Ad Wechalekar

Organ transplantation in hereditary apolipoprotein AI amyloidosis

Patients with hereditary apolipoprotein AI (apoAI) amyloidosis often have extensive visceral amyloid deposits, and many develop end‐stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoAI amyloidosis who were followed for a median (range) of 16 (4–28) and 9 (0.2–27) years from diagnosis of amyloidosis and transplantation, respectively. Eight of 10 patients were alive, seven with a functioning graft at censor. Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of multisystem failure following severe trauma more than 13 years after renal transplantation. The renal transplant of one patient failed due to recurrence of amyloid after 25 years. Amyloid disease progression was very slow and the natural history of the condition was favorably altered in both cases in which the liver was transplanted. Failing organs in hereditary apoAI amyloidosis should be replaced since graft survival is excellent and confers substantial survival benefit.

Outcomes of heart transplantation for cardiac amyloidosis: subanalysis of the spanish registry for heart transplantation.

Amyloidosis (Am), a systemic disease, has poor prognosis because of organ damage produced by protein deposition in the extracellular space. Although heart transplantation (HTx) is possible, donor availability concerns and high mortality make this approach controversial. The Spanish Registry for Heart Transplantation includes 25 Am patients (54 ± 9 years): 13 with AL type, 2 with AA and 10 with TTR mutation. Fifteen patients (60%) died during follow‐up (4.9 ± 1.3 years): 9 AL‐Am patients, both AA‐Am patients and 4 with TTR‐Am. HTx survival for Am patients was similar to patients without Am at 1 month but significantly worse at 5 years: 46% versus 78% (p < 0.02). Of 10 AL‐Am patients undergoing successful HTx, 4 died of systemic Am. Stem cell transplantation was performed in 3 (1 died of acute rejection). Five of 10 patients with TTR‐Am underwent liver transplant; 4 remained alive at the last follow‐up. Findings include poor outcome for AL‐Am patients despite HTx and better survival for TTR‐Am patients if HTx is associated with liver transplantation. Given the shortage of donors and poor outcome for Am patients, we would recommend that HTx be reserved for patients without or with mild systemic Am and be supplemented by additional therapies as indicated.

Differential Myocyte Responses in Patients with Cardiac Transthyretin Amyloidosis and Light-Chain Amyloidosis: A Cardiac MR Imaging Study

PURPOSE To investigate cardiac magnetic resonance (MR) imaging measurements of extracellular volume (ECV) and total cell volume in immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) in order to evaluate the amyloid and myocyte volumes. MATERIALS AND METHODS All ethics were approved, and participants provided written informed consent. Of the 257 subjects who were recruited, 92 had AL (mean age, 62 years ± 10), 44 had mutant ATTR (mean age, 68 years ± 10), and 66 had wild-type ATTR (mean age, 75 years ± 7). In addition, eight healthy subjects with ATTR mutations (mean age, 47 years ± 6) and 47 healthy volunteers (mean age, 45 years ± 15) participated. All participants underwent equilibrium contrast material-enhanced cardiac MR imaging. ECV and total cell volume were measured in the heart. T test, χ(2), and one-way analysis of variance with posthoc Bonferroni correction were used. RESULTS Both the left ventricular indexed mass and ECV were elevated in patients with amyloidosis. For left ventricular indexed mass, mean AL was 107 g/m(2) ± 30; mean mutant ATTR was 137 g/m(2) ± 29; and mean wild-type ATTR was 133 g/m(2) ± 27 versus 65 g/m(2) ± 15 in healthy subjects (P < .0001 for all measures). For ECV, mean AL was 0.54 ± 0.07, mean mutant ATTR was 0.60 ± 0.07, and mean wild-type ATTR was 0.57 ± 0.06 versus 0.27 ± 0.03 in healthy subjects (P < .0001 for all measures). Patients with ATTR had a higher total cell volume than did healthy subjects (mean, 53 mL/m(2) ± 12 vs 45 mL/m(2) ± 11; P = .001), but in patients with AL, total cell volume was normal (mean, 47 mL/m(2) ± 17 vs 45 mL/m(2) ± 11; P > .99). The result is that, in patients with AL, all of the increase in left ventricular indexed mass is extracellular volume, whereas in patients with ATTR, the increase is extracellular, with an additional 18% increase in the intracellular space. CONCLUSION Quantification of ECV measures cardiac amyloid deposition in both types of amyloidosis and shows that amyloid deposition is more extensive in patients with ATTR than in those with AL; however, ATTR is associated with higher cell volume, which suggests concomitant cell hypertrophy.

A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis

Despite improvements in therapy amyloid light-chain (AL) amyloidosis, there are few studies comparing different regimens. Here we present a matched comparison with 69 patients in each cohort examining upfront therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) vs cyclophosphamide, thalidomide and dexamethasone (CTD). On an intention-to-treat basis, the overall response rates were 71.0% vs 79.7% in the CVD and CTD arms, respectively, (P=0.32). A higher complete response (CR) rate was observed in the CVD arm (40.5%) vs CTD (24.6%), P=0.046. One-year overall survival (OS) was 65.2% and 66.7% for CVD and CTD, respectively (P=0.87). The median progression-free survival (PFS) was 28.0 and 14.0 m for CVD and CTD, respectively (P=0.039). In a landmark analysis assessing outcomes performed at 6 months, the CR rate with CVD was 59.6% vs 34.0% for CTD (P=0.03). The 1-year OS was 96% with CVD and 92% with CTD (P=0.40). The median PFS with CVD was not reached and was 19.2 m with CTD, P=0.028). In summary, both regimens are unable to overcome the high rate of early deaths in AL amyloidosis. However, CVD correlates with improved depth of response and superior PFS supporting its use in the frontline setting. Further optimisation and better supportive-care strategies are required to increase the proportion of patients fully benefiting from therapy.

High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.

To the Editor: The articles by Meier et al.1 and Carroll et al.2 and the corresponding editorial by Messé and Kent3 (March 21 issue) illustrate a major problem in clinical trials. When it is not obvious which of two therapies is better, sufficient numbers of events are essential to reach a conclusion. Performing a prospective, randomized trial is not enough. In the PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism),1 primary-end-point events occurred in only 18 patients in the two groups, even though 414 patients and 29 international sites participated. Any difference may have been due to chance. The investigators in the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)2 trial enrolled 980 patients at 69 sites, yet there were only 25 primaryend-point events. The proper conclusion of these studies, even though they were well designed and carefully performed, is that too few events were observed to draw any conclusion. When the Early Breast Cancer Trialists’ Collaborative Group4 performed the first metaanalysis of the value of adjuvant tamoxifen — one of the most effective medications in our pharmacopoeia — for breast cancer, only 6 of 42 randomized trials had shown significant benefit. Only trials with many patients and many events are likely to overcome the play of chance.To the Editor: The articles by Meier et al.1 and Carroll et al.2 and the corresponding editorial by Messé and Kent3 (March 21 issue) illustrate a major problem in clinical trials. When it is not obvious which of two therapies is better, sufficient numbers of events are essential to reach a conclusion. Performing a prospective, randomized trial is not enough. In the PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism),1 primary-end-point events occurred in only 18 patients in the two groups, even though 414 patients and 29 international sites participated. Any difference may have been due to chance. The investigators in the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)2 trial enrolled 980 patients at 69 sites, yet there were only 25 primaryend-point events. The proper conclusion of these studies, even though they were well designed and carefully performed, is that too few events were observed to draw any conclusion. When the Early Breast Cancer Trialists’ Collaborative Group4 performed the first metaanalysis of the value of adjuvant tamoxifen — one of the most effective medications in our pharmacopoeia — for breast cancer, only 6 of 42 randomized trials had shown significant benefit. Only trials with many patients and many events are likely to overcome the play of chance.

AA amyloidosis complicating the hereditary periodic fever syndromes.

OBJECTIVE AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre. METHODS Disease activity was monitored by serial measurement of serum amyloid A. Renal function was assessed by measurement of serum creatinine and albumin levels, the estimated glomerular filtration rate, and proteinuria from 24-hour urine collections. The amyloid load was measured by serum amyloid P scintigraphy. RESULTS Twenty-four patients had familial Mediterranean fever, 12 patients had tumor necrosis factor receptor-associated periodic syndrome, 6 patients had cryopyrin-associated periodic syndromes, and 4 patients had mevalonate kinase deficiency. The median age at onset of HPFS was 5 years; median age at presentation with AA amyloidosis was 38 years. Diagnosis of an HPFS had not been considered prior to presentation with AA amyloidosis in 23 patients (50%). Eleven patients (24%) had end-stage renal failure (ESRF) at presentation; of these, 3 had received transplants prior to referral. A further 13 patients developed ESRF over the followup period, with 10 undergoing renal transplantation. The median time to progression to ESRF from onset of AA amyloidosis was 3.3 years (interquartile range [IQR] 2-8), with a median time to transplant of 4 years (IQR 3-6). Eleven patients (24%) died. The median survival in the entire cohort was 19 years from diagnosis of AA amyloidosis. Of the 37 patients who were treated successfully, or in whom at least partial suppression of the underlying HPFS was achieved, 17 (46%) showed amyloid regression, 14 (38%) showed a stable amyloid load, and 2 (5%) showed increased amyloid deposition over the followup period. CONCLUSION AA amyloidosis remains a challenging and serious late complication of HPFS; however, outcomes are excellent when HPFS is diagnosed early enough to allow effective treatment, thus preventing or retarding further amyloid deposition and organ damage.

INCREMENTAL VALUE OF CMR FOR THE DIAGNOSIS OF CARDIAC INVOLVEMENT IN PATIENTS WITH END STAGE RENAL FAILURE AND SYSTEMIC AMYLOIDOSIS

Background: Cardiac involvement may occur in up to 50% of patients with amyloidosis and portends an adverse prognosis. Non-invasive diagnosis, particularly in the setting of chronic renal failure (CRF), remains imprecise due echocardiographic changes from concomitant pathology. CMR with typical late gadolinium enhancement (LGE) is a highly speciic method for diagnosis of cardiac amyloidosis in patients without CRF. Although nephrogenic systemic ibrosis (NSF) has been reported in patients with CRF after gadolinium, the incidence is rare. We sought to determine the incremental diagnostic value of LGE CMR in patients with systemic amyloidosis/light chain deposition disease (LCDD) and CRF in whom echocardiography and clinical signs were equivocal.