Aplastic anemia ppt

1.  DEFINITION
 ETIOPATHOGENESIS
 CLINICAL FEATURES
 INVESTIGATIONS
 DIAGNOSIS
 PROGNOSIS
 SPECTRUM OF AA
 AA VS HYPOCELLULAR MDS
 AA VS PNH
 TREATMENT
 REFRACTORY AA
 ARTICLES
 REFERENCES

3.  CBP:
-Pancytopenia
- low/absent reticulocytes
-normocytic or macrocytic RBC
-MCV raised
- Presence of
- immature myeloid forms : MDS or Leukemia
- nucleated RBC(leucoerythroblasts) : Marrow fibrosis or tumor invasion
- abnormal platelet : MDS or peripheral destruction

4.  BONE MARROW:
-Procedural clue- readily aspirated
- grossly pale
- dry tap points to fibrosis
- generally, HSCs occupy <25% marrow space, rest fat
- residual HSCc should have normal morphology
- presence of granuloma indicate infective pathology.
VALENTINA SANGIORGIO MD-PATHOLOGY OUTLINES

5.  In one study, MRI of marrow of spine/pelvis/femur done on 20 patients was able to
distinguish patients with hypoplastic MDS from those with AA relics primarily on the
finding of multinodular or inhomogeneous foci superimposed on either a normal or a
fatty background.
 DD-hemosiderosis, AA on treatment with regenerating HSCs.
 EVIDENCE OF CLONAL DISEASE BY MRI IN PATIENTS WITH HYPOPLASTIC MARROW DISORDERS 1991 by The American Society of Hematology. William
Negendank, David Weissman,

6. B.Illustrates the inhomogeneously cellular pattern of MDS.
D.STIR image of the patient confirms a mixture of fatty and cellular regions.

9.  Major prognostic determinant: blood count
 With the advent of multiple treatment options, survival rates have fairly
improved.
 Early response to therapy correlates directly with long term survival.
 Recovery translates to independence from transfusion and leucocyte count
suffiecient to ward off infections. (>200/microl)
 Severe disease is characterized by either 2 out of 3
- Absolute neutrophil count <500/microL
- Platelet <20000/microL
- absolute reticulocyte count <60000/microL
 In patients on immunosuppression, absolute retic >25000/microL and lymphocytes
>1000/microL better predictors.

10. • Some patients with hypoplastic marrow disorders, including AA, are at risk for clonal evolution to MDS and leukemia.
• REVIEW ARTICLE ON APLSTIC ANEMIA 2018 BY NEAL YOUNG-NEJM.ORG

11. REVIEW ARTICLE ON APLSTIC ANEMIA 2018 BY NEAL YOUNG-NEJM.ORG

12. Aplastic anemia Hypoplastic MDS
Dysplasia Less common More common
Blasts Absent Variable
CD34 Absent Normal
BM hypocellular RBC in hotspots,
immature myeloid
precursors, dysplastic
megakaryocytes
PNH clone Frequent Less common

13.  “Escape clones”
- HSCs lacking HLA gene –loss of chromosome 6p- escape damage by immune mech
- prevalent in 10-15%
- hypothesized to explain clonal expansion of “PNH cells” in aplastic anemia-lacking GPI
 Either can progress to the other.
 In classic hemolytic PNH, the PNH clone is large, above 50%. (indication for
anticomplement therapy with eculizumab)
 CAN BE DIFFERENTIATED BASED ON FLOW CYTOMETRY- CD 55 AND CD 59
NEGATIVE

14.  1. CURATIVE
- HEMATOPOIETIC STEM CELL TRANSPLANTATION
- IMMUNOSUPPRESIVE THERAPY
- ANTITHYMOCYTE GLOBULIN
- CYCLOSPORINE
- ELTROMBOPAG
 2. SUPPORTIVE
*Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia
The CMC Experience- By Dr. Biju George. 1985-2013. IST >65%RR, HSC>90%

15.  Best suited for younger age group.
 In adults, increased chance of graft vs host diseases.
 HLA matching pre-requisite.
 Matched related donor > matched unrelated donor. Survival same, GVHD twice as
high.
 Haploidentical donor also considered now.
 Cyclophosphamide therapy for suppression of GVHD used.
 long-term survival rate of > 80-90% among young children , 50% for> 40 years of
age.
 Blood transfusion from family members avoided to prevent sensitization
histocompatibility antigens.

16.  1. ANTITHYMOCYTE GLOBULIN
- 40mg/kg over 4 hours for 4 consecutive days
- Pretreatment with Glucocorticoids at 2mg/kg/ day to prevent serum sickness.
- Infusion related reactions
- via central line
 2. CYCLOSPORINE
-6mg/kg/day on 1st day in 2 divided doses. With target blood levels astrough
level between 200 and 400 ng/mL
-Either to continue same for 6 months and then taper or taper after 1 year.
- renal parameters and regular BP monitoring

17.  3. ELTROMBOPAG
- non peptide thrombopoietin receptor agonist
- trilineage response suggests action on hematopoietic stem cells
- 150mg /day as an oral tablet on empty stomach
- interacts with dairy products and other tetravalent ions.
- added as first line with ATG
- markedly increases overall and complete response rates.
*Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia Matthew
J. Olnes, M.D., Ph.D., Phillip Scheinberg (July 2012)
-25 patients, 12 Weeks, 50mg-150mg/day, 44% response
* Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia( 2017)
-overall response rates at 6 months were 80%-90%, Complete response was defined as an
absolute neutrophil count of at least 1000 per cubic millimeter, a hemoglobin level of at least
10 g per deciliter, and a platelet count of at least 100,000 per cubic millimeter.

18.  ANDROGENS
- Direct effect on upregulating telomerase activity.
- Trial of 3-4 months can be done on patients with moderate AA with
suspected telomere defect.

19.  INFECTIONS
- BROAD SPECTRUM ANTIBIOTICS TO BE STARTED EMPIRICALLY
- G-CSF –IN REFRACTORY CASES BUT INCREASED RISK OF CLONAL EVOLUTION
-Pneumocystis carinii prophylaxis given. Risk of maortality ranges between 15% and 45%
Pentamidine>trimethoprim+sulfomethoxazole as it is myelosuppressive
- ANTI FUNGAL AGENTS – NOT ROUTINELY ADDED, ASSESS AND DECIDE
 PROPHYLACTIC PLATELET TRANSFUSIONS
-TARGET : >10000/microL
- SDP preferred. Irradiated preferred.
-Menstruation can be suppressed by oral estrogens or nasal FSH/LH antagonists.
- Avoid Aspirin, NSAIDS

20.  RBC transfusions
-done if patient symptomatic. Generally done at 7g/dl 0r 9g.dl if underlying
cardiac disease
- Leucoreduced irradiated transfusions preferred to reduce risk of CMV
infections
and GVHD.
- Iron chelators (deferasirox) are added in chronic anemia patient.(>50
transfusions)

21. Recent advances in treatment of aplastic anemia (November 2014) The Korean Journal of Internal Medicine

22.  For patients who have not responded to IST after 6 onths of therapy, HSC-
matched related donor can be considered upto 65 yrs of age, balancing risk vs
benefit.
 Patients not previously treated with ATG can be given combined therapy.
 Patients previously treated with equine ATG, repeat dose should be avoided i/v/o
high chance of serum sickness.
 Patients previously not treated with eltromobag can be treated with the same.
 Newer drugs:
1. Romiplostim- parenteral thrombopoeitin receptor agonist.(55%response)
2. Alemtuzumab-monoclonal antibody against anti-CD52 (33%response)
3. High dose cyclophosphamide- 50mg/day for 4 days- severe toxicity
(40%response)

23.  A promising immunosuppressive strategy of cyclosporine
alternately combined with levamisole is highly effective for
moderate aplastic anemia. Xingxin Li 1, Yingqi Shao, Meili Ge, Jun Shi
- 118 patients with mAA-42 newly diagnosed and 76 chronic
- CSA 3 mg/kg per day
- LMS 150 mg per day
- response rates were of 100 and 86.8 % for newly diagnosed and chronic group,
respectively.
- 2 yr follow up-11 patients relapsed and no patients evolved to clonal disorders.

24.  Romiplostim in patients with refractory aplastic anaemia previously treated with
immunosuppressive therapy: a dose-finding and long-term treatment phase 2
trial (Aug 2019)
-April 14 and Nov 24, 2014
- 35 pt
-over 53 weeks
- at four dose cohorts: romiplostim 1 μg/kg (n=7), 3 μg/kg (n=9), 6
μg/kg (n=9), and 10 μg/kg (n=10). ’
-55% had platelet response during weeks 46-53

25.  HARRISON’S MANUAL OF MEDICINE 20TH E
 NEJM ARTICLE ON APLASTIC ANEMIA BY NEAL YOUNG
 EVIDENCE OF CLONAL DISEASE BY MRI IN PATIENTS WITH HYPOPLASTIC
MARROW DISORDERS ,William Negendank, David Weissman,
 Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia
The CMC Experience- By Dr. Biju George
 Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia Matthew J. Olnes,
M.D., Ph.D., Phillip Scheinberg, M.D., Katherine R. Calvo, M.D.,Ronan Desmond, M.D., Yong
Tang, M.D., Ph.D., Bogdan Dumitriu, M.D.,
 How I treat Aplastic anemia by Neal young, Phillip Scheinberg (AUG 2012)
 Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia( 2017)
Danielle M. Townsley, M.D., Phillip Scheinberg,
 Hematopoietic Growth Factors in the Treatment of Acquired Bone Marrow Failure
States Judith C.W. Marsh,a Arnold Ganser,b and Michael Stadler
 Pneumocystis jirovecii pneumonia: still a concern in patients with haematological
malignancies and stem cell transplant recipients (2016) Journal of Antimicrobial
Chemotherapy