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KOS 2007: The Role of High-Dose Therapy in AL-Amyloidosis
By Raymond Comenzo, MD
Raymond Comenzo, MD
Hematology Service
Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York, NY, USA

Hematology Service
Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York, NY, USA


Systemic light-chain (AL-)amyloidosis is treated by eliminating the clonal cells producing the free light chains (FLC) that cause the disease, allowing patients to survive and amyloid organ damage to stabilize or improve. Only one-third of newly diagnosed untreated patients with systemic AL-amyloidosis have sufficient organ reserves to tolerate high-dose melphalan with stem cell transplant (SCT). Post-SCT, two-thirds of patients experience at least a partial hematologic response (a 50% reduction in clonal plasma cells) but only half of the responders achieve a complete hematologic response, the optimal outcome with respect to survival and organ recovery. The remaining one third of patients do not respond and are treatment failures with a poor prognosis. Considering that the clonal plasma cells in AL-amyloidosis are indolent and non-proliferative, lack of response is less surprising than the fact that 30% of patients achieve complete hematologic responses. How melphalan is so effective is unclear.

The early experience with SCT in AL-amyloidosis was characterized by a 20% to 40% treatment-related mortality due to toxicities such as sudden cardiac death, intractable hypotension and massive gastrointestinal hemorrhage.(1) Improved patient selection and risk-adapted melphalan dosing have reduced treatment-related mortality to less than 5% at our center and elsewhere. Risk-adapted melphalan dosing aims to reduce treatment-related mortality, and is based on observed differences in melphalan-related toxicity and age-related survival in patients with AL-amyloidosis. This approach allows SCT to be a treatment platform not a high-risk strategy. Recently, we combined the platform of risk-adapted melphalan and SCT with adjuvant therapy (thalidomide and dexamethasone) in those failing to achieve a complete hematologic response post-SCT.(2) We are now evaluating the same approach with adjuvant bortezomib and dexamethasone.

In order to appreciate the role of high-dose melphalan and SCT in the treatment of systemic AL-amyloidosis one must consider the low-intensity therapies and the importance of patient selection. The goal remains eliminating the clonal plasma cells and FLC and supporting the patient over the time needed to achieve a hematologic response and organ stabilization or improvement. The conundrum of low-intensity therapy is that, though usually well tolerated, it is often ineffective because progression of amyloid organ-disease continues. Monthly oral melphalan and prednisone was the first therapy to show benefit in phase III trials.(3) Median survival was prolonged from 8 to 18 months and for the 20% who responded and survived more than 3.5 years there was a 20% incidence of myelodysplasia creating a risk of secondary leukemia. A multi-center phase II trial testing pulse dexamethasone followed by maintenance dexamethasone and alpha-interferon led to hematologic responses in 53% of patients; 24% achieved a complete response and median survival was 31 months.(4) In a phase II trial using monthly oral melphalan and dexamethasone, the response rate was 67% with 33% complete responses.(5) There were 2 treatment-related deaths in the first 100 days of therapy and 1 patient subsequently developed myelodysplasia but median survival exceeded 4 years. Many consider oral melphalan and dexamethasone the standard therapy for non-SCT patients. The combination is easily administered, usually for 6 to 12 months depending on the response of the FLC, and is similar to melphalan-based SCT except for the risk of myelodysplasia and secondary leukemia. In those failing melphalan and dexamethasone, clinical trials using bortezomib or lenalidomide should be sought; both agents are active. Thalidomide is active but difficult for patients to tolerate.(6)

The development of risk-adapted melphalan dosing and the application of SCT as initial therapy were both based on clinical trials. In the largest phase II clinical trial of high-dose melphalan and SCT, untreated patients enrolled within a year of diagnosis were stratified and randomized to initial SCT or SCT after 2 cycles of oral melphalan and prednisone.(7) The 100-day treatment-related mortality was 20% and 12% died in association with stem cell mobilization. At 5 years the overall survival was 50% for immediate and 39% for delayed SCT. Fewer patients randomized to initial oral therapy underwent SCT due to progression of disease; this affected patients with cardiac involvement disproportionately. Post-SCT survival was a function of the number of affected organ systems and the presence of cardiac involvement. With 4 years follow-up, median survival had not been reached for patients with either 1 or 2 major organ systems involved (of heart, kidneys, liver/GI tract and peripheral nervous system) or no symptomatic cardiac involvement,. In contrast, for those with > 3 organs involved or cardiac involvement, median survivals ranged from 5 to 10 months highlighting the importance of patient selection. Patients at high risk of dying in SCT were those with symptomatic 3- or 4-organ system involvement or cardiac amyloid associated with recurrent pleural effusions, cardiac syncope or symptomatic arrhythmias.

In a multi-center randomized prospective phase III trial, SCT was compared with oral melphalan and dexamethasone.(8) Comparisons of response rates and survival between those alive at least 3 months post-SCT and those who completed at least 3 months of oral melphalan and dexamethasone showed no difference. For both groups the hematologic response rates were 65%. Median survival was 48 months for SCT and 58 months for oral therapy. Surprisingly no cases of myelodysplasia were reported in the oral melphalan group. This phase III trial did not clearly define a standard therapy for AL. However, a case-cohort analysis has shown a survival advantage in good performance-status patients treated with SCT and quality of life improves in patients who respond to transplant.(9,10) The difference between 12 or 18 months of oral melphalan and dexamethasone and high-dose melpahlan with SCT is that, as in myeloma, transplant is not a final therapy but rather a platform for therapy with low risk of myelodysplasia. It is a useful initial therapy to which adjuvant treatments can be added in order to improve response rates.

In a phase II trial we tested the combined approach of SCT and adjuvant thalidomide and dexamethasone.2 Patients received SCT with risk-adapted melphalan dosing, and those not achieving a hematologic complete response at 3 months post-SCT received 9 months of thalidomide (50-200mg nightly) and dexamethasone (20mg/m2, 1-3 pulses monthly). Treatment-related mortality was 4.4% (2 of 45 patients) and at 3 months post-SCT 61% of patients had hematologic responses. Nearly half of those on adjuvant therapy had improved responses at 12 months including 6 who achieved complete responses. The response rate at 12 months was 77% with 38% complete responses; there was no difference in response rate based on the dose of melphalan. With a median follow-up of 29 months, median survival has not been reached. Further study of such combined approaches is warranted, employing SCT as a platform for therapy.

Blood stem cells have been mobilized with granulocyte colony-stimulating factor (G-CSF) and rare deaths have been reported during mobilization in patients with symptomatic cardiac amyloid or multisystem disease. Catastrophic complications though rare include a pulmonary syndrome associated with hypoxia and rupture of the spleen requiring emergent surgery. Currently we recommend that G-CSF be given at 6mcg/kg every 12 hours with collection beginning on day 5, and employ in-hospital monitored mobilization for patients at risk of hypoxia, hypotension or syncope.

In patients achieving complete or near complete hematologic responses, organ recovery can be variable. The liver can regenerate, regress to normal size and regain normal function. Peripheral and autonomic nervous system involvement can be reversed. Proteinuria can decline dramatically over months and years but creatinine clearance rarely improves and the kidneys remain at risk from non-amyloid insults. Recovery from cardiac involvement remains problematic. Only 20% of cardiac patients with hematologic responses show objective improvement by echocardiogram. With serial studies showing brain natriuretic peptide (BNP) decline in conjunction with FLC response, we now know that less injury or strain occurs as the precursor protein is eliminated. Despite complete hematologic responses, patients with cardiac amyloid can experience cardiac dysfunction and sudden arrhythmic events. The utility of low-dose anti-arrhythmic agents or anticoagulation in the management of cardiac patients remains to be prospectively defined.

High-dose melphalan with SCT for AL-amyloidosis is effective in patients with limited disease when they are treated at centers with low treatment-related mortality. It provides a platform for testing novel adjuvant therapies post-SCT with the goal of maximizing the complete hematologic response rate. Its role may change if outcomes with low-intensity therapies improve as novel agents are tested in combination with traditional ones such as cyclophosphamide, melphalan and dexamethasone. The development of anti-plasma cell monoclonal antibody therapy will also have a major impact on treatment strategies and patient outcomes.(11) Patients with systemic AL-amyloidosis should be treated whenever possible on clinical trials in order to advance our understanding and management of the disease.

1. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood. 2002;99:4276-4282.
2. Cohen AD ZP, Reich L, Hassoun H, Teruya-Feldstein J, Filippa DA, Clark B, Stubblefield M, Fleisher M, Nimer SD, Comenzo RL. Risk-adapted Melphalan with Stem Cell Transplant (SCT) and Adjuvant Dexamethasone +/- Thalidomide Achieves Low Treatment-related Mortality and High Hematologic Response Rates. In: Skinner M, ed. XIth International Symposium on Amyloidosis Boca Raton, FL: Taylor & Francis Group LLC; Publication pending, 2007.
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. Dhodapkar MV, Hussein MA, Rasmussen E, et al. Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood. 2004;104:3520-3526.
5. Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004;103:2936-2938.
6. Comenzo RL. Managing systemic light-chain amyloidosis. J Natl Compr Canc Netw. 2007;5:179-187.
7. Sanchorawala V, Wright DG, Seldin DC, et al. High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial. Bone Marrow Transplant. 2004;33:381-388.
8. Jaccard A MP, Leblond V, et al Autologous Stem Cell Transplantation (ASCT) Versus Oral Melphalan and High-Dose Dexamethasone in Patients with AL (Primary) Amyloidosis: Results of the French Multicentric Randomized Trial (MAG and IFM Intergroup). . Blood 2005;106:127a.
9. Dispenzieri A, Kyle RA, Lacy MQ, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood. 2004;103:3960-3963.
10. Seldin DC, Anderson JJ, Sanchorawala V, et al. Improvement in quality of life of patients with AL amyloidosis treated with high-dose melphalan and autologous stem cell transplantation. Blood. 2004;104:1888-1893.
11. Zhou P OA, Bonvini E, et al. The inhibitory Fcγ-receptor IIB (CD32B) is highly expressed on clonal plasma cells from patients with systemic light-chain (AL) amyloidosis and provides a target for monoclonal antibody therapy In: Skinner M, ed. XIth International Symposium on Amyloidosis Boca Raton, FL: Taylor & Francis Group LLC; Publication pending, 2007.

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