Prognostic Relevance of Cytogenetic Chromosomal Abnormalities on Outcome Among AL Amyloidosis Patients in the Netherlands
Authors: Abbink Leonie , Brink Mirian , Roeloffzen Wilfried , Poddighe Pino , Minnema Monique C. 
Published: November 2021

Abstract
Introduction Systemic light chain (AL) amyloidosis is a clonal plasma cell neoplasm, that carries a poor prognosis. Treatment is adapted from protocols as used in MM, and include bortezomib-based (PI) regimens with or without stem cell transplantation (SCT). PI-based regimens have improved treatment responses and outcomes. Cytogenetic analysis has become an important tool in the diagnostic process of plasma cell disorders, and evidence for prognostic significance of specific genetic abnormalities in relation to therapy efficacy is recognized in systemic AL amyloidosis. Thus far, this prognostic significance has been evaluated in single center institutions.
Aim This nationwide, population-based study aimed to assess the impact of cytogenetic abnormalities on hematological response and survival among patients with systemic AL amyloidosis treated with PI-based regimens.
Methods We identified 349 patients ≥18 years with systemic AL amyloidosis diagnosed between 2017 and 2019 in the Netherlands Cancer Registry, with survival follow-up until February 1, 2021. Data on therapeutic strategy was known for all individual patients. The cytogenetic aberrations studied include gain(1q), hyperdiploidy, del(17p), and IGH rearrangements, i.e. t(11;14), t(4;14), t(14;16), and t(v;14q32) (non-specified IGH rearrangement). Hematological response and overall survival (OS) were evaluated in relation to cytogenetic aberrations. OS was defined as death by any cause post-diagnosis. Uni- and multivariable analysis for establishing independent predictors of OS, i.e. age, sex, cytogenetic assessment and SCT, was performed using Cox regression. Patients diagnosed at autopsy (n=4), patients who did not start first-line therapy (n=64) or received other therapies (n=37), and patients with systemic AL amyloidosis related to Waldenström Macroglobulinemia (n=10) were excluded.
Results In our analytic cohort, 234 patients (median age 67 years; 62% males) were treated with PI-based regimens. Of these patients, 153 (65%) were ≤70 years at diagnosis. SCT was performed in 70 (30%) patients following PI-based regimens. For 170 (73%) patients, cytogenetic assessment was performed. IGH rearrangements were observed in 76 patients (45%), comprised of t(11;14) in 27 patients, t(4;14) in 3 patients, t(14;16) in 2 patients and non-specified IGH rearrangements in 44 patients. Furthermore, 26 patients carried a gain(1q), 4 patients a del(17p), and 33 patients were hyperdiploid. Due to the limited patient number with del(17p), response and OS was not evaluated for this subgroup.
A complete remission (CR; n=53), very good partial response (VGPR; n=66), or partial remission (PR; n=55) was accomplished for 74% of the patients, ≥VGPR for 51% of the patients. The reached hematological response was irrespective of the detected cytogenetic abnormalities. In detail, ≥VGPR was 56% for patients with a t(11;14), 62% for patients with a gain(1q), 55% for patients with hyperdiploidy, and 50% for patients with an IGH rearrangement and this was not statistical significant different from patients without these cytogenetic abnormalities.
The 3-year OS was 61% for patients treated with PI-based regimens. For patients with a cytogenetic assessment (n=170), there was no significant difference in 3-year OS between patients with or without a t(11;14) (69% vs. 66%, respectively; p=0.70), with or without gain(1q) (57% vs. 68%, respectively; p=0.58), with or without hyperdiploidy (72% vs. 65%, respectively; p=0.63), or with or without an IGH rearrangement (59% vs. 72%; p=0.21). Only SCT was an independent predictor for reduced risk of mortality in uni- and multivariable analyses, overall as well as for the specific cytogenetic subgroups.
Conclusion In this Dutch 'real world' population of AL amyloidosis patients treated with PI-based regimens, 74% had a ≥PR and 51% had ≥VGPR. The 3-year OS was 61%. We evaluated the cytogenetic data of 170 patients, but could not confirm a relation between PI-based regimens and outcome, overall as well as in specific cytogenetic subgroups. Patient numbers of the cytogenetic subgroups were low and we could not determine the partner gene in 44 patients with an IGH rearrangement. To the best of our knowledge, this is the first population-based study to evaluate the prognostic relevance of cytogenetic abnormalities in relation to hematological response and OS among systemic AL amyloidosis patients.

Disclosures
Minnema: Alnylam: Consultancy; Kite/Gilead: Consultancy; Jansen-Cilag: Consultancy; BMS: Honoraria; Celgene: Other: Hospitality.