Per Frisk

Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study.

Summary:We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1–10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.

Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia

Summary:We describe pubertal development and growth in 17 children who underwent bone marrow transplantation (BMT), including total body irradiation (TBI) for ALL. Seven children also received cranial irradiation (CI) and five boys testicular irradiation. All underwent transplantation before (n=15) or at the beginning of (n=2) puberty and reached a final height (FH). Puberty started spontaneously in all boys not given testicular irradiation. All boys who received testicular irradiation developed hypergonadotrophic hypogonadism. Puberty started spontaneously in two girls and was induced with increasing doses of ethinylestradiol in two girls. In two girls, a low dose of ethinylestradiol was given until menarche. In one girl with early onset of puberty and short stature, puberty was blocked with a GnRH analogue. The standard deviation score for height decreased significantly from BMT to FH, both in the children who received TBI only (−1.1, P=0.005) as well as in those given additional CI (−1.7, P=0.027). Most of the loss occurred during puberty. In all, 10 children received growth hormone (GH) treatment. CI, young age at BMT, and short duration of GH treatment were predictors of height loss after BMT. Although limited by the small and heterogeneous sample, our study supports the use of early GH treatment in children with decelerating growth rate and low GH levels.

Glucose metabolism and body composition in young adults treated with TBI during childhood.

After SCT in childhood, survivors may develop disorders of glucose metabolism. The role of obesity is controversial. We measured insulin sensitivity using the homeostasis model assessment (HOMA) and the frequently sampled i.v. glucose tolerance test (FSIVGTT), as well as body composition using dual-energy X-ray absorptiometry in 18 young adults median 18.2 years after SCT and compared them with matched controls. We also measured growth hormone (GH) secretion, and levels of leptin and adiponectin. HOMA showed insulin resistance in eight patients (44%), as opposed to none of the controls (P=0.008) and FSIVGTT showed a decreased sensitivity index in the patients (2.98 vs 4.54 mU/L/min, P=0.042). Dual energy X-ray absorptiometry showed a higher percentage fat mass in the patients (34.9 vs 24.3%, P=0.011), which correlated inversely with the sensitivity index (r=−0.52, P=0.032). The patients had a lower peak value of GH (GHmax 9 vs 20.7 mU/L, P=0.002). Time post SCT correlated with percentage fat mass and inversely with GHmax. The patients had higher levels of leptin and lower levels of adiponectin, even after adjustment for fat mass. We propose that the decreased insulin sensitivity may primarily be explained by the adverse body composition, which may owe to long-standing GH deficiency.

Both CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells from patients with B-cell malignancy express cytolytic markers and kill autologous leukaemic B cells in vitro.

Cytotoxic CD4+ T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and seem to be involved in the regulation of malignant B cells. The CD4+ T regulatory cells (Tregs) can regulate various immune cells, including B cells, by inducing their apoptosis. Hence, different subgroups of CD4+ T cells may be involved in the regulation of malignant B cells. In this study, the cytotoxic phenotype and function of various CD4+ T‐cell subgroups were investigated in patients with B‐cell malignancies. Peripheral blood was collected from patients with CLL, various B‐cell lymphomas, healthy adult donors, children with precursor B‐cell acute lymphoblastic leukaemia (pre‐B ALL) and from healthy children. CD4+ T cells (CD3+ CD4+ FoxP3−), Tregs (CD3+ CD4+ CD127low FoxP3+) and CD127high FoxP3+ T cells (CD3+ CD4+ CD127high FoxP3+) were analysed for their expression of the cytolytic markers CD107a and Fas ligand. Patients with CLL had increased CD107a expression on all tested T‐cell subgroups compared with healthy donors. Similar results were found in patients with B‐cell lymphomas whereas the CD107a expression in children with pre‐B ALL was no different from that in healthy controls. Fas ligand expression was similar between patient cells and cells of healthy donors. CD4+ T cells and Tregs from patients with CLL and healthy donors were subsequently purified and cultured in vitro with autologous B cells. Both subgroups lysed B cells and killing was confirmed by granzyme ELISAs. In conclusion, cytotoxic populations of CD4+ T cells, including Tregs, are present in patients with B‐cell malignancy and may be an important factor in immune‐related disease control.

Vascular density in childhood acute lymphoblastic leukaemia correlates to biological factors and outcome

The issue of angiogenesis and its clinical relevance in childhood acute lymphoblastic leukaemia (ALL) is controversial. In the present study, microvessel density (MVD), analysed in 185 diagnostic bone marrow biopsies, was higher in T‐cell ALL compared to B‐cell precursor (BCP)‐ALL (P = 0·013). In the BCP group, cases with t(12;21) were characterized by a low MVD while patients with high‐hyperdiploid leukaemia (HeH, 51–61 chromosomes) showed a high MVD compared to other BCP patients (P = 0·001 and 0·002 respectively). There was a correlation between MVD and white blood cell (WBC) count in high‐risk BCP patients (P = 0·021). In addition, BCP patients with a high marrow reticulin fibre density and high MVD had an unfavourable outcome compared to the other BCP patients (P = 0·002). The fraction of vessels in which lumina were filled with blasts (blast congested vessel fraction) correlated strongly with WBC count (P < 0·001). These findings indicate that the angiogenic process interacts with other stroma‐factors, such as reticulin fibre density, in its effect on outcome, and is coupled to both the ALL genotype and phenotype. One possible implication is that different subtypes of childhood ALL may respond differently to anti‐angiogenic drugs as a supplement in first‐line treatment.

Disease of the liver following bone marrow transplantation in children: incidence, clinical course and outcome in a long-term perspective

Sixty‐four consecutive cases of allogeneic (n= 16), autologous (n= 47) or syngeneic (n= 1) bone marrow transplantation (BMT) in children with haematological or lymphoid malignancy, aplasia or metabolic disease were reviewed to assess the incidence, clinical presentation and outcome of liver disease. Median follow‐up time was 5 y (1.0‐10). No liver diagnosis was established at the pre‐transplant check‐up. During the first 100d post‐transplant, 81% of the patients had impaired liver function as documented by various biochemical parameters. Three of 64 patients (5%) met diagnostic criteria for veno‐occlusive disease. Four (25%) of the 16 receiving allografts were diagnosed as having acute graft vs host disease (GVHD) with liver involvement (grades II‐III). No patient died of liver disease. During the late post‐transplant follow‐up, one patient developed HCV hepatitis after packed erythrocyte transfusion. Four patients were diagnosed as having chronic GVHD with liver involvement; three of them also had an episode of CMV hepatitis. At their latest follow‐up, the patients with chronic GVHD had aminotransferase values 1.5–3 times the normal, whereas all other long‐term survivors had normal or near‐normal liver function tests. We conclude that the incidence of serious liver disease was low in this paediatric population of bone marrow recipients.

Cataracts after autologous bone marrow transplantation in children.

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4‐10 y (median 8y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity < 0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well‐preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT.

Decreased bone mineral density in young adults treated with SCT in childhood: the role of 25-hydroxyvitamin D

We measured bone mineral density (BMD) with dual-energy X-ray absorptiometry in the total body, at the lumbar spine, at the femoral neck and in the total hip, in 18 young adults with a median of 18.2 years after SCT. Fifteen patients had undergone auto-SCT and all patients had received TBI. The patients had significantly lower BMD in the total body, at the femoral neck, and in the total hip compared with age- and sex-matched controls. Six of 18 patients (33%) had low bone mass (z-score <−1) at one or more measurement sites, as opposed to two of the controls (11%, P=0.29). We found no significant influence of growth hormone levels or of untreated hypogonadism on BMD variables. Levels of 25-hydroxy (25(OH)) vitamin D were lower among the patients (35.2 vs 48.8 nmol/L, P=0.044) and were significantly correlated with total body BMD in the patient group (r=0.55, P=0.021). All six patients with low bone mass had hypovitaminosis D (⩽37 nmol/L as opposed to 4 of the 11 (36%) patients without low bone mass (P=0.035). In conclusion, we found decreased BMD in SCT survivors, which may in part be caused by 25(OH) vitamin D deficiency.

Skin infection caused by Mycobacterium szulgai after allogeneic bone marrow transplantation

Summary:Infections are responsible for a large part of the morbidity and mortality after BMT because of the sustained impairment of host defenses. We report a case of cutaneous infection caused by Mycobacterium szulgai in a boy who underwent BMT with marrow from a matched unrelated donor.

Normal long-term parathyroid function after autologous bone marrow transplantation in children.

Abstract:  Parathyroid function was recently reported to be affected in more than one‐third of pediatric BMT patients conditioned without irradiation. Our aim was to describe parathyroid function in children with malignant hematological disease after autologous BMT with and without TBI. PTH, albumin‐corrected serum calcium, and serum phosphate were analyzed in 35 children followed for six months to nine yr after BMT. Twelve patients were conditioned with chemotherapy alone, and 23 patients received TBI as well. In the TBI group, 11 patients had previously received additional CRT. We found normal levels of PTH in children post‐BMT, with the exception of four patients (11%) who showed transient PTH elevation during the first year of follow‐up, There was no difference between those who had received irradiation and those who had not. Serum calcium was unchanged after BMT. An age‐corrected quotient of serum phosphate decreased slightly. Renal function which was normal before BMT decreased slightly in both groups after BMT, but was within the normal range. Parathyroid function was found to be normal during the time frame of this study, irrespective of whether irradiation had been given.