#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

Background:

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.  

Methods:

Study Design

• Retrospective study utilizing the prospectively generated Center for International Blood and Marrow Transplant Research (CIBMTR) database. 

• 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

• Defined according to the system proposed at the 10th International Symposium on Amyloidosis in 2004. 
• New criteria were proposed to define hematologic response and progression based on free light-chain (FLC) analysis.  In this registry, FLC and cardiac biomarkers were only collected after 2008. 
• The 2012 hematologic or cardiac response criteria was unable to be applied retrospectively. 
• In regards to organ response, only renal responses were reported in this analysis.  

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.    

Results:

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

#amyloidosisJC 11/11/15 @ 9 pm EST: targeting the amyloid fibril with anti-SAP therapy

The first two #amyloidosisJC chats were a huge success, and with this installment we hope to build on that. The second journal club, in particular, was fantastic. With Raymond Comenzo (Tufts), Vaishali Sanchorawala (Boston University), and Brendan Weiss & Adam Cohen (both from Penn) participating, it felt like we had the Eastern Conference All-Star team playing. Not to mention over a dozen other engaged participants. This week, with an extremely interesting article on anti-fibrillar therapy being discussed, maybe we can tempt the Western All-Stars into joining...? Mayo? MDACC? Stanford? I'll pester them. Whoever suits up this week, I am certain Drs. Adam Waxman and Brendan Weiss (same Brendan Weiss) will co-moderate a thoughtful and educational discussion.

[special thanks to Dr Waxman for his hard work preparing the original draft of this summary!]

The Article: 

“Therapeutic Clearance of Amyloid by Antibodies to SerumAmyloid P Component.” Richards et. al. NEJM,2015; 373(12):1106-14.

Background:

The systemic amyloidoses are rare diseases characterized by protein misfolding, leading to insoluble amyloid fibril tissue deposition and consequent organ dysfunction. It is the organ deposition, particularly cardiac, that leads to morbidity and mortality. There are over 20 subtypes of systemic amyloidosis. Immunoglobulin light chain (AL) amyloidosis is the most common subtype and is characterized by clonal plasma cell or B-cell expansion and production of misfolded immunoglobulin light chains (LC) that form amyloid and also are directly toxic to organs. Commonly affected tissues and organs include the kidney, liver, heart, and spleen. Currently, the treatment of AL amyloidosis focuses primarily on prevention of light chain production through the use of anti-plasma cell therapy. In other systemic amyloidoses, there are no non-experimental methods to reduce the precursor protein that forms toxic amyloid fibrils. A fundamental problem in the management of the systemic amyloidoses is the development of a treatment to address amyloid that is already deposited in the tissues. A fibril constituent common to all subtypes of amyloidosis is serum amyloid P (SAP). This study explores an early but promising therapy that targets SAP with a monoclonal antibody to stimulate macrophage-mediated clearance of deposited amyloid, which has been previously shown to be effective in a murine model (Bodin, et al. Nature 2010).

The authors (Richards, et al.) performed a phase I clinical trial of a combination of a small molecule CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid) that has been shown to deplete circulating SAP (serum amyloid P component) followed by administration of a humanized monoclonal anti-SAP antibody that has been shown in preclinical models to stimulate macrophage driven destruction of SAP-containing amyloid deposits. This study describes the first-in-human experience using these agents, including serial assessment of deposited amyloid load in tissues.

Methods:

This is a prospective, single center (National Amyloidosis Center in the United Kingdom), open-label phase I dose escalation study of 16 patients. All patients had biopsy proven systemic amyloidosis; different types of amyloidosis were included. Patients with clinical evidence of cardiac involvement were excluded, as were potentially child bearing women.

CPHPC was administered for 3 days until SAP concentration decreased to below 2.0 mg/L. Patients then received escalating doses of anti-SAP antibody. The last 7 patients received a tailored dose based on the pretreatment SAP load as determined by SAP scintigraphy.

Changes in tissue amyloid content were assessed by whole-body I-SAP scintigraphy at baseline and 42 days post-treatment. Patients were also assessed for retention of tracer at 24 hours by CT. Equilibrium MRI of the heart, liver, and spleen as well as transient elastography (to measure liver stiffness) were performed on days 6, 14, 21, and 42). 42 days was chosen as this was the length of time for SAP to reach equilibrium between the plasma and amyloid components.

Results:

Patient characteristics and response data are shown in Table 1, below. Eight patients had AL amyloidosis, 4 had AFib amyloidosis, 2 had AA amyloidosis, and one had AApoA1. Four of the first 6 patients had small amounts of amyloid in the kidney and spleen. Patient 3 was removed from the study due to poor venous access. Patients 7 – 16 all had moderate to large amounts of amyloid deposition.

Adverse events were mild and included headache and nausea during infusion of CPHPC. Symptoms of transient warmth, flushing, headache, transient changes in heart rate, diarrhea, nausea, and abdominal discomfort during infusion of the anti-SAP antibody were reportedly mitigated with changes in infusion rate. 

There were no changes in serial echocardiography and there were no significant changes in serum troponin T or NT-proBNP concentration.

Rapid depletion of circulating SAP was achieved. Depletion was greater in patients with small or moderate load than in those with a high pre-treatment amyloid load. The half-life of the anti-SAP antibody was found to be around 16 hours in patients with small amyloid load and closer to 4 hours for patients with a large load, consistent with a rapid sequestration.

Correlative studies of immune markers showed that the 9 patients receiving >200 mg of antibody had a transient increase in IL-6, IL-8, CRP, and serum amyloid A protein. Patients receiving >1 mg/kg had a prolonged decrease in complement C3 levels for about a week.

Table 1:

Patient information (amyloid type and response to therapy)

Patients were assessed for amyloid elimination at 42 days after treatment. 6 of 8 patients with liver involvement receiving >200 mg of antibody had a significant decrease in liver stiffness. 5 of these same 8 patients had an overall improvement on their SAP scintigraphy corresponding to decreased amyloid load at 42 days. MRI showed normalization of extracellular volume in 3 patients. Figure 1 shows representative decrease in C3 level and changes in SAP-scintigraphy in patients 8 and 13.

Figure 1:

Response details for two patients 

Author’s Conclusions:

·       Infusion of anti-SAP antibody after CPHPC infusion was safe in patients with systemic amyloidosis with relatively low, transient, infusional side-effects

·       Anti-SAP antibody cleared faster in patients with large hepatic amyloid loads, consistent with rapid binding to their target

·       6/8 patients receiving >200 mg of antibody showed evidence of reduced amyloid load on imaging, even in patients who presumably had continued production of amyloidogenic precursors Including some patients with active AL amyloidosis)

·       Correlative studies of immune markers are consistent with a proposed mechanism of phagocytosis of C3-opsonized complexes by macrophage infiltration as seen in preclinical models

·       Patients with clinically significant cardiac and renal involvement will be included in the next phase of the trial

Our Comments:

·      This small, phase 1 study demonstrates first-in-human data showing a potential decrease in amyloid load among nine out of sixteen enrolled patients with minimal adverse events.

·      Larger confirmatory studies are necessary as is a longer period of follow up to see if decrease in amyloid load at 42 days is a clinically meaningful endpoint

    The optimal dosing and timing of CPHPC and anti-SAP need to be further studied.

·      Patients receiving lower doses of anti-SAP disproportionally had non-AL amyloidosis compared to patients receiving >200 mg and having improvement in amyloid load who mostly (7/9) had AL amyloidosis, which could confound results.

·      Response assessments used non-standard modalities (anti-SAP scintigraphy, liver elastography, extracellular volume by MRI), all of which will need further validation.

·      Delivery of this agent to patients with cardiac disease will need to be done carefully, as the impact of macrophage phagocytosis in the heart on cardiac function is not yet known.

#amyloidosisJC 11/4/15 @ 9 pm EST: examining the prognostic and predictive relevance of cytogenetics in AL amyloidosis

CLICK HERE FOR A LINK TO THE FULL TEXT OF THE ARTICLE

Background

Light chain (AL) amyloidosis is a rare plasma cell dyscrasia which causes morbidity and mortality through deposition of toxic amyloid fibrils. Although the prognostic significance of specific cytogenetic aberrations in the plasma cell malignancy multiple myeloma is established, the relevance of cytogenetics in AL amyloidosis is still being defined. Several recent retrospective studies including this study by Bochtler et al., have attempted to characterize the significance of chromosome aberrations in AL amyloidosis. This paper seeks to establish translocation t(11;14), as a predictive marker of poor response to bortezomib. This is important because bortezomib-based regimens (such as Vel/Dex) are often used as front-line treatment for AL amyloidosis. In this disease where patients often have progressive multi-organ damage, selection of an efficacious regimen to rapidly establish disease control is crucial. This paper raises the question of whether cytogenetic studies could guide treatment of AL amyloidosis.

Methods

·      Retrospective, single-center study of 101 consecutive transplant ineligible AL amyloidosis patients who received Vel/Dex as first-line therapy. These patients had high-risk clinical features such as severe cardiac or kidney involvement. Patients with concurrent stage II/III MM or IgM paraprotein were excluded.

·      Outcomes assessed included hematologic response after 3 cycles (by consensus criteria for PR, VGPR), hemEFS (hematologic relapse, hematologic progression, start of a second-line therapy, death) and OS. Early deaths counted as remission failures on intent-to-treat basis.

·       High-risk aberrations were defined as t(4;14), t(14;16) and deletion 17p13.

·      After backward variable selection, validation and calibration of the final multivariable model was done using a CyBorD-treated cohort (32 patients).

Results

Patient Characteristics 

Most patients in Vel/Dex and CyBorD cohorts had cardiac involvement (91% vs 88%) and around half had renal involvement in both cohorts

HemEFS

·      Median hemEFS 4.7 mo with median F/U of 24.0 months and hematologic events in 84/101 patients. The t(11;14)-positive group had inferior hemEFS (median hemEFS 3.4 months vs 8.8 months in t(11;14)-negative group; p=.002). Median hemEFS in high-risk group was 10.3 months vs 3.9 months in patients without high-risk aberrations (P=.15).

Overall Survival (OS)

·      Median OS was 15.7 mo with median F/U time of 24.1 months and 53 observed deaths. t(11;14) predicted for shorter OS with median OS 8.7 months vs 40.7 months in t(11;14)-negative group (P=.05). High risk aberrations conferred favorable prognosis (median OS = NR for high-risk v 10.6 months for absence of high-risk aberrations; P=.04).

Remission Rates

·      95/101 (94%) pt had initial dFLC >50mg/L and thus evaluable for ≥VGPR

·      30 (32%) achieved ≥VGPR after 3 cycles, 24 (25%) attained PR and 21 (22%) did not achieve remission, 20 (21%) had early death before remission assessment. ≥VGPR rates worse in t(11;14)-positive patients compared with t(11;14)-negative patients [14/61 (23%) versus 16/34 (47%) patients, P=.02].  High-risk aberrations had favorable remission rates compared to those without [8/12 (67%) versus 21/80 (26%), P=.008]

Multivariable testing in Vel/Dex Cohort with Clinical and Cytogenetic Factors

·      By Cox regression, t(11;14) and dFLC were the only two statistically significant prognostic markers for both OS and hemEFS. NT-pro-BNP reached statistical signification for OS. Thus t(11;14) is an independent negative risk factor in the Vel/Dex treated cohort. 

    A final model developed: hemEFS, t(11;14), sex, dFLC, NT-proBNP and dose reduction. For OS, t(11;14), dFLC and NT-proBNP. For outcome remission ≥VGPR, t(11;14) and age.

External validation using CyBorD cohort

·      ≥VGPR rate after 3 cycles, 24% (4/17) in t(11;14)-positive compared with 80% (8/10) in t(11;14)-negative patients. Median hemEFS 5.7 months in all 32 patients, 4.0 months in t(11;14)-positive and NR in t(11;14)-negative patients (P=.01). Median OS for both groups NR. Median F/U was 7.5 months. Calibration analysis of final models performed which showed that all trained predictors had a trend for better prediction of the outcome in the CyBorD validation cohort.

Authors’ Conclusions

• Cytogenetic aberrations are important independent prognostic factors in AL.
• Bortezomib is less beneficial to patients with t(11;14) 
• Bortezomib overcomes the poor prognosis of patients with high-risk aberrations.

Our Comments

• Study was of small sample size and would need confirmation with other studies, prospectively and multi-center ideally

• A potential criticism is the validation using a CyBord-treated cohort rather than additional Vel/Dex-treated patients. CyBorD cohort followup duration is a lot shorter than the Vel/Dex cohort. Despite this, results seen in the CyBord patients seem consistent with those described for the Vel-Dex cohort

• Paper suggests that cytogenetics may have predictive as well as prognostic significance.

Special thanks to Sandy Wong (@SandyWong02111) from Tufts University for her efforts preparing this summary. Looking forward to co-moderating this journal club discussion with her.