saa 101: an introductory course to severe aplastic...

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SAA 101: An Introductory Course to Severe Aplastic Anemia

David A. Margolis, MDProfessor of Pediatrics/Medical College of Wisconsin

Program Director/Children’s Hospital of Wisconsin BMT Program

Objectives

Review the diagnostic evaluation done for a patient presenting with low blood counts.counts.Review the data regarding treatment options.Answers to common questions.

What is Aplastic Anemia

Acquired Aplastic Anemia is a disease caused by too few hematopoietic progenitor cells leading to too few redprogenitor cells leading to too few red blood cells, white blood cells, and platelets.Acquired Aplastic Anemia needs to be differentiated from an inherited bone marrow failure syndrome.

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HEALTHY BONE MARROW APLASTIC BONE MARROW

CRITERIA for SEVERITY of APLASTIC ANEMIA

SEVERE AA (SAA)PERIPHERAL BLOOD (2 of 3):

PMN < 500/ulPLATELETS < 20,000/ulRETICULOCYTES < 20,000/ul (< 1%)

MARROW: hypocellularVERY SEVERE AA (VSAA): PMN < 200MILD AA: LESS AFFECTED THAN SAA

When Should I think of Aplastic Anemia?

Presenting symptoms are most often the same signs as any bone marrow disorder.Bruising and Petechiae

Diff i l D ITP/ liDifferential Dx: ITP/malignancyFatigue/Pallor

Differential Dx:AIHA/ Infection/malignancyRecurrent Fevers

Acquired Neutropenia/malignancy

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Diagnostic Procedures:CBC with manual differential/retic countBone Marrow Aspirate and Biopsyp p yChromosomes/Flow Cytometry to look for malignancy.


Important Lab Tests once called “Aplastic Anemia”:

CD59 expression to look for evidence of paroxysmal notcurnal hemoglobinuriaDEB testingTelomere Length analysis

The Bone Marrow is Aplastic: Is it Acquired Aplastic Anemia?

Important to discriminate between an inherited bone marrow failure syndrome and acquired aplastic anemia.and acquired aplastic anemia.Proper treatment is based on the correct diagnosis.www.marrowfailure.cancer.gov

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Not all aplasia is SAA: Inherited Bone Marrow Failure Syndromes

“Not just for pediatric presentations”Fanconi AnemiaDyskeratosis CongenitaDyskeratosis CongenitaSchwachman-Diamond Syndrome

Telomeres 101

Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal.Molecular mechanisms have evolved to maintain telomere length and protective function.Mutations in the genes that maintain and protect telomeres cause human disease.Dyskeratosis Congenita is the classic disease of telomere biology.

My patient has acquired SAA: What was the trigger?

Inciting event leads to an immune mediated destruction of blood progenitor cells

Young et al. Blood, 15 October 2006, Vol. 108, No. 8, pp. 2509-2519

Trigger is usually not identifiedCheck for CMV, EBV, HHV-6, Parvovirus, Hepatitis virusesHistory of jaundiceMedication history Exposures

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HSCRBC

The Bone Marrow Garden-Healthy

RBC RBC

HSC

HSC

HSC

WBC

PLATELET

FLOWERSSEEDS

WBC WBC

PLATELETPLATELET

HSCRBC

The Bone Marrow Garden-Under Attack

RBC RBCT cells

T cellsHSC

HSC

HSC

WBC

PLATELET

FLOWERSSEEDS

WBC WBC

PLATELETPLATELET

T cells

T cells

T cells

HSC

The Bone Marrow Garden-Aplastic

T cells

T cellsHSC

HSC

HSC

FLOWERSSEEDS

T cells

T cells

T cells

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The Bone Marrow Garden-Treatment

HSCT cells

T cells

FLOWERSSEEDS

HSC

HSC

HSC

T cells

T cells

T cells

Immune Suppression Medications


HSCT cells

FLOWERSSEEDS

HSC

HSC

HSC



HSCT cells

FLOWERSSEEDS

HSC

HSC

HSC


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The Bone Marrow Garden-Immune Suppression Treatment

HSCT cells

FLOWERSSEEDS


The Bone Marrow Garden-BMT Treatment

HSCT cells

HSC

FLOWERSSEEDS


HSC

HSCHSC

HSC

HSC

HSCHSC

RBC

The Healthy Bone Marrow Garden

RBC RBCHSCBMT

HSC

WBC

PLATELET

FLOWERSSEEDS

WBC WBC

PLATELETPLATELET

HSC

HSC

IST

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Case 1

15 year old male with newly diagnosed SAANo prior transfusions.pOne sibling has run away from the family and is not in contact.Alternatives: Search for the sibling or start an alternative treatmentPolice recommended contacting the media.

Conventional Transplant

HLA matched sibling transplants are an established curative approach to SAA.Outcomes to consider are survivalOutcomes to consider are survival, acute GVHD, chronic GVHD, rejection.Long-term outcomes to consider include survival, chronic GVHD, late cancers, and fertility.

The Seattle Experience-CY/ATGKahl et al. British Journal of Haematology 2005

1988-2004N=81Median age 25 years (2 63y)Median age=25 years (2-63y)Median Duration of SAA=2 months (two weeks-12 years)Cyclophosphamide 200 mg/kg and ATG (equine) 90 mg/kgMTX/CSA GVHD prevention

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Discussion Point-Survival Kahl et al. British Journal of Haematology 2005

78% had performance scores of 100%13% had 90%, 9%<80

87% Survival

Seven (all with cGVHD) had avascular joint necrosis.17 successful pregnancies

(9 females and 7 partners of male patients)

The Seattle Experience-CY/ATGKahl et al. British Journal of Haematology 2005

Rejection

Grade II-IV GVHD

Discussion Point-cGVHDKahl et al. British Journal of Haematology 2005

Risk factors for cGVHD:

Age >38 years Higher total nucleated marrow cell dose.

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Discussion Point-Late CancersKahl et al. British Journal of Haematology 2005

6 patients developed cancer.1 PTLD associated with GVHD.with GVHD.1 colon cancer, 3 skin cancers, one mouth cancer (all alive and cancer free)Higher cancer rate in those with cGVHD.

Adult Data (>40 yo)Published 2010 out of Seattle

BBMT Sangiolo et al.

N=23 patients transplanted from 1988CY200+ATGCY200+ATG65% Survival30% Grade II GVHD; very little grade III/IV25% cGVHDInfections prior to BMT affected survivalRecommend Considering BMT even for older adults

Take Home Message

Matched sibling BMT is the treatment of choice for SAA in children and young adults due to the excellent long termadults due to the excellent long term survival with very few late effects.Even older patients can benefit from matched sibling BMT.

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Case 2

3 year old girl with newly diagnosed SAA3 siblings no HLA match3 siblings, no HLA matchPlan to use Immune Suppression Treatment

Immune Suppression Therapy

Multiple approaches.NHLBI and EBMT set the benchmarks.NHLBI “gold standard” isNHLBI “gold standard” is ATG/CSA/Prednisone.http://patientrecruitment.nhlbi.nih.gov/AplasticAnemia.aspxHopkins (and others) use of cyclophosphamide.

http://patientrecruitment.nhlbi.nih.gov/AplasticAnemia.aspx

Alemtuzumab (Campath)r-ATG/CSA vs. h-ATG vs. CampathEltrombopag if low platelets onlyEltrombopag if low platelets onlyRituximab for Moderate AA

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ALL PATIENTS-60% survival

RESPONSE AT THREE MONTHS

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

Late Events After Immunosuppressive Therapy

RELAPSE-up to 40% CLONAL EVOLUTION:

MDS/MONOSOMY 7

Copyright restrictions may apply.

10-15%

Take Home MessageIntensive Immune Suppression Therapy with ATG/CSA/Prednisone remains the treatment of choice for those without a matched sibling.Response at 3 months is crucial for futureResponse at 3 months is crucial for future decisions.Relapse/Clonal evolution are issues.Data supports very slow tapers of CSAUse of tacrolimus instead of CSA for those with problems with CSA.

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Case 3

13 year old female with SAA2 siblings, no HLA matchI S i T NImmune Suppression Treatment-No ResponseSecond Course of Immune Suppression-Still Transfusion Dependent?Alternative Donor BMT

Alternative Donor Transplant

Historically, the major barriers to survival have b

60

80

100

val %

been rejection and GVHD.

0

20

40

60

0 0.5 1 1.5 2 2.5 3 3.5 4

DEEGNMDP SERIESBBMT 5:243, 1999

Surv

iv

Years

THE DELICATE BALANCETHE DELICATE BALANCE--The Milwaukee ApproachThe Milwaukee Approach

HLA=

HLA=

TBI TDEPLETION

REJECTION GVHD

BC

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Survivorship

• Lance Armstrong Foundation (LAF) defines cancer survivorship as living “with”, “through” and “beyond” cancer , g y(SAA).

THE DELICATE BALANCETHE DELICATE BALANCE--RevisitedRevisited

TBI TDEPLETION

HLA=

HLA=

REJECTION GVHD

BC/DM

What have we learned from historical alternative donor data?

We need an alternative donor transplant regimen that:

Prevents rejectionPrevents GVHDPrevents GVHDPrevents late effects Has excellent long term survival☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺

Deeg et al. and Bacigalupo et al. have published multicenter data with the above goals in mind.

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The “De-escalating TBI” ExperienceDeeg et al. BBMT 2001

1994-1999; 14 centersN=50Median age=14 years (1-46y)Median Duration of SAA=14 months (3 months-264 months)Cyclophosphamide 200 mg/kg and ATG (equine) 90 mg/kg with de-escalation of TBI (3x200cGy; 2x200; 1x200)MTX/CSA GVHD prevention

Survival was 58% at two years.Shorter disease duration and younger age improved survival.

The “De-escalating TBI” ExperienceDeeg et al. BBMT 2001

Unexpectedly high rate of diffuse alveolar damage.Data is the basis for current North American CTN trial:

Cyclophosphamide de-escalation trial.Fludarabine/ATG/TBI 200 and de-escalating cyclophosphamide starting at 150 mg/kg total CY

The EBMT ExperienceBacigalupo et al. BMT 2005

1998-2004, 13 centersN=38Median age=14 years (3-37y)Median age 14 years (3 37y)Median Duration of SAA=20 months (6 weeks-10 years)Fludarabine 30 mg/m2 x 3; CY 10 mg/kg x 4; Thymoglobulin 3.75 mg/kg x 4Low dose MTX/CSA GVHD prevention

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•Overall survival is 73%

•7 cases of graft rejection or graft failure (5 alive)failure (5 alive)

•aGVHD II-III in 11%

•cGVHD in 27%

•Deaths were due to graft failure, EBV-PTLD, hemorrhage.


•Excellent survival without any TBI in the younger cohort.

•EBMT current trial uses a similaruses a similar regimen with 200 cGy TBI to try to promote engraftment for those over the age of 14 years.

Figure 1. Actuarial survival of 52 SAA patients receiving FCA and 48 SAA patients receiving FCA + 2Gy TBI

Copyright ©2010 Ferrata Storti Foundation

Bacigalupo, A. et al. Haematologica 2010;95:976-982

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Figure 3. Actuarial survival of patients grafted within 2 years of diagnosis or later: the difference is highly significant (P=0.0004)



Figure 2. (A) Effect of age in patients receiving FCA (left panel), stratified by the median age of 13 years



BMT Options

10/10 (or 12/12) UNR donor marrow BMTKnown mismatched UNR donor marrow BMT with use of HPC processing.gCord Blood Transplant including Double Cord Blood Transplant.Parent to Child BMT.Talk with with SAA/BMT physician re: pro’s and con’s of each approach.

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THE DELICATE BALANCETHE DELICATE BALANCE--Questions to Ask: 2010 and beyondQuestions to Ask: 2010 and beyond

T Replete Marrow

FludarabineBased

? CY ? TBI? ATG

? Cam-path

? Timing

? PBSC

? Cord

? TCD PBSC

? Haplo

vs.Unr

BC/DM

REJECTION GVHD

Take Home Message

Alternative donor transplant is a feasible option for many patients with SAA.SAA.Exciting area with improving outcomes with less toxic regimens.Timing?!!

Conclusions: BMT for SAA

CY/ATG provides excellent results for patients with an HLA matched sibling.Outcomes with alternative donor transplants are improving with regimens that should lead to fewer late effects.With improving outcomes with less toxic transplant, please consider alternative donor BMT earlier for patients not having a good initial response to ATG.

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SAA: Common Practical Questions?

Can this disease be fatal?YesDeath due to invasive fungal infections orDeath due to invasive fungal infections or bleeding.As the data shows, many people will survive.


Where can I turn to learn more?

Aplastic Anemia &MDS International Foundationwww.aamds.org


When should we give RBC transfusions?When you need to.Hemoglobin around 6 g/dlHemoglobin around 6 g/dl.Irradiated, Filtered, CMV negative.

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When should we chelate?Liver biopsy is “gold standard”MRI may replace liver biopsyMRI may replace liver biopsy.Consider Cardiac MRIFerritin above 1500-2000Oral chelator: Exjade (deferasirox)


When should we give platelet transfusions?

When the patient has symptoms.When the patient has symptoms.5-10KSingle Donor Pheresis ProductIrradiated, Filtered, CMV negative


What is the role for GCSF?No data suggests it leads to a response.Some data suggesting ANC>500 will helpSome data suggesting ANC>500 will help prevent invasive fungal infections.I try to keep ANC >500 with as little GCSF as possible.

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Can my child go to school?I think so.Infection risk at school is primarily virusInfection risk at school is primarily virus based.Viruses can slow down recovery, so I leave it up to parents.

THANK YOU!

ANY QUESTIONS

saa 101: an introductory course to severe aplastic...

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