Table Of ContentRD
123. 5
A939
1995
Health
Technology
I
Assessment
Number
5
Autologous Peripheral
Stem-Cell Transplantation
U.S. Department of Health and Human Services
Public Health Service
Agency for Health Care Policy and Research
Rockville, Maryland
Department of Health and Human Services
Donna E. Shalala, Ph.D., Secretary
Public Health Service
Philip R. Lee, M.D., AssistantSecretary forHealth
Agencyfor Health Care Policy and Research
Clifton R. Gaus, Sc.D., Administrator
NATIONAL INSTITUTES OF H
NIH LIBRARY
Health
NOV 14 1996
Technology
BLDG 10, 10 CENTER DR.
BETHESDA, MD 20892-1150
Assessment
Number
5
Autologous Peripheral
6tem-Cell Transplantation
U.S. Department of Health and Human Services
Public Health Service
Agency for Health Care Policy and Research
Rockville, Maryland
August 1995
AHCPR Pub. No. 95-0074
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Abstract
Autologous peripheral stem-cell transplantation (APSCT)hasbeenextensively
appliedto support cancerpatients who have undergonehigh-dose chemotherapy
(HDCT) and sufferfromthe effects ofotherwiseprolonged orirreversible
myelosuppression. The APSCTprocess involves harvesting ofautologous
progenitorcells from apatient’s circulatingblood (vialeukapheresis),
cryopreservation ofthe cells, andsubsequent intravenous infusion forbone
marrow hematopoietic reconstitution (HR). Althoughpluripotent stemcells,
capable ofmultilineage differentiation, cannotbe distinguishedbymorphologic
criteria, they canbe characterizedas being CD34+ cells capable ofindefinite self-
renewal in situ andlong-term self-renewal in cell cultures. Bone marrow and
peripheral bloodare common sources ofautologousprogenitorcells. Current
techniques to identify andseparate CD34+cells foruse in APSCThave resulted
in fewertumorcells being infusedthan ifunseparatedperipheral stemcells (PSC)
weretransplanted, with no differences notedinHR. Chemotherapy- and
cytokine-inducedmobilization results in increases inprogenitorcells,
necessitating fewerphereses to harvest sufficientnumbers ofprogenitorcells for
engraftment. This assessmentaddresses the safety, efficacy, and cost-
effectiveness ofthe use ofPSC forHRand improvingpatient outcome, as well as
the indications and criteria forpatient selection forthe use ofAPSCT. Available
information from studypanels, research centers, institutions, andgovernment
agencies is reviewed; randomized clinical tests (orlackthereof) are discussed; and
comparisons are madebetween APSCT and autologous bonemarrow
transplantation (ABMT), an acceptedtherapy intreatmentofsome malignancies
(e.g., leukemia andlymphoma). The author concludes that existing evidence
indicates that PSC canprovide satisfactory HR, andthe rate ofHR via PSC does
not seem consistently different from that ofABMT. The clinical importance of
HR
continues tobe secondaryto the primary issue ofthepatientbenefits of
HDCT
in terms ofantitumorresponse, palliation, or survival.
u
Foreword
The Office ofHealthTechnology Assessment (OHTA) evaluates the risks, benefits,
and clinical effectiveness ofnew orunestablished medical technologies. In most
instances, assessments address technologies that are being reviewed forpurposes of
coverage by federally fundedhealthprograms.
OHTA’s assessmentprocess includes a comprehensive review ofthe medical
literature and emphasizes broad and openparticipation from within and outside the
Federal Government. A range ofexpert advice is obtainedby widelypublicizing the
plans forconducting the assessmentthroughpublication ofan announcement in the
FederalRegisterand solicitation ofinput from Federal agencies, medical specialty
societies, insurers, and manufacturers. The involvement ofthese experts helps ensure
inclusion ofthe experienced and varying viewpoints needed to round out the data
derived from individual scientific studies inthe medical literature.
OHTA analyzed and synthesized data and information received from experts and the
scientific literature. The results are reported inthis assessment. Each assessment
represents a detailed analysis ofthe risks, clinical effectiveness, and uses ofnew or
unestablished medical technologies. Ifan assessment has been prepared to form the
basis fora coverage decisionby a federally financed health care program, it serves as
the Public Health Service’s recommendation to that program and is disseminated
widely.
OHTA is one component ofthe Agency forHealth Care Policy and Research
(AHCPR), Public Health Service, Department ofHealth and Human Services.
Thomas V Holohan, M.D., FACP Clifton R. Gaus, Sc.D.
Director Administrator
Office ofHealthTechnology Assessment Agency for Health Care Policy
and Research
Questions regarding this assessment shouldbe directed to:
Office ofHealth Technology Assessment
AHCPR
Willco Building, Suite 309
6000 Executive Boulevard
MD
Rockville, 20852
Telephone: (301) 594-4023
iii
Contents
Background 2
Rationale 3
Review of Available Information 3
Discussion 5
Institutional Comments 8
Public Health Service Comments 9
Summary and Conclusions 9
References 9
V
I )
Autologous Peripheral Stem-Cell Transplantation
Prepared by: Harry Handelsman, D.O.
Autologous peripheral stem-cell transplantation leukaphereses (during a 1- to 2-week period) either in
(APSCT) is aprocess in which autologous progenitor an unperturbed (steady) state, during the transient
cells are harvested from a patient’s circulating blood phase ofblood count overshoot occurring during
via leukapheresis techniques and commonly recovery from chemotherapy- or radiotherapy-induced
cryopreserved (with orwithout enrichment) for myelosuppression, and/or enhanced by mobilization
subsequent intravenous infusion to effect using cytokines (commonly the recombinant growth
hematopoietic reconstitution (HR) ofthe bone marrow factors granulocyte-colony stimulating factor (G-CSF
(BM) after severe cytopenia associatedwithhigh-dose orgranulocyte-macrophage-colony stimulating factor
chemotherapy (HDCT) and/orradiotherapyregimens (GM-CSF).14-27-30-35 This mobilization results in a
used to treat various malignancies.1-2 Pluripotent stem substantial (albeit transient) rise in the number of
cells (capable ofmultilineage-differentiation) cannot be circulating progenitor cells; however, the mechanism(s)
distinguishedby morphologic criteria. However, they by which this is accomplished remains poorly
can be characterized as being CD34+ cells possessing understood.36-39 The use ofcytokine mobilization may
indefinite self-renewal capacity in situ and long-term be problematic because ofthe possibility ofstimulating
self-renewal capacity demonstrated in cell cultures.3-7 the proliferation ofresidual malignant cells, forcing
Although the literature commonly treats stem cells as such cells from marrow into the peripheral circulation
being synonymous with progenitor cells, pluripotent (comobilization), and inducing differentiation of
stem cells are in fact the primitive precursors ofmore pluripotent stem cells to more committed progenitor
committedprogenitorcells, which in turn are cells.40
precursors ofall the mature blood cell lineages.79 In a recent report, current techniques to identify and
Bone marrow transplantation (BMT) associatedwith separate CD34+ cells for use in APSCT resulted in
HDCT, which has achieved the status ofan accepted fewertumor cells being infused than ifunseparated
therapy in the treatment ofsome malignancies, e.g., peripheral stem cells (PSC) were transplanted, with in-
leukemia and lymphoma, is also beingproposed as a differences noted in the resultant HR.41
treatment ofchoice for some selected subsets of Although optimal methods and appropriate timing m
patients with othertumors, e.g., breast cancer and harvesting remain uncertain (as do the quantity and
multiple myeloma.1-10 Stem cells are administered as quality ofthe cells), PSC are commonly collected
supportive care to circumvent the morbidity and during outpatient leukapheresis using a continuous
mortality associated withhigh-dose treatment regimens flow blood cell separator.42 44 Approximately 9-14 1 oi
which are used in attempts to effect a cure orprolonged blood are processed over a 2- to 4-hour period. he
I
survival inpatients at high risk fortreatment failure or majority ofthe blood cells and plasma are returned u
recurrent cancerusing conventional therapy.11-13 Both the patient, and a final volume ofapproximately .'m
i
BM and peripheral blood are currently common mL is collected and cryopreserved (although
BM
sources ofautologous progenitorcells, and to date, occasionally stored unfrozen for short-term use)
has been the primary source.1415 In the future, cultured The relatively few progenitors seen in peripheral
stem cells derived from fetal liver or obtained from blood require an average of6-10 phercses i»\cr
: :
umbilical cordblood may provide a reliable source of of5-7 days to obtain sufficient numbers of\ell ' :
stem cells as an alternative to autologous cells for engraftment.46-47 Chemotherapy-induced m--hi
transplants.16-23 results in a 10- to 20-fold increase in the numb '
BM
Hematopoietic stem cells usually reside within progenitors, and another 10- to 100-fold in< ;
sinusoids.24 However, smallernumbers (1/10-1/100 of be seen after the administration ofcytokine
thatpresent in BM) normally circulate in the peripheral These increases ofprogenitor cells im b- tl pa
blood.25-30 These canbe harvestedby multiple and number) in the peripheral blood wrvcm i.-d
1
numberofphereses required to obtain adequate surrounding the dose-response curve have been
” ”
numbers ofcells for successful engraftment to 1- regarded as “promising 72-73 and “suggestive 66 but
5 38.4 ,46,48 However, such yields are not obtainable in continue to be debated and are not yet proven as
heavily pretreatedpatients.3544'49-52 Peripheral stem conclusive, especially with respect to long-term
cells have been commonly measured as colony- benefit.12-38-54-63-65-72-80 It has been suggested that
forming-unit granulocyte-macrophage progenitorcells improved durability ofresponses and survival
(CFU-GM), or CD34+ cells 53 55 Although the advantage both appearto be mostly dependent on such
.
definition ofan adequate harvest is uncertain, at least prognostic factors as tumor stage andpatients’
one million purifiedprogenitorcells, 20 x 104 CFU- performance statusbefore therapy8184
.
GM, or2 x 107 CD34+ cells/kgbody weight or A recent metaanalysis of60published studies of
approximately 3-6 x 109 mononuclear cells/kg body dose-intensive regimens used intreating small-cell lung
weight are thought to be potentially adequate for cancer failedto demonstrate apositive correlation
successful transplants in adults28-41-56'57'58 and 3 x 105 between dose intensity and outcome.85 Excepting some
cells/kg in children.27-36-49 A recent report indicated lymphomas and leukemias in which randomized trials
effective HRusing unprocessed whole blood after have beenperformed, RCTs will continue to be
progenitor cell mobilization using cytokines alone 59 requiredto determine the extent to which dose intensity
.
The primary issues addressed inthis assessment determines outcome.78-86-89
BM
(prepared forthe Office ofCivilian Health and Medical The use of rescue aftermyelotoxic therapy does
Program ofthe Uniformed Services) are the safety and not solve theproblems ofnonhematologic toxicity,
effectiveness ofPSC forpromoting HR and improving which continue to be a dose-limiting barrierto full
patient outcome and the indications andpatient exploitation ofhigh-dose escalation regimens applied
selection criteria for the use ofAPSCT. to patients with advancedorrefractory
malignancies.19°-92
Background
High-dose chemotherapy usually compromises most
The use ofautologous bone marrow transplantation ofthe stem cells capable ofproviding HR, which has
(ABMT) has been extensively applied as a technique to been defined as recovery ofneutrophils to greaterthan
support patients after HDCT that would otherwise be 500/pL, platelets greaterthan 20,000/pL, and
associated with unacceptable morbidity andmortality hematocrit greaterthan 25 percent.43 Questions
related to infection and bleeding as a consequence of concerning the necessity ofstem-cell rescue for
prolonged or irreversible myelosuppression.46-60 This achieving permanent hematopoietic recovery have not
has occurred without convincing evidence derived from been completely resolved andwill require prospective
randomized clinical trials (RCTs).61 The benefits of RCTs.81-85 Recent reports have documented the
HDCT
such support therapies include reduced severity and feasibility ofsubablative regimens with
duration ofblood count nadirs, fewer infection and intensive supportive care (including the use of
bleeding episodes, reduced requirements forred cell or cytokines) without the need ofstem-cell transplants
platelet transfusions, fewertreatment delays, and and achievedresults comparable to outcomes seen with
shorter hospitalizations.u-62-63 However, despite such autologous stem-cell transplants.80-93 97 Cytokines
support (commonly requiring several weeks of alone have been shown to accelerate neutrophil
hospitalization), treatment-related mortality is in the recovery, but those in current clinical use do not affect
range of5 percent to 25 percent, with the lowerrates platelet recovery.98 The nature ofthe stem cells
reported in more recent trials.39-46-6469 providing long-term hematopoiesis has not been
The initial rationale for HDCT is basedprimarily on established, and the specific circulating pluripotent
preclinical chemotherapy trials demonstrating a steep stem cell has not been identified and may exist only in
dose-response curve (correlation between the early stages ofembryogenesis (although other
chemotherapy dosage and tumorresponse) and the progenitorcells appearto be able to differentiate into
hypothesis that dose-intensive therapy is associated the various blood cell lineages).1-9-44-99 It is possible
with increased tumor responses and survival rates.70-71 that some autochthonous progenitorcells are resistant
Data from some clinical trials and retrospective clinical to the effects ofchemotherapy orradiotherapy and are
reviews attempting to confirm the hypothesis the ultimate source ofmarrow recovery and long-term
2
