patients, two were not candidates for high-dose therapy, based on poor ... receive anti-arrythmic therapy. Keywords: amyloid; heart; stem cell; transplant; chemo-.
Bone Marrow Transplantation, (1999) 24, 853–855 1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt
High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant N Saba, DM Sutton, HJ Ross, S Siu, RM Crump, A Keating and AK Stewart Autologous Blood and Marrow Transplant Program, The Toronto Hospital, Toronto, Ontario, Canada
Summary: Dose-intensive chemotherapy with PBSC support was recently reported to be feasible in cardiac amyloidosis with some patients achieving post-transplant improvement in performance status. At our center, 11 patients with symptomatic primary systemic amyloidosis and predominant cardiac involvement confirmed by biopsy or increased wall thickness on echocardiogram were evaluated for high-dose therapy. The average time from diagnosis to referral was 11 months (4–26 months). Of the 11 patients, two were not candidates for high-dose therapy, based on poor performance status. The remaining nine patients proceeded to PBSC collection. Three patients died during the mobilization period: two of rapid atrial fibrillation, and the third secondary to progressive heart failure. Six patients proceeded to transplantation. However, one died of sudden cardiac arrest the day of melphalan administration, one following hypotension related to stem cell infusion, and one of hypotensive shock the day following stem cell infusion. Three patients recovered and left the hospital, but one died of a cardiorespiratory event at home within 6 weeks of discharge. Both surviving patients demonstrate objective improvement. A decision to use high-dose therapy and stem cell support in cardiac amyloidosis must balance the substantial morbidity of the procedure with the potential benefits. Transplant regimens should avoid cardiotoxic agents such as cyclophosphamide and DMSO and patients should receive anti-arrythmic therapy. Keywords: amyloid; heart; stem cell; transplant; chemotherapy
Light chain-associated (AL) amyloidosis is a well recognized complication of plasma cell disorders.1 It is an infiltrative process characterized by the extracellular deposition of insoluble fibrillar immunoglobulin light chains in the kidneys, heart, liver, autonomic and peripheral nerves.2 Despite treatment with oral melphalan and prednisone, median survival is close to 18 months from the time of diagnosis and is even shorter for patients with cardiac amyloid.3,4 Dose-intensive chemotherapy with mobilized blood stem cell support was recently reported to be feasible in Correspondence: Dr K Stewart, The Princess Margaret Hospital, 610 University Avenue, 5th floor – Room 126, Toronto, ON, M5G 2C4, Canada Received 29 March 1999; accepted 27 May 1999
patients with cardiac amyloidosis with some patients subsequently achieving improvement in their performance status.5–7 Nevertheless, the advanced stage of cardiac amyloidosis in most patients at presentation raises questions about the suitability of such aggressive modes of therapy for the majority of patients since referral and selection bias may potentially account for the positive results reported so far. In view of the high mortality for cardiac amyloid patients reported at other institutions5–7 we now report our own toxicity data to fuel further debate about the merits of stem cell transplant in this disease. We report the outcome of 11 primary amyloidosis patients with predominant cardiac involvement who were evaluated for high-dose therapy at our center and highlight the unique difficulties in transplanting primary cardiac amyloid. Patients and methods Eleven patients with primary systemic amyloidosis and predominant cardiac involvement confirmed by symptoms and endomyocardial biopsy or increased wall thickness on echocardiogram were evaluated for high-dose therapy. Patients with secondary, localized, senile amyloidosis, or overt multiple myeloma were not included. Patients with primary amyloidosis whose primary symptomatology was not cardiac were also excluded. Patient characteristics and main clinical manifestations of AL are listed in Table 1. Median age was 57 years (range: 49–65 years). Four of the 11 had clinical congestive heart failure. Four of 11 patients had co-existent nephrotic syndrome at the time of diagnosis. Four had hepatomegaly and an alkaline phosphatase level of ⬎200 IU/l. Two of 11 patients had renal insufficiency documented by a serum creatinine of ⬎200 IU/l. One patient had neuropathy documented by postural hypotension. Formal autonomic nerve testing was not performed. Two patients had clinical or laboratory evidence of five organ involvement by amyloidosis, two patients had four organs involved, two had three organs involved, and four had two or less organs clinically involved. The average time from diagnosis to referral was 11 months (4–26 months). Five of 11 patients had received chemotherapy prior to transplant: four received melphalan to a total dose of ⬍200 mg, of whom one received additional chemotherapy with cytoxan. One patient received cytoxan alone. Of the 11 original patients, two were not candidates for high-dose therapy based on poor performance status: inotrope dependence, and progressive jaundice, respectively. The remaining nine patients proceeded to PBSC col-
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Table 1
Male/Female Median age (years) Prior therapy None Melphalan ⬍200 mg Melphalan + cytoxan Cytoxan Clinical manifestation at the time of referral Nephrotic syndrome ⬎3000 mg/24 h Congestive heart failure Hepatomegaly and alkaline phosphatase ⬎200 IU/l Renal insufficiency (Serum creatinine ⬎200 mol/l) Neuropathy: postural hypotension ⬎5 ⬎4 ⬎3 ⭐2
episodes of hypotensive shock associated with stem cell re-infusion noted.8
Patients characteristics
organs organs organs organs
involved involved involved involved
Monoclonal protein Kappa Lambda Conditioning regimen Melphalan 140 mg/m2 i.v. and 12 Gy TBI Melphalan 140 mg/m2 alone
5/6 57 (49–65) 6 3 1 1 4/11 4/11 4/11 3/11 1/11 2/11 2/11 2/11 5/11 6/11 5/11 4 2
lection following cyclophosphamide (2.5 g/m2) and G-CSF (10 g/kg) (n = 5), or after cardiac toxicity from cyclophosphamide was suspected, G-CSF alone (n = 4). The conditioning regimen for six patients proceeding to transplant consisted of high-dose melphalan 140 mg/m2 and TBI 1200 cGy (n = 4), or in the last two patients melphalan 140 mg/m2 (n = 2). The transplant regimen was reduced after excess toxicity became evident. Toxicity Of the nine patients who proceeded to PBSC collection, five received 2.5 g/m2 cyclophosphamide as a mobilizing agent. Three of these five patients died during the mobilization period, whereas none of the four patients who received G-CSF alone died during mobilization. Two deaths resulted from refractory atrial fibrillation, and the third secondary to progressive heart failure. Six patients proceeded to transplantation with melphalan 140 mg/m2 and TBI 1200 (n = 4), or melphalan 140 mg/m2 (n = 2); three died in hospital during the transplantation procedure two of whom were in the radiation induction group. One patient in the radiation group died of a sudden cardiac arrest prior to receiving radiation on the day of melphalan therapy, one following hypotension related to stem cell infusion, and the third (melphalan alone) secondary to hypotensive shock the day following stem cell infusion. Three patients recovered and left the hospital. However, one subsequently died suddenly of a cardiorespiratory event at home 1 month following discharge. Three patients, including both survivors developed rapid atrial arrhythmias during the neutropenic nadir. In comparison, over 100 myeloma patients were transplanted at our institution in the past 5 years with no cardiac arrythmia-related deaths or
Response Two patients remain alive. One has a documented improvement in myocardial wall thickness, defined as 2 mm decrease in the thickness of the posterior wall on echocardiogram; and the other exhibits a marked improvement over pre-transplant performance status (NYHA class 3 to class 1) without obvious echocardiographic improvement at this time. Statistical analysis Univariate analysis was performed to identify factors that predicted mortality. To further define appropriate selection criteria, we looked at the correlation between mortality and a number of pre-transplant characteristics, including: performance status, number of organs involved, hypotension, thickness of the posterior wall on echocardiogram, ejection fraction, serum creatinine (Cr), prior use of melphalan, and the presence of hypogammaglobulinemia. For all variables a Fisher exact test was used. No statistically significant associations were found between death and the variables analyzed, reflecting the small patient numbers. Discussion The life expectancy for patients with AL amyloidosis is only 13–18 months1,2 and only 20% of patients with AL amyloidosis respond to traditional low-intensity melphalan chemotherapy,3,4 which does not completely eradicate the monoclonal plasma cells and therefore, does not usually halt the progression of the disease. Historically, patients have been excluded from trials of high-dose melphalan therapy because of concerns regarding toxicity particularly in the setting of allogeneic transplant.9,10 Nevertheless, in the few allogeneic transplant cases reported, objective amelioration of amyloid-related organ dysfunction, including cardiac function have occurred.11 Early reports using autologous stem cell transplantation also reported prolonged survival and responses providing a basis for further exploration of this therapeutic modality.12–14 Indeed, subsequent investigation of high-dose therapy in amyloid has been promising. At Boston University 13 of 21 patients with AL amyloidosis had a complete response of their clonal plasma cell disorder to high-dose melphalan with an associated improvement of markers of amyloid organ involvement.5,6 In this series, predominant cardiac involvement, present in eight patients, carried a negative prognostic value, with only 38% of patients alive at follow-up compared to 82% survival for patients without predominant cardiac involvement at baseline. In another series, nine toxic deaths were reported among 21 patients with systemic amyloidosis treated with high-dose therapy in France by Moreau et al;7 three out of a total of six patients with documented cardiac amyloidosis had a toxic death. In the latter report, patients with fewer than two clinical manifestations at the time of high-dose therapy had a better prognosis for both response and survival. Thus, in the only two series of autologous trans-
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plant for amyloid reported so far, mortality in patients with predominant cardiac involvement was eight of 14 or 57%. At our center only two out of 11 patients referred for transplant for primary cardiac amyloidosis remain alive. Of six patients who actually received a transplant, three died during the procedure. This 50% mortality rate is entirely in keeping with that observed in other small series and fails to account for the additional mortality observed in the weeks or months immediately prior to or following the transplant procedure. Overall, only two of nine patients considered eligible for transplant are alive and well more than 6 months after referral. High mortality, may in part reflect our initial use of cyclophosphamide for PBSC mobilization, use of radiation at the time of transplant and the infusion of DMSO preserved grafts. Although it is probable that a lack of adequate selection criteria contributed to these results, even patients with relatively good performance status had adverse outcomes. Indeed, as the numbers were small, no statistically predictive variables for survival of cardiac amyloid patients during transplantation could be defined. We conclude that in patients with cardiac amyloidosis, the decision to proceed to high-dose melphalan should weigh carefully the relative risks inherent in the disease and those associated with high-dose therapy. In our opinion, every effort should be made to minimize the possible risks involved: including mobilization with growth factor alone, infusion of DMSO-depleted grafts, avoidance of radiation in the conditioning regimen and use of cardiac monitoring and prophylactic anti-arrythmic therapies. The latter is recommended based on the near universal development of atrial arrythmias in our patients. Finally, given the inherent difficulties in transplanting such patients, it is recommended that such individuals should only be transplanted on clinical trial protocols in specialized centers with adequate cardiac support units. References 1 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32: 45–49.
2 Gertz MA, Kyle RA, Greipp PR et al. Response rates and survival in primary systemic amyloidosis. Blood 1991; 77: 257–262. 3 Skinner M, Anderson JJ, Simms R et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 1996; 100: 290–298. 4 Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisolone and colchicine. New Engl J Med 1997; 336: 1202–1207. 5 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. 6 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. 7 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. 8 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 (in press). 9 Mehta J, Nagler A, Slavin S. Marrow transplantation in multiple myeloma (letter). New Engl J Med 1992; 326: 1087. 10 Gharton G. Marrow transplantation in multiple myeloma (letter). New Engl J Med 1992; 326: 1087. 11 Guillaume S, Straetmans N, Jadoul M et al. Allogeneic bone marrow transplantation for AL amyloidosis. Bone Marrow Transplant 1997; 20: 907–908. 12 Barlogie B. Marrow transplantation in multiple myeloma (letter). New Engl J Med 1992; 326: 1088. 13 Moreau P, Milpied N, de Faucal P et al. High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement (letter). Blood 1996; 87: 3063–3064. 14 Van Buren M, Hene RJ, Verdonck LF et al. Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Ann Intern Med 1995; 122: 508–510.
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