The American journal of pediatric hematology/oncology最新文献

Purpose: To investigate the role of bone marrow transplantation in patients with severe sickle cell anemia (SCA).

Patients and methods: We have designed a protocol for selecting patients with severe SCA who may benefit from bone marrow transplantation (BMT). On the basis of this protocol, a girl 3 9/12 years of age who had severe recurrent pain crises and splenic dysfunction received a BMT from her brother, who is homozygous for hemoglobin A.

Results: Transplantation resulted in prompt engraftment, followed by durable hematologic and immunologic reconstitution with donor cells. One year after BMT, the patient continued to do well. She did not experience any graft versus host disease, her growth velocity increased, and recovery of splenic function was demonstrated. Since undergoing BMT, she has not experienced any painful crises.

Conclusions: Bone marrow transplantation is an effective therapeutic modality that should be considered in patients with severe SCA.

Purpose: We have reviewed the results of bone marrow transplantation in 30 patients with thalassemia major who were treated in the United States.

Patients and methods: Ten patients who underwent transplantation in Seattle and 20 patients from five other U.S. centers were identified through a survey of the International Bone Marrow Transplant Registry. These transplants were performed between November 1981 and April 1992 in patients with diverse ethnic backgrounds and ranged in age from 6 months to 14 years (median 4.0 years). Twenty-seven of the 30 patients received marrow from a human leukocyte antigen (HLA)-identical sibling or other family member, one patient received HLA-matched marrow from an unrelated donor, and two patients were given haploidentical but HLA-mismatched marrow from a related donor. Cytoreductive (preparative) therapy varied among institutions and pretransplant risk categories. In general, patients were given busulfan (12-24 mg/kg) or dimethylmyleran (5 mg/kg) in combination with cyclophosphamide (120-240 mg/kg). A subset of patients were given total body irradiation (TBI) at a dose of 720 cGy followed by cyclophosphamide (120 mg/kg).

Results: Sixteen of 27 patients (59%) who received marrow from an HLA-identical family member are event-free survivors, with a duration of follow-up ranging from 2 months to > 10 years after transplantation. Six of these 27 patients (22%) had recurrence of thalassemia and five (19%) died. The estimated actuarial rate of thalassemia recurrence was 24% and the rate of event-free survival was 57%. Only one of the three patients who received marrow from HLA-nonidentical or unrelated donors survives event-free. Liver biopsies were not routinely performed before transplant. Thus, classification of patients into Lucarelli risk groups was not possible. A modified risk classification was devised by using liver size and iron status assessed by the regularity of chelation and the serum ferritin level. With use of this classification, there was no significant difference in event-free survival between transplant risk groups.

Conclusions: The findings observed in this small series of patients confirms that thalassemia can be cured with bone marrow transplantation. Although most patients are event-free survivors, a significant number experienced recurrence of their disease. A cooperative multicenter trial of U.S. transplant centers may be necessary to evaluate the use of marrow transplantation for thalassemia and to determine optimal treatment.

Purpose: As of June 1992, five patients with sickle cell disease had been treated by matched sibling bone marrow transplantation in the United States.

Patients and methods: Three patients underwent transplantations for complications related to sickle cell disease, two with previous cerebrovascular accidents (CVAs) and one who had had multiple severe vasoocclusive crises. Two patients had other indications for allogeneic bone marrow transplantation: one had acute myeloid leukemia and the other had Morquio's disease. The patients' ages ranged from 3 to 10 years, and four were girls. Ages of the donors ranged from 4 to 13 years; four of the donors were boys and three carried the sickle cell trait. For four patients, the preparative regimen consisted of busulfan and cyclophosphamide given either alone or combined with antithymocyte globulin (ATG). The patient with leukemia was prepared with cyclophosphamide and total body irradiation (TBI). The regimens for prophylaxis of graft-versus-host disease (GVHD) included various combinations of cyclosporine A, methotrexate, and prednisone.

Results: The patient with Morquio's disease failed to engraft but underwent a successful retransplantation from the same donor. All patients eventually demonstrated donor engraftment and the donor's hemoglobin electrophoretic pattern posttransplant. Two patients had moderately severe GVHD of the skin and gastrointestinal tract, which resolved with prednisone therapy. One of these patients developed transient chronic GVHD involving the skin. Other acute complications included mild venoocclusive disease of the liver, central line infection with bacteremias, uterine hemorrhage in one patient, and pseudomonas sepsis in another.

Conclusions: Both patients who underwent transplantation after CVAs have experienced subsequent neurological events. However, with a median follow-up of 16 months (range 8 months to 9.3 years), all patients are surviving in good to excellent clinical condition and appear to have benefitted from treatment by bone marrow transplantation.

Purpose: The National Marrow Donor Program (NMDP) of the United States has nearly 650,000 unrelated potential marrow donors in its registry and > 1,225 marrow transplants have been performed.

Patient and methods: In 1991, 43% of patients who requested a search found at least one HLA-A-, -B-, -DR-identical donor in the files. The chance of finding a donor match is much better within one's own ethnic group. The individuals enrolled in the donor file are 67.0% white, 3.8% black, 3.0% Asian, 3.9% Hispanic, and 0.8% Native American. Therefore, patients who belong to ethnic minorities are at an obvious disadvantage in obtaining marrow donors. Because of this deficiency, the program has embarked on an aggressive campaign of recruitment of minority donors.

Results: Reciprocal search agreements with other countries have made another 200,000 potential donors available, but it is not likely that black patients will find help by this route.

Conclusions: Several efforts are being made to speed up the search process and to ensure more accurate definition of identities. These efforts include prospective HLA-DR typing of donors in the file, storage of a sample of frozen blood from each donor to permit class II typing (HLA-DR, -DQ) by DNA techniques, and eliminating the mixed lymphocyte culture test as a requirement for designating a given donor as HLA identical.

Purpose: The rate of progression of major organ failure in sickle cell anemia is genetically controlled. It is the direct consequence of the sickle cell-evoked vasculopathy.

Patients and methods: Presence of the beta S gene cluster haplotypes and alpha gene deletions as genetic markers indicate the expected frequency of illness and the risk of end-stage major organ failure. The risk of irreversible soft tissue organ failure is greatest in patients with a Central African Republic (CAR) chromosome, whereas morbidity is consistently lowest in patients with a Senegalese chromosome. Presence of alpha-thalassemia-2 decreases the risk of soft tissue organ failure in all haplotype combinations.

Results: Other laboratory abnormalities, when combined with haplotype and alpha gene status, also predict the risk of clinical morbidity. The mean hemoglobin level (or red blood cell count) is lowest in patients with the most severe clinical manifestations. On the other hand, the platelet count and leukocyte count as well as the plasma fibrinogen level are elevated in the sickest patients. A threshold level of hemoglobin F at 1.2 g/dl (approximately 20% hemoglobin F) decreases the risk of major organ failure and is attained most frequently in those with a Senegalese chromosome. Hemorheologic findings observed during the most stable state of patients with sickle cell anemia indicate two trends: (a) the mean percentage of dense red cells is nearly twice as high in the maximal severity patients as compared with the minimal severity patients; and (b) mean red cell rigidity is greatest in the maximal severity group and least in the minimal severity group. These findings suggest that a greater percentage of dense, poorly deformable red cells are present in sickle cell patients in the genotypic category of maximal severity.

Conclusions: The combination of the beta S gene cluster haplotype and alpha-gene status correlates with both phenotypic laboratory findings (hematologic profile) and morbidity. These associations increase our ability to predict clinical severity and the future risk of major organ failure.

The difference between research and innovative therapy is based on the goals rather than the risks or newness of the therapy. The threat to patients from research is not that an untested treatment may be hazardous. Instead, the danger is that the loyalty of their physician may be compromised by the goals of research. In the traditional conception of research, it is assumed that we know what constitutes standard therapy and how effective it is. The goal of research is to compare the effectiveness of an innovation with the standard therapy. However, when rapid progress is being made, it becomes difficult to measure improvements due to introduction of new therapies. It is difficult to determine which of many successful therapies is "best." As a result, rapid progress makes all therapies, including both new ones and old ones, nonvalidated therapies. In such situations, scientific norms about the degree of certainty that we must have in order to judge a therapy as being efficacious are based on the values of the individuals involved; rather than on any value-free statistical or scientific calculations. There are identifiable communities (ethnic groups) that are specifically effected by certain genetic diseases, as well as communities consisting of patients who have certain nongenetic diseases. When these groups (patient advocates) and communities are politically organized, they should be consulted and allowed to participate in the process of devising strategies to evaluate new therapies.

Purpose: Therapy of sickle cell disease with hydroxyurea is experimental.

Patients and methods: We have begun a randomized blinded clinical trial to determine its clinical utility. The efficacy of this drug is unproved and its risks, which include mutagenesis, teratogenesis and carcinogenesis, are poorly understood. These risks are explicitly stated in our consent forms. A significant number of patients who are asked to enroll refuse to enter the study. This refusal is probably because of individual variations in perception of risk and personal inconvenience, as well as differences in perception of personal benefit. We have a few hints as to which patients are more likely to produce increased amounts of fetal hemoglobin, but our findings do not indicate which patients are most likely to show a good clinical response.

Results: Our study group decided not to treat patients under 18 years of age with hydroxyurea until clinical efficacy of the drug is proved in adults. We have criteria for selecting patients for entry into our ongoing study, but the criteria are based more on study design than on an estimate of present or future severity of the manifestations of sickle cell disease.

Conclusions: Features of our previous study and results of the present trial may be helpful in defining indications for bone marrow transplantation in children with sickle cell disease.

Purpose: Although it is clear that sickle cell disease is curable with bone marrow transplantation, there are few objective criteria that are helpful in the identification of suitable candidates for this aggressive and potentially life-threatening procedure. This disease is characterized by a highly variable clinical course, and there is a need to intervene with marrow transplant before the onset of disease-mediated chronic organ damage. These factors high-light the need for a clinical severity index that can prospectively identify patients who are at high risk for a turbulent clinical course and a poor prognosis.

Patients and methods: We used the Cooperative Study of Sickle Cell Disease data base to identify features of the disease in early childhood (i.e., < 2 years of age) that are associated either with significant morbidity later in childhood or early mortality. Our study population includes the 1,944 children who entered the study before 12 years of age. Univariate analysis showed that factors associated with the occurrence of cerebrovascular accident (51 patients) include hematocrit, rate of change of pocked red cell count, and polymer fraction at 40% oxygen saturation (PF40). Only low hematocrit was predictive of death in this pediatric cohort (45 disease-related deaths).

Results: Our ability to identify other potential factors that correlate with these outcome measures is limited by their small numbers. Hence, it was necessary to designate a different endpoint whose relationship with various clinical and laboratory parameters could be assessed. To accomplish this, a distribution of acute events, which were defined as any episode of pain or acute chest syndrome, was calculated. Also, the age-specific "expected" event rate, defined as the mean number of events per patient-year of observation, was determined.

Conclusions: The relationship between various aspects of sickle cell disease and high positive deviance from the expected event rate will be assessed in a cohort of 519 children who entered the study prior to 7 months of age and were followed beyond their second birthday.

Purpose: To determine who might qualify for allogeneic bone marrow transplantation (BMT), we reviewed the medical records of all 143 patients with sickle cell anemia under the age of 16 years who were registered at our center.

Patients and methods: A total of 135 records were complete and were used to estimate donor availability and disease severity. The mean number of siblings per patient was two, but this number decreased to 0.73 if half-siblings and siblings who had sickle cell anemia were excluded. Probability calculations indicated that a human leukocyte antigen (HLA)-matched sibling donor would be available for only 18% of patients with sickle cell disease.

Results: With regard to clinical severity, if only stroke and chronic debilitating pain are considered criteria for bone marrow transplantation, only 16% of sickle cell patients would qualify, but with use of the broader criteria of the National Collaborative Study, 38% of patients would qualify. However, not all parents will consent to have bone marrow transplantation for their child, and only a minority of patients (18%) will have an HLA-matched sibling donor. Thus, as few as 1-2% of the total population of children with sickle cell anemia will ultimately qualify for marrow transplantation. Increasing the number who can undergo transplantation will require increasing the size of the donor pool.

Conclusions: Search for other therapies not based on marrow transplantation should continue. For the majority of patients with sickle cell disease, these nontransplant treatments offer the best chance for enabling patients to achieve greater longevity and a better quality of life.