Kirkwood, Amy A.

PURPOSE Outcomes in systemic light chain (AL) amyloidosis have improved with modern therapy limiting utility of existing risk stratification models. We validate a new staging system, incorporating longitudinal strain (LS) to the biomarker-based (NT-proBNP and Troponin-T) staging system in the contemporary treatment era (2015-2024). METHODS AL International Staging System (AL-ISS) was derived from a cohort of patients with AL amyloidosis from the UK National Amyloidosis Centre (2015-2019). The model was validated in patient cohorts from Europe (Greece, Italy, the Netherlands, and Switzerland), the United States (2015-2024), and the United Kingdom (2020-2024). RESULTS In total, 2,493 patients were included (derivation, n = 573; validation n = 1,920). In a multivariable model for the derivation cohort, LS ≥ –9% and cardiac biomarkers at previously validated thresholds (NT-proBNP 332 ng/L and 8,500 ng/L and high-sensitivity troponin T ≥ 50 ng/L) were independent poor prognostic factors stratifying patients into stages I, II, IIIA, IIIB, and IIIC. In the validation cohort, the patient stages were stage I: 317 (17%), II: 782 (41%), IIIA: 551 (29%), IIIB: 174 (9%), and IIIC: 96 (5%), respectively (first-line daratumumab treated: 826; 43%). With a median follow-up of 34 months, median overall survival (OS) was not reached (NR); estimated 1-year, 2-year, and 3-year OS was 82%, 74%, and 70% respectively. The median survival for stages I to II, IIIA, IIIB, and IIIC were NR, 67, 26, and 7 months (1-year OS IIIC 53% v 68% for IIIB in the daratumumab-treated patients), respectively ( P < .001). External validation exhibited good predictive performance: 12-month calibration slope was 1.09, Harrell C 0.69, Royston D 1.19, and R 2 D 0.25. Stage IIIC independently discriminated the poorest outcome across all cohorts. CONCLUSION This defines and validates a new staging system from systemic AL amyloidosis with robust identification of an ultra-poor risk stage (IIIC) in contemporarily treated patients.

Abstract Background: Despite recent therapeutic advances in AS cHL, PET-adaptive chemotherapy-based regimens remain a first-line treatment option, especially for patients (pts) without access to novel agents. Most PET-adaptive regiments start with either 2 cycles of escBEACOPP (escBEACOPP2) or ABVD (ABVD2) prior to interim PET assessment (iPET), followed by treatment de-escalation or intensification by iPET result. There have been no direct comparisons of escBEACOPP2 vs ABVD2 PET-adaptive regimens. Additionally, the AS-Hodgkin Lymphoma International Prognostication Index (A-HIPI) score (Rodday JCO 2023) has not been fully explored in escBEACOPP2 regimens. Therefore, we utilized multiple analytic approaches to compare outcomes of PET-adaptive escBEACOPP2 and ABVD2 regimens, while adjusting for and assessing the effect of the baseline A-HIPI score. Methods: Through the global HoLISTIC Consortium (www.hodgkinconsortium.com), we obtained individual patient data from 4 AS clinical trials of newly diagnosed cHL pts treated with PET-adaptive escBEACOPP2 (AHL2011) or ABVD2 (SWOG0816, RATHL, HD0607) regimens. Pts were restricted to age 18 to 65 years (y), stage IIB-IV, and PET-adapted treatment arms. Positive iPET was based on Deauville score &gt;3. Treatment effects of escBEACOPP2 vs ABVD2 (reference) on 5y progression-free survival (PFS) and overall survival (OS) were first evaluated using Cox models. Importantly, baseline disease risk was adjusted for using the 5y PFS or OS A-HIPI score (including stage, sex, age, bulk, lymphocyte count, albumin, white blood cell count), where higher scores indicate higher predicted risk (scale 1-100). The A-HIPI was modeled per 1 standard deviation (SD) increase. Our multistate model (MSM) comprised 4 health states: diagnosis, sustained remission at 1yr, treatment failure, and death from any cause. Pts all started in the diagnosis state and transitioned to other states without return to prior states. We assessed the impact of treatment on transitions (except binary sustained remission at 1y) that involved ≥5 pts per treatment group, adjusting for A-HIPI for all transitions. All effects are reported as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Results: 2,381 AS cHL pts were included (n=372 for escBEACOPP2, n=2009 for ABVD2). For escBEACOPP2 and ABVD2 groups (median follow-up 60 and 56 months), respectively, the mean baseline A-HIPI scores (i.e., predicted 5y PFS event rate) were 25.1 (SD=6.3) and 22.9 (SD=6.5), the rates of positive iPET were 11.3% and 17.0%, 5y PFS was 87.0% and 79.5%, and 5y OS was 96.3% and 94.6%. In Cox models, escBEACOPP2 was associated with significantly improved PFS compared to ABVD2 (aHR=0.54, 95% CI=0.39-0.73); the aHR for OS was 0.67 (95% CI=0.37-1.19). Notably, higher risk A-HIPI score was associated with significantly worse PFS (aHR=1.42, 95% CI=1.31-1.54) and OS (aHR=1.60, 95% CI=1.47-1.76), independent of treatment. In the MSM, the effect of escBEACOPP2 compared to ABVD2 regimens was modeled in 3 transitions with adjustment for A-HIPI score: those treated with escBEACOPP2 had lower likelihood of treatment failure with (aHR=0.38, 95% CI=0.22-0.66) or without (aHR=0.61, 95% CI=0.40-0.92) sustained remission at 1y; the aHR for treatment failure to death was 0.55 (95% CI=0.25-1.22). Higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure and death without sustained remission at 1y (aHR=1.43, 95% CI=1.28-1.61 and aHR=2.50, 95% CI=1.80-3.49, respectively). Furthermore, higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure after achieving sustained remission at 1y (aHR=1.29, 95% CI=1.12-1.48) as well as death after treatment failure (aHR=1.54, 95% CI=1.27-1.86). Conclusions: Comparing newly diagnosed adult AS cHL PET-adaptive regimens with adjustment for baseline A-HIPI score, we found pts treated with escBEACOPP2 on AHL2011 had improved PFS versus pooled pt data from 3 ABVD2 trials. Using MSM, we further demonstrated that escBEACOPP2 was associated with a lower likelihood of treatment failure with or without achieving sustained remission at 1yr. In addition, baseline A-HIPI score was associated with PFS and OS, which was independent of treatment. Finally, higher baseline A-HIPI scores maintained prognostic impact throughout the disease course, including increased risk of treatment failure for pts in remission at 1yr and death after treatment failure.

Abstract Background: Systemic AL amyloidosis is an incurable disorder caused by misfolded light chain fibrils. Survival is determined by the extent of cardiac involvement and response to therapy. Mayo 2012 (stage I-IV) and European modified Mayo 2004 (stage I-IIIB) prognostic scores were developed in a historic treatment era, prior to widespread bortezomib and daratumumab use. These no longer discriminate those with the poorest outcomes. We presented a new model sub-stratifying IIIB into a high risk, ‘IIIC’ group, incorporating longitudinal strain (LS) to the European modified score (IIIC: LS &gt;-9% + NT-proBNP &gt;8500ng/L + high-sensitivity troponin T [hs-TnT] &gt;50ng/L) in the bortezomib-era (2015-2019) last year (Khwaja et al, ASH 2024). Here, we present an independent external validation of the IIIC model in the modern treatment era. Methods: The ‘IIIC model’ was derived from a large real-world cohort of adults from the UK National Amyloidosis Centre (2015-2019). Performance was externally validated across Europe (Greece, Italy, Netherlands, Switzerland), USA (2015-2024) and UK (2020-2024). Survival estimates were generated from diagnosis to death or last follow-up using the Kaplan-Meier method and groups compared using Cox regression (using Stata v18). Stage IIIB and IIIC were defined as follows IIIB: LS &lt;-9%, NT-proBNP &gt;8500ng/L, hs-TnT &gt;50ng/L and IIIC: LS &gt;-9%, NT-proBNP &gt;8500ng/L, hs-TnT &gt;50ng/L, respectively. Stage I, II and IIIa were defined as previously described in the European modification of Mayo 2004 staging system. Results: 2493 patients were analysed from 2015-2024 (derivation, n=573; validation: Europe, n=374, USA n=458, UK, n=1088). In the derivation cohort, LS ≥-9% and standard cardiac biomarkers (NT-proBNP 332ng/L and 8500ng/L and hs-TnT&gt;50ng/L) were selected as independent prognostic factors in a multivariable model. In the European and UK validation cohort (n=1462), median age at diagnosis was 67 years (range 35-95) with 1014 (69%) cardiac and 869 (60%) renal involvement. Median difference in involved and uninvolved free light chain (dFLC) was 181 mg/L (range 0-24933), NT-proBNP 1911ng/L (range 42-70000), hs-TnT 45ng/L (range 3-1221) and LS -14.7% (range -3- -28). In the US cohort median NT-proBNP was 1764 (range 13-71000) and hs-TnT 44 (6-687). Applying the new model staging, the patient stages were across Europe and UK were stage I: 224 (15%), II: 627 (43%), IIIA: 396 (27%), IIIB: 139 (10%) and IIIC: 76 (5%), respectively. 592 (41%) were treated with first-line daratumumab-based regimens. In the US dataset stage I: 103 (22%), II: 176 (38%), IIIA: 131 (29%), IIIB: 48 (10%) and IIIC: 16 (3%), respectively. 234 (51%) were treated with first-line daratumumab-based regimens. At a median follow-up of 30 months (95% CI 28-32) in the European and UK validation cohort, estimated median overall survival (OS) was not reached and 2-year OS was 74% (95% CI 72-77). Median survival for stages I-II, IIIA, IIIB and IIIC were not reached (NR), 67, 31 and 10 months, respectively (p&lt;0.001). Hazard ratios for stage II, IIIA, IIIB, IIIC were 2.01 (95% CI 1.32-3.07), 3.51 (95% CI 2.31-5.35), 5.67 (95% CI 3.60-8.91) and 11.12 (95% CI 6.93-17.87), respectively (p&lt;0.001). This was confirmed in the US cohort with a median survival for respective stages were NR, NR, NR, 8 and 2 months (p&lt;0.001). External validation in the European and UK cohorts exhibited good predictive performance: 12-month calibration slope was 1.00 (95% CI 0.81-1.20, p=0.98), Harrel's C was 0.90 (95% CI 0.76-1.00), Royston's D 1.07, R2D 0.21 (95% CI 0.15-0.28). In 1462 patients with dataset available, stage IIIC discriminated the poorest outcome despite a greater proportion treated with first-line daratumumab v IIIB in the validation cohort (59% v 40%, p=0.008). 12-month OS for IIIC v IIIB was 44% (95% CI 32-55) v 69% (95% CI 60-76), specificity for 12-month OS 97% v 92% and diagnostic odds ratio 6.62 v 2.36. Conclusions: This study validates the new staging system from stage I-IIIC with robust identification of an ultra-poor prognostic group (Stage IIIC) in a contemporarily treated patient cohort. Despite novel therapies, the OS remains &lt;12 month in the IIIC group and also poor in stage IIIB with median OS 31 months compared to a median of &gt;5 years for all other stages. This staging system can be considered as a new standard of care for risk stratification of AL amyloidosis. Novel approaches are required for patients with advanced risk.

Background: Although advanced stage cHL typically has excellent disease outcomes, 20-30% of patients (pts) experience treatment failure. In addition, decision-making is challenging given varying treatment options and incomplete prognostic data across the disease course. Pre-treatment factors, such as those incorporated into the Advanced Stage Hodgkin Lymphoma International Prognostication Index (A-HIPI), predict 5 year (y) overall survival (OS) and progression-free survival (PFS) (Rodday JCO 2023). Other than interim PET (iPET) results, it is unknown what factors influence cHL disease states mid-therapy. Using multistate modeling (MSM) and individual pt data from the HoLISTIC Consortium, we refined prognostication across the cHL disease course, specifically assessing the relationships between A-HIPI, iPET and end of treatment (EOT) response, and whether the A-HIPI and iPET provide independent prognostic information. Methods: We analyzed 1240 pts aged 18-65y with newly diagnosed Stage IIB, III or IV cHL treated on 2 advanced stage PET-adapted trials (RATHL, SWOG0816). All pts first received 2 cycles of ABVD; those with a negative iPET (Deauville score (DS) ≤3) received ABVD or AVD, and those with a positive iPET (DS &gt;3) received BEACOPP. In contrast to other methods, MSMs incorporate multiple disease states into one model, account for censoring and competing risks, and estimate transitions between disease states using different covariates. Our MSM had 6 states: diagnosis, negative iPET, positive iPET, EOT non-progression (e.g., DS ≤ 3), treatment failure, and death. Treatment failure included progression or relapse. All pts start at the diagnosis state and can transition to other states without return to prior states. Transition states with &lt;5 events were excluded. The MSM was estimated using a multivariable Cox model with censoring at 5y. Covariates were the 5y PFS A-HIPI (comprised of stage and continuous age, lymphocyte count and albumin), which was included for all transitions, and iPET, which was included for transitions from EOT non-progression and from treatment failure. Higher scores on the 5y PFS A-HIPI indicate lower risk of progression or death; the A-HIPI was modeled for a 1 standard deviation (SD) increase. We calculated probabilities of 5y treatment failure for 4 sample pts based on low (70) and high (85) A-HIPI scores, positive and negative iPET, and EOT non-progression. Results: Median age was 33y (Q1=25, Q3=45), 56% were male, 23% were stage IIB, 40% III and 37% IV, and mean A-HIPI was 77 (SD=7). Median follow-up was 75 months (Q1=53, Q3=92). At iPET, 80% (95% CI 78%, 83%) were negative and 16% (95% CI 14%, 18%) were positive. At EOT, 90% (95% CI 89%, 92%) were in the non-progression state. At 5y, 75% (95% CI 73%, 78%) were in the non-progression state, 16% (95% CI 14%, 19%) had experienced treatment failure, and 9% (7%, 11%) had died. Better A-HIPI scores (per SD) were associated with lower rates of transitioning from diagnosis to positive iPET (HR=0.80, p&lt;0.01) and from positive iPET to treatment failure (HR=0.58, p=0.04). Better A-HIPI scores (per SD) were also associated with lower rates of transitioning from EOT non-progression to treatment failure (HR=0.78, p&lt;0.01) and from treatment failure to death (HR=0.64, p&lt;0.01), adjusting for iPET. Positive iPET was associated with an increased rate of transitioning from EOT non-progression to treatment failure (HR=1.90, p&lt;0.01), adjusting for A-HIPI. The probability of 5y treatment failure for 4 sample pts was: 25% for low A-HIPI and positive iPET; 20% for high A-HIPI and positive iPET; 13% for low A-HIPI and negative iPET; and 12% for high A-HIPI and negative iPET. Conclusions: We created a novel MSM that refines prognostication across the cHL disease course by incorporating pre- and post-treatment factors (e.g., iPET) to estimate transitions to future disease states. Although the A-HIPI was developed using pre-treatment factors to predict 5y OS and PFS, we found that it was also associated with transitions to interim disease states, including iPET and EOT response. The A-HIPI and iPET each provided independent prognostic information, supporting the use of both in estimating cHL outcomes. Future analyses will develop clinical prediction models using MSMs that also incorporate varying frontline and salvage treatments and treatment-specific late effects, with the goal of providing individualized information across the disease course.