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Keywords:

  • autologous stem cell transplantation;
  • systemic AL amyloidosis

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS ( Table II)
  5. DISCUSSION
  6. References

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transpantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (±10.8) and 29.9% (±14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance <30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.

Primary systemic amyloidosis (AL) is a plasma cell dyscrasia characterized by deposits of fibrillar aggregates of monoclonal immunoglobulin light chains in vital organs ( Kyle & Gertz, 1995). Although therapy with oral melphalan and prednisone (MP) results in objective responses, treatment is still inadequate, and the median survival of large cohorts of patients with AL is always <2 years ( Kyle et al, 1986 , 1997; Gertz et al, 1991 ; Skinner et al, 1996 ). Recently we and others have proposed high-dose chemotherapy followed by stem cell rescue as therapy for AL ( Mariette et al, 1995 ; Moreau et al, 1996 ; Comenzo et al, 1996 ; van Buren et al, 1995 ). This approach is promising but the feasibility of such a procedure remains to be evaluated. Here we report the Intergroupe Français du Myélome (IFM) group experience of 21 cases of autologous stem cell transplantation (ASCT) for AL over the last 4 years.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS ( Table II)
  5. DISCUSSION
  6. References

Patients

Between June 1993 and March 1997, the IFM group performed 21 ASCT in patients with AL. AL was diagnosed by tissue biopsy in all cases. Selection criteria for ASCT were not specified, and the number of patients with AL who could not proceed to ASCT was not known. Patients with secondary, familial, senile, localized amyloidosis, or overt symptomatic multiple myeloma were not included in this study. Informed consent was obtained from all patients.

The patients' characteristics and main clinical manifestations of AL ( Gertz et al, 1991 ; Skinner et al, 1996 ; Kyle et al, 1997 ) are listed in Table I. 10 patients did not receive any chemotherapy before ASCT, and first-line therapy consisted of melphalan and prednisone (MP) in five (median six courses), or VAD regimen (vincristine, doxorubicin and dexamethasone) in six cases (median three courses), without any clinical response. The conditioning regimens consisted of high-dose melphalan (HDM) alone in 18 cases, either 140 mg/m2 (seven) 200 mg/m2 (11), or associated with 12 Gy total body irradiation in three cases.

Table 1. Table I. Patient characteristics.Thumbnail image of

Measurements of response

Response was assessed according to previously defined criteria ( Gertz et al, 1991 ; Kyle et al, 1997 ): a 50% reduction in 24 h protein loss without an increase in serum creatinine level during follow-up in case of nephrotic syndrome; a complete return to normal creatinine level in case of renal insufficiency; a total resolution of clinical symptoms of congestive heart failure and an improvement in the echocardiogram with reduction in the features of amyloid infiltration, such as a 2 mm decrease in the thickness of the interventricular septum or a 20% increase of the ejection fraction in case of cardiac involvement; a reduction in the size of the liver by at least 2 cm and a 50% decrease in serum alkaline phosphatase; and a disappearance or a reduction of more than 50% of serum and urine monoclonal protein. Tissue biopsies were not performed in each responding patient so that the histological regression of amyloid deposits could not be used as a response criterion.

Statistical analysis

Actuarial survival curves were constructed according to the Kaplan-Meier method. Overall survival (OS) was calculated from the day of stem cell reinfusion to the date of death from any cause. Event-free survival (EFS) was calculated from the day of stem cell reinfusion to the date of documented relapse, progressive or non-responding disease, or death from any cause. Univariate analysis was performed to identify factors that predicted for both OS and EFS. Data included in this analysis were as follows: sex, age, chemotherapy prior ASCT, time from diagnosis to ASCT, dose of i.v. melphalan (140 v 200 mg/m2), chief clinical manifestations of AL at the time of ASCT ( Gertz et al, 1991 ; Skinner et al, 1996 ; Kyle et al, 1997 ), i.e. symptoms of congestive heart failure, neuropathy, hepatomegaly associated with alkaline phosphatase > 200 IU/l, creatinine clearance < 30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, and the number of clinical manifestations of AL at the time of ASCT.

RESULTS ( 2 Table II)

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS ( Table II)
  5. DISCUSSION
  6. References
Table 2. Table II. Clinical manifestations at the time of ASCT and outcome. +: affected; −: not affected.Thumbnail image of

Toxicity

Nine toxic deaths were observed within the first month following transplantation from multi-organ failure (acute renal failure + oedema with pleural and pericardial effusions + hepatic dysfunction; n = 5), multi-organ failure + severe bleeding (n = 1), multi-organ failure + sudden death attributed to cardiac arrhythmia (n = 1) and sudden death due to cardiac arrhythmia (n = 2).With a median follow-up of 14 months (7–50), 12/21 patients are alive. The actuarial 4-year survival is 57.1% (±10.8%) for the whole group of patients.

Response

Ten of 12 surviving patients experienced response with improved organ function in the predominant sites of involvement, i.e. cardiac involvement alone in three cases, nephrotic syndrome alone in four cases, liver involvement alone in two cases and liver involvement associated with a nephrotic syndrome in the remaining case. 3/10 responding patients (patients 1, 3 and 12) experienced complete remission of plasma cell dyscrasia with normal bone marrow biopsy samples and disappearance of detectable M protein documented both by serum and urine immunofixation electrophoresis. One patient (no. 1) relapsed biologically without clinical symptoms of AL with reappearance of the M protein 32 months after ASCT ( Table II, Fig 1), whereas electrophoresis results of patients 3 and 12 remained normal 41 and 15 months after ASCT respectively. Two patients were alive without any modification of the disease, 17 and 10 months after ASCT respectively. For the whole group of patients, the actuarial 4-year EFS was 29.9% (±14.5%) (Fig 1).

image

Figure 1. Fig 1. Event-free survival of systemic AL amyloidosis patients following ASCT. Good prognosis: fewer than two clinical manifestations at ASCT; poor prognosis: two or more clinical manifestations at ASCT.

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Prognostic factor

One single parameter was predictive for both OS and EFS: the number of clinical manifestations at the time of ASCT. When patients had fewer than two clinical manifestations among the five criteria previously described at the time of ASCT the 4-year OS and EFS were 91.7% and 46.3% respectively, compared with 11.1% for both parameters when two or more major clinical manifestations were documented before ASCT (P = 0.0002 for OS and P = 0.0008 for EFS, two-sided Fisher's exact test) (Fig 1).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS ( Table II)
  5. DISCUSSION
  6. References

The prognosis of AL is extremely poor and most patients usually die within 2 years of diagnosis despite therapy ( Kyle et al, 1986 , 1997; Gertz et al, 1991 ; Skinner et al, 1996 ). To date, MP may be considered as the standard treatment in this disease ( Kyle et al, 1997 ), but no cure is known and all physicians are desperately looking for new effective treatment options ( Gillmore et al, 1997 ; Falk et al, 1997 ). A recent prospective and randomized trial of 220 patients comparing three regimens for AL has shown that MP is a better therapy than colchicine, or a combination of melphalan, prednisone and colchicine. This association resulted in objective responses and prolonged survival of up to 5 years in only 15% of the patients with a median duration of survival in the MP group of 18 months, compared with 8.5 months in the colchicine group and 17 months in the group treated with MP plus colchicine ( Kyle et al, 1997 ).

Taking into account the relationship between dose and response established in patients with multiple myeloma treated with melphalan, we and others have proposed the use of HDM with ASCT in AL in order to eliminate the plasma cell clone producing amyloidogenic proteins ( Moreau et al, 1996 ; Comenzo et al, 1996 , 1997). A small number of cases with encouraging results have been reported. The team from Boston University even described three cases of complete remission of plasma cell dyscrasia among five patients treated with HDM 200 mg/m2 plus ASCT ( Comenzo et al, 1996 ). All five experienced improved organ function in the predominantly involved organs. In this report, all five patients had normal renal, hepatic and cardiac functions at the time of ASCT.

Despite the potential bias of selection related to a retrospective uncontrolled multi-centre experience, our study confirms the feasibility of high-dose therapy and ASCT in a subset of patients without any organ dysfunction or fewer than two main clinical manifestations, including patients with isolated clinical symptoms of congestive heart failure, isolated renal insufficiency or nephrotic syndrome. In this situtation, dramatic clinical improvements can be achieved. On the contrary — and this is the major finding of this study — when two or more organ dysfunctions are documented, intensive therapy and ASCT was associated with an intolerable risk of toxic death of >75%, which precludes the use of such a strategy. This simple parameter could be used as a selection criterion for ASCT in patients with AL.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS ( Table II)
  5. DISCUSSION
  6. References
  • 1
    Comenzo, R.L., Falk, R.H., Reisinger, J., Dubrey, S., Finn, K., Sarnacki, D., Berk, J., Dember, L., Bergethon, P., LaValley, M., Sanchorawala, V., Vosburgh, E., Skinner, M. (1997) AL amyloidosis frequently remits after dose-intensive melphalan with blood stem cell support: outcomes in 55 patients. VI International Workshop on Multiple Myeloma, Boston, abstract 6-5.
  • 2
    Comenzo, R.L., Vosburgh, E., Simms, R.W., Bergethon, P., Sarnacki, D., Finn, K., Dubrey, S., Faller, D.V., Wright, D.G., Falk, R.H., Skinner, M. (1996) Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood, 88, 2801 2806.
  • 3
    Falk, R.H., Comenzo, R.L., Skinner, M. (1997) The systemic amyloidoses. New England Journal of Medicine, 337, 898 909.
  • 4
    Gertz, M.A., Kyle, R.A., Greipp, P.R. (1991) Response rates and survival in primary systemic amyloidosis. Blood, 77, 257 262.
  • 5
    Gillmore, J.D., Hawkins, P.N., Pepys, M.B. (1997) Amyloidosis: a review of recent diagnosis and therapeutic developments. British Journal of Haematology, 99, 245 256.
  • 6
    Kyle, R.A. & Gertz, M.A. (1995) Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Seminars in Hematology, 32, 45 59.
  • 7
    Kyle, R.A., Gertz, M.A., Greipp, P.R., Witzig, T.E., Lust, J.A., Lacy, M.Q., Therneau, T.M. (1997) A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicine. New England Journal of Medicine, 336, 1202 1207.
  • 8
    Kyle, R.A., Greipp, P.R., O'Fallon, W.M. (1986) Primary systemic amyloidosis: multivariant analysis for prognostic factors in 168 cases. Blood, 68, 220 224.
  • 9
    Mariette, X., Clauvel, J.P., Brouet, J.C. (1995) Intensive therapy in AL amyloidosis and light-chain deposition disease. (Letter). Annals of Internal Medicine, 123, 553.
  • 10
    Moreau, P., Milpied, N., De Faucal, P., Petit, T., Herbouiller, P., Bataille, R., Harousseau, J.L. (1996) High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement. (Letter). Blood, 87, 3063 3064.
  • 11
    Skinner, M., Anderson, J.J., Simms, R., Falk, R., Wang, M., Libbey, C.A., Jones, L.A., Cohen, A.S. (1996) Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. American Journal of Medicine, 100, 290 298.
  • 12
    Van Buren, M., Hené, R.J., Verdonck, L.F., Verzijlbergen, F.J., Lokhorst, H.M. (1995) Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Annals of Internal Medicine, 122, 508 510.