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Renal Response After High-Dose Melphalan and Stem CellTransplantation Is a Favorable Marker in Patients With Primary

Systemic Amyloidosis

Nelson Leung, MD, Angela Dispenzieri, MD, Fernando C. Fervenza, MD, PhD,Martha Q. Lacy, MD, Rafael Villicana, MD, Joao L. Cavalcante, MD, and Morie A. Gertz, MD

Background: Primary systemic (AL) amyloidosis is a rare plasma cell disorder characterized by soft-tissueeposition of monoclonal light chain fragments. High-dose melphalan followed by autologous stem cell transplan-ation currently has become the treatment of choice. Favorable outcome is ensured with achievement of hemato-ogic response, but little is known about organ response. This study was undertaken to determine the prognosticmportance of renal response after high-dose melphalan and stem cell transplantation. Methods: All patients withL amyloidosis who underwent autologous stem cell transplantation between 1996 and December 2002 wereelected for study. Renal response is defined as a 50% or greater reduction in proteinuria with less than 25% declinen renal function. Exclusion criteria included pretransplantation dialysis therapy or dialysis dependence posttrans-lantation, treatment mortality, lack of proteinuria assessment posttransplantation, and baseline proteinuria withrotein less than 1 g/d. Results: Of 105 patients, 47 were excluded for stated reasons. Renal response was achieved

n 60.3% of evaluated patients. Proteinuria was reduced by greater than 90% in 37.9% and returned to normal in5.5%. Median response time was 12 months. Renal response was associated with a greater increase in serumlbumin level (P � 0.001), maintenance of renal function (P < 0.001), and better survival (P � 0.0003). Renalesponders had better survival regardless of hematologic response (P � 0.01 to 0.05). Conclusion: Currently,igh-dose melphalan followed by stem cell transplantation is the most effective treatment for AL amyloidosis forhose who are eligible. Our data show that renal response after high-dose melphalan followed by stem cellransplantation is associated with improved survival. Renal response is an independent marker of treatmentuccess and can be used in cases in which determination of hematologic response is difficult. Am J Kidney Dis 46:70-277.2005 by the National Kidney Foundation, Inc.

NDEX WORDS: Primary systemic (AL) amyloidosis; stem cell transplantation; proteinuria; response; renal;

elphalan.

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RIMARY SYSTEMIC (AL) amyloidosis isthe sequela of a plasma cell dyscrasia in

hich monoclonal light chain fragments are de-osited in soft tissues in a fibrillar pattern.1-4

his relentless process eventually leads to pro-ressive organ failure. All visceral organs areusceptible, but renal manifestations are the mostommon.5 Most patients develop proteinuria,ith more than one third in the nephrotic range,hereas renal insufficiency afflicts approxi-ately half the patients. Risk of end-stage renal

isease is greatest when both features are present.5

From the Divisions of Nephrology and Hematology, Mayolinic, Rochester, MN.Received January 18, 2005; accepted in revised form May

, 2005.Originally published online as doi:10.1053/j.ajkd.2005.05.010

n June 21, 2005.Address reprint requests to Nelson Leung, MD, Mayo

linic, 200 First St SW, Eisenberg S-24, Rochester, MN5905. E-mail: leung.nelson@mayo.edu© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4602-0010$30.00/0

rdoi:10.1053/j.ajkd.2005.05.010

American Journal of K70

he development of end-stage renal disease nega-ively impacts on the outcome of these patients.6

edian survival after starting dialysis therapy isnly 8 months.7 Whether renal failure representshe severity of the disease or has a direct role inccelerating mortality is unknown.

The goal of most therapy for patients with ALmyloidosis is to reduce or eliminate productionf the paraprotein. Complete hematologic re-ponse was rare with conventional chemothera-eutic agents, with partial response seen in 20%o 30% of those treated.8-11 Unfortunately, manyatients died before response could be achieved,esulting in a median survival of only 18 monthsn many of these trials.8,9,11,12 Successful use ofigh-dose melphalan followed by autologoustem cell transplantation in patients with mul-iple myeloma prompted its use in those with ALmyloidosis.13 In the largest series to date, theomplete hematologic response rate was as highs 40% after treatment.14 Five-year survival forhese selected patients was 82%. Patients withematologic response were more likely to achieve

enal response, but there were exceptions.14,15

idney Diseases, Vol 46, No 2 (August), 2005: pp 270-277

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RENAL AMYLOIDOSIS AFTER STEM CELL TRANSPLANTATION 271

pproximately 11% of patients achieved a renalesponse without complete hematologic re-ponse. Outcomes of these patients were notpecified because survival was correlated onlyith hematologic response. We reason that organ

esponse, specifically renal response, also shoulde a favorable marker after high-dose melphalannd stem cell transplantation. Recently, we re-orted risk factors for renal insufficiency imme-iately after conditioning in this group of pa-ients.16 In the present study, we turn our attentiono details of renal response and its impact onurvival after stem cell transplantation.

METHODS

atientsMedical records of consecutive patients with AL amyloid-

sis who underwent high-dose melphalan and stem cellransplantation at our institution between 1996 and Decem-er 2002 were reviewed. The diagnosis of amyloid wasased on the demonstration of apple-green birefringence onissue biopsy specimens stained with Congo red. Tissueslso were stained with antibodies to � and � to confirm theight chain origin of amyloid deposits. Supporting evidenceor AL amyloidosis included the presence of a monoclonalrotein in either serum or urine or clonal expansion oflasma cells in bone marrow. Patients with secondary, famil-al, and localized (cutaneous involvement or carpal tunnelyndrome) amyloidosis were not eligible for intensive treat-ent. Written informed consent was obtained before study

ntry for all patients. Both the protocol and consent formere approved by the Institutional Review Board at theayo Foundation in accordance with the Declaration ofelsinki.

ligibilityOnly patients with significant renal involvement were

tudied. Patients must have a minimum of 1 g/d of pro-einura at baseline with or without renal insufficiency. Thoseho received dialysis before stem cell transplantation orho were dialysis dependent afterward were excluded. Pa-

ients who died within the first 100 days (treatment-relatedortality) also were excluded because renal response could

ot be evaluated.All patients had baseline laboratory values obtained be-

ore stem cell transplantation. Laboratory values were reas-essed during follow-up visits at 3 to 6 months posttransplan-ation and every 6 to 12 months thereafter, depending on thelinical situation. All patients underwent glomerular filtra-ion rate determination at baseline by means of either 24-our creatinine clearance or short iothalamate clearance.16

uring follow-up visits, renal function usually was assessedy means of serum creatinine level, although iothalamatelearance or creatinine clearance was performed on someatients. Proteinuria was measured by means of 24-hour

ollection. M

obilization and ConditioningStem cells were mobilized by using either pulse cyclophos-

hamide (3 g/m2) with granulocyte-macrophage colony-timulating factor (5 �g/kg/d; n � 33) or granulocyteolony-stimulating factor alone (n � 72). Conditioningonsisted of either melphalan (100, 140, or 200 mg/m2)lone (n � 88) or melphalan (140 mg/m2) with total-bodyrradiation consisting of 2 Gy twice daily for 3 days (n �7). Details of mobilization and conditioning are describedlsewhere.17

efinition of ResponseRenal response is defined as a 50% reduction in protein-

ria after stem cell transplantation. Only patients with lesshan 25% decline in renal function by means of either serumreatinine level or glomerular filtration rate were analyzed toxclude other factors that could result in the reduction inroteinuria. Hematologic response was determined as a 50%eduction in measurable monoclonal protein levels or com-lete eradication by immunofixation if monoclonal proteinas too small to be quantified.18 Renal relapse is defined as aersistent increase in proteinuria after a 50% reductionreviously had been achieved.Data are expressed as median and range for continuous

ariables and percentage for categorical variables. Statisticalnalyses were performed using JMP software (SAS Institutenc, Cary, NC) for chi-square, t-test, Pearson correlationoefficient, analysis of variance, and logistic regression.atient survival was calculated by using the Kaplan-Meierethod and compared using the log-rank test. Significanceas considered for P less than 0.05.

RESULTS

During the study period, 105 patients with ALmyloidosis underwent treatment with high-doseelphalan followed by stem cell transplantation

t our institution. Forty-five patients were ex-luded from the study. Reasons for exclusionere lack of significant renal involvement (23atients), treatment-related mortality (16 pa-ients), requiring dialysis before (2 patients) orfter transplantation (3 patients), and lack ofrine protein measurement after treatment (1atient). Of the remaining 60 patients, 2 patientshat had a greater than 25% decline in renalunction also were excluded. Patient follow-upsanged from 3 to 72 months (Fig 1). No patientas lost to follow-up. Longer follow-ups were

vailable for responders than nonresponders (33.6ersus 16.2 months, respectively; P � 0.001).atients were well matched in all baseline charac-

eristics (Table 1).Thirty-five patients (60.3%) met criteria for

enal response after stem cell transplantation.

edian time to accomplish this was 12 months,

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LEUNG ET AL272

ut varied from 3 to 36 months. Eleven patientsid not achieve a renal response until after 12onths or more. A transient increase in protein-

ria was observed in 6 responders before reach-ng 50% reduction. Neither delayed response norransient increase in proteinuria predicted overallesponse or relapse. Of nonresponders, 9 patientsad some reduction in proteinuria, but had noteached a 50% reduction at the time of the study.ive of these patients had a greater than 30%eduction.

High-dose melphalan and stem cell transplan-ation are capable of substantially improvingenal manifestations of AL amyloidosis (Fig 2).

Fig 1. Graph shows the number of patients evaluatrotein measurement were listed as evaluated.

Table 1. Baseline Patient Cha

Nonresponders

o. of patients 21ge (y) 60 (42–70)ale sex (%) 47.6rine protein (g/d) 5.1 (1.2–18.5)(%) 14.3elphalan dose (mg/m2)200 (%) 61.9140 (%) 38.1100 (%) 0

erum creatinine (mg/dL) 1.1 (0.6–2.0)lomerular filtration rate(mL/min/1.73 m2)

74.0 (32–55)

erum albumin (g/dL) 2.0 � 0.7 (1.1–3.

NOTE. To convert serum creatinine in mg/dL to �mol/L

ultiply by 0.01667; albumin in g/dL to g/L, multiply by 10.

roteinuria was reduced by greater than 90% in7.9% of patients and completely normalizedprotein � 93 mg/d) in 15.5% of patients (Fig 3).

edian time to normalization was 24 monthsrange, 18 to 36 months). Renal function tendedo remain stable or improve in responders (Fig). Nonresponders were more likely to experi-nce a decline in renal function (P � 0.001). Inddition, the decline was more severe because3.8% experienced a greater than 50% decline inenal function. Renal function diminished by6.6% and 50% in 2 patients with a greater than0% reduction in proteinuria. Data from these 2atients were not included in the analysis, but

ach follow-up visit. Only patients with a 24-hour urine

stics and Treatment Modality

Renal Responders P

35 Not applicable54 (37–69) 0.06

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RENAL AMYLOIDOSIS AFTER STEM CELL TRANSPLANTATION 273

heir outcomes are mentioned next. Renal re-ponse resulted in greater improvement in serumlbumin levels. Serum albumin levels increasedrom 2.4 to 3.6 g/dL (24 to 36 g/L) in respondersersus 2.0 to 2.4 g/dL (20 to 24 g/L) in nonre-ponders (P � 0.001).

Longer survival was seen in patients with aenal response (Fig 5; P � 0.0003). Medianurvival was 40 months for nonresponders, butad not been reached in responders. Three re-ponders died (8.6%) compared with 6 nonre-ponders (26.1%). Relapse was the cause ofeath for 2 responders at 27 and 28 months

Fig 2. Averaged change in proteinuria after stem cemained significant after 3 months. The abscissa scal

Fig 3. Number of patients evaluated at each follow

esponse at each follow-up; stacked columns, percentage of r0% reduction in proteinuria.

osttransplantation. The other patient died else-here of unknown cause 66 months posttrans-lantation. All 6 nonresponders died of progres-ion of their disease. Death occurred earlier foronresponders (median, 1.2 years [range, 0.7 to.7 years] versus 2.4 years [range, 2.3 to 5.4ears]), but did not reach significance (P �.13). Six responders experienced a relapse afterchieving renal response. One patient had under-one a second stem cell transplantation and 2atients died, as previously mentioned. One ofhe 2 patients excluded for excessive decline inenal function died 12 months after transplanta-

nsplantation. Differences in proteinuria became andt linear.

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ion. The other patient was alive at the 48-monthollow-up.

Hematologic response was achieved in 72.4%f this subgroup after stem cell transplantation.enal response was much more common inematologic responders than nonresponders82.8% versus 17.2%; odds ratio, 4.8; P � 0.03).verall, 10.3% developed a renal response with-

Fig 4. Renal function of renal responders and non-esponders after high-dose melphalan and stem cellransplantation. Decline indicates greater than 10%ecrease in renal function; unchanged, less than 10%hange; improved, greater than 10% increase in renalunction. Patients with renal response to high-doseelphalan and stem cell transplantation were more

ikely to preserve or improve renal function (P �.0004).

Fig 5. Survival after high-dose melphalan and stem cell traifference in survival was compared by using log-rank test (P

ut a hematologic response, and 22.4% achievedhematologic response without a renal response.

n this population, univariate analysis showedematologic response was marginally significantn predicting survival after stem cell transplanta-ion (P � 0.055), but not in multivariate analysisP � 0.18). Conversely, renal response was atrong predictor of survival in both (P � 0.0005nd 0.0002). In subgroup analysis, we looked athe individual effect of renal response and hema-ologic response on survival (Fig 6). In renalesponders, survival was similar regardless ofhether hematologic response was achieved (P0.42), but was enhanced in non–renal respond-

rs when hematologic response was achieved (P0.04). Conversely, renal response was advan-

ageous regardless of hematologic response (P �.01 with hematologic response versus P � 0.05ithout).

DISCUSSION

Currently, high-dose melphalan followed bytem cell transplantation appears to be the mostffective treatment for patients with AL amyloid-sis.10,11,14 Although selection bias cannot beompletely excluded, a recent study concludedhat patients treated with stem cell transplanta-ion had a definite survival advantage.19,20 Trans-lant recipients had a 75% 4-year survival rateompared with 43% in case controls who did not

nsplantation in renal responders and nonresponders.< 0.003).

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RENAL AMYLOIDOSIS AFTER STEM CELL TRANSPLANTATION 275

ndergo transplantation. The better outcomeikely was the result of greater rates of hemato-ogic response. This is supported by the study ofkinner et al,14 in which 85% of patients whochieved a complete hematologic response werelive at 5 years compared with less than 50%ith an incomplete response.Although hematologic response has been the

old standard of therapeutic efficacy, it has draw-acks. First, changes can be difficult to detect inome patients in whom monoclonal protein ismall or undetectable. The free light chain assayan be helpful, but it is difficult to interpret in theetting of changing renal function.21 The biggesteakness is that hematologic response does not

nsure a good outcome. A small percentage ofatients still die of their disease despite eradica-ion of the plasma cell dyscrasia.14,22 Many ofhese patients died as a result of cardiac compli-ations. Time lag between hematologic responsend organ response and the presence of irrevers-ble damage are factors likely to have a role.lthough the median time for hematologic re-

ponse time is 3.6 months, organ response oftenakes much longer.17 Unless the organ damage iseversed, these patients remain vulnerable to theffects of AL amyloidosis.

Our study confirms that renal response is an

Fig 6. Survival after stem cell transplantation by thematologic response (HR). Survival advantage was s

ogic response (�HR; P � 0.04). In renal responders, he

mportant therapeutic end point after stem cell t

ransplantation. This finding is consistent withesults of previous studies.23-25 Renal responseas used to establish the efficacy of melphalan inof the earlier clinical trials.12,26 It also was used

s a criterion in the dexamethasone and inter-eron-� trial.27 The current study confirms theffectiveness of stem cell transplantation at re-ersing renal manifestations of AL amyloidosis.early 40% evaluated had more than a 90%

eduction in proteinuria, and normal urinary pro-ein excretion was restored in 15.5% of patients.enal response can be slow because half the

esponders took 12 months or longer to meetriteria. This is not unexpected because reversinghe renal damage in patients with other diseasesequires a similar, if not longer, duration. Aecent study showed remission can take up to 24onths to achieve in patients with membranous

lomerulonephritis.28 In patients with diabetes,early 10 years were needed for the Kimmelstiel-ilson lesions to resolve after successful pan-

reas transplantation.29

The survival advantage we noted in our pa-ients who achieved renal response without hema-ologic response deserves further mention. Simi-ar to the study of Dember et al,15 10.3% of ouratients achieved renal response without hemato-ogic response. Although the true prognosis of

sence (�) or absence (–) of renal response (RR) andin renal nonresponders (–RR) who attained hemato-

ogic response did not affect prognosis (P � 0.42).

e pre

hese patients cannot be confirmed because of

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LEUNG ET AL276

heir small number, there are reasons to believechieving organ response may be as good asematologic response. First, the optimal level ofaraprotein reduction has not been establishedor this disease. Although improvement in sur-ival is well shown with “complete hematologicesponse,” which requires total elimination ofhe paraprotein or plasma cell clones, the 50%eduction in circulating free light chain used inhis study also has been shown to be beneficial.18

hus, there is no consensus on the minimumevel of monoclonal protein reduction required tonsure a good outcome. This explains how someatients have prolonged survival after stem cellransplantation despite never having met criteriaor hematologic response. Even more importanthan the quantity is the amyloidogenic tendencyr toxicity of the light chain. Severe nephroticyndrome has been reported in patients withardly any renal amyloid deposits, whereas oth-rs with abundant amounts have little protein-ria.25,30,31 This suggests that the degree oflasma cell clone elimination necessary for or-an response may differ depending on the toxic-ty of the circulating light chains. Finally, asoted, hematologic response does not guaranteeurvival because patients die of their preexistingrgan dysfunction. Obviously, the goal of therapyn patients with AL without myeloma is reversalf organ failure. Organ response therefore shoulde an important consideration when planningurther therapy.

This study has limitations. The number ofatients was small, reflecting the rarity of thisisease. Furthermore, a sizable portion of pa-ients was disqualified or could not be evaluated.ack of renal involvement and treatment-relatedortality made up the majority of these patients.smaller number of patients who developed

enal failure and became dialysis dependent alsoould not be evaluated. The most controversial ishe elimination of patients who died before therst follow-up. We realize this would artificially

mprove our results, but decided to exclude themecause this study is designed to evaluate out-ome based on renal response, not overall out-ome. Finally, there is more than 1 definition forematologic response. For example, Boston Uni-ersity uses complete hematologic response,hich requires no evidence of monoclonal pro-

ein or plasma cell clones at 1 year. However, in l

his study, we used criteria detailed by Lachmannt al,18 which only required a 50% reduction inree light chains.14 Differences in the definitionotentially could alter results of our study.There also are disadvantages with using reduc-

ion in proteinuria to assess response to treat-ent. As mentioned, response delay and tran-

ient elevation in proteinuria can occur and maye mistaken for treatment failure or relapse.enal injury also can occur during the transplan-

ation process and may contribute to the delay inenal response.32 Other renal diseases also maynterfere with the assessment. One patient whoas thought to have experienced a relapse was

ound to have advanced diabetic nephropathy onenal biopsy. Her proteinuria improved after ag-ressive treatment with an angiotensin-convert-ng enzyme inhibitor and blood pressure control.

Conversely, we show that achieving renal re-ponse is reassuring after stem cell transplanta-ion, even when hematologic response is notertain or assessable. Other organ response, espe-ially the heart, would likely have the samerognostic implication. However, assessment ofesponse remains difficult in some cases. In Eu-ope, measurement of total-body amyloid loadith iodine 123-labeled serum amyloid P compo-ent scintigraphy has been used to determinereatment response.33-35

Unfortunately, this test is not available in thenited States and experience with it is limited.etter markers of response or residual diseasere still needed to ensure prompt treatment forhose who need it and continue observation forhose who do not.

ACKNOWLEDGMENTThe authors thank Tessa R. Leung for her contributions in

he editing of this report.

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RENAL AMYLOIDOSIS AFTER STEM CELL TRANSPLANTATION 277

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