- Email: [email protected]
Stem cell transplantation for the management of primary systemic amyloidosis
Stem Cell Transplantation for the Management of Primary Systemic Amyloidosis Morie A. Gertz, MD, Martha Q. Lacy, MD, Angela Dispenzieri, MD, Dennis A. Gastineau, MD, Michael G. Chen, MD, PhD, Stephen M. Ansell, MD, PhD, David J. Inwards, MD, Ivana N. M. Micallef, MD, Ayalew Tefferi, MD, Mark R. Litzow, MD PURPOSE: To review the characteristics and outcomes of amyloidosis patients treated with high-dose chemotherapy and stem cell reconstitution. SUBJECTS AND METHODS: Sixty-six patients with biopsyproven amyloidosis received transplants between March 1996 and January 2001. All patients had evidence of a clonal plasma cell dyscrasia; those with nonimmunoglobulin forms of amyloidosis were excluded, as were those who had no symptoms of amyloidosis, purpura, carpal tunnel syndrome, or symptomatic multiple myeloma. RESULTS: Amyloid was seen clinically in the kidneys (n ⫽ 45 patients), heart (n ⫽ 32), peripheral nerves (n ⫽ 11), and liver (n ⫽ 11). A monoclonal protein was found in the serum in 46 patients and in the urine in 57 patients. The median daily urinary protein loss was 4.1 g. Septal thickness, measured by echocardiography, ranged from 7 to 24 mm (median, 12 mm); 8 patients had a septal thickness ⱖ16 mm. Ten patients received
transplants 1 year or more after diagnosis. All patients received melphalan-based chemotherapy; 17 patients were conditioned with total body irradiation. Nine patients required dialysis, 7 of whom died. Treatment-related mortality for stem cell transplantation was 14% (9/66). After a median of 25 months of follow-up after transplantation, the percentage of patients alive with one organ involved was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (0 of 1). Hematologic responses were seen in 33 patients and organ responses in 32 patients. The 2-year actuarial survival of all patients was 70%. CONCLUSION: The number of organs involved before stem cell transplantation for amyloidosis is the most important factor in predicting subsequent survival. Stem cell transplantation should be considered as a treatment option for selected patients with amyloidosis. Am J Med. 2002;113:549 –555. ©2002 by Excerpta Medica, Inc.
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of light-chain amyloid required a serum or urine monoclonal light chain or the presence of clonal plasma cells in the bone marrow (5). Baseline evaluation of patients included immunofixation of serum and urine and an echocardiogram. For the purpose of counting organ involvement, tongue enlargement, carpal tunnel syndrome, and purpura were not included. All patients gave written informed consent in accordance with Minnesota law and the Institutional Review Board of the Mayo Foundation. Criteria for overall and hematologic response were based on standard criteria (6); for hematologic response criteria, these conform to those published for multiple myeloma (7). All patients who had a measurable serum or urine M protein were monitored for changes in the size of the M peak. A response required a 50% reduction in the size of the peak in the serum or urine after transplantation. When only a light chain was detectable or the immunoglobulin protein was not quantifiable, a response required complete eradication of the light chain by immunofixation. The organ-based response criterion required for renal amyloidosis was a 50% decrease in 24hour albumin excretion. In patients with hepatic involvement, a response required a 50% reduction in the serum alkaline phosphatase level. Echocardiographic regression of cardiac amyloidosis required a 2-mm decrease in the thickness of the interventricular septum or an increase of 20% in the ejection fraction.
myloidosis results from the extracellular deposition of insoluble immunoglobulin light-chain fragments in the heart, kidneys, liver, and nerves, which leads to progressive dysfunction of these organs and, ultimately, to death (1). In unselected patients, median survival ranges from 12 to 17 months (2,3). Autologous stem cell transplantation for patients with amyloidosis increases response rates compared with conventional chemotherapy (4). The purpose of this paper is to review the Mayo Clinic experience with stem cell transplantation for patients with amyloidosis.
METHODS Amyloidosis was confirmed with a Congo red–stained tissue biopsy specimen in all patients. Patients whose disease was limited to only cutaneous involvement, purpura, or carpal tunnel syndrome were excluded. The diagnosis From the Division of Hematology and Internal Medicine (MAG, MQL, AD, DAG, SMA, DJI, INMM, AT, MRL) and the Division of Radiation Oncology (MGC), Mayo Clinic, Rochester, Minnesota. This study was supported in part by the Mayo Hematology Malignancies Program, Rochester, Minnesota. Requests for reprints should be addressed to Morie A. Gertz, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, or [email protected]. Manuscript submitted July 18, 2001, and accepted in revised form April 9, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved.
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Table 1. Characteristics of Patients with Amyloidosis (n ⫽ 66) before Autologous Stem Cell Transplantation Characteristic (unit) Male sex Age (years) Albumin (g/dL)
Number (%) or Median (Range) 37 (56) 54 (31–70) 2.8 (1.0–4.4)
Creatinine (mg/dL) Alkaline phosphatase (U/L) Serum M protein (g/dL) 24-hour urine protein (g) Urine M protein (g/d) Marrow plasma cells (%) Echocardiogram septal thickness (mm) Ejection fraction (%) 2-microglobulin (g/mL)
1.1 (0.6–3.9) 187 (67–936) 0.1 (0.1–2.6) 4.1 (0.02–21) 0.20 (0.004–1.273) 5 (1–48) 12 (7–24) 66 (28–80) 2.1 (1–7.96)
The target progenitor cell number was 5 ⫻ 106 CD34⫹ cells per kilogram of body weight, but patients were considered for transplantation if a minimum of 2 ⫻ 106 cells per kilogram of body weight were collected. Apheresis was performed with the processing of 11 to 14 L of blood in a 4-hour period. Patients were hospitalized for the management of neutropenic fever, mucositis, or dehydration. Supportive care included prophylactic fluoroquinolone antibiotics and fluconazole.
Statistics The main endpoint of the study was survival until December 2001 (median, 25 months; range, 0 to 65 months). Overall survival was estimated by the KaplanMeier method (8). Analysis of the effects of potential risk factors on survival was performed using the Cox proportional hazards model (9). In the model, age was assessed by decade, and cardiac ejection fraction and marrow plasma cells were assessed in increments of 10%. The multivariate analysis consisted of stepwise variable selection. Laboratory data obtained at baseline were compared between groups using chi-squared tests for categorical data and two-sample t tests and rank sum tests for continuous variables. All statistical tests were two sided, and the threshold for significance was set at 0.05. All analyses were performed using StatView (Abacus Concepts, Berkeley, CA).
RESULTS We studied 66 patients who underwent transplantation between March 8, 1996, and January 17, 2001 (Table 1). All except 5 patients had evidence of an M protein in urine or serum (Table 2 ); 23 (35%) had light chains and 43 (65%) had light chains. At the time of diagnosis, signs or symptoms of amyloid were seen in the kidney in 45 patients (68%), the heart in 32 patients (48%), periph550
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Number (%) Abnormal
Abnormal Values
29 (44) 19 (29) 10 (15) 10 (15) 5/46 (11) 40 (61) 10/57 (18) 8 (12) 8 (12) 9 (14) 6 (9)
⬍2.5 ⬍2.0 ⬎2.0 ⬎375 ⬎1.5 ⬎3.0 ⬎0.5 ⬎20 ⱖ16 ⬍60 ⬎4
eral nerves in 11 patients (17%), the liver in 11 patients (17%), and the autonomic nervous system in 4 patients (6%). Nine patients (14%) had an ejection fraction ⬍60% at transplantation. Nine of 12 patients had a positive rectal biopsy, 29 had a positive renal biopsy, 6 of 7 had a positive liver biopsy, 16 had a positive endomyocardial biopsy, 1 had a positive sural nerve biopsy, 46 (75%) of 61 patients had deposits in the fat aspirate, and 49 (78%) of 63 had amyloid deposits in the bone marrow. Twenty-eight of the patients had previously received treatment for amyloidosis; 14 had received high-dose corticosteroids, 13 had received cytotoxic chemotherapy, primarily melphalan based, and 1 patient had been treated with iododoxorubicin. The time from the histologic diagnosis of amyloidosis to stem cell transplantation ranged from 1.3 to 74.7 months, with a median of 5 months. Ten patients received transplants more than 1 year after the diagnosis of amyloidosis.
Conditioning and Stem Cell Mobilization Thirty-three patients had their stem cells mobilized with cyclophosphamide (1.5 g/m2) on 2 consecutive days, folTable 2. Serum and Urine Immunoglobulins* Protein
Serum
Urine Number of Patients
None IgA IgG IgG M Biclonal
20 2 8 11 7 15 2 1
9
17 40
* All patients had clonal plasma cells in bone marrow samples; 5 patients did not have an M protein. Ig ⫽ immunoglobulin.
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Figure 1. Box plot distribution of the number of aphereses required for two different mobilization strategies. Upper bars indicate the 90th percentile; lower bars indicate the 10th percentile. The rectangle encloses the 25th and 75th percentile values. The median is given by the center bar.
lowed by granulocyte-monocyte colony-stimulating factor (5 g/kg/d); the other 33 patients received only granulocyte colony-stimulating factor (10 g/kg/d). The CD34 yield in 61 patients was 2.01 to 50.93 per kilogram, with a median of 6.37 ⫻ 106 per kilogram. In the patients treated with cyclophosphamide, a median of three leukapheresis sessions was required to achieve more than 2 ⫻ 106 CD34 cells per kilogram of body weight. Sixteen of the 33 patients required more than three leukaphereses (range, 1 to 10). For those patients treated with growth factor alone, the median number of leukaphereses was two. Only 3 patients required more than three collections (range, one to four). The difference in the number of collections required was statistically significant (Figure 1, P ⬍0.01). Forty-nine patients received melphalan alone as a conditioning regimen: 200 mg/m2 in 38 patients, 140 mg/m2 in 7 patients, and 100 mg/m2 in 4 patients. Seventeen patients received melphalan (140 mg/m2) with total body irradiation (12 Gy). All patients had stem cells infused on day 0.
Engraftment One patient died 6 days after transplantation and was not evaluable for engraftment of granulocytes. The remaining 65 patients achieved a granulocyte count of 500/L between day 7 and day 33, with a median of 12 days after transplantation. Six patients died without achieving a platelet count of 20,000/L. One patient is alive with a platelet count of less than 20,000/L, and 59 patients achieved an untransfused platelet count of 20,000/L
from day 6 to day 98, with a median of day 14. Two patients with a platelet count greater than 20,000/L never achieved a platelet count of 50,000/L. Both patients received oral melphalan chemotherapy before stem cell collection.
Transplant-Related Complications Transplantation was associated with substantial morbidity and mortality. At this time, 14 patients (21%) had died, 9 because of transplant-related complications, including gastrointestinal tract bleeding with multiorgan failure (n ⫽ 4), cardiac arrhythmia, pulmonary embolus, disseminated aspergillus, pneumonia, and aspiration pneumonia (in a patient with autonomic failure). There were five subsequent deaths due to progressive cardiac or autonomic nervous system amyloid. Nine patients required dialysis following transplantation, of whom 7 died subsequently, 1 survived and is on long-term hemodialysis, and 1 had complete recovery of renal function. Eight of these 9 patients had renal amyloid before transplantation. The pretransplant serum creatinine level in the 9 patients who required dialysis ranged from 0.9 to 3.9 mg/dL (median, 1.7 mg/dL). The serum creatinine level ranged from 0.6 to 2.2 mg/dL (median, 1.1 mg/dL) in the 57 patients who did not require dialysis (P ⬍0.01). There was no difference in median urine protein loss between the two groups: 4.2 g/d versus 4.0 g/d (P ⬎0.2). None of the 9 transplant patients with an ejection fraction of less than 60% died after transplantation. Of the 8 patients with ventricular septal thickness ⱖ16 mm, 1 died 22 months after transplantation because of progressive
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Table 3. Observed Responses in Patients with Amyloidosis following Stem Cell Transplantation Variable Conditioning Melphalan (200 mg/m2) Melphalan (140 mg/m2) Melphalan (100 mg/m2) Melphalan (140 mg/m2) ⫹ total body irradiation Total
Number
Organ Hematologic Both Hematologic Any Only Only and Organ Response
38 7 4 17
3 2 0 4
7 0 0 3
13 2 1 7
23 /38 4 /7 1 /4 14 /17
66
9
10 Patients
23
42 /66
Number (%) Organ* Renal Cardiac Peripheral neuropathy Liver Autonomic neuropathy Hematologic
23 /45 (51) 6 /32 (19) 1 /11 (9) 6 /11 (55) 1 /4 (25) 33 /66 (50)
* Among patients with evidence of amyloidosis in that organ before transplantation.
cardiac amyloid; the other 7 are still alive. One patient, who had received melphalan (192 mg) before stem cell mobilization, developed a dysmyelopoietic syndrome 29 months after transplantation. The number of days in the hospital ranged from none to 78 (median, 14 days). Fifteen patients were hospitalized for more than 30 days. Thirty-five patients had bacteremia, and 1 had fungemia during the neutropenic period. The most common microbial isolate from the blood was coagulase-negative Staphylococcus (n ⫽ 16 patients). Seven patients had lifethreatening gastrointestinal tract hemorrhages after transplantation; 4 of these patients died. After a median of 25 months of follow-up after transplantation the percentage of patients surviving who had one organ involved pretransplantation was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (1 patient only).
The median time to achieve a response (a hematologic or organ response to transplantation) among the 42 patients was 3.6 months, but 6 patients, all of whom had renal amyloid, took more than 1 year before a response was demonstrable. Of the 32 patients with organ responses, the median time to response was 3.8 months (range, 0.6 to 28.5 months). In univariate analyses, the 2-microglobulin level, serum creatinine level, serum M spike, and number of organs involved before transplantation were associated with mortality (Table 4). In a multivariate analysis, serum creatinine level (hazard ratio [HR] ⫽ 2.8 per mg/dL; 95% confidence interval [CI]: 1.2 to 6.3; P ⫽ 0.04) and the number of organs with amyloid before transplantation (HR ⫽ 2.3; 95% CI: 1.2 to 4.4; P ⫽ 0.01) were independently associated with mortality (Figure 2).
Response There have been 33 hematologic responses (50%) and 32 organ responses (48%); 42 patients (64%) had either a hematologic or an organ response (Table 3). There was no difference in response rates based on the conditioning regimen. There were 26 patients with biopsy-proven renal amyloidosis who satisfied the criteria for either an organ response or a hematologic response. The range of urinary protein loss in these patients was from 1.1 to 21 g/d (median, 7.1 g/d). Two of these patients required dialysis after transplantation; they achieved a hematologic response but were considered organ nonresponders due to renal failure. Of the remaining 24 patients, the urinary protein loss after transplantation ranged from 0.05 to 6.7 g/d (median, 1.4 g/d); 12 patients had a reduction in urinary protein loss to less than 1 g/d. 552
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DISCUSSION Melphalan and prednisone have been used to treat amyloidosis since 1971 (10), but only a minority of patients respond, and the median survival does not exceed 2 years (11,12). Because stem cell transplantation benefits patients with multiple myeloma (13), its use in the management of amyloidosis is logical (14). An initial report showed a clinical response in 5 patients who underwent autologous stem cell transplantation (15). With greater experience, the hematologic response rate was 62% and the organ response rate was 65% of the 25 patients (4). Subsequently, the results were updated to include 102 patients, with a complete hematologic response rate of 55% (16).
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Table 4. Univariate Associations with Mortality after Transplantation Variable (unit)
Hazard Ratio (95% Confidence Interval)
P Value
Age (per 10 years) Male sex Number of involved organs Serum M protein (per g/dL) Urine M protein (per g/d) Serum albumin (per g/dL) Serum creatinine (per mg/dL) Cardiac ejection fraction (per 10% decrease) Serum 2-microglobulin (g/mL) 24-hour urine protein (per g/d) Percentage of marrow plasma cells (per 10% increase) Interventricular septal thickness (per mm) C-reactive protein
1.1 (0.65–2.0) 2.2 (0.8–6.4) 3.4 (1.7–6.7) 2.3 (1.1–5.1) 1.5 (0.3–6.8) 1.0 (0.5–1.8) 4.2 (1.9–9.4) 1.0 (0.9–1.1) 1.4 (1.1–1.9) 1.0 (0.9–1.1) 0.99 (0.94–1.04) 1.1 (0.95–1.4) 1.7 (0.85–3.4)
0.96 0.25 0.006 0.03 0.43 0.76 0.002 0.66 0.002 0.19 0.70 0.15 0.26
However, stem cell transplantation has substantial complications. For example, in our experience, patients with a serum creatinine level greater than 1.5 mg/dL have a greater risk of requiring dialysis during therapy. The overall treatment-related mortality of 14% far exceeds the rate in patients with multiple myeloma, which is less than 1% at our institution. This suggests that underlying organ dysfunction results in excess morbidity after chemotherapy. Indeed, in a multicenter survey, mortality from transplant-related complications was 43%, although 10 of the 12 survivors responded (17,18). Another multicenter survey reported a 30% treatment-related mortality, but a 57% response (19). Saba et al. (20) re-
ported a high treatment-related mortality in patients with cardiac amyloid. Other toxicities include severe respiratory depression (21), tumor lysis syndrome (22), and intestinal perforation (23). Seizures have been reported in 2 patients (24). In spite of the high mortality associated with transplantation, the response rate we observed exceeds that seen with conventional-dose chemotherapy. However, patients eligible for transplantation have a more favorable prognosis than do those who are not eligible (25). Within our sample, the number of organs involved was strongly associated with mortality, and we now consider patients with involvement of three or more organs to be
Figure 2. Survival of patients with amyloidosis by the number of organs involved pretransplantation. November 2002
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poor candidates for transplantation. However, echocardiographic evidence of amyloidosis did not appear to affect survival, at least among patients without symptomatic heart failure. Total body irradiation was deleted from our conditioning regimen because of the higher rates of severe mucositis (26,27). Six patients took more than 1 year to demonstrate an organ response, suggesting that even if transplantation stops the synthesis of immunoglobulin light-chain precursor proteins, it takes time for the amyloid deposits to be resorbed by the body. The longest time to a response was 28.5 months in a patient who had a urine protein excretion of 9.7 g/d that decreased to 860 mg/d 28 months after transplantation. The optimal method of mobilizing stem cells in patients with amyloidosis is unknown (28). In multiple myeloma, stem cell yields appear to be greater when chemotherapy is combined with a growth factor (29,30). In amyloidosis, it appears that growth factor alone provides better stem cell yields, although we have had one death related to respiratory distress syndrome from growth factor (31). Oral melphalan reduces the stem cell yield and should be avoided in transplant-eligible patients (32,33). We do not yet have sufficient follow-up to assess the actuarial median survival or the long-term risk of the myelodysplastic syndrome (34) or relapse. However, we believe that our results indicate that autologous stem cell transplantation is an effective therapy for many patients with amyloidosis.
REFERENCES 1. Bellotti V, Merlini G. Current concepts on the pathogenesis of systemic amyloidosis. Nephrol Dial Transplant. 1996;11(suppl 9):53– 62. 2. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45–59. 3. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997; 336:1202–1207. 4. Comenzo RL, Vosburgh E, Falk RH, et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood. 1998;91:3662–3670. 5. Gertz MA, Greipp PR, Kyle RA. Classification of amyloidosis by the detection of clonal excess of plasma cells in the bone marrow. J Lab Clin Med. 1991;118:33–39. 6. Gertz MA, Kyle RA, Greipp PR. Response rates and survival in primary systemic amyloidosis. Blood. 1991;77:257–262. 7. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the European Group for Blood and Marrow Transplant (EBMT). Br J Haematol. 1998;102:1115– 1123. 8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481. 554
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9. Cox DR. Regression models and life-tables. J R Stat Soc [B]. 1972; 34:187–202. 10. Jones NF, Hilton PJ, Tighe JR, Hobbs JR. Treatment of “primary” renal amyloidosis with melphalan. Lancet. 1972;2:616 –619. 11. Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments. Br J Haematol. 1997;99:245–256. 12. Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978;52:818 – 827. 13. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Franc¸ ais du Myelome. N Engl J Med. 1996;335:91–97. 14. Gertz MA, Lacy MQ, Gastineau DA, et al. Blood stem cell transplantation as therapy for primary systemic amyloidosis (AL). Bone Marrow Transplant. 2000;26:963–969. 15. Comenzo RL, Vosburgh E, Simms RW, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood. 1996;88: 2801–2806. 16. Comenzo RL. Hematopoietic cell transplantation for primary systemic amyloidosis: what have we learned? Leuk Lymphoma. 2000; 37:245–258. 17. Moreau P. Autologous stem cell transplantation for AL amyloidosis: a standard therapy? Leukemia. 1999;13:1929 –1931. 18. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. 1998;101:766 –769. 19. Gillmore JD, Apperley JF, Craddock C, et al. High-dose melphalan and stem cell rescue for AL amyloidosis. In: Kyle RA, Gertz MA, eds. Amyloid and Amyloidosis 1998 —The Proceedings of the VIIIth International Symposium on Amyloidosis, August 7–11, 1998, Rochester, Minnesota, USA. New York: Parthenon Publishing Group; 1999: 102–107. 20. Saba N, Sutton D, Ross H, et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant. 1999;24:853–855. 21. Benekli M, Anderson B, Wentling D, et al. Severe respiratory depression after dimethylsulphoxide-containing autologous stem cell infusion in a patient with AL amyloidosis. Bone Marrow Transplant. 2000;25:1299 –1301. 22. Akasheh MS, Chang CP, Vesole DH. Acute tumour lysis syndrome: a case in AL amyloidosis. Br J Haematol. 1999;107:387. 23. Schulenburg A, Kalhs P, Oberhuber G, et al. Gastrointestinal perforation early after peripheral blood stem cell transplantation for AL amyloidosis. Bone Marrow Transplant. 1998;22:293–295. 24. Schuh A, Dandridge J, Haydon P, Littlewood TJ. Encephalopathy complicating high-dose melphalan. Bone Marrow Transplant. 1999; 24:1141–1143. 25. Dispenzieri A, Lacy MQ, Kyle RA, et al. Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol. 2001;19:3350 – 3356. 26. Lahuerta JJ, Martinez-Lopez J, Grande C, et al. Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma. Br J Haematol. 2000;109:138 –147. 27. Abraham R, Chen C, Tsang R, et al. Intensification of the stem cell transplant induction regimen results in increased treatment-related mortality without improved outcome in multiple myeloma. Bone Marrow Transplant. 1999;24:1291–1297.
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induced pulmonary toxicity. J Hematother Stem Cell Res. 2000;9: 635–643. 32. Gertz MA, Lacy MQ, Inwards DJ, et al. Factors influencing platelet recovery after blood cell transplantation in multiple myeloma. Bone Marrow Transplant. 1997;20:375–380. 33. Tricot G, Jagannath S, Vesole D, et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood. 1995;85:588 – 596. 34. Cuzick J, Erskine S, Edelman D, Galton DA. A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis. A report to the Medical Research Council’s working party on leukaemia in adults. Br J Cancer. 1987;55:523–529.
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transplants 1 year or more after diagnosis. All patients received melphalan-based chemotherapy; 17 patients were conditioned with total body irradiation. Nine patients required dialysis, 7 of whom died. Treatment-related mortality for stem cell transplantation was 14% (9/66). After a median of 25 months of follow-up after transplantation, the percentage of patients alive with one organ involved was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (0 of 1). Hematologic responses were seen in 33 patients and organ responses in 32 patients. The 2-year actuarial survival of all patients was 70%. CONCLUSION: The number of organs involved before stem cell transplantation for amyloidosis is the most important factor in predicting subsequent survival. Stem cell transplantation should be considered as a treatment option for selected patients with amyloidosis. Am J Med. 2002;113:549 –555. ©2002 by Excerpta Medica, Inc.
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of light-chain amyloid required a serum or urine monoclonal light chain or the presence of clonal plasma cells in the bone marrow (5). Baseline evaluation of patients included immunofixation of serum and urine and an echocardiogram. For the purpose of counting organ involvement, tongue enlargement, carpal tunnel syndrome, and purpura were not included. All patients gave written informed consent in accordance with Minnesota law and the Institutional Review Board of the Mayo Foundation. Criteria for overall and hematologic response were based on standard criteria (6); for hematologic response criteria, these conform to those published for multiple myeloma (7). All patients who had a measurable serum or urine M protein were monitored for changes in the size of the M peak. A response required a 50% reduction in the size of the peak in the serum or urine after transplantation. When only a light chain was detectable or the immunoglobulin protein was not quantifiable, a response required complete eradication of the light chain by immunofixation. The organ-based response criterion required for renal amyloidosis was a 50% decrease in 24hour albumin excretion. In patients with hepatic involvement, a response required a 50% reduction in the serum alkaline phosphatase level. Echocardiographic regression of cardiac amyloidosis required a 2-mm decrease in the thickness of the interventricular septum or an increase of 20% in the ejection fraction.
myloidosis results from the extracellular deposition of insoluble immunoglobulin light-chain fragments in the heart, kidneys, liver, and nerves, which leads to progressive dysfunction of these organs and, ultimately, to death (1). In unselected patients, median survival ranges from 12 to 17 months (2,3). Autologous stem cell transplantation for patients with amyloidosis increases response rates compared with conventional chemotherapy (4). The purpose of this paper is to review the Mayo Clinic experience with stem cell transplantation for patients with amyloidosis.
METHODS Amyloidosis was confirmed with a Congo red–stained tissue biopsy specimen in all patients. Patients whose disease was limited to only cutaneous involvement, purpura, or carpal tunnel syndrome were excluded. The diagnosis From the Division of Hematology and Internal Medicine (MAG, MQL, AD, DAG, SMA, DJI, INMM, AT, MRL) and the Division of Radiation Oncology (MGC), Mayo Clinic, Rochester, Minnesota. This study was supported in part by the Mayo Hematology Malignancies Program, Rochester, Minnesota. Requests for reprints should be addressed to Morie A. Gertz, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, or [email protected]. Manuscript submitted July 18, 2001, and accepted in revised form April 9, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved.
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Table 1. Characteristics of Patients with Amyloidosis (n ⫽ 66) before Autologous Stem Cell Transplantation Characteristic (unit) Male sex Age (years) Albumin (g/dL)
Number (%) or Median (Range) 37 (56) 54 (31–70) 2.8 (1.0–4.4)
Creatinine (mg/dL) Alkaline phosphatase (U/L) Serum M protein (g/dL) 24-hour urine protein (g) Urine M protein (g/d) Marrow plasma cells (%) Echocardiogram septal thickness (mm) Ejection fraction (%) 2-microglobulin (g/mL)
1.1 (0.6–3.9) 187 (67–936) 0.1 (0.1–2.6) 4.1 (0.02–21) 0.20 (0.004–1.273) 5 (1–48) 12 (7–24) 66 (28–80) 2.1 (1–7.96)
The target progenitor cell number was 5 ⫻ 106 CD34⫹ cells per kilogram of body weight, but patients were considered for transplantation if a minimum of 2 ⫻ 106 cells per kilogram of body weight were collected. Apheresis was performed with the processing of 11 to 14 L of blood in a 4-hour period. Patients were hospitalized for the management of neutropenic fever, mucositis, or dehydration. Supportive care included prophylactic fluoroquinolone antibiotics and fluconazole.
Statistics The main endpoint of the study was survival until December 2001 (median, 25 months; range, 0 to 65 months). Overall survival was estimated by the KaplanMeier method (8). Analysis of the effects of potential risk factors on survival was performed using the Cox proportional hazards model (9). In the model, age was assessed by decade, and cardiac ejection fraction and marrow plasma cells were assessed in increments of 10%. The multivariate analysis consisted of stepwise variable selection. Laboratory data obtained at baseline were compared between groups using chi-squared tests for categorical data and two-sample t tests and rank sum tests for continuous variables. All statistical tests were two sided, and the threshold for significance was set at 0.05. All analyses were performed using StatView (Abacus Concepts, Berkeley, CA).
RESULTS We studied 66 patients who underwent transplantation between March 8, 1996, and January 17, 2001 (Table 1). All except 5 patients had evidence of an M protein in urine or serum (Table 2 ); 23 (35%) had light chains and 43 (65%) had light chains. At the time of diagnosis, signs or symptoms of amyloid were seen in the kidney in 45 patients (68%), the heart in 32 patients (48%), periph550
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Number (%) Abnormal
Abnormal Values
29 (44) 19 (29) 10 (15) 10 (15) 5/46 (11) 40 (61) 10/57 (18) 8 (12) 8 (12) 9 (14) 6 (9)
⬍2.5 ⬍2.0 ⬎2.0 ⬎375 ⬎1.5 ⬎3.0 ⬎0.5 ⬎20 ⱖ16 ⬍60 ⬎4
eral nerves in 11 patients (17%), the liver in 11 patients (17%), and the autonomic nervous system in 4 patients (6%). Nine patients (14%) had an ejection fraction ⬍60% at transplantation. Nine of 12 patients had a positive rectal biopsy, 29 had a positive renal biopsy, 6 of 7 had a positive liver biopsy, 16 had a positive endomyocardial biopsy, 1 had a positive sural nerve biopsy, 46 (75%) of 61 patients had deposits in the fat aspirate, and 49 (78%) of 63 had amyloid deposits in the bone marrow. Twenty-eight of the patients had previously received treatment for amyloidosis; 14 had received high-dose corticosteroids, 13 had received cytotoxic chemotherapy, primarily melphalan based, and 1 patient had been treated with iododoxorubicin. The time from the histologic diagnosis of amyloidosis to stem cell transplantation ranged from 1.3 to 74.7 months, with a median of 5 months. Ten patients received transplants more than 1 year after the diagnosis of amyloidosis.
Conditioning and Stem Cell Mobilization Thirty-three patients had their stem cells mobilized with cyclophosphamide (1.5 g/m2) on 2 consecutive days, folTable 2. Serum and Urine Immunoglobulins* Protein
Serum
Urine Number of Patients
None IgA IgG IgG M Biclonal
20 2 8 11 7 15 2 1
9
17 40
* All patients had clonal plasma cells in bone marrow samples; 5 patients did not have an M protein. Ig ⫽ immunoglobulin.
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Figure 1. Box plot distribution of the number of aphereses required for two different mobilization strategies. Upper bars indicate the 90th percentile; lower bars indicate the 10th percentile. The rectangle encloses the 25th and 75th percentile values. The median is given by the center bar.
lowed by granulocyte-monocyte colony-stimulating factor (5 g/kg/d); the other 33 patients received only granulocyte colony-stimulating factor (10 g/kg/d). The CD34 yield in 61 patients was 2.01 to 50.93 per kilogram, with a median of 6.37 ⫻ 106 per kilogram. In the patients treated with cyclophosphamide, a median of three leukapheresis sessions was required to achieve more than 2 ⫻ 106 CD34 cells per kilogram of body weight. Sixteen of the 33 patients required more than three leukaphereses (range, 1 to 10). For those patients treated with growth factor alone, the median number of leukaphereses was two. Only 3 patients required more than three collections (range, one to four). The difference in the number of collections required was statistically significant (Figure 1, P ⬍0.01). Forty-nine patients received melphalan alone as a conditioning regimen: 200 mg/m2 in 38 patients, 140 mg/m2 in 7 patients, and 100 mg/m2 in 4 patients. Seventeen patients received melphalan (140 mg/m2) with total body irradiation (12 Gy). All patients had stem cells infused on day 0.
Engraftment One patient died 6 days after transplantation and was not evaluable for engraftment of granulocytes. The remaining 65 patients achieved a granulocyte count of 500/L between day 7 and day 33, with a median of 12 days after transplantation. Six patients died without achieving a platelet count of 20,000/L. One patient is alive with a platelet count of less than 20,000/L, and 59 patients achieved an untransfused platelet count of 20,000/L
from day 6 to day 98, with a median of day 14. Two patients with a platelet count greater than 20,000/L never achieved a platelet count of 50,000/L. Both patients received oral melphalan chemotherapy before stem cell collection.
Transplant-Related Complications Transplantation was associated with substantial morbidity and mortality. At this time, 14 patients (21%) had died, 9 because of transplant-related complications, including gastrointestinal tract bleeding with multiorgan failure (n ⫽ 4), cardiac arrhythmia, pulmonary embolus, disseminated aspergillus, pneumonia, and aspiration pneumonia (in a patient with autonomic failure). There were five subsequent deaths due to progressive cardiac or autonomic nervous system amyloid. Nine patients required dialysis following transplantation, of whom 7 died subsequently, 1 survived and is on long-term hemodialysis, and 1 had complete recovery of renal function. Eight of these 9 patients had renal amyloid before transplantation. The pretransplant serum creatinine level in the 9 patients who required dialysis ranged from 0.9 to 3.9 mg/dL (median, 1.7 mg/dL). The serum creatinine level ranged from 0.6 to 2.2 mg/dL (median, 1.1 mg/dL) in the 57 patients who did not require dialysis (P ⬍0.01). There was no difference in median urine protein loss between the two groups: 4.2 g/d versus 4.0 g/d (P ⬎0.2). None of the 9 transplant patients with an ejection fraction of less than 60% died after transplantation. Of the 8 patients with ventricular septal thickness ⱖ16 mm, 1 died 22 months after transplantation because of progressive
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Table 3. Observed Responses in Patients with Amyloidosis following Stem Cell Transplantation Variable Conditioning Melphalan (200 mg/m2) Melphalan (140 mg/m2) Melphalan (100 mg/m2) Melphalan (140 mg/m2) ⫹ total body irradiation Total
Number
Organ Hematologic Both Hematologic Any Only Only and Organ Response
38 7 4 17
3 2 0 4
7 0 0 3
13 2 1 7
23 /38 4 /7 1 /4 14 /17
66
9
10 Patients
23
42 /66
Number (%) Organ* Renal Cardiac Peripheral neuropathy Liver Autonomic neuropathy Hematologic
23 /45 (51) 6 /32 (19) 1 /11 (9) 6 /11 (55) 1 /4 (25) 33 /66 (50)
* Among patients with evidence of amyloidosis in that organ before transplantation.
cardiac amyloid; the other 7 are still alive. One patient, who had received melphalan (192 mg) before stem cell mobilization, developed a dysmyelopoietic syndrome 29 months after transplantation. The number of days in the hospital ranged from none to 78 (median, 14 days). Fifteen patients were hospitalized for more than 30 days. Thirty-five patients had bacteremia, and 1 had fungemia during the neutropenic period. The most common microbial isolate from the blood was coagulase-negative Staphylococcus (n ⫽ 16 patients). Seven patients had lifethreatening gastrointestinal tract hemorrhages after transplantation; 4 of these patients died. After a median of 25 months of follow-up after transplantation the percentage of patients surviving who had one organ involved pretransplantation was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (1 patient only).
The median time to achieve a response (a hematologic or organ response to transplantation) among the 42 patients was 3.6 months, but 6 patients, all of whom had renal amyloid, took more than 1 year before a response was demonstrable. Of the 32 patients with organ responses, the median time to response was 3.8 months (range, 0.6 to 28.5 months). In univariate analyses, the 2-microglobulin level, serum creatinine level, serum M spike, and number of organs involved before transplantation were associated with mortality (Table 4). In a multivariate analysis, serum creatinine level (hazard ratio [HR] ⫽ 2.8 per mg/dL; 95% confidence interval [CI]: 1.2 to 6.3; P ⫽ 0.04) and the number of organs with amyloid before transplantation (HR ⫽ 2.3; 95% CI: 1.2 to 4.4; P ⫽ 0.01) were independently associated with mortality (Figure 2).
Response There have been 33 hematologic responses (50%) and 32 organ responses (48%); 42 patients (64%) had either a hematologic or an organ response (Table 3). There was no difference in response rates based on the conditioning regimen. There were 26 patients with biopsy-proven renal amyloidosis who satisfied the criteria for either an organ response or a hematologic response. The range of urinary protein loss in these patients was from 1.1 to 21 g/d (median, 7.1 g/d). Two of these patients required dialysis after transplantation; they achieved a hematologic response but were considered organ nonresponders due to renal failure. Of the remaining 24 patients, the urinary protein loss after transplantation ranged from 0.05 to 6.7 g/d (median, 1.4 g/d); 12 patients had a reduction in urinary protein loss to less than 1 g/d. 552
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DISCUSSION Melphalan and prednisone have been used to treat amyloidosis since 1971 (10), but only a minority of patients respond, and the median survival does not exceed 2 years (11,12). Because stem cell transplantation benefits patients with multiple myeloma (13), its use in the management of amyloidosis is logical (14). An initial report showed a clinical response in 5 patients who underwent autologous stem cell transplantation (15). With greater experience, the hematologic response rate was 62% and the organ response rate was 65% of the 25 patients (4). Subsequently, the results were updated to include 102 patients, with a complete hematologic response rate of 55% (16).
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Table 4. Univariate Associations with Mortality after Transplantation Variable (unit)
Hazard Ratio (95% Confidence Interval)
P Value
Age (per 10 years) Male sex Number of involved organs Serum M protein (per g/dL) Urine M protein (per g/d) Serum albumin (per g/dL) Serum creatinine (per mg/dL) Cardiac ejection fraction (per 10% decrease) Serum 2-microglobulin (g/mL) 24-hour urine protein (per g/d) Percentage of marrow plasma cells (per 10% increase) Interventricular septal thickness (per mm) C-reactive protein
1.1 (0.65–2.0) 2.2 (0.8–6.4) 3.4 (1.7–6.7) 2.3 (1.1–5.1) 1.5 (0.3–6.8) 1.0 (0.5–1.8) 4.2 (1.9–9.4) 1.0 (0.9–1.1) 1.4 (1.1–1.9) 1.0 (0.9–1.1) 0.99 (0.94–1.04) 1.1 (0.95–1.4) 1.7 (0.85–3.4)
0.96 0.25 0.006 0.03 0.43 0.76 0.002 0.66 0.002 0.19 0.70 0.15 0.26
However, stem cell transplantation has substantial complications. For example, in our experience, patients with a serum creatinine level greater than 1.5 mg/dL have a greater risk of requiring dialysis during therapy. The overall treatment-related mortality of 14% far exceeds the rate in patients with multiple myeloma, which is less than 1% at our institution. This suggests that underlying organ dysfunction results in excess morbidity after chemotherapy. Indeed, in a multicenter survey, mortality from transplant-related complications was 43%, although 10 of the 12 survivors responded (17,18). Another multicenter survey reported a 30% treatment-related mortality, but a 57% response (19). Saba et al. (20) re-
ported a high treatment-related mortality in patients with cardiac amyloid. Other toxicities include severe respiratory depression (21), tumor lysis syndrome (22), and intestinal perforation (23). Seizures have been reported in 2 patients (24). In spite of the high mortality associated with transplantation, the response rate we observed exceeds that seen with conventional-dose chemotherapy. However, patients eligible for transplantation have a more favorable prognosis than do those who are not eligible (25). Within our sample, the number of organs involved was strongly associated with mortality, and we now consider patients with involvement of three or more organs to be
Figure 2. Survival of patients with amyloidosis by the number of organs involved pretransplantation. November 2002
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poor candidates for transplantation. However, echocardiographic evidence of amyloidosis did not appear to affect survival, at least among patients without symptomatic heart failure. Total body irradiation was deleted from our conditioning regimen because of the higher rates of severe mucositis (26,27). Six patients took more than 1 year to demonstrate an organ response, suggesting that even if transplantation stops the synthesis of immunoglobulin light-chain precursor proteins, it takes time for the amyloid deposits to be resorbed by the body. The longest time to a response was 28.5 months in a patient who had a urine protein excretion of 9.7 g/d that decreased to 860 mg/d 28 months after transplantation. The optimal method of mobilizing stem cells in patients with amyloidosis is unknown (28). In multiple myeloma, stem cell yields appear to be greater when chemotherapy is combined with a growth factor (29,30). In amyloidosis, it appears that growth factor alone provides better stem cell yields, although we have had one death related to respiratory distress syndrome from growth factor (31). Oral melphalan reduces the stem cell yield and should be avoided in transplant-eligible patients (32,33). We do not yet have sufficient follow-up to assess the actuarial median survival or the long-term risk of the myelodysplastic syndrome (34) or relapse. However, we believe that our results indicate that autologous stem cell transplantation is an effective therapy for many patients with amyloidosis.
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9. Cox DR. Regression models and life-tables. J R Stat Soc [B]. 1972; 34:187–202. 10. Jones NF, Hilton PJ, Tighe JR, Hobbs JR. Treatment of “primary” renal amyloidosis with melphalan. Lancet. 1972;2:616 –619. 11. Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments. Br J Haematol. 1997;99:245–256. 12. Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978;52:818 – 827. 13. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Franc¸ ais du Myelome. N Engl J Med. 1996;335:91–97. 14. Gertz MA, Lacy MQ, Gastineau DA, et al. Blood stem cell transplantation as therapy for primary systemic amyloidosis (AL). Bone Marrow Transplant. 2000;26:963–969. 15. Comenzo RL, Vosburgh E, Simms RW, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood. 1996;88: 2801–2806. 16. Comenzo RL. Hematopoietic cell transplantation for primary systemic amyloidosis: what have we learned? Leuk Lymphoma. 2000; 37:245–258. 17. Moreau P. Autologous stem cell transplantation for AL amyloidosis: a standard therapy? Leukemia. 1999;13:1929 –1931. 18. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. 1998;101:766 –769. 19. Gillmore JD, Apperley JF, Craddock C, et al. High-dose melphalan and stem cell rescue for AL amyloidosis. In: Kyle RA, Gertz MA, eds. Amyloid and Amyloidosis 1998 —The Proceedings of the VIIIth International Symposium on Amyloidosis, August 7–11, 1998, Rochester, Minnesota, USA. New York: Parthenon Publishing Group; 1999: 102–107. 20. Saba N, Sutton D, Ross H, et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant. 1999;24:853–855. 21. Benekli M, Anderson B, Wentling D, et al. Severe respiratory depression after dimethylsulphoxide-containing autologous stem cell infusion in a patient with AL amyloidosis. Bone Marrow Transplant. 2000;25:1299 –1301. 22. Akasheh MS, Chang CP, Vesole DH. Acute tumour lysis syndrome: a case in AL amyloidosis. Br J Haematol. 1999;107:387. 23. Schulenburg A, Kalhs P, Oberhuber G, et al. Gastrointestinal perforation early after peripheral blood stem cell transplantation for AL amyloidosis. Bone Marrow Transplant. 1998;22:293–295. 24. Schuh A, Dandridge J, Haydon P, Littlewood TJ. Encephalopathy complicating high-dose melphalan. Bone Marrow Transplant. 1999; 24:1141–1143. 25. Dispenzieri A, Lacy MQ, Kyle RA, et al. Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol. 2001;19:3350 – 3356. 26. Lahuerta JJ, Martinez-Lopez J, Grande C, et al. Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma. Br J Haematol. 2000;109:138 –147. 27. Abraham R, Chen C, Tsang R, et al. Intensification of the stem cell transplant induction regimen results in increased treatment-related mortality without improved outcome in multiple myeloma. Bone Marrow Transplant. 1999;24:1291–1297.
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induced pulmonary toxicity. J Hematother Stem Cell Res. 2000;9: 635–643. 32. Gertz MA, Lacy MQ, Inwards DJ, et al. Factors influencing platelet recovery after blood cell transplantation in multiple myeloma. Bone Marrow Transplant. 1997;20:375–380. 33. Tricot G, Jagannath S, Vesole D, et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood. 1995;85:588 – 596. 34. Cuzick J, Erskine S, Edelman D, Galton DA. A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis. A report to the Medical Research Council’s working party on leukaemia in adults. Br J Cancer. 1987;55:523–529.
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