Amyloidosis: 2019 Update - prIME Oncology...Misconceptions About Amyloidosis •“If this were amyloidosis, the light chains would be more elevated and increase over time” Truth:

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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


Clinical Manifestations of Amyloidosis

GI = gastrointestinal; PNS = peripheral nervous system

Mollee P, et al. Intern Med J. 2014;44(1):7-17.


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.


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



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



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


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


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


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


Subtyping of Amyloid is Critical in Any Patient Newly Diagnosed With Amyloid

Mollee P, et al. Intern Med J. 2014;44(1):7-17.


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]


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.


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


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


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


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


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)

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Amyloidosis: 2019 Update - prIME Oncology...Misconceptions About Amyloidosis •“If this were amyloidosis, the light chains would be more elevated and increase over time” Truth: