| Abstract|| |
The results of the Pediatric Bone Marrow Transplant Program at The King Faisal Specialist Hospital and Research Center (KFSH & RC) from June 1993 to October 1995 were reviewed for a preliminary report on the outcome of children undergoing bone marrow transplantation (BMT) particularly in relation to mortality and morbidity. A total of 64 bone marrow transplants were performed on 60 patients during this period of time. The study patients included 28 with acute leukemia, 10 with severe combined immune deficiency, five with chronic myeloid leukemia, four with Fanconi's anemia and 13 others with miscellaneous disorders. The average hospitalization period was six weeks per patient. Forty three of these patients (72%) were alive and disease-free after a median follow-up of 14 months (range 1-27 months). Eight patients died from transplant-related toxicity within 100 days of BMT. One patient died of chronic graft versus host disease (GVHD) of the liver. Eight patients with acute leukemia relapsed within one year after BMT. Further details regarding the preparative regimens, toxicity of BMT, GVHD and disease-free survival are reviewed in this report.
Keywords: Bone marrow transplantation, Children.
|How to cite this article:|
El Solh H, Al-Nasser A, Al-Sudairy R. Bone Marrow Transplantation in Children: The King Faisal Specialist Hospital Experience. Saudi J Kidney Dis Transpl 1996;7:194-8
|How to cite this URL:|
El Solh H, Al-Nasser A, Al-Sudairy R. Bone Marrow Transplantation in Children: The King Faisal Specialist Hospital Experience. Saudi J Kidney Dis Transpl [serial online] 1996 [cited 2020 Mar 31];7:194-8. Available from: http://www.sjkdt.org/text.asp?1996/7/2/194/39527
| Introduction|| |
Bone marrow transplantation (BMT) has been frequently used for the therapy of different hematological malignancies, primary immune deficiency disease and hematological disorders in children  . The BMT program at the King Faisal specialist Hospital and Research Center (KFSH & RC) was started in 1984 utilizing a 10-bed unit. Transplants were performed on both adult and pediatric patients in this unit until June 1993, when the pediatric BMT unit was created as a separate unit geographically and administratively. Between 1984 and 1993, a total of 329 pediatric and adult allogenic bone marrow transplants and 80 autografts (56 bone marrow and 24 peripheral blood stem cell) have been performed in our unit.
In June 1993, the pediatric BMT program re-evaluated the indications and priority for BMT. Initially, two existing rooms equipped with high energy participate air (HEPA) filters arid modified reverse isolation procedures were utilized. The number of rooms was increased to four in January 1994. [Table - 1] shows the indications laid down for BMT in children at KFSH & RC. The objective of this report is to evaluate the activities and outcome of the pediatric allogenic BMT program. Keeping in mind that the duration of follow-up is short, some valuable observations and conclusions can be made particularly in relation to the feasibility of such a program, selection of patients for BMT, and transplant-related morbidity and mortality.
| Patients and Methods|| |
Between June 1993 and October 1995, 60 pediatric patients underwent allogenic BMT at KFSH & RC. The age range was one month to 15 years with a median of six years. There were 44 males and 16. females. [Table - 2],[Table - 3] show the distribution of cases according to etiology classified into malignant and non-malignant disorders. Fifty seven patients received bone marrow from full-HLA matched donors, two patients from 1-antigen mismatch related donors and one patient from haplo-identical parent.
[Table - 4] shows the preparative regimen used in conditioning these patients for BMT. In general, we used cyclophosphamide (Cy) in a dose of 60 mg/kg/day for two days, and fractionated total body radiation (TBI) in a total dose of 1200 rads given in six fractions over three days for patients with acute lymphoblastic leukemia (ALL). Busulfan (Bu: 16 mg/kg) and Cy (200 mg/kg) were used for acute non-lymphoblastic leukemia (ANLL), chronic myeloid leukemia (CML), both adult and juvenile type myelodysplastic syndrome (MDS), Wiscott-Aldrich syndrome (WAS) and partial albinism with immune deficiency (PAID). Patients with severe combined immune deficiency (SCID) received either no preparative regimen or Cy (200 mg/kg) depending on the absence or presence of natural killer cells as determined by immunophenotyping performed on peripheral blood. One patient with diamond blackfan syndrome received anti-thymocyte globulin (ATG) at a total dose of 90 mg/kg given over 3 days in addition to Bu and Cy. Patients with Fanconi's anemia received Cy (20 mg/kg), ATG (90 mg/kg) and thoracoabdominal radiation (TAL:400 cGy). Patients with acquired severe aplastic anemia (SAA) received Cy (200 mg/kg) in addition to ATG (90 mg/kg) since they were heavily transfused with blood products prior to BMT. One patient with beta thalassemia major who had a second BMT that was performed five years after the first one, received Cy (200 mg/ kg) and TBI (1200 cGy). This patient had rejection after the first transplant and developed multiple antibodies against red blood cells making it difficult to provide him with compatible blood transfusion on a regular basis. One patient with paroxysmal nocturnal hemoglobinuria (PNH) had a severe course of the disease with several episodes of hemolysis and abdominal pain requiring frequent hospitalization. She ultimately developed antibodies against red blood cells putting her in life-threatening situations due to lack of availability of compatible blood transfusions. This patient received Cy (200 mg/kg) and Bu (16 mg/kg) in addition to ATG (90 mg/kg). The patient with hemophagocytic lymphohistiocytosis (HLH) received Bu and Cy as preparative regimen. One patient with ALL received etoposide (VP16) at a dose of 60 mg/kg and TBI (1200 rads). Also, a similar regimen was given to a patient with CML relapsed one year post-BMT.
Graft versus host disease (GVHD) prophylaxis was given to all patients. The standard regimen used at KFSH & RC has been the combination of cyclosporin and a short course of methotrexate. Patients who were below one year of age or had severe combined immune deficiency (SCID) received cyclosporin only. Patients with positive serology for cytomegalovirus (CMV) and/or herpes simplex virus (HSV) received prophylaxis with acyclovir (500 mg/m 2 q8 hr for CMV and 250 mg/m 2 for HSV). Patients with negative serology for CMV who received bone marrow from CMV negative donors were given only CMV negative blood products. All patients received intravenous immunoglobulin at a dose of 500 mg/kg once weekly till day-90 post-transplant for prophylaxis of infection and GVHD. Trimethoprim-sulphamethoxazole was used for pneumocystis carinii prophylaxis preBMT and was given from day-2 until evidence of engraftment (absolute neutrophil count > 500). All patients received irradiated blood products. On an average, the target nucleated cell count for each patient is 3 x 10 8 /kg. In our group of patients, the range of nucleated cell count was 2.5-6.5 x 10 8 /kg with a median of 3.5 x 10 8 /kg.
| Results|| |
Of the 60 patients in our study, nine died within 100 days of BMT. The causes of death and the original hematological diseases of the patients who died are shown in [Table - 7].
Five patients with ANLL, and three patients (with ALL, MDS, and juvenile CML) relapsed within two to six months of BMT. One patient with adult CML relapsed almost one year after first BMT and was salvaged by a second transplant utilizing VP16 and TBI.
Two patients died prior to determination of engraftment status. One patient with MDS had partial engraftment and was found to have persistent disease. Two patients did not engraft and died after second transplant, one with acquired SAA who received reconditioning with Cy and TAB and another patient with thalassemia who received reconditioning with ATG.
Graft Versus Host Disease
Nineteen of 55 patients (engrafted) developed acute GVHD. This rate of 35% is similar to what has been described in several international studies  . All these patients had involvement of the skin (16 had Grade I-II and 3 had Grade III-IV). Seven of these patients had GVHD of the liver and only three had gut GVHD. Of interest is that when the occurrence of GVHD was analyzed in patients with malignant disorders, only 13% (1/8) of the patients who had relapse and 45% (12/26) of those in remission, developed GVHD. This finding is consistent with the observation of other workers that GVHD provides graft versus leukemia effect which has a role in preventing relapse  .
Periodic assessment of these patients did not show significant sequelae except for one patient who had infantile ALL and was transplanted using Bu/Cy regimen, developed restrictive pulmonary disease. However, she maintained activity without requiring oxygen therapy. Another patient had panophthalmitis in association with pseudomonas septicemia resulting in loss of vision of the left eye, within two months post-BMT. At 2-years post-BMT however, he was healthy, active and had normal vision in the right eye.
The short duration of follow-up in our study patients might explain the relative lack of long-term complications expected to occur in children post-BMT  .
| Discussion|| |
The disease-free survival (72%, with a median follow-up of 14 months) is very encouraging despite the short-term follow up. The following observations were made in relation to specific disease categories.
One of 10 evaluable patients with ALL relapsed so far; however, the duration of follow-up is short and re-evaluation is crucial when long-term results are available. Five of the 15 patients with ANLL relapsed (significantly higher than ALL) which implies that more effective preparative regimen for eradication of leukemia is required. One patient with adult CML relapsed almost one year after the first transplant and was salvaged using VP16 and TBI and had no evidence of disease clinically and hematologically 11 months post-BMT.
Non-malignant Hematological Disorders
Three of four patients with Fanconi's anemia are alive, well and have normal bone marrow reconstitution post-BMT. One patient who tolerated the preparative regimen well and had three cell line engraftment, developed meningitis and pulmonary aspergillosis. He recovered but unfortunately had intracranial hemorrhage, suspected to be secondary to trauma, and died two months post-BMT. These four patients underwent BMT utilizing a preparative regimen reported by Kohil-Kumar, et al  . Review of KFSH & RC experience concerning Fanconi's anemia prior to 1993, utilizing Cy (20 mg/kg) and TBI (600 cGy), showed that 5 out of 10 patients were cured with BMT  . Patients with acquired SAA benefitted from the addition of ATG to Cy in preparation for BMT, especially if they were heavily transfused pre-BMT.
Eight of 10 patients with SCID were alive and well and had normal immune function. Two patients who were poor candidates due to pulmonary complications with infection (one patient had RSV and another CMV) died within 100 days from BMT. One patient who received mismatched BMT from a related donor (his mother) engrafted, but died of CMV pneumonia. T-cell depletion using lectin agglutination and Erosetting was employed in this case. Patients with WAS  and PAID  did very well and had uneventful course during and after BMT.
Four patients underwent second BMT due to engraftment failure or relapse (one patient with thalassemia and another with aplastic anemia failed to engraft, one with adult CML relapsed and another with MDS had partial engraftment and persistent disease). The only patient who had a successful second BMT was the one in whom it was performed one year from the first transplant when the patient was in the second chronic phase of the disease (adult CML).
In conclusion, the results of the pediatric BMT program at KFSH & RC over the last two years have been comparable to those reported in the literature as far as transplant-related morbidity and mortality is concerned. The duration of follow-up is short and the long-term outcome is yet to be determined. One of the most important factors in improving the outcome is the selection of patients focusing on giving priority to those who have shown response to chemotherapy for patients with leukemia (in first remission for ANLL and second remission for ALL); minimal blood product transfusions pre-BMT for patients with non-malignant hematologic disorders and absence of organ dysfunction or persistent infection at the time of BMT.
| References|| |
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Hassan El Solh
Director, Pediatric Bone Marrow and Transplant Program, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7]