Successful unrelated umbilical cord blood transplantation in children with Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency and variable degrees of neutropenia. SDS patients are at risk of developing myelodysplasia, aplastic anemia, and leukemic transformation. The role and timing of allogeneic hematopoietic stem cell transplantation (HSCT) in SDS remain controversial. We report three SDS patients with severe aplasia transplanted using unrelated umbilical cord blood (UCB). Patients received melphalan (180 mg/m2), etoposide (1200 mg/m2), anti-thymocyte globulin (90 mg/kg), and total lymphoid irradiation (500 cGy); graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and prednisone. Myeloid engraftment occurred promptly with absolute neutrophil count >500 cells/mm3 on day 15 +/- 5 and all patients displayed 100% donor chimerism by 2 months post transplant. The major complication of transplant was GVHD, with all patients developing grade II or III acute GVHD, one progressing to chronic extensive GVHD. Patients are alive 309, 623, and 2029 days post transplant. Factors important in HSCT outcome for SDS may include transplantation at a young age, avoidance of cyclophosphamide, and adequate GVHD prophylaxis. Importantly, these cases also suggest that unrelated UCB, in the absence of a matched family member, is an excellent alternative stem cell source for SDS patients undergoing HSCT.

Effect of in vivo lymphocyte-depleting strategies on development of lymphoproliferative disorders in children post allogeneic bone marrow transplantation.

T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I-II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III-IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein-Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.

Low rejection rate when using unrelated or haploidentical donors for children with leukemia undergoing marrow transplantation.

Thirty-nine children with leukemia were entered into a bone marrow transplantation study comparing the use of unrelated donors who were HLA-Dr identical and matched at least with three of the four HLA-A or B loci, with haploidentical related donors. Although marrows were prepared by T lymphocyte depletion in vitro, the rejection rate of marrow in these patients was only 13% (5/39). Four patients had early rejections, and three of these four had autologous recovery immediately without evidence of leukemic recurrence. The fifth had a delayed rejection occurring approximately 2 1/2 months after transplant. These results were achievable by an ablative regimen incorporating increased immunosuppression. Although the small sample size does not yet permit evaluation of outcome comparing one donor type versus another, the early findings document a high rate of successful engraftment.

Successful program to prevent aspergillus infections in children undergoing marrow transplantation: use of nasal amphotericin.

Aspergillus infections in the pediatric bone marrow transplant (BMT) patients are usually fatal. We began the use of a prophylactic nasal spray of amphotericin in 1990. This nasal spray was provided in addition to low-dose intravenous amphotericin. During the time of this study, the number of fatal cases of aspergillus in the pediatric BMT population was reduced significantly from 13.8% to 1.8% (P < 0.0025) thereby suggesting that the use of nasal amphotericin in this population helps to prevent fatal aspergillus infections. The lack of significant side-effects and the ease of administration make this a very helpful preventive measure in the supportive care of pediatric bone marrow transplant patients.

Poor outcome in children with refractory/relapsed leukemia undergoing bone marrow transplantation with mismatched family member donors.

The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1-19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6-10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III-IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients.

Complete heart block in association with graft-versus-host disease.

An infant who received haploidentical BM for severe combined immunodeficiency (SCID) developed acute, reversible complete heart block in association with an exacerbation of GVHD. Respiratory distress and myocardial dysfunction were also seen with this and previous GVHD exacerbations. The patient had not received chemotherapy or radiation prior to BMT. The complete heart block resolved after 1 week of intensive immunosuppression. The association of complete heart block with GVHD is important because the heart block is potentially reversible with prompt, aggressive control of the GVHD.

Successful allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. Patients with SDS have varying degrees of marrow aplasia, which can be severe or progress to leukemic transformation. While allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for the hematologic disturbances of SDS, a recent review of the literature reveals few survivors. Poor outcome with HSCT is often related to excessive cardiac and other organ toxicity from transplant preparative therapy. We describe two young children with SDS who developed aplastic anemia and subsequently underwent successful allografting using a non-cardiotoxic conditioning regimen. Case 1 received marrow from an HLA-identical sibling while case 2 received partially matched umbilical cord blood from an unrelated donor. Both patients are presently alive and well with sustained donor engraftment and excellent hematopoietic function at 36 and 22 months post-HSCT.

Cutaneous mucor infection treated with wide excision in two children who underwent marrow transplantation.

Cutaneous mucor infection developed in two children who had undergone bone marrow transplantation for treatment of leukemia. One infection occurred before transplantation, and the other occurred during the period of profound neutropenia after transplantation. Both children were treated with an extensive wide excision of the infected area, and there was no evidence of mucor along the resected edges of tissue. Both patients received extensive treatment with either amphotericin (case 1) or amphotericin and itraconazole (case 2). These two cases represent aggressive management of cutaneous mucor infections, which is believed to be required for the successful completion of a marrow transplantation procedure.

Treatment type and symptom severity among oncology patients by self-report.

Oncology patients receiving chemotherapy (n=109) and radiation therapy RT (n=161) reported symptom concerns and severity on the 25-item therapy-related symptom checklist (TRSC). Secondary analysis of the self-reports of the two treatment groups was done using the Mann-Whitney U Test. Thirteen symptoms differed significantly between the two groups. RT patients reported significantly greater severity of five symptoms (p<0.05) during therapy. Chemotherapy patients reported significantly greater severity of eight different symptoms. The other 14 items showed a heterogeneous pattern of self-reported patient symptom concerns. The TRSC appears to be a clinically useful self-report checklist that captures the more important symptom concerns of both RT and chemotherapy patients. Earlier efforts to develop this checklist are reviewed briefly.

Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies.

Relapse after allogeneic hematopoietic SCT (HSCT) carries a poor prognosis and is a common cause of death. Outcomes of children who relapse post HSCT are not well known. In this retrospective multicenter study we included 532 patients who underwent allogeneic HSCT and examined the outcomes of 160 patients (30%) who relapsed. Treatment options after relapse included (i) palliative therapy with non-curative intent (n=43), (ii) salvage chemotherapy (without a second HSCT, n=55) or (iii) salvage chemotherapy followed by a second HSCT (n=62). Sixty two patients underwent a second HSCT. The 1-year disease-free survival (DFS) for those given palliative therapy, chemotherapy alone and who underwent a second transplant was <1%, 9% and 50% (P=<0.0001), respectively. The DFS at 1 and 2 year was 50% and 35%, respectively, among the patients who received a second transplant versus 9% and 2% in those who did not (P=<0.0001). In multivariable analysis longer time to relapse (P=0.04) and undergoing a second HSCT (P<0.001) were associated with improved outcome. Withdrawal of immunosuppressive therapy, followed by curative intent chemotherapy should be offered to all patients who relapse after an allogeneic HSCT. A second HSCT should be considered, especially in patients who respond to salvage chemotherapy.

Alpha-interferon therapy for lymphoproliferative disorders developing in two children following bone marrow transplants.

Two children developed lymphoproliferative processes following marrow transplantation. One of the two lymphoproliferative processes was documented to be Epstein-Barr virus (EBV)-associated. Both children received an extended course of alpha-interferon and gammaglobulin and responded with the disappearance of the lymphoproliferative process. Side effects from the alpha-interferon were minimal. Previous experience with EBV-associated lymphoproliferative processes following marrow transplantation have been usually fatal. This report further substantiates that alpha-interferon has a role in the treatment of EBV-associated lymphoproliferative processes following marrow transplantation.

Monoclonal antibody T-cell-depleted HLA-haploidentical bone marrow transplantation for Wiskott-Aldrich syndrome.

Four patients with Wiskott-Aldrich syndrome received bone marrow transplants (BMT) using monoclonal antibody T cell-depleted HLA-haploidentical marrow from a family member donor. The patients did not receive a significantly larger inoculum of mature T cells than other recipients of T cell-depleted marrow transplants. All four patients achieved quick engraftment, and three of the four patients are alive and well today. The three living patients have all had a complete return of normal T-cell and B-cell function. Infectious complications in the surviving patients were minimal; however, all three experienced some degree of graft-versus-host disease (GVHD). Two of these three patients received GVHD prophylaxis. The patient not receiving GVHD prophylaxis experienced severe GVHD and had a difficult posttransplant course. The patient who did not survive was chronically ill before BMT, whereas the other patients were in relatively good health at the time of BMT. Since the majority of individuals with this disease lack a matched bone marrow donor, our results using partially matched donors suggest that a greater number of patients can be successfully treated for Wiskott-Aldrich syndrome and that outcome is related to control of GVHD and state of health before BMT. Marrow transplantation should be offered earlier in the disease course before the onset of major infectious problems.

Ten-year experience of unrelated bone marrow donor transplants in children with malignant and non-malignant conditions.

Children who require a marrow transplant may receive such hematopoietic cells from one of many sources. This study reviews the experience of one center with 58 children who received marrow from unrelated donors over a 10-year period. These children had a variety of malignant and non-malignant diseases. During that time period, only three of these children had failed to meet engraftment criteria. All donor marrow specimens were T-lymphocyte-depleted using an antibody/complement methodology. No difference was demonstrated in outcome between donors who were perfectly HLA-DR DNA matched versus those who were only partially matched. The increased size of various marrow donor registries has increased the number of potential donors available for these patients. The lack of a requirement for perfect matching means that there is an ever-increasing number of donors available. No graft-versus-host disease (GvHD) or grade III-IV GvHD was associated with a poorer outcome. Stable, long-term engraftment with minimal morbidity has been demonstrated in these children as evidenced by stability of survival curves by two years after marrow transplant.

Prostaglandin E1 bladder instillations to control severe hemorrhagic cystitis.

Severe hemorrhagic cystitis developed in 6 children after marrow transplantation, 3 of whom had a viral etiology. All 6 patients received instillations of prostaglandin E1 directly into the bladder and 5 of the 6 had complete resolution of hematuria. This finding contrasts with our previous experience with severe hemorrhagic cystitis, particularly the type due to a viral infection, persisting in the face of numerous bladder manipulations. We encourage the use of this nontoxic treatment to gain further information regarding its effect on the bladder epithelium. The mechanism of action remains completely unknown.

Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: functional analyses of lymphocytes and correlation with immunophenotypic recovery following transplantation.

Reconstitution of the immune system following T-cell-depleted bone marrow transplantation (BMT) in children has yet to be fully elucidated. Thus, we prospectively studied the recovery of immune function in 64 children who underwent T-lymphocyte-depleted marrow transplants using either matched family member donors or matched unrelated donors. We measured in vitro posttransplantation proliferative responses to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, and Candida albicans antigen and assessed unidirectional allogeneic mixed-lymphocyte culture (MLC) responses at various times. A total of 129 healthy individuals served as normal controls for these assays. Responses to T-cell mitogens normalized within 12 months posttransplantation, while MLC responses normalized by 9 months. The presence of graft-versus-host disease (grade II or greater) and cytomegalovirus infection was associated with delays in immune function recovery. Importantly, immune function recovery correlated temporally with a rise in peripheral lymphocyte count. In contrast, the CD4/CD8 ratio was not predictive of immune recovery. Knowledge of immune function recovery may guide clinicians in devising strategies to minimize the risk of infection post-BMT.

Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery.

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report.

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.