30 November, 2015

#amyloidosisJC 12/1/2015: A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.

This is the 5th and final pre-symposium installment of #amyloidosisJC, with the following summary by travel grant awardee and article author Paolo Milani. Dr. Milani is from the esteemed Pavia Amyloidosis group, and is currently spending some time at Mayo Clinic. Needless to say, he'll be bringing a high level of knowledge to this journal club. Starting in January, 2016, #amyloidosisJC will be a monthly online journal club activity.

The article:

Giovanni Palladini1, Ute Hegenbart3, Paolo Milani1, Christoph Kimmich3, Andrea Foli1, Anthony D. Ho3, Marta Vidus Rosini1, Riccardo Albertini2,3, Remigio Moratti5, Giampaolo Merlini1,2,3 and Stefan Schönland3

  1. Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
  2. Department of Molecular Medicine, University of Pavia, Pavia, Italy;
  3. Amyloidosis Center, Division of Hematology, Oncology, and Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; and
  4. Clinical Chemistry Laboratory, and 5Scientific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy


Immunoglobulin light-chain (AL) amyloidosis is caused by a usually small plasma cell clone synthesizing light chains undergoing conformational changes that lead to their aggregation and deposition in tissues. The kidney is involved in 70% of patients, but little is known on progression or reversibility of renal involvement. Renal involvement results in significant morbidity, and renal failure limits the therapeutic options. Previously, criteria defining renal response and progression were based on the International Society of Amyloidosis (ISA) consensus criteria of 2005 but the clinical significance of each have never been validated. The goal of this study was to identify and validate criteria by assessing the risk of dialysis in 732 consecutive, previously untreated patients with AL amyloidosis with renal involvement evaluated at 2 European referral centers: the Pavia Amyloidosis Research and Treatment Centre and the Heidelberg Amyloidosis Centre.


The databases of the Pavia Amyloidosis Research and Treatment Centre and of the Heidelberg Amyloidosis Centre were systematically searched for subjects with renal involvement diagnosed between 2004 and 2012. Baseline evaluation at each center included a complete physical examination, assessment of amyloid organ involvement, echocardiography, cardiac biomarkers measurement of serum creatinine concentration and of 24-hour urinary protein excretion, serum and urine immunofixation electrophoresis, and quantitation of free light chain (FLC).

The study end point was renal survival, defined as the time from diagnosis to dialysis initiation. The authors assessed the impact of baseline variables and of their changes with therapy on renal survival . The Italian cohort was used as the testing population and the German series as the validating cohort.

Cox models were fitted to compute hazard ratios and 95% confidence intervals for progression to dialysis, identifying baseline variables predicting renal survival. Receiver operating characteristic (ROC) analyses based on progression to dialysis at 2 years identified the thresholds of baseline variables best predicting renal survival.


Patient Characteristics:

A total of 71 (15%) patients required dialysis in the Italian group and 84 (31%) in the German series.

Patients’ survival from dialysis initiation was not significantly different in the 2 cohorts [median survival was 39 months in the Pavia cohort and 24 months in the Heidelberg cohort (P=0.102)]. Hemodialysis was chosen in most cases, and only 11 patients underwent peritoneal dialysis (9% of the 155 subjects requiring dialysis), 8 in the Italian cohort and 3 in the German cohort.

Factors predicting renal survival:
Renal survival was influenced by proteinuria, eGFR, and, to a lesser extent, by serum albumin. The thresholds best discriminating patients who progressed were 5 g/24 h for urinary protein loss and 50 mL/min per 1.73 m2 for eGFR. Based on these cutoffs, it was possible to design a staging system sharply discriminating 3 groups with significantly different risk of progression to dialysis, with none (renal stage I), 1 (renal stage II), or both (renal stage III) risk factors, respectively (Figure 1A). These results were validated in the Heidelberg cohort (Figure 1B).

Criteria for renal resposne and progression:
For the identification of response and progression criteria, the authors performed a landmark analysis on 472 patients (64%), 301 in the Italian cohort and 171 in the German cohort, who were evaluated for response 6 months after treatment initiation. A ROC analysis based on progression to dialysis at 2 years from the landmark date performed in the testing cohort (Italian series) showed that changes in proteinuria, eGFR, and dFLC (difference between involved [amyloidogenic] and uninvolved free light chain) were able to discriminate subjects progressing to dialysis. The cutoff that identify renal response was a 30% decrease in proteinuria. A 25% decrease in eGFR identified a renal progression. Obtaining a very good partial response (dFLC <40 mg/L) or complete response (negative serum and urine immunofixation and normal FLC ratio) was able to improve renal outcome not only in renal stage II but also in renal stage III patients, indicating that successful treatment can improve renal outcome also in high-risk subjects.  

Finally, they tested the applicability of the novel renal response and progression criteria, related to renal survival, in patients who had response assessment data at an even earlier time point (3 months), 133 in the Italian cohort and 69 in the German cohort, in a 3-month landmark analysis. Given the relatively small number of cases, they performed this analysis in the overall study population of 202 evaluable patients. We found that the proposed response and progression criteria retained their prognostic significance.

Authors’ conclusions:

The progression of renal dysfunction is accurately predicted by baseline proteinuria and eGFR. These 2 variables identify low-risk patients who are unlikely to require dialysis and subjects who are at very high risk of renal failure. Secondly, early changes in eGFR and proteinuria should be used to assess treatment efficacy, in addition to the currently recognized hematologic and cardiac response criteria.

Our comments:

The renal staging system formulated by Palladini and colleagues significantly divided the population of patients with renal AL amayloidosis in low-, intermediate- and high-risk of progression to dialysis. This staging could be a useful tool for the routine patients’ management and could be added in the stratification of patients enrolled in clinical trials.
The identification and validation of renal response and progression criteria that can be assessed at 3 and 6 months is an other important implication of this work. However, it is important to note that the morbidity of renal involvement is not restricted to the minority of patients who develop end stage renal disease.

Finally, we think that it will be important to confirm these data in a prospective setting. Ongoing randomized trials would be the ideal setting.

29 November, 2015

#amyloidosisJC 11/29/15 @ 9 pm EST: Improving Transplant Outcomes for Pts with AL Amyloidosis Between 1995 and 2012

link to article: http://jco.ascopubs.org/content/33/32/3741.full.pdf+html

The role of autologous stem cell transplantation (ASCT) in AL amyloidosis is controversial.  Single center studies have reported durable, high hematologic responses,  organ dysfunction improvement and improved survival.  However, a prospective randomized clinical trial by Jaccard et al in 2007 comparing ASCT with oral melphalan and dexamethasone showed inferior survival in the ASCT group.  The inferior outcomes were related to high early mortality (EM) of 26% in the transplantation arm.  This high early mortality rate could be attributed to patient selection and peritransplant management, the inclusion of patients with severe cardiac involvement, as well as the fact that most transplantation centers in this study were low volume centers.  With earlier disease detection and risk stratification of patients with cardiac amyloid and better peritransplantation supportive care, single centers have reported post-transplantation EM rates of <5%.  The authors hypothesized that outcomes of autotransplantation in AL amyloidosis have improved over time.  

Study Design

  • Transplantation data from over 320 centers around the world
  • The data includes disease type, age, sex, date of diagnosis, graft type, conditioning regimen, post-transplantation disease progression, survival, and cause of death
  • Registration and research data were collected at pre transplantation, at 100 days post transplantation, at 6 months post transplantation, and annually thereafter until death or last follow up.  

Patient Population
  • Patients included:
    • Patients registered with the CIBMTR in N. America between 1995 and 2012
    • Autotransplantation for AL amyloidosis within 24 months of diagnosis 
  • Data from these patients were analyzed in 3 cohorts based on year of transplantation:
    • 1995-2000
    • 2001-2006
    • 2007-2012
  • This dataset was assessed for survival outcomes 
  • A subgroup of 354 patients with detailed research data who underwent transplantation between 2001-2012 were analyzed for hematologic and organ responses as well as in multivariable analyses.  Characteristics of this subset was compared with the registration set to confirm that this was a representative random sample.  

Definition of EM:
  • Mortality from any cause after transplantation within the defined time window of 30 and 100 days. 

Hematologic and renal response and progression

Center Effect
  • Because there is wide variability in numbers of transplantations performed by centers in this 18-year period, center effect was calculated by using the mean number of transplantations performed for AL amyloidosis per year over 4 years between 2009-2012. 
  • Maximum likelihood testing was performed using various cut points of transplantations per year. 
  • It was established that a minimum of 4 transplantations per year was an informative divider for this analysis.    

Patient Characteristics
  • Table 1 displays the characteristics of the entire group from 1995-2012 (n=1536).  Table 2 shows the subset with detailed data from 2001-2012 (n=354). 
  • Median age of transplantation was 56 years, with increasing age of transplantation with successive time cohorts. 
  • Most patients underwent transplantation within 6 months of diagnosis. 
  • The underlying plasma clone was lambda in 72% of patients. 
  • M-spike non quantifiable in 42%. 
  • Distribution of cardiac and renal involvement was similar.  Renal without cardiac involvement was most frequent pattern.  
  • There was no difference in number of organs involved between the 2001-2006 group and 2007-2012 groups, with four or more organs involved in 12% vs 11% patients respectively.  
  • More patients received treatment before transplantation in the 2007-2012 group (33% vs 13%, p<0.001).   

Table 1: Characteristics of 1536 pts who underwent first autoHCT for AL

Table 2: baseline characteristics of the 2001-2012 subgroup

Early Mortality and Causes of Death in all 1536 patients
Figure 1A shows EM for all 3 groups.
  • Mortality at 30 days
    • 1995-2000:11% (95% CI, 7% to 17%)
    • 2001-2006: 5% (95% CI, 4% to 7%)
    • 2007-2012: 3% (95% CI, 2% to 4%)
  • Mortality at 100 days  
    • 1995-2000: 20% (95% CI, 14% to 27%)
    • 2001-2006: 11% (95% CI, 8% to 13%)
    • 2007-2012: 5% (95% CI, 4% to 7%)
  • Time from diagnosis to transplantation did not affect EM.  
    • < 6months: 12% (95% CI, 8% to 17%).  
    • 6-12 months: 5% (95% CI, 1% to 11%).
    • 12-24 months: 8% (95% CI, 2% to 18%)
  • Causes of death within 100 days
    • Amyloid and organ failure (83%)
    • Infection (8%)
    • Nonengraftment (3%)
    • Unknown causes (6%)

OS in 1536 patients
  • Median follow up of 56 months
  • 1, 3, and 5 year OS increased over time (p<0.001)
    • 1995-2000: 75% (95% CI, 65% to 82%), 64% (95% CI, 56% to 72%), 55% (95% CI, 46% to 63%)
    • 2001-2006: 85% (95% CI, 81% to 87%), 72% (95% CI, 68% to 75%), 61% (95% CI, 57% to 65%)
    • 2007-2012: 90% (95% CI, 88% to 92%), 83% (95% CI, 80% to 86%), 77% (95% CI, 72% to 82%)
  • No difference in OS based on time from diagnosis to transplantation (p=0.22)
    • < 6months: 73% (95% CI, 67% to 79%)
    • 6-12 months: 81% (95% CI, 71% to 89%)
    • 12-24 months: 81% (95% CI, 61% to 92%)
  • 3 year OS for patients with cardiac amyloidosis improved (p=0.59)
    • 2001-2006: 62% (95% CI, 48% to 75%)
    • 2007-2012: 67% (95% CI, 52% to 80%)
  • 3 year OS for patients with renal and without cardiac amyloidosis improved (p=0.03)
    • 2001-2006: 78% (95% CI, 68% to 86%)
    • 2007-2012: 89% (95% CI, 82% to 95%)

Figure 1 

Figure 2: Trends in (A) OS for cardiac AL amyloidosis; (B) OS for renal, noncardiac AL; (C) EM based on center experience and (D) time trends in improvement in EM among centers

Response rates in subset of 354 patients
  • The breakdown of hematologic and renal response rates are shown in Table 3.

Center effects in subset of 354 patients
  • 81 low volume centers performed <4 AL transplantations a year
  • EM worse in low volume centers (p=0.01)
  • 30 day mortality
    • Low volume: 5% (95% CI, 3% to 7%)
    • High volume: 1% (95% CI, 0.4% to 3%)
  • 100 day mortality
    • Low volume: 7% (95% CI, 5% to 10%)
    • High volume: 3% (95% CI, 2% to 6%)
  • No statistically difference found for age, KPS, HCT-CI, cardiac amyloidosis, number of organs involved, melphalan conditioning dosage, pretransplantation chemotherapy between high and low volume centers
  • Both high and low volume centers had improvement in EM in 3 time cohorts (p<0.01)

Multivariable analysis in subset of 354 patients
Adjusted analysis show no difference between 2001-2006 cohort and 2007-2012 cohort for EM, PFS, or OS.  After 9 months the relapse and/or progression rate was lower in 2007-2012 cohort.  

Author's Conclusions:
  • Impressive reduction in EM has been achieved in recent years, superior to reported TRM of 24% from the only randomized clinical trial in this setting
  • Cardiac amyloid continues to be associated with worse outcomes, with no improvement in outcomes of these patients over time.
  • Center experience with AL transplantation important in reducing EM, with high volume centers (defined as having performed 4 or more transplants a year) with better outcomes.
  • 5 year survival in most recent cohort is comparable to data from specialized single centers.

Our Comments:

  • No cardiac staging information was reported.  Although there was no difference in the proportion of patients with cardiac involvement between the cohorts, the lack of information about cardiac biomarkers and staging make it difficult to determine the reasons for improvement in outcome over time.  
  • Better patient selection could account for the improvement in EM over time, as well as the differences in outcomes between high volume and low volume centers.  
  • This study looked at a cohort of patients between 1995-2012.  However, there was only detailed data reported on organ involvement and hematologic markers in patients treated between 2001-2012.  
  • Newer approaches to the treatment of advanced cardiac amyloidosis is needed.  
  • Although this was not a prospective controlled trial, the fact that this study shows EM rates approaching those reported by specialized centers is encouraging.  
  • A multi-institutional study involving high volume centers comparing transplantation versus non-transplantation therapy (with emergence of newer anti plasma cell therapies) is warranted.  
  • Role for induction therapy in patients with BM plasmacytosis of >10% should be looked at with respect to OS and EFS