Aplastic Anemia - aamds.org Anemia.pdf · 5/4/2018 2 Pancytopenia Due to Increased Cell Destruction...
Transcript of Aplastic Anemia - aamds.org Anemia.pdf · 5/4/2018 2 Pancytopenia Due to Increased Cell Destruction...
5/4/2018
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Aplastic AnemiaAAMDS International Foundation
Houston, TX, April 2018
Lawrence Rice, MD
Chief, Division of Hematology
The Methodist Hospital
Professor of Medicine
Weill Cornell Medical College
Adjunct Professor, Baylor Coll Med
Houston, Texas
8 Year Remission
• 60 yo woman presented in 2008 mucosal bleeding, severe thrombocytopenia
• Also severe anemia and leukopenia
• Past Hx: Diabetes and Hypertension
• Multiple Txs for 3 weeks –> Transfer here
• Bone marrow showed Aplastic Anemia
• Rx: ATG/CsA
• One month later, all counts normal
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Elements of the Blood
•Plasma
•Cellular Elements
Red Blood Cells
Platelets
White Blood Cells:
Neutrophils
Lymphocytes
Others
Wintrobe
Tubes
• Aplastic Anemia – Defined as pancytopenia with hypocellular bone marrow
• Incidence in Europe and USA about 2 per million people per year; higher (2-3X) in Asia, Mexico
• Can be Congenital (espec. Children) or Acquired
• Any Age – median 30s; Some studies find Acquired AA most common in 30s and over 60
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Background
Marsh W, et al. Brit J of Haem. 2009;140:43-70.
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PancytopeniaDue to Increased Cell Destruction
Autoimmune (Evans’ Syndrome)
Hypersplenism
Overwhelming Sepsis
Paroxysmal Nocturnal Hemoglobinuria
PancytopeniaDue to Decreased Production
Aplastic Anemia
Acute Leukemia
Myelodysplastic Syndrome
Megaloblastic Anemias
HIV Infection
Hairy Cell Leukemia
Lymphomas, Myeloma
Acute and Chronic Viral Infections
Marrow Infections and Granulomas
Other Tumors
Myelofibrosis
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Hairy Cell LeukemiaDiagnostic procedures in patients with pancytopenia.
Andrea Bacigalupo Blood 2017;129:1428-1436
©2017 by American Society of Hematology
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Response to Therapy
Complete• Hemoglobin >10 g/dL• Neutrophil count >1x109/L• Platelet count >100 x 109/L
Partial
• Improvement in all cell lines• Transfusion independent• No infection• Neutrophil count >0.5 x 109/L
Minimal• Transfusion dependent• Neutrophil count >0.5 x 109/L
NoneFailure to improve or death prior to day 180
Classification of AA
Non-Severe AA
Patients not fulfilling criteria for severe or very severe aplastic anemia
Severe AA
• Bone marrow cellularity <25%• Neutrophil count <0.5 x 109/L• Platelet count < 20 x 109/ L• Reticulocyte count <20 x 109/ L
Very SevereAA
• Bone marrow cellularity <25%• Neutrophil count <0.2 x 109/L• Platelet count < 20 x 109/ L• Reticulocyte count <20 x 109/ L
• In 1970s, 80-90% of patients died of complications of pancytopenia
• Standard treatment:
– HLA identical sibling donor transplantation• 75-90% chance of long term cure
– Immunosuppression with antithymocyteglobulin (ATG) + cyclosporine A (CsA)• 60-80% response rate
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Treatment
Rosenfeld S, et al. JAMA 2003;289:1130-1135.
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Treatment Algorithm
Marsh W, et al. Brit J of Haem. 2009;140:43-70.
Young College Student• 18 yo man, college student, presented 1 yr
ago, few months progressive fatigue
• Hgb 4.5, WBC 1.54, plate 18; BM: AA
• Declines up-front marrow transplantonly sib found HLA-identical
• ATG/CsA/eltrombopag
• Last Tx 10 months ago
• Now, Hgb 14.8, WBC 3.0, plate 140
• Continues eltrombopag and low dose CsA
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A strong age effect in patients with aplastic anemia, after transplantation from an HLA identical sibling.
Andrea Bacigalupo Blood 2017;129:1428-1436
©2017 by American Society of Hematology
The age effect in UD transplants: best outcome is seen for very young patients, for whom first-line UD BMT may be considered.
Andrea Bacigalupo Blood 2017;129:1428-1436
©2017 by American Society of Hematology
8 Yr Remission, Relapse, Retreat
• July 2016 – 3 wks progressive fatigue and bruising
• Hgb 8.3, WBC 0.7 (2% polys), plate 5, retics 0.3%
• Bone marrow severely aplastic (5%0
• Retreated with ATG/CsA
• Counts markedly improved within 3 weeks
• Now: Hgb 10, WBC 4.5, plate stay 50s
• On relatively low dose CsA
• Also receives ESA for renal anemia (creat 1.6)
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Horse vs. Rabbit ATG
Scheinberg P, et al. N Engl J Med 2011;365:430-8.
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Previous Institutional Experiences
Study Location N Duration Results
Ellis R, et al. Military Medicine 2002;167:541-545
Kansas Medical Center
31 adults
22 years • 81% transfusion independence• 63% complete response
Kao S, et al. British Journal of Haematology2008;143:738-743.
Toronto, Canada
20 adults
14 years • 60% achieved complete/partial response• 30% no response• 2-year cumulative response 42%• 2-year incidence of relapse 30%
Quillen K, et al. Haematologica2009;94:1661-1668.
Bathesda, Maryland
32 adults + children
10 years • 34% achieved complete response• 28% achieved partial response• 38% achieved progressive disease
Doney K, et al. Ann Intern Med 1997;126:107-15.
Seattle, Washington
227 adults + children
13 years • 18% complete response• 16% partial response• 10% minimal response• 54% no response
Paquette R, et al. Blood 1995;85:283-290.
Los Angeles, California
155 adults
11 years • 48% total response• 12% complete response• 35% partial response• 29% no response• 16% early death (< 3 months after ATG)
*All studies retrospective
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Results
Patient Demographics, N = 31 (%)
Males 19 (61%)
Equine ATG 25 (81%)
Rabbit ATG 6 (19%)
Previous TreatmentsPrednisone, CsA, MTX, BMT, Epoetin Alfa, Daclizumab
13 (42%)
AA Classification• Non-severe AA• Severe AA• Very severe AA
8 (26%)19 (61%)4 (13%)
Cyclosporine use 26 (84%)
Paroxysmal Nocturnal Hemoglobinuria (PNH) status known
11 (35%)
PNH positive 4 (13%) 26
Results
10.0% 30.0% 50.0% 70.0% 90.0%
Equine (n = 25)
Rabbit (n = 6)
Total (n = 31)
84.0%
83.3%
83.8%
Response Rates
Overall Response Rates
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Results
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
3 months 6 months 9 months 12 months
79%
61%67%
59%
83% 83%
50%
60%
Equine
Rabbit
Average Platelets
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Results
0
20
40
60
80
100
120
Start 3 mos 6 mos 9 mos 12 mos
Pla
tele
ts k
/μ/L
Correlation Between Severity of AA and Response Rate
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Results
0.0% 20.0% 40.0% 60.0% 80.0% 100.0%
Non-severe AA
Severe AA
Very severe AA
62.5%
52.6%
50.0%
87.5%
78.9%
100.0%
Response
at 6
months
Response
at 12
months
n = 4
n = 19
n = 8
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Results
Common Adverse Effects, n (%)
Fever 15 (48.4%)
Chills/rigors 8 (25.8%)
Edema 5 (16.1%)
Hives/rash 4 (12.9%)
Joint/muscle pain 3 (9.7%)
Nausea/vomiting 2 (6.5%)
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67 YO Car Dealer• Jan 2012 – DOE, fatigue
Hx HBP on lisinoprilHgb 6, WBC 1.7, plate 9Tx 4u RBCs, plate, transfer MethodistBM X 2: Aplastic
• Jan 30: Day 1 ATG/CsA
• Mid March: Hgb 9.1, WBC 3.5, plate 39
• June 1: Tremors, ataxia, dysarthria, fallsHgb 13.9; CsA D/Ced
• Oct 10: Hgb 8.1, WBC 2.2, plate 14 31
Eltrombopag in refractory severe AADesmond R, Blood 123:1818, 2014
• 43 patients SAA at NIH, failed at least one course ATG-based Rx
• Response 17 (40%) at 3-4 mos, often bi-or tri-lineage
• Most patients continued to improve counts in extension phase: 7 tri-lineage
• 5 with normal or near normal stopped Rx med. 28 mos and all continue remission (13+ mos)
• 2 responders and 6 NR got new cytogen abnl33
Treatment Options• Immunosuppressive Rx
-- horse or Rabbit ATG
-- cyclosporine A
-- rabbit ALG
-- CAMPATH
-- high dose cyclophosphamide
-- sirolimus; mycophenolate
• Eltrombopag
• Allo-BMT Options: Matched sib, MUD, haplo (cord)
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Aplastic Anemia
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13 Year Remission
• In 2004, 67 yo man presented with fatigue, SOB
• Hgb 6.8, WBC 2.0: 20% neutrophils, plate 18K, Reticulocytes low
• Bone marrow severely hypocellular, normal cytogenetics = Aplastic Anemia
• Admitted for ATG/CsA
• Brief readmission fevers, rash, low platelets
• Continued periodic Txs until 4 months later
• Then, all counts normal. Later d/c CsA
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13 Yr Remission, then Evolution
• Routine check-up Oct. 2017:Hgb 11, WBC 3.0, plate 57K
• Bone Marrow: Low normal cellularity,dyspoietic changes, cytogenetics –7
• Progressive anemia; failed EPO Rx
• April 2018: 1st RBC Tx for Hgb 7.3,WBC 2.4, plate 30K
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A Different Kind of Evolution
• Sept 2007, 12 yo boy presented with severe AA
• No bone marrow match; Rx ATG/CsA
• Counts recovered; continues low dose CsA to this day
• At Dx, no PNH clone; 2009 – small clone
• 2014, age 19, epidsodes red urine; clone bigger
• May 2015 – Hgb 8.4, WBC 3.2, plate 83, LDH 1400; began eculizumab
• Now, Hgb 9.4, Retics 11%, LDH 283, clone 97%
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Variants of Aplastic Anemia
• Amegakaryocytic Thrombocytopenia
• Pure RBC Aplasia
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Pure RBC Aplasia• 75 yo man with hx coronary dz, stents
• Severe anemia; blood Txs x 6 beginning 2015
• Eval: EGD X 2, colonscopy X 2
• 3 bone marrows: Dx Pure RBC Aplasia
• Rx brief steroid, then CsA prompt normalization of Hgb
• CsA stopped for rising creat severe anemia, Txs
• CsA resumed prompt remission now tapered to very low dose with normal Hgb
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Pure red cell aplasia
• Congenital PRCA
• diamond-blackfan, fanconi, dyserythropoietic anemia
• Primary PRCA
• Secondary PRCA (acquired)
• Infection (parvovirus, hepatitis)
• Autoimmune dz (SLE, sjogren’s, RA, CTD)
• LPD (lymphoma, CLL, LGL leukemia), thymoma
• Solid tumor (thyroid CA, RCC)
• Pregnancy
• Medications – EPO, Azathioprine, allopurinol, Dilantin, sulfonylureas, etc)
. Djaldetti et al. / Biomedicine & Pharmacotherapy 57 (2003) 326–332
Pure red cell aplasia - RxBritish Journal of Haematology, 142, 505–514
Steroid CsA Cytoxan
Response rate 30-62% 65-87%7-20%(40-60%)
Time to respond 2-5 weeks 12 weeks 11 weeks
maintenance required required ?
RFS 33 m 103m ?
OS 14 yr 12 yr ?