Ute Hegenbart

A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis.

Treatment outcomes of patients with cardiac stage III light chain (AL) amyloidosis remain poorly studied. Such cases have been excluded from most clinical studies due to perceived dismal prognosis. We report treatment outcomes of 346 patients with stage III AL amyloidosis from the United Kingdom, Italy, Germany, and Greece. Median overall survival (OS) was 7 months with OS at 3, 6, 12, and 24 months of 73%, 55%, 46%, and 29%, respectively; 42% died before first response evaluation. On an intention-to-treat basis, the overall hematologic response rate was 33%, including a complete response rate of 12%. OS rates at 12 and 24 months, respectively, for 201 response evaluable patients were 88% and 85% for complete responders, 74% and 53% for partial responders, and 39% and 22% for nonresponders. Forty-five percent of responders achieved an organ response. Amino-terminal fragment of brain-type natriuretic peptide (NT-proBNP) >8500 ng/L and systolic blood pressure (SBP) <100 mm Hg were the only factors that independently impacted OS and identified an especially poor prognosis subgroup of patients with a median OS of only 3 months. Outcome and organ function of stage III AL amyloidosis without very elevated NT-proBNP and low SBP is improved by a very good hematologic response to chemotherapy.

Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death

BACKGROUNDnCardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias.nnnOBJECTIVEnThe purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis.nnnMETHODSnNineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD.nnnRESULTSnDuring a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely.nnnCONCLUSIONnPatients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light-chain amyloidosis

The prognosis of advanced cardiac light‐chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis.

AL amyloidosis patients with low amyloidogenic free light chain levels at first diagnosis have an excellent prognosis

The difference between involved minus uninvolved serum free light chains (dFLC) has been established as an invaluable hematologic parameter in systemic amyloid light chain (AL) amyloidosis. However, patients with an initial dFLC level <50 mg/L are currently deemed not evaluable for response to therapy. Therefore, we aimed to characterize this subgroup of patients and to define novel hematologic response parameters. We retrospectively analyzed 783 AL patients newly diagnosed at our center between 2002 and 2016. Patients with a dFLC level <50 mg/L showed smaller bone marrow plasmacytosis compared to patients with a dFLC level ≥50 mg/L (7% vs 10%, P < .001), but no significant differences in all analyzed chromosomal aberrations. Cardiac involvement was less frequent (45% vs 80%, P < .001) and less severe (Mayo 2004 stage III: 18% vs 51%, P < .001), whereas kidney involvement was more prevalent (83% vs 53%, P < .001) and proteinuria was higher (7.3 g/L vs 5.0 g/L, P < .001). In multivariate analyses, a dFLC level <50 mg/L appeared to be an independent prognostic factor with respect to overall survival (hazard ratio [HR] = 0.50, P = .003) and renal survival (HR = 0.56, P = .020). Patients with a dFLC level <50 mg/L showed a higher proportion of complete hematologic response after first-line therapy compared to patients with a dFLC level ≥50 mg/L (39% vs 9%, P < .001). Receiver-operating characteristics analysis identified a low-dFLC partial response (dFLC <10 mg/L for patients with a dFLC between 20 and 50 mg/L), which predicted overall and renal survival already at 3 months after the start of therapy. Importantly, a parallel Italian study validated this new hematologic remission parameter. The outcome of prospective clinical trials might be adversely influenced by exclusion of the favorable clinical subgroup with an initial dFLC <50 mg/L. We propose the appreciation of dFLC in hematologic response assessment for all patients with a baseline dFLC >20 mg/L.

Response to bendamustine is associated with a survival advantage in a heavily pretreated patients with AL amyloidosis

Combinations of older drugs and novel agents are constantly improving the outcome of chemotherapy in light chain (AL) amyloidosis [1]. Bendamustine has demonstrated activity in multiple myeloma and Waldenström macroglobulinemia (WM) [2] and is being evaluated in a phase II trial in relapsed AL amyloidosis patients (NCT01222260). In the present study, we retrospectively evaluated the safety and efficacy of bendamustine and prednisone in 125 patients with AL amyloidosis treated in two European referral centers.

First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability and survival

TO THE EDITOR:nnLight-chain amyloidosis (AL) is a rare systemic protein deposition disorder that belongs to the group of plasma cell dyscrasias. Approximately 10% to 22% of cases are associated with symptomatic multiple myeloma or Waldenstrom macroglobulinemia (WM). The disease is characterized by

Respiratory muscle weakness and inefficient ventilation in heart failure due to light-chain amyloidosis

Background. Cardiac involvement in light-chain amyloidosis (AL) frequently results in heart failure with dyspnoea. In heart failure due to ischemic or idiopathic etiology, respiratory muscle dysfunction and ventilatory inefficiency contribute to symptoms and are independent prognostic predictors. However, in patients with AL, respiratory muscle function has not been elucidated. Methods. In 46 consecutive male patients with AL, lung function, maximal inspiratory (Pimax) and expiratory (Pemax) mouth occlusion pressures, cardiopulmonary exercise testing, echocardiography, and cardiac biomarkers were prospectively studied. Results. Pimax and Pemax were reduced, P0.1 did not differ between controls and AL. Pimax and Pemax were reduced in AL with congestive heart failure compared with asymptomatic patients (median (range) 5.4 (2.3–12.4) kPa vs 10.4 (6.5–14.0) kPa; p < 0.05). Respiratory muscle weakness occurred in systolic and diastolic LV dysfunction. Pimax was associated with peak exercise oxygen uptake, respiratory inefficiency, wall thickness, and N-terminal pro-brain natriuretic peptide. Conclusions. Respiratory muscle dysfunction and ventilatory inefficiency correlates well with intraventricular septum thickness and peak oxygen uptake and are present even in patients with diastolic dysfunction. Respiratory muscle dysfunction might contribute to dyspnea and exercise limitation and appears to represent a marker of cardiac impairment even in diastolic heart failure. Further studies of Pimax as a potential non-invasive prognostic marker are needed.

Flow in a fibril-forming disease

In this issue of Blood, Muchtar and colleagues report on the prognostic value of multiparametric flow cytometry (MFC) to measure clonal plasma cell burden at diagnosis and at end of treatment in patients with amyloid light-chain (AL) amyloidosis.1

Amyloid in bone marrow smears in systemic light-chain amyloidosis

Abstract We performed a prospective sensitivity analysis to detect amyloid in bone marrow (BM) smears stained with Congo red (CR) and according to Pappenheim of patients with systemic light-chain (AL) amyloidosis. Results were directly compared to routine BM histology and fat aspiration. We analysed 198 BM smears from patients with the diagnosis or suspicion of systemic AL amyloidosis. Ultimately, the diagnosis could be established for 168 patients. Amyloid was detected on BM smears with CR in 33% (56/168). All patients suspicious for amyloid on Pappenheim staining (nu2009=u200939) showed substantial amyloid infiltration on CR. No patient without systemic AL amyloidosis stained positive. Sensitivity for routine BM histology was 57% (74/129) and for fat aspiration 96% (134/140). Patients with amyloid on BM smears had significantly more hepatic (42 vs. 9%, pu2009<u2009.001), renal (78 vs. 43%, pu2009<u2009.001) and gastrointestinal involvement (40 vs. 22%, pu2009<u2009.01) and less commonly cardiac involvement (58 vs. 76%, pu2009<u2009.03) and consecutively no adverse prognosis. CR staining of BM smears cannot be recommended as a primary screening tool for systemic AL as its overall sensitivity is far inferior to BM histology and fat aspiration. However, we recommend using the technique when suspecting amyloid on Pappenheim staining to establish the diagnosis of systemic AL amyloidosis.

Relapse incidence and leukemia-free survival (LFS) in patients (pts) older than age 60 with AM undergoing stem cell transplantation: A report of the East German Study Group Hematology and Oncology (OSHO).

6523 Background: Complete remission rates similar to those of younger pts are obtained in elderly AML pts (OSHO AML 1997). However, OS and LFS remain dismal because of extremely high relapse rates. In the AML 2004 study, reduced intensity conditioning SCT was introduced to reduce relapse in patients with a compatible related/unrelated donor. In this analysis we compared outcome of patients with a donor to patients without a donor.nnnMETHODSnOf the 663 pts, 597 were entered into the study specific arm and 66 in the common arm of the German Intergroup Study. Of those 447 and 52 pts were evaluable, respectively. The majority of pts were male (56.9%), the median age 68 years and the median Karnofsky score 80%. Karyotype was normal in 46.9% and unfavorable in 21.2%, while 55.9% had de novo AML. Induction therapy consisted of AraC 100 mg/m2 c. i. over 7 days / Daunorubicin 60 mg/m2 i.v. on days 3 - 5 in the standard arm and of AraC 2g/m2 on days 1, 3, 5 and 7 / mitoxantrone 10 mg/m2 i.v. day 1 - 3 in the study arm. SCT were performed following reduced intensity conditioning.nnnRESULTSnCR was observed in 62% of pts after induction in the study arm and in 62% in the standard arm. A total of 76 pts had a stem cell donor and 129 no donor. There was no significant difference between the populations except for median age 68 in the chemotherapy vs. 65 a in the SCT arm (p<0.001). OS at 3 a was 35 ± 6% in the chemotherapy compared to 49 ± 6% in the SCT arm. Accordingly, LFS at 3 a was 27 ± 5% for chemotherapy as compared to 39 ± 7% in the SCT arm (p=0.04) and due to reduced relapse incidence (73±5% vs. 45±7%, respectively; p 0.001). Only SCT and favorable risk cytogenetics were independent factors for increased LFS. Both variables were independent risk factors for lower relapse rate, as was de novo AML. In contrast, high WBC at diagnosis and SCT were significantly associated in a multivariate analysis with increased treatment related mortality.nnnCONCLUSIONSnSCT in comparison to chemotherapy is associated with increased LFS and lower relapse independently of cytogenetic risk. The biggest differences in LFS and relapse between SCT and chemotherapy were noted among pts with high risk cytogenetic disease.