Aplastic Anemia Treatment Guidelines

Aplastic anemia is defined as pancytopenia and hypocellular marrow in the absence of an abnormal infiltration and no increase of reticulin fibrosis.
Clinical presentation:Anemia, Hemorrhage, infection

Investigations:
Complete Blood Count with differential
Reticulocyte count
Peripheral blood smear examination
Bone marrow aspiration and biopsy
Bone marrow cytogenetic study
Flow cytometry for GPI-anchored proteins
Vitamin B12 and folate level
Liver function test
Viral studies : Hepatitis A, B and C, EBV, HIV
Antinuclear antibody and anti dsDNA
Chest X-ray
Abdominal ultrasound (optional)
Cardiac echocardiogram (optional)
Peripheral blood chromosome breakage analysis to exclude Fanconi anemia or peripheral blood gene mutation analysis for dyskeratosis congenita if clinical features.

Definition of Severity
Severe AA (Camitta et al, 1975)
Bone Marrow cellularity < 25%, or 25-50% with <30% residual hematopoietic cells.
AND
2 out of the following 3 factors:
Absolute neutrophil count < 0.5 X 109 /L
Platelet count <20 X 109 /L
Reticulocyte count <20 X 109 /L

Very severe AA (Bacigalupo et al, 1988)
As for severe AA but neutrophils < 0.2 X 109 /L

Non-severe AA
Patients not fulfilling the criteria for severe or very severe AA.

Treatment Guidelines: Newly Diagnosed Severe AA

Severe AA (please see definition above)
MRD: Matched Related Donor
1MMRD: 1-Antigen MisMatched Related Donor
ATG: Anti-Thymocyte Globulin
CSA: Cyclosporine
HLA: Human Leukocyte Antigen
MUD: Matched Unrelated Donor

Treatment Guidelines: Newly Diagnosed Non-Severe AA

ATG: Anti-Thymocyte Globulin
CSA: Cyclosporine
CBC: complete blood count with differential
AA: Aplastic Anemia
BMT: Bone Marrow Transplant
BM: Bone Marrow
RBC: Red Blood Cell

Immunosuppressive Therapy

Anti-Thymocyte Globulin (ATG) and cyclosporine (CSA): The combination of ATG and ciclosporin is associated with response rate 60-80% with current 5 years survival rate of 75-85%.

Indication
1. Patients with non-severe AA who are transfusion dependent on RBC and platelet or have significant neutropenia.
2. Patients with severe AA who are older than 50 years.
3. Patients with severe AA who are younger than 50 years who lack an HLA-identical sibling donor (MRD or 1MMRD

Source of ATG
Based on availability: Rabbit ATG vs. Horse ATG

In a randomized study of 120 patients, a large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%) as compared with rabbit ATG (37%) p<0.001). Overall survival at 3 years also differed, with a survival rate of 96% in the horse-ATG group as compared with 76% in the rabbit-ATG group (P=0.04). (Scheinberg et al, N Engl J Med 2011; 365:430-438).

Currently, ongoing randomized study led by Dr Kojima is investigating the dose of rabbit ATG as a factor in teh response to therapy in Aplastic Anemia. Please email him directly to get more information: kojimas@med.nagoya-u.ac.jp

In most countries in APAC region, rabbit ATG has been used as the immunosuppressive agent of choice and has been associated with favorable outcomes.

Allogeneic Stem Cell Transplant

HLA-identical sibling donor transplantation
Allogeneic stem cell transplantation from HLA-identical donor is potentially curative and is the treatment of choice in children and young adult newly diagnosed SAA.
More recent cohorts outcome of SAA patients after HLA-identical sibling transplantation in the ranges of 20 to 30 years, 30-40 years, and 40-50 years tend to be similar, thus the cutoff is undergoing a shift toward patients older than 50 years.
Data of 517 children (0-19 years) with SAA who undergone BMT from The Japanese Society for Hematopoietic Cell Transplantation showed that patient survival outcome of 1MMRD transplantation was comparable to MRD. (Kojima et al., 2012)

Indication for HLA-identical sibling stem cell transplantation
1. have severe or very severe AA
2. are younger than 50 years
3. have an HLA compatible sibling donor (MRD or 1MMRD)

Source of stem cells

There was significant worse survival and more chronic GVHD in patients using PBSC from HLA-identical sibling compared with BM stem cells, so it is recommended that bone marrow stem cells should be used. (Schrezenmeire et al, 2007)

Umbilical cord blood stem cells are associated with a lower risk of acute and chronic GVHD compared to bone marrow stem cells (Gluckman et al, 1977; Baker et al, 2001), however it has been use in a small number of patients with aplastic anemia because of low number of hematopoietic cells that can be obtained from a donation and associated with high rate of graft failure.

Haploidentical stem cell transplantation could be selected as a donor candidate for patients who need urgent transplantation but it is associated with lower overall survival compared with matched sibling donor bone marrow stem cells. (Kojima; Chen et al, 2012 and Yagasaki Blood 2011)

Conditioning regimens

The current standard regimen used is high dose cyclophosphamide 50 mg/kg x 4 days and ATG 1.5 vials/10 kg x 3 days with methylprednisolone 2 mg/kg x 3 days.

Patients who have received less than 20 units of platelet transfusionmay not need ATG as part of the conditioning regimen for allogeneic stem cell transplant (Blood. 2007;109:4582-4585 and personal communication Dr Issaragrisil; surapolsi@gmail.com).

Patients who are older than 40 years may receive a reduced intensity conditioning regimen, using cyclophosphamide 1200 mg/m2, fludarabine 120 mg/m2 and rabbit ATG 3mg/kg daily x 3 days or equine ATG at 30mg/kg daily x 3 days.

The recommended post-transplant immunosuppression is cyclosporine 5 mg/kg per day, in two divided doses, start on day-1 for 12 months with slow tapering beginning at 9 months plus short course methotrexate 15 mg/m2 on day-1, then 10 mg/m2 on day+3, +6, and +11. (Schrezenmeire et al, 2000) The addition of ATG with cyclophosphamide did not improve outcome (Champlin et al, 2007)

Supportive Care

Give prophylactic platelet transfusion when platelet count < 10 X 10e9 /L ( or <20X 10e9 /L in the presence of fever or pregnancy). (Kelsy et al, 2003)

Give irradiated blood products to patients having ATG treatment and who are transplant candidates. (Schrenmeier et al, 2000)

Recombinant Erythropoeitin is ineffective in AA.
G-CSF may be considered for severe systemic infection.

Prophylactic antibiotic and antifungal drugs should be given to patients with absolute neutrophil count <0.2 X 10e9 /L.

Treatment Guidelines

APHCON is dedicated to the development of evidence-based practice guidelines and the unification of a continuing medical education program for the APAC region.

Evidence based practice guidelines will be reviewed for APAC region as a whole as well as individual sub-regions
The disease panel will include KOLs from the region as well as lead investigator(s) from USA and EUROPE
Guidelines will be published online on the APHCON website and will be revised on an annual basis
Special session will be conducted at annual meetings for discussion of the published guidelines

APLASTIC ANEMIA GUIDELINES

APHCON met in Bangkok, Thailand on August 31, 2012 during the AUBH2012 to initiate the process of establishing APHCON Aplastic Anemia Practice Guidelines to be updated from time to time.