Abstract
Lymphadenopathy as a manifestation of amyloidosis is rare. Of 3008 new patients with amyloidosis evaluated from 1994 to 2013 at a single center, 47 (1.6%) presented with lymph node ...enlargement leading to a biopsy and the diagnosis. We conducted a retrospective review of the initial presentation, time to progression, and treatment outcomes for these patients. Upon initial evaluation, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement. Thirty-nine patients (83%) had systemic AL amyloidosis at initial evaluation or developed it on follow up; there was a single case each of AA, wtTTR and V122ITTR and one untyped amyloidosis. Eleven patients (23%) had IgM monoclonal gammopathy and 3 (6%) had histology consistent with lymphoplasmacytic lymphoma. Of the 14 patients with isolated lymphadenopathy, 10 (71%) eventually progressed to other organ disease requiring treatment at a median time of 10 months (range 4-71). This series demonstrates that patients presenting with amyloid lymphadenopathy usually have AL amyloidosis, and should have a thorough evaluation for other organ involvement at diagnosis. If present, treatment should be similar to that of other patients with systemic AL amyloidosis, but if not, patients should be monitored regularly for development of other organ disease over time.
We report on the clinical presentation and histopathology of a series of seven patients with localized amyloidosis of the breast. These patients were diagnosed by biopsy performed to rule out ...malignancy because of calcifications seen by mammography, and represented 0.5% of patients referred to the Amyloid Treatment and Research Program at Boston University Medical Campus in an 18-year period. The patients ranged in age from 35 to 75, median 63 years. None of these seven patients had evidence of a systemic plasma cell dyscrasia or amyloidosis in other organs, nor did systemic disease develop with a median follow-up of 6 years. Thus, other than excisional biopsy to exclude malignancy, no systemic therapy is indicated for this disorder.
Monoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney ...transplantation outcomes in MIDD are limited.
This was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation.
The 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years, P = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment.
As treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation.
Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The ...leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.
•A biomarker staging system for AL amyloidosis using thresholds of BNP >81 pg/mL and TnI >0.1 ng/mL strongly correlates with NT-proBNP-based systems.•This new BNP-based staging system predicts overall survival in patients with AL amyloidosis.
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Summary
With limited existing data on hereditary factors in light chain (AL) amyloidosis, we conducted a study of patients with plasma cell dyscrasias or lymphoproliferative disorders in their family ...history. Among 1621 patients, we identified 44 probands (2·7%) with 52 relatives affected. The most common disorders in family members were multiple myeloma (48%) and AL amyloidosis (18%). Light chain isotype was 100% congruent in families with known clonal immunoglobulin for both members. Despite matching light chain isotype, organ involvement varied between members in families with multiple cases of AL amyloidosis. These findings help generate hypotheses about familial influences in AL amyloidosis.
Background:
Minimal residual disease (MRD) assessment can provide an index of robust disease control, particularly if MRD negativity is sustained over time. Whereas MRD status has well-established ...prognostic implications in multiple myeloma, its role in light chain (AL) amyloidosis-a related but biologically distinct plasma cell disorder-is presently under investigation.
Aims:
The aims of our study were to evaluate (1) major organ deterioration-progression-free survival (MOD-PFS) based on MRD status and (2) MRD evolution patterns during disease surveillance for patients with AL amyloidosis in hematologic complete response (hemCR) after therapy.
Methods:
We established MRD status using multiparametric 10-color flow cytometry of bone marrow aspirates. At least 2 x 10 6 events were measured using a Beckman Coulter Navios Flow Cytometer and analyzed by Kaluza Software (sensitivity level of ≤10 -5). Sequential MRD testing was performed (≥12 months apart) for patients returning for follow-up. We evaluated hematologic and organ responses or progression based on consensus guidelines (Palladini, 2012). MOD-PFS was defined as time from hemCR achievement to major organ deterioration (i.e., the kidney or heart), hematologic progression or death from any cause (whichever occurred first). Presence of MRD was not used to guide treatment decisions.
Results:
A total of 96 patients with hemCR after therapy were tested, of whom 46 (48%) were MRD negative and 50 (52%) MRD positive on first assessment. The median estimated clone size for those with MRD positivity was 3.4 x 10 -4 (range 1.4 x 10 -5 to 5.7 x 10 -3). Baseline characteristics were similar between groups, except for greater use of daratumumab and ≥2 lines of therapy to achieve hemCR in the MRD-negative group. MRD positivity correlated with a higher level of involved free light chains (iFLC) in the serum at the time of MRD assessment (23.4 mg/L vs 17.3 mg/L, P = .011). In regard to organ responses, patients with MRD negativity had a significantly higher rate of renal response (91% vs 67%, P = .017) but a similar rate of cardiac response (74% vs 68%, P = .668).
After a median follow-up of 50 months from hemCR achievement, the MRD-negative group demonstrated a superior MOD-PFS (HR 0.38, 95% CI 0.16-0.88, P = .034). Progression or organ deterioration events in the MRD-negative group occurred early after hemCR achievement, while in the MRD-positive group these events continued to occur over time. A total of 8 patients had died, including 4 in each group.
Sequential MRD testing (median 12 months apart, range 12-28 months) was performed for 43 patients, of whom 16/19 (84%) had sustained MRD negativity; 21/24 (88%) had persistent MRD positivity; and 6/43 (14%) had MRD conversion. No patient received therapy between MRD assessments. Among those with sustained MRD negativity, there were 2 major organ deterioration events. The 3 patients who experienced loss of MRD negativity (which occurred at 12, 107 and 114 months after last treatment) had no progression or organ deterioration events. Of those with persistent MRD positivity, 13 (62%) had durable hemCR and organ responses; moreover, 4/14 (29%) and 1/11 (9%) of these patients attained even deeper renal and cardiac responses, respectively, in the interval between sequential MRD testing. Clone progression (defined as >1-log growth in MRD clone size) was observed in 3/21 (14%) patients with persistent MRD positivity, none of whom demonstrated hematologic relapse.
Conclusions:
We evaluated the dynamics of MRD status in relation to clinical outcomes and found that patients with MRD negativity had longer survival free from hematologic progression, major organ deterioration or death. Longer prospective follow-up is needed to determine whether this translates into an overall survival benefit. MRD conversion occurred in a small proportion (14%) of patients, but was not linked to adverse outcomes. Understanding the role of cross-sectional MRD testing for clinical disease tracking in AL amyloidosis requires further analysis with larger sample size.
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Sanchorawala: Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pfizer: Honoraria; Karyopharm: Research Funding; Sorrento: Research Funding; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding.
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Background: Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from ...the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients (pts) with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 28-day Cycles (Cyc). Bortezomib (1.3 mg/m
2
), cyclophosphamide (300 mg/m
2
maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (Cyc 1–2) and every 2 weeks (wk) (Cyc 3–6). After Cyc 6, pts in the DARA-VCd group received DARA SC alone every 4 wk for up to 24 Cyc from first dose. Disease status was evaluated every 4 wk in Cyc 1–6 and every 8 wk after Cyc 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Results: Of 388 randomized pts, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median treatment duration was 18.5 months (mo) for DARA-VCd and 5.3 mo for VCd; 78 pts (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio OR 5.9; 95% CI 3.7–9.4; P< 0.0001). More pts achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; P< 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 mo). Cardiac response rates were higher with DARA-VCd than VCd at 6 mo (42% vs 22%) and at 12 mo (57% vs 28%); renal response rates were 54% vs 27% at 6 mo and 57% vs 27% at 12 mo. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From Cyc 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of pts. There were no systemic administration-related reactions with DARA-VCd after Cyc 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. Conclusions: Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. Clinical trial information: NCT03201965.
Background: The median age at diagnosis for systemic AL amyloidosis is reported to be 64 years. A small number of patients are diagnosed at a much younger age, i.e., before 40 years. The ...characteristics and prognosis of these patients are not well known, and perhaps they require unique considerations due to the earlier onset of disease. A closer understanding of this patient population could help guide management approach and improve long term outcomes. Aim: In this study, we aimed to describe the presenting clinical features, hematologic profiles and outcomes of young patients with AL amyloidosis. Methods: Patients with systemic AL amyloidosis and age ≤ 40 years at diagnosis who presented to the Boston University Amyloidosis Center between 2000 and 2023 were identified from our prospectively maintained database of consented patients (ClinicalTrials.gov Identifier: NCT00898235). All patients had clinicopathological evidence of systemic AL amyloidosis, with positive Congo red staining of a biopsy specimen and evidence of a plasma cell dyscrasia. We collected clinical data both from the database and medical records of these patients. Overall survival (OS) rates were estimated using the Kaplan-Meier method, and hazard ratios (HR) computed from multivariable Cox proportional hazard models for OS. Results: Of 1,722 patients with AL amyloidosis evaluated during the study period, we identified 45 (2.6%) patients who were diagnosed at ≤ 40 years of age. The median age was 37 years (range 21-40) and only 4 patients were ≤ 30 years of age. Presenting characteristics are shown in Table 1. Notably, this cohort had a median B-type natriuretic peptide of 87 pg/mL (range 0-2,346), troponin-I of 0.012 ng/mL (range 0-3.192), interventricular septum of 11 mm (range 5-18), and 6-minute walking distance (6MWD) of 396 meters (range 183-731). The median time from symptom onset to diagnosis was 8 months (range 1-72). The majority (n = 32, 71%) were treated with high-dose melphalan and stem cell transplantation (HDM/SCT) as frontline therapy. Meanwhile, 11 patients received non-SCT treatments, including melphalan/dexamethasone (7%), daratumumab-CyBorD (4%), CyBorD (2%), bortezomib/dexamethasone (2%), and dexamethasone alone (2%). Of the evaluable patients (n = 31), 39% achieved hematologic complete response to any regimen at 6-12 months following treatment. With a medianfollow-up of surviving patients of 9.0 years, the median OS was 16.7 years (95% CI 11.6-16.9). Of the cohort, a total of 20 patients (44%) died. Patients treated with HDM/SCT had median OS of 16.9 years; meanwhile, those treated with non-SCT therapies had a median OS of 1.3 years. On multivariate analysis, time from symptom onset to diagnosis of >6 months (HR 2.21, p = 0.21) and 6MWD < 400 meters (HR 1.37, p = 0.66) were independently associated with increased risk of mortality. Conclusions: Young patients with AL amyloidosis who are diagnosed before 40 years of age have a prolonged survival if treated with intensive treatment with HDM/SCT if eligible. Longer time to diagnosis from symptom onset and 6-minute walk distance are important prognostic factors in this patient population.
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