Q J Med 2000; 93: 257-260
© 2000 Association of Physicians
Editorial |
Prospects for effective treatment of AL amyloidosis?
The Trafford Department of Renal Medicine, Royal Sussex County Hospital, Brighton BN2 5BE Department of Haematology, Oxford Radcliffe Hospital, Oxford Oxford Kidney Unit, The Churchill, Oxford Radcliffe Hospital, Oxford
Systemic amyloidosis is a condition characterized by the extracellular deposition of insoluble fibrillar proteins, leading to organ dysfunction. Its various forms are classified according to the nature of the precursor protein constituent of the fibril for example: immunoglobulin light chains in AL amyloidosis, heavy chains in AH amyloid, serum amyloid A protein, (a component of the acute-phase response) in AA amyloid, and a heterogeneous group of abnormal proteins in the familial amyloidoses (reviewed in reference 1) (Figure 1
). AL amyloidosis is at present considered an incurable disease, with 8 months median survival from the time of diagnosis. The prognosis depends on the dominant organ system affected: patients with cardiac involvement have a median survival of 6 months, compared to 21 months in those with renal disease.
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Although there is no treatment which will lead to the resolution of amyloid, regression and clinical improvement have been achieved in those forms of amyloid for which treatment of the underlying disorder is available. This is important, for the presence of amyloid does not preclude supportive and substitution treatment, e.g. dialysis for renal failure. It is now possible to demonstrate this reduction in the amyloid load using 123I-SAP scintigraphy. This novel technique relies on the fact that all amyloid contains a glycoprotein—amyloid P component—which is in dynamic equilibrium with serum amyloid P (SAP). 123I-labelled SAP injected intravenously into normal human subjects is catabolized and cleared with a half-life of 24 h. In patients with amyloid, the labelled SAP is taken up by deposits, and scintigraphic imaging combined with clearance studies gives an indication of the amyloid load and its distribution.2
There is now good evidence of regression of AA amyloidosis in patients with juvenile rheumatoid arthritis treated with chlorambucil. Proteinuria diminishes, the amyloid load detected by 123I-SAP scintigraphy is reduced, and survival is prolonged.3,4 Similarly, treatment of Familial Mediterranean Fever with colchicine, which reduces the frequency of acute attacks, prevents the development of amyloid.5 The ß2-microglobulin-containing amyloid seen in patients on chronic dialysis regresses following successful renal transplantation.6 Finally, familial amyloid polyneuropathy, which results from a mutant transthyretin, improves after liver transplantation and hence a switch to the production of normal protein.7 In this issue of QJM, Gillmore and colleagues report the successful treatment by combined liver and kidney transplantation of a patient with liver and renal failure caused by another of the familial amyloidoses. In this case the amyloid precursor was an abnormal fibrinogen variant. As with familial amyloid polyneuropathy, the abnormal amyloid precursor is produced in the liver but in this case the liver was also severely affected by amyloid deposition. They were able to show dramatic and rapid clearance of the amyloid deposits in the spleen, the other major organ affected, following transplantation. A previous isolated kidney transplant had been lost with amyloid deposition, and familial fibrinogen 
-chain amyloidosis can be added to the list of conditions, such as primary hyperoxaluria, in which combined liver and kidney transplantation has become the treatment of choice.
Can a similar benefit be achieved by treating the cause of AL amyloidosis? Suppressing the plasma cell clone producing the amyloidogenic light chain is difficult because the cells have a low turnover and are therefore relatively resistant to chemotherapy. However, reports of a few patients treated as for myeloma, who survived much longer than expected,8–10 prompted research into the use of cyclical melphalan and prednisolone. The efficacy of any treatment can be judged by its effect on patient survival and on the organ infiltrated with amyloid. Response criteria for heart, renal, liver and haematological disease have been defined by Gertz et al.11 In brief, a renal response is defined as a >50% reduction in urinary protein loss in the absence of an increase in creatinine; a hepatic response a >50% reduction in the alkaline phosphatase with a decrease in size of the liver of more than 2 cm; and a cardiac response a decrease in the thickness of the interventricular septum of >2 mm or an increase in the ejection fraction of >20%.
In 1978, Kyle et al. reported the outcome in 55 patients with biopsy-proven AL amyloidosis entered into a randomized placebo-controlled double-blind study comparing standard doses of melphalan and prednisolone with placebo. Patients in the treatment arm fared better both in terms of survival and morbidity. Ten of 24 patients with nephrotic syndrome who received melphalan and prednisolone had a >50% reduction in proteinuria.12 They went on to report long-term follow-up of 153 patients who received melphalan and prednisolone for between 24 and 36 months. Response was measured against well-defined clinical criteria, including the disappearance of any paraprotein that had been present, although no attempt was made to look for histological evidence of regression and 123I-SAP scanning was not available. Twenty-seven (18%) fulfilled these criteria, with a median time to response of 12 months, and the median survival of responders was 7.5 years.11 These results were encouraging, but only a minority of patients responded, and improvement was often not evident until after a year of treatment. No prognostic features that identified responders could be identified, thus a large number of patients would need to be exposed to prolonged cytotoxic treatment with no benefit. Moreover, about 1 : 4 of 27 responders died from leukaemia/myelodysplasia, a complication attributed to the alkylating agent.
Because colchicine is effective in preventing amyloid in Familial Mediterranean Fever, even in patients whose acute attacks are not abrogated, and it inhibits the development of AA amyloid in a mouse model,13 it was tested in patients with AL amyloidosis. A study of 53 patients documented an improvement in survival from a median of 6 months to 17 months amongst those receiving colchicine, compared with historical controls.14 This finding resulted in two further large randomized studies being undertaken, neither showing any benefit from the addition of colchicine. In the first, 100 patients received either colchicine alone or colchicine together with melphalan and prednisolone. Patients in the melphalan/ prednisolone arm survived longer with a median of 12 months vs. 7 months, but the difference was not statistically significant.15 The other, involving 220 patients, had three treatment arms: colchicine alone, melphalan/prednisolone and colchicine/melphalan/prednisolone. Median survival in the two groups receiving melphalan/prednisolone was very similar, 17 months with and 18 months without colchicine, whereas in the colchicine-alone arm, it was only 8.5 months. Patients who had a demonstrable reduction in their paraprotein fared best, with a median survival of 50 months. Thirty-four patients (15%) survived 5 years or longer, of whom only three received colchicine alone.16
More aggressive chemotherapeutic regimens have been adopted for some patients. These are based on those used in the treatment of multiple myeloma and include ‘VAD’, the combination of vincristine, doxorubicin and dexamethasone. A small open trial of four patients with amyloidosis given VAD, reported in 1988, did show a 50% reduction in serum paraprotein in two patients but there was no survival benefit.17 More recently, in a retrospective review of 53 patients treated in one institution, nine received VAD, and when compared with other alkylating agents, there was a significant improvement in survival from a median of 10 months to over 17 months. However, cardiac and neurological toxicity is a feature of this combination, and might be exacerbated in a condition with cardiac and neurological involvement. One patient had a cardiac arrest and another developed peripheral neuropathy.18 The role of VAD in amyloidosis needs further evaluation. Gertz et al. have recently reported a randomized controlled trial comparing conventional melphalan and prednisolone treatment with a multiple alkylating agent protocol of vincristine, carmustine, melphalan, cyclophosphamide, and prednisolone in 101 patients with biopsy-proven primary amyloidosis stratified for organ involvement. Survival and response rates were not different.19 More, it seems, is not necessarily better.
A chance observation of clinical improvement in a patient with AL amyloidosis following treatment with 4'-iodo-4'-deoxydoxorubicin, an experimental derivative of doxorubicin, led to the intriguing suggestion that it may be able to mobilize the amyloid deposits themselves.20 Certainly it appears to bind all forms of amyloid, although the nature of the interaction is unknown.21 If binding in some way interfered with the bonding of the adjacent ß sheets essential to the formation of amyloid fibrils, then it is possible that the deposits could be gradually broken down. If the effect of deoxydoxorubicin is confirmed, a new class of drugs will need investigation.
The key to successful treatment of AL amyloidosis must be the elimination of the plasma cell clone. High-dose chemotherapy with peripheral blood stem cell (PBSC) support is a widely used treatment in patients with myeloma,22 and in the last few years a number of reports of this treatment in patients with AL amyloid have been published. The potential of this approach was demonstrated in a 32-year-old woman with AL amyloidosis unresponsive to melphalan and prednisolone, who underwent syngeneic bone-marrow transplantation from her identical twin, following high-dose cyclophosphamide and whole-body irradiation. There was clinical improvement after 6–12 months, and the 123I-SAP scan showed a reduction in the amyloid load.23
Comenzo et al. treated 25 patients with melphalan 200 mg/m2 and PBSC support.24 With a median follow-up of 24 months, 62% were alive and the median survival had not been reached. Two-thirds of the survivors had responded to treatment, with the remainder having stable disease. These are promising results. However the median age of patients was 48 years, compared to 65 years in unselected series, patients with severe organ dysfunction were excluded, and 18/25 patients were already 3–12 months from diagnosis at the time of high-dose treatment, suggesting that this was a series of patients who were already likely to have a survival longer than the median. Other reports of high-dose treatment in patients with amyloid have produced similar results, and have confirmed the high treatment-related mortality (up to 43%) in patients with amyloid involvement in two or more organs, and particularly high mortality in those with congestive cardiac failure.25,26 Patients with AL amyloid deemed ineligible for very-high-dose melphalan were treated in one study with an intermediate dose of 100 mg/m2 with PBSC support.27 The plan was to use two intermediate dose cycles, but in fact only 5/30 patients received both cycles. Six of the 30 patients died within 100 days of treatment, and at a median follow-up of 24 months, 17 (57%) patients were alive, with only five of them having had a disease response.
The treatment of AL amyloid remains very unsatisfactory. Oral melphalan and prednisolone should be tried, and high-dose treatment offered to those who are fit enough to tolerate it. For this group of patients, more intensive treatment may offer a survival advantage compared to standard treatment. There remain a number of challenges for the future. Stem-cell harvesting techniques need to be refined in order to hasten marrow recolonization and to reduce the number of tumour cells transferred, for example by selecting CD34+ve cells and screening for tumour markers using polymerase chain reaction-based assays.28,29 Treatment protocols require development, for example, with regard to timing (are tandem treatments superior to single courses?) and optimization of melphalan dosage in relation to the patients' co-morbid conditions.30
Acknowledgments
We are grateful to Dr Robert Kyle for reviewing the manuscript.
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