevance. This might be an appropriatearea for funding mechanisms such as SmallBusiness Innovation Research grants.

It is critical to identify all important inherited and acquired geneticalterations that contribute to the development of hematologic diseases inorder to develop personalized treatment for each patient.


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hematology research on health care has been crucialin many areas outside of hematologic disease, suchas solid tumor oncology, cardiovascular disease,and lung disease. Past successes demonstrate howwell hematology research ndings can be appliedto other areas of medicine. These advances notonly have led to increases in the success rates intreating many diseases, but also have spawnedmultiple biotechnology and pharmaceutical venturesthat increase employment, and export of goods andservices, at a time when both are sorely needed.

Funding for hematology research is an investment inthe nations health. It is vital that research funding isincreased to allow investigators to address the difcultproblems facing the eld described in this document.This will permit the major advances in understandingthe molecular defects behind a hematologic disease

to be translated into novel diagnostics and targetedtherapeutics. Given the diverse array of public healthinterests that will benet from this research, federalagencies should coordinate their hematology fundingin order to produce the greatest impact on specichigh-need areas. A multi-agency approach woulddeliver advances faster, more economically, andmore efciently, in that duplication of effort would bedecreased. Thus, Requests for Applications in theareas listed here, co-sponsored by multiple agencies,will be important for future progress.

For hematologists, the status quo is simply notacceptable. Despite the notable successes discussedpreviously, there is much to be done. Too many patientsstill suffer from and die from hematologic diseases,and hematologists remain committed to investigation,treatment, and cure of these diseases.

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to courtesy of Robert Hromas, MD


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Support for the eld of hematology shouldbe among the top priorities in health carebecause it will have a dramatic impact onthe future of health care in America andaround the world in all areas of medicine.


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American Society of Hematology2021 L Street NW, Suite 900Washington, DC 20036Phone: 202-776-0544Email:[email protected]: www.hematology.org

ASH Agenda Brochure 0221

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