STEM CELL TRANSPLANTATION IN SICKLE CELL DISEASE IN NIGERIA? PROPOSED

SELECTION CRITERIA

Dr. T.T. Wakama

Presentation to the 36th Annual Scientific and General

Meeting of the NSHBT

21st August 2008

Collaboration

Round Table Discussion

• What Next?Overwhelming need for BMT in SCA in

Nigeria? Entry point for BMT in Nigeria through

collaboration with the Italian teamIndividual hospitals can go ahead with

their initiativesConstitution of two committees

1. Committee on Bone Marrow Transplantation constituting of

i. Microbiogist

ii. National Blood Transfusion Service

iii. Histopathologist

iv. Chemical Pathologist

v. Haematologist

vi. Health planner

vii. Finance

viii. Paediatrician

ix. Rep: NABDA

C’ttee Contd

2. Committee on review of Patient selection criteria

• 5 – man committee

1.Dr. TT Wakama (Haematologist NHA)

2.Dr. Seyi Oniyangi (Paediatrician NHA)

3.Dr. PO Ladipo (Obstetrician NHA)

4.Dr. Sunday Ocheni (Haematologist UNTH)

5.Dr. C. Nwauche (Haematologist UPTH)

Mandate!

Review Selection Criteria for BMT in patients with SCA in Nigeria

Present report to NSHBT at Ife 2008 meeting

INTRODUCTION

• Successful allogeneic haematopoietic stem cell transplantation (SCT) is currently the only cure for sickle cell disease

• The results of transplantation are best when performed in children with a sibling donor who is HLA-identical

Parkman R. The application of bone marrow transplantation to the treatment of genetic diseases. Science 1986; 232: 1373-1378

Lane PA, Buchanan GR, Hutter JJ, Austin RF, Britton HA, Rogers ZR et al. Sickle cell disease in children and adolescents : Diagnosis, Guidelines for comprehensive care, and care paths and protocols for management of acute and chronic complications. November 2001

INTRODUCTION

• The goal of SCT in SCD is to eliminate the sickle erythrocyte and its cellular progenitors and replace them with donor haematopoietic pluripotent stem cells that produce erythrocytes expressing at best no sickle haemoglobin or at worse quantities similar to the trait condition.

INTRODUCTION

• The risk of severe adverse events from SCT should be weighed against the possibility of preventing serious complications from sickle cell disease

• Published experience in children less than 16 years of age shows that:

≈ 80% with Hb SS who undergo SCT from an HLA-identical sibling donor will have sustained engraftment and elimination of all sickle-related symptoms.

Ten to 15% of patients will reject the stem cell graft, ≈ 5% will succumb from complications of the procedure

including graft versus host disease

INTRODUCTION

• Wide scale implementation of SCT for SCD has been limited by the inability to predict the clinical severity of SCD for a given child and often by the lack of an HLA-identical sibling without SCD

INTRODUCTION

• The first published reports of SCT for SCD involved patients who had other more deadly hematological or genetic disorders that were the primary indication for SCT

Johnson FL et al. N Engl J Med 1984; 311:780-3, Milpied NHJ et al. Lancet 1988;ii:328-9

• This initial experience showed elimination of SCD with engraftment of donor hematopoietic stem cells.

• In the following decade or more, considerable discussion centered on who should be considered and when they should be referred for transplantation

Nagel RL. Seminars in Hematology 1991;28:233-4, Davies SC. Archives of Disease in Childhood 1993;69:176-7,

Platt OS et al.N Engl J Med 1996;335:426-8

INTRODUCTION

• The first limited series of patients who underwent transplantation as specific therapy for sickle cell disease comprised a group of families from Africa living at the time in Belgium

Vermylen C et al. Lancet 1988; 1:1427-8.

• Based in part on the very good outcome experienced by these initial patients, several multicenter phase II studies for children with symptomatic sickle cell disease were conducted in North America and Europe.

Walters MC et al. N Engl J Med 1996; 335:369-76,

Vermylen C et al. BMT1998; 22:1-6.

INTRODUCTION

• Children were felt to be better candidates for SCT than adult pts bc of their lower risk of transplant-related complications such as graft-versus-host disease (GVHD), and bc of a presumed lower burden of sickle-related organ damage.

Summary of Results of SCT from HLA-identical sibling donors

After a period of follow up extending up to11 years:• > 90% of pts survive• ≈ 85% survive free from sickle cell disease• Sickle cell disease recurred in ≈ 10% of patients • Neurologic complications such as seizures

occurred frequently after transplantation, requiring development of preventative measures

Abboud MR et al. BMT1996; 17:405-7

Summary of Results of SCT from HLA-identical sibling donors

• Among pts who had stable engraftment of donor cells, no subsequent sickle cell-related clinical events occurred and their pre-existing sickle cell-related organ damage stabilized Vermylen C et al. BMT 1998; 22:1-6, Walters MC et al. Blood

2000; 95:1918-24, Hernigou P et al. Journal of Bone & Joint Surgery - American Volume 1997; 79:1726-30

• Splenic function also recovered Ferster A et al. Blood 1993; 81:1102-5

Summary of Results of SCT from HLA-identical sibling donors

• Some patients developed mixed donor-host hematopoietic chimerism after transplantation that was stable

Sullivan K et al. BMT 1997; 19, Suppl 2:102-105

Interestingly, these patients had no symptoms from sickle cell disease.

• Primary and secondary amenorrhea were common among females after transplantation

• Most patients likely will be infertile.

Vermylen C et al. BMT 1998; 22:1-6, Walters MC et al. Blood 2000; 95:1918-24

Summary of Results of SCT from HLA-identical sibling donors

• The risk of secondary cancers after SCT remains uncertain but it is estimated to be less than 5 percent. Curtis RE et al. N Engl J of Med 1997; 336:897-904.

• Linear growth was normal or accelerated after transplantation in most patients

Vermylen C et al. Bone Marrow Transplantation 1998; 22:1-6, Walters MC et al. Blood 2000; 95:1918-24

Transplantation from alternative sources of stem cells

• Umbilical Cord Blood (UCB) and hematopoietic cells from volunteer donors are alternative sources of hematopoietic stem cells that could increase the number of donors for sickle cell disease patients

• UCB transplantation for sickle cell disease has been successful. No published report exists of transplantation from volunteer unrelated donors.

Brichard B et al. Journal of Pediatrics 1996; 128:241-3

• UCB possibly produces less GVHD than does standard SCT Rocha V et al. BMT 1998; 21 Suppl 3:S59-62

• A disadvantage of UCB transplantation is slower hematopoietic engraftment and perhaps a higher rate of graft rejection

Gluckman E et al. N Engl J of Med 1997; 337:373-81 • The relatively low number of hematopoietic stem cells

recovered from UCB effectively limits the procedure to children

• Strategies for transplantation from unrelated volunteer stem cell donors must surmount the histocompatibility barriers associated with higher rates of GVHD and graft rejection to become viable options

HCT for adults with sickle cell disease

• Very little information exists concerning the outcome after SCT among adults

• The risk of death with the procedure may be higher, due in part to the higher frequency of GVHD. Sullivan KM et al. Seminars in Hematology 1991; 28:250-

9

• Non-myeloablative preparation before SCT could clinically correct sickle cell disease with lower risk of severe complications.

Storb R et al. Annals of the New York Academy of Sciences 1999; 872:372-5

• The aim of non-myeloablative preparation before SCT is to establish stable donor-host hematopoietic chimerism after transplantation, which might provide a significant clinical benefit to patients.

• If successful, this approach might improve the safety profile of SCT for older people with advanced organ damage from sickle cell disease

INCLUSION/EXCLUSION CRITERIA IN SELECTING SCD PTS FOR SCT

• Wide scale implementation of SCT for SCD has been limited by the inability to predict the clinical severity of SCD for a given child and often by the lack of an HLA-identical sibling without SCD.

• Most current studies in SCT in SCD base their Inclusion/Exclusion Criteria on the publication by Walters MC et al in 1996.

Walters MC, Patience M, Leisenring W, et al. Bone Marrow Transplantation for sickle cell disease N Engl J Med 1996 ; 335: 369-376

INCLUSION CRITERIAWalters MC et al. N Engl J Med 1996 ; 335: 369-376

Sickle cell disease (sickle cell anaemia, sickle cell-hemoglobin C disease or sickle cell-ß-thalassaemia)

Age less than 16 yearsHLA-identical related donor

One or more of the following:

1. Stroke or central nervous system event lasting longer than 24 hours2. Acute hest syndrome with recurrent hospitalizations

or previous exchange transfusions3. Recurrent vaso-occlussive pain (≥ 2 episodes per year for several years)

or recurrent priapism4. Impaired neuropsychological function and abnormal cerebral MRI scan

5. Stage I or II sickle lung disease6. Sickle nephropathy (moderate or severe proteinuria or

a glomerular filtration rate 30-50% of the predicted normal value)7. Bilateral proliferative retinopathy and major visual impairment in at least one eye

8. Osteonecrosis of multiple joints9. Red cell alloimmunization (≥ 2 antibodies) during long term transfusion therapy

EXCLUSION CRITERIAWalters MC et al. N Engl J Med 1996 ; 335: 369-376

Age > 15 yearsLack of availability of HLA-identical donor

One or more of the following:

1. Karnofsky or Lansky functional performance score < 70

2. Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy

3. Severe renal impairment (glomerular filtration rate, <30% of the predicted normal value)

4. Severe residual functional neurologic impairment (other than hemiplegia alone)

5. Stage III or IV sickle lung disease

6. Demonstrated lack of compliance with medical care

7. Seropositivity for the human immunodeficiency virus

Outcome of pts in the study by Walters MC et al. (N Engl J Med 1996 ; 335: 369-

376)After a median of 23.9 months (range 10.1-

51.0):

• 20 pts were alive, 16 of whom had stable engraftment with donor haematopoietic cells. 22 children were studied

• Kaplan-Meier estimates of survival & event-free survival at 4 years were 91% & 73% respectively

Outcome of pts in the study by Walters MC et al. (N Engl J Med 1996 ; 335: 369-376)

• Cumulative incidence of graft rejection was 18%

• 1 pt died 3 months after SCT from intracerebral haemorrhage

• 1 pt died one year after SCT from chronic GVHD & obliterative bronchiolitis

Effects of SCT on End-Organ Function Walters MC et al. N Engl J Med 1996 ; 335: 369-376

• All 8 survivors with a history of stroke & stable donor cell engraftment had no progression of cerebral disease

• 2 pts with”silent” cerebral infarction before SCT had no changes on cerebral MRI

• Pulmonary functions evaluated in 4 of 5 pts with recurrent episodes of acute chest syndrome b4 SCT had stable pulmonary function

• No patient with engraftment had vaso-occlusive crisis after SCT

The Italian Team experience in SCT in SCD

13 patients with SCA transplanted since 1988

92 % survival85% Cured (1 death, 1 rejection)Use protocol 26 adopted for Thalassaemia

(No difference between the two haemoglobinopathies as

far as BMT is concerned)

Impact of Hydroxyurea Treatment for SCD before SCT

• Brachet C et al. studied the impact of Hydroxyurea treatment for sickle cell disease b4 SCT Brachet C et al. BMT 2004;33:799-803

• 24 pts were transplanted for severe SCD• 13 were grafted after previous treatment with

Hydroxyurea• 20 of the 24 children had stable engraftment and

remained free of SCD related symptoms after SCT

• 19 currently alive and cured of SCD

Impact of Hydroxyurea Treatment for SCD before SCT

• Their study was grouped into 3• Compared to the other two grps that had no

previous exposure to Hydroxyurea,there were no cases of absent engraftment, mixed stable chimerism,or late rejection in the Hydroxyurea group

• They concluded that pre-transplant treatment with HU seems to be associated with a lower incidence of rejection/absent engraftment in severe SCD pts Brachet C et al. BMT 2004;33:799-803

Recommendations of the Abuja Committee for Inclusion/Exclusion Criteria for SCT in SCD in Nigeria

• INCLUSION CRITERIA (a + b + c + at least one under d

a) Established diagnosis of Sickle Cell Disease (HbSS, HbSC, HbS-B Thalassemia)

b) Availability of HLA- matched sibling or unrelated Stem Cell donor (preferably: HbAA >HbAC > HbAS).

c) Age of patient ≤ sixteen years. (17-35 yrs could be enlisted in a latter trial group)

d) At least one of the following clinical complications:I) Sickle Cell Disease-related neurological deficits, stroke or

impaired neuropsychiatric function or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study.

II) Recurrent acute sickle chest syndrome (> two episodes) which has failed to respond to trial of Hydroxycarbamide of at least six months or where Hydroxycarbamide is contraindicated.

INCLUSION CRITERIA (a + b + c + at least one under d)

d) continues:III) Recurrent severe debilitating pain (including

priapism) due to vaso-occlusive crisis which has failed to respond to trial of Hydroxycarbamide of at least six months or where Hydroxycarbamide is contraindicated.

IV) Sickle Cell Nephropathy (moderate-severe proteinuria or Glomerular Filtration Rate of 30%-50% of predicted normal value)

V) Bilateral proliferative retinopathy or major visual impairment of at least one eye.

VI) Osteonecrosis of multiple joints.VII) Transfusion dependence and alloimmunisation to

Red cell antibodiesVIII) Sickle Cell Disease relapsing after previous

Haematopoietic stem cell transplantation

Recommendations of the Abuja Committee for Inclusion/Exclusion Criteria for SCT in SCD in Nigeria

EXCLUSION CRITERIA (Any one or combinations of the following)

I) Age of patient > sixteen yearsII) Non-availability of HLA- matched stem cell DonorIII) Acute hepatitis, Liver cirrhosis or severe portal

fibrosis on liver biopsyIV) Severe renal impairment (GFR less than 30% of

predicted normal value)V) HIV / AIDS in potential recipient.VI) Lansky performance score < 70%VII) Pulmonary hypertensionVIII) Severe residual functional neurologic impairment

(other than hemiplegia alone)

LANSKY PERFORMANCE STATUS FOR CHILDREN

100Fully active, normal

90 Minor restrictions in physically strenuous activity

80 Active, but tires more quickly

70 Both greater restriction of and less time spent in play activity

60 Up and around, but minimal active play; keeps busy with quieter activities

50 Gets dressed but lies around much of the day, no active play but able to participate in all quiet play and activities

40 Mostly in bed; participates in quiet activities

30 In bed; needs assistance even for quiet play

20 Often sleeping; play entirely limited to very passive activities

10 No play; does not get out of bed

0 Unresponsive

Further Reading/References

1. Management & Therapy of Sickle Cell Disease: Hematopoietic Cell Transplantation.

Mark Walters, M.D. Oakland Children's Hospital Oakland, California www.sickle.bwh.harvard.edu/sickle_bmt.htmlAccessed 16th August, 2008

2. Walters MC, Patience M, Leisenring W, et al. Bone Marrow Transplantation for sickle cell disease N Engl J Med 1996 ; 335: 369-376

3. The European Blood & Marrow Transplantation (EBMT) Handbook, 5th edition (2008 Revised Edition)

Appreciation

Dr. Sunday OcheniDr. OP OgbeThe Italian team led by Prof LucarelliAll the local resource personsAll participants

THANK YOU FOR BEING AN ATTENTIVE AUDIENCE

Thank you for listening and God Bless