For years, considerable attention was devoted to just getting it right: figuring outhow to do a transplantation as safely as possible and preventing acute complicationsduring the first 100 days from unraveling the effort. Tremendous advances in trans-plantation practice have made this therapy safer and outcomes have improved. Inrecent years, attention has shifted increasingly to other important considerations.Questions as to how to identify who should undergo transplantation as early in theirtreatment as possible, how to decide between the various transplantation donoroptions, and how to handle the transplantation survivor no longer under the directcare of the transplantation clinician but receiving care in the community are allreceiving increasing attention.

This issue contains a transcript of an educational program sponsored by the NationalMarrow Donor Program in December 2006 presented as a satellite symposium at theAmerican Society of Hematology annual meeting. Dr. Forman discusses the thorny issueof identifying which patients are suitable candidates for transplantation and whoseprospects for long-term survival would be best served by proceeding to transplantationas early in the course of the disease as possible. Dr. Weisdorf discusses the new optionof cord blood, which already has an established role in transplantation for children andis now being extensively evaluated in adults. Dr. Lee describes the late complicationsthat occur in survivors and strategies for screening, prevention, early intervention, andpatient education. Dr. Beatty presents the community physician’s perspective in refer-ring a patient for transplantation and emphasizes the importance of 2-way communica-tion. Dr. Rizzo emphasizes the importance of clinical trials in determining the role oftransplantation in various diseases and in improving transplantation outcomes.

With continuing growth in transplantation activity and more transplantation sur-vivors, communication between transplantation clinicians and community physi-cians is crucial. Also, empowering transplantation survivors to engage in healthmaintenance and promotion behaviors by providing information directly to them isimportant. The American Society for Blood and Marrow Transplantation, NationalMarrow Donor Program, Center for International Blood and Marrow Transplant Research,and a variety of patient advocacy groups are working to provide greater awarenessto physicians and patients either singly or increasingly in partnership.

Examples include publication of guidelines for transplantation timing(www.marrow.org), evidence-based guidelines for the role of transplantation for spe-cific diseases (www.asbmt.org), educational materials for community physicians andpatients about what health problems to look for in transplantation survivors, suggestedscreening procedures for health maintenance (www.asbmt.org), and web sites thatprovide patient and family resources and expert medical advice to individual patientqueries (www.bmtinfonet.org, www.bonemarrow.org, www.nbmtlink.org, and others).

The frontiers of transplantation knowledge are indeed being expanded in many dif-ferent ways.

R E V I E W SVOLUME 17 NO 1 2007

A P ub l i c a t i o n o f t h e Ame r i c a n S o c i e t y f o r B l o o d a n d Ma r row Tr a n s p l a n t a t i o n

Issues in Hematology, Oncology, and Immunology

IN TH I S I S S U E

Blood and MarrowTRANSPLANTATION

ASBMTAmerican Society for Bloodand Marrow Transplantation

TM

INTRODUCTION 1

MEMBERSHIP APPLICATION 2

ASBMT NEWS 3

CME PROGRAM:SYMPOSIUM REPORT 4Posttransplantation Patient Care: Tailored Prevention and ManagementStrategies

Introduction 5Dennis L. Confer, MD

Planning and Management for 5Related and Unrelated DonorTransplantation: Day 10 to Day 100Stephen J. Forman, MD

Unique Considerations for 7Patients Receiving Cord BloodTransplantsDaniel Weisdorf, MD

Routine Long-term Follow-up 9of Hematopoietic Cell TransplantationSurvivorsStephanie Lee, MD, MPH

Long-Term Care of the Bone 10Marrow Transplantation Patient: TheReferring Doctor’s PerspectivePatrick G. Beatty, MD, PhD

Clinical Trials: Past Trials and 12Current and Future NeedsJ. Douglas Rizzo, MD, MS

CME ASSESSMENT TEST 15

CME ANSWER SHEET 15

CME EVALUATION FORM 16

Extending the Frontiers of HematopoieticCell TransplantationJohn R. Wingard, MD, Editor

Be a part of a national organizationestablished to promote

education, research, andmedical development in the field ofblood and marrow transplantation.

Full Membership is open to individuals holding an MD or PhD degree with demon-strated expertise in blood and marrow transplantation as evidenced by either the pub-lication of two papers on hematopoietic stem cell transplantation–related research asrecorded by curriculum vitae, or documentation of two years of experience in clinicaltransplantation as recorded by curriculum vitae or letter from the director of a trans-plant center attesting to the experience of the candidate.

Associate Membership is open to individuals with an MD or PhD degree who other-wise do not meet the criteria for full membership.

Affiliate Membership is available to allied non-MD or non-PhD professionals whohave an interest in blood and marrow transplantation. This category is especiallyappropriate for nursing and administrative staff of bone marrow transplant cen-ters, collection centers, and processing laboratories, and for professional staff ofcorporations that provide products and services to the field of blood and marrowtransplantation.

In-Training Membership is open to fellows-in-training in bone marrow transplanta-tion programs. A letter from the transplant center director attesting to the appli-cant’s training status is required.

Included in the membership fee is a one-year subscription to Biology of Blood andMarrow Transplantation..

To become a member of ASBMTcopy and return this page with the

required documentation and annual dues to:

ASBMT85 West Algonquin Road, Suite 550

Arlington Heights, IL 60005

name position

institution

address

city state zip/postal code country

telephone number fax number

email address

Membership:� full $175 � associate $175 � affiliate $125 � in-training $75

PRELIMINARY APPLICATION

PRESIDENT

Robert Soiffer, MDPRESIDENT-ELECT

Helen E. Heslop, MDVICE PRESIDENT

Claudio M. Anasetti, MDIMMEDIATE PAST PRESIDENT

Robert Negrin, MDSECRETARY

Daniel J. Weisdorf, MDTREASURER

C. Fred LeMaistre, MDDIRECTORS

H. Kent Holland, MDNeena Kapoor, MDGinna G. Laport, MDStephanie J. Lee, MD, MPHPaul J. Martin, MDWilliam J. Murphy, PhDScott D. Rowley, MDJeffrey R. Schriber, MDMarcel R. M. van den Brink, MD, PhDEDITOR-IN-CHIEFBiology of Blood and Marrow TransplantationRobert Korngold, PhDEDITORBlood and Marrow Transplantation ReviewsJohn R. Wingard, MD

EXECUTIVE OFFICE

American Society for Blood andMarrow Transplantation

85 West Algonquin Road, Suite 550Arlington Heights, IL 60005-4425(847) 427-0224; fax (847) 427-9656 e-mail: mail@asbmt.org

PUBLISHING AND PRODUCTION SERVICES

CJP Medical Communications,a division of Carden JenningsPublishing Co., Ltd.

Blood and Marrow Transplantation Reviews is publishedquarterly by CJP Medical Communications.375 Greenbrier Dr., Suite 100, Charlottesville,VA 22901phone (434) 817-2000; fax (434) 817-2020

© 2007 by the American Society for Blood and MarrowTransplantation. All rights reserved.

Printed in the United States of America.

The opinions and recommendations expressed herein arethose of the individual authors and in no way reflect thoseof the society, sponsor, or Carden Jennings Publishing.

This publication is supportedby an unrestricted

educational grant from theNational Marrow Donor

Program.

ASBMTAmerican Society for Bloodand Marrow Transplantation

TM

2

REVIEWSBlood and Marr owTRANSPLANTATIONASBMT News

ASBMT

Robert Soiffer Installed as President;Claudio Anasetti Elected Vice President

Robert Soiffer, MD, chief of the Division of Hematologic Malignancies atDana-Farber Cancer Institute and associate professor of medicine at HarvardMedical School, Boston, has been installed as president of the American Societyfor Blood and Marrow Transplantation.

Claudio Anasetti, MD, professor of oncology and medicine at the Universityof South Florida, and program leader of the Blood and Marrow TransplantProgram at H. Lee Moffitt Cancer Center and Research Institute, Tampa, is thenewly elected and installed vice president, to become president in 2009.

The installation of new officers and directors occurred at the society’s annualmeeting, the BMT Tandem Meetings, on February 10 in Keystone, Colorado. Theelection was by mail ballot among members of the society in December and January.Newly elected and installed directors are:

•Jeffrey Rodney Schriber, MD, of the City of Hope/Samaritan Bone MarrowTransplantation Program in Phoenix

•Paul J. Martin, MD, of the Fred Hutchinson Cancer Research Center andthe University of Washington in Seattle

•Ginna G. Laport, MD, of the Division of Bone Marrow Transplantation atStanford University in Stanford, California.

Helen Heslop, MD, was elevated to president-elect and will assume the pres-idency in 2008. She is professor of medicine and of pediatrics and director ofadult stem cell transplantation at the Center for Cell and Gene Therapy, BaylorCollege of Medicine, Houston.

The new ASBMT president, Dr. Soiffer, is co-director of Hematopoietic StemCell Transplantation at Dana-Farber and Brigham and Women’s Hospital. Healso is the chair of the Pharmacy and Therapeutics Committee at Dana-Farber.

He is a member of the executive steering committee of the Bone MarrowTransplant Clinical Trials Network (BMT-CTN), and a member of three of the

network’s committees: toxicity, acute myeloid leukemia, and graft-versus-hostdisease. He is a member of the Chronic Myelogenous Leukemia Committee ofthe National Comprehensive Cancer Network (NCCN).

State of the Science Symposium To Be Held June 7-8 in Michigan

A State of the Science Symposium is being organized by the Blood andMarrow Transplant Clinical Trials Network (BMT-CTN).

The conference will be held June 7-8 at the University of Michigan BiomedicalScience Research Building. Details and registration information can be found onthe BMT-CTN Web site at www.bmtctn.net.

New FACT Accreditation Standards PublishedUpdated requirements for accreditation of hematopoietic progenitor cells

transplant facilities are contained in the newly published Third Edition of theFACT-JACIE International Standards for Cellular Therapy Product Collection,Processing and Administration.

Major updates occur at three-year intervals for the standards, which aremaintained by the Foundation for the Accreditation of Cellular Therapy (FACT).

Among the significant changes in the new edition are:•Expanded quality management standards throughout•Compatibility with FDA and European Union directives, including coreGood Tissue Practices, donor eligibility, documentation requirements andbiohazard warnings

•Redefined procedure volume requirements for clinical, collection and lab-oratory facilities

•Expanded requirements for pediatric competencies•Incorporation of recommendation for ISBT 128 terminology and labelingThe new third edition of the Standards is available from the FACT

Accreditation Office. Telephone (402) 427-8030.

3

New post-transplant guidelines for patients and physicians

A Guide to Protecting Your Health after Transplant: Recommended Tests and ProceduresThese new guides — in an autologous version and an allogeneic version — provide checklists for patients and physicians regarding proper long-term follow-up care after a marrow, PBSC or cord blood transplant.

Both guides can be downloaded from: www.cibmtr.org/posttransplant

These guides were produced by the NMDP for the Consumer Advocacy Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR).

Stay abreast of transplant advances and resourcesSubscribe to the National Marrow Donor Program’s Advances in Transplantation e-newsletter for medical professionals at www.marrow.org/md

10625; Jan 2007

4

ASBMT REVIEWSBlood and MarrowTRANSPLANTATIONSymposium Report

Faculty DisclosureConsistent with the current Accreditation

Council for Continuing Medical Educationpolicy, the provider must be able to show thateveryone who is in a position to control thecontent of an educational activity has disclosedall relevant financial relationships. The speak-ers for this symposium have indicated the fol-lowing possible conflicts of interest.

Dr. Dennis Confer indicated no conflicts ofinterest.

Dr. Stephen Forman indicated no conflictsof interest.

Dr. Daniel Weisdorf has received researchsupport from AnorMED, Merck, Amgen,Genzyme, SuperGen, and Ligand and hasreceived advisory board honoraria forGenzyme, Pharmion, and Schering-Plough.

Dr. Stephanie Lee indicated no conflicts ofinterest.

Dr. Patrick G. Beatty indicated no conflictsof interest.

Dr. J. Douglas Rizzo indicated no conflictsof interest.

Program Description This publication will explore practical

consideration for posttransplantation care inkey areas, including strategies for relatedversus unrelated donor transplants and cordblood recipients. Using case studies, a trans-planter and a nontransplanter will providetheir perspectives for care once a patientleaves the transplantation center. They willdiscuss routine monitoring, benign signsand symptoms that should be addressed,and emergency presentation cases. The roleof clinical trials will be addressed.

Learning Objectives • Describe similarities and differences in man-

agement of related versus unrelated donortransplantation patients.

•• Identify differences in postmanagementstrategies for patients receiving cord blood.

•• Apply long-term monitoring guidelines.•• Describe signs of serious complications.•• Discuss clinical trials in posttransplantation

care.

Accreditation Statement The Medical College of Wisconsin is

accredited by the Accreditation Councilfor Continuing Medical Education to pro-vide continuing medical education forphysicians.

Designation of Credit StatementThe Medical College of Wisconsin desig-

nates this educational activity for a maximumof 1.0 AMA PRA Category 1 Credit. Physiciansshould only claim credit commensurate withthe extent of their participation in the activity.

National Marrow Donor ProgramThe National Marrow Donor Program

facilitates unrelated marrow, peripheral bloodstem cell, and cord blood transplantation.The Program provides research, medical edu-cation, and patient advocacy to extend andimprove lives through innovations in trans-plantation.

Posttransplantation Patient Care:Tailored Prevention and Management Strategies

Adapted from a symposium held prior to the 2006 American Society of Hematology Annual Meeting on December 8, 2006, in Orlando, Florida.This symposium was sponsored by the Medical College of Wisconsin.

ASBMT

Dennis L. Confer, MDNational Marrow Donor Program

Minneapolis, Minnesota

Stephen J. Forman, MDCity of Hope Comprehensive Cancer Center

Duarte, California

Daniel Weisdorf, MDAdult Blood and Marrow Tranplant Program

Minneapolis, Minnesota

Stephanie Lee, MD, MPHDana-Farber Cancer Institute

Boston, Massachussetts

Patrick G. Beatty, MD, PhDUniversity of Utah School of Medicine

Salt Lake City, Utah

J. Douglas Rizzo, MD, MSMedical College of Wisconsin

Milwaukee, Wisconsin

Faculty

5

REVIEWSBlood and MarrowTRANSPLANTATION

ASBMT

Planning and Managementfor Related and UnrelatedDonor Transplantation: Day10 to Day 100

Stephen J. Forman, MDTransplantation requires considerable

coordination involving the team identifying adonor, the team performing the transplanta-tion, the treating physician, and the commu-nity. Important issues include awareness ofthe clinical situations under which allogeneictransplantation is considered for adults, dif-ferences in decision making for patients whoare being considered for unrelated donortransplantation, and the similarities and dif-ferences in the care and management withinthe first 100 days of patients who haveundergone related or unrelated donor trans-plantation.

Clinical Indications and Decision-Making for Adult AllogeneicTransplantation

Diseases that are treatable by related andunrelated-donor allogeneic hematopoietictransplantation include the malignant disor-ders of the hematopoietic and immunologicsystems (Table). Timing, indications, andother aspects of transplantation differ depend-ing on prognosis and disease characteristics atdiagnosis. The decision of whether transplan-tation should be performed early versus at thetime of relapse and progression is based onresponse to therapy, the nature of the disease,and the available therapeutic options. Age isno longer a barrier to transplantation; patientsin their 70s have undergone successful trans-plantation, and the spectrum of diseases andages for which transplantation is an optioncontinues to expand.

Patients whose disease is responsive tochemotherapy and who go into early remission

with 1 cycle of therapy are better candidates fortransplantation than patients who require 2 ormore cycles of therapy to achieve remission.For patients with good-risk cytogenetics whogo into remission with 1 cycle of therapy, curerates are so high that transplantation can beheld as a back-up treatment, whereas for manypatients with poor-risk disease, transplantationis the only potentially curative treatment.Another consideration is the duration ofresponse. It remains difficult to determinewhether a patient who relapses after primarytherapy will have a better outcome with repeatchemotherapy or transplantation. For relapsedacute myelogenous or lymphocytic leukemia(AML or ALL), reinduction chemotherapyoptions are limited and transplantation is likelyto be used after relapse, but for relapsed low-grade lymphoma, 2 or 3 or more courses oftreatment may be tried before transplantation.

Another important consideration is thatoptimal safety and efficacy of an unrelated

Introduction

Dennis L. Confer, MDThe use of hematopoietic cell transplanta-

tion, particularly in the unrelated donor setting,is increasing annually. At the same time, trans-plantation-related early mortality in the first100 days to 1 year is decreasing. As morepatients survive months and years after trans-plantation, aspects of patient management arechanging. For the primary care physicians andthe hematologist/oncologists who made theoriginal diagnosis and referred the patients fortransplantation, the need to provide longer-term care is increasing. To address this need, wepresent an overview of changing strategies andcare practices that relate to posttransplantationcare, beginning immediately after transplanta-tion and moving forward, through long-termcare and, ultimately, quality-of-life assessments.

From the inception of the NationalMarrow Donor Program (NMDP) in 1987,when it facilitated 2 bone marrow transplan-tation procedures, there has been a steadyincrease in transplantation treatment. From1987 through the mid 1990s, all unrelatedtransplantations used bone marrow. Then, inthe mid 1990s, the first peripheral blood stemcell transplantations from unrelated donorswere performed. The use of this new proce-dure increased rapidly after 2000, so that nowapproximately 70% of transplantations fromadult unrelated donors use peripheral blood

stem cells (PBSC) and only 30% use bonemarrow. Bone marrow is still preferred forpediatric patients, but for adults there hasbeen a dramatic switch from bone marrow toPBSC even though the comparative benefits ofPBSC and marrow continue to be defined.

The number of cord blood transplantationsfacilitated by the NMDP, which is probablyabout half of the cord blood transplantationsperformed in the United States, has also growndramatically, actually doubling between the2005 and 2006 October 1 through September30 fiscal years. During this period, the trans-plantations facilitated by NMDP increased by22% in just 1 year, and much of that increasewas because of the growth in cord blood trans-plantation and the increase in the number ofolder transplant recipients.

Along with the dramatic increase in thenumber of transplantations there has been acontinuous reduction in 1-year treatment-related mortality. Data from the Center forInternational Blood and Marrow TransplantResearch (CIBMTR) combined with NMDPdata show decreasing transplantation-relatedmortality not only for autologous transplanta-tion, for which mortality has always been low,but also for HLA-identical sibling transplanta-tion, alternative related transplantation, andunrelated donor transplantation. Within eacharea, transplantation-related mortality variesaccording to the type of disease and the stage ofthe disease. For example, there is clearly a dif-

ference in transplantation-related mortality inpatients with acute myelogenous leukemiacompared with patients with immune deficien-cies. Some variation is probably attributable tothe difference in age of recipients, but it is alsodue to the differing clinical characteristics ofthe underlying disorders. Mortality also varieswithin the leukemias according to the stage ofthe disease. Patients who undergo transplanta-tion earlier in the course of their disease, in thefirst or second complete remission, do betterand survive longer. Thus one of our mostimportant messages for practicing hematolo-gist/oncologist is to refer patients for transplan-tation at a time when they are most likely toreceived the full benefits of the procedure.

Another challenge facing those who providehealth care to transplantation patients is a pos-itive one. The increasing population of patientswho achieve long-term survival through trans-plantation will need multi-year follow-up, dur-ing which they will be in the care of the refer-ring hematologist/oncologist for a much longerperiod of time than has occurred in the past.The CIBMTR, in collaboration with the NMDP,has recently developed 2 posttransplantationguides (an autologous version and an allo-geneic version) that transplantation patientsand their physicians can use to track long-termfollow-up care. These free guides can bedownloaded from the CIBMTR web site(www.cibmtr.org/posttransplant). [Editor’snote: See page 3 to preview guides.]

donor transplantation occur when the allelesof the donor and recipient are matched.HapLogic and other advanced NMDP infor-matics tools have been developed so that anallele-level match can sometimes be identifiedin an unrelated donor as quickly as in arelated donor. Molecular matching of an unre-lated donor and recipient narrows the differ-ence in outcome, so proceeding with earlytransplantation is an option for patients whodo not have a sibling donor but have a mole-cularly matched unrelated donor.

Although allele-level matching can now beperformed for related and unrelated patientsundergoing transplantation, there may not bean allele-matched donor available, and forpatients with rare alleles a perfectly matcheddonor frequently cannot be identified. Thepotential gain of extending the donor searchto find a fully compatible donor must beweighed against the harm of lengthening thetime from diagnosis to transplantation.

Risk categories can be useful for determin-ing whether to accept the risk for some degreeof imperfect matching, and disease status candetermine how long to wait for an idealdonor. For low-risk patients for whom trans-plantation is most likely to be curative, suchas patients with chronic myelogenousleukemia (CML) and low-grade lymphoma,results with allele-level donor matchingapproximate those achieved with a siblingdonor. Thus waiting for a good match to pro-ceed with transplantation may improve out-comes for low-risk patients, provided theirdisease does not progress during the delay.Disease control outweighs allele-level match-ing, however, for intermediate-risk patients(those with more advanced disease such asCML who undergo transplantation more than2 years after diagnosis or have AML in remis-sion or myelodysplastic syndrome [MDS])and high-risk patients (those in relapse orwith more advanced MDS with blasts or poor-risk cytogenetics).

Patients for whom allogeneic transplanta-tion should be considered early includepatients with AML or ALL who do not go intoremission in the first 1 or 2 cycles ofchemotherapy and patients for whom trans-plantation offers the only possibility of cureand can be successful in 20% to 40% ofpatients. Patients with CML resistant to kinaseinhibitors such as imatinib mesylate are cur-able by transplantation [1]. MDS withincreased blasts or with poor-risk cytogeneticsand AML with poor risk cytogenetics generallyare curable only by transplantation. Other dis-eases for which early transplantation should beconsidered are myelofibrosis, low-grade lym-phoma with a short remission after chemoim-munotherapy, and chronic lymphocyticleukemia (CLL) refractory to fludarabine.

Care of Patients UndergoingRelated or Unrelated DonorTransplantation

Donor Identification and SelectionFor all patients, even if transplantation is

not considered an immediate option, HLAtyping and the assessment of the possibility ofeither a related- or unrelated-donor transplan-tation should be part of the initial evaluation.Because the process of finding a donor cantake several months, knowing the family orthe unrelated donor situation early in thecourse of the disease allows better planningfor patient care.

Preparative Regimen The choice of pretransplantation regimen

is affected by patient disease status and age.Patients with advanced disease are more likelyto be managed with a full-intensity regimen,whereas older patients with a disease that isunder control are often managed with areduced-intensity regimen. With reduced-intensity transplantation, patients in their 60sand early 70s are potential candidates fortransplantation. Also factored into this equa-tion is the curative potential of transplanta-tion, which is based in part on the specificdisease. A significant component of the cura-tive effect of all transplants is the graft-versus-leukemia (GVL) effect, but GVL sensitivityvaries. Some diseases, such as CML, CLL, andlow-grade lymphoma, are dramatically sensi-tive, and the GVL effect may still be curativewith a reduced-intensity regimen, whereasALL is least sensitive, and the role of GVL inthe disease cure is less clear.

Posttransplantation Patient Care

Graft-versus-Host DiseaseGraft-versus-host disease (GVHD) treat-

ment is related to the stem-cell source anddegree of mismatch. Immune suppressionregimens differ for patients with a perfectlymatched sibling or unrelated donors andthose with mismatched donors.Corticosteroids are the best GVHD therapybut are not optimal, and studies are underwayto find alternatives that offer a more completeand durable response for patients with signif-icant GVHD. Other current treatment optionsinclude rabbit antithymocyte globulin and T-cell depletion. Patients who have acute GVHDduring the first 100 days are more likely tohave chronic GVHD and therefore are morelikely to have later problems that must beaddressed by their primary care physician.

Mucositis, which is a primary source ofpatient discomfort in the early posttransplan-tation period, is related to the preparative reg-imen and GVHD prophylaxis, particularlyradiation-based regimens with etoposide andGVHD prophylaxis with methotrexate. Effortsare ongoing to find novel GVHD preventionregimens that will eliminate the need formethotrexate.

InfectionsReactivation of latent herpes simplex virus

in the oral or genital area is common, so allseropositive patients should receive earlyposttransplantation prophylaxis until they areno longer on immunosuppressive medication.Herpes zoster reactivation occurs in 40% ofallogeneic transplant recipients. Acyclovir,which most transplant recipients receive for 1year, is fairly effective in preventing reactiva-tion, but after 1 year reactivation may stilloccur when the acyclovir therapy is stopped.Because herpes zoster vaccine is a live virus, itis not appropriate for patients on immuno-suppressive drugs.

Most cytomegalovirus (CMV) reactivationoccurs between day 20 and day 80 posttrans-plantation. CMV was once the cause of deathbefore day 100 in 20% of transplantationpatients, but now because of pre-emptivestrategies, death from CMV in the first 100days is rare. All transplantation programsscreen for the virus and treat with oral orintravenous ganciclovir for positive culture orpolymerase chain reaction rather than waitingfor overt disease. New, more effective meansof CMV control include new drugs and donor

6

ASBMT REVIEWSBlood and MarrowTRANSPLANTATION

Diseases Treatable by Related and Unrelated Allogeneic Donor Transplantation

Acute myelogenous leukemiaAcute lymphocytic leukemiaMyeloproliferative disease/myelofibrosisMyelodysplastic syndromeMultiple myelomaB-cell lymphoma (low grade, mantle cell, large cell)Chronic myelogenous leukemiaChronic lymphocytic leukemiaAplastic anemia

7

REVIEWSBlood and MarrowTRANSPLANTATION

ASBMT

immunization with CMV as a way of transfer-ring to the recipient an immune system that ismore likely to control CMV. If CMV isdetected during the first 100 days posttrans-plantation, even if it is successfully treated,the patient needs ongoing monitoring for pos-sible late reactivation.

Bacterial infections are related to the extentand duration of neutropenia. Hospitalizedpatients must be monitored for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus. All patients are screenedfor Clostridium difficile before transplantation,but C difficile should be ruled out if a patientdevelops diarrhea after transplantation.

All patients require fungal prophylaxis.Risk factors for fungal infection include neu-tropenia and steroid use. Pneumocystis pro-phylaxis is needed by all patients in the earlyposttransplantation period and must continueas long as the patient is on immunosuppres-sive therapy. Physicians need to be aware thatantifungal drugs may interact with immuno-suppressive drugs.

Case Presentations HighlightingPretransplantation Management

Relapsed AMLThe first patient illustrates circumstances

commonly encountered in patients by physi-cians and transplantation centers. A 37-yearold male patient with FAB AML with normalcytogenetics, a disease category that has nei-ther a good nor poor risk, responded to treat-ment and went into remission after 1 monthof induction therapy and then received 3months of consolidation therapy.Approximately 6 months later, the patientdeveloped thrombocytopenia with leukemicrelapse and was referred for evaluation forallogeneic transplantation.

Because the cure rate for normal cytoge-netic AML is, at best, 35% to 40%, the patient’sfamily should be tissue typed at diagnosis anda search for an unrelated donor should be per-

formed. If a suitable donor is found, the deci-sion must be made either to perform reinduc-tion therapy or go directly to transplantation.Factors affecting this decision are how quicklytransplantation can be performed, the dura-tion of first remission, and the tumor burden.For patients who relapse within 1 or 2 monthsafter achieving a remission, the rate of secondremission is approximately 50%. Thus thispatient, who relapsed within a few months, isunlikely to go back into remission, so unlesshe has the option to participate in an investi-gational trial, if the tumor burden is relativelylow and a suitable donor is available, the besttreatment option is transplantation without areinduction attempt with an intensive pretrans-plantation regimen. Under these circum-stances, the patient has a 40% to 50% chanceof cure. With a high tumor burden, for exam-ple a white count of 100,000 with relapse,reinduction therapy is needed to attain betterdisease control before transplantation even if asuitable donor is available. If a donor is not yetavailable, reinduction with an investigationalor other agent should be initiated while thedonor search is ongoing.

Fludarabine Refractory B-Cell CLLThis patient is a 47-year-old man with B-

cell CLL diagnosed 8 years earlier. Over thecourse of the next several years the diseaseprogressed, and the patient began treatmentwith a fludarabine/rituxan regimen with agood response for approximately 2 years, buteventually his disease became refractory to flu-darabine treatment. Most CLL patients do wellwith a fludarabine-based regimen, but patientswho have a very short response or no responseshould be tissue typed and assessed for donoravailability. Fludarabine-refractory CLL, asseen in this patient, is a disease for which theGVL effect is probably the strongest compo-nent of the transplantation regimen. A strikingfeature of transplantation for CLL is that thedisease will still be present on day 30. TheGVL effect is there, but it develops over time.

Secondary MDSThe third patient is a 55-year-old woman

with MDS secondary to chemotherapy forbreast cancer and without a related donor.This is an example of a patient for whom onlyrecently transplantation may have beenimpossible but is now an option because newepigenetic-based therapies that affect methyla-tion or acetylation to allow better diseasemanagement. After treatment with the epige-netic agent azacytidine and identification ofan unrelated donor, this patent was able toundergo transplantation. So for secondaryversus primary MDS, with poor outcomerelated to disease, if a sibling-matched donoris available then immediate transplantation isindicated; if no sibling donor is available, epi-genetic therapy should be initiated, and thentransplantation should be performed if anunrelated donor is found.

ConclusionsAllele-level matching narrows the differ-

ences in outcome between related and unre-lated donor transplantation in patients withlower-risk disease and allows a physician toconsider matched unrelated transplantationearlier in the course of disease. Age is nolonger a barrier, and the management princi-ples are exactly the same for older andyounger patients. Long-term follow-uprequires close communication among thetransplantation team, the physician, and thepatient and family, beginning at diagnosis.The process of finding a suitable donor shouldbegin even before transplantation is consid-ered as an immediate treatment option so thatthe patient and physicians can explore avail-able options and time the transplantationbased on the biology of the disease.

Reference

1. Holtz M, Forman SJ, Bhatia R. Growth factor stimu-lation reduces residual quiescent chronic myelogenousleukemia progenitors remaining after imatinib treat-ment. Cancer Res. 2007;67:1113-1120.

Unique Considerations forPatients Receiving CordBlood Transplants

Daniel Weisdorf, MDThe field of umbilical cord blood trans-

plantation (UCBT) is still in its infancy, andwe are still trying to understand how UCBTdiffers from other forms of transplantation.

Biological features of UCB cells suggest theymight be suitable and perhaps even better assources of hematopoietic cells for transplan-tation. UCB hematopoietic stem cells arehighly proliferative, and this rapid prolifera-tion can overcome the limited cell dose avail-able in a single-cord unit. Because these cellshave a naïve immune system, recipients mayhave satisfactory outcomes with partiallymatched transplantation, thus extending the

donor pool to ethnic and racial minoritygroups for whom finding allele-matchedadult donors can be difficult, if not impossi-ble. Another advantage is that the supply ofUCB cells is unlimited, because every babyborn is a potential donor. UCB units thathave been characterized, typed, and screenedfor infectious disease markers can be frozenand stored and then shipped rapidly to atransplantation center.

8

ASBMT REVIEWSBlood and MarrowTRANSPLANTATION

Data on long-term outcomes are not cur-rently available for sufficient numbers ofUCBT recipients. To date, however, matched-pair analyses have shown similar survivalrates for patients, primarily children, whoreceived partially matched UCBT and thosewho received reasonably well-matched unre-lated donor transplants [1]. On the basis ofthese results, UCBT is now a standard optionfor the management of pediatric patients, par-ticularly those with pediatric leukemia.

Cell Dose and UCBT OutcomesExperience with UCBT has revealed that the cell

dose is critical. An analysis of neutrophil engraft-ment in approximately 100 UCBT showed thatpatients who received <1.7 x 107 cells/kg of recipi-ent weight had slow, incomplete neutrophil recov-ery that led to high transplantation-related mortality[2]. These results suggest that 2 x 107 cells/kg mightbe the minimum cell dose for a satisfactory graft(Figure 1), but further validation is needed.

Other Factors Affecting UCBTOutcomes

Although we can overcome some HLA bar-riers with UCB, matching is still important. Itis not yet clear, however, how to balancematching with cell dose. The greater the num-ber of recipient-donor mismatches, the greaterthe rate of adverse events. Some evidence sug-gests that a larger cell dose can compensate fora greater mismatch, whereas a smaller dosemay lead to better outcomes for closelymatched cord blood. Even with a satisfactorilysized cord blood unit, graft failure is a possi-bility with UCBT and requires considerationand planning ahead of time. The risk of graftfailure increases in adults as compared to chil-dren, probably because of increased body size.

Data comparing outcomes of cord bloodgrafting versus unrelated donor bone marrow[3] indicated that neutrophil recovery wasslower and less complete in adults receivingUCBT than in those who received eithermatched or partially matched unrelated donorbone marrow. Newer data, however, suggestthat outcomes may be improving. A morerecent published study [4] showed thatplatelet recovery in cord blood recipients isless rapid than in bone marrow transplantrecipients, but cord blood leads less often tograft failure than it did in the early phase. Therate of graft failure with unrelated UCBT hasbeen 20% to 30% overall, with an additionalrisk of late graft failure. With the currentunderstanding that grafts must contain a siz-able cell dose (2 to 5 x 107 cells/kg), the rateof graft failure is 5% to 10%.

Graft Failure in UCBTBecause graft failure occurs in as many as

5% or 10% of UCBT patients even with a well-matched, suitably sized cord blood unit, it isimportant to anticipate the need for backupgrafts. Along with choosing the primary graftto be used for the transplantation, the avail-ability of suitable backup grafts, either cordblood or unrelated donor, should be assessed.Patients should be monitored for evidence ofrecovery of donor hematopoiesis; if this doesnot occur by day 35, a second graft should berequested and immunosuppressive condition-ing initiated. As many as 50% of patients whohave graft failure can be rescued by a plannedapproach initiated before day 50 posttrans-plantation, when the patient may have persist-ing neutropenia and mycotic infection.

Double-unit UCBT with 2 closely andsuitably matched cord bloods may provide

better engraftment because each unit is anindependent immune system; they will notreject each other, and by providing a biggerand more effective graft to adult patientstheir use may lead to improved recovery andsurvival (Figure 2). Double-unit UCBT is notchosen preferentially over single UCBT butoffers an option for patients for whom nosatisfactorily sized single-cord graft is avail-able. In these patients, adding the secondunit leads to successful engraftment inalmost 90% of cases.

A surprising finding with this procedure isthat recipients of double-unit UCBT hadlower rates of relapse than single UCBT recip-ients. In 109 patients with acute leukemia infirst or second remission, the difference inrelapse rates was statistically significant, afinding suggesting that doubling the UCBunits has an important immunological effectthat might lead to reduction in relapse.

Although the problem of limited cell dose,which compromises early outcomes, might beovercome by double-unit UCBT, many adultswho undergo this procedure have advanced-stage disease, have undergone extensive priortherapy, or have poor fitness, all of which maylead to a high treatment-related mortality rateindependent of cell dose. The use of a reduced-intensity non-myeloablative conditioning regi-men in such patients has led to higher rates ofsuccessful engraftment with single- and dou-ble-unit UCBT. The transplantation-relatedmortality rate with this non-ablative approachwas only 18% at 6 months, and the 3-year sur-vival rate is approximately 44%, suggestingthat UCBT may be an effective option for adultswho are too old or too sick for conventionalmyeloablative approaches.

With both myeloablative and reduced-intensity or non-myeloablative transplanta-tion, rates of acute graft-versus-host disease(GVHD) are higher in UCBT patients than inpatients with grafts from other sources,approximately 40% with single-unit UCBTand 66% with double-unit UCBT. This higherrate of GVHD does not completely explain thedecreased risk of relapse. Research is ongoingto investigate the possible association of thegraft-versus-leukemia potency of double-unitUCBT with modest or more serious GVHD.Comparison of chronic GVHD in UCBT andunrelated-donor transplant recipients hasshown that in UCBT recipients, chronicGVHD seemed more responsive to immuno-suppressive therapy, leading to lower non-relapse mortality at 1 year.

Figure 1. Minimum cell dose for umbilical cord blood transplantation.

9

REVIEWSBlood and MarrowTRANSPLANTATION

ASBMT

It has been postulated that UCB recipientsmay be at higher risk of ongoing late infections,but across the whole spectrum of types ofinfections, higher infection rates have not beenobserved. Data on infections after adult UCBTcompared to either peripheral blood or bonemarrow transplantation showed that seriousinfection rates were a little higher after cordblood, but infection-related mortality was sim-ilar at 100 days. CMV disease rates were simi-lar in the 2 groups, although the CMV infec-tions appeared earlier after UCBT, possiblybecause UCB donor grafts are CMV seronega-tive and CMV naïve, therefore not providingany effective T-cell protection against CMVreactivation, but the overall risk was not differ-ent. The bacterial infection rate was somewhathigher in UCB recipients, but the fungal infec-tion rates were similar in the 2 populations.Thus, evidence to date does not indicate thatUCBT leads to more frequent infections.

ConclusionsUCBT studies reflect a dramatic learning

curve from the late 1990s to current experi-ence. Reports of outcomes of early grafts,particularly for adults, that were done withtoo small a graft probably do not contributeto an understanding of what can beexpected now that we know how large acord blood unit should be to achieve satis-factory outcomes.

UCBT is associated with more graft fail-ure. Because graft failure can be anticipatedto occur in 5% to 10% of patients, it must beplanned for ahead of time. Excess acute orchronic GVHD does not seem to occur withUCBT. Double-unit UCBT, although itimproves engraftment, leads to more fre-quent acute GVHD but not more frequenttransplantation-associated mortality or morefrequent chronic GVHD. UCBT does notseem to be associated with a greater fre-

quency in early or late infections, but thequality and functional capacity of theimmune system after UCBT has yet to bebeen evaluated.

Double-unit UCBT appears to havepotent graft-versus-malignancy effects, man-ifested by the lower relapse rates after 2 ver-sus 1 UCB grafts, an effect that is beinginvestigated in a prospective pediatric trial.Overall, published reports indicate that sur-vival after UCBT is similar, and for someselected populations may be superior, tothat with unrelated donor transplantation.More experience is needed to move the fieldof cord blood transplantation beyond itsinfancy.

References

1. Barker JN, Davies SM, DeFor T, Ramsay NK,Weisdorf DJ, Wagner JE. Survival after transplantation ofunrelated donor umbilical cord blood is comparable tothat of human leukocyte antigen-matched unrelateddonor bone marrow: results of a matched-pair analysis.Blood. 2001;97:2957-2961.2. Wagner JE, Barker JN, DeFor TE, et al.Transplantation of unrelated donor umbilical cord bloodin 102 patients with malignant and nonmalignant dis-eases: influence of CD34 cell dose and HLA disparity ontreatment-related mortality and survival. Blood.2002;100:1611-1618. 3. Laughlin MJ, Eapen M, Rubinstein P, et al.Outcomes after transplantation of cord blood or bonemarrow from unrelated donors in adults with leukemia.N Engl J Med. 2004;351:2265-2275.4. Takahashi S, Iseki T, Ooi J, et al. Single-institute com-parative analysis of unrelated bone marrow transplanta-tion and cord blood transplantation for adult patients withhematologic malignancies. Blood. 2004;104:3813-3820.

Figure 2. Double-unit umbilical cord blood transplantation.

Routine Long-term Follow-up of Hematopoietic CellTransplantation Survivors

Stephanie Lee, MD, MPHLate non-relapse mortality is a tragic

outcome of otherwise successful trans-plantation, and long-term transplantationsurvivors suffer substantial morbidityfrom chronic graft-versus-host disease(GVHD) and treatment-related effects.Whether optimal medical care can preventthese late effects is not known, but it isreasonable to assume that good medicalcare can minimize their impact and, con-versely, poor medical care can probablyexacerbate them.

Optimizing Long-termPosttransplantation Follow-up

Five concepts underlie the optimalapproach to routine follow-up. The first isclearly the prevention of complications thatcan be avoided in at-risk patients. For compli-cations that cannot be prevented, screening isimportant because in most cases early detec-tion increases the likelihood of successfultreatment. For existing complications, appro-priate intervention is essential. Patient educa-tion is also very important so that patients willbe involved in their own care and reportsymptoms that occur between visits. Finally,serious problems must be rapidly identified sothat appropriate interventions can be initiated.

The need for infection prophylaxis and vac-cinations is a familiar aspect of preventive care

of posttransplantation patients. Good dentalhygiene and minimization of sun exposure arealso important strategies because transplanta-tion patients are at a higher risk for dentalcaries and oral cancer, and sun exposure canexacerbate chronic GVHD and increase thealready higher risk of posttransplantation skincancers. Even before transplantation, condi-tioning regimens can be selected that minimizethe risk of late complications. Another preven-tive strategy is fertility preservation, whichoften requires pretransplantation proceduressuch as sperm or embryo cryopreservation.

Screening and early detection involvescreening for cancer recurrence and lateeffects of treatment, but general health screen-ing is also important. In the general popula-tion, internists often do such screenings, but

Long-term Care of theBone MarrowTransplantation Patient:The Referring Doctor’sPerspective

Patrick G. Beatty, MD, PhDTension exists between transplantation

physicians and the physicians who are

involved in the care of patients before andafter transplantation but did not perform theactual transplantation. The information pro-vided here is meant to enable transplantationphysicians to understand the perspective ofthe referring physician. Most important is therecognition that transplantation patients makeup a very small percentage of patients seen ata busy hematology/oncology practice.Another consideration is that the referringdoctor’s relationship with the patients and

their families can be disrupted by the trans-plantation process. And finally, referring doc-tors tend to remember the bad outcomes, sotransplantation physicians can play an impor-tant role in renewing hope and optimism.

Accessing Patient Outcome Data Referring hematology/oncology practices do

not routinely track patient outcomes for theirown use, particularly for transplantation patients,but they tend to remember the outcomes that

10

ASBMT REVIEWSBlood and MarrowTRANSPLANTATION

for transplantation patients, oncologists ortransplantation physicians may assume therole of the primary care provider.

Posttransplantation care can be providedthrough 2 types of follow-up visits. Routineinterval visits involve history and physicalexams to assess for the presence of new signsand symptoms, routine diagnostic studies, andreview of medications. Time-dependent evalu-ations involve checking all the systems for earlysigns of any problems and include regularlyscheduled vaccinations, dental and eye exams,and screening procedures for new and old can-cers. Such evaluations, often scheduled on thebasis of time from transplantation and patientage, include assessments of endocrine function,thyroid function, and bone health.

Long-term follow-up involves every organsystem because for each system there is at leastone potential catastrophic event that requiressurveillance. Secondary malignancies are asso-ciated with chronic GVHD or the conditioningregimen. Non-melanoma skin cancer, squa-mous cell and basal cell, is the most commonsecondary malignancy. The rates for solidtumors in posttransplantation patients are2.2% at 10 years and 6.7% at 15 years. In 5-year survivors, cancer risks compared with thegeneral population are highest for bone, oral,connective tissue, liver, brain, and thyroid can-cer and melanoma. Breast cancer becomesmore common in 10-year survivors. Most ofthese cancers are unusual and lack effectivescreening approaches. Thus it is importantthat follow-up exams include careful skin andmouth exams, feeling the thyroid for nodules,and checking the mammogram in women.

Items to be addressed in a comprehensive 1-year long-term follow-up visit are presented inthe Table. The goal is to maintain patient healthand to use the opportunity, given the fact thatthe patient sees medical practitioners frequentlyand has had a brush with death, to providemore attention to health and better health care

maintenance afterwards. In addition to surveil-lance for secondary malignancies, screeningtests that are appropriate for the general popu-lation also apply to transplantation patients.Colorectal cancer screening is recommended atage 50, or sooner if there is a family history. Forbreast cancer, regular mammograms every 1 to2 years are recommended to begin at age 40 or50, but should begin earlier in women whohave had radiation therapy. Regular PAP smearsfor cervical cancer should begin at age 21 or theonset of sexual activity. For prostate cancerscreening there is no consensus, with someorganizations recommending fairly extensiveworkup including prostate-specific antigen anddigital rectal exam, and others saying that datado not support these procedures.

In long-term survivors the most commoncause of death is cardiovascular disease.Recommendations are to check blood pres-sure every year and to treat it if it is consis-tently over 140/90. Lipids, cholesterol, andhigh-density lipoproteins should be checkedevery 5 years starting at age 35 for men andage 45 for women. Screening for diabetes isalso recommended.

Patient care can be enhanced by coopera-tion between the oncologist or transplantationphysician and other physicians such as aninternist who can help with cancer screening,cardiovascular risk factors, and bone healthand a dentist who can help with oral cancerscreening. Written materials can also facilitateclinical care. These may include patient self-assessment, screening questions, and lists ofrecommended tests based on time since trans-plantation. Materials available for patients par-ticipating in their own long-term care includethe National Marrow Donor Program’s “LivingNow” pamphlets, which include informationabout specific topics, including medications,signs and symptoms of chronic GVHD, familyrelationships, and going back to work. Patientinvolvement is important because patients and

families are the most invested in maintainingthe best possible long-term health. Patientempowerment is associated with improvedsatisfaction and outcomes.

ConclusionsLong-term follow-up of transplant sur-

vivors involves prevention, screening, appro-priate interventions, patient education, andrapid identification and treatment of seriousconditions. More and more resources areavailable to help manage the multitude oftasks and enable patients to become betterpartners in maintaining their health. What wereally want to do is bring the survival curvefor transplantation patients up to that of thegeneral population. To achieve this, healthcare providers must be vigilant for complica-tions and think long-term about conditionsthat have nothing to do with transplantationbut can still affect a patient’s health.Ultimately, making transplantation a successinvolves trying to prevent patient death fromsomething other than the original disease andits treatment.

Components of a 1-year Follow-up Visit

Complete blood count with differential, chemistry panel (liver function tests, glucose, creatinine)

Immunoglobulin levelsFasting lipid panelVirology screen (hepatitis, cytomegalovirus)Immunization titersEndocrine evaluation: thyroid, sex hormonesIron studiesImmunosuppressive drug levelsBone marrow aspirateSkin biopsyPulmonary function testsSchirmer testDual energy x-ray absortiometry to assess bone densityChest x-rayEye and dental examGynecological exam/mammogram (women)Prostate-specific antigen (men)

11

REVIEWSBlood and MarrowTRANSPLANTATION

ASBMT

were bad. Thus the referring physician’s perspec-tive regarding transplantation tends to be coloredby memories of the most heart-wrenching expe-riences, whereas patients who did well or aredoing well do not come to mind immediately. Apossible remedy for this situation may be fortransplantation programs themselves to providedetailed outcome summaries to the referringphysicians. Many programs send out survivalcurves, but these may not seem relevant to refer-ring doctors, who may need more detailed infor-mation about the patients that have come out oftheir particular practice.

Referring physicians have different rela-tionships with their patients than the academiccenter. They know the patients and the fami-lies very well and have a community status,which causes the families to view these physi-cians as sources of information. Thus thesedoctors would benefit from frequent outcomeupdates through brief communications, possi-bly in the form of physician-to-physician con-ferences. Communication regarding adverseevents is essential because as soon as some-thing goes wrong at the academic center ortransplantation program, the families will startcalling the referring physician for information.If the referring physician has no knowledge ofthe complication, it becomes a very awkwardand difficult situation.

On the business side, the care of trans-plantation patients takes a particularly largeamount of time for which the referring prac-tice is not reimbursed, so these patients fre-quently entail expenses that outweigh the rev-enue they generate. Posttransplantationpatients must take many medicines that fre-quently are not routinely available in the com-munity. They may be the only person in thecommunity who has ever taken a certaindrug, the pharmacy may never have heard ofit, and when they research the drug the phar-macists may not understand why the patientis taking it. Thus community physicians needmore information and time to get these drugsinto the pharmacy. Reimbursement for thesedrugs and for treatment may also becomes adifficult issue. If the patient reaches a lifetimeinsurance maximum, it is frequently the refer-ring practice that must cope with a patientwho no longer has the ability to pay for care.

Requests to provide follow-up data canalso create difficulties for referring practices.Understanding complicated transplantationcases requires complicated data, and privatepractices may have limited data managementcapabilities. In particular, private practices do

not have a system that provides funding sup-port for data collection and data management.Frequently the doctors end up filling out theforms, if they are filled out at all, because onlythe doctors with enough familiarity with thesecomplicated issues are able to fill out theforms. Easing the data-reporting burden is ahuge challenge, however. New legislation inthe United States requires transplantationcenters to report outcomes, including long-term outcomes, on all of their allogeneictransplantation patients, so every transplanta-tion patient who comes back to the practicewill have at least some requests for follow-updata on an annual basis.

Referring physicians would benefit frombeing able to directly contact someone whounderstands what is going on and can givesome advice. Frequently the doctor whoreferred the patient is not the same as the doc-tor who is taking care of the patient posttrans-plantation, who may be the family physicianwho sent them to the hematologist/oncologistin the first place.

Management ofPosttransplantation Complications

Long-term adverse outcomes of transplan-tation that are familiar to transplantationphysicians may be perplexing to the referringpractice. Images and biopsy specimens maybe difficult for the pathologist in the referringcommunity to interpret and frequently mustbe sent to the transplantation center to beexamined by someone who is familiar withthe complications that can be encounteredwith transplantation.

With respect to cytomegalovirus, patientsmay come back with instructions to docytomegalovirus monitoring. If samples mustbe sent to a laboratory for analysis, however,results may not come back in a timely fashion,a problem that does not occur at transplanta-tion centers but that transplantation physi-cians should be aware of.

Diagnosis of fungal infections is very impor-tant because effective therapies are available thatcan be managed in the referring practice. Mostpractices have experience managing pneumo-cystis and bacterial infections in patients withAIDS or leukemia and lymphomas in the non-transplantation setting and will have the aware-ness and skill to diagnose and manage thesecomplications in posttransplantation patients.

Differentiating complications caused bygraft-versus-host disease from infectious com-plications is essential for planning appropriate

treatment. For example, when liver enzymemonitoring indicates disease, graft-versus-host disease of the liver is commonly sus-pected, but viruses, particularly hepatitis Cand B, may be the cause (Figure). It is impor-tant to keep those infections in the differentialdiagnosis because the therapy is dramaticallydifferent. Differential diagnosis of gastroin-testinal disorders in posttransplantationpatients is also difficult because Clostridiumdifficile and other infections can mimic graft-versus-host disease. Screening pulmonaryfunction tests are important and may requireassistance from the transplantation teambecause abnormalities may be detectable only

Differential diagnosis of posttransplanta-tion liver disease. A, Graft-versus-host dis-ease (GVHD) of the liver. B, Chronic hepati-tis C virus infection after allogeneichematopoietic cell transplantation (HCT).Arrows indicate normal small bile ducts,which rule out liver GVHD. C, Fulminanthepatitis B after HCT.

with high-resolution computed tomographicscanning, which may not be readily availablein the immediate community.

Disease RelapseFrom the perspective of the referring physi-

cian, relapse is the most devastating of all out-comes. Patient hopes are now dashed and thepromise of the transplantation has to be re-eval-uated by the patient and family. Inevitably thequestion arises as to whether all of the difficulty

in getting through the transplantation wasworth it. The questions that the referring physi-cian faces involve the possible role of re-induc-tion, donor lymphocyte infusions, and potentialretransplantation options, decisions that requireinput from the transplantation team.

ConclusionsTransplantation physicians who understand

the difficulties faced by referring physicians cando much to improve the situation and thus

optimize the long-term care of their patients.The patients who have relapsed are etched inthe minds of the local practitioners, who hate tosee relapse happen. When relapse does occur,the transplantation physicians can provide sup-port and advice to ease the difficulty of provid-ing ongoing treatment. With ongoing treatmentadvances, the transplantation physicians andcenters may also provide continued hope.

[This report was presented at the sympo-sium by Dr. Confer on behalf of Dr. Beatty.]

12

ASBMT REVIEWSBlood and MarrowTRANSPLANTATION

Clinical Trials: Past Trials andCurrent and Future Needs

J. Douglas Rizzo, MD, MSClinical trials help to advance patient care.

Many current care practices, particularly in theearly posttransplantation period, are supportedby randomized clinical trials, and gaps in ourknowledge that hinder the delivery of optimumcare might be addressed by current or futureclinical trials. In the hematopoietic transplanta-tion setting, where the numbers of patients arelimited, clinical trials are difficult to do andrequire cooperation between transplantationphysicians and nontransplantation practitionersin both academic and non-academic settings toenroll patients in well-designed clinical trialsthat can help us advance our clinical practice.

Well-run clinical trials require substantialfunding to support the costs associated withdeveloping protocols, enrolling patients, col-lecting data, monitoring safety, and analyzingresults. In addition, patient accrual presents aparticular challenge in clinical trials in thehematopoietic cell transplantation setting. Eachyear, a few patients undergo hematopoietic celltransplantation. Because these patients are het-erogeneous in regard to disease, disease stage,age, type of donor and graft, and transplanta-tion technique, very few are eligible for clinicaltrials at any but the largest transplantation cen-ters. Patient accrual for clinical trials of long-term posttransplantation care is even more dif-ficult than for the early posttransplantationperiod. Physicians who care for posttransplan-tation patients in the community must becomemore active in patient recruitment for vitallyneeded clinical research in this area.

Designing Clinical TrialsProspective clinical trials provide the best

evidence for improving clinical practice becausethe experimental design and the approach to

supportive care are very well defined. The datato be collected and the definitions for the end-points are pre-specified to avoid bias on the partof the physicians who enroll and follow thepatients. Randomized control groups can elimi-nate selection bias and allow for comparablegroups across the study arms.

The Blood and Marrow Transplant ClinicalTrials Network (BMT-CTN) was established in2001 to conduct scientifically meritoriousmulti-center trials in an efficient manner(Table 1). The BMT-CTN seeks to improvetransplantation outcomes by providing adurable infrastructure to serve as a platformfor developing and evaluating promising ther-apies in high-quality multi-center studies thatgive definitive answers as quickly as possible.Areas of research include the expansion ofdonor availability and graft sources, reduc-tions in transplantation-related regimen toxic-ity, improvement in the prevention and treat-ment of graft-versus-host disease (GVHD),improvement in the treatment and preventionof infection, better ways to control and pre-vent relapse, improvement of late immunereconstitution, and prevention of late adverseevents after transplantation.

Changes in Practice throughClinical Trials

Many supportive care practices in usetoday have been derived from results of clini-cal trials performed over the last 20 years, andongoing trials will continue to be a major fac-tor in ongoing advances in patient care. Threeareas that have been a focus of clinicalresearch in transplantation patients are infec-tion, GVHD, and regimen-related toxicity.

Infections are a major cause of morbidityand mortality after transplantation, accountingfor at least 20% of deaths. In particular, long-term immunosuppression leads to high riskfor infection. Infections that pose the greatestrisk include invasive fungal infections. Clinical

trials performed in the early 1990s demon-strated that fluconazole prophylaxis preventedfungal infections, with continued survival ben-efit and decreased GVHD of the gut at 8 yearsposttransplantation. The emergence of resis-tant species and breakthrough infections withmore aggressive species such as aspergillus andzygomicides are ongoing problems that ongo-ing and future studies will help to address. Arandomized trial comparing micafungin, anechinocandin with broader antifungal cover-age, and fluconazole was published in 2004.This study found micafungin statistically supe-rior to fluconazole in preventing fungal infec-tion after hematopoietic cell transplantation.Patients who received prophylaxis with mica-fungin experienced fewer breakthrough infec-tions with aspergillus species; however, thisdifference was not statistically significant.

A current BMT-CTN study is addressing theissues of resistant and emerging species by com-paring fluconazole with voriconazole, whichsome centers currently use as fungal prophy-laxis even though its effectiveness has not yetbeen proven in a randomized clinical trial. Thisstudy, with a targeted accrual of 600 patients at35 sites, has the primary endpoint of survivalfree from probable or proven invasive fungalinfection and secondary endpoints of incidenceof invasive fungal infections, duration of anti-fungal therapy, and incidence of acute andchronic GVHD. The results of this trial, whichshould be available in a year, may help guideboth early and later fungal prophylaxis.

Reducing the risk of azole-resistant speciesand the emergence of more aggressive speciesremains a high priority. Depending on theresults of the voriconazole trial, a trial compar-ing micafungin with voriconazole may be veryrelevant in the next few years. New therapiessuch as posaconazole and a future generationof antifungals are also likely to lead to moreclinical trials. The development of pre-emptivediagnostic testing, which may allow us to limit

13

REVIEWSBlood and MarrowTRANSPLANTATIONASBMT

antifungal agent exposure to those patientswho are at the highest risk, and improvedunderstanding of patient immune recovery andtesting for donor innate immune response, anancillary study in the current voriconazole trial,may allow us to further refine fungal therapy.

Viral infections also pose a substantial riskfor transplant recipients. Risk is highest in theearly posttransplantation period but contin-ues in the long term for any patient whoremains on immunosuppressant therapy.Reduced incidence of cytomegalovirus (CMV)mortality can be attributed to recent treatmentadvances. Two different approaches are pro-phylaxis, with the antiviral drug ganciclovirgiven to all seropositive patients, and earlydiagnosis and initiation of pre-emptive ther-apy at the time of detection. Clinical trials inthe early 1990s showed decreased risk of tis-sue-invasive CMV infection in transplantrecipients treated with prophylactic ganci-clovir compared with placebo. Prophylaxiswith oral valacyclovir seems to be more effec-tive than acyclovir, and initial prevention withacyclovir followed either by valacyclovir orintravenous ganciclovir seems to give equiva-lent results. Ganciclovir is associated with arisk of myelosuppression, and pre-emptivetherapy allows for initiation and discontinua-tion of the drug based on sensitive detectionstrategies. Culture-based early detection fol-lowed by ganciclovir is more effective thanplacebo, and polymerase chain reaction-guided detection methods seem to be moresensitive than culture techniques. Patientstreated with pre-emptive therapy based onantigenemia results seem to have an increasedrisk of CMV invasive disease within the first100 days after transplantation compared to

those treated with prophylactic ganciclovir.After day 100, however, the risk is no differ-ent; survival is similar with both strategies,and patients in the antigenemia-guided grouphave a decreased risk of fungal infection.

Once antigenemia has been detected,treatment results with foscarnet appear to beequivalent to those with ganciclovir. Both pro-phylactic and pre-emptive strategies are cur-rently in use, although pre-emptive strategiesare more prevalent in transplantation centers.

The oral prodrug of ganciclovir, valganci-clovir, may yield higher bloodstream drug lev-els than intravenous ganciclovir. Thisapproach requires caution, however, becausemany patients with CMV also have co-existingGVHD, which may affect drug absorptionwhen it involves the gastrointestinal tract [1].

No known prophylaxis exists for some viralinfections that are common and occasionallydevastating in transplant recipients (Table 2).Future clinical trials may focus on new antivi-ral agents with a reduced risk of myelosup-pression, used either pre-emptively or prophy-lactically, maribavir being the most promising.

Another major complication of transplanta-tion is acute GVHD, for which considerableprogress has been made in prevention and treat-ment. Because the incidence of GVHD in allo-geneic recipients is high even with treatment, asare the resulting morbidity and mortality, pre-vention of GVHD remains a high priority.

The optimal strategy for the prevention ofGVHD is not yet clear. Two general approachesproven to reduce the incidence of acute GVHDare immunosuppressants, most commonlycyclosporine and methotrexate, and the removalof T-cells from the allograft. T-cell depletion isassociated with adverse consequences, especially

an increased risk of relapse [2]. Bothcyclosporine and methotrexate have beenproven in clinical trials to reduce the incidenceof severe acute GVHD, with no clear superiorityfor either agent, but as many as 40% to 50% ofpatients who receive prophylaxis still developsignificant GVHD. Combinations of bothcyclosporine and methotrexate appear to reducethe risk of acute GVHD and improve survivalrates when compared to either agent alone.

Clinical trial results during the 1990s makethe combination of cyclosporine and methotrex-ate standard prophylaxis for GVHD in allogeneicrecipients. Even with combination therapy, theincidence of GVHD is 25% to 30%. Additionalclinical trials have explored the benefit of a 3-drug regimen that includes corticosteroids aswell as cyclosporine and methotrexate, corticos-teroids being the most effective drug for initialtherapy of established GVHD. These trials haveproduced mixed results, suggesting no clearbenefit from the addition of corticosteroids tocyclosporine/methotrexate for the prevention ofGVHD and a possible increased risk of infectionwith more myelosuppression.

Newer immunosuppressants also offeropportunities for better GVHD prevention.Trials comparing tacrolimus and methotrexatewith cyclosporine and methotrexate havedemonstrated a decreased incidence of acuteGVHD in both related and unrelated donortransplant recipients. Although the use oftacrolimus was actually associated with lowersurvival rates despite the decreased incidenceof grade II-IV GVHD, this result may be attrib-utable to the significantly higher percentage ofpatients with more advanced disease in thetacrolimus arm than in the control arm.

With these data, the combination oftacrolimus and methotrexate is becoming a morecommon prophylaxis regimen than cyclosporineand methotrexate. Despite these current prophy-lactic strategies, however, substantial numbers ofpatients still develop GVHD, and many have sig-nificant toxicities with current treatmentapproaches. The use of methotrexate is associ-ated with both mucositis and liver toxicity.

The BMT-CTN has just opened a random-ized clinical trial to investigate the effective-ness and toxicity, including mucositis andliver toxicity, of sirolimus combined withtacrolimus compared to methotrexate andtacrolimus in transplantation patients withHLA-identical sibling donors. The secondaryendpoints for this trial include engraftment,chronic GVHD, thrombotic microangiogra-phy, and disease-free survival.

Table 1. Blood and Marrow Transplant Clinical Trials Network, Established in November 2001

Mission� Conduct scientifically meritorious multicenter trials in an efficient manner to improve transplant outcomes� Provide the infrastructure to allow promising therapies to be developed/evaluated in high-quality multicenter studies that give definitiveanswers as rapidly as possible

Major Areas to be AddressedExpansion of donor availability and alternative graft sources� Reduction in regimen-related toxicity� Improved prevention and treatment of graft-versus-host disease� Improved control of malignancy (decreased recurrence) � Better prevention and treatment of infection� Better prevention and treatment of late effects, including better immune reconstitution

Current Clinical Trials Network clinical trials include:� Voriconazole Fungal Prophylaxis� Graft-versus-Host Disease Prophylaxis� Graft-versus-Host Disease Treatment� Therapy for Idiopathic Pneumonia Syndrome

14

REVIEWSBlood and MarrowTRANSPLANTATION

ASBMT

Many clinical trials have focused on theprevention of GVHD through T-cell depletion,the removal of alloreactive T-cells from theinfused graft product. Multiple strategiesinclude di�erent selectivity and di�erent waysto manipulate the graft product. Many trialshave demonstrated success at reducing GVHD,but with an increased risk of graft failure andrelapse. The latter is particularly relevant forthose diseases for which alloreactivity plays arole in disease control, chronic myelogenousleukemia (CML) being the hallmark disease.

The BMT-CTN is currently conducting aphase II study to determine whether T-celldepletion using CD34 selection reducesGVHD without increasing the risk of graft fail-ure or relapse. The single-arm study will alsoexplore immune reconstitution associatedwith CD34 selection and may further ourunderstanding of late immune recovery.

Corticosteroids are the �rst line of therapyfor patients with severe acute GVHD. In stan-dard �rst-line therapy, methoprednisolone initi-ated at a dose of 2 mg/kg has been shown to beas e�ective as higher dose therapy. For patientswho are unresponsive to treatment, the dosemay be increased, but many of these patientsstill do not respond. Failure of �rst-line corti-costeroid therapy indicates a bad prognosis.

Although many second-line alternativesare available to treat acute GVHD, none is anoptimal choice for GVHD unresponsive tocorticosteroid therapy or for use in combina-tion with corticosteroids to achieve betterearly control. Another randomized clinicaltrial is underway to test 4 drugs that could becombined with corticosteroids as the initialtherapy for newly diagnosed GVHD,mycophenolate, the tumor necrosis factor-inhibitor etanercept, denileukin di�tox, andpentostatin. A novel study design will evalu-ate the most promising combination to bringforward in a prospective phase III randomizedclinical trial comparing combination treat-ment to corticosteroids alone.

Organ toxicity is another major complica-tion of transplantation and is frequentlyrelated to pretransplantation conditioning

regimens. Throughout the posttransplantationperiod, 5% to 50% of allogeneic recipientsdevelop some form of lung toxicity such asidiopathic pneumonia syndrome. Currentstandard therapy with corticosteroids is sub-optimal, and mortality rates are high.

Etanercept may interfere with the pathogen-esis of idiopathic pneumonia syndrome, whichis believed to be largely in�ammatory, and mayimprove the response rates when combinedwith corticosteroids. A clinical trial is investigat-ing etanercept, with the primary endpoint beingresponse to treatment. Another novel feature ofthis study is that serum in bronchoalveolarlavage �uid will be obtained from all patientsand evaluated to investigate the biology of theidiopathic pneumonia syndrome.

Most randomized trials have focused on theearly posttransplantation period and have notaddressed care strategies for the large and grow-ing number of long-term survivors who faceclinically signi�cant complications such aschronic GVHD, late infections, organ toxicity,and secondary malignancies, along with dimin-ished quality of life and functional status. Long-term care recommendations still await goodclinical trials. Early mortality unfortunatelyreduces the number of patients at risk for latecomplications and therefore the number ofpatients who are eligible for clinical trials.Another di�culty is that whereas patients aregenerally “captive” while undergoing treatmentat a transplantation center, once they returnhome they are much less accessible for enroll-ment into clinical trials; some complications areharder to diagnose, and some patients may notreturn to the transplantation center. Thuspatient accrual for meaningful clinical trials tolook at late posttransplantation complicationsrequires better communication between trans-plant physicians and physicians who care forposttransplantation patients in the community.

Some clinical trials of patients in the lateposttransplantation period are underway. Aplanned clinical trial will compare sirolimus,rituximab, and pulse corticosteroids addedto the standard therapy with corticosteroidsin a calcineurin inhibitor for patients whohave chronic GVHD. Other clinical trialsinclude a multicenter prospective random-ized trial to investigate the promising agentmycophenolate mofetil. E�orts are alsofocused on collecting clinical trial data toguide supportive care recommendations inthe late posttransplantation period. Most tri-als focus on the early e�ects after transplan-tation, but many ongoing trials within the

BMT-CTN are collecting data on quality oflife for transplant recipients. These �ndingswill be used to plan future clinical trials tofurther our understanding of the quality oflife defects experienced by some transplan-tation patients. For some BMT-CTN studies,such as the voriconazole trial, long-termoutcomes may follow through the observa-tional database mechanisms of the Centerfor International Blood and MarrowTransplant Research, which can also providedata on the late e�ects of early trial inter-ventions.

Many BMT-CTN trials involve collection ofspecimens that will be examined for biologicdeterminants related to late adverse e�ects.For some common complications ofhematopoietic cell transplantation, such asdelayed immune reconstitution, all patientscould be eligible for clinical trials. For exam-ple, a trial to compare the most appropriatetime to initiate reimmunization, currently rec-ommended at 1 year by the United StatesCenters for Disease Control, may discovermarkers that would indicate whether or notpatients have adequate immune recovery by 1year and may bene�t from delayed reimmu-nization.

ConclusionsAlthough clinical trials in the hematopoi-

etic cell transplantation setting present manychallenges, previous randomized clinical trialshave provided a reasonable body of evidencethat stands behind our current supportivecare practices. The BMT-CTN, a new platformfor randomized trials in transplantationpatients, is conducting high-quality trials toinform the next generation of supportive careproviders. Clinical trials to guide preventionstrategies and treatment in the late posttrans-plantation period are still needed and willrequire broad support from both academicand community partners to accrue su�cientnumbers of patients and thus achieve ade-quate power to inform meaningful conclu-sions for optimal patient care.

References

1. Einsele H, Reusser P, Bornhauser M, et al. Oral val-ganciclovir leads to higher exposure to ganciclovir thanintravenous ganciclovir in patients following allogeneicstem cell transplantation. Blood.2006;107:3002-3008.2. Pavletic SZ, Carter SL, Kernan NA, et al. In�uenceof T-cell depletion on chronic graft-versus-host disease:results of a multicenter randomized trial in unrelated mar-row donor transplantation. Blood.2005;106:3308-3313.

Table 2. Common and Potentially Devastating ViralInfections with No Known Prophylaxis

AdenovirusHuman herpes virus 6Respiratory virusesPolyoma BK virusHuman neurotropic JC virusEpstein-Barr virus

15

REVIEWSBlood and MarrowTRANSPLANTATION

CME Assessment Test Answer SheetRelease Date: March 31, 2007 Last Review Date: March 31, 2007 Expiration Date: March 31, 2008

Instructions(1) Read the articles in the publication carefully. (2) Circle the correct response to each question on the Answer Sheet. (3) Complete theevaluation Form. (4) To receive CME credit, fax the completed Answer Sheet and Evaluation Form to the office of Continuing andProfessional Education (414-456-6623) or mail to the Office of Continuing Medical Education, Medical College of Wisconsin, 8701 WatertownPlank Road, Milwaukee, WI 53226. No processing fee is required.

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

REVIEWSBlood and MarrowTRANSPLANTATION REVIEWSBlood and MarrowTRANSPLANTATION

Posttransplantation Patient Care: Tailored Prevention and Management Strategies

CME Assessment Test 1. Which of the following is true regarding treatment planning for trans-

plantation patients?A. Because of donor shortages, the NMPD requests that donor searches not be

conducted unless transplantation is the only treatment option.B. Transplantation treatment is not an option for patients with secondary

MDS.C. The search for a suitable donor should begin at the time of diagnosis.D. None of the above.

2. Which of the following is true regarding the care of unrelated donortransplant recipients? A. Immune suppression regimens are the same as for related donor transplant

recipients.B. Finding an allele-level matched unrelated donor takes much longer than

finding an allele-level matched related donor.C. Early transplantation is an option for patients who do not have a sibling

donor but have a molecularly matched unrelated donor.D. None of the above.

3. Which if the following is true regarding umbilical cord blood transplan-tation (UCBT)? A. Adequate cell dose is important for successful outcome.B. Graft failure is rare in UCBT.C. GVHD rates are much lower with UCBT than with transplants from other

sources.D. None of the above.

4. Which of the following is true regarding cancer screening in long-termtransplantation survivors?A. Breast cancer rates in long-term survivors 10 years posttransplantation are

higher than those in the general population.B. In addition to screening for secondary cancers, patients should have the

same screening tests recommended for the general population.C. Nonmelanoma skin cancers are the most common secondary cancer post-

transplantation.D. All of the above.

5. In long-term posttransplantation survivors, death is most commonly dueto which of the following?A. Disease relapse.B. Cardiovascular disease.C. Complications of chronic graft-versus-host disease.D. Secondary cancer.

6. Which of the following concepts underlie optimal routine follow-up forposttransplantation patients?A. Prevention of complications that can be avoided in at-risk patients.B. Appropriate screening and intervention.C. Patient education.D. All of the above.

7. Which of the following characterize the relationship of the referringphysician and the transplantation patient?A. When the patient is undergoing the transplantation procedure, the refer-

ring physician no longer needs to provide information to concerned familymembers.

B. Patient relapse and other bad outcomes can be devastating to the referringphysician.

C. Referring practices rely on transplantation patients for much of their income.D. All of the above.

8. Which of the following is true regarding interaction between transplan-tation physicians and physicians who care for transplantation patients inthe community?A. The transplantation physician should keep the community physician aware

of adverse events that occur during transplantation.B. Requests by transplantation physicians for follow-up data can create diffi-

culties for referring practices.C. Long-term adverse outcomes of transplantation that are familiar to trans-

plantation physicians may be perplexing to the referring practice.D. All of the above.

9. Which of the following is true regarding clinical trials of hematopoietictransplantation patients?A. Few trials have included patients in the late posttransplantation period.B. Patient homogeneity makes patient accrual an easy task.C. Many referring physicians are actively involved in patient recruitment.D. None of the above.

10. Effective prophylaxis is available for which of these common and poten-tially devastating viral infections in posttransplantation patients?A. Human herpes virus 6.B. Adenovirus.C. Epstein-Barr virus.D. None of the above.

ASBMT

16

ASBMTAmerican Society for Bloodand Marrow Transplantation

TMNon-Profit Organization

U.S. PostagePAID

Charlottesville, VirginiaPermit No. 232

ASBMT

Would you benefit from additional CME programs on this topic? Yes No

I have read these articles on posttransplantation patient care,published in Blood and Marrow Transplantation Reviews, and haveanswered the CME test questions and completed the Evaluation Formfor this activity.

Signature Date

Last Name First Name MI Degree

Specialty Affiliation

Address

City State Postal Code

Phone Fax E-mail

Please evaluate the effectiveness of this CME activity on a scale of1 to 5, with 5 being the highest, by circling your choice. Fax withthe Answer Sheet to the Office of Continuing and ProfessionalEducation, 414-456-6623, or mail to the Office of ContinuingMedical Education, Medical College of Wisconsin, 8701 WatertownPlank Road, Milwaukee, WI 53226.

Overall Quality of the CME Activity 1 2 3 4 5

Articles in the publication were presented in a clear and effective manner. 1 2 3 4 5

The material presented was current and clinically relevant. 1 2 3 4 5

Educational objectives were achieved. 1 2 3 4 5

The CME activity provided a balanced, scientifically rigorous presentation of therapeutic options related to the topic, without commercial bias. 1 2 3 4 5

Please comment on the impact (if any) that this CME activity mighthave on your management of patients.

CME Evaluation Form