Solid Organ Transplantation in AL Amyloidosis
Abstract
Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2–13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.
Introduction
Amyloidosis is a multisystem disorder characterized by deposition of protein as insoluble fibrils, which disrupt tissue structure and function. Despite the heterogeneity of the precursor proteins which form amyloid fibrils in vivo, the structure and properties of all amyloid fibrils are remarkably similar. Classification of amyloidosis is based upon the precursor protein from which the fibrils are derived. In AL amyloidosis, which has an age-adjusted incidence in the United States of 5.1–12.8 million patients per year (1) and is the commonest type of acquired amyloidosis, the fibrils are derived from monoclonal immunoglobulin light chains produced by clonal dyscrasias which are usually of a subtle nature (2).
AL amyloid can deposit in almost any organ. Systemic AL amyloidosis may present with dysfunction of a single organ or alternatively, there may be amyloid deposition and dysfunction of multiple organ systems concomitantly. Untreated, it is a progressive and almost universally fatal disease. Deposition of amyloid in the kidneys presents with varying degrees of proteinuric chronic kidney disease (CKD) and may lead to end-stage renal disease (ESRD). In a recent study, 42% of patients presenting with renal AL amyloidosis required renal replacement therapy (RRT) during the course of their disease (3). AL amyloid deposits in the heart typically cause a restrictive cardiomyopathy characterized by concentric ventricular wall thickening and diastolic dysfunction resulting in congestive heart failure (CHF) (4). Once CHF has supervened in AL amyloidosis, prognosis is poor with a median survival of 4–6 months (5). Hepatic AL amyloid can present indolently with hepatomegaly or deranged liver function tests or occasionally with liver failure or hepatic rupture (6), and is usually associated with presence of extensive extrahepatic deposits (7). Hyperbilirubinemia in the context of hepatic AL amyloid confers a particularly poor prognosis of <4 months (8).
In the absence of available treatment to disperse existing amyloid deposits, therapy of AL amyloidosis revolves around attempting to reduce the abundance of amyloidogenic monoclonal serum free light chains with myeloma-type chemotherapy to slow or halt ongoing amyloid deposition. Despite considerable advances in chemotherapy in recent years leading to improved median survival times (9), a significant proportion of patients have advanced, unsalvageable organ dysfunction by the time they are diagnosed with systemic AL amyloidosis, and the majority of patients continue to die from their disease. Furthermore, patients with advanced cardiac and hepatic involvement are usually too unwell at presentation to tolerate the doses of chemotherapy that are required to successfully suppress their underlying clonal disease.
The role of solid organ transplantation in AL amyloidosis is contentious due to shortage of donor organs. Previous small series have shown inferior outcomes with heart (10) and kidney transplantation among patients with AL amyloidosis compared to those with other causes of cardiac and renal failure, respectively. Deaths have been associated with both recurrence of amyloid in the graft or progressive deposition of amyloid in nontransplanted organs. We present here the clinical management and outcome in 45 patients with AL amyloidosis attending a single national center over a 25-year period who were selected to receive solid organ transplants, and highlight in particular, the disease- and treatment-related factors that are likely to influence outcome with solid organ transplantation during the modern era of effective chemotherapy.
Materials and Methods
Patients
All patients who underwent renal, cardiac or liver transplantation for organ failure secondary to AL amyloidosis between 1984 and 2009 were identified from the UK National Amyloidosis Centre (NAC) database. Only patients without multiple myeloma underlying their AL amyloidosis received solid organ transplants. In addition, selection criteria for renal and cardiac transplantation included absence of extensive disease outside the failing organ. A good ECOG performance status was required for renal transplantation in contrast to cardiac transplantation, where performance status prior to the procedure was poor. Patients who underwent orthotopic liver transplantation (OLT) were those with a poor prognosis due to extensive liver amyloid associated with clinical decompensation. Among 2272 patients with systemic AL amyloidosis followed up in our center during the 25-year period, the 45 (2.0%) patients presented here were not the only cases who fulfilled the above criteria; listing for solid organ transplantation was also dependent upon attitudes to transplantation in AL amyloidosis within each transplant center which varied substantially.
The diagnosis of amyloidosis was confirmed histologically in all cases. Among cases where amyloid was confirmed histologically but immunohistochemical staining with antibodies against all known amyloid fibril proteins excluded AA amyloidosis but was nondiagnostic of AL type, the following criteria were required for inclusion; evidence of a clonal B-cell dyscrasia; absence of amyloidogenic mutations in the genes encoding transthyretin, fibrinogen A α-chain, apolipoprotein AI, apolipoprotein A2 and lysozyme (to rule out hereditary forms of amyloidosis) (11); absence of a chronic inflammatory disorder.
Assessment and monitoring at the National Amyloidosis Centre
Assessment at the baseline NAC visit, repeated 6–12 monthly, included clinical evaluation, detailed biochemical tests of renal, hepatic and cardiac function including NT-proBNP, serum and urine immunoelectrophoresis, electrocardiographic and echocardiographic studies. Serial whole body anterior and posterior scintigraphic imaging after administration of 123I-labeled serum amyloid P component (SAP) using an Elscint Superhelix gamma camera was undertaken to establish baseline and change in whole body amyloid load, as previously described (12). Labeled SAP studies were interpreted by a panel of physicians with experience of over 10 000 SAP scans.
Organ involvement by amyloid was determined according to international consensus criteria (13). Baseline hematological investigations included bone marrow aspirate, trephine and skeletal survey. Serum free light chains (FLCs) were prospectively followed at 1–3 monthly intervals in all patients after January 2002 and, prior to this date, were measured retrospectively from stored sera obtained during all visits to our center. A complete clonal response (CR) following chemotherapy was defined as no evidence of a monoclonal protein on serum and urine immunoelectrophoresis and normalization of the FLCs in the context of normal renal function or normalization of the FLC ratio in the context of renal impairment. No response (NR) was defined as a reduction of less than 50% of the serum paraprotein or the amyloidogenic FLC. A partial hematologic response (PR) following chemotherapy was defined as any response not fulfilling the criteria for CR or NR.
Preoperative transplant assessments and postoperative immunosuppression regimens were according to local protocol in each case. Different regimens of chemotherapy and/or stem cell transplantation were administered at different times in relation to solid organ transplantation in each of the patient groups.
The medical care was performed with informed consent from each patient in accordance with the Declaration of Helsinki. Institutional review board approval for the study was obtained from the Royal Free Hospital Ethics Committee.
Results
Liver transplantation
Nine patients, all of whom had a dominant hepatic presentation of amyloidosis, received OLT for systemic AL amyloidosis (Table 1). Three cases had underlying lambda light chain secreting plasma cell dyscrasias and six had an amyloidogenic kappa secreting clone. Median (range) age at diagnosis of amyloidosis was 56 (range 29–66) years and median (range) time from symptom onset to diagnosis of amyloidosis was 2.3 (0–10.6) months. Median (range) time from diagnosis to OLT was 5.5 (1.5–10.5) months. Pre-OLT SAP scintigraphy revealed a large total body amyloid load in all cases. Patients were followed for a median (range) of 0.9 (0–12.5) years from OLT.
| Patient no./1sex | Age at symptom onset | Total body amyloid load by SAP scintigraphy at presentation | 2Extrahepatic organ involvement at presentation by consensus criteria | Time from diagnosis of amyloid to OLT (months) | 3Chemotherapy treatment pre-OLT/treatment post-OLT | 4Clonal response to treatment | Timing of clonal response relative to OLT (months) | Clonal relapse after treatment (yes/no) | Recurrence of graft amyloid by SAP scintigraphy | Timing of amyloid recurrence or last SAP scan after OLT with no evidence of recurrence (months) | 5Dead/alive | Time from OLT to censor or death (years) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (M) | 54 | Large | N | 6 | N/S | CR | +60 | N | Y | 31 | A | 12.5 |
| 2 (M) | 44 | Large | N | 9 | N/C+S | PR | +17 | N | Y | 7 | A | 5.7 |
| 3 (M) | 61 | Large | N | 5 | C/C | PR | +10 | N | Y | 10 | D | 0.9 |
| 4 (M) | 31 | Large | N | 6 | C/N | NR | – | – | N | 11 | D | 0.9 |
| 5 (M) | 66 | Large | K,H,A | 2 | N/N | N/A | – | – | N | 3 | D | 0.4 |
| 6 (F) | 63 | Large | K,H | 8 | N/C | CR | +24 | N | N | 24 | D | 2 |
| 7 (F) | 56 | Large | H | 1 | N/N | N/A | – | – | – | – | D | 0 |
| 8 (F) | 29 | Large | N | 10 | C/S | PR | −4 | N | – | – | D | 0.4 |
| 9 (F) | 60 | Large | G | 2 | N/N | N/A | – | – | – | – | D | 0.3 |
- 1M, male; F, female.
- 2N, none; K, kidneys; H, heart; A, autonomic nervous system; G, gastrointestinal tract.
- 3N, none; C, chemotherapy; S, stem cell transplantation.
- 4NR, no response; PR, partial response; CR, complete response; N/A, not applicable.
- 5A, alive; D, dead.
One and 5-year patient survival from transplantation among those receiving OLT was 33% and 22%, respectively. Causes of death among the six patients who died within the first year were as follows: intraoperative death due to cardiac decompensation (1 case), sepsis (3 cases), sudden unexplained death (1 case) and declining renal function (1 case).
Three patients (5, 7 and 9; Table 1) were too unwell to receive chemotherapy treatment at any point during the course of their illness and died within 5 months of OLT. The remaining six patients received chemotherapy, including stem cell transplantation after OLT in three cases (patients 1, 2 and 8; Table 1). Two patients without extra hepatic organ dysfunction at the time of OLT, both of whom subsequently underwent and responded to stem cell transplantation (patients 1 and 2), were alive at censor 12.5 and 5.7 years after OLT without evidence of graft failure despite asymptomatic recurrence of liver amyloid. Among the four remaining cases to receive chemotherapy, three died within 2 years of OLT despite achieving a clonal response with chemotherapy (patients 3, 6 and 8). The remaining case who did not achieve a clonal response to chemotherapy (patient 4) died 0.9 years after OLT.
Four patients (1–4) developed rapidly progressive proteinuria following OLT associated with preexisting renal amyloid deposits. Interestingly, this occurred even in patients 1 and 2, despite good clonal responses to chemotherapy. Patient 1, who had a clonal CR with stem cell transplantation, underwent deceased donor renal transplantation 9.4 years after OLT. His CKD had been thought to be multifactorial from amyloid, hypertension and immunosuppression. There was no evidence of recurrent renal amyloid in the graft by SAP scintigraphy 2.5 years after renal transplantation, despite deterioration of renal allograft function to an eGFR at the time of censor of 29 mL/min.
Renal transplantation
Twenty-two patients, all of whom presented with renal dysfunction, received renal transplants (19 deceased donor and 3 live donor) after reaching end-stage renal failure secondary to AL amyloidosis (Table 2). Twelve patients had an underlying lambda light chain secreting plasma cell dyscrasia and 10 had an amyloidogenic kappa clone. Median (range) age at diagnosis of amyloid was 54 (41–68) years and median (range) time from symptom onset to diagnosis was 5.8 (0–58.2) months. Median (range) time from diagnosis to renal transplantation was 55.0 (12.3–204.6) months and from commencement of dialysis to renal transplantation was 26.7 (0.8–98.3) months. Median (range) follow-up from renal transplantation was 4.8 (0.2–13.3) years. Only 3/22 patients had amyloidotic extrarenal organ dysfunction at the time of renal transplantation; of the liver (patient 4; Table 2), heart (patient 17) and nerves (patient 21) in one case each. Seventeen of 22 patients had SAP scintigraphy before renal transplantation with extrarenal amyloid deposits evident by this technique in all but one such case.
| Patient no./1sex | Age at symptom onset | 2Total body amyloid load by SAP scan at RTx | 3Extrarenal organ involvement at RTx | Time from diagnosis of amyloid to RTx (months) | 4Chemotherapy treatment pre-RTx/post-RTx | 5Clonal response to treatment | Timing of clonal response relative to RTx (months) | 6Clonal relapse after initial (first line) chemotherapy | Timing of clonal relapse relative to RTx (months) | 7Graft failure/time from RTx to failure (years) | 8Dead/alive | Time from RTx to censor or death (years) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (F) | 40 | L | N | 84 | S/N | CR | −75 | N | N | A | 4.7 | |
| 2 (M) | 56 | M | N | 52 | C+S/N | PR | −42 | N | N | A | 2 | |
| 3 (F) | 41 | L | N | 68 | C/C | PR | −63 | Y | −9 | N | A | 7.6 |
| 4 (F) | 62 | L | 12 | N/C | NA | NA | N | D | 5.8 | |||
| 5 (F) | 50 | N | 39 | C/C | NA | NA | Y/13.1 | D | 13.3 | |||
| 6 (F) | 46 | M | N | 55 | C/N | PR | −42 | N | N | A | 6.3 | |
| 7 (F) | 61 | N | 66 | N/C | PR | 79 | N | N | D | 7.5 | ||
| 8 (M) | 57 | N | 32 | S+C/C | PR | −24 | Y | 50 | N | A | 5.3 | |
| 9 (F) | 51 | L | N | 57 | S+C/N | CR | −50 | N | N | A | 7.5 | |
| 10 (M) | 57 | S | N | 55 | C/N | PR | −44 | N | N | D | 0.2 | |
| 11 (F) | 60 | L | N | 115 | C/N | CR | −85 | Y | 28 | N | A | 2.7 |
| 12 (M) | 49 | M | N | 30 | C/C | NA | NA | N | D | 6.5 | ||
| 13 (M) | 45 | L | N | 160 | C/N | PR | −138 | N | N | A | 3.9 | |
| 14 (M) | 54 | M | N | 66 | C/N | PR | −48 | N | N | A | 4.7 | |
| 15 (F) | 43 | S | N | 204 | C/C | NA | NA | N | D | 5.3 | ||
| 16 (F) | 66 | N | N | 28 | C/N | NR | NR | N | D | 4.8 | ||
| 17 (F) | 65 | H | 61 | N/N | NA | NA | N | D | 1.9 | |||
| 18 (F) | 53 | M | N | 62 | C/C | NA | NA | N | A | 9.8 | ||
| 19 (F) | 58 | S | N | 48 | C+S/N | PR | −30 | N | N | D | 1.3 | |
| 20 (F) | 41 | S | N | 123 | C/N | NA | NA | Y/0.9 | D | 2.8 | ||
| 21 (M) | 45 | M | P, A | 32 | C/C | PR | −25 | Y | 3 | N | A | 1.3 |
| 22 (M) | 63 | S | N | 51 | C/C | PR | −45 | N | N | A | 0.5 |
- 1M, male; F, female.
- 2S, small; M, moderate; L, large; N, none.
- 3N, none; L, liver; H, heart; P, peripheral neuropathy; A, autonomic neuropathy.
- 4N, none; S, stem cell transplantation; C, chemotherapy.
- 5NA, not applicable; NR, no response; PR, partial response; CR, complete response.
- 6Y, yes; N, no; NA, not applicable.
- 7Y, yes; N, no.
- 8A, alive; D, dead.
There were no perioperative deaths. By Kaplan–Meier analysis, median estimated patient survival from diagnosis was 13.0 years, from dialysis was 9.1 years and from renal transplantation was 6.5 years. Among 10 patients who died, cause of death was sepsis (six cases), gastrointestinal hemorrhage (one case; patient 20), cardiac decompensation (one case; patient 10) and was unknown in two cases. The patient who died of cardiac failure did not have echocardiographic features of cardiac amyloidosis preoperatively but was discovered at autopsy to have coronary vessel amyloid in the absence of myocardial infiltration.
Nineteen patients received chemotherapy or SCT before renal transplantation to try and halt amyloid deposition and thereby prevent progressive impairment of their native amyloidotic kidneys. Acute irreversible kidney injury and dialysis dependence associated with hypotension was precipitated in four of five patients who underwent SCT (patients 1, 2, 8 and 19), the remaining case (patient 9) being dialysis dependent prior to SCT. Due to the lack of a prechemotherapy FLC sample, 4/19 patients were not evaluable for a clonal response. Among 15 evaluable patients, 14 had a clonal response to treatment (11 PR, 3 CR) and 1 (patient 16) had NR. All of the complete responders (patients 1, 9 and 11) were alive at censor, with two cases (patients 1 and 9) maintaining a clonal CR for 10.9 and 11.7 years, respectively, from first line treatment. Three patients (patients 4, 7, 17) in whom the diagnosis of AL amyloidosis was not confirmed prior to renal transplantation, did not receive chemotherapy before renal transplantation. Patient 17 did not receive chemotherapy at any point. Ten patients received chemotherapy after renal transplantation, eight of whom had received chemotherapy earlier in the course of their disease. No transplant failed due to recurrent amyloid despite evidence of amyloid within the renal allografts of five patients (patients 5, 7, 12, 14 and 18) detected by SAP scintigraphy a median (range) of 5.6 (4.4–7.8) years from renal transplantation. Two grafts failed, one from chronic allograft nephropathy (patient 5) and one from scarring related to recurrent transplant pyelonephritis (patient 20). One case (patient 18) developed proteinuria from graft amyloid 6.2 years after renal transplantation but this resolved after successful chemotherapy with preservation of renal allograft function at censor 3.6 years later.
Cardiac transplantation
Fourteen patients, 13 of whom presented with advanced cardiac failure and 1 of whom developed cardiac amyloidosis during follow-up for gastrointestinal amyloid, received cardiac transplants (Table 3). Eleven cases had an underlying lambda light chain secreting plasma cell dyscrasia and three cases had an amyloidogenic kappa clone. Median (range) age at diagnosis of amyloidosis was 52 (38–58) years and median (range) time from symptom onset to diagnosis was 10.0 (1.0–25.1) months. Median (range) time from diagnosis to cardiac transplantation was 6.3 (0–73.6) months. Median (range) follow-up from cardiac transplantation was 4.4 (0–10.1) years. At the time of cardiac transplantation, 8 patients had no extracardiac amyloid according to amyloid consensus criteria; four had amyloidotic dysfunction of one other organ and two patients had dysfunction of two other organs.
| Patient no./1Sex | 2Age at symptom onset | 3Echo before HTx (IVS/LVPW thickness, mm) | 4Extracardiac amyloid Pre-HTx (Consensus criteria) | Diagnosis to HTx (months) | 5Chemotherapy treatment pre-HTx/post-HTx | 6Clonal response to treatment | Time to clonal response relative to HTx (months) | Clonal relapse after initial treatment | Timing of clonal relapse relative to HTx (months) | Recurrence of amyloid by echo/time to recurrence (months) | Dead/alive | Time from HTx to censor or death (years) | 7Cause of death |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (M) | 58 | 18/18 | N | 9 | C/C+S | PR | −7 | Y | 18 | Y/97 | A | 9 | N/A |
| 2 (F) | 59 | U | N | 10 | C/C+S | PR | −1 | Y | 15 | N | A | 4.7 | N/A |
| 3 (M) | 52 | 18/19 | P | 32 | C/S | PR | −13 | N | N | A | 2.2 | N/A | |
| 4 (F) | 57 | 16/15 | N | 1 | N/S | CR | 19 | N | N | A | 1.8 | N/A | |
| 5 (M) | 43 | 18/17 | K | 2 | N/S | CR | 5 | N | N | D | 10.1 | SCD | |
| 6 (M) | 51 | U | K | 5 | N/C | CR | 43 | N | Y/28 | D | 9.7 | IC | |
| 7 (M) | 51 | 15/14 | N | 8 | N/S | PR | 23 | Y | 82 | Y/82 | D | 9.7 | PCA |
| 8 (M) | 55 | U | N | 5 | N/C+S | CR | 30 | Y | 83 | Y/83 | D | 7.5 | PCA |
| 9 (M) | U | U | N | 0 | N/C | NR | U | D | 4.6 | PEA | |||
| 10 (F) | 51 | 15/16 | K, P | 26 | C/N | PR | −16 | Y | 17 | N | D | 4.1 | PEA |
| 11 (F) | 50 | U | K, L | 9 | N/C | NR | N | D | 2.7 | PEA | |||
| 12 (M) | 51 | 15/15 | G | 74 | C/N | PR | −65 | Y | −1 | N | D | 0.0 | PF |
| 13 (M) | 46 | 16/18 | N | 2 | N/N | N/A | N/A | D | 0.0 | LA | |||
| 14 (M) | 38 | 18/18 | N | 3 | N/C+S | PR | 4 | N | Y/23 | D | 2.8 | PCA |
- 1M, male; F, female.
- 2U, unknown.
- 3IVS, interventricular septal thickness; LVPW, left ventricular posterior wall thickness.
- 4N, none; P, peripheral neuropathy; K, kidneys; G, gastrointestinal tract; L, liver.
- 5N, none; C, chemotherapy; S, stem cell transplantation.
- 6N/A, not applicable; NR, no response; PR, partial response; CR, complete response.
- 7N/A, not applicable; SCD, sudden cardiac death; IC, ischemic colitis; PCA, progressive cardiac amyloidosis; PEA, progressive extracardiac amyloidosis; PF, pump failure; LA, lung amyloid.
Median survival from cardiac transplantation by Kaplan–Meier analysis was 7.5 years for the entire cohort. There were two perioperative deaths (patients 12 and 13; Table 3) one from left ventricular failure and another from high right-sided cardiac pressures, shown at autopsy to be due to pulmonary amyloid. Among eight patients who underwent SCT after cardiac transplantation, median survival from cardiac transplantation was 9.7 years compared to 3.4 years among cases that did not undergo SCT (p = 0.01). No patient who underwent SCT after cardiac transplantation had major extracardiac organ dysfunction at the time of SCT.
All patients received chemotherapy during the course of their disease apart from the single case (patient 13; Table 3) who died perioperatively. Five patients were fit enough to receive chemotherapy before cardiac transplantation (patients 1, 2, 3, 10 and 12) and they all achieved a partial hematologic response. All but three cases (patients 10, 12 and 13) received chemotherapy after cardiac transplantation, including SCT in eight patients.
Amyloid recurred in the cardiac allografts of five patients (patients 1, 6, 7, 8 and 14), all of whom had persistence or relapse of their hematologic disease, and was first detected a median of 82.6 (22.6–96.8) months from cardiac transplantation. Four of these five cases died and a further three cases died from progressive extracardiac amyloid (patients 9, 10 and 11). There was a single unexplained sudden cardiac death in a patient who remained in hematologic CR (patient 5), which was not felt to be associated with progressive amyloidosis.
Discussion
This is the largest series of both cardiac and renal transplantation for systemic AL amyloidosis and reports the first cohort of patients with decompensated hepatic AL amyloidosis to undergo OLT. In comparison to transplantation for nonamyloid organ failure, outcomes among OLT recipients were very poor, but were comparable among this highly selected group of heart and kidney transplant recipients.
Despite recent advances in management of AL amyloidosis (9,14), many patients continue to present with advanced, irreversible amyloidotic end-organ damage and nearly 30% die within 1 year of diagnosis (9). The role of solid organ transplantation in AL amyloidosis remains contentious due to concerns about recurrence within the graft and progressive disease outside the graft. Most series of renal (15) and cardiac (10) transplantation in amyloidosis however, predate the discovery that systemic chemotherapy which successfully suppresses monoclonal light chain production can halt ongoing AL amyloid deposition (16,17). Some published transplant series even include patients with unknown or multiple amyloid types (18,19).
The patients reported here were carefully selected for their transplant procedure and comprised less than 2% of all patients with systemic AL amyloidosis assessed at the NAC during this period. These patients received standard antirejection immunosuppressive regimens according to local protocols in the absence of any existing data to support a modified immunosuppressive strategy in this particular disease. Selection criteria for cardiac transplantation included advanced cardiomyopathy, age under 60 years, and absence of myeloma or extensive extracardiac amyloidosis. The substantially more prolonged survival among patients who received SCT after cardiac transplantation in this series compared to those who did not proceed to SCT suggests that patients who are predicted to be fit enough to receive SCT after the cardiac transplant procedure may benefit most from cardiac transplantation. Patients with advanced amyloid cardiomyopathy, are usually too unwell to tolerate aggressive chemotherapy before cardiac transplantation, and given their predisposition to sudden cardiac death, should probably be listed for urgent cardiac transplantation with a view to subsequent chemotherapy or SCT. Selection criteria for renal transplantation included ESRD, age under 70 years, absence of myeloma or extensive extrarenal amyloidosis, ECOG performance status of 1 or 2, and, wherever possible, sufficient suppression of the underlying plasma cell dyscrasia by chemotherapy to prevent ongoing amyloid accumulation according to serial SAP scans. Importantly, only 3/22 patients in this series were in clonal CR prior to renal transplantation, although they had nearly all received chemotherapy and achieved at least a clonal PR. We, like others (20), believe that chemotherapy should usually be administered prior to consideration of renal transplantation in systemic AL amyloidosis, although reasonable outcomes have previously been reported with renal transplantation followed by autologous stem cell transplantation in a small number of patients with AL amyloidosis (21). Selection criteria for OLT included decompensated hepatic AL amyloidosis, age under 70 years and absence of clinically significant cardiac involvement by amyloid. Analogous to recipients of cardiac allografts, patients with decompensated liver disease are usually too unwell to receive chemotherapy prior to OLT, and the patients reported in the current series were scheduled to receive chemotherapy or SCT after OLT.
In this series, 4/9 (44%) OLT recipients were too unwell to receive chemotherapy at any stage after the transplant, mainly due to presence of extensive extrahepatic amyloid (22), and all such patients died within 1 year of the procedure. Among 5/9 patients who did receive chemotherapy after OLT, two were alive at censor including one who developed subsequent ESRD, the remaining three deaths occurring 0.4, 0.9 and 2 years after OLT. The 1- and 5-year patient survival following OLT of 33% and 22%, respectively, in this series compares very poorly to all-cause OLT survival estimates which exceeds 87% and approaches 75%, respectively, in the USA (23) and 82% and 71%, respectively, in Europe (http://www.eltr.org). It remains to be determined whether OLT combined with newer chemotherapy regimens, such as those containing a proteosome inhibitor, that might be better tolerated and induce a more rapid hematologic effect than older combinations, may play a role in treatment of patients with decompensated hepatic AL amyloidosis in the future.
Outcomes with renal transplantation in this cohort were good. Interestingly, no renal allografts failed from recurrent amyloid despite the fact that only three patients achieved a clonal CR with chemotherapy. Two of 10 deaths in renal transplant recipients were related to extrarenal amyloid deposits and current data supports renal transplantation in those AL patients who have a preserved ECOG performance status, little or no clinically significant extrarenal amyloidosis, and have achieved at least a clonal PR with prior chemotherapy. One area of contention is whether dialysis-dependent patients without extrarenal amyloidosis should receive chemotherapy while on dialysis, the sole purpose of which is to achieve a clonal response to permit listing for renal transplantation, or whether such patients should undergo renal transplantation followed by chemotherapy/SCT to prevent ongoing amyloid deposition (21). This series, which reports the best outcomes of any to date, supports attempting to achieve a clonal response prior to renal transplantation. The median patient survival of 6.5 years from renal transplantation is impressive considering the patients were transplanted over the course of 15 years and included three cases in whom the diagnosis of AL amyloidosis was unknown at the time of renal transplantation. In addition, the median patient survival from dialysis of 9.1 years in these 22 patients is distinctly better than the 3.6 years from dialysis in our nontransplanted AL amyloidosis ESRD patients (unpublished observations), although much of this difference is likely to reflect selection bias.
Survival among patients presenting with advanced cardiac AL amyloidosis in the absence of cardiac transplantation remains dismal (14,24). Up to one third of patients with AL amyloidosis die within 12 months of diagnosis, frequently from cardiac involvement (9). Furthermore, even among patients who survive for longer than 12 months, quality of life is generally poor with persistent and severe limitation of physical activity. The median patient survival from cardiac transplantation of 9.7 years among those who received subsequent SCT in this series is comparable to US ‘all-cause’ cardiac transplant survival (25). Successful outcomes among patients with dominant and isolated cardiac AL amyloidosis who receive sequential cardiac and stem cell transplantation have been widely reported in recent years (26–28). Successful outcomes have also been reported in small numbers of patients with chemotherapy followed by cardiac transplantation (29), but in our experience the risks of chemotherapy in patients with advanced cardiac amyloidosis are substantial, and clinical benefits are very delayed. Whenever there is likely to be a substantial delay before the cardiac transplant however, careful administration of high-dose dexamethasone or bortezomib, both of which have the potential to induce a rapid clonal response while preserving the option of recovering stem cells in the future, ought to be considered.
In summary, this series reports outcomes following cardiac, renal and liver transplantation among a highly selected cohort of patients with AL amyloidosis. Solid organ transplantation in AL amyloidosis should be accompanied by chemotherapeutic strategies to halt ongoing amyloid production and a multidisciplinary approach to the selection, peritransplant and hematologic management of such patients involving transplant physicians, transplant surgeons and hematologists is mandatory.
Acknowledgments
We thank our many colleagues for referring and caring for the patients; D. Rowczenio, A. Hughes, E. Pyart, D. Gopaul and D. Hutt for their technical and clinical support at the National Amyloidosis Centre. We would particularly like to thank Dr N. Banner and the clinical team at Harefield Hospital and Drs A. Stangou, J. O’Grady and Professor N. Heaton from the Institute of Liver Studies, King's College Hospital, London, who performed most of the heart and liver transplants, respectively. We thank J. Berkeley for expert preparation of the paper.
