5/4/2018

1

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

2

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

5

Background

Marsh W, et al. Brit J of Haem. 2009;140:43-70.

5/4/2018

2

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

5/4/2018

3

Hairy Cell LeukemiaDiagnostic procedures in patients with pancytopenia.

Andrea Bacigalupo Blood 2017;129:1428-1436

©2017 by American Society of Hematology

15

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

16

Treatment

Rosenfeld S, et al. JAMA 2003;289:1130-1135.

17

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

18

5/4/2018

4

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)

22

23

Horse vs. Rabbit ATG

Scheinberg P, et al. N Engl J Med 2011;365:430-8.

24

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

5/4/2018

5

25

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

27

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

28

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

29

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

30

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%)

5/4/2018

6

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)

34

Aplastic Anemia

5/4/2018

7

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

38

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

39

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%

40

Variants of Aplastic Anemia

• Amegakaryocytic Thrombocytopenia

• Pure RBC Aplasia

41

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

42

5/4/2018

8

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 ?