Hematopoietic stem cell

transplantation for sickle cell

disease

Hazza Al-zahrani

KFSHRC-Riyadh

SCD major Health Burden in KSA

• endemic in southern and eastern

• prevalence remains higher than that in other countries

- Per 10,000 population

• East prov. 145 cases

• South 24 cases

• Western 12 cases

• central 6 cases Al-Qurashi Saudi Med J 2008

• SCD trait carriers: 2–27% of the population of KSA

Jastaniah Ann Saudi Med 2011

Challenges in Controlling SCD in Saudi Arabia

consanguineous marriages (57.7%->80% )

• How to overcome this issue?

- Awareness programs:

• Education of people regarding the effects of consanguineous marriages

- Premarital Screening Program and the Genetic Counseling Program

• mandatory for all couples

• free at all government facilities

• Results:

• Adult 4.2% carriers

• 0.26% of the population is affected by SCD

• reduced the number of voluntary cancelations of at-risk marriage

proposals by 60%

• increased by 5-fold over 6 years

Memish Six-year outcome of the national

premarital screening and genetic

counseling program for sickle cell disease

and b thalassemia in Saudi Arabia Ann

Saudi Med (2011)

Ann Saudi Med 2011

Disability-Adjusted Life Year (DALY)

One DALY

one lost year of "healthy" life

Sum: measurement of the gap between current health status and an ideal

health situation where the entire population lives to an advanced age, free of

disease and disability.

Feb 2017 Journal of Epidemiology and Global Health M Alosaimi

Feb 2017 Journal of Epidemiology and Global Health M Alosaimi

KFSHRC Experience:

• SCD adults have many comorbidities

- Many are ineligible to full intensity Conditioning

- Repeated transfusion + chr Inflam. Rejection risk

• Intensifying conditioning loose the patient

• Reducing conditioning loose the graft

• Anything in the middle medium size results

Background-Challenges

Hypothesis:

SCD is a chronic inflammatory

Needs Anti-inflammatory

induction before BMT Needs MAC or close to MAC to

prevent relapse

Hypothesis:

SCD is a stem cell disease

Adults with Tx-dependent SCA

may be alloimmunized

Adults with high Risk SCA

cannot tolerate MAC

Pre-BMT Steroids

ATG with conditioning

Reduced Toxicity Condtioning

“RTC)

AIM OF THE STUDY: assess safety & efficacy of

1. Pre-conditioning: Steroids+ HU & HyperTransfusion

2. Reduced Toxicity Conditioning : FLA, iv-Bu + LD-ATG

in young adults with Sickle Cell Anemia (SCA).

Patient population :

• Adolescents and Adults (>14 years)

• Sickle Cell Anemia

Indications for Transplantation 1. Recurrent severe VOC

2. Recurrent ACS

3. Stroke (none-debilitating)

4. AVN

5. Tx-dependence

6. Pulm . HTN (Mod)

Eligibility for Transplantation 1. The presence of matched Sib or EF-

donor

2. Age > 14

3. Performance: (KPS <=2 ; ECOG >70%)

4. NO Chr. active hepatitis due to HBV/HCV

5. NO HIV/AIDS

6. Consent

SCD SCT at KFSHRC

Patients

• Started 2011

• 38 cases of high risk SCD

- 5 cases per year

- Age: 14-35 yrs

- Median age 17 years

- Comorbidities

• Non : 26%

• 1 patient had also smoldering Myeloma

Patients: Indications of HSCT

• Recurrent severe VOC (n:25; 100%)

• Acute chest syndrome (n: 10; 40% )

• stroke or silent brain insult (8; 32% )

including Moya Moya (2; 8%)

• AVN (n; 8; 32%)

• Moderately severe (O2-dependent)

pulmonary HTN in 1 patient

Sex distribution of the 39 donors Sex distribution of the 39 patients

56% females and 44% males

Donor and Recipient Sex

91.2

5.9

2.9

ABO Compatibility

Compatible

Minor

Major

Donors

• HLA-matching was 10/10 in all pairs (100%)

• 8 donors (32%) SCA trait

• Identical siblings (20 BM, 4 PB and 1 BM+PB)

• CD34+ cell dose

- 4.7 x106/kg (2.7-7.81 ) for Marrow

- 7 x106/kg for the peripheral blood

Comorbidities

score 0 score 1 score 2 score 3 score 4

Score 0

Score 1 Score 2

Score 3

Score 4

https://qxmd.com/calculate/calculator_108/hematopoietic-cell-transplantation-specific-comorbidity-index-hct-ci

Comorbidities

https://qxmd.com/calculate/calculator_108/hematopoietic-cell-transplantation-specific-comorbidity-index-hct-ci

• Conditioning

- IVBU14/FLU/ATG

- Gvhd PROPHYLAXIS :

• MTX +CSA

• Stem cell dose average 6.12 X106/Kg

- 3.2-8 X106/Kg

• Jan 2011\till Jan 2018

• 3 required boost and 3 required DLI

SCD SCT at KFSHRC

MAC

CSA CSA

HIT+RTC

TRM

TRT

GVHD !

• Less/No delay

• Less/No crisis

• Less TRT

• No TRM

• Less Rejection &

• Less GVHD

• Well Being !!!!

• Outpatient BMT ?

• Fertility: Better ?

Change of paradigm of Conditioning

H. I. T.

RTC

Total WBC during pre-conditioning

phase

0

2

4

6

8

10

12

14

16

18

1 2 3 4 5 6 7 8 9

To

tal W

BC

(x

10^

9/L

)

-8 week -6week -4week -2week

ALLOGENEIC PROGENITOR STEM CELL TRANSPLANT

PROGRAM

ADULT HEMATOLOGY/ BMT UNIT

DATE 1 Feb

2015

2 Feb

2015

3 Feb

2015

4 Feb

2015

5 Feb

2015

6 Feb

2015

7 Feb

2015

8 Feb

2015

9 Feb

2015

10 Feb

2015

11 Feb

2015

Days Mon Tue Wed Thurs Fri Sat Sun Mon Tue Wed Thurs

BMT/PBSCT DAY -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0

FLUDARA 40mg/m2

x x x x

IV-

BUSULFAN 0.8 mg/kg q6hx

14 doses

4 doses

4 doses

4 doses

2 . Doses

.

ATG Thymoglobulin; Genzyme

1.5 mg/kg

x x x

PHENYTOIN

X X X X X X

“Keppra”

Levetiracetam x

Rest Day

X

HSCT

X

SICKLE CELL-BMT IV-BUSULFAN/FLUDARABINE and ATG o HEIGHT: _________cm WEIGHT: _________kg BSA: _________

o ALLERGIES: _________

o NOTE: This regimen is for the exclusive use for Sickle Cell Conditioning.

ALLOGENEIC PROGENITOR STEM CELL TRANSPLANT PROGRAM ADULT HEMATOLOGY/ BMT UNIT- KFSHRC, Riyadh, SA

160 mg/m2

11.2 mg/kg

4.5 mg/kg

.

Engreftment

• Granulocytes

- Median day 19

• Platelets

- Median day 20

Figure 1A. Kinetics of Neutrophil drop and engraftment after RTC-conditioning for Allo-sib

HSCT in adults with severe SCA .

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

d0 d2 d+4 d+6 d+8 d+10d+12d+14d+16d+18d+20d+22d+24d+26d+28

Ne

utr

op

hil c

ou

nt/

ul

Figure 1B. Kinetics of platelet drop and engraftment after RTC conditioning for

Allo-sib HSCT adults with severe SCA (n=21)

0

50

100

150

200

250

300

350

400

450

500

d0 d2 d+4 d+6 d+8 d+10 d+12 d+14 d+16 d+18 d+20 d22 d+24 d+26 d+28 d+30

Pla

tele

t c

ou

nt

(x1000/u

l)

Complications of SCT in SCD

KFSHRC experience

• Fungal infections

- 11%

• Varicella zoster Infection:

- 14.7%

• CMV pcr detection:

- 70% pre-emptively treated

- 0% CMV disease

Peri-transplant complications

• Mucositis

- grade I in 6 (24)%

- grade II in 2 (8) %

- Grade III in 2( 8)%)

• one (4%) patient bled due to gastritis and possible pulmonary invasive fungal disease in one (4)

• New minor stroke with monoparesis in a patient with Moya Moya disease that recovered in a few days

• One patient developed severe hypertension

• PRESS in 2 patients, fits in 3 patients

- one other patient developed PRES-like syndrome at Hb S of 32% treated and recovered after exchange transfusion.

• TMA in 1 patient treated with Fresh frozen plasma infusion, fits with change level of consciousness in one treated with Exchange transfusion and resolved within a few hours,

Mohamed S.Y, 2017

Complications of SCT in SCD

KFSHRC experience

• Mucositis:

- 70%

• Hemorrhagic cystitis :

- 1 patient 2.9%

• Veno-occlusive Disease of the liver

1 patient 2.9%

SCD SCT KFSHRC

Acute GVHD

70% are grade I-II

SCD SCT KFSHRC

Chronic GVHD

Graft Stability

Boost 3

DLI 3

Boost+DLI Boost+DLI

Fig 2. Kinetics of Myeloid (M) and lymphoid (L) Chimerism after RTC conditioning for Allo-Sib HSCT in adults with severe SCA

N:1

8

0

20

40

60

80

100

120

1 Mo 2Mo 3Mo 4mo 6Mo 1Y 15 mo 18mo 21 mo 24mo 30 mo

0

20

40

60

80

100

120 Cyclosporine

1980s-2007 SCA transplant

experience

Study US

collaborati

ve

French Belgian CIBMTR

n 59 87 50 67

Median age

(y) 9.9 9.5 7.5 10

EFS 85 85 86 82

GVHD 12 12.6 20 22

Horan JT et al., 2005

Bernaudin F et al., 2007

Krishnamurti m et al.,2007

Angelucci E et al.,2009

Pre- HU & pre BMT fertility preservation

HU naïve (pre –HU) On HU & pre BMT

Semen analysis (SA)

optimal Suboptimal Suboptimal optimal

Exchange

Hold HU

Qmo SA

Up to 6moif if

improving

Collect

Resume HU

Transfuse

or

Exchange

qMo SA

Up to 3 mo

Collect

Start HU

1Death

• 16-year-old male SCD

• History of TB lymphadenitis and he completed ant tuberculous therapy June 2016

• post neurosurgery for Moya-Moya

• Dec 2016 AlloSCT well for 4 months

• Secondary graft failure, S/P Stem cell boost on March 30th & 31st

• septic shock ARDS

• Medivac transfer

- Severe sepsis, septic shock

- Acute respiratory failure, ARDS

- Bilateral pneumothoraces

- CNS hemorrhage

- HLH

- Chronic hypernatremia

Af. Fi. 16 year old girl SCD

Acute chest syndrome mechanical ventilator subglottic stenosis

Laparoscopic cholecystectomy

Tonsillectomy

History of recurrent chest infection, community-acquired pneumonia

hydroxyurea 6 tables

History of pancytopenia secondary to hydroxyurea overdose

Frequent admission

History of AVN of Rt shoulder

11 January 2011 for allogenic sibling SCT

The donor: 3-year-old sister ABO incomp. (AO)

pre-implantation genetic diagnosis for selection

Conclusion

HSCT remains the only curative therapy for SCD

HLA-identical sibling transplantation in patients with SCD

offers excellent overall and disease free survival

Risk of GVHD, infections, infertility, and other long-term

transplant complications, limits widespread use of SCT but our

results are relatively low toxicity allowing SCT in patients with

significant morbidity

Post SCT cyclophosphamide is being explored at our

center

graft failure rate was low and manageable with boost and DLI

long-term follow up is needed