Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first-line treatment of systemic light chain amyloidosis in the UK.

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. RESULTS: A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.

Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. METHODS: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. RESULTS: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups. CONCLUSIONS: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

Cardiac biomarkers are prognostic in systemic light chain amyloidosis with no cardiac involvement by standard criteria.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 µmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis.

OBJECTIVE: Cytomegalovirus (CMV) is an opportunistic herpesvirus, and reactivation of infection is possible in immunocompromised patients. Historically, the risk for haematology patients is restricted to those treated with an allogeneic transplant or T-cell depleting agents. Bortezomib is a highly efficacious proteasome inhibitor widely used to treat multiple myeloma and light chain (AL) amyloidosis patients. The objective of this small prospective study was to quantify the risk of CMV reactivation associated with bortezomib treatment. METHODS: Fifty-seven consecutive multiple myeloma or AL amyloidosis patients commencing bortezomib-based therapy were included. Viral copy numbers were established at baseline and then at fortnightly intervals during treatment. Pre-emptive anti-viral treatment was initiated in patients with a viral load >7500 copies/mL. RESULTS: Reactivation of CMV was detected in 39% (n = 12/31) of seropositive bortezomib treated patients compared with 0% of CMV seronegative patients. Detectable DNAemia developed during the first two cycles of treatment in 83% (n = 10/12) patients. Anti-viral treatment was initiated in 42% (n = 5/12), but no cases of active CMV disease were seen. CONCLUSION: This study suggests that there is a substantial risk of CMV reactivation in CMV-seropositive plasma cell dyscrasia patients treated with bortezomib.

A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re-evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant-related mortality (TRM) and overall survival (OS) were analysed. The median OS post-ASCT was 87 months [95% confidence interval (CI): 77-106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29-55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35-2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19-3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994-2000: 18·8%; 2001-2006: 13·6%; 2007-2012: 6·2%; 2013-2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long-term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis.

Real world outcomes of pomalidomide for treatment of relapsed light chain amyloidosis.

Pomalidomide is a next-generation immunomodulatory agent with activity in relapsed light chain (AL) amyloidosis, but real world outcomes are lacking. We report the experience of the UK National Amyloidosis Centre. All patients with AL amyloidosis treated with pomalidomide between 2009 and 2017 were included. Data was collected on treatment toxicity and clonal response. Survival was calculated by the Kaplan-Meier method and outcomes reported on an intent-to-treat (ITT) basis. A total of 29 patients treated with pomalidomide were identified. Haematological responses at 3 months were: complete response (CR) nil, very good partial response (VGPR) 10 (35%), partial response (PR) 9 (31%), stable or progressive disease 7 (24%), unevaluable 3 (10%). On an ITT basis (n = 28), responses at 6 months were: CR- nil, VGPR-11 (39%), PR-2 (7%) and the remaining patients were non-responders 15 (53%). Median overall survival was 27 months (95% confidence interval 15·7-38·1 months). Median progression free survival (PFS) was 15 months (95% confidence interval 6·24-23·77). In conclusion, pomalidomide has activity in patients with relapsed AL amyloidosis. Responses are rapid and early responses may be predictive of a sustained overall response. Deep responses (VGPR or better) are seen in only a third of all patients and combination therapy needs to be explored.

Acquired haemophilia A diagnosed during pregnancy.

Pregnancy-associated haemophilia A is an uncommon, acquired bleeding disorder which usually presents post-partum; very rarely it may present during pregnancy. No consensus guidelines exist on the management of this condition in pregnancy and very few cases have been reported in the literature. Here we describe the case of a woman presenting with acquired haemophilia A during pregnancy and outline the management of her bleeding disorder. We contrast her case with that of two other women, presenting to the same tertiary referral centre, with acquired haemophilia A presenting post-partum. These cases highlight the heterogeneous management of this condition and how it may be successfully managed in pregnancy.

Treatment-free interval as an additional measure of efficacy in a large UK dataset of transplant ineligible myeloma patients.

Treatment of transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) requires a balance between disease control and maintaining quality of life (QoL). Patients value treatment-free remission periods in this incurable condition, as they are associated with better QoL. We set out to study clinical outcomes of consecutive TNE NDMM patients in routine care treated in Thames Valley Cancer Network between 2009 and 2017. The primary outcome was the evaluation of the treatment-free interval (TFI) after 1st and subsequent lines of therapy in the total cohort and in individual subgroups, according to age (≤75 vs. >75 years), and co-morbidities using Charlson Co-morbidity Index (CCI): mild: 0-2 vs. moderate: 3-4 vs. severe: ≥5). Secondary outcomes include response rates, overall survival (OS) and progression-free survival (PFS) between subgroups: according to age and according to co-morbidities. In a total cohort of 292 patients, median TFI (IQR) was longest after first-line therapy 6.9 months (1.4-16.9), reducing after second line therapy to 1.8 months (.7-6.9), and after third line therapy to 0.6 months (0.2-1.5). Median TFI followed the same trend across the different subgroups, by age (≤75, >75 years) and by CCI (0-2, 3-4, ≥5). Overall response rate (ORR) to first line therapy for total cohort was 67%, with responses categorised as complete response (CR): 21%, very good partial response: 16%, partial response: 30%, stable disease: 18%, and progressive disease: 8%. ORR in individual subgroups by age were (≤75: 70% vs. >75: 63%), and by CCI (0-2: 65% vs. 3-4: 71% vs. ≥5: 77%). Median OS and PFS for the total cohort were (30.2 months, 95% CI: 23.8-36.9), and (9 months, 95% CI: 7.9-9.8), respectively. Patients aged >75 years showed a significant reduction in OS and PFS compared to those ≤75 years of age: OS (49.0 vs. 22.4 months, p<0.0001, HR: 2.08, 95% CI: 1.5-2.8), PFS (9.7 vs. 8.0 months, p<0.01, HR: 1.47, 95% CI: 1.1-1.9). Median OS was significantly reduced with worsening co-morbidities: (CCI 0-2: 52.4 months vs. CCI 3-4: 33.0 months vs. CCI ≥5: 24.0 months, p = 0.01, HR: 1.43, 95% CI: 1.1-1.9). Median PFS was significantly reduced in the severely co-morbid subgroup (CCI 0-2: 9.4 months vs. CCI 3-4: 9.6 months vs. CCI ≥5: 7.1 months, p = 0.025, HR: 1.3, 95% CI: 1.0-1.6). This study demonstrated that first line therapy in the TNE NDMM setting resulted in the longest TFI which was modest at a median of 6.9 months, and decreased significantly following subsequent lines of therapy and across the different subgroups by age and by co-morbidities. Therapy objective should be to maximise the benefit of first line treatment. We envisage that the recent shift towards a continuous therapeutic approach will benefit TNE patients in view of improved survival data demonstrated by a number phase 3 trials. When continuous therapy is not appropriate due to patient choice or toxicities, an efficacious (not limited to thalidomide and bortezomib) but tolerable first line FDT strategy, which can maximise TFI and maintain a good QoL, remains a reasonable alternative approach.

Amyloidosis Diagnosed in Solid Organ Transplant Recipients.

BACKGROUND: Development of amyloidosis post solid-organ transplantation has not been reported, although plasma cell neoplasms are a rare form of posttransplant lymphoproliferative disorder, which could be complicated by light chain amyloidosis (AL) amyloidosis. METHODS: We searched our database of 5112 patients seen between 1994 and 2018 with a diagnosis of amyloidosis post solid-organ transplant. Patients were excluded if the amyloid diagnosis preceded the transplant date. The indication and type of organ transplant were recorded in addition to the amyloidosis type, organs involved, treatment given, and survival. RESULTS: Thirty patients were identified. The median age at diagnosis with amyloidosis was 52 years (range 33-77). The median time from transplantation to diagnosis was 10.5 years (0.58-36). The grafts were kidney (N = 25, 83.3%), liver (N = 2, 6.7%), heart (N = 2, 6.7%), and combined heart, lung, and kidney (N = 1, 3.3%). The type of amyloidosis was systemic AL (N = 14, 47%), serum amyloid A amyloidosis (AA) (N = 11, 37%), localized AL (N = 3, 10%), wild-type transthyretin amyloidosis (ATTR) (N = 1, 3.3%), and amyloid of uncertain type (N = 1, 3.3%). Renal graft dysfunction was seen in 11 of 25 (44%) cases. Median graft survival was 185 months (96-269), and median survival from diagnosis with amyloidosis was 45 months (2-89); median survival by amyloidosis type was localized AL: 64 months (20-67), systemic AL: 23.5 months (0-95), ATTR amyloidosis: 17 months, and AA, 15 months (0-77). CONCLUSIONS: This series is the first description of amyloidosis post solid-organ transplant; 30 cases among 5112 amyloid patients >24 years suggests that amyloidosis may occur post solid-organ transplantation with an overall poor survival.