Challenges of Using NT-Probnp for Response Assessment in Systemic AL Amyloidosis - Analysis of a Prospective Study

Abstract

INTRODUCTION Treatment outcomes in AL amyloidosis are dependent on the hematological response to chemotherapy translating into organ responses. Cardiac biomarker, N-terminal brain pro-natriuretic peptide (NT-proBNP), is the main determinant of cardiac response in AL amyloidosis. Strongly supported by the amyloidosis community, the FDA is considering use of NT-proBNP as the primary end point for clinical trials. A number of questions on the exact details on NT-proBNP in AL remain unanswered - rate of decrease over time, timing of NT-proBNP measurement (6 months or 12 months) and values to use as a baseline. We report the use of serial NT-proBNP measurements for cardiac response assessment at 6 months and 12 months addressing some of these questions. PATIENTS AND METHODS All patients (n=650) recruited in the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre from Sept 2009 to Jan 2014 with a minimum follow of 12 months and available NT-proBNP at 0, 6 and 12 months were included in this study. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was cardiac response as defined by NT-proBNP (Palladini et al JCO 2012). Correlation with 6 minute walk test was done where available. RESULTS A total of 343 patients were identified. The median age was 64 yrs. Organ involvement was: cardiac - 72%, renal - 73% and liver - 12% (median - 2 organs). The median creatinine was 90 _mol/L, median dFLC was 150 mg/L (range 10-15898 mg/L). The median NT-proBNP was 966 ng/L (range 33-30872 ng/L). The Mayo disease stage was: stage 1 - 26%, stage 2 - 47% and stage 3 Ð 27%. Serial six minute walk test results were available in 71 patients. Treatment was: thalidomide based regimes (mainly CTD) 56%, CyBorD Ð 30%, Melphalan-Dexamethasone - 5% and SCT 1%. A total of 204 patients had baseline NT-proBNP >650 ng/L (the threshold defined for NT-proBNP to be assessable for cardiac response) and were included in response analysis. Partial hematological response (or better) was seen in 92%, ³ VGPR in 66% and 22 (8%) were non-responders. The median decrease in dFLC was 85% over baseline at six months. The median NT-proBNP at baseline (for the response assessable group n=204) was 2669 ng/L. At six months, the median NT-proBNP had increased significantly to a median 3258ng/L (p<0.0001). At 12 months, there was a significant decrease in the NT-proBNP to a median of 2097 pMol/L (p=0.014). There was a discordance in NT-proBNP response at 6 and 12 months in 42 (44%) of patients (Figure 1). At six months, 52 (25%) patients had achieved NT-proBNP response and at 12 months 94 patients (46%) achieved an NT-proBNP response. When NT-proBNP at the 6 month time point was used as a baseline for response assessment, at 12 months, 106 (52%) patients met the criteria for a cardiac response. There was no significant difference in the median six minute walk test at baseline, 6 m and 12 months was 390m, 370m and 400 m. The six minute walk distance improved by greater than 10% over baseline at 6 and 12 months in 12% and 20% patients, worsened by more than 10% in 32% and 27% patients with change of less than 10% in the remainder. The median survival for this cohort has not been reached at 5 years with 60% survival at 7 years. Contrary to published data, NT-proBNP response at six months had a non-significant impact on survival whilst the NT-proBNP response at 12 months significantly impacted survival (median not reached for responders vs. 67 months for the non-responders; p<0.0001). CONCLUSIONS This study shows the median NT-proBNP increased at six months over the baseline. There was a marked discrepancy in NT-proBNP at 6 months and 12 months Ð with a clear mis-classification of nearly half of all eventual cardiac responders. Consequently, the NTproBNP measurements at six months did not have a significant impact on survival whilst there was a marked impact at 12 months. NT-proBNP, as a primary end point, measure too early has potential for giving false negative results as a trial end point. This study highlights the critical importance of the timing of NT-proBNP measurements in response assessment for AL amyloidosis for clinical trials to avoid false negative results. FIgure 1 FIgure 1. Disclosures Wechalekar: Janssen: Honoraria; Celgene: Honoraria; Glaxo Smith Kline: Honoraria; Takeda: Honoraria.

Proposed Cardiac End Points for Clinical Trials in Immunoglobulin Light Chain Amyloidosis: Report From the Amyloidosis Forum Cardiac Working Group

“…59,60 This suggests that timing and type/duration of therapy are critical aspects to take into consideration. 61…”

“…59,60 This suggests that timing and type/duration of therapy are critical aspects to take into consideration. 61 Cardiac response criteria based on NT-proBNP changes with plasma cell reduction therapy have been defined by a multicenter collaboration 17 and have been shown to be useful in both retrospective and prospective studies (Table 3). Meaningful thresholds are established for both response (decline of >30% and >300 ng/L if baseline >650 ng/L) and for progression (increase of >30% and >300 ng/L if baseline >650 ng/L).…”

Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis

“…Finally, validated biomarkers that track with cardiac response to therapy are needed to rigorously assess the cardiac efficacy of emerging therapeutics in AL and ATTR. Challenges associated with NT-proBNP have been discussed, and also include optimal timing of NT-proBNP assessment (104). Whereas serial cardiac magnetic resonance imaging studies may be useful in clinical trials, this strategy is unlikely to be feasible in clinical practice.…”

Эффективность И Токсичность Индукционной Терапии У Пациентов С Впервые Диагностированным Системным AL-амилоидозом: Результаты Проспективного Одноцентрового Клинического Исследования

“…В этой связи крайне важным аспектом является токсичность терапии BorCyDex при AL-A. По данным литературы, токсичность III-IV степени при использовании схемы BorCyDex составляет 20-50 % [4,18]. Вместе с тем, по другим данным, нежелательные серьезные побочные эффекты на фоне этой терапии были единичными [8].…”