amyloid mayo paper_ contributed by dr_marwan_alakasheh_medicsindex member

8/14/2019 Amyloid Mayo Paper_ Contributed by Dr_marwan_alakasheh_Medicsindex Member

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Mayo Clin Proc. July 2006;81(7):880-888 www.mayoclinicproceedings.com880

HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSISORIGINAL ARTICLE

From the St. Vincents Comprehensive Cancer Center, New York, NY (D.H.V.);Center for International Blood and Marrow Transplant Research, MedicalCollege of Wisconsin, Milwaukee (W.S.P.); King Hussein Medical Center,Amman, Jordan (M.A.); Department of Statistics and Actuarial Science, Uni-versity of Waterloo, Waterloo, Ontario (C.B.); Princess Margaret Hospital,Toronto, Ontario (D.E.R.); Manitoba Blood and Marrow Transplant Program

and CancerCare, Manitoba, Winnipeg (C.N.B.). Other members of the PlasmaCell Disorders Working Committee of the Center for International Blood andMarrow Transplant Research are listed at the end of the article.

This study was supported by Public Health Service grant U24-CA76518 fromthe National Cancer Institute, National Institute of Allergy and InfectiousDiseases, and National Heart, Lung, and Blood Institute; Office of NavalResearch; Health Resources Services Administration; and American Associa-tion of Blood Banks, Aetna; AIG Medical Excess; American Red Cross; AmgenInc; anonymous donation to the Medical College of Wisconsin; AnorMED Inc;Berlex Laboratories Inc; Biogen IDEC Inc; Blue Cross and Blue Shield Associa-tion; BRT Laboratories Inc; Celgene Corp; Cell Therapeutics Inc; CelMedBiosciences; Cubist Pharmaceuticals; Dynal Biotech LLC; Edwards Life-sciences RMI; Endo Pharmaceuticals Inc; Enzon Pharmaceuticals Inc; ESPPharma; Fujisawa Healthcare Inc; Gambro BCT Inc; Genzyme Corporation;GlaxoSmithKline Inc; Histogenetics Inc; Human Genome Sciences; ILEX On-cology Inc; Kirin Brewery Company; Ligand Pharmaceuticals Inc; Merck &Company; Millennium Pharmaceuticals; Miller Pharmacal Group; MillimanUSA Inc; Miltenyi Biotec; National Center for Biotechnology Information;National Leukemia Research Association; National Marrow Donor Program;

NeoRx Corporation; Novartis Pharmaceuticals Inc; Novo Nordisk Pharmaceuti-cals; Ortho Biotech Inc; Osiris Therapeutics Inc; Pall Medical; Pfizer Inc;Pharmion Corp; QOL Medical; Roche Laboratories; StemCyte Inc; StemcoBiomedical; StemSoft Software Inc; SuperGen Inc; Sysmex; The MarrowFoundation; THERAKOS, a Johnson & Johnson Co; University of Colorado CordBlood Bank; Valeant Pharmaceuticals; ViaCell Inc; ViraCor Laboratories; WBSaunders Mosby Churchill; and Wellpoint Health Network.

Individual reprints of this article are not available. Address correspondence toChristopher N. Bredeson, MD, MSc, CancerCare Manitoba, 675 McDermotAve, Winnipeg, Manitoba, R3M 3H8, Canada (e-mail: [email protected]).

2006 Mayo Foundation for Medical Education and Research

For editorialcomment,see page 874

High-Dose Therapy and Autologous Hematopoietic Stem Cell

Transplantation for Patients With Primary Systemic Amyloidosis:

A Center for International Blood and Marrow Transplant Research Study

DAVID H. VESOLE, MD, PHD; WALESKA S. PREZ, MPH; MARWAN AKASHEH, MD; CHRISTIAN BOUDREAU, PHD;DONNA E. REECE, MD; AND CHRISTOPHER N. BREDESON, MD, MSC, FORTHE PLASMA CELL DISORDERSWORKING COMMITTEEOFTHE CENTERFOR INTERNATIONAL BLOODAND MARROW TRANSPLANT RESEARCH

OBJECTIVE: To determine the outcome of high-dose therapy withautologous hematopoietic stem cell transplantation (HSCT) in pa-tients with primary systemic amyloidosis reported to the Center forInternational Blood and Marrow Transplant Research (CIBMTR).

PATIENTS AND METHODS: A total of 107 recipients of autologousHSCT for amyloidosis from 48 transplantation centers were re-ported to the CIBMTR between 1995 and 2001. Hematologic andorgan responses were assessed at 100 days and 1 year. Trans-plantation-related mortality (TRM) was assessed at day 30 afterHSCT. A multivariate analysis assessed factors that influencedoverall survival.

RESULTS: Improvement at day 100 was seen in 1 or more amyloid-osis-affected sites (bone marrow, kidney, l iver, and/ or heart) in28 (36%) of 77 pat ients; the 1-year responses included completeresponse (16%), part ial response (16%), stable disease (31%),and disease progression (10%). With a median follow-up of 30months, the 1- and 3-year survival rates were 66% (95% confi-dence int erval [CI] , 56%-75%) and 56% (95% CI, 45%-66%), re-spectively. The day 30 TRM was 18% (95% CI, 11%-26%). In themultivariate analysis, only the year of transplantation (patientswho most recently underwent transplantation) was associatedwith post-HSCT survival (P=.02).

CONCLUSION: In this multi-institutional CIBMTR study, the 3-yearsurvival rate was comparable to single-center results, wit h patientswho more recently underwent transplantat ion faring better. Of note,the TRM was higher than that reported by single centers, whichmay reflect dif ferences in patient select ion and/ or experience intreating this challenging disease. We hope that a better under-standing of the recently recognized prognostic factors and morestringent patient selection will result in lower TRM and improvedsurvival.

Mayo Clin Proc. 2006;81(7) :880-888

CI = confidence interval; CIBMTR = Center for International Blood andMarrow Transplant Research; HSCT = hematopoietic stem cell trans-plantat ion; KPS = Karnofsky performance score; TRM = t ransplantat ion-related mortality

Primary systemic amyloidosis is an uncommon plasma

cell dyscrasia, with approximately 2500 cases diag-nosed yearly in North America. In this disease, monoclonalimmunoglobulin light chains are produced by malignantplasma cells, resulting in amyloid fibril deposition in vitalorgans, leading to progressive, fatal multisystem failure.The median survival for treated patients is approximately18 months compared with 12 months for untreated patients;the median survival for patients with symptomatic cardiacinvolvement is only 6 months.1,2

Conventional therapy for primary systemic amyloidosishas historically been with melphalan and prednisone.3 Re-sponse rates are observed in 20% to35% of patients, which results in amodest increase in survival. More re-cently, dexamethasone, dexamethasonecombined with interferon, thalidomide-

or anthracycline-based regimens, and other novel therapieshave been studied with comparable response rates.4-9

With the favorable outcomes observed with high-dosechemotherapy and autologous hematopoietic stem celltransplantation (HSCT) in multiple myeloma, pilot trials totest this approach in primary systemic amyloidosis werepursued.10-15 These pilot trials, which predominantly used

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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Mayo Clin Proc. July 2006;81(7):880-888 www.mayoclinicproceedings.com 881

HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS

high-dose melphalan, again based on the experience inmultiple myeloma, showed encouraging results: the hema-tologic response rate was approximately 60%; organ re-sponse rates were also observed but at a lower rate. Unfor-tunately, these early pilot trials were associated with a high

transplantation-related mortality (TRM) of 15% to 25%. Inpatients with AL cardiomyopathy, mortality approached65%.10,12 More recently, clinical trials conducted with morestringent patient selection criteria have reported a lowerTRM of 10% to 15%.16-23

Since primary systemic amyloidosis is a rare entity,only a few academic programs have a specific focus onthe treatment of this disease. In the United States, theprimary research centers are the Mayo Clinic in Roches-ter, Minn, and Boston University in Boston, Mass. Mostpatients with primary systemic amyloidosis, however, aretreated outside these 2 centers. Although the outcomes ofHSCT in primary systemic amyloidosis at the MayoClinic and Boston University are impressive, it is impor-tant to determine whether comparable outcomes can bereproduced in the general academic community. To thisend, in 2001, the Center for International Blood and Mar-row Transplant Research (CIBMTR) initiated a study ofautologous HSCT outcomes in patients with primary sys-temic amyloidosis.

PATIENTS AND METHODS

DATA SOURCESThe CIBMTR is a research affiliation of the International

Bone Marrow Transplant Registry, the Autologous Bloodand Marrow Transplant Registry, and the National MarrowDonor Program that comprises a voluntary working groupof more than 450 transplantation centers worldwide thatcontribute detailed data on consecutive allogeneic and au-tologous HSCTs to a Statistical Center at the Health PolicyInstitute of the Medical College of Wisconsin in Milwau-kee or the National Marrow Donor Program CoordinatingCenter in Minneapolis, Minn. Participating centers are re-quired to report all transplantations consecutively; compli-ance is monitored by on-site audits. Patients are followedup longitudinally, with yearly follow-up. Computerizedchecks for errors, physicians review of submitted data, and

on-site audits of participating centers ensure data quality.Observational studies conducted by the CIBMTR are per-formed with a waiver of informed consent and in compli-ance with Health Insurance Portability and AccountabilityAct regulations as determined by the institutional reviewboard and the privacy officer of the Medical College ofWisconsin.

The CIBMTR collects data at 2 levels: registration andresearch. Registration data include disease type, age, sex,

pretransplantation disease stage and chemotherapy respon-siveness, date of diagnosis, graft type (bone marrow and/or blood-derived stem cells), high-dose conditioning regi-men, posttransplantation disease progression and sur-vival, development of a new malignancy, and cause of

death. Requests for data on progression or death for regis-tered patients are made at 6-month intervals. All CIBMTRteams contribute registration data. Research data are col-lected on a subset of registered patients selected by using aweighted randomization scheme and include detailed dis-ease and pretransplantation and posttransplantation clin-ical information.

PATIENTSThree hundred four patients were registered as having un-dergone autologous HSCT for primary systemic amyloid-osis between 1995 and 2001. Of these 304 patients, com-prehensive patient, disease, and transplant characteristicswere available for 107 patients (35%). All patients in-cluded in the study were determined to have amyloidosisbased on tissue biopsy findings. The definitions of organinvolvement are as follows: renal, positive biopsy result ortotal urinary protein excretion greater than 3.5 g/24 h;hepatic, positive liver biopsy result or hepatomegaly (liver>12 cm); and cardiac, positive cardiac biopsy result, inter-ventricular septal wall thickness greater than 15 mm, leftventricular ejection fraction of 40% or less, or New YorkHeart Association cardiac dysfunction class II to IV. Thenumber of transplantations per center were as follows:25 centers performed 1 transplantation only, 8 centers

performed 2 transplantations, 7 centers performed 3 trans-plantations, 2 centers performed 5 transplantations, and 1center performed 15 transplantations. No patients fromBoston University or the Mayo Clinic were included inthis study. Patient, disease, and transplant characteristicsand overall survival of those with or without comprehen-sive data were similar. Eligible cases came from 48 re-porting centers. Median follow-up of survivors was 30months (range, 3-82 months).

END POINTSAt the time of this analysis, there were no universallyaccepted response criteria for amyloidosis. The response

criteria for this study were defined as follows. A partialhematologic response was defined as a more than 50%decrease in urine and/or serum paraprotein levels, and acomplete hematologic remission was defined as a negativeurine and/or serum protein electrophoresis result. An organresponse was defined as either improvement or lack ofimprovement in 3 organ systems: renal, hepatic, and car-diac. The determination of improvement was determinedby the reporting center and not based on specified objective



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criteria. Recently, a uniform system was proposed at the10th International Amyloidosis Symposium in April 2004.These criteria were subsequently presented at the Decem-ber 2004 American Society of Hematology meeting.24 Be-cause of limitations inherent in the collection of registry

data, it is not possible to retrospectively apply these criteriato the existing data set. Transplantation-related mortalitywas defined as all causes of death within 30 days aftertransplantation.

STATISTICAL ANALYSESEstimates of overall survival were calculated using theKaplan-Meier estimator, with SE estimated by the Green-wood formula. Ninety-five percent confidence intervals(CIs) were calculated using log-transformed intervals. Po-tential prognostic factors for survival were evaluated in amultivariate analysis using Cox proportional hazards re-gression.25 The variables considered in the multivariateanalysis were age at transplantation, sex, Karnofsky perfor-mance status (KPS) before transplantation (80% vs>80%), prior chemotherapy (no treatment vs melphalanwith or without other therapy vs other chemotherapy vsother single agent), lines of therapy (1 vs >1), organinvolvement at anytime before transplantation (1 vs >1organ), cardiac involvement at anytime before transplanta-tion (no vs yes), time from diagnosis to transplantation,conditioning regimen (melphalan alone vs others), and yearof transplantation (1995-1997 vs 1998-1999 vs 2000-2001). All computations were made using the procedurePHREG in the statistical package SAS, version 8 (SAS

Institute Inc, Cary, NC). Forward stepwise variable selec-tion at a .10 significance level was used to identifycovariates associated with the main outcome. In the model,the assumption of proportional hazards was tested for eachvariable using a time-dependent covariate and graphicmethods. All variables considered in the multivariateanalysis satisfied the proportionality assumption. The finalmultivariate model was built using a forward stepwisemodel selection approach. Factors significant at a P=.05level were kept in the final model. Examination for centereffects used a random effects or frailty model.26 We foundno evidence of correlation between center and any of theoutcomes. All P values are 2-sided.

RESULTS

PATIENT CHARACTERISTICSThe median patient age was 55 years (range, 31-71 years),with a male-female ratio of 60:40. All patients had a bi-opsy-confirmed diagnosis of primary systemic amyloid-osis. The paraprotein isotypes were IgG (36 [35%] of 102patients), IgA (10 [10%] of 102 patients), light chain only

(45 [44%] of 102 patients), other (2 [2%] of 102 patients),and none (9 [9%] of 102 patients). A pretransplantationKPS less than 80 was reported in 23 (23%) of 101 patients;42 (42%) of 101 patients had a KPS equal to 80, and 36(36%) had a KPS of 90 or 100 (Table 1).

ORGAN INVOLVEMENTThe kidney was the most commonly reported involvedorgan, with urinary protein levels that exceeded 200 mg/24 hobserved in 57 (93%) of 61 evaluated patients. Forty-four(72%) of 61 evaluated patients had nephrotic syndromerange proteinuria (protein >3 g/24h) and 37 (41%) of 90had hypoalbuminemia. Approximately one third had anelevated serum creatinine level; 31 (29%) of 106 had creat-inine levels greater than 2 mg/dL. Although not part of ourdefinition of hepatic involvement, approximately one third(35/99) had elevated serum alkaline phosphatase levelsgreater than 1.5 times the institutional upper limit of nor-mal, a marker that has been reported as consistent withhepatic involvement. Peripheral neuropathy was reportedin one fourth of the patients. Cardiac involvement wasdocumented by biopsy in 28 (26%) of 106 patients; subjec-tive symptoms were reported in 34 (45%) of 76 patients(New York Heart Association class II).

Most patients had only single organ involvement,whereas 35 (33%) of 107 had 2 or more organs involved;however, 16 (15%) of 107 did not have organ (heart, kid-ney, liver) involvement as per the definition given in thePatients and Methods section. Some of these patients hadevidence suggestive of early involvement, such as a urinary

protein level less than 3.5 g/24 h or an alkaline phosphataselevel more than 1.5 times normal but no hepatomegaly andno liver biopsy.

PRIOR THERAPYApproximately one third of patients had received notherapy before HSCT. Of those patients who received priortherapies, melphalan-based regimens were the most com-monly used. Three fourths of the patients were minimallytreated: 37 (35%) of 105 with no prior therapy and 42(40%) of 105 with one prior treatment regimen. One fourthof the patients had 2 or more lines of prior therapy. Themedian time from diagnosis to transplantation was 6

months (range, 1-178 months), and the time from firsttreatment to transplantation was within 6 months in 76(75%) of 102 patients. Seventeen (17%) of 102 patients had6 to 12 months of prior therapy, and only 9 (9%) of 102 hadmore than 1 year of prior treatment.

PREPARATIVE REGIMENSAs has been observed in other primary systemic amyloid-osis transplantation studies, most transplantation centers



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used single-agent melphalan as the preparative regimen: 89(83%) of 107 patients received melphalan alone, 8 (7%) of107 patients received total-body irradiationcontainingregimens, and 10 (9%) of 107 patients received other regi-

mens. Most patients (70 [85%] of 82) received melphalan(130 mg/m2). Six patients were enrolled in tandem autolo-gous transplantation protocols; 3 additional patients under-went tandem transplantations.

RESPONSEResponses at day 100 were seen in at least one organsystem (hematologic, renal, hepatic, and/or cardiac) in 28(36%) of the 77 patients with organ-specific data available.

Since response to therapy in patients with primary systemicamyloidosis may occur during a prolonged period, some-times exceeding a year, response was evaluated 1 year afterHSCT.15 With regard to hematologic response, 34 (32%) of

107 patients had an objective response to transplantationequally divided between complete response (17 [16%]) andpartial response (17 [16%]); 33 (31%) had stable disease,and 11 (10%) had progressive disease. The TRM was 27%(29/107 patients). Five of the 6 patients who had enrolled ina tandem transplantation protocol completed both trans-plantations. Three additional patients subsequently under-went tandem transplantations. The 1-year responses forthese 9 patients were as follows: 3 with partial responses, 3

No. (%) ofCharacteristics evaluable patients*

Total No. of centers 48Total No. of patients 107

Median age of patients (y) (range) 55 (31-71)Male 64 (60)Pretransplantation Karnofsky score (n=101)

80 36 (36)

Median serum monoclonal immunoglobulin,g/dL (range) (n=31) 0.3 (0-6)

Cardiac ejection fraction 40% (n=81) 3 (4)Interventricular septal thickness >15 mm

(n=40) 6 (15)New York Heart Association class

(n=76)I 42 (55)II 25 (33)III 8 (11)IV 1 (1)

Protein excretion >200 mg/24h (n=61) 57 (93)Alkaline phosphatase greater than the upper

limit of normal (n=99) 47 (47)Creatinine >2 mg/dL (n=106) 31 (29)Albumin


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with stable disease, 1 with progressive disease, and 2deaths from transplantation-related causes. Renal, hepatic,or cardiac responses were also reported at 1 year aftertransplantation. For renal involvement, of 32 evaluatedpatients, 15, 11, and 6 were reported to have improved,stable disease, or progressed, respectively. For hepatic in-volvement, of 19 evaluated patients, 11, 4, and 4 werereported to have improved, stable disease, or progressed,respectively. Cardiac involvement was reported as im-proved, stable, or progressed in 7, 4, and 4 of 15 assessedpatients, respectively.

OVERALL SURVIVALOverall survival after transplantation is shown in Figure 1.The 1-year survival rate was 66% (95% CI, 56%-75%) andthe 3-year survival rate was 56% (95% CI, 45%-66%) forthe 107 patients. One-year survival rates in patients basedon pretransplantation organ involvement (cardiac, renal,hepatic) were 72% (95% CI, 61%-82%) if 0 or 1 organ wasinvolved and 54% (95% CI, 38%-70%) if 2 or more organswere involved (Table 2; P=.11). The median overall sur-vival for all patients was 47.2 months. Survival was similarwhether there was reported cardiac involvement or not(56% [95% CI, 37%-74%] vs 69% [95% CI, 58%-79%];P=.50). We compared overall survival in patients who

underwent transplantation in 2000-2001 with overall sur-vival in patients who underwent transplantation in 1995-1999. Both 1-year (77% vs 58%) and 3-year (74% vs 48%)survival rates were superior in the patients who more re-cently underwent transplantation (P=.04) (Figure 2). Patient,disease, and treatment characteristics of the patients in the 2groups based on year of transplantation were similar. Im-provement of transplantation results over time was con-firmed in the multivariate analysis of prognostic factors.

CAUSESOF DEATHNineteen patients (18%; 95% CI, 11%-26%) died of infec-tion or organ failure within 30 days of transplantation. Car-diac failure was the most commonly reported organ-specificcause of death, occurring in 7 (37%) of 19 patients: 3 deathsoccurred in patients with known cardiac involvement beforetransplantation, and 4 deaths occurred in patients withoutknown cardiac involvement before transplantation. An addi-tional 26 patients died beyond 30 days after transplantationdue to disease progression (n=18) or other causes (n=8). Ofthese, 3 deaths from transplantation-related toxic effects(acute respiratory distress syndrome, interstitial pneumoni-

tis, and infection) occurred between day 30 and day 100 aftertransplantation.

FIGURE 1. Probability of survival after autotransplantations for amyloidosis.

TABLE 2. Univariate Analysis of Transplantation OutcomesAmong Patients Receiving Autotransplants for Amyloidosis by

Organ Involvement at Anytime Before Transplantation*

At 1 y At 3 y P value

Overall 66 (56-75) 56 (45-66)Organ involvement anytime

before treatment .111 organ (n=72) 72 (61-82) 60 (47-73)>1 organ (n=35) 54 (38-70) 46 (29-64)

Cardiac involvementanytime before treatment .50

No (n=78) 69 (58-79) 56 (43-69)Yes (n=28) 56 (37-74) 51 (32-70)

Liver involvement anytimebefore treatment .07

No (n=75) 71 (60-81) 62 (50-74)Yes (n=29) 59 (41-76) 46 (27-65)

Renal involvement anytimebefore treatment .32

No (n=20) 64 (42-84) 36 (14-62)Yes (n=77) 63 (52-74) 59 (48-70)

*CI = confidence interval.

Overall survival (95% CI)

Time (y)

95% Pointwise confidence inter val

95% Pointwise confidence inter val

Survivalprobability(%)

100

80

60

40

20

0

0

1 2 3 4



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eligibility criteria and treatment regimens from the varioustransplantation centers that may allow for higher-risk pa-tients. Alternatively, the higher mortality may be a factor ofinexperience in caring for these patients who often havemultisystem compromise in contrast to patients with mul-tiple myeloma, although no center-specific effect wasidentified in multivariate analysis. Even at transplantationcenters experienced in the care of patients with primarysystemic amyloidosis, the TRM for such patients undergo-ing HSCT approaches 10% to 15% compared with 1% to2% for those with multiple myeloma. However, in multi-variate analysis, patients who have more recently under-gone transplantation had a superior outcome. This findingmay reflect improved patient selection and/or increased

experience in caring for patients with primary systemicamyloidosis along with improvements in supportive careduring the past 10 years.

In contrast to most other reports, neither cardiac in-volvement nor multiple organ involvement was predictiveof overall survival in the current study. This may be afeature of the sample size in this study. However, of note,the Mayo Clinic experience did not observe a relationshipbetween cardiac involvement by conventional assessmentand overall survival.15 This finding may also reflect thenature of studies conducted using an observational data-base that reports activities of member centers withoutdictating practices. Specifically, not all patients were sys-

tematically evaluated in the same manner for organ in-volvement before or after transplantation, and some pa-tients may potentially have had organ involvement that wasnot characterized by the transplantation program.

To improve transplantation outcomes in primary sys-temic amyloidosis, it is necessary to address disease-relatedand treatment-related factors. Regarding disease-related fac-tors, we now have a better understanding of primary sys-temic amyloidosisassociated prognostic factors: probrain

natriuretic peptide, cardiac troponin,2-microglobulin, and

the number of organs involved.21-23,33 This informationshould be incorporated into the development of treatmentstrategies with more stringent patient selection criteriaand risk-directed therapy.16,18,22 Ultimately, this shouldresult in lower TRM and improved survival. Future stud-ies should incorporate these biologic prognostic factorsand evaluate their value in HSCT. To maximize theknowledge gained from performing transplantations inpatients with primary systemic amyloidosis and to usethat information to design future prospective trials or tomake treatment decisions for patients not eligible for clin-ical trials, centers must commit to systematically evaluat-ing patients with primary systemic amyloidosis before and

after transplantation for potential prognostic factors andorgan involvement in such a way that the data can bepooled for analysis between centers. Ideally, centersshould share their experience by reporting their data tonational and multinational cooperative transplantation reg-istries, such as the European Group for Blood and MarrowTransplantationand the CIBMTR because they provide adifferent perspective from that of the disease-focused ex-pert center.

Transplantation outcomes should improve with betterpatient selection based on prognostic factors and poten-tially the use of comorbidity scores, as has been introducedin allogeneic transplantation studies.34 Morbidity and mor-

tality may also be improved through the use of a moretolerable transplantation regimen, such as a lower dose ofmelphalan. Unfortunately, lowering the dose of melphalanto reduce toxic effects has resulted in less pronouncedresponse rates in some studies22 but marginally so in otherstudies.16 Another approach would be to administermelphalan in combination with a cytoprotectant agent suchas amifostine or keratinocyte growth factor (palifermin). Inmyeloma, it has been demonstrated that amifostine as a

TABLE 3. Review of Reported Hematopoietic Stem Cell Transplantationfor Primary Systemic Amyloidosis*

No. of TRM OSStudy patients (%) (%) Prognostic factors

CIBMTR 107 18 at 30 d 56 at 3 y None

Boston, Mass16

205 13 at100 d 60 at 3 y 2 organs; cardiacMayo Clinic22 171 12 at 100 d 21.5 mo if 2 2 organs/


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cytoprotectant agent allowed for administration of single-agent melphalan to 280 mg/m2.35 In this regard, the EasternCooperative Oncology Group has initiated a phase 1/2study of dose-escalating melphalan with amifostine as acytoprotectant. Palifermin was recently shown to reduce

mucositis in patients undergoing radiation-based autolo-gous HSCT.36 Furthermore, if the transplantation-relatedmorbidity and mortality can be adequately reduced, it maybe possible to safely administer multiple cycles of dose-intensive therapy with HSCT,37,38 as has been shown to beeffective in multiple myeloma.39

Finally, although the median overall survival withHSCT for primary systemic amyloidosis approaches 4years in our study and 5 years in other studies, there doesnot appear to be a plateau of survival curves.15,16 The obser-vation that a graft-vs-myeloma effect afforded by allo-reactive T lymphocytes can result in long-term diseasecontrol in some patients with myeloma undergoing alloge-neic transplantation40,41 may be predictive of a similar out-come in patients with primary systemic amyloidosis. Theuse of allogeneic transplantation for primary systemicamyloidosis, particularly with reduced-intensity condition-ing regimens, has just started to be evaluated in pilot stud-ies.42,43 These transplantations should be performed onlywithin well-designed clinical trials at centers with expertisein the management of transplantation-related complica-tions, such as graft-vs-host disease. All patients with pri-mary systemic amyloidosis should be considered for clini-cal trials and may benefit by referral for evaluation toprograms that specialize in the study and care of these

patients.

CONCLUSION

In this multi-institutional CIBMTR study, the 3-year sur-vival was comparable to single-center results, with patientswho had more recently undergone transplantations faringbetter. Of note, the TRM was higher than that reported bysingle centers, which may reflect differences in patientselection and/or experience in treating this challenging dis-ease. We hope that a better understanding of the recentlyrecognized prognostic factors and more stringent patientselection will result in lower TRM and improved survival.

Other Members of the Working Committee. A. Bashey, MD,PhD, BMT Group of Georgia, Atlanta; M. W. Brunvand, MD,Rocky Mountain Cancer Center, Denver, Colo; A. Dispenzieri,MD, Mayo Clinic College of Medicine, Rochester, Minn; C. O.Freytes, MD, University of Texas Health Science Center, SanAntonio; R. P. Gale, MD, PhD, Ziopharm Oncology, Los Ange-les, Calif; J. Gibson, MD, MBBS, PhD, Royal Prince AlfredHospital, Campertown, Australia; S. A. Giralt, MD, M.D. Ander-

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10. Comenzo RL, Vosburgh E, Falk RH, et al. Dose-intensive melphalanwith blood stem-cell support for the treatment of AL (amyloid light-chain)amyloidosis: survival and responses in 25 patients.Blood. 1998;91:3662-3670.

11. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survivaland response after high-dose therapy and autologous stem cell transplantationin systemic AL amyloidosis: a report on 21 patients.Br J Haematol . 1998;101:766-769.

12. Saba N, Sutton D, Ross H, et al. High treatment-related mortality incardiac amyloid patients undergoing autologous stem cell transplant. Bone

Marrow Transplant. 1999;24:853-855.13. Sanchorawala V, Wright DG, Seldin DC, et al. An overview of the use of

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amyloid mayo paper_ contributed by dr_marwan_alakasheh_medicsindex member

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