Validation of new renal staging system in AL amyloidosis treated with high dose melphalan and stem cell transplantation
Authors: Andrea Havasi, Lauren Stern, Stephen Lo, Fangui Sun, Vaishali Sanchorawala
Journal: American Journal of Hematology (2016)

To The Editor: Palladini et al. 1 recently validated simple criteria for baseline staging of renal disease associated with AL amyloidosis. It is imperative to predict the course of progression to end stage renal disease (ESRD) in AL amyloidosis, as development of ESRD markedly increases morbidity and leads to treatment limitations. The proposed staging system based on universally available measurements (i.e., proteinuria and eGFR) sharply discriminated three groups of patients with different probabilities of reaching ESRD. Stage I: eGFR ≥ 50 mL/min/1.73 m2 and <5 g/24 hr proteinuria; Stage II: either eGFR < 50 mL/min/1.73 m2 or ≥5 g/24 hr proteinuria; Stage III: eGFR < 50 mL/min/1.73 m2 and ≥5 g/24 hr proteinuria. However, this study included patients with newly diagnosed AL amyloidosis regardless of their treatment modality. Only 9.7% (Pavia) and 29.5% (Heidelberg) of patients underwent high-dose melphalan and stem cell transplantation (HDM/SCT). Here, we report on whether this new renal staging system predicts development of ESRD in AL amyloidosis patients with renal involvement when treated with HDM/SCT. Four hundred and twenty-one consecutive patients with AL amyloidosis treated with HDM/SCT at the Amyloidosis Center, Boston University School of Medicine, from July 1994 to December 2008 were included in the analysis. Patients were treated on several sequential institutional review board–approved protocols during the study period and the data were collected prospectively. Baseline patient characteristics, organ involvement and prior treatment modalities are detailed in Cibeira et al. 2. Of note, 43% of the evaluable and surviving patients achieved a complete hematologic response following HDM/SCT. Hematologic relapse occurred in 28% of these patients with an estimated median time to relapse of 12.7 years. In this cohort of 421 patients, 331 patients (78%) had renal involvement according to the consensus criteria of International Society of Amyloidosis published in 2005 3. Thirty-three patients who were on dialysis at the time of SCT were excluded from further analysis. Reversible acute kidney injury episodes were not included 4. Kaplan-Meier graphs were used for survival analysis with log rank tests to compare the difference in the overall survival distributions. Cox models were fitted to compute hazard ratios and 95% confidence intervals. Deaths that occurred before reaching ESRD were censored. The proportional hazard assumption was evaluated by testing the interaction between the indicators of interest with time. Analysis was performed using SAS 9.3 software (SAS Institute INC., Cary, NC) and P-value <0.05 was defined as statistically significant. In this study, patients had a median serum creatinine of 1 mg/dL (range 0.3–11.7), median eGFR of 77 mL/min/1.73 m2 (range 5–135) and median proteinuria of 6.3 g (range 0.5–58) from 24-hr urine collection prior to undergoing HDM/SCT. The largest proportion of patients (52%) had stage II disease, mainly due to meeting the criteria of > 5 g/24 hr of proteinuria, whereas 30% and 17% of the patients had stage I and stage III disease, respectively. Median renal survival was 13.4 years with a median follow-up of 10.7 years (range, 0.2–21.2) (Fig. 1A). Median survival of ESRD patients from dialysis initiation was 39 months. Cox regression analysis confirmed that both proteinuria >5 g/24 hr (HR 2.05; 95% CI, 1.13–3.7; P < 0.01) and eGFR <50 mL/min/1.73 m2 (HR 2.16; 95% CI, 1.28–3.66; P < .004) were independent determinants of progression to ESRD. Figure 1B shows the risk of progression to dialysis according to renal stage. Patients with stage II renal disease had a 2.5 (95% CI, 1.1–5.6; P = 0.03) times increased risk of developing ESRD compared to stage I patients while patients with stage III renal disease had a 4.7 (95% CI, 1.9 to 11.7; P < 0.01) times increased risk. The 2-year dialysis risk was 0% in renal stage I, 3% in stage II and 14% in stage III (Table 1). Fifty-nine (19%) of patients developed ESRD during the follow-up period. ESRD occurred in 7.7%, 23.9%, and 29.4% of stage I, II, and III patients, respectively. (A) Renal survival from diagnosis. (B) Progression to dialysis according to renal stage. Stage I: eGFR ≥ 50 mL/min/1.73 m2 and <5 g/24 hr proteinuria; Stage II: eGFR < 50 mL/min/1.73 m2 or ≥5 g/24 hr proteinuria; Stage III: eGFR < 50 mL/min/1.73 m2 and ≥5 g/24 hr proteinuria. Median overall survival was longer in our HDM/SCT population: 8.2 years compared to 3.9 years (Pavia) and 2.5 years (Heidelberg). Similarly, renal survival was also significantly longer in our cohort in all three renal stages compared to Palladini et al. 1 (Fig. 1A,B). Hazard ratios for proteinuria > 5 g/24 hr and eGFR < 50 mL/min/1.73 m2 were lower in our cohort (Pavia-Heidelberg cohort: proteinuria HR of 3.9 and 7.2; eGFR HR of 7.2 and 5.7, respectively). Interestingly, the majority of end-stage renal disease events in the Pavia-Heidelberg cohort occurred during the first 2 years while dialysis events occurred more evenly during the follow-up period in this study. The 2-year dialysis risk was also lower in all three renal stages compared to the Pavia-Heidelberg cohort 5 (Table 1). Similar to Palladini et al., there was no significant difference in overall survival among the three renal stages (data not shown) indicating that renal involvement at baseline does not impair overall survival. Of note, a recent study showed that patients who required dialysis within 30 days of HDM/SCT did have worse overall survival 6. Median overall survival of ESRD patients from dialysis initiation was 39 months, which is similar to the Pavia and Heidelberg cohort (39 and 24 months, respectively) suggesting that mortality is driven by ESRD after starting dialysis. Renal survival in AL amyloidosis is longer in the highly selected group of patients who are eligible to undergo HDM/SCT. Renal organ damage is potentially reversible after successful treatment of the underlying plasma cell dyscrasia. Hazard ratios for progression to dialysis using proteinuria > 5 g/24 hr or eGFR < 50 mL/min/1.73 m2 were substantially lower in our cohort. Because of our higher initial renal response rate and prolonged survival after HDM/SCT, there were more late renal relapses occurring in some longer surviving patients. This led to an even distribution of ESRD events over time and increased the duration of dialysis free survival from HDM/SCT. The difference in renal outcomes in the three stages was lower in our cohort (Fig. 1B). For example, the current renal staging system discriminates less well between stage I and stage II patients in the first 2 years after HDM/SCT and there is no clinically meaningful difference between these two groups at early time points. After ∼10 years of follow-up, however, there is a better separation of the renal survival curves confirming that patients who are diagnosed early in the disease process with less advanced renal organ damage are less likely to progress to ESRD in the long term. In summary, the new renal staging system for prediction of progression to ESRD is validated in patients with AL amyloidosis undergoing HDM/SCT as well, however, with less precision. In this patient population, a different staging system might need to be developed to predict more accurately the progression to ESRD. Andrea Havasi,1,2 Lauren Stern,1,2 Stephen Lo,2 Fangui Sun,3 and Vaishali Sanchorawala2,4* 1Department of Nephrology, Boston University School of Medicine, Boston, Massachusetts; 2Amyloidosis Center, Boston University School of Medicine, Boston, Massachusetts; 3Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts; 4Section of Hematology-Oncology, Boston University School of Medicine, Boston, Massachusetts Contract grant sponsor: Amyloid Research Fund at Boston University School of Medicine (to V.S., L.S., A.H.); Contract grant sponsor: NIH; Contract grant number: KO8DK090143 (to A.H.).