revised January 3, 2001

Author:
Mark Walters, M.D.
Oakland Children's Hospital
Oakland, California

MANAGEMENT AND THERAPY OF SICKLE CELL DISEASE: HEMATOPOIETIC CELL TRANSPLANTATION

Introduction

Hematopoietic cell transplantation (HCT) can possibly cure a variety of genetic disorders, including sickle cell disease1. The goal of this treatment is to eliminate the sickle erythrocyte and its cellular progenitors and replace them with donor hematopoietic pluripotent stem cells that produce erythrocytes expressing at best no sickle hemoglobin or at worse quantities similar to the trait condition. The risk of severe adverse events after transplantation is weighed against the possibility of preventing serious complications from sickle cell disease. These complications can produce extensive morbidity and in some cases, early death. The first reports of a successful transplantation (level IV evidence) have been confirmed and extended by several multicenter level III investigations (Table 1). To date, nearly all the transplants performed have utilized HLA-identical sibling donors, which limits the number of sickle cell patients eligible for this therapy. No level II or I studies exist to support this therapeutic option for sickle cell disease. However, as new therapies are developed that prevent and treat graft-versus-host and host-versus-graft reactions (which are the primary contributors to the histocompatibility barriers), transplantation likely will take on added importance for selected patients with sickle cell disease.

Indications for HCT

Table 1. Supporting Evidence for HCT in Sickle Cell Disease
Study Description
First Author
Strength of Evidence
Case report
Johnson2, Milpied3
IV
Patient series
Vermylen7,27
IV
HCT trial proposed
Thomas28
V
Collaborative HCT trial
Walters8
III
European collaborative trial
Vermylen29
III
Long-term impact of HCT
Vermylen9, Walters12
III
UCB report
Brichard20, Minero30
IV

The first published reports of HCT for sickle cell disease involved patients who had other more deadly hematological or genetic disorders that were the primary indication for transplantation2,3 (Table 1). This initial experience showed elimination of sickle cell disease 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 transplantation4-6. 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 Belgium7. 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 Europe8,9. Children were felt to be better candidates for bone marrow transplantation than adult patients because of their lower risk of transplant-related complications such as graft-versus-host disease (GVHD), and because of a presumed lower burden of sickle-related organ damage. Table 2 summarizes the inclusion and exclusion criteria for enrollment adopted by one multicenter study.

Current results of HCT from HLA-identical sibling donors

Approximately 150 patients have undergone HCT from HLA-identical siblings worldwide9-12. The combined results of 3 level III studies have demonstrated that more than 90% of patients survive and approximately 85% survive free from sickle cell disease after transplantation with a period of followup that extends to 11 years. Sickle cell disease recurred in approximately 10% of patients after transplantation. Neurologic complications such as seizures occurred frequently after transplantation, requiring development of preventative measures13-15. Among patients who had stable engraftment of donor cells, no subsequent sickle cell-related clinical events occurred and their pre-existing sickle cell-related organ damage stabilized9,12,16. Splenic function also recovered17. Some patients developed mixed donor-host hematopoietic chimerism after transplantation that was stable18. Interestingly, these patients also had no symptoms from sickle cell disease. Primary and secondary amenorrhea were common among females after transplantation and most patients likely will be infertile9,12. The risk of secondary cancers after HCT remains uncertain but it is estimated to be less than 5 percent19. Linear growth was normal or accelerated after transplantation in most patients9,12.
Table 2. Eligibility Criteria for HCT for Sickle Cell Disease
Inclusions
  • Patients < 16 years of age with sickle cell anemia (SS or Sb0-thalassemia)
  • One or more of the following complications: 
    • Stroke or CNS event lasting longer than 24 hours
    • Recurrent acute chest syndrome
    • Recurrent vaso-occlusive painful episodes
    • Impaired neuropsychologic function and abnormal cerebral MRI scan
    • Stage I-II sickle lung disease
    • Sickle nephropathy (GFR 30-50 percent of predicted normal)
    • Osteonecrosis of multiple joints

      •  


Exclusions

  • Patients > 16 years of age
  • HLA-non-identical donor
  • One or more of the following conditions:
    • Lansky performance score <70 percent
    • Acute hepatitis or biopsy evidence of cirrhosis
    • Renal impairment (GFR <30 percent predicted normal)
    • Stage III-IV sickle lung disease

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 successful20. No published report exists of transplantation from volunteer unrelated donors. UCB possibly produces less GYHD than does standard bone marrow transplantation (level III evidence)21. A downside to UCB transplantation is slower hematopoietic engraftment and perhaps a higher rate of graft rejection22. 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. Currently, no protocol for transplantation from alternative sources of stem cells exists, although pilot clinical investigations are being explored.

HCT for adults with sickle cell disease

Very little information exists concerning the outcome after HCT among adults. The risk of death with the procedure may be higher, due in part to the higher frequency of GVHD23. The risk of death clearly is greater after HCA-identical bone marrow transplantation in adults with sickle cell disease relative to transplants in younger patients with b -thalassemia24. Non-myeloablative preparation before HCT could clinically correct sickle cell disease with lower risk of severe complications25. The aim 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 HCT for older people with advanced organ damage from sickle cell disease. Several ongoing investigations seek to test this hypothesis.
 

Summary of the State of the Art

Currently, HCT is the only therapy that can cure sickle cell disease. The results of transplantation are best when performed in children with a sibling donor who is HLA-identical. While there appears to be a considerable benefit to those who survive with stable engraftment of donor cells, there are also significant health risks to those who undergo this treatment. Therefore, careful discussions with families by health care professionals experienced in the care of patients with sickle cell disease and with HCT should be conducted to ensure informed consent for this procedure. Presently, HCT is reserved for patients who have experienced significant complications of sickle cell disease, such as stroke, recurrent episodes of acute chest syndrome or intractable vaso-occlusive pain. With better understanding of the complex pathophysiology of sickle cell disease, we may one day have clinical or genetic markers that reliably predict a severe clinical course. We could then apply HCT before significant complications occur. Current research efforts are aimed at expanding donor availability by overcoming graft-versus-host and host-versus-graft reactions. Non-myeloablative preparation for the purpose of establishing stable donor-host hematopoietic chimerism could further reduce the toxicity of HCT. These efforts in aggregate should expand the role of HCT in treating patients with sickle cell disease.

Recommendations

Children with sickle cell disease who experience significant, non-infectious complications caused by vaso-occlusion should be considered for HCT. If full-siblings are available, HLA typing should be performed (refer to Table 2). Families should receive counseling about the collection of UCB from future pregnancies26. For severely affected children who have HLA-identical sibling donors, families should be informed of the risks, benefits and alternatives to interventions such as HCT. These carefully selected patients should be offered the treatment option of HCT. No level II study exists to recommend HCT over an alternate intervention such as chronic blood transfusion.

Treatment Protocol

The treatment plan outlined below is that followed by one of the multicenter investigations of HCT for sickle cell disease8:
 
Treatment
Day ó9 to -6
Day -5
Day -4
Day -3
Day -2
Day -1
Day 0
posttransplant
Busulfan
X
          
X
-
Cyclophosphamide  
X
X
X
X
    
-
Anti-thymocyte globulin
X
X
X
-
Marrow infusion            
X
-
CSP          
X
X
Through day +90
Methotrexate               Single doses on days +1, 3, 6, 11

Doses:
*Busulfan 3.5 mg/kg/day orally for a total dose of 14 mg/kg

Cyclophosphamide 50 mg/kg/day intravenously for a total dose of 200 mg/k

Horse Anti-thymocyte globulin 30 mg/kg/day intravenously for a total dose of 90 mg/kg
GVHD prophylaxis:

Cyclosporine 3 mg/kg intravenously divided every 12 hours

Methotrexate 15 mg/m2 intravenously on day 1, and 10 mg/m2 on days 3 , 6, and 11.

*Busulfan pharmacokinetics should be performed if busulfan is administered orally.

To reduce the risk of neurologic complications after HCT, the following measures should be followed13:
 
Neurologic guidelines after HCT
Prophylactic anti-convulsant medications 

Maintain a platelet count above 50,000 per mm3
Strict control of hypertension
Avoidance of polycythemia by maintaining Hgb between 9 ó 11 gm/dl
Prompt repletion of magnesium

Abbreviations: CNS, central nervous system; GFR, glomerular filtration rate; MRI, magnetic resonance imaging; RBC, red blood cell.

REFERENCES:

  1. Parkman R. The application of bone marrow transplantation to the treatment of genetic diseases. Science 1986; 232:1373-8.
  2. Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FTd. Bone-marrow transplantation in a patient with sickle-cell anemia. New England Journal of Medicine 1984; 311:780-3.
  3. Milpied NHJ, Garand R, and David A. Bone-marrow transplantation for sickle-cell anaemia. Lancet 1988; ii:328-29.
  4. Nagel RL. The dilemma of marrow transplantation in sickle cell anemia. Seminars in Hematology 1991; 28:233-4.
  5. Davies SC. Bone marrow transplantation for sickle cell disease. Archives of Disease in Childhood 1993; 69:176-7.
  6. Platt OS, Guinan EC. Bone marrow transplantation in sickle cell anemia--the dilemma of choice [editorial; comment]. New England Journal of Medicine 1996; 335:426-8.
  7. Vermylen C, Fernandez Robles E, Ninane J, Cornu G. Bone marrow transplantation in five children with sickle cell anaemia. Lancet 1988; 1:1427-8.
  8. Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease [see comments]. New England Journal of Medicine 1996; 335:369-76.
  9. Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplantation 1998; 22:1-6.
  10. Giardini C, Galimberti M, Lucarelli G, et al. Bone marrow transplantation in sickle-cell anemia in Pesaro. Bone Marrow Transplantation 1993; 12 Suppl 1:122-3.
  11. Bernaudin F. Resultats et indications actuelles de l'allogreffe de moelle dans la drepanocytose. Pathologie Biologie 1999; 47:59-64.
  12. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Blood 2000; 95:1918-24.
  13. Walters MC, Sullivan KM, Bernaudin F, et al. Neurologic complications after allogeneic marrow transplantation for sickle cell anemia [see comments]. Blood 1995; 85:879-84.
  14. Ferster A, Christophe C, Dan B, Devalck C, Sariban E. Neurologic complications after bone marrow transplantation for sickle cell anemia [letter; comment]. Blood 1995; 86:408-9.
  15. Abboud MR, Jackson SM, Barredo J, Holden KR, Cure J, Laver J. Neurologic complications following bone marrow transplantation for sickle cell disease. Bone Marrow Transplantation 1996; 17:405-7.
  16. Hernigou P, Bernaudin F, Reinert P, Kuentz M, Vernant JP. Bone-marrow transplantation in sickle-cell disease. Effect on osteonecrosis: a case report with a four-year follow-up. Journal of Bone & Joint Surgery - American Volume 1997; 79:1726-30.
  17. Ferster A, Bujan W, Corazza F, et al. Bone marrow transplantation corrects the splenic reticuloendothelial dysfunction in sickle cell anemia. Blood 1993; 81:1102-5.
  18. Sullivan K, Walters, MC, Patience, M, Leisenring W, Buchanan, GR, et al. Collaborative Study of Marrow Transplantation for Sickle Cell Disease: Aspects Specific for Transplantation of Hemoglobin Disorders. Bone Marrow Transplantation 1997; 19, Suppl 2:102-105.
  19. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation [see comments]. New England Journal of Medicine 1997; 336:897-904.
  20. Brichard B, Vermylen C, Ninane J, Cornu G. Persistence of fetal hemoglobin production after successful transplantation of cord blood stem cells in a patient with sickle cell anemia [see comments]. Journal of Pediatrics 1996; 128:241-3.
  21. Rocha V, Chastang C, Souillet G, et al. Related cord blood transplants: the Eurocord experience from 78 transplants. Eurocord Transplant group. Bone Marrow Transplantation 1998; 21 Suppl 3:S59-62.
  22. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. New England Journal of Medicine 1997; 337:373-81.
  23. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Seminars in Hematology 1991; 28:250-9.
  24. Lucarelli G, Clift RA, Galimberti M, et al. Bone marrow transplantation in adult thalassemic patients. Blood 1999; 93:1164-7.
  25. Storb R, Yu C, Sandmaier BM, et al. Mixed hematopoietic chimerism after marrow allografts. Transplantation in the ambulatory care setting. Annals of the New York Academy of Sciences 1999; 872:372-5; discussion 375-6.
  26. Lubin BH, Eraklis M, Apicelli G. Umbilical cord blood banking. Advances in Pediatrics 1999; 46:383-408.
  27. Vermylen C, Cornu G, Philippe M, et al. Bone marrow transplantation in sickle cell anaemia. Archives of Disease in Childhood 1991; 66:1195-8.
  28. Thomas ED. The pros and cons of bone marrow transplantation for sickle cell anemia. Seminars in Hematology 1991; 28:260-2.
  29. Vermylen C, Cornu G. Bone marrow transplantation for sickle cell disease. The European experience. American Journal of Pediatric Hematology-Oncology 1994; 16:18-21.
  30. Miniero R, Rocha V, Saracco P, et al. Cord blood transplantation (CBT) in hemoglobinopathies. Eurocord. Bone Marrow Transplantation 1998; 22 Suppl 1:S78-9.

    31.  

HomeBWHMGHHMS