Predictive value of the new renal response criteria in AL amyloidosis treated with high dose melphalan and stem cell transplantation
Authors: Andrea Havasi, Gheorghe Doros, Vaishali Sanchorawala
Journal: American Journal of Hematology (2018)

Palladini et al. recently developed new renal response and progression criteria assessed at 6 months after treatment for AL amyloidosis.1 These new criteria predicted renal survival and development of end stage renal disease (ESRD) at 2 years after initiation of treatment in two cohorts of patients, from Pavia and Heidelberg. The management of patients with AL amyloidosis requires frequent assessment of hematologic and organ response in order to identify progression and switch to effective second-line therapies. Prevention of renal progression leading to ESRD is imperative, as development of ESRD markedly increases morbidity and leads to treatment limitations. The cutoffs for predicting renal outcomes were a ∼30% decrease in proteinuria (or a drop of proteinuria below 0.5 g/24 hours) in the absence of renal progression and a ∼25% decrease in estimated Glomerular Filtration Rate (eGFR). This study by Palladini et al. included patients with newly diagnosed AL amyloidosis regardless of their treatment modality. Only 9.7% of patients from Pavia cohort and 29.5% of Heidelberg cohort underwent high-dose melphalan and stem cell transplantation (HDM/SCT). Here, we report whether these new renal response criteria evaluated at six-month after treatment retain their prognostic significance with respect to renal survival in patients with AL amyloidosis treated with high HDM/SCT. Four hundred and twenty-one consecutive patients with AL amyloidosis treated with HDM/SCT 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 have been detailed previously by Cibeira et al.2 Of note, 43% of the evaluable and surviving patients achieved a complete hematologic response following HDM/SCT. 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. Patients with reversible acute kidney injury episodes occurring within one month of SCT were not included. Kaplan–Meier graphs were used for survival analysis with log rank tests to compare the difference in the overall survival distributions. Landmark analysis was used for assessment of renal response. 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 9.4 software (SAS Institute Inc., Cary, NC) and P value <.05 was defined as statistically significant. At the initial evaluation (prior to undergoing HDM/SCT), patients had a median serum creatinine of 1 mg/dL (range 0.3–11.7), median eGFR of 66 mL/min/1.73 m2 (range 4–154), and median proteinuria of 6.4 g/24 hours (range 0.5–58). Two hundred and fifty-nine patients had data available for survival analysis after HDM/SCT but not every patient had a full evaluation at our institution at every 6 months. The total number of patients evaluated for renal response assessment at our center at 6-, 12-, and 24 months were 224, 208, and 173, respectively. Fifty-five (21%) patients reached ESRD during the follow-up period. Two patients died or started dialysis between HDM/SCT and the 6-month visit. Nine and twenty-two patients died or started dialysis between the 6- and 12-month visit and the 12- and 24-month visit, respectively (consort diagram in Supplemental File). Median overall survival was 7.9 years (95% CI 6.9-9.1) following HDM/SCT, which is favorable to 3.9 years (Pavia cohort) and 2.5 years (Heidelberg cohort) as reported by Palladini et al.1 Similarly, renal survival was also longer in our cohort compared to that reported by Palladini et al.1 and Havasi et al.4 Median renal survival was 13.5 years with a median follow-up of 6.9 years (range, 0.4–20.8). The 2-year dialysis risk was also lower compared to the Pavia–Heidelberg cohort: 0% in renal stage I, 3% in stage II, and 14% in stage III renal disease.4, 5 Median time to renal response, defined as 30% decrease in proteinuria or drop of proteinuria below 0.5 g/24 hours in the absence of ≥25% decrease in eGFR, was 12.3 months (range, 2.9–146.7), while median time to renal progression was 13.3 months (range, 0.1–149.7). Renal response defined as ≥30% decrease or below 0.5 g/24 hour of proteinuria was achieved by 29.5% of patients at 6 months, 38.5% at 12 months, and 43.0% at 24 months after HDM/SCT. Interestingly, renal response assessed at 6 months after HDM/SCT did not predict future renal outcome (P = .09), however, renal response at 12 months after HDM/SCT did predict renal outcome (Figure 1). The hazard ratio for renal response at 12 months was 0.42 (95% CI 0.19-0.9) with a P value of .026. Renal progression defined as ≥25% decrease in eGFR occurred in 27.6% at 6 months, 30.9% at 12 months, and 38.1% at 24 months after HDM/SCT. Surprisingly, renal progression at 6 or 12 months was not able to predict development of ESRD and need for dialysis (P = .4 and .18) but renal progression at 24 months was able to predict ESRD (P = .006) (Figure 1). Moreover, renal progression at 6 months was not associated with shorter overall survival (P = .18) but renal response at 6 months was associated with better overall survival, with the median being 7.9 years versus 10.4 years (P = .01). The two-year dialysis risk was lower in our HDM/SCT patients compared to the Pavia and Heidelberg cohorts: 0% in patients who had renal response at 6 months and was 5% in patients who had renal progression (Supporting Information Figure 2), but again, the difference was not statistically significant when the patients were evaluated at 6 months. Progression to dialysis in the overall population according to the novel response and progression criteria (6-, 12-, and 24-month analysis). Renal progression is defined as a decrease in eGFR ≥ 25%. Renal response is defined as a decrease in proteinuria ≥ 30% or a drop of proteinuria below 0.5 g/24 h in the absence of renal progression. Several retrospective studies have addressed the issue of renal response to treatment in AL amyloidosis but none specifically in patients undergoing HDM/SCT.1, 6, 7 Renal survival in AL amyloidosis is longer in this 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. It was suggested that assessment of renal response using criteria proposed by Palladini et al. at 6 months (or even earlier, at 3 months) would allow adjustment of treatment strategy to achieve better organ response. In contrast, in our study, renal response or renal progression assessed at 6 months did not predict future renal outcome. We found that the proposed renal response criteria had prognostic significance only when it was evaluated at 12 months post HDM/SCT and the renal progression criteria only at 24 months after HDM/SCT. We believe that these differences are related to the treatment modality used for AL amyloidosis and the selection criteria for HDM/SCT. We acknowledge the limitations related to landmark analysis with respect to other factors and biases causing interference. Based on our data, assessing the adequacy of response to therapy based on markers of renal response and progression at 6 months after HDM/SCT might be too early and could potentially lead to unnecessary toxic treatments. This research was supported by Amyloid Research Fund at Boston University School of Medicine and NIH grant KO8DK090143 (A.H.). Authors declare no competing financial conflict. A.H. and V.S. designed research, collected and analysed data and wrote manuscript. G.D. performed statistical analysis. Additional Supporting Information may be found online in the supporting information tab for this article. 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