Osteonecrosis in children after allogeneic hematopoietic cell transplantation: study of prevalence, risk factors and longitudinal changes using MR imaging.

Osteonecrosis after hematopoietic SCT (HCT) has seldom been addressed in pediatric populations. At our institution, since January 2002, children undergoing allogeneic HCT (alloHCT) receive yearly follow-up magnetic resonance imaging (MR) of hips and knees. To estimate the prevalence, longitudinal changes and associated risk factors for osteonecrosis after alloHCT, we reviewed MRs for children who underwent single alloHCT during the study period. We analyzed 149 of 344 patients who had post-HCT MR imaging performed (84 males; median age 11 years (range, 0.5-21 years)), median follow-up time was 32.6 months (range, 2.8-97.2 months). In all, 44 (29.5%) developed osteonecrosis of hips and/or knees; of those, 20 (45%) had at least 30% epiphyseal involvement. In 23 (52%), osteonecrosis lesions were identified in the first and in 43 (98%) by the third yearly scan. Knees were more frequently involved than hips; severity of osteonecrosis was greater in hips. Those who had pre-alloHCT osteonecrosis, two patients' hips and six patients' knees resolved completely; three patients' osteonecrosis lesions regressed after alloHCT. On risk factor analysis, age at time of alloHCT (P=0.051) and osteonecrosis identified by MRs before alloHCT (P=0.001) were the primary risk factors. This analysis shows that preventive strategies for osteonecrosis in this population should focus on measures to minimize risk factors before alloHCT.

Prevalence of osteonecrosis and associated risk factors in children before allogeneic BMT.

Osteonecrosis (ON) is a debilitating long-term complication of allogeneic BMT (allo-BMT), but may begin before allo-BMT in some children because of their primary disease treatment. Therefore, to estimate the prevalence and associated risk factors for ON before allo-BMT, we conducted a retrospective analysis of magnetic resonance (MR) studies of 118 children who underwent first allo-BMT at our institution between December 2000 and September 2007. Of the 118 consecutive patients, 107 (90.7%) underwent prospective MR studies irrespective of symptoms (69 males; median age at allo-BMT 12.9 years), and 11 underwent MR studies for symptoms. Among the 107 who had prospective imaging, 23 (21.5%) had ON; nearly 50% had at least 30% epiphyseal involvement. Knees were more frequently involved than were hips; severity of ON was greater in hips. ON prevalence before allo-BMT was 23.72% when all 118 patients were included in the denominator. Risk factor analysis, limited to MR studies performed irrespective of symptoms, revealed female gender (P=0.049) and age 10 years at the time of MR study (P=0.03) as significant risk factors, and primary diagnosis of lymphoid malignancies and aplastic anemia trended toward significance. ON before allo-BMT is a common occurrence in children.

Dental abnormalities in children preparing for pediatric bone marrow transplantation.

The purpose of our study was to describe the types and frequencies of altered dental development in pediatric patients preparing for bone marrow transplantation (BMT). Retrospective review of the medical records and panoramic radiographs of all patients who underwent BMT at St Jude Children's Research Hospital between 1990 and 2000 for whom pre-BMT dental examination and panoramic radiography records were available. All patients were treated on institutional protocols. We recorded patient demographics and radiographic evidence of microdontia, hypodontia, taurodontia, root stunting, caries, enamel pearls, and pulpal calcifications. The 259 patients identified (150 male and 109 female) had a median age of 12.82 years (range, 3.18-25.93 years) at the time of BMT. In total, 203 were Caucasian, 38 were African-American, and 18 were of other races. In all, 150 (57.9%) had abnormal dentition. The most common dental abnormalities were caries (n=84), pulpal calcifications (n = 34), and dental extractions (n = 33). Developmental abnormalities occurred less frequently: taurodontia (n = 8), hypodontia (n = 10), microdontia (n = 11), and root stunting (n = 11). Dental abnormalities are prevalent in children undergoing BMT. Pre-transplant oral hygiene and dental examination should be standard care in order to minimize potential sites of infection.

Dental abnormalities after pediatric bone marrow transplantation.

Our purpose was to describe the types and frequencies of altered dental development in pediatric patients following bone marrow transplantation (BMT). A retrospective review of the medical records and panoramic radiographs of all patients who underwent BMT at St Jude Children's Research Hospital between 1990 and 2000, for whom pre-BMT and post-BMT dental examination and panoramic radiography records were available, is presented. All patients were treated on institutional protocols. We recorded patient demographics and radiographic evidence of microdontia, hypodontia, taurodontia, root stunting, caries, enamel pearls, dental restorations/extractions and pulpal calcification. The 99 patients identified (52 males, 47 females) had a median age of 13.5 years (range, 3.4-25.9 years) at the time of BMT. In all, 73 were Caucasian, 15 were African-American, and 11 were of other races. The frequency of radiographically evident root stunting in permanent teeth was significantly increased after BMT (P<0.001), but there was no significant change in the frequency of other dental abnormalities after BMT. Dental abnormalities are prevalent in survivors of childhood BMT, but only root stunting appeared to progress with BMT.

Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation.

Our purpose was to evaluate frequency and severity of bone mineral decrements and frequency of osteonecrosis in survivors of pediatric allogeneic bone marrow transplantation (alloBMT). We retrospectively reviewed demographic information, treatment, magnetic resonance (MR) imaging studies (hips and knees), and bone mineral density (BMD) studies of 48 patients as measured by quantitative computed tomography (QCT). In all, 24 patients were male; 37 were Caucasian. Median age at alloBMT was 10.3 years (1.6-20.4 years). Of the 48 patients, 43 underwent QCT. Median time between alloBMT and imaging was 5.1 years (1.0-10.2 years). Median BMD Z-score was -0.89 (-4.06 to 3.05). BMD Z-score tended to be associated with female sex (P=0.0559) but not with age at BMT, race, primary diagnosis, time from alloBMT, T-cell depletion of graft, total-body irradiation, or acute/chronic graft-versus-host disease (GVHD). MR showed osteonecrosis in 19 of 43 (44%). We found no associations between osteonecrosis and sex, race, diagnosis, age at BMT, history of GVHD, time from BMT, or T-cell depletion. Seven patients (15%) had MR changes of osteonecrosis and BMD Z-scores of less than -1 s.d. We conclude that pediatric alloBMT survivors have decreased BMD and are at risk of osteonecrosis. They should be monitored to assure early intervention that may ameliorate adverse outcomes.

Hemorrhagic cystitis after allogeneic bone marrow transplantation in children: clinical characteristics and outcome.

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5-619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P =.021) or had received T cell-depleted grafts (P =.017), grafts from unrelated donors (P =.021), a lower total nucleated cell dose (P =.032), or antithymocyte globulin (P =.0446). Multiple regression analysis revealed male sex (beta =.97; P =.027) and unrelated donor graft recipients (beta =.83; P =.039) to be significant factors.

Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation.

Twenty-three children with de novo acute myelogenous leukemia (AML) (n = 20), secondary AML (n = 1), or non-Hodgkin's lymphoma (NHL) (n = 2) underwent allogeneic bone marrow transplantation (alloBMT) for graft failure (n = 1) or recurrent malignancy (n = 22) between February 1992 and August 1999 following autologous BMT (ABMT). Induction chemotherapy was given to 14 patients and nine patients went directly to alloBMT. Five received marrow from matched siblings, 14 from matched unrelated donors and four from mismatched family members. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Nine patients are alive disease-free between 627 and 2433 days (1.7-6.7 years) post BMT resulting in a 4-year DFS of 39%. Eight patients relapsed at a median of 206 days (range, 35-669 days) post alloBMT and all eventually died. Eight patients (two of whom also relapsed) died of RRT. Although RRT and relapse remain significant problems, a significant percentage of pediatric patients failing ABMT may be cured with alloBMT.

Transfer of EBV-specific CTL to prevent EBV lymphoma post bone marrow transplant.

EBV-associated lymphoproliferative disorders (EBV-LPD) are a significant problem after hemopoietic stem cell transplantation from unrelated donors or mismatched family members. Risk factors include T-cell depletion, MHC mismatch, and intensity of immunosuppression. New therapeutic strategies involve cellular immunotherapy approaches and both donor T-cells and EBV-specific cytotoxic T lymphocytes (CTLs) have proven to be effective therapies. EBV-specific CTL has also proved to have a major impact on the incidence of this complication when used prophylactically.

Bone marrow transplantation for therapy-induced acute myeloid leukemia in children with previous lymphoid malignancies.

Twenty-one children who developed therapy-related acute myeloid leukemia after treatment for acute lymphoblastic leukemia received allogeneic bone marrow transplants between January 1990 and June 1997. All had previously received epipodophyllotoxin-containing regimens and 11 had cytogenetic abnormalities involving 11q23. Induction chemotherapy was given to 13 patients and eight patients went directly to BMT. Eleven received marrow from matched siblings, eight from matched unrelated donors and two from haploidentical family members. Conditioning regimens included cyclophosphamide (CY), cytarabine, and total body irradiation. Four patients are alive disease-free between 1118 and 1825 days post-BMT resulting in a 3-year DFS of 19%. Ten patients relapsed at a median of 150 days (range 30-664 days) post-BMT and all eventually died of disease. Seven patients died of regimen-related toxicity. The outlook for patients with therapy-related AML/MDS remains poor and more effective therapy is needed.

Response of steroid-resistant graft-versus-host disease to lymphoblast antibody CBL1.

Therapy of steroid-resistant graft-versus-host disease (GVHD) with antibodies to T cells or cytokines is of limited value because GVHD is mediated by a pleomorphic group of effective cells and cytokines. CBL-1, a murine monoclonal antibody, recognises an antigen on activated T cells, B cells, and natural killer cells. We administered CBL-1 to ten patients with grade III or IV steroid-resistant GVHD. Complete remissions occurred in five cases and partial remissions in four. The organ system(s) affected by GVHD was not a predictor of response. CBL-1 was well tolerated and did not exacerbate post-transplant immunodeficiency. Our findings support the use of CBL-1 in primary prophylaxis for GVHD.