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RD 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 vMrinniiHrviil|WBM» hM Rp I /2SS Apt \4 ufa; 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