C. Bone Marrow and PBSC Transplantation

1. Sickle cell anemia and hematopoietic cell transplantation: When is a pound of cure worth more than an ounce of prevention? Walters MC. Pediatr Transplant. 2004;8 Suppl 5:33-8.

This is a thoughtful review by a physician experienced in hematopoietic cell transplantation (HCT) of patients with sickle cell anemia. As the title of the article suggests, the emphasis is on the topic of indications for transplantation in this patient population.

To consider transplantation for sickle cell anemia, there should be compelling strength in the benefit of cure compared to the risk of HCT. The most important risks of conventional HCT include GVHD, infertility, delayed immune reconstitution with infection, treatment-related malignancy, and death. The benefit for those who survive free of disease include the potential for prolonged lifespan, freedom from clinical vaso-occulsive events, and with it, an improved quality of live, and cessation of anemia and RBC transfusions.

Experience to date suggests that children rather than adults are most likely to have a successful outcome. Until now, patients with adverse sickle events that portend a morbid outcome or early mortality have been treated. However, perhaps it is now appropriate to consider patients at risk for adverse events and intervene with HCT before these occur. Thus, patients who remain at high-risk for a primary stroke (as screened by cranial ultrasonography) might make suitable HCT candidates. (See i. Sickle Cell Disease, B. Neurologic Findings, citations #4 and #5)

Also, a means for screening presymptomatic sickle cell patients during early childhood who are likely to have severe disease was suggested by work from the Cooperative Study of Sickle Cell Disease (CSSCD). This clinical severity index utilizes three clinical and laboratory parameters that include the leukocyte count, the presence of severe anemia defined as hemogloblin less than seven, and having an episode of dactylitis in the first year of life to identify young children at increased risk for severe disease.

Some have suggested that having sickle cell anemia alone is adequate justification, given the problems that most patients on average experience life-long.

The author also discusses various transplant options including attempts to accomplish stable mixed chimerism after non-myeloablative HCT, and the use of sources of stem cells other than the bone marrow of HLA-identical siblings. Early reports of successful umbilical cord blood transplantation are reviewed and, in one study utilizing cord blood from related donors, the 2-year probability of event-free survival was 90%. The author concludes with the optimistic note that transplantation from stem cell sources such as umbilical cord blood may become routine, and thus make transplantation available to more patients.

(Comment: For further discussion of the indications for hematopoietic cell transplantation in sickle cell disease, go to the Home page, Interactive Forums, Medical Professionals, or click HERE.)

2. A Review regarding hematopoietic cell transplantation for sickle cell disease: Hematopoietic stem cell transplantation in sickle cell disease. Vermylen C. Blood Rev 2003; 17:163-166.

The need for curative therapy is indicated by the fact that the Cooperative Study of Sickle Cell Disease, a prospective study of 3,764 US patients, showed that sickle cell disease in Black Americans decreased life expectancy by 25-30 years. Morbidity is also a concern, with a devastating stroke sometimes the first symptom of the disease. Further, cognitive impairment is a problem, the magnitude of which is just beginning to be appreciated.

Current results: Among 201 patients who received an HLA-identical sibling transplantation worldwide, overall survival is 91%, disease-free survival (DFS) is 82%, rate of rejection 8%, and incidence of cGVHD 12%. Nine percent of patients died of complications related to transplantation; GVHD was noted as the leading cause of death. Young patients, transplanted early, did even better with overall survival, event-free survival, and DFS rates of 100%, 93% and 93%, respectively

Long-term benefits and side effects: For all patients with stable engraftment, disease-associated manifestations and hemolytic anemia disappeared. Growth was normal except in patients receiving steroids for GVHD. Gonadal dysfunction was observed in almost all girls transplanted, although a successful pregnancy has been reported in a patient who had undergone BMT for thalassemia and had received the same conditioning regimen employed for sickle cell anemia. Boys have normal sexual maturation but some of them have abnormal LH, FSH or testosterone tests.

(Comment: Only a minority of patients in need of a hematopoietic cell transplant will have an HLA-matched family member. The excellent results with related donor transplants in young children (100% survival and 93% DFS) suggest that hematopoetic cell transplantation should be extended to other patients in need. Matched unrelated-donor BMT or PBSC transplants cannot have a big impact on the problem of sickle cell disease because of the low probability of finding a well-matched donor in registries. The high degree of HLA polymorphism in this population is a major factor and will prevent a high rate of HLA-matching even if the present low percentage of African-American donors in the registries is significantly improved. The less stringent criteria for HLA-matching in cord blood transplantation would seem to provide the most feasible approach to curing sickle cell disease (see next article). The need is great because each year about 1,500 infants in the United States and about 156,000 infants worldwide are diagnosed with sickle cell disease.)

3. Will developments in allogeneic transplantation influence treatment of adult patients with sickle cell disease? Chakrabarti S, Bareford D. Biol Blood Marrow Transplant. 2004;10:23-31.

This review points out that patients with sickle cell disease have a 25 to 30 year reduction in life expectancy compared with the general black population. The mortality increases sharply every decade after 20 years of age. Further, the clinical course often worsens in adult hood, even if symptoms were mild and organ functions were optimum in childhood. There has been little progress in the treatment of these patients and the only curative option is allogeneic stem cell transplantation. More than 160 patients with sickle cell disease have undergone transplantation, almost exclusively in patients younger than 16 years old (with matched sibling donors) who have severe manifestations of the disorder. Even though the more severely affected patients underwent allogeneic transplantation, the overall survival was 90 to 94% and the disease-free survival varied between 82 and 84%.

Although the review emphasizes management of highly symptomatic adults, the authors discuss a study that included 14 asymptomatic or minimally symptomatic patients which resulted in 100% overall survival, 93% event-free survival, and no instance of grade III or IV acute GVHD or extensive chronic GVHD. They stress that the popular concept that allogeneic transplantation is too toxic to be offered to less symptomatic patients is challenged by these findings. Allogeneic transplantation is more likely to be successful if it is considered earlier than later.

The authors indicate that the results of related cord blood transplantation in children with sickle cell disease are extremely encouraging, with one study having overall survival of 100% and disease-free-survival of 90%. The probability of acute and chronic GVHD was 11% and 6%, respectively.

(Comment: Since only about 30% of patients in need of a transplant will have a related hematopoietic cell donor, major benefit to the sickle cell community of transplantation can only occur with unrelated donors. However, bone marrow and/or peripheral blood stem cell products from unrelated donors are very difficult to locate for sickle cell disease patients because of the extreme polymorphism of the HLA system in blacks, and because only a small percentage of donors in registries are black. Thus, umbilical cord bloods which require a less stringent match are essential for providing major benefit to large numbers of sickle cell disease patients. One wonders why larger numbers of young patients are not transplanted. (The comment after citation #1 is also pertinent.)

4. Hematopoietic stem cell transplantation in children with sickle cell disease. Yeager AM. Blood Therapies in Medicine 2004;4:40-47.

In this review the author points out that the median survival of patients with sickle cell disease (SCD) is 42 years for males and 48 years for females, representing a 25-30 year reduction in life expectancy compared with blacks without SCD. The three major high-risk complications are cerebrovascular accidents (CVAs), acute chest syndromes (ACS) and severe recurrent pain crises.

The only curative therapy for SCD is allogeneic stem cell transplantation. More than 200 children and young adults with high-risk SCD have undergone stem cell transplantation using related donors. Most of these patients had one or more high-risk manifestations of SCD (i.e., CVA, recurrent ACS or recurrent severe vaso-occulsive crisis), or other complications such as abnormal CNS imaging studies, abnormal neuropsychological testing, recurrent priapism, nephropathy, retinopathy, osteonecrosis or alloimmunization against red cells. The outcome data regarding 198 patients from the largest series of allogeneic BMT from HLA-matched sibs indicate that the overall survival is 91% with an event-free survival rate of 83%. Treatment related mortality was approximately 9%.

These studies clearly demonstrate that related allogeneic transplantation can establish normal erythropoiesis, abrogate symptoms and eliminate the need for chronic transfusions. In patients with stable engraftment, none had episodes of pain, stroke or ACS after BMT, and most had stabilization or improvement in organ function. Almost all of these patients have normal performance status.

However, the author states that HLA-matched sibs are available for <15% of otherwise eligible patients. Finding a well-matched adult donor from marrow donor registries is difficult for African-Americans because of the highly polymorphic HLA system, and there are no reports of unrelated BMT for SCD. In contrast, cord bloods with an adequate HLA match will be more readily available than BMT donors because cord bloods require HLA-matching that is less stringent than for BMT. Indeed, it is estimated that a cord blood matched for four or more HLA antigens can be fund for at least 90% of children with SCD. Accordingly, evaluation of hematopoietic cell transplantation from alternative donors, especially cord bloods from unrelated donors is an important area of investigation. The authors suggest that trials of unrelated placental blood cell transplantation should be limited to patients with high-risk complications and only in the context of clinical trials with Institutional Review Board approval. (For a discussion of this aspect of transplantation in sickle cell disease, go to the Home page, click on Interactive Forums, Medical Professionals, or click HERE.)

5. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, Amylon M, Sullivan KM, Storb RF, Walters MC. Biol Blood Marrow Transplant. 2003;9:519-28.

The authors describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression.

Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%-85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism.

However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation.

These results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions.

6. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Bone Marrow Transplant. 2005;35:171-7.

The authors point out that most transplants for patients with hemoglobinopathies have combined myeloablative doses of busulfan and cyclophosphamide with HLA-identical sibling marrow transplantation. Overall, approximately 85% of children with severe sickle cell disease and β-thalassemia major were cured, and as a result of improved supportive care measures, the risk of transplant-related mortality was less than 10%. However, outcomes were poorer in older patients who had evidence of organ damage from iron-overload or from vaso-occlusion. Accordingly, investigations were initiated to explore alternative regimens that might reduce the toxicity, such as the use of a nonmyeloablative preparative regimen.

Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed.

At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. The authors concluded that they failed to identify a regimen that was both minimally toxic and effect and that their results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies.

(Comment: Although the results in this report and those in the previous citation (# 5) are discouraging, they are at the same time very informative. The authors indicate that it appears that more intensive pretransplant regimens will be necessary to ensure engraftment in this patient population. A similar opinion is expressed by the authors of citation #4 in the Bone Marrow and PBSC Transplantation section on thalassemia.

Also to be noted is the choice of patients. In their introduction, the authors cite reports indicating an 85% cure rate and a transplant-related mortality of less than 10% in children. It appears that a major breakthrough will be necessary to transplant with a high degree of success older patients with organ damage caused by iron-overload or vaso-occulsion. Once again the question arises as to whether it would be preferable to transplant young children before organ damage occurs.

See: Home page, left column: Interactive Forums for Medical Professionals, What are the appropriate criteria for unrelated cord blood transplantation of children with sickle cell disease?)