Amyloidosis: 2019 Update - prIME Oncology...Misconceptions About Amyloidosis •“If this were...
Transcript of Amyloidosis: 2019 Update - prIME Oncology...Misconceptions About Amyloidosis •“If this were...
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Amyloidosis: 2019 Update
Jonathan L. Kaufman, MD
Associate Professor
Hematology & Oncology
Winship Cancer Institute of
Emory University
2Winship Cancer Institute | Emory University
Amyloidosis
• Protein conformation/Deposition disorder
• AL amyloidosis
• Hereditary amyloidosis– Transthyretin (mutated)
– Fibrinogen Aα
– Apolipoprotein AI and AII
– Lysozyme
– Gelsolin
• Secondary amyloidosis
Merlini G, et al. J Clin Oncol. 2011;29(14):1924-1933; Mollee P, et al. Intern Med J. 2014;44(1):7-17.
AL = immunoglobulin light chain
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Clinical Manifestations of Amyloidosis
GI = gastrointestinal; PNS = peripheral nervous system
Mollee P, et al. Intern Med J. 2014;44(1):7-17.
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AL Amyloidosis
• Monoclonal plasma cell disorder
• 3000 cases annually in the United States[a]
• 10% of patients are < 50 years old[b]
• Presenting symptoms are varied
• Delays in diagnosis are common
a. Quarta CC, et al. Circulation. 2012;126(12):e178-182.
b. Desport E, et al. Orphanet J Rare Dis. 2012;7:54.
5Winship Cancer Institute | Emory UniversityLousada I, et al. Adv Ther. 2015;32(10):920-928.
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What makes it hard?
• No two amyloidosis patients alike
• The most frequent symptoms are vague Fatigue
Dyspnea
Swelling
Easy bruising
• Front-line doctors (primary care, cardiology, nephrology, hem/onc) have only limited experience with the disease
• Multi-organ involvement is often not appreciated by a gaggle of specialists working independently
• Biopsies may be non-diagnostic if Congo red staining isn’t requested; pathologic expertise and good controls are required
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Localized Vs Systemic Amyloidosis
• Localized amyloidosis is still AL amyloidosis and will type as such
• In localized amyloidosis, the precursor immunoglobulin light chain is made at the site of amyloid deposition
• Abnormal serum free light chain values or M proteins can be seen in localized amyloidosis patients
• Bone marrow should not have clonal plasmacytosis
• Fat should be negative and organs are spared
• Classic examples of localized amyloidosis Tracheobronchial
Bladder
Lymph node
Cutaneous
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Misconceptions About Amyloidosis
• “If this were amyloidosis, the light chains would be more elevated and increase over time” Truth: light chain elevations are typically modest and usually stable
• “The fat biopsy was negative, so they don’t have amyloid” 15% of patients with AL will have a negative abdominal fat aspirate
• “The plasma cells are <20% in the marrow and don’t have CRAB symptoms, so I don’t need to treat the patient with chemotherapy” AL amyloidosis with organ involvement always requires treatment, marrow plasma cells
of 5%-10% are typical
Some soft tissue only patients and GI patients may be observed
• “I see myeloma patients, but never see amyloid” 1 in 5 myeloma patients will develop amyloid
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Clinical Manifestations of AL Amyloidosis
Merlini G, et al. N Engl J Med. 2003;349(6):583-596.
12Winship Cancer Institute | Emory UniversityDonnelly JP, Hanna M. Cleveland Clinic J Med. 2017;84(12 Suppl 3):12-26.
13Winship Cancer Institute | Emory UniversityMerlini G, Stone MG. Blood. 2006;108(8):2520-2530.
CLL = chronic lymphocyte leukemia; MM = multiple myeloma; NHL = non-Hodgkin lymphoma;
WF = Waldenström macroglobulinemia
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AssayN = 110
% Positive (CI)*
FLC / ratio 91 (84–96)
Serum IFE 69 (60–78)
Urine IFE 83 (74–89)
Serum IFE + urine IFE 95 (90–99)
FLC / ratio + urine IFE 91 (84–96)
FLC / ratio + serum IFE 99 (95–100)
All 3 assays 99 (95–100)
Establishing the Clinical Diagnosis
*CI, confidence interval determined by the exact binomial distribution.
Katzmann JA, et al. Clin Chem. 2005;51(5):878-881.
FLC = free light chain; IFE = Immunofixation electrophoresis
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Fat+ Marrow+ 62%
Fat+ Marrow– 11%
Fat– Marrow+ 15%
Fat– Marrow– 13%
Establishing the Diagnosis by “Noninvasive” Testing (N = 151)
Gertz MA, et al. Hematology Am Soc Hematol Educ Program. 2004:257-282.
16Winship Cancer Institute | Emory UniversityMerlini G, et al. J Clin Oncol. 2011;29(14):1924-1933.
Diagnostic Algorithm for Systemic Amyloidosis
XRT = x-ray telescope
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Subtyping of Amyloid is Critical in Any Patient Newly Diagnosed With Amyloid
Mollee P, et al. Intern Med J. 2014;44(1):7-17.
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In a Patient With MGUS Found to Have Cardiac Amyloidosis, Do You Need to Subtype?
• Prevalence of MGUS in older adults[a]
• Higher prevalence in blacks[b]
• 143 cases of cardiac biopsy-proven amyloidosis[c]
– 81(57%) - ATTR, 62 (43%) – AL
– 76 (53%) had MG detected including 20 with ATTR
a. Kyle RA, et al. N Engl J Med. 2006;354(13):1362-1369; b. Kyle RA, et al. Oncology (Williston Park). 2011;25(7):578-586; c.
Maleszewski JJ, et al. Cardiovasc Pathol. 2013;22(3):189-194.
[a]
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Staging of AL Amyloidosis
• 2012 revised staging system– dFLC (involved-uninvolved free light chain) ≥ 180 mg/L (18 mg/dL)
– NT-proBNP ≥ 1800 pg/mL
– cTnT ≥ 0.025 ng/mL
Kumar S, et al. J Clin Oncol. 2012;30(9):989-995.
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Bone marrow
plasma cell
clone
Clonal-free
light chainsMisfolded
light chains
(AL)
Organ AL deposition
leading to dysfunction
Effective chemotherapy
available
Needs time for endogenous clearance.
Chemotherapy can worsen eg, fluid
retention, cardiotoxicity, neuropathy.
Need for clinical trials with
fibril-directed therapies
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To Transplant or Not to Transplant?
• High transplant-related mortality (24% in RCT)[1]
• Patient selection is critical[2]
– NT-proBNP > 5000 pg/mL, serum TnT > 0.06 ng/mL early mortality
• Center experience also key[3]
– Centers > 4 AL transplants/year had better survival outcomes
• Induction treatment pretransplant?– CyBorD can convert transplant ineligible to eligible[4]
– May test ability of patients to tolerate treatment[5]
– BMPC > 10%[e]
1. Jaccard A, et al. N Engl J Med. 2007;357(11):1083-1093; 2. Gertz MA, et al. Bone Marrow Transplant. 2013;48(4):557-561; 3. D’Souza
A, et al. J Clin Oncol. 2015;33(32):3741-3749; 4. Mikhael JR, et al. Blood. 2012;119(19):4391–4394; 5. Hwa YL, et al. Am J Hematol.
2016;91(10):984-988.
BMPC = bone marrow clonal plasma; RCT = randomized controlled trial
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Treatment algorithm for immunoglobin light chain amyloidosis.
Merlini G, et al. J Clin Oncol. 2011;29(14):1924-1933.
CR = complete response; CTD = thalidomide-cyclophosphamide-dexamethasone; HDM/SCT = high-dose intravenous melphalan supported with autologous hematopoietic SCT; HR = heart response; NR = no response; OHT = orthotopic heart transplantation; SCT = stem cell transplantation; PR = partial response
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DARA SC Plus CyBorD in Patients With Newly Diagnosed AL Amyloidosis: ANDROMEDA
• Safety run-in results of ANDROMEDA
• Summary of overall best hematologic response based on IACC guidelines
– Preliminary efficacy: all but 2 patients demonstrated hematologic responses
Comenzo RL, et al. J Clin Oncol. 2018;36(suppl): Abstract 8011.IACC = International Amyloidosis Consensus Criteria; SC = subcutaneous; VGPR = very good partial response
24Winship Cancer Institute | Emory UniversityJoseph NS, Kaufman JL. Curr Hematol Malig Rep. 2018;13(3):212-219.
IMID = immunomodulatory drug ORR = overall response rate
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Conclusions
• AL amyloidosis remains a challenge to diagnose and treat
• Amyloid subtyping is critical in establishing diagnosis
• Autologous transplant remains an important part of treatment in selected patients
• Improved plasma cell-directed therapy improves outcomes
• Clinical trials comparing dara-VCD to VCD are ongoing
• Organ-directed therapy with antibodies are ongoing
Dara-VCD = daratumumab-bortezomib-dexamethasone
Risk adapted AL Amyloidosis Treatment
Low risk NT-proBNP≤5000,
BNP<81 pg/mL, and
TnI < 0.1 ng/mL
● Velcade 1.3 mg/m2 SQ days 1,8,15
● Dexamethasone 20 mg PO days 1,8,15
● Cytoxan 300 mg/m2 PO/IV days 1,8,15 (max 500 mg)
Intermediate risk NT-proBNP>5000 or
both of the following
BNP > 81 pg/mL and
TnI > 0.1 ng/mL
● Cycle 1 - Velcade 1 mg/m2 & dexamethasone 12 mg PO days
1,8,15. Cytoxan 200 mg/m2 PO day 1.
● Starting with cycle 2, add Velcade 1.3 mg/m2 days 1,8,15.
● Starting with cycle 3, add cytoxan 300 mg/m2 days 1 & 8.
High risk NT-proBNP>8500 or
BNP > 700 pg/mL
● Cycle 1 - Velcade 0.7 mg/m2 days 1,8,15 plus Dexamethasone 8 mg
PO days 1,8,15.
● Starting with cycle 2, modify Velcadel to 1 mg/m2 and add cytoxan
300 mg PO days 1,8,15
Very high risk NT-proBNP>8500 and
SBP < 100 mm Hg
● Melphalan 4 mg/day x 3 weeks with prednisone 10 mg TIW x 3
weeks, hold for 2 weeks, then resume 4 mg daily M-F.
● Hold dose for WBC<3 or platelets < 50K.
Diomede L, et al, Blood. 2014;123(23):3534-3552; Wechaleka et al, Blood, 2015, Abstract 732; Lilleness B, et al. Blood. 2019;133(3):215-223;
Kumar S, et al. J Clin Oncol. 2012;30(9):989-995.
Doxycycline 100 mg BID (after meals)