PRIMARY AMYLOIDOSIS

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PRIMARY AMYLOIDOSIS

• WARREN BRENNER
• GRAND ROUNDS 10/17/03

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• 53 yr old white female with past medical Hx of
  HTN, GERD and depression presented with a 6 week
  history of fatigue and progressive weight loss
  (210-176) pounds over 4 months.
• Found to have elevated alkaline phosphatase of
  1600 on routine labs and was referred for
  further evaluation.

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• No further significant past medical or surgical
  history
• No significant family history
• Non smoker and non drinker
• Only relevant history on ROS was intermittent
  tingling in fingertips for many months,
  occasional nausea, and RUQ pain.

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• Relevant physical findings Normal vitals except
  tachycardia at 100 bpm.
• 10cm liver edge felt below RCM
• Labs WCC 9.7 HGB 14.2 Plat -568 Creatinine
  0.9 Alb 3.9 Alk P 1408 ALT 36 AST 78
  Bilirubin 1.2 TP 8.1 gammaGT 1317 Coags
  normal

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• UA protgt300mg/dl
• 24 hour urine protein 4485 mg/24hr
• SPEP No monoclonal protein
• IF serum negative
• IF urine ? light chain

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• BM biopsy 5 plasma cells. Areas of marrow
  replaced by eosinophilic dense material stained
  by congo red.
• Liver biopsy extensive eosinophilic dense
  material throughout portal tracts and lobular
  sinusoids.

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PRIMARY AMYLOIDOSIS
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INTRODUCTION

• Disease characterized by extracellular deposition
  of pathologic insoluble fibrillar proteins in
  organs and tissues.
• Term amyloid first coined by Virchow in mid 19th
  century (meaning starch or cellulose).
• Amyloid found to stain with congo red, appearing
  red microscopically in normal light but apple
  green when viewed in polarized light.
• Fibrillar nature and beta pleated sheet
  configuration described by electron microscopy in
  1959.

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• Linear non branching aggregated fibrils with a
  diameter of 8-10nm and ß pleated sheet
  conformation by xray diffraction. NEJM Volume
  349583-596 August 7, 2003 Number 6
• The ß sheets consist of strands of polypeptides
  in a zigzag formation. Contigous ß sheet
  polypeptide chains constitute a protofilament.
  Generally 4-6 protofilaments are wound around one
  another to form an amyloid fibril

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• Amorphous homogenous, hyalin-like eosinophilic
  appearance of amyloid under light microscopy.

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PROPERTIES

• Amyloid is a generic term that refers to
  extracellular deposition of fibrils composed of
  LMW subunits of a variety of proteins, many of
  which circulate as constituents of plasma.
• At least 21 different protein precursors of
  amyloid fibrils are known.
• All deposits contain a non-fibrillar
  glycoprotein, amyloid P component (AP).
• AP directly derived from the normal circulating
  protein serum amyloid P, which is structurally
  related to CRP.

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AL AMYLOIDOSIS

• Part of the spectrum of plasma cell dyscrasias.
• Cellular source of AL amyloid is always a single
  clone of the B-lymphocytic lineage, usually
  exhibiting the morphologic appearance of plasma
  cells.
• Underlying clonal proliferative disorder may be
  frankly neoplastic (iemultiple myeloma) or
  conversely a low grade proliferation of
  monoclonal plasma cells.

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• Among MM patients, amyloidosis reported with
  variable frequency, but rarely exceeds 20.
• Majority of patients without myeloma associated
  AL, occurs in the setting of an apparently
  benign monoclonal gammopathy.
• Characterized by low concentrations of monoclonal
  Igs in serum/urine and an often occult low grade
  monoclonal plasma cell proliferation in BM.

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A Long-Term Study of Prognosis in Monoclonal
Gammopathy of Undetermined SignificanceRobert A.
Kyle, M.D., Terry M. Therneau, Ph.D., S. Vincent
Rajkumar, M.D., Janice R. Offord, B.S., Dirk R.
Larson, M.S., Matthew F. Plevak, B.S., and L.
Joseph Melton, III, M.D.Volume
346564-569February 21, 2002 Number 8

• In long term follow up from the Mayo clinic of
  241 pts with MGUS, AL was found in 8 pts 6-15
  years after detection of a serum monoclonal Ig.
  In a series of 1596 pts with AL only 0.4 showed
  delayed progression to overt MM.
• AL may occur in the absence of any detectable
  monoclonal Ig in serum/urine. (- 11-15 have
  non secretory AL).
• AL occasionally reported with other B cell
  neoplasm's.

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PATHOGENESIS

• Consists of intact molecules of monoclonal Ig
  light chains, fragments of their variable region
  or both.
• Demonstration of substitutions at specific
  positions in the light chain variable region has
  led to the suggestion that these replacements
  destabilize light chains and thereby increase the
  likelihood of fibrillogenesis.
• This is consistent with the hypothesis that the
  amyloidgenic potential is inherent in the
  structure of the variable region of a limited
  number of monoclonal light chains.

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BLOOD,15 May 2003.Vol 101,No 10Abraham et al
Immunoglobulin light cahin variable region genes
influence clinical presentation and outcome in
ALB

• Ig light chain variable genes have been shown to
  influence clinical presentation and outcome in AL
  by displaying specific organ tropism.
• V?I family 70 had soft tissue involvement and
  50 had renal.
• V?II, V?III(3r), V?I and V?vI(6a) gene segments
  have shown a strong association with AL if their
  prevalence's are compared with those in
  polyclonal conditions.
• Patients with clones derived from the V?vI germ
  line gene more likely to present with predominant
  renal involvement.
• Patients with V?II have predominantly cardiac
  involvement.

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• IgH chain translocations are also found in AL
  especially t(1114).
• Monosomy 18 is also frequently found as well as
  deletions of chromosome 13.
• ? to ? ratio is approx 13
• LCD Non amyloid Ig deposition predominantly of
  ? and usually the constant region. Forms granular
  rather than fibrillar deposits and mainly affects
  the kidneys.

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Misdiagnosis of Hereditary Amyloidosis as AL
(Primary) AmyloidosisHelen J. Lachmann et al,
NEJMVolume 3461786-1791 June 6, 2002 Number
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• Reactive systemic amyloid(AA).
• Hereditary systemic Amyloidosis amyloid fibrils
  usually derived from genetic variants of
  transthyretin, apolipoprotein A1, lysozyme or
  fibrinogen A a chain.
• Lachmann et al in a study from the UK revealed
  that of 350 pts in whom the diagnosis of AL was
  made and with no family history, 9 had
  hereditary amyloid and of these 24 had a low
  grade monoclonal gammopathy.

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INCIDENCE

• Incidence roughly 8.9 per million person year.
• M 60-65
• Median age at diagnosis approximately 60 with
  only 1 being lt40.

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DIAGNOSIS

• Based on clinical suspicion and established by
  tissue biopsy.
• After biopsy obtained the type of Amyloidosis
  must be determined.
• Search for plasma cell dyscrasia with IF of serum
  and urine. 90 of pts with AL will have
  monoclonal Ig or light chains.
• Immunostaining variable as standard antisera to
  ? and ? may not recognise antigenic epitopes in
  the course of proteolytic processing and antisera
  usually directed to constant region determinants.

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UPToDAte Online 11.2Accessed 9/30/03
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• Imaging techniques Technetium Tc 99m
  pyrophosphate binds avidly to many types of
  amyloid. Quantitative assessment not possible and
  strongly positive results usually only occur in
  pts with severe disease. Technetium labeled
  aprotinin may be more sensitive.
• Quantitative scintigraphy can be done with
  iodine-123- labeled serum amyloid P component
  (sensitive for AL, ATTR and AA amyloid).

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CLINICAL ASPECTS

• Clinical manifestations are extremely varied and
  depend primarily on the organs predominantly
  involved and extent of tissue deposition.
• Histology usually reveals deposition in almost
  any organ except the CNS.
• Initial symptoms are frequently fatigue and
  weight loss which are non specific.

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Molecular Mechanisms of AmyloidosisGiampaolo
Merlini, M.D., and Vittorio Bellotti, M.D., Ph.D.
NEJMVolume 349583-596.Aug 7,2003.No 6
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CARDIAC

• May present with rapid and progressive onset of
  CHF.
• Characteristically, features are predominantly of
  right sided CHF.
• ECG low voltage and may have a pattern of MI in
  absence of CAD.
• ECHO concentrically thickened ventricles with
  normal-small cavity and diastolic dysfunction on
  doppler.
• Clinical clue is marked worsening of failure when
  CCB used.

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Echocardiogram revealing thickened walls with
small chambers
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RENAL

• Nephrotic syndrome present in 30-50 at
  diagnosis.
• Nephrotic syndrome and renal failure develop only
  rarely during course of the illness if not
  present at time of diagnosis.
• ? BJP have been associated with inferior survival
  as compared with ?BJP or no monoclonal protein,
  irrespective of serum creatinine.

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HEPATIC/SPLENIC

• Involvement of liver common.
• Hepatomegaly may be striking at presentation and
  usually disproportionate to extent of liver
  enzyme abnormalities (except alkaline phosphatase
  which is frequently elevated).
• Presence of jaundice is an adverse prognostic
  factor and MST from onset of jaundice is only 3
  months.
• Patients may present with severe intrahepatic
  cholestasis.
• Massive splenic deposition may result in
  functional hyposplenism.

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• Macroglossia occurs in 10-20
• Amyloid can be found within any part of the GI
  tact and may infiltrate parenchyma, organs and
  nerves.
• Peripheral neuropathy may be presenting
  manifestation or develop subsequently during the
  course of the illness (history of carpal tunnel
  frequently elicited).
• Neuropathy usually distal, symmetric and
  progressive. Cranial nerve and autonomic nerve
  involvement also well described.
• Motor neuropathy rare.

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• AL arthropathy may simulate RA. Most striking
  appearance is the shoulder pad sign secondary
  to swelling of the shoulder joints.
• Vascular infiltration may result in easy bruising
  especially in the eyelids and flexural regions.
  Purpuric lesions typically occur above the
  nipple.
• Factor X deficiency (acquired) can occur in up to
  10 of pts and over 2/3 of pts with acquired
  factor X deficiency have systemic Amyloidosis.

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PROGNOSIS

• Serious disease with high mortality.
• Overall median survival after diagnosis is lt
  2years in most series.
• Patients with co-existent MM have a poorer
  prognosis.
• Survival time largely dependent upon the organ
  system predominantly involved.
• Cardiac involvement is major determinant of
  prognosis and most common cause of death MST
  from onset of CHF is 7 months.

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• Renal failure is second major cause of death.
  Median survival approx 2.4 years among pts with
  NS.
• Hepatic amyloid median survival of 9 months
  (death often d/t cardiac or renal involvement
  though).
• Other predictors of poor survival in various
  multivariate analysis include CHF, BJP in urine,
  hepatomegaly and weight loss (in fist year after
  diagnosis).
• Serum ß2 microglobulin also highly significant
  predictor of poor prognosis independent of serum
  creatinine.

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MANAGEMENT

• Amyloidosis is a dynamic process and the aim of
  chemotherapy is to suppress the B cell clone
  which produces amyloidogenic light chains.
• Standard treatment for pts is alkylating based
  therapy and 20-30 achieve a measurable organ
  response.
• Various prospective randomized trials have shown
  that conventional Melphalan and prednisone
  results in an increase in survival but the
  clinical response rates are low and slow.

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A Trial of Three Regimes for Primary
AmyloidosisKyle R. A., Gertz M. A., Greipp P.
R., Witzig T. E., Lust J. A., Lacy M. Q.,
Therneau T. M.N Engl J Med 1997 3361202-1207,
Apr 24, 1997.

• Results of a a large trial of 220 pts by Kyle et
  al in 1997 clarified the role of colchicine in AL
  Amyloidosis.
• Median duration of survival was 8months for the C
  group, 18 months for the MP group and 17 months
  for the MPC group.
• Median survival for pts with cardiac amyloid was
  5 months, 16 months for pts with renal
  involvement and 34 months for those with PN.
  Survival was best in those patients showing a 50
  reduction in serum or urine paraprotein levels.

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Gertz MA et alA multicenter Phase II trial of
4-iodo 4 deoxydoxorubicin(IDOX) in
AL.Amyloid.2002 Mar9(1)24-30Palladini et al A
Modified high-dose dexamethasone Regime for AL.
Br J Haematology.2001 Jun113(4)1044-6Prospectiv
e Randomized Trial of Melphalan and Prednisone
Versus Vincristine, Carmustine, Melphalan,
Cyclophosphamide, and Prednisone in the Treatment
of Primary Systemic Amyloidosis Morie A. Gertz,
Martha Q. Lacy, John A. Lust, Philip R. Greipp,
Thomas E. Witzig, and Robert A. Kyle

• VAD has also been shown to be an effective regime
  and in an open trial median survival was not
  reached after gt17 months of F/U.
• High dose dexamethasone alone does not appear to
  be superior to MP.
• Therapy with multiple alkylating agents does not
  result in a higher response rate or longer
  survival compared with standard MP.
• IDOX(4-Iodo-4-deoxydoxorubicin was found in a
  multicenter phase II trial not to be effective at
  the doses used.
• Pulse decadron with maintenance IFN may also be
  an effective regime.

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Autologous stem cell transplantation for primary
systemic amyloidosis raymond L.Comenzo and Morie
A.GertzBlood.2002994276-4282Eligibility for
Hematopoietic Stem-Cell Transplantation for
Primary Systemic Amyloidosis Is a Favorable
Prognostic Factor for Survival Angela
Dispenzieri et alJCO Jul 15 2001 3350-3356

• High dose chemotherapy and autologous transplant
  Various trials have been done. Death secondary
  to transplant fairly high in some of the trials
  and the most striking feature was the prognostic
  value of the number of clinical manifestations of
  amyloidosis at the time of transplant. The
  patients entering trials of HDCT often have less
  severe disease and may do relatively well with
  conventional chemotherapy.
• This was shown in a retrospective review at Mayo
  where patients with AL who would have been
  eligible for transplant had a MST of 42 months
  with standard therapy compared with the expected
  MST of 18 months for all patients with AL.

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• Patients with 1-2 organ involvement and
  uncomplicated cardiac disease are good candidates
  for SCT while patients with gt2 organs involved or
  with advanced heart disease are at high risk of
  dying.
• A multicenter phase III trial is underway where
  patients are randomized to receive HD melphalan
  and SCT or oral melphalan/decadron.
• Overall, RR appear to be higher with SCT but
  morbidity and mortality are clearly higher than
  in patients with other hematological malignancies.

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CONCLUSIONS

• Systemic, uncommon disease with poor long term
  survival.
• Symptoms often vague and recognition of syndromes
  associated with amyloidosis is key.
• In general, current therapy is suboptimal
  although new treatment options including
  thalidomide, proteosome inhibitors, antisense
  oligonucleotides and SCT hold promise for the
  future.