Bor-Sheng Ko. Hematology Division, Department of Internal Medicine, National Taiwan University Hospital
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1 Bor-Sheng Ko Hematology Division, Department of Internal Medicine, National Taiwan University Hospital On behalf of Members of Aplastic Anemia Consensus Meeting
2 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
3 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
4 Pancytopenia with a hypocellular bone marrow in the absence of abnormal infiltration or increased reticulin. It can be inherited or acquired. Inherited disorders: Fanconi anemia, Dyskeratosis congenita Schwachman Diamond syndrome. In this guideline, only acquired aplastic anemia will be discussed.
5 Complete Blood Count with WBC differential count Reticulocyte count Peripheral blood smear examination Bone marrow aspiration and biopsy Bone marrow cytogenetic study Flow cytometry for GPI-anchored proteins (optional) To find subclones of PNH
6 Biochemistry, including liver function test and renal functions Viral studies : Hepatitis A, B and C, EBV, HIV Markers for autoimmune diseases: ANA and anti-dsdna Chest X-ray
7 Abdominal ultrasound (optional) Cardiac echocardiogram (optional) Workups to exclude inherited marrow failure (optional): Peripheral blood chromosome breakage analysis to exclude Fanconi anemia Peripheral blood gene mutation analysis for dyskeratosis congenita
8 Classification: Severe aplastic anemia (SAA) very severe aplstic anemia (VSAA) non-severe aplastic anemia (NSAA) Definition of SAA: BM cellularity < 25% (or BM cellularity 25-50% with <30% residual hematopoietic cells), AND 2 of the following 3 factors: (1). Absolute neutrophil count < 0.5 x 10 9 /L (500/uL) (2). Platelet count <20 X 10 9 /L (20,000/uL) (3). Reticulocyte count <20 X 10 9 /L (20,000/uL)
9 VSAA : defined as AA with BM and PB pictures fulfilling SAA criteria but absolute neutrophil count < 0.2 x 10 9 /L (200/uL) NSAA: AA with BM and PB pictures not fulfilling the criteria for SAA
10 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
11 IST with ATG+CsA is then recommended for: (Grade B recommendation, Level IIb evidence) (1). SAA patients who are older than 40 years, OR (2) SAA patients who are younger than 40 and have no HLA-matched sibling donors OR (3). NSAA patients who are dependent on transfusion. the regimen of rabbit ATG (Thymoglobulin, mg/Kg/d x 5 days)+csa is still the treatment of choice in Taiwan for IST.
12 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
13 Allo-HSCT from HLA-matched sibling donors is then the first choice of treatment for SAA in patients aged less than 40 years. (Grade B recommendation, Level IIb evidence) Allo-HSCT from HLA-matched sibling donors is also a reasonable choice when immediate life-threatening conditions encountered in elder SAA, or early after IST in all SAA patients, (Grade C recommendation, Level IV evidence).
14 URD-allo-HSCT is recommended in SAA patients who fail IST, and have good performance status and available donor(s). (Grade B recommendation, Level IIb evidence) UCB-HSCT and Haploidentical HSCT can be used for treating SAA, but more investigation is required for determining proper indications. BM stem cells are a better source of stem cells, especially in young patients, but PBSCs are still an acceptable choice. (Grade B recommendation, Level IIa evidence)
15 Cyclophosphamide (50mg/Kg/d x 4 days) with or without ATG is a commonly used conditioning regimen for SAA, and other regimens are also effective and can be used. In patients older than 40 y/o or with significant comorbidity, reduced-intensity regimens is also safe and tolerable in SAA.
16 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
17 Taking the relative low costs and acceptable toxicity into consideration, danazol can be used in SAA patients who are not eligible for HLA-matched sibling or unrelated allo-hsct and fail IST. (Grade B recommendation, Level IV evidence) Danazol is also a reasonable choice of treatment in transfusion-dependent non-saa patients. (Grade B recommendation, Level IV evidence)
18 Newly-diagnosed SAA or VSAA 40 y/o Age 1 > 40 y/o HLA-matched siblings available Not available 1. IST (ATG+CsA) 2. Searching MUD Allo-HSCT with HLAmatched siblings Yes Response at 4 months 2 No Maintain CsA or taper slowly over 12 months or more OR Otherwise Available, good performance, age<65y/o and patient s wiliings HLA-matched siblings or MUD Danazol* 2 nd IST (ATG+CsA) Allo-HSCT with HLAmatched siblings or MUD Yes Response No Yes Response at 4 months No Maintain danazol* Other treatment options: 1. 2 nd IST 2. Allo-HSCT with alternative donors 3. Supportive care 4. Investigational drugs Maintain CsA or taper slowly over 12 months or more Other treatment options: 1. Danazol 2. 3 rd IST 3. Allo-HSCT with alternative donors 4. Supportive care 5. Investigational drugs * Level IV evidence, Grade A recommendation
19 Newly-diagnosed NSAA Inherited marrow failure syndrome excluded No RBC or PLT transfusion dependent Yes Observation Become transfusion dependent OR Physician s judgment OR Danazol* IST (ATG+/-CsA) Yes Response No Yes Response at 4 months No Maintain danazol* Other treatment options: 1. IST (ATG+/- CsA) 2. Allo-HSCT with alternative donors 3. Supportive care 4. Investigational drugs Maintain CsA or taper slowly over 12 months or more Other treatment options: 1. Danazol 2. 2 nd IST 3. Allo-HSCT with alternative donors 4. Supportive care 5. Investigational drugs * Level IV evidence, Grade A recommendation
20 Diagnosis and classification: Treatment review in guideline: IST Allo-HSCT Algorithm Other issues
21 Prophylactic platelet transfusion is recommended when platelet is less than 0.5x10 9 /L (10,000/uL), or less than 2.0x10 9 /L (20,000/uL) in the presence of fever or bleeding diathesis. (Grade C recommendation, Level IV evidence) Empirical use of irradiated blood components may be used to avoid transfusion-related graft-versushost disease. (Grade C recommendation, Level IV evidence)
22 Routine use of recombinant human EPO in aplastic anemia is not recommended because of ineffectiveness. (Grade C recommendation, Level IV evidence) Prophylactic G-CSF is not recommended also; however, a short course of G-CSF may be useful in treating patients with infection. (Grade C recommendation, Level IV evidence)
23 Iron overload can result in significant problems in AA patients with heavy transfusion. Iron chelation is then recommended in aplastic anemia patients when the serum ferritin is more than 1000 ng/ml and further packed RBC transfusion is expected. (Grade C recommendation, Level IV evidence)
24
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