Amyloidosis. James J. Stark, MD, FACP Medical Director Cancer Program Maryview Medical Center. Professor of Medicine Eastern Virginia Medical

Transcription

1 Amyloidosis James J. Stark, MD, FACP Medical Director Cancer Program Maryview Medical Center Professor of Medicine Eastern Virginia Medical School

2 68 y.o. man admitted to MMC in March, 2005 with difficulty breathing worsening over several weeks Several years history of monoclonal gammopathy without other features of multiple myeloma Paralyzed left hemidiaphragm for several years Known pericardial effusion since November, 2004 without hemodynamic embarrassment

3 , continued Physical Examination: Atrial fibrillation/flutter with rapid ventricular response Rales at both lung bases No abdominal organomegaly Acneiform rash over back; would soon develop infiltrative erythematous rash over cheeks

4 Laboratory Evaluation Normal CBC except for mild anemia Hyponatremia (Na + 126); BNP 242 Immunofixation electrophoresis of serum: Monoclonal gammopathy 1.2gm/dl IgG-κ IgA, IgM markedly decreased Immunofixation electrophoresis of urine: monoclonal IgG heavy chain with associated κ light chain but < 20mg/24hr Xrays. Echocardiogram.

5 Hospital Course Underwent pericardial window and open lung biopsy Pathology.

6 Hospital Course Underwent pericardial window and open lung biopsy Pathology. Post-operatively developed atrial flutter and had a somewhat stormy convalescence

7 After Discharge Seen in office still very weak and dyspneic Referred to bone-marrow transplantation unit at MCV for consideration of auto-bmt as treatment of primary amyloidosis Underwent bone marrow biopsy as part of ongoing evaluation. modified to B-cell non-hodgkin s lymphoma with secondary paraprotein production and resultant amyloidosis

8 Additional Workup at MCV Special stains done on lung biopsy specimen Κ light chains seen in amyloid deposition in lung; no λ light chains seen Presumptive evidence of so-called AL amyloidosis

9 Ongoing Management Receiving six cycles of CVP chemotherapy to try to achieve major cytoreduction of his lymphoma hoping to shut down amyloid factory Thus far remains weak and depleted Anticipate repeat CT chest and bone-marrow biopsy after six cycles are done Possibility of high-dose therapy with stem-cell rescue still an option, although general condition argues against approach

10 Amyloidosis Tissue biopsy sine qua non Usually kidney or liver biopsy done for workup of unknown problem Associated bleeding diathesis makes biopsy of internal organs potentially hazardous Gingival biopsy not usually done because other sites are less painful

11 Diagnostic Sensitivity Organ Sensitivity (%) Abdominal fat pad Rectum Bone Marrow Biopsy Skin* *Only positive when skin appears abnormal

12 , continued Amyloid fibrils identified by ability to bind Congo Red (leads to green birefringence under polarized light) and by characteristic appearance on electron microscopy (not routinely done)

13 Major Types of Amyloidosis AL (Primary) AA (Secondary) Deposition of fragments of monoclonal light chains Seen with multiple myeloma and Waldenström s Macroglobulinemia and, rarely, with B-cell Non- Hodgkin s Lymphoma Deposition of serum amyloid A; degraded into fragments, deposited into tissues Seen with chronic inflammatory conditions Rhematoid Arthritis Bronchiectasis Osteomyelitis FMF

14 Bone Marrow Biopsy in Primary (AL) Amyloidosis Staining for λ light chain strongly positive Presence of monoclonal light chains in bone marrow can help distinguish AL from AA

15 Renal Biopsy in AL Amyloidosis Staining with anti-κ lightchain antibody

16 Renal Biopsy in Secondary (AA) Amyloidosis Glomerulus strongly positive for AA protein

17 AL Amyloidosis caused by non-hodgkin s Lymphoma Series of six cases from Memorial Sloan Kettering Cancer Center* Their database has >200 pts with amyloidosis; therefore <3% of pts have NHL Most had bulky lymphadenopathy and organ infiltration 1/6 had IgG-κ as did our patient 2/6 underwent HDC+PBSC Survival prolonged in most cases regardless of therapy; no predictability to clinical course *Cohen et al Br. J. Haematology 124:309, 2004

18 AA Amyloidosis in Association with NHL Only 2 cases reported in literature, one studied in detail* Bulky lymphoma with incidental amyloid in kidney in retroperitoneum at autopsy One patient had chronic hepatitis-c as well Relationship between NHL and AA unclear *Zhu Human Pathology 35:1041, 2004

19 What Causes Amyloid Deposition? The Problem of Mis-Folding Amyloidosis is one of a family of diseases resulting from the accumulation of abnormal relatively inert protein Other such diseases probably include Alzheimer s disease, Type II diabetes, Huntington s Disease Key event is a disturbance in protein folding resulting in altered threedimensional structure and deranged function Basic Basic Science Science

20 Mis-Folding, Continued Κ and λ light chains are unique in nature for variability of amino-acid sequences Some variations on sequence result in abnormal folding of proteins Some folding configurations are so rigid as to render polypeptide inert, allowing its buildup Basic Basic Science Science

21 The Beta-Sheet Rigid Folding Pattern Basic Basic Science Science Make-up of side chains conveys rigidity

22 Amyloid Rigidity, continued Such rigidity conveyed by unique sequence of peptide fragments of light chains Rigidly folded polypeptide resistant to digestion by ubiquitous proteolytic enzymes normally present Amyloid material builds up in vital organs, e.g., kidney, liver and heart Basic Basic Science Science

23 of Amyloidosis AA or secondary Amyloidosis is largely treated by attacking the offending event. of AL is under heavy reconsideration: What constitutes success? Do you need to see a major anti-tumor effect against NHL to see regression of amyloid deposition? Is there a role for high-dose chemotherapy with stemcell rescue?? What do patients actually die from when they do succumb?

24 Rationale for Mortality of AL is very high Survival 51, 16 and 5% at 1, 5 and 10 years in largest series of 810 patients from Mayo Clinic* All long-term survivors in this study received some form of chemotherapy (study not randomized to test efficacy of chemo vs. supportive care) Many patients die of end-organ failure from amyloid deposition, not from B-cell neoplasm Traditional oral alkylating therapy (melphalan) led to bone-marrow failure relatively quickly and ruled out subsequent high-dose therapy with stem-cell rescue (stem cells were damaged with initial treatment) *Kyle Blood 93:1062, 1999

25 Attempts to Improve Upon Therapy Numbers of patients so small as to make difficult conducting of prospective randomized trials Most published studies compare results to theoretical expected outcomes Therapy to be successful needs to result in reversal of chronic end-organ damage

26 Traditional Old-style myeloma treatment with Melphalan and Prednisone Resulted in modest improvement with some patients losing their monoclonal gammopathy Chronicity of therapy limited by bonemarrow toxicity of melphalan

27 High-Dose Therapy with Stem-Cell Rescue Based on leap of faith that more is better True in NHL and multiple myeloma but not necessarily true in a disease with a potential disconnect between tumor burden of host and symptoms/organ damage Very toxic treatment in people who already have significant end-organ damage All that said, the following study reports on a large well-done single-arm non-blinded study of HDCC and PBSC rescue in patients with AL

28 Algorithm for patient selection and treatment with high-dose melphalan and stem-cell transplantation Skinner, M. et. al. Ann Intern Med 2004;140:85-93

29 Survival curve for all patients (top) and for patients with cardiac versus noncardiac involvement (bottom) Skinner, M. et. al. Ann Intern Med 2004;140:85-93 Cardiac involvement very important in predicting outcome This mortality rate higher than would be seen from B-cell neoplasm alone

30 Survival curves according to hematologic response at 1 year from treatment Remission also counts Skinner, M. et. al. Ann Intern Med 2004;140:85-93

31 Comparison of the Clinical Features of Patients with AL Amyloidosis according to Eligibility Status for with High-Dose Melphalan and Stem-Cell Transplantation Skinner, M. et. al. Ann Intern Med 2004;140:85-93

32 Effect of Melphalan Dose on the Probability of a Complete Response for All Light Chain Combinations Associated with AL Amyloidosis in 181 Patients Recall dose dependent on age; only modest effect seen; age rather than dose may be key

33 Organ Improvement at 1 Year according to Hematologic Response in 181 Patients In general better remissions result in better organ improvement

34 How do these results compare to best available conventional treatment?

35 Traditional vs. High-Dose Chemotherapy Single somewhat controversial series comparing oldstyle therapy over the last 20 years with HDCC/PBSC rescue Non-randomized but from single institution Patients matched for: Age Gender Time from presentation LVEF Renal function Additional much larger group also analyzed to look at effect of improvements in conventional therapy on outcome

36 Survival among 3 groups PBSC group (n=63) Contemporaneous Controls (n=63) Historical Controls (n=806) Dispenzieri Blood 103:3960, 2004

37 Criticism of Study Conventional arm (n=63) (middle curve) used therapy which did not include high-dose steroids and/or thalidomide Jaccard et al report a much better outcome with melphalan and high-dose dexamethasone than that report in contemporaneous control group in Dispenzieri They recommend true randomized control trial to answer question (difficult to do!) Jaccard et al Blood 104:2990, 2004

38 Conclusions Nasty disease with outcome dependent on deposition of toxic but inert material without concomitant overwhelming of host with tumor burden Patients die of end-organ damage before they die from the underlying B-cell neoplasm HDCC looks promising but needs to be adapted to patients who are more typical of the AL patient i.e., chronically ill. Current reports look at ideal treatment subjects by and large Earlier diagnosis before end-organ damage would be highly desirable but not clear how to accomplish in this rare disease other than by heightened awareness by the already astute physician Our patient has uncertain future at best; marginal candidate for HDCC, seriously ill with debility and end-organ damage By product of study of AL is better understanding of how proteins fold; may be useful in the future Basic Basic Science Science Conclusion Conclusion

39 For more information and a copy of this talk.visit Thanks for your attention! Basic Basic Science Science Conclusion Conclusion