Five of our eight patients who underwent sequential OHT/ASCT are alive with a good functional status (NYHA Class I) at a median follow-up of 56 months (range 7 to 101 months). None have evidence of recurrent amyloidosis, with four remaining in complete hematologic remission. The actuarial survival of these patients () is 60% at 7 years, which is not significantly different from the outcomes of 17,389 patients collected in the database of the ISHLT who underwent OHT for non-amyloid heart disease during the same time. This is in contrast to the previously reported overall survival of 39% at 4 years in 10 patients with AL amyloidosis who received a cardiac transplant without ASCT 12
. Gilmore et al recently reported sequential OHT/ASCT in five patients with AL cardiac amyloidosis. Two died from progressive amyloidosis and three are alive, including one who developed progressive PCD that was successfully treated with high-dose corticosteroids 15
. Lacy and colleagues from the Mayo Clinic have also published a series of 11 patients undergoing sequential OHT/ASCT. They reported a 5-year overall survival rate of 62%, but overall survival was only 25% at 8 years. Two patients died from transplant-related toxicity and three died from progressive amyloidosis 16
. In contrast, the actuarial disease-free survival (without recurrent amyloidosis) in our patients at 8 years is 60%. The factors responsible for this possible improvement may include patient selection (less severe systemic amyloidosis) and improvements in supportive care post-ASCT.
Although these small series included only carefully selected patients, the results indicate that good outcomes are achievable in patients with severe cardiac AL amyloidosis following OHT if their PCD is successfully treated afterwards. This is a significant step forward from the outcomes of the ten patients in Hosenpud’s study who received OHT without subsequent ASCT, the majority of whom developed progressive amyloidosis involving major organs and recurrent amyloid deposition in their cardiac allografts.
The plasma cell dyscrasia relapsed in three of our seven evaluable patients 12 to 52 months following ASCT, but only one patient (patient #5) had biopsy-proven evidence of amyloid in the cardiac allograft. This is the only patient who had clinically significant fluid retention during the stem cell mobilization and after ASCT, and she eventually died from progressive amyloidosis complicated by multi-organ failure. Of note, patients with fluid retention syndrome are being increasingly recognized to have a particularly poor prognosis 20
. Interestingly, amyloid deposition in the transplanted heart of this patient was believed to have had little, if any, clinical significance; there was no echocardiographic evidence of amyloid cardiomyopathy. In contrast to our experience, five out of eleven patients reported by Lacy et al. showed amyloid deposition in the cardiac allograft, though none of them had symptoms, echocardiographic evidence, or biochemical evidence of cardiac amyloidosis 16
. A similar observation was reported by Hosenpud et al. where the majority of patients undergoing OHT without subsequent ASCT died from progressive disease involving the major organs and had recurrent amyloid deposition in the allograft, but cardiac amyloidosis had no apparent clinical significance 12
. Gilmore, in contrast, showed that relapse of the plasma cell dyscrasia following ASCT was associated with characteristic echocardiographic evidence of cardiac amyloidosis and rise in serum NT-pro-BNP15
. While conclusions are limited by the small sample size in our study, the observation of a lack of clinically significant recurrent amyloidosis in the transplanted heart despite the presence of clear disease progression in other organs might be due to an “altered” amyloidogenic property of light chains with particular respect to the “allogeneic” heart. It is possible that, in time, additional patients will demonstrate clinical manifestations of cardiac amyloidosis if light chain production is not adequately controlled.
Unfortunately, patients with AL amyloidosis and severe heart failure have an extraordinarily poor prognosis upon completing their cardiac transplant evaluation. Out of 26 patients evaluated, 18 patients were carefully selected and listed with the OPTN for OHT/ASCT, but only half survived to OHT. Nine patients died while waiting for OHT (DPT group) either due to cardiac causes or other complications of systemic amyloidosis; one patient had progression to multiple myeloma. With regards to patient characteristics, there were no significant differences between the patients who received sequential OHT/ASCT and the patients who did not (DPT). However, the patients in the former group had a significant improvement in their clinical outcomes following OHT/ASCT, and this raises the possible need for a change in cardiac donor allocation. The earlier application of plasma cell targeted therapeutic approaches with newer agents, such as bortezomib and lenalidomide21,22
, which are effective and better tolerated than conventional chemotherapeutics, beginning at the time of the evaluation process may be beneficial, and improve patients’ chances for receiving an OHT. A similar approach may also be considered for patients who are not ready for ASCT after OHT since a prolonged time without treatment may allow progression of the amyloidosis and therefore both impair the candidacy of these patients for ASCT and increase their transplant-related mortality.
Our observation of a similar survival in patients with amyloid heart disease undergoing sequential heart and stem-cell transplant to those in the ISHLT registry undergoing heart transplant for other diagnoses is subject to several limitations. Survival after cardiac transplantation has continued to improve in patients with advanced heart failure due to causes other than amyloidosis. We have observed recurrent plasma-cell disease in several of our patients after sequential heart and stem-cell transplantation that may limit their future survival. Thus, it is possible that survival in the two groups of patients beyond the time described may differ.
In conclusion, the tandem approach of OHT followed by high-dose melphalan and ASCT is a feasible strategy and can improve the survival of carefully selected patients with systemic AL amyloidosis who present with overt heart failure. A multidisciplinary approach dedicated to early diagnosis, appropriate and timely screening for OHT/ASCT, and a multimodality PCD-specific strategy incorporating both high-dose melphalan/ASCT and non-transplant steps (prior to OHT, after OHT, and following ASCT) is currently underway at the MGH to address AL amyloidosis patients who present with severe cardiac amyloidosis.