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Blood First Edition Paper, prepublished online March 11, 2013; DOI 10.1182/blood-2012-12-473066
A European collaborative study of treatment outcomes in 346
patients with cardiac stage III AL amyloidosis
Ashutosh D Wechalekar1, Stefan O. Schonland2, Efstathios Kastritis3, Julian D
Gillmore1, Meletios A. Dimopoulos3, Thirusha Lane1, Andrea Foli4, Darren Foard1,
Paolo Milani4, Lisa Rannigan1, Ute Hegenbart2, Philip N Hawkins1, Giampaolo
Merlini4 and Giovanni Palladini4
1
National Amyloidosis Centre, University College London Medical School, London,
United Kingdom;
2
Amyloidosis Centre, Heidelberg University Hospital, Heidelberg, Germany;
3
Department of Clinical Therapeutics, University of Athens School of Medicine,
Athens, Greece;
4
Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San
Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy
Running Title: Treatment outcome in Stage III AL amyloidosis
Key Words: AL Amyloidosis, Cardiac stage III, treatment
Address for Correspondence:
Dr Ashutosh Wechalekar
National Amyloidosis Centre
University College London Medical School (Royal Free Campus)
Rowland Hill Street
London NW32PF, UK
Email: [email protected]
Phone: +44-207-433-2758
[1]
Copyright © 2013 American Society of Hematology
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Key Points:
1. Deep clonal responses improve outcomes and can change the natural history of
advanced (cardiac stage III) AL amyloidosis.
2. NT-proBNP >8500 ng/L and systolic blood pressure <100 mm of Hg identify a
very poor risk subgroup of stage III AL amyloidosis.
Abstract:
Treatment outcomes of patients with stage cardiac III AL amyloidosis remain poorly
studied. Such cases have been excluded from most clinical studies due to perceived
dismal prognosis. We report treatment outcomes of 346 patients with cardiac stage
III AL amyloidosis from in UK, Italy, Germany and Greece. Median overall survival
(OS) was 7 months with OS at 3, 6, 12 and 24 months of 73%, 55%, 46% and 29%,
respectively. 42% died before first response evaluation. On intention to treat (ITT)
basis, the overall haematological response rate was 33%, including a complete
response rate (CR) of 12%. OS rates at 12 and 24 months, respectively, for 201
response evaluable patients were: for complete responders - 88% and 85%; partial
responders - 74% and 53%; and non-responders - 39% and 22%.
45% of
responders achieved an organ response. NT-proBNP >8500 ng/L and systolic blood
pressure (SBP) <100 mm of Hg were the only factors that independently impacted
OS and identified an especially poor prognosis subgroup of patients with median OS
of only 3 months. Outcome and organ function of stage III AL amyloidosis without
very elevated NT-proBNP and low SBP is improved by a very good haematological
response to chemotherapy.
[2]
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Introduction
Systemic light chain (AL) amyloidosis is a rare multisystem disease caused by
the deposition of misfolded immunoglobulin light chain protein in various tissues and
organs. Patients with AL amyloidosis present with non-specific symptoms frequently
leading to a delay in diagnosis1, and over a third of patients present with advanced
disease. Cardiac involvement is the leading cause of morbidity and mortality in AL
amyloidosis 2. Elevated serum cardiac biomarkers (brain type natriuretic peptide
(BNP), its more stable N-terminal fragment (NT-proBNP) and cardiac troponin T/I)
usefully define advanced disease3-5. Even modest elevations of serum NT-proBNP
at presentation may be predictive of developing clinically significant cardiac
involvement during the disease course 6. The staging system reported by the Mayo
Clinic group, based on the combination of elevated serum levels of NT-proBNP and
cardiac troponin T or I at presentation, has become the standard for staging patients
at diagnosis
7,8
. The median overall survival of patients with stage I, stage II and
stage III AL amyloidosis was 26.4, 10.5, and 3.5 months respectively using NTproBNP and troponin-T/I staging in the original description of the system in 2004 7.
A recent revision that incorporates the difference between involved and uninvolved
serum free light chain concentration (dFLC) as a further criteria may be even more
discriminatory9. The Mayo staging system has since become one of the chief criteria
for patient selection (or exclusion) in clinical trials.
We and others have reported high response rates with treatment
improving outcomes
15
10-14
and
in AL amyloidosis. Although some recent single centre data
suggests better outcomes in stage III patients than previously reported5,16 , the
perceived poor prognosis of stage III AL amyloidosis has led to the exclusion of such
patients from nearly all prospective treatment studies.
[3]
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We report the features and treatment outcomes of a large group of patients
with stage III AL amyloidosis attending four major European amyloidosis centres.
Stage III AL amyloidosis encompasses a heterogeneous group of patients among
whom the prognosis of a substantial sub-group may be improved through a complete
haematological response to chemotherapy.
Patients and Methods
Study Participants and Assessments
Three hundred forty six newly diagnosed patients with systemic AL amyloidosis
assessed at the amyloidosis centres in London (UK) (71 patients), Pavia (Italy) (164
patients), Heidelberg (Germany) (92 patients) and Athens (Greece) (19 patients)
between January 2001 to December 2010 and had Mayo stage III disease were,
retrospectively, included in this study. Stage III disease was defined as NT-proBNP
>332 ng/L and cardiac troponin T >0.035 µg/L or Troponin I >0.1µg/L7.
The
presence of amyloid deposition was confirmed by characteristic birefringence after
Congo red staining of a tissue biopsy.
immunohistochemical
/
AL type amyloidosis was confirmed by
immuno-electron
microscopy
staining
supported
by
demonstration of a plasma cell dyscrasia and, where necessary, by exclusion of
hereditary amyloidosis by demonstration of wild type sequence for the genes
encoding known hereditary amyloidogenic proteins.17
All patients were treated
according to local protocols using cyclical chemotherapy regimens previously
described
10,11,18-20
which included oral melphalan dexamethasone (MDex),
alkylator-thalidomide-dexamethasone combination, bortezomib or lenalidomide
combination regimes.
All patients had rigorous protocolized assessments at
baseline and after chemotherapy which included evaluation of clonal disease
[4]
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(including serum free light chains (FLC)) and detailed assessment of amyloidotic
organ function.
NT-ProBNP and Troponin T or Troponin I concentrations were
measured by standard commercially available assays used in the local laboratories.
The study was performed with institutional review board approval and informed
consent was obtained from each patient in accordance with the Declaration of
Helsinki.
Outcome measures
Organ involvement, hematological and amyloidotic organ responses were assessed
according to the Consensus Opinion from the 10th International Symposium on
Amyloid and Amyloidosis21. A very good partial response (VGPR) using difference
between the involved and uninvolved FLC (dFLC) was defined as dFLC <40mg/L.
Performance status was assessed as described by the Eastern Cooperative
Oncology Group (ECOG) criteria.22 The primary outcome measure was overall
survival (OS) and impact of hematological response to treatment (HR) on survival.
Statistics
Statistical analysis was undertaken using the SPSS 20 (SPSS, Chicago, USA)
software package. Survival was assessed by the method of Kaplan and Meier and
compared by log rank test. Categorical variables were compared with Chi squared or
Fishers tests as appropriate. Continuous variables with a normal distribution were
compared with a paired or unpaired t-test as appropriate and those where a normal
distribution was not confirmed were compared with Mann-Whitney test or Wilcoxon
rank sum test as appropriate. All p values were 2-sided with a significance level of
0·05. ROC analysis with death at 1 year was used to identify threshold for NT[5]
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proBNP and systolic BP which were then analyzed as dichotomous variables.
Serum free light chain level cut off were explored based on previously reported dFLC
value (>180mg/L) and a median for the series. Cox models were fitted to compute
hazard ratios (HR) and 95% confidence intervals (95%CI) for death for a series of
potential predictors. The proportional hazard assumption was tested and satisfied in
all cases. All responses to treatment were assessed on an intention to treat basis.
Patients who died prior to response assessment were classified as non-responders.
A landmark analysis was conducted for patients surviving beyond three months.
Results
A total of 346 patients were included in this study. The baseline characteristics are
given in Table 1.
338 (97%) had cardiac involvement according to the
echocardiographic criteria.
There was renal involvement in 216 (62%) and liver
involvement in 77 (22%) patients. This cohort of patients had a median presenting
NT-proBNP 9106 ng/L (range 379-216.187); and cardiac troponin I (TnI) – 0.18
ng/ml (range 0.1-12) or cardiac troponin T (TnT) 0.09 ng/ml (range 0.04-8.2). The
median left ventricular wall thickness was 15 mm (7-24) and ejection fraction was
53% (range 12-81%). 22% of patients had an ejection fraction of <30%. 57% had
dyspnoea ≥ New York Heart Association (NYHA) class 3 and 28% had ECOG
performance status ≥ 3.
Treatments given were: Bortezomib combinations - 23 (7%), MDex - 154
(44%), thalidomide combinations - 96 (28%), lenalidomide combinations - 13 (4%),
other
regimes
(including
melphalan-prednisolone,
dexamethasone
alone,
cyclophosphamide-dexamethasone/prednisone) 31 (9%). 29 (8%) were deemed too
ill for treatment or died prior to treatment initiation. 118 (34%) patients completed a
[6]
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full planned course of chemotherapy. 50 (14%) and 32 (9%) stopped after one and
two cycles of chemotherapy, respectively, due to death or toxicity. 201 patients
(58%) were evaluable for response. The median time to response evaluation was
5.6 months with 15% evaluated within 3 months and another 24% within 4 months
(total 39% within 4 months of starting chemotherapy). On an intention to treat basis,
114 (32%) achieved a haematological response - the haematological responses are
given in Table 2.
57% of the evaluable patients achieved a haematological
response. The response rates, on an intention to treat basis, with MDex, CTD,
bortezomib combinations or lenalidomide combinations were all low from 32% to
43% (Table 2).
The median overall survival (OS) for the cohort was 7.1 months (Figure 1a).
The estimated overall survival at 3, 6, 12 and 24 months was 73%, 55%, 46% and
29% respectively.
Patients who died within three months of diagnosis had
significantly higher NT-proBNP (median 11794 ng/L vs.7957 ng/L ; p=0.0002), lower
systolic blood pressure (median 100 mm vs. 110 mm of Hg of Hg; p=0.002), higher
presenting serum dFLC (median 348 mg/L vs. 218 mg/L; 0.002), higher proportion of
patients had NYHA grade 3-4 dyspnoea (65% vs. 45%; p=0.0001) and ECOG
performance status ≥3 (45% vs. 20%; p=0.0001).
Factors affecting overall survival on univariate and multivariate analysis are
given in Table 3. Using ROC analysis, NT-proBNP cut-off identified for death at 1
year was 8500 ng/L (AUC 0.68; p<0.0001) and a SBP cut off of 100 mm of Hg (AUC
0.69, p<0.0001). On univariate analysis, factors significantly associated with poorer
overall survival were: NTproBNP >8500 ng/L, SBP <100 mm of Hg, NYHA grade IV
dyspnea, presence of congestive heart failure and presence of liver involvement.
[7]
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The mean LV wall thickness did not significantly impact survival. Presenting dFLC
level was significant on univariate analysis using previously reported
9
cut-off of
dFLC >180mg/L or median for the series dFLC >230 mg/L or using threshold of >500
mg/L. On a multivariate analysis, presenting NT-proBNP >8500 ng/L and SBP <100
mg of Hg were the only two independent factors impacting survival (Figures 1b-d).
Rather surprisingly, dFLC, which has been identified as a significant factor impacting
OS in other studies, was not significant on multivariate analysis using the previously
reported cut-off value of 180 mg/L, or using the median for the current series of 230
mg/L, or >500 mg/L. A landmark analysis was conducted for patients alive at three
months. In the multivariate model for the patients in the landmark analysis, NTproBNP >8500 ng/L, SBP <100 mg of Hg and lack of haematological response to
treatment were significant independent factors associated with especially poor
overall survival.
The overall survival, at 12, 24 and 48 months respectively, for patients
evaluable for a haematological response was (Figure 2a): for those patients in a
complete haematological response (CR) - 88%, 85% and 76%; for patients in a
partial haematological response (PR) - 74%, 53% and 33%; and for non-responders
39%, 22% and 14%.
The estimated OS at 12, 24 and 48 months for patients
achieving a dFLC-VGPR (but not a CR) was 81%, 68% and 54%, respectively and
was significantly better than patients achieving a partial response (log rank
p<0.0001). Based on the presence or absence of NT-proBNP >8500 ng/L or SBP
<100 mm of Hg (labelled hence as high risk factors), the two parameters identified in
the multivariate analysis, it was possible to stratify the stage III AL patients into three
groups. Patients with none, either or both of these factors present had an overall
survival of 25 months, 6 months and 3 months respectively (Figure 1d). The impact
[8]
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of depth of haematological response on survival was assessed in these three patient
subgroups. On an intention to treat basis, the OS for patients with neither of the two
high risk factors was (Figure 2b): CR – median not reached, PR – 69 months and NR
- 7 months. The OS for patients with only one of the two high risk factors was (Figure
2c): CR – 59 months, PR 23 months and NR 4 months. Only 34% (16/47) patients
with two high risk factors were assessable for treatment response and, although
there was a suggestion of better outcomes amongst responders, numbers are too
few to make any significant conclusions (Figure 2d).
On an intention to treat basis, organ responses were seen in 52 (15%)
patients. This accounted for 26% of patients evaluable for a haematological
response and 45% of patients achieving at least a partial haematological response.
Using NT-proBNP to define cardiac response (>30% and 300 ng/L decrease over
baseline), on an ITT basis, 43 (12%) achieved a cardiac response. Additionally, 17
(5%) had a renal and 11 (3%) had a liver response. Of the patients evaluable for a
haematological response, 21% had a cardiac response. The patients who achieved
a cardiac response had a median 94% decrease in dFLC over the baseline. The
median involved free light chain value at time of response assessment in cardiac
responders was 25mg/L and dFLC 9.5 mg/L. 16/52 (30%) of the patients achieving
a cardiac response had NT-proBNP >8500 ng/L. Five (9%) with a cardiac response
had NT-proBNP >8500 ng/L and SBP <100 mm of Hg – the median survival of these
5 patients was 19 months.
Discussion
This study reports the treatment outcomes of a large cohort of patients with
advanced AL amyloidosis (Mayo stage III disease) from four major European
[9]
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amyloidosis centres and illustrates the complexity of AL amyloidosis. This study
shows that a good haematological response will translate into improved survival in
many patients with stage III AL amyloidosis – and identifying these patients early is
critical.
However, nearly half of all patients with very advanced stage III AL
amyloidosis still die within six months of diagnosis either due to disease progression
or possibly decompensation of organ function from treatment toxicity. This group
remains a major unmet medical need for treatment strategies using agents targeting
the amyloid deposits.
Cardiac biomarkers-based staging system originally reported by the Mayo
group, using troponin T/I and NT-proBNP, is the current standard for staging patients
with AL amyloidosis. The outcomes of patients with Mayo stage III disease is poor
and the median survival reported in the initial Mayo series was just 3 months.
Recent studies report improved outcomes of patients with AL amyloidosis with
median survival in unselected cases improving to nearly 4 years
disease to 8-9 months
23
and in stage III
5,16
. Although this large cohort confirms the earlier reports
that overall the survival of stage III patients has improved (median OS 7 months), the
outcomes are still dismal with 27% deaths within three months of diagnosis and 2year estimated survival of only 29%.
The current findings show that patients defined as stage III AL amyloidosis
encompass a heterogeneous spectrum. The recent update from the Mayo group
reported strong prognostic impact of dFLC on survival in unselected patients with AL
amyloidosis
9
which may help to refine disease classification but the cardiac
biomarker thresholds used to define disease stages were different from the previous
Mayo report 7. This study which included only stage III patients as per the 2004
definition
7
was not designed to replicate those findings. In this cohort, patients with
[10]
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high presenting dFLC had worse outcomes but dFLC was not an independent
predictor of survival. NT-proBNP >8500 ng/L and presenting supine systolic blood
pressure <100 mm of Hg were independent markers of poor prognosis. The data in
this study is unable to assess utility of increasing troponin value for prognosis as
different centres used either Troponin-T or troponin-I measurements. If patients had
either NT-proBNP >8500 ng/L or SBP <100 mm of Hg or both, the overall survival
was 6 months and 3 months, respectively, compared to 25 months in absence of
these two markers of poor prognosis. NT-proBNP is well established in prognosis of
AL amyloidosis and this study suggests that a very high absolute presenting NTproBNP value is a useful marker to identify patients at risk of early death. Supine
systolic blood pressure was a simple and interesting marker of poor outcome
identified in this study. We acknowledge its limitations – optimal blood pressure
measurement needs to be standardised (supine vs. standing; average over a few
days vs. single reading) and has a potential to be influenced by diuretics and other
cardiac drugs – but given it universal applicability and simplicity, it should be
considered for further prospective validation.
Patients with systemic AL amyloidosis diagnosed and treated in the era
before availability of novel plasma cell therapeutic agents had poor haematological
responses (and consequently worse outcomes)24. We and others have reported
improving treatment outcomes in AL amyloidosis in recent years - haematological
response rates of nearly 65% for MDex
dexamethasone
combinations
12,13
11
28
or CTD
25
;
74% for bortezomib-
and over 90% for bortezomib-alkylator-dexamethasone
. Prospective studies in AL also report similar response rates with
MDex 26 and bortezomib
thalidomide
10
27
. We have previously reported, in small case series, that
or melphalan based regimes
[11]
29
fail to improve outcomes in stage III
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patients. Most prospective clinical trials in AL amyloidosis have excluded patients
with stage III disease.
In the current series, 146 (42%) patients died before
response assessment and on an intention to treat basis, just over one third of all
patients achieve a haematological response.
The very high response rates
previously reported with bortezomib (or indeed other regimes) by us
13
11,12
and others
are not replicated in this cohort. There is a suggestion of higher CR rates for
patients treated with bortezomib in the current cohort (26% with bortezomib vs. 11%
and 15% for thalidomide combinations or MDex respectively) (Table 2) but
retrospective nature, potential selection bias and small numbers treated with
bortezomib remain major confounders. The overall haematological response in this
cohort remains disappointing. The main factor is a very high proportion of early
deaths. There was a suggestion that CR rates were lower in patients with one or two
of the high risk factor identified in this study. A possible factor, which is difficult to
analyse in this retrospective series, is the treatment intensity and delays – which are
frequent due to marked toxicity in this fragile patient group and may also account for
lower CR rates in advanced stage III disease.
The analysis of haematological response impacting overall survival in AL
amyloidosis is difficult to interpret since patients who tolerate chemotherapy and
reach point of response assessment are a self selecting “better risk group” compared
to the early deaths – making interpretation of even intent to treat analysis difficult.
Prospective studies with cycle by cycle data analysed using a time updated
response model may provide more valid results – another limitation of the current
cohort. With these caveats, on an intent to treat basis, in this series, patients who
achieve a complete haematological response had significantly better outcomes
(median OS 59 months) compared to partial responders (median OS 28 months).
[12]
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Patients who achieved a dFLC-VGPR also had significantly better outcomes
compared to partial responders – suggesting that dFLC-VGPR is a valid treatment
end point in this patient group. Using NTproBNP >8500 ng/L and SBP <100 mm of
Hg as markers of more advanced stage III disease, amongst patients with neither
high risk marker - a haematological response (CR or PR) to first treatment
significantly improved survival. In the group with presence of either one of the two
high risk factors - a CR significantly improved survival but patients who only achieve
a PR still had a high proportion of early deaths which was not significantly different
from those who did not respond to chemotherapy. This suggests that a profound
(and early) clonal response is critical to improving the survival of these patients.
Achieving this aim remains difficult and prospectively evaluating novel combinations
with synergistic mechanisms of action, thereby allowing lower doses of each
individual agent to be used – thus engendering tolerance - are urgently needed. In
the UK, one such study (REVEAL trial) is testing two bortezomib combinations using
subcutaneous reduced dose bortezomib in stage III AL amyloidosis.
Other
international studies are planned. Autologous stem cell transplant (ASCT) has been
reported to be feasible (and safe) in selected patients with cardiac amyloidosis
30
.
Due to highly conservative patient selection criteria for ASCT in our centres, only one
patient had ASCT in the current series. The role of ASCT in selected stage III
patients, especially in the era of highly effective combination chemotherapy, needs
further clarification.
The final goal of therapy in AL amyloidosis is translation of the haematological
responses into an organ response. In this series, only 15% of all patients achieved
an organ response. The 32% of total patients who were able to receive enough
therapy and live long enough to achieve a haematological response, 45% had a
[13]
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cardiac response as defined by the cardiac biomarkers and all patients who had a
cardiac response had achieved dFLC-VGPR and >90% decrease in dFLC over
baseline.
Striving for a very good haematological response is critical for
improvement in organ function which appears to be possible even in patients with
advanced presenting disease.
The most advanced stage III patients pose a particular challenge, and
accurate identification of such patients is important. In this cohort, the patients with
stage III disease who had both NT-proBNP >8500 ng/L and SBP <100 mm of Hg
had very poor outcomes and only 34% of these patients were assessable for
haematological response. Although there was a suggestion that responders had
better outcomes, the small numbers make it unclear whether chemotherapy really
improved survival in this patient sub-group. There is often substantial toxicity due to
chemotherapy in these very ill patients which will invariably have a negative impact
on the quality of life. In this subgroup, especially in the elderly, the difficult issue for
discussion with patient and family of using only best supportive care approach,
aimed at giving the maximum quality of life has to be considered. Strategies directed
targeting the amyloid deposits such as immunotherapy
31
or drugs like doxycycline32,
if proven to be clinically useful, may be life saving in this patient group.
In summary, stage III AL amyloidosis is a heterogeneous disease.
Responses to chemotherapy appear to change the natural course of the disease in
patients with less advanced stage III AL amyloidosis. This highlights the critical
importance of early diagnosis in AL amyloidosis – routine adoption of simple
strategies like checking NT-proBNP levels and urine for the presence of albumin
during monitoring of patients with monoclonal gammopathy may help early
diagnosis.
The outcomes of patients who achieve an excellent haematological
[14]
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response (CR/VGPR) are significantly better than lesser degree of clonal response
and can translate into improved organ function. High NT-proBNP and low systolic
blood pressure at presentation identify a very poor risk sub-group within the stage III
patients – this needs further prospective validation.
Studies assessing novel
combination regimes using proteasome inhibitors are in progress but a persistent
high early death rate identifies an urgent unmet medical need for treatment
strategies directly targeting the amyloid fibrils.
[15]
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Acknowledgements
We acknowledge all the clinical staff, histopathology and genetic laboratories at the
respective hospitals. We acknowledge the hematologists in UK, Italy, Greece and
Germany who treated patients reported in this study.
Conflicts of Interests
Ashutosh D Wechalekar – Honorarium from Janssen Cilag; Stefan O. Schonland Honorarium from Celgene and Janssen Cilag; Efstathios Kastritis - Nil; Julian D
Gillmore – Nil; Meletios A. Dimopoulos - Honoraria from Celgene and Orthobiotech;
Thirusha Lane – Nil; Andrea Foli
Rannigan
–
N Hawkins
–
Nil; Darren Foard
–
Nil; Paolo Milani
–
Nil; Lisa
Nil; Ute Hegenbart - Honorarium from Celgene and Janssen Cilag; Philip
–
Nil; Giampaolo Merlini - Advisory board: Millennium and Neotope;
Honoraria: Neotope and Pfizer; Giovanni Palladini - Honorarium from Celgene and
Janssen Cilag.
Author Contribution:
Ashutosh D Wechalekar - designed study, performed research, analysed data, wrote
paper;
Stefan O. Schonland - performed research and wrote paper; Efstathios
Kastritis - performed research and wrote paper;
research, Meletios A. Dimopoulos
-
Julian D Gillmore
-
performed
performed research and wrote paper, Thirusha
Lane - performed research, Andrea Foli
-
performed research, Darren Foard
-
performed research, Paolo Milani - performed research, Lisa Rannigan - performed
research, Ute Hegenbart
-
performed research, wrote paper , Philip N Hawkins
–
designed study, performed research and wrote paper, Giampaolo Merlini - designed
study, performed research and wrote paper; Giovanni Palladini - designed study,
performed research, analysed data, wrote paper
All authors approved the final version of the manuscript
[16]
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Table 1: Baseline Characteristics
Parameter
(% with missing data)
Baseline (n=346)
Median (range)/
Number of patients
(%)
Age in yrs (Median) (0%)
Monoclonal light chain (0.8%):
66(37 - 88)
Deaths within 3
months (n=103)
Median (range)/
Number of patients
(%)
68 (42-83)
κ
λ
Serum
monoclonal
protein (including light chain band
only)
Serum monoclonal protein >5g/L
dFLC median (range) (mg/L)
Serum Creatinine (mg/dL) (1%)
24-hour Proteinuria (g/24 hours)
(7%)
eGFR (ml/min) (1%)
Systolic blood pressure (mm of
Hg) (9%)
Systolic Blood Pressure ≤100 mg
of Hg
Patients with eGFR < 40 ml/min
NT-proBNP (ng/L) (0%)
NT-proBNP >8500 ng/L
Cardiac Troponin-T (ng/ml)+ (0%)
+
Cardiac Trononin-I (ng/ml) (0%)
Organ Involvement*
Liver Involvement (0.5%)
Renal Involvement (0.5%)
Mean LV wall thickness (39%)
Ejection fraction (39%)
Soft tissue involvement (0.5%)t
Peripheral neuropathy (0.5%)
Autonomic neuropathy (0.5%)
Gastrointestinal tract (0.5%)
Total number of organs*(0.5%)
1 organ
2 organs
3 or more organs
ECOG performance status (2%)
≤1
2
≥3
NYHA class (9%)
NYHA class 1
NYHA class 2
NYHA class 3 or 4
73 (21%)
274 (79%)
270 (78%)
20
83
80 (77%)
0.66
0.75
36 (10%)
230 (12-8140)
1·3 (0.5 – 9.5)
1.7 (0-16)
13 (12%)
348 (10-8140)
1.3 (0.5-8.7)
1.5 (0-16)
0.377
0.002*
0.99
0.74
49 (ESRD-152)
109 (65-210)
48 (ESRD-152)
103 (70-210)
0.0002**
93 (27%)
50 (48%)
128 (37%)
9106 (379-216187)
182 (52%)
0.1 (0.04-8.2)
0.18 (0.1-12)
18184 (609-179300)
69 (67%)
0.22 (0.04-1.87)
0.52 (0.1-8.2)
0.0002**
77 (22%)
216 (62%)
15 (5- 30)
53(12-81)
66 (19%)
56 (16%)
55(16%)
52 (15%)
28 (27%)
64 (63%)
16.7 (7-30)
55 (27-81)
19 (18%)
11 (11%)
18 (17%)
12 (12%)
0.15
0.99
82 (24%)
129 (37%)
136 (39%)
28 (27%)
34 (33%)
40 (39%)
0.33
0.38
0.99
132 (38%)
114 (33%)
95 (27%)
20 (19%)
37 (36%)
46 (45%)
0.0001**
0.45
0.0001**
50(14%)
84 (24%)
8 (9%)
24 (26%)
0.02
0.89
182 (52%)
71 (65%)
0.0001**
+
P
value*
0.02
0.86
0.88
0.77
0.32
Troponin I measured in patients from Pavia (n=164) and Troponin T in all other
patients.
*p values calculated between patients who died within three months and those alive
after three months.
[20]
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
**Highly significant p values (bold)
Table 2: Haematological responses
Regime
n
M-Dex
Thalidomide combination
Bortezomib combination
Lenalidomide combination
154
96
23
13
ORR
(ITT)
40%
32%
43%
38%
CR
(ITT)
15%
11%
26%
0%
PR
(ITT)
25%
21%
13%
38%
ORR
(evaluable)
60%
64%
62%
41%
ORR-overall response rate, CR- complete response, PR- partial response, ITT –
intention to treat analysis
[21]
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Table 3 Univariate and multivariate analysis of factors affecting overall survival
Factor
Renal involvement
Liver involvement
Presence of CHF+
NYHA class
NYHA 1-2
NYHA 3-4
dFLC
dFLC (> or ≤180)*
Univariate
Multivariate at
baseline**
Multivariate for 3
months landmark
analysis**
P value;
HR (95% CI)
0.89;
1.01 (0.78-1.91)
0.034;
1.3 (1.02-1.8)
0.031;
1.7 (1.05-2.9)
P value;
HR (95% CI)
P value;
HR (95% CI)
0.79;
1.04 (0.73-1.5)
0.90;
1.09 (0.26-4.6)
0.33
0.6 (0.6-52.3)
0.39;
1.2 (0.7-1.9)
0.06;
1.4 (0.9-2.2)
0.98;
0.98 (0.24-4.0)
0.86;
0.89 (0.22-3.4)
0.14;
0.53 (0.23-1.2)
0.28;
0.69 (0.35-1.3)
0.002;
1.5 (1.17-2.0)
0.28;
1.2 (0.85-1.6)
0.17;
1.1 (1.07-3.1)
0.21;
1.1 (0.8-1.9)
0.26
1.2 (0.98-2.4)
0.001;
1.7(1.6-3.05)
<0.001;
2.2 (1.2-2.3)
0.017;
1.9 (1.1-3.2)
0.001;
2.3 (1.4-3.8)
dFLC (< or ≥ 289 mg/L)*
dFLC (< or ≥ 500mg/L)
SBP (as continuous variable)
SBP (>100 mm or ≤ 100mm)
NT-proBNP (<or ≥8500 ng/L)
Mean LV wall thickness
0.003;
1.15 (1.1-1.9)
<0.0001;
0.98 (0.98-0.99)
<0.0001;
1.6 (1.2-2.1)
<0.0001;
2.4 (1.8-3.1)
0.66;
1.06 (.096-1.05)
Haematological Response
CR
PR
Ref
0.025;
2.6 (1.1-6.4)
<0.0001
7.3 (3.1-16)
NR
* Separate multivariate models were generated using dFLC > or ≤180mg/L,
dFLC < or ≥ 289 mg/Land dFLC < or ≥ 500 mg/L
** Separate multivariate models were generated for all patients at baseline
and a landmark analysis was done at three months for those patients who
were assessable for response to treatment at/after three months
+
CHF – congestive heart failure; NYHA – New York Heart Association: dFLC
– difference between involved and uninvolved free light chain; SBP systolic
blood pressure in mm of Hg; LV – left ventricle; CR – complete response, PR
– partial response, NR – no response
[22]
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Figure 1: 1a) Overall survival of the whole cohort. The median follow up of
the whole cohort was 6.5 months and of live patients was 21 months 1b)
Overall survival stratified by presenting NT-proBNP – significantly poorer OS
for patients with presenting NT-proBNP >8500 ng/L.
1c) Overall survival
stratified by presenting systolic blood pressure (mm of Hg) – significantly
poorer OS for patients with SBP <100 mm of Hg at presentation. 1d) Overall
survival stratified by high risk factors (presenting NT-proBNP >8500 ng/L and
low SBP <100 mm of Hg): Presence of none, one or two high risk factors
identified three groups with median OS of 26 months vs. 6 months vs. 3
months respectively (p<0.0001).
Figure 2: 2a) Overall survival stratified by haematological response on an
intention to treat basis. 2b) Overall survival by haematological response in
patients with NT-proBNP <8500 ng/L and SBP >100 mm of Hg. 2c) Overall
survival by haematological response in patients with either NT-proBNP
>8500ng/L or SBP <100 mm of Hg. 2d) Overall survival by haematological
response in patients with both NT-proBNP >8500 ng/L and SBP <100 mm of
Hg
[23]
Figure 1a
Figure 1b
Figure 1c
Figure 1d
Figure 2a
Figure 2b
Figure 2c
Figure 2d
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Prepublished online March 11, 2013;
doi:10.1182/blood-2012-12-473066
A European collaborative study of treatment outcomes in 346 patients with
cardiac stage III AL amyloidosis
Ashutosh D. Wechalekar, Stefan O. Schonland, Efstathios Kastritis, Julian D. Gillmore, Meletios A.
Dimopoulos, Thirusha Lane, Andrea Foli, Darren Foard, Paolo Milani, Lisa Rannigan, Ute Hegenbart,
Philip N. Hawkins, Giampaolo Merlini and Giovanni Palladini
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