Clinical Outcomes and Effectiveness of Heart Transplantation in Patients With Systemic Light-chain Cardiac Amyloidosis : Transplantation

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Original Clinical Science—General

Clinical Outcomes and Effectiveness of Heart Transplantation in Patients With Systemic Light-chain Cardiac Amyloidosis

Jeong, Hyehyun MD1; Hwang, Inhwan MD1,2; Kim, Jwa Hoon MD, PhD1,3; Cho, Hyungwoo MD, PhD1; Kim, Min-Seok MD, PhD4; Lee, Sang Eun MD, PhD4; Choi, Hyo-In MD, PhD4,5; Jung, Sung-Ho MD, PhD6; Lee, Jae Won MD, PhD6; Yun, Tae-Jin MD, PhD6; Park, Jeong-Jun MD, PhD6,7; Kim, Miyoung MD, PhD8; Go, Heounjeong MD, PhD9; Park, Chan Sik MD, PhD9; Yoon, Dok Hyun MD, PhD1; Kim, Jae-Joong MD, PhD4

Author Information
doi: 10.1097/TP.0000000000004230

Abstract

INTRODUCTION

Immunoglobulin light-chain (AL) amyloidosis is characterized by the deposition of misfolded monoclonal light chains resulting in organ damage. Cardiac amyloidosis occurs when amyloid fibrils are deposited in the heart, leading to progressive cardiac dysfunction. Although the exact prevalence is unknown, more than half of AL amyloidosis patients have been reported to have cardiac involvement.1,2

Cardiac involvement is a major determinant of survival in those with AL amyloidosis.3 Survival differs widely by stage, and it is well known that elevated levels of cardiac biomarkers are associated with poor clinical outcomes.4 In advanced stages, median overall survival (OS) is limited to 4–7 mo.5,6 Although systemic therapeutics comprise the mainstay of treatment aiming to decrease the synthesis of the immunoglobulin light chain by reducing the clonal plasma cells, improvement of cardiac function occurs infrequently.7 Therefore, heart transplantation (HTPL) has been implemented for those with cardiac dysfunction as a way of restoring critical organ function. Previous small-scale retrospective studies have reported favorable outcomes among patients who have undergone HTPL followed by systemic treatment8-10; however, because of the limited number of patients, there is a paucity of evidence regarding specific indications for HTPL, as well as the prognostic implications of baseline characteristics among HTPL recipients.

We aimed to explore prognostic factors, responses to systemic treatment, and clinical and graft outcomes after HTPL, as well as to identify subgroups who would benefit from HTPL among patients with AL cardiac amyloidosis.

MATERIALS AND METHODS

Patients

Patients diagnosed with AL amyloidosis with cardiac involvement between January 2007 and December 2020 were included in the study. We excluded patients who were transferred and lost to follow-up after the initial diagnosis. This study was approved by the institutional review board of Asan Medical Center and performed according to the ethical standards of the institutional research committee and the Declaration of Helsinki. The institutional review board granted a waiver of informed consent for this retrospective study.

Assessments

We used the Mayo 2004 staging system with European modification as determined by brain natriuretic peptide (BNP) and cardiac troponin I levels for risk stratification as N-terminal probrain natriuretic peptide and troponin T were not available in the earlier part of the study period (cutoffs for staging, BNP 81 ng/L, cardiac troponin I 0.1 ng/mL; stage I, II, III refer to 0, 1, and 2 variables above the cutoffs, respectively; stage III was further divided into stage IIIa and IIIb by BNP ranges of 81–700 ng/L and BNP > 700 ng/L, respectively).5 The diagnostic evaluation included serum-free light chain (sFLC) assay, protein electrophoresis and immunofixation electrophoresis for serum and urine, bone marrow biopsy, echocardiography, abdominal fat pad biopsy, and biopsy of symptomatic organs as clinically indicated. Organ involvement of amyloidosis was defined per the previously reported consensus criteria.11 For example, renal involvement was defined as 24 h urine protein >0.5 g/d and predominantly albuminuria. During the study period, indications for HTPL in our institution included: (1) left ventricular ejection fraction (LVEF) ≤40%; (2) Mayo 2004 European stage III; or (3) New York Heart Association class III or IV heart failure, in the absence of multiorgan involvement of amyloidosis including kidney causing renal insufficiency. After HTPL, routine surveillance with echocardiography and endomyocardial biopsy was performed.

Hematologic responses were evaluated by determining the differences between involved and uninvolved free light chain (dFLC) levels as described previously (Table S1, SDC, https://links.lww.com/TP/C468),12 and patients were divided into responders (complete, very good partial, or partial response) and nonresponders (no response or progression). For cardiac responses, changes in the BNP level were used and categorized into response (≥50 ng/L and ≥30% reduction in BNP), progression (≥50 ng/L and ≥30% increase in BNP), and stable (<50 ng/L or <30% change in BNP).13

Statistical Analysis

Baseline characteristics were assessed by a descriptive method. OS was defined as the time from diagnosis to death of any cause. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable prognostic factor analyses were performed using Cox proportional hazards modeling. Variables that show significant associations with OS in the univariable analyses and known prognostic factors in cardiac amyloidosis were included in the multivariable model. Landmark analyses assessing the association between treatment response and survival were performed in the 8th and 12th wk after initial systemic treatment. Patients who died or underwent HTPL before landmark time points were excluded from the landmark analyses. All tests were 2-sided, and P < 0.05 were considered statistically significant. Statistical analyses were performed using R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Overall Patient Characteristics

Between January 2007 and December 2020, 80 cardiac amyloidosis patients were diagnosed and identified. Seven patients were excluded because they were lost to follow-up immediately after diagnosis, and a total of 73 were included in the analysis. Autologous stem cell transplantation (ASCT) and HTPL were first performed in 2013 in the study population.

Among these patients, 72 (98.6%) received systemic treatment. Melphalan-based regimens (n = 19/28 [67.9%]) were the most commonly used ones in the earlier period (2007–2012), whereas immunomodulatory drugs and proteasome inhibitor-based regimens were the most frequently used treatment in the later period (n = 34/45 [75.6%]) (2013–2020) (Table S2, SDC, https://links.lww.com/TP/C468). Fourteen patients were listed for HTPL, of which 12 patients (16.4%) underwent HTPL, whereas the remaining 2 patients died before HTPL because of sudden cardiac arrest. A total of 13 patients (17.8%) underwent ASCT. Of the 12 patients who received HTPL, 6 patients underwent ASCT after HTPL, whereas the remaining 6 patients did not because of poor performance (n = 3), old age (age > 65 y, n = 2), or patient preference (n = 1).

The baseline characteristics of the patients are presented in Table 1. Overall, the baseline characteristics were similar between patients who underwent HTPL and those who did not, including age and performance status at diagnosis, dFLC level, and sFLC ratio. The Mayo 2004 European stage and proportions of patients with renal involvement of amyloidosis also did not differ between groups; however, no patients in the HTPL group had renal insufficiency with an estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 at diagnosis, whereas 26.2% of patients in the non-HTPL group had renal insufficiency. Additionally, patients in the HTPL group tended to have lower LVEF values (median 48% versus 57%, P = 0.085) and higher BNP levels (median 772.5 versus 567.5, P = 0.060) at diagnosis with marginal statistical significance.

TABLE 1. - Baseline characteristics
All patientsn = 73 No HTPLn = 61 HTPLn = 12 P
Age, median (range) 62 (36–82) 61 (36–82) 62.5 (39–72) 0.470
Sex (%) 1.000
 Male 42 (57.5) 35 (57.4) 7 (58.3)
 Female 31 (42.5) 26 (42.6) 5 (41.7)
ECOG PS (%) 0.796
 0–1 42 (57.5) 36 (59.0) 6 (50.0)
 ≥2 31 (42.5) 25 (41.0) 6 (50.0)
BMI at diagnosis
 Median (range) (kg/m2) 22.7 (18.3–31.2) 22.9 (18.3–31.2) 22.3 (18.8–28.8) 0.434
Light chain subtype (%) 0.513
 Free kappa 24 (32.9) 19 (31.1) 5 (41.7)
 Free lambda 49 (67.1) 42 (68.9) 7 (58.3)
Concurrent multiple myeloma (%) 43 (58.9) 36 (59.0) 7 (58.3) 1.000
Risk categories n = 62 n = 50 n = 12
Mayo 2004 European stage at diagnosis (%) 1.000
 I–II 21 (33.9) 17 (34.0) 4 (33.3)
 IIIa 15 (24.2) 12 (24.0) 3 (25.0)
 IIIb 26 (41.9) 21 (42.0) 5 (41.7)
Cardiac markers
 LVEF, median (range) (%) 57 (14–73) 57 (21–73) 48 (14–66) 0.085
 LVEF ≤ 50% (%) 32 (44.4) 25 (41.7) 7 (58.3) 0.458
 IVS thickness, median (range) (mm) 12 (9–22) 13 (9–22) 12 (11–16) 0.913
 LPVW thickness, median (range) (mm) 13 (7–23) 13 (7–23) 12 (11–16) 0.834
 E/e′ ratio, median (range) 21 (8–46) 21 (8–46) 22 (15–43) 0.509
 SBP ≤100 mm Hg 32 (43.8%) 28 (45.9%) 4 (33.3%) 0.628
 BNP, median (IQR) (ng/L) 631.0 (393.2–1483.8) 567.5 (292.8–1180.2) 772.5 (587.2–2146.2) 0.060
 NT-proBNP, median (IQR) (ng/L) 2811.0 (1880.0–5993.0) 2811.0 (1880.0–5993.0)
 TnI, median (IQR) (ng/mL) 0.1 (0.1–0.5) 0.1 (0.1–0.4) 0.2 (0.1–0.5) 0.630
Extracardiac organ involvement 52 (71.2%) 45 (73.8%) 7 (58.3%) 0.308
 Kidney 19 (26.0%) 17 (27.9%) 2 (16.7%) 0.720
 Liver 7 (9.6%) 7 (11.5%) 0 (0.0%) 0.591
 Soft tissue 13 (17.8%) 11 (18.0%) 2 (16.7%) 1.000
 Gastrointestinal tract 35 (47.9%) 29 (47.5%) 6 (50.0%) 1.000
 Peripheral nerve 11 (15.1%) 10 (16.4%) 1 (8.3%) 0.678
Hematologic and urinary markers
 dFLC, median (IQR) (mg/dL) 486.3 (200.6–1348.6) 486.3 (200.6–1155.8) 659.1 (364.3–1890.4) 0.464
 sFLC ratio, median (IQR) 29.4 (10.7–84.3) 28.2 (10.7–66.3) 55.3 (12.5–348.3) 0.186
 BMPC, median (IQR) (%) 10.8 (5.6–15.9) 10.5 (5.8–15.3) 13.8 (4.4–21.1) 0.406
 BMPC ≥20% 10/72 (13.9%) 7/60 (11.7%) 3/12 (25.0%) 0.354
 eGFR, median (IQR) (mL/min/1.73 m2) 76.0 (62.0-90.0) 72.0 (43.0–90.0) 87.0 (74.8–99.2) 0.061
 eGFR < 50 mL/min/1.73m2 16 (21.9%) 16 (26.2%) 0 (0.0%) 0.057
 Urine protein, median (IQR) (mg/d) 244.2 (112.7–1306.2) 263.6 (123.8–1306.2) 195.0 (109.2–805.4) 0.563
 Proteinuria > 3.5 g/d 11/62 (17.7%) 9/50 (18.0%) 2/12 (16.7%) 1.000
 Serum albumin, median (IQR) (g/dL) 3.1 (2.4–3.5) 3.0 (2.4–3.4) 3.5 (3.2–3.6) 0.013
 Serum albumin < 3.4 g/dL 45 (61.6%) 41 (67.2%) 4 (33.3%) 0.048
BMI, body mass index; BMPC, bone marrow plasma cell; BNP, brain natriuretic peptide; dFLC, the difference between involved and uninvolved free light chain; E/e′ ratio, the ratio of the peak early mitral inflow velocity I over the early diastolic mitral annular velocity (e′); ECOG PS, Eastern Cooperative Oncology Group performance status; eGFR, estimated glomerular filtration rate; HTPL, heart transplantation; IQR, interquartile range; IVS, interventricular septum; LPVW, left posterior ventricular wall; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal probrain natriuretic peptide; SBP, systolic blood pressure; sFLC, serum-free light chain; TnI, troponin I.

HTPL Patient Characteristics

Among the 12 patients who underwent HTPL, 2 underwent upfront HTPL after diagnosis because of life-threatening heart failure, whereas the other 10 received 1 line of systemic treatment before HTPL. The median time from diagnosis to HTPL was 3.7 mo (95% confidence intervals [CI], 0.9-5.2). Overall, dFLC decreased significantly from diagnosis to the time of HTPL (median 659.1 [interquartile range {IQR}, 364.3–1890.4] at diagnosis versus 18.6 [IQR, 16.5–101.4] at HTPL, P = 0.004); however, neither BNP level nor LVEF significantly improved during this period (BNP, median 772.5 ng/L [IQR, 587.2–2146.2] at diagnosis versus 1077.0 ng/L [IQR, 691.0–2895.5] at HTPL, P = 0.470; LVEF, median 48% [range: 14–66] versus 48% [range: 17–59] at HTPL, P = 0.470). The proportion of patients whose systolic blood pressure (SBP) was <100 mm Hg was 33.3% (n = 4) at diagnosis and 91.7% (n = 11) at HTPL (P = 0.371). At the time of the transplant, 83.3% (n = 10) were on inotropes. Among those, 2 required intensive care, including inotropes to maintain blood pressure and extracorporeal membrane oxygenation before transplant.

Survival Outcomes and Causes of Death

During the median follow-up duration of 80.7 mo (95% CI, 67.3-96.4), 51 patients (69.9%) died. Overall, the median OS of the study population was 20.0 mo (95% CI, 6.1-54.6; Figure 1A). By HTPL status, the median OS were not reached versus 11.8 mo (95% CI, 4.3-45.0, P = 0.022), the 3-y survival rates were 73.3% (95% CI, 37.9%-90.6%) versus 40.6% (95% CI, 28.2%-52.6%), and the 5-y survival rates were 61.1% (95% CI, 25.5%-83.8%) versus 32.0% (95% CI, 20.3%-44.4%) among patients who underwent HTPL versus who did not, respectively (Figure 1B). By ASCT status, the median OS were 100.1 mo (95% CI, 20.0 not estimated [NE]) versus 11.8 mo (95% CI, 3.8-41.0; P = 0.023), the 3-y survival rates were 76.9% (95% CI, 44.2%-91.9%) versus 39.2% (95% CI, 26.8%-51.4%), and the 5-y survival rates were 64.1% (95% CI, 28.2%-85.5%) versus 31.0% (95% CI, 19.3%-43.3%) among patients who underwent ASCT versus who did not, respectively (Figure 1C).

F1
FIGURE 1.:
Overall survival (A) for entire patient population, (B) by heart transplantation status, and (C) by ASCT status. ASCT, autologous stem cell transplantation; CI, confidence interval; HTPL, heart transplantation; NE, not estimated.

Among the 51 patients who died, causes of death were identifiable in 34 patients (30 in the non-HTPL group and 4 in the HTPL group). Sixteen (47.1%) died of heart failure, and 5 (14.7%) had sudden cardiac deaths. In other words, 61.8% of the deaths with identifiable causes were directly attributable to heart problems. Of note, no patient who underwent HTPL died of cardiac causes. On the other hand, infection was the leading cause of death in the HTPL group with 3 out of 4 deaths, versus the non-HTPL group with 7 of 30 deaths.

Post transplant Survival Outcomes and Graft Outcomes

The 1- and 3-y survival rates after HTPL in HTPL recipients (n = 12) were 91.7% (95% CI, 53.9%-98.8%) and 73.3% (95% CI, 37.9%-90.6%), respectively. None of those died within 30 d after the transplant. Survival rates did not differ between patients who underwent upfront HTPL (n = 2) and those who underwent HTPL after systemic treatment (n = 10) with 3-y survival rates of 100% (95% CI, NE) and 67.5% (95% CI, 29.1-88.2) (log-rank P = 0.333), respectively. Routine endomyocardial biopsies were performed after transplantation, and 5 of 12 HTPL recipients (41.7%) had evidence of graft rejection of any grade during follow-up. Four improved after intervention, but 1 required a second HTPL at 16.9 mo from the first HTPL because of cardiac allograft vasculopathy. Seven patients (58.3%) experienced hematologic progression after HTPL. Among those, 1 patient experienced a recurrence of cardiac amyloidosis.

Prognostic Factor Analysis

Univariable and multivariable cox regression analyses for OS were performed to identify potential prognostic factors (Table 2). In the univariable and multivariable analyses, extracardiac involvement of amyloidosis other than kidney and eGFR < 50 mL/min/1.73 m2 were associated with poor OS.

TABLE 2. - Univariable and multivariable analyses for overall survival
Variables Univariable analysis Multivariable analysis
HR (95% CI) P HR (95% CI) P
Age ≥ 70 y 1.23 (0.66-2.29) 0.515 Not included
Female sex 0.96 (0.55-1.67) 0.872 Not included
ECOG PS ≥ 2 1.36 (0.77-2.42) 0.292 Not included
LVEF ≤ 50% 1.14 (0.65-2.02) 0.652 Not included
SBP > 100 mm Hg 0.69 (0.39-1.21) 0.191 Not included
BMPC ≥ 20% 2.43 (1.18-4.99) 0.016 1.77 (0.78-3.99) 0.172
Concurrent myeloma 1.23 (0.69-2.20) 0.488 Not included
dFLC > 180 mg/dL 1.13 (0.55-2.34) 0.734 0.70 (0.31-1.59) 0.392
Mayo 2004 European stage
 I–II Reference Reference
 IIIa 1.24 (0.55-2.82) 0.603 1.14 (0.47-2.76) 0.772
 IIIb 1.96 (0.95-4.08) 0.071 1.33 (0.60-2.94) 0.476
Renal involvement of amyloidosis 1.12 (0.61-2.07) 0.705 Not included
Proteinuria > 3.5 g/24h 1.42 (0.67-3.02) 0.358 Not included
eGFR < 50 mL/min/1.73m2 1.96 (1.07-3.62) 0.030 2.32 (1.11-4.84) 0.025
Serum albumin < 3.4 g/dL 1.80 (1.00-3.39) 0.050 1.67 (0.78-3.54) 0.186
Extracardiac involvement of amyloidosis (nonrenal) 2.10 (1.16-3.81) 0.015 2.46 (1.19-5.09) 0.016
BMPC, bone marrow plasma cell; CI, confidence interval; dFLC, the difference between involved and uninvolved free light chain; ECOG PS, Eastern Cooperative Oncology Group performance status; eGFR, estimated glomerular filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.

Treatment Responses to Systemic Therapy and Survival Outcomes

Landmark analyses were performed to assess the associations between the response to treatment and OS. Landmark points included the 8th and the 12th wk after starting treatment. Excluding those who died, had HTPL before landmark points, and had upfront HTPL, 48 patients and 45 patients were included in the 8th-wk and the 12th-wk landmark analyses, respectively. BNP was followed-up at the 8th-wk and the 12th-wk landmark points in 34 and 26 patients, respectively. At the 8th wk, 32 of 48 (66.7%) and 4 of 34 (11.8%) patients achieved hematologic and BNP responses, respectively; at the 12th wk, 31 of 45 (68.9%) and 5 of 26 (19.2%) patients achieved hematologic and BNP responses, respectively. The proportions of patients who achieved hematologic or BNP responses did not significantly differ between patients who underwent HTPL and those who did not (Table 3). Although the hematologic response was significantly associated with OS, BNP responses at the 8th and the 12th wk were not (Figure S1, SDC, https://links.lww.com/TP/C468).

TABLE 3. - Response to systemic treatment at landmark times
Week 8 Week 12
Entiren = 48 No HTPLn = 41 HTPLn = 7 P  a Entiren = 45 No HTPLn = 38 HTPLn = 7 P  a
Hematologic response 0.398 0.407
 CR 3 (6.2%) 3 (7.3%) 0 (0.0%) 5 (11.1%) 3 (7.9%) 2 (28.6%)
 VGPR 11 (22.9%) 10 (24.4%) 1 (14.3%) 12 (26.7%) 12 (31.6%) 0 (0.0%)
 PR 18 (37.5%) 13 (31.7%) 5 (71.4%) 14 (31.1%) 10 (26.3%) 4 (57.1%)
 SD 15 (31.2%) 14 (34.1%) 1 (14.3%) 12 (26.7%) 11 (28.9%) 1 (14.3%)
 PD 1 (2.1%) 1 (2.4%) 0 (0.0%) 2 (4.4%) 2 (5.3%) 0 (0.0%)
BNP response n = 34 n = 28 n = 6 0.559 n = 26 n = 19 n = 7 0.588
 Response 4 (11.8%) 3 (10.7%) 1 (16.7%) 5 (19.2%) 3 (15.8%) 2 (28.6%)
 Stable 14 (41.2%) 12 (42.9%) 2 (33.3%) 7 (26.9%) 5 (26.3%) 2 (28.6%)
 Progression 16 (47.1%) 13 (46.4%) 3 (50.0%) 14 (53.8%) 11 (57.9%) 3 (42.9%)
aP values were for comparison between responders vs nonresponders (for hematologic responses, partial response, or better vs others; for BNP responses, response vs others).
BNP, brain natriuretic peptide; CR, complete response; HTPL, heart transplantation; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

Subgroup Analyses for HTPL

Figure 2 and Table S3 (SDC, https://links.lww.com/TP/C468) show median OS and 95% CI in each subgroup by HTPL status. Patients who underwent HTPL tended to achieve more prolonged survival in almost all the subgroups, including sex, ECOG performance status, light chain type, percentage of bone marrow plasma cells, concurrent multiple myeloma, extracardiac involvement, Mayo 2004 European stage, dFLC level, and LVEF, just except for patients with urine protein ≥3.5 g/d at diagnosis.

F2
FIGURE 2.:
Subgroup analyses for overall survival by HTPL status. Note: Bar indicates median OS; black line indicates 95% confidence interval. BMPC, bone marrow plasma cell; dFLC, the difference between involved and uninvolved free light chain; ECOG, Eastern Cooperative Oncology Group performance status; HTPL, heart transplantation; LVEF, left ventricular ejection fraction; Mayo, Mayo 2004 European staging; MM, multiple myeloma; OS, overall survival.

DISCUSSION

We analyzed the clinical outcomes of patients with AL cardiac amyloidosis, focusing on the clinical benefits of HTPL. The 5-y survival rates were significantly higher in the HTPL group with 61% versus 32%. We also found that heart problems are the major causes of death in non-HTPL recipients, whereas none died of cardiac causes in the HTPL group. These highlight the importance of recovering adequate cardiac function in patients with cardiac amyloidosis and suggest that HTPL can dramatically change the disease course in appropriately selected patients. We also found that extracardiac involvement of amyloidosis and poor renal function (eGFR < 50 mL/min/1.73m2) are important prognostic factors in those patients.

Despite the clinical importance of restoring cardiac function via HTPL, the consensus has not yet been reached regarding indications of HTPL. Interestingly, we observed longer survival in those who underwent HTPL in almost all the subgroups, including high-risk groups such as those with extracardiac involvement, higher dFLC levels at diagnosis, or bone marrow involvement of plasma cells; however, there seems to be a tendency for shorter survival in HTPL recipients among those with heavy proteinuria. Additionally, no patients with impaired renal function, which was the significant prognostic factor, underwent HTPL in our cohort. Therefore, whereas the limited extracardiac organ dysfunction per se might not be a contraindication for HTPL, concurrent severe renal dysfunction, or heavy proteinuria should be taken into consideration against HTPL.10

Additionally, we analyzed the hematologic and BNP response rates to systemic treatment at the 8th-wk and the 12th-wk landmarks after the initiation of systemic therapy and their associations with survival outcomes. Compared with the relatively high hematologic response rates of over 67%, the BNP response rates were modest, below 20% during the same period. Interestingly, whereas the hematologic responses were significantly associated with survival at both landmarks, BNP responses did not. We suppose this insignificant association between BNP response and survival is possibly attributable to lower and delayed cardiac response rates,14 the risk of early death and sudden cardiac deaths, and the confounding effects of patients who underwent HTPL after the landmark points.

Although the optimal timing for HTPL is not established, it is usually determined by the availability of donors, and systemic treatment is instituted in the meantime. Given the importance of systemic control and the high response rate to systemic therapy, achieving a hematologic response is desirable and expected before HTPL for most patients; however, emergent HTPL might be the only therapeutic option for critical heart problems at diagnosis. Two patients underwent upfront HTPL for life-threatening heart failure from our cohort, and they recovered after HTPL and could successfully undergo systemic treatment. We could also find low rates of recurrent cardiac amyloidosis and significant graft rejection leading to the retransplant (1 in each), consistent with previous studies.15 Additionally, half of the patients could successfully undergo ASCT after HTPL. Taken together, we believe that the “continuum-of-care” to prolong survival is possible by HTPL with subsequent systemic treatment.

Our study is limited by its single-center, retrospective design and the low number of HTPL recipients. Also, robust statistical comparison between groups of patients who did and did not receive HTPL is limited, as such comparison would only be possible via a randomized, prospective design, which would not be feasible considering the severity and rarity of the disease. Also, the effects of unmeasured clinical factors influencing the physicians’ decisions to perform HTPL cannot be excluded. Finally, as our study included patients over a long period, changes in the treatment pattern during the study period should be taken into account when interpreting the results. Nonetheless, we collected and analyzed multiple clinical factors in detail to minimize such effects. Despite these limitations, our study yielded information about treatment responses, detailed survival analysis according to clinical characteristics, prognosis after HTPL, and causes of death among patients with AL cardiac amyloidosis, where prospective trial-based evidence is challenging to establish.

In conclusion, active and appropriate patient selection and application of HTPL with systemic treatment can achieve long-term survival for patients with AL cardiac amyloidosis.

ACKNOWLEDGMENTS

RN Shin Kim and RN Kyoungmin Lee contributed to the collection and management of the patient dataset.

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