Citations

Introduction: The utility of amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after starting treatment has not been explored. Given the high early mortality in this disease, restaging remote from the diagnosis may have clinical value. We designed this study to evaluate whether the currently used staging systems are prognostic when applied at 3 and 6 months from starting first-line treatment, and whether stage migration impacts survival. Methods: This is a retrospective study including patients with systemic light chain amyloidosis diagnosed between January, 1st 2006 and June, 30th 2019 and were seen in Mayo Clinic, Rochester, MN within 90 days of diagnosis; the analysis included 535 and 301 patients who had restaging data available for at least one of the staging systems at 3 and 6 months, respectively. Patients were grouped into 4 stages using the 2015 European modification of the Mayo 2004 staging system based on values of cardiac biomarkers (cardiac troponin T and NTproBNP), and using the Mayo 2012 staging system based on cardiac biomarkers and the difference in serum free light chain concentration (dFLC). Overall survival (OS) was calculated from the time of re-staging until death or last follow up. Results: Using the modified Mayo 2004 staging system at 3 months from starting first-line treatment, median OS was 11.8 [95%CI: 11.4-not reached (NR)], 10.8 (95%CI: 9.4-NR), 4.6 (95%CI: 2.8-6.7), and 1.1 (95%CI: 0.7-2.6) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 3 months, OS was 11.8 (95%CI: 10.9-NR), 9.0 (95%CI: 6.2-NR), 5.2 (95%CI: 3.3-6.1), and 0.8 (95%CI: 0.7-1.1) years in patients with stage I, II, III, and IV, respectively (Figure 1a &b). Using the modified Mayo 2004 staging system at 6 months from starting first-line treatment, median OS was NR (95%CI: NR-NR), 9.8 (95%CI: 6.2-NR), 5.4 (95%CI: 3.2-9.0) and 0.9 (95%CI: 0.6-3.7) years in patients with stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012 staging at 6 months, OS was NR (95%CI: 8.4-NR), NR (95%CI: 7.9-NR), 4.6 (95%CI: 3.0-6.5), and 0.9 (95%CI: 0.2-1.8) years in patients with stage I, II, III, and IV, respectively (Figure 1c &d). On multivariate analysis, advanced (stage > 2) modified Mayo 2004 stage (HR: 1.6, P=0.004) and advanced (stage > 2) Mayo 2012 stage (HR: 2.4, P<0.001) at 3 months were associated with decreased survival independent of cardiac response, hematologic response, and transplantation status. Although advanced Mayo 2004 stage at 6 months was associated with decreased survival, it was not statistically significant (HR: 1.5, P=0.09). In contrast, advanced Mayo 2012 stage at 6 months was independently associated with decreased survival (HR: 2.1, P=0.02). For both systems, worsening stage at 3 months or at 6 months was associated with a worse survival than retaining the original stage. In contrast, improving stage as compared to remaining in same stage was not associated with better survival at 3 or 6 months (Table 1). When the analysis was restricted to patients who had an advanced stage at diagnosis, improving stage at 3 months was associated with longer survival compared to retaining the original stage, with both modified Mayo 2004 (10.8 vs. 3.3 years, P<0.001) and Mayo 2012 (8.1 vs. 2.6 years, P<0.001) staging systems. At 6 months, stage improvement was associated with longer survival than retaining the original stage when the modified Mayo 2004 staging system was used (NR vs. 5.0 years, P=0.02), but it was not statistically significant when the Mayo 2012 staging system was used (5.9 vs. 3.7 years, P=0.12). Conclusion: The modified Mayo 2004 and the Mayo 2012 staging systems have independent prognostic value when used for restaging after 3 and 6 months from initiation of first-line treatment. Migration to a higher stage from diagnosis predicts decreased survival, compared to retaining the same stage. Stage improvement is associated with a better OS in patients with advanced stage at diagnosis. Disclosures Dispenzieri: Alnylam, Intellia, Janssen, Takeda, Pfizer, Prothena, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy. Dingli:Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Alexion: Consultancy; Apellis: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Janssen: Consultancy, Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Gertz:Alnylam: Consultancy; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Amyloidosis Foundation: Research Funding; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; International Waldenstrom Foundation: Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Cellectar: Other; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Karyopharm: Consultancy; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Sanofi: Research Funding.

Background: Patients with Waldenström Macroglobulinemia (WM) tend to present at an older age. Frailty, resulting from comorbidities and reduced organ function, poses unique challenges to the management of WM in the elderly. Age above 65 years, is an established unfavorable prognostic factor in WM. However, data specifically pertaining to the very elderly patient population are scant. The impact of advanced age (≥75 years at diagnosis) on the clinical features and outcomes of patients with symptomatic/active WM were studied. Methods: Patients with active WM, evaluated at Mayo Clinic, Rochester between January 1996 and December 2018 were included in the study. The characteristics and laboratory parameters at presentation of the cohort of patients with the age ≥75 years were compared to those of the younger (age <75 years) cohort. The median follow-up and overall survival (OS) were assessed from active disease to last follow-up or death using the Kaplan Meier method. Because older age is a confounding factor for deaths from unrelated causes, the cause-specific survival (CSS) was calculated. Deaths were deemed WM-related if patients died from progressive disease, transformation with antecedent WM, concomitant light chain (AL) amyloidosis, infection associated with WM or anti-WM therapy related toxicity, while patients who died from other causes were considered to have a WM-unrelated death. The patients who died from causes unrelated to WM were censored at death for CSS analysis. The OS of the cohort of the very elderly patients was compared to that of a cohort of the general US population, matched for age, sex as well as follow-up from the calendar-year of diagnosis, to assess the degree to which WM impacts survival. Results: Among 949 consecutive patients, with a median follow-up of 8.4 years [95% Confidence Interval (CI): 7.7-9.3 years] from active disease, the median age at diagnosis was 65 years (range: 31-93 years). Of 177 patients (19%) who were ≥75 years of age at the onset of active WM, 173 (98%) received anti-WM therapy. The baseline characteristics of the 2 cohorts (patients ≥75 years of age versus <75 years) are outlined in Table 1. The patients in the age ≥75 years cohort were noted to have lower IgM levels and serum albumin, and higher serum LDH and serum β-2 microglobulin compared to the age <75 years cohort. A higher proportion of patients in the age <75 years cohort had coexisting AL amyloidosis at diagnosis. The frequency of MYD88L265P mutation was similar between the 2 cohorts (p=0.2). During the 23-year period, there was an increase in the proportion of patients ≥75 years who were diagnosed with active WM (12% during the 1996-2003 period, 18% during 2004-2010, 25% during 2011-2018; P<0.0001). In the elderly WM cohort, the most frequently used frontline treatment was rituximab monotherapy (36%), followed by rituximab-alkylating agent-based regimen (31%). Of 177 patients with age ≥75 years, 89 (50%) patients were deceased at the time of last follow-up and 58% (52/89) of all deaths in age ≥75 years were attributable to WM. By contrast, 303 (39%) out of the 772 patients in the age <75 years cohort were deceased at last follow-up, with 73% (224/303) deaths attributable to WM. The CSS for patients with age ≥75 years was 10.9 years (95% CI: 7.3-11.7 years) versus 14.7 years (95% CI: 13.2-15.7 years) for age <75 years [Risk ratio 2.1(95% CI: 1.5-2.8); p<0.0001]. At the 1 and 2 year follow-up, WM-related mortality was 6.8% and 11.9%, respectively, for patients with age ≥75 years versus 2.6% and 4.9%, respectively, for the younger cohort. The median OS of patients with age ≥75 years from the diagnosis of active WM was 5.9 years (95% CI: 4.2-7.3 years) compared to the OS of 8.3 years for an age, sex and calendar-year-matched cohort, derived from the general US population (p<0.001), Figure 1. Conclusion: Patients who are ≥75 years of age at the time of diagnosis of active WM present with certain poor prognostic features, including higher serum LDH and β-2 microglobulin and lower serum albumin compared to their younger counterparts. The impact of advanced age is underscored by a poorer WM-specific survival for the subset of patients with the age ≥75 years compared to the younger cohort. Furthermore, although active/symptomatic WM is typically an indolent malignancy, it adversely affects OS of the very elderly patients as suggested by the comparison with an age, sex and calendar-year matched cohort of the general US population. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding. Gertz:Ionis/Akcea: Other: personal fee; Alnylam: Other: personal fee; Prothena: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Annexon: Other: personal fee; Appellis: Other: personal fee; Amgen: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Physicians Education Resource: Other: personal fee; Abbvie: Other; Celgene: Other; Research to Practice: Other; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Other; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Janssen: Other: personal fee. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; MorphSys: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Sanofi-Genzyme: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Kumar:Sanofi: Research Funding; Kite Pharma: Consultancy, Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; MedImmune: Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; BMS: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria.