AIMS: To investigate whether serum amyloid A protein (SAA) and C-reactive protein (CRP) concentrations could be used in the management of beta thalassaemic patients undergoing bone marrow transplantation (BMT). METHODS: Serum SAA and CRP concentrations were determined in paired samples from 66 patients with beta thalassaemia before and after BMT. Serum SAA concentrations were determined by an enzyme linked immunoassay (EIA); serum CRP concentrations were determined by a nephelometric assay. RESULTS: Serum SAA concentrations before transplantation were significantly higher in the group that subsequently rejected the transplant than the group without complications. SAA concentrations increased after BMT in acute graft versus host disease (GvHD) and rejection. No significant increase in SAA or CRP was found in chronic GvHD. Increases in serum in SAA and CRP concentrations were not related to concomitant infection episodes. CONCLUSIONS: The different acute phase response in acute GvHD and rejection compared with chronic GvHD suggests that different immunopathogenic mechanisms are responsible.
Loss of bone mass is usually detected after bone marrow transplantation (BMT) during the early post-transplant period. However, little is known about the long-term effects of BMT on bone metabolism. We have prospectively investigated 11 patients undergoing BMT. Bone mineral density (BMD) was measured before BMT, and 1, 2, and 3 yr after BMT. Serum markers of bone turnover were serially measured before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 yr after BMT. The mean change in the lumbar spine (L2-4) BMD, calculated as the percent change from the baseline to the level at 1, 2, and 3 yr was -4.7% (NS), -1.1% (NS), and +6.4% (p<0.05), respectively. The mean change in the total proximal femur BMD from the baseline to the level at 1, 2, and 3 yr was -8.5% (p<0.01), -8.7% (p<0.05) and -5.6% (p<0.05), respectively. In summary, there was little decline in lumbar BMD at 1 yr following BMT and gradual recovery until 3 yr. In contrast, femoral BMD decreased much more than the lumbar area at 1 yr and did not recover until 3 yr. The mechanism of skeletal site-selective differences in the changes of BMD needs to be elucidated.
Introduction: High-dose chemotherapy and bone marrow transplantation result in direct and indirect changes in cardiac function. the finding suggests a decreased left ventricular diastolic compliance after high-dose cyclophosphamide treatment, but the effects of bone marrow transplantation (BMT) on cardiac diastolic function are less studied. We aimed to evaluate changes before and after the procedure in cardiac diastolic function in patients undergoing BMT. Design and methods: We designed this study to evaluate the effects of BMT on diastolic cardiac function. Patients with lymphoma (Hodgkin’s and non-Hodgkin’s), multiple myeloma, and solid tumors who were candidates for autologous BMT were selected for the study. The patients underwent a cardiac consultation and echocardiography before their admission for BMT. E-wave velocity and time to relaxation by tissue Doppler echocardiography in the septal, lateral, anterior, inferior, anteroseptal, and posterior wall; and the E-wave velocity of the right ventricle (RV) were measured before and after BMT. Result: Thirty patients fulfilled our inclusion criteria and entered the study. The mean diastolic function measures were calculated before and after BMT. E-wave velocity in the septal, lateral, anterior, inferior, anteroseptal and posterior walls after transplantation decreased by 19.2% (p=0.008), 14.5% (p=0.008), 22.19% (p=0.3), 18.9% (p<0.001), 21.9% (p=0.01), and 7.5% (p=0.01), respectively. The time to relaxation decreased by 13.5%, 13.7%, 12.4%, 11.4%, 11.1%, and 13.1%, respectively, after transplantation (p<0.001). E-wave velocity of RV decreased 15.6% after BMT (p=0.02). Conclusion: Data regarding alterations in diastolic functioning after BMT are scarce. This study suggests that diastolic function alters after BMT.
Bone marrow transplantation; echocardiography; tissue Doppler
Bone marrow transplantation (BMT) represents a cure for nonmalignant hematological disorders. However, compared with the stringent conditioning regimens used when performing BMT to treat hematological malignancies, the reduced intensity conditioning regimen used in the context of nonmalignant hematological disorders leads to substantially higher rates of BMT rejection, presumably due to an intact immune system. The relevant patient population typically receives transfusion support, often including platelets, and the frequency of BMT rejection correlates with the frequency of transfusion. Here, we demonstrate that immunity to transfused platelets contributes to subsequent BMT rejection in mice, even when the BMT donor and recipient are MHC matched. We used MHC-matched bone marrow because, although immunity to transfused platelets is best characterized in relation to HLA-specific antibodies, such antibodies are unlikely to play a role in clinical BMT rejection that is HLA matched. However, bone marrow is not matched in the clinic for minor histocompatibility antigens, such as those carried by platelets, and we report that transfusion of minor histocompatibility antigen–mismatched platelets induced subsequent BMT rejection. These findings indicate previously unappreciated sequelae of immunity to platelets in the context of transplantation and suggest that strategies to account for minor histocompatibility mismatching may help to reduce the chance of BMT rejection in human patients.
AIM—To examine the
long term effect of bone marrow transplantation (BMT) on ovarian
function in girls.
who underwent BMT before menarche, had been disease free for more than
six years, and were over 14 years of age at the time of study were
investigated. The preparative regimen consisted of irradiation and
chemotherapy. The occurrence of menarche and changes in basal serum
follicle stimulating hormone (FSH) concentrations were studied.
patients achieved menarche at a median age of 12.8 years. Age at
transplant was significantly younger in patients who achieved menarche
than in those who did not (mean (SD), 7.2 (0.5) v
11.1 (1.7) years). Basal FSH began to rise to menopausal
concentrations after 10 years of age, and the girls who did not
experience menarche had a sustained rise in FSH concentrations. Among
those with raised FSH concentrations, five girls experienced menarche
while serum FSH values were decreasing and four achieved menarche while
FSH remained raised.
incidence of menarche suggests a favourable outcome of ovarian function
in girls who undergo BMT at a young age.
Cardiac function is influenced by bone marrow transplantation (BMT). Studies have shown the various cardiotoxic effects of high-dose chemotherapy. In this study, we aimed to determine the effects of BMT on cardiac systolic function using echocardiographic indices.
Materials and Methods:
Patients with lymphoma (Hodgkin's and non-Hodgkin's), multiple myeloma, and solid tumors which were candidates for autologous BMT were selected. The tissue Doppler S wave velocity in left ventricular echocardiographic segments and the Swave velocity in right ventricle, the left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), and ejection fraction (EF) were measured before and after BMT.
Nineteen patients studied. The mean systolic function variable measures were calculated before and after BMT. The tissue Doppler S mean decreased in the septal, lateral and anterior walls by 8%, 7.9%, and 4.9% (P = 0.017), respectively. The tissue Doppler S mean increased in the inferior, anteroseptal and posterior walls by 1%, 0.6%, and 6.1%, respectively (not significant). The right ventricle Doppler S mean decreased by 7.5% after BMT (P = 0.03). The LVEDD and LVESD decreased significantly by 4.8% (P = 0.003) and 3.3% (P = 0.015), respectively, following BMT. The ejection fraction increased by about 7% after BMT (P = 0.05).
The tissue Doppler S increased in all LV walls in patients with an EF less than 47%; surprisingly, tissue Doppler S decreased in all patients with an EF greater than 47%; and the ejection fraction increased by 13.6% and 3.1% in patients with a pre-BMT EF less than 47% and above 47%, respectively.
Bone marrow transplantation; echocardiography; systolic function; tissue Doppler
the frequency and type of neurological complications after bone marrow
transplantation (BMT) with an HLA identical unrelated donor or a
mismatched related donor (alternative donors) to the neurological
complications after matched sibling BMT for standard and high risk
leukaemia or myelodysplastic syndromes.
analysis of consecutively treated patients with
(a) BMT from alternative donors (n=39),
(b) treated with matched sibling BMT for
standard risk leukaemia, myelodysplastic syndromes, or aplastic anaemia
(n=53), and (c) treated with matched sibling BMT for high risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=49).
RESULTS—A total of 72 neurological complications were found. Most of these occurred within
the first 6 months after transplant. Thirty six patients developed a
severe neurological complication: 17Alternative donor patients (44%)
by contrast with six standard risk patients (11%) and 13 high risk
patients (27%; p<0.005). The most frequent complication was a
metabolic encephalopathy occurring in 18% of patients. Most of the
encephalopathies were caused by either the transplant procedure,
cyclosporin, systemic infections, microangiopathic thrombopathy, or by
complications induced by graft versus host
disease. Infections of the CNS developed in 9% of patients,
cerebrovascular lesions in 3%.
neurological complications are more frequent after BMT from alternative
donors. This is mainly due to increased treatment related morbidity and
to more profound immunosuppression after BMT from alternative donors.
Cataract development in bone marrow transplanted (BMT) patients was studied prospectively. There were 61 children, transplanted before the age of 18 years, who survived more than 1 year after transplantation. Patients transplanted for leukaemia (n = 43) were conditioned before BMT with cyclophosphamide (Cy) and total body irradiation (TBI). Patients with severe aplastic anaemia (SAA) (n = 9) only received Cy. None of the patients with SAA developed cataracts. All children with leukaemia, who were followed for at least 3 years (n = 37), developed lens posterior subcapsular cataracts (PSC). Cataract extraction was performed in 28 eyes, on average 5.1 years (range 3-9 years) after BMT. Postoperative corrected visual acuity was similar to that before BMT. The majority of cases needed laser capsulotomy within 2 years after cataract extraction. TBI seems to be the main cause for the high incidence of cataract after BMT. A relationship to steroid administration could not be proved, but a contributory effect is not excluded.
We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.
Sickle cell anemia; Bone marrow transplantation; Long-term follow-up
Procalcitonin (PCT) is an early marker of bacterial infection but little is known about its value in neutropenic allogeneic bone marrow transplant (BMT) recipients. We collected plasma from 12 recipients of T-cell-depleted HLA-matched related BMT recipients who had been treated preemptively with meropenem from the day after BMT for at least 15 days. PCT and C-reactive protein (CRP) concentrations were determined on BMT days 1, 5, 8, 12, and 15, and their relationship to inflammatory events (IE), including mucositis, microbiologically and clinically defined infections, acute graft-versus-host disease (GVDH), and unexplained fever, was then determined. The PCT concentrations were all low and never exceeded 4 μg/liter, unlike CRP concentrations, which spanned the full range up to 350 mg/liter. All patients had mucositis, and there was no significant difference between PCT concentrations associated with mucositis alone and those associated with an additional IE on BMT days 1 to 12. However, on BMT day 15, the mean concentrations of PCT were 0.37 ± 0.05 μg/liter for the 10 patients that had an additional IE, compared with 0.11 ± 0.03 μg/liter for the 2 patients with mucositis only (P = 0.012), and GVHD rather than infection was involved in six cases. PCT was also not a sensitive marker of gram-positive bacteremia or pulmonary aspergillosis. Thus, PCT is of little value in discriminating infections from other inflammatory complications that occur following allogeneic BMT.
Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases.
Freshly harvested near-infrared fluorescence-labeled cells were noninvasively observed for 24 h after BMT using a photon counting device to track their homing process. In a congenic BMT model, the homing of Alexa Fluor 750-labeled donor cells in the tibia was detected less than 1 h after BMT. In addition, subsequent cell distribution in an intraBM BMT model was successfully monitored for the first time using this method. In the allogeneic BMT model, T-cell depletion decreased the near-infrared fluorescence (NIRF) signals of the reticuloendothelial system.
This approach in several murine BMT models revealed that the transplanted cells homed within 24 h after transplantation. NIRF labeling is useful for tracking transplanted cells in the initial phase after BMT, and this approach can contribute to in vivo studies aimed at improving the therapeutic outcomes of BMT.
AIMS--Animal studies have shown that antigens present within the gut play an important role in the development of acute graft versus host disease (GvHD) following allogeneic bone marrow transplantation (BMT). In previous studies, inert sugars have been found to penetrate the small bowel mucosa after conditioning therapy for BMT; endotoxaemia can also occur during acute GvHD. Data on absorption of antigenic proteins across the gut following BMT in humans have not been presented as yet. METHODS--Six patients undergoing allogeneic BMT were studied to determine whether enteric ovalbumin absorption increased or endotoxaemia developed during acute GvHD. RESULTS--Three patients had minimal antigenaemia and no detectable endotoxaemia before receiving conditioning therapy. At the onset of acute GvHD, however, much higher ovalbumin concentrations were detected in those patients with severe antigenaemia. Serum concentrations of specific antiovalbumin IgG and IgA, or antiendotoxin IgM or IgG had no bearing on detectable IgG or IgM ovalbumin or endotoxin concentrations. In five of six patients, small bowel permeability increased, as tested by the lactulose/mannitol sugar absorption test, but detectable ovalbumin absorption increased in only three of these and only two developed endotoxaemia. CONCLUSIONS--Antigens present within the gut can cross the mucosal epithelium during acute GvHD, probably resulting in an enhanced immune response.
It is generally agreed that euthyroid sick syndromes (ESS) are associated with an increased production of cytokines. However, there has been scarce data on the relationship thyroid hormone changes and cytokines among the patients undergoing bone marrow transplantation (BMT). Because interleukin-8 (IL-8) has been identified as a potent proinflammatory and interleukin-10 (IL-10) as an antiinflammatory cytokine, we studied the relation between thyroid hormone parameters and these cytokines following BMT. We studied 80 patients undergoing allogeneic BMT. Serum T3 decreased to nadir at post-BMT 3 weeks. Serum T4 was the lowest at the post-BMT 3 months. Serum TSH sharply decreased to nadir at 1 week and gradually recovered. Serum free T4 significantly increased during 3 weeks and then returned to basal level. Mean levels of serum IL-8 significantly increased at 1 week after BMT. Mean levels of serum IL-10 significantly increased until 4 weeks after BMT. No significant correlation was found between serum thyroid hormone parameters and cytokines (IL-8, IL-10) after adjusting steroid doses during the entire study period. In conclusion, ESS developed frequently following allogeneic BMT and cytokine levels were increased in post-BMT patients. However, no significant correlation was found between serum thyroid hormone parameters and these cytokines.
Partial splenectomy was performed on 30 patients with homozygous beta thalassaemia to reduce blood requirements and to avoid the risk of overwhelming postsplenectomy infections; 24 patients had thalassaemia major and six thalassaemia intermedia. Five patients received a high transfusion regimen before and after surgery and 25 a lower one. Follow up after surgery ranged from one to four years. Partial splenectomy improved the long term haematological state in the six patients with thalassaemia intermedia. Recurrence of hypersplenism occurred in nine of the 24 patients with thalassaemia major, however, and complete splenectomy was required. Serum IgM concentrations were not significantly modified by surgery. The mean (SD) residual spleen after surgery was 4.45 (2.36) cm measured by scintigraphy. No severe infections occurred after surgery; however, most patients were routinely treated with phenoxymethylpenicillin and the protective effect of the remaining spleen could not be exactly determined. Because of the possibility of recurrence of hypersplenism, routine partial splenectomy when splenectomy is needed in thalassaemia major is not advised, except in children under 5 years whose risk of overwhelming postsplenectomy infection is greatest.
outcome following neonatal bone marrow transplantation (BMT) for severe
combined immunodeficiency (SCID) when there is a family history of a
previously affected sibling, and to compare results with those
published for in utero BMT.
retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD)
complications after BMT, and T and B lymphocyte function. Thirteen
patients received 18 stem cell transplants: four whole marrow, one cord
blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD
unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide.
RESULTS—All are alive
and well (six months to 11.5 years after BMT). Six had grade I-II
acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT
for poor T cell function, one had a third BMT for graft failure and
chronic GvHD, and one had a third BMT for graft failure. Twelve have
good in vitro proliferation to T cell mitogens, and all have normal
serum IgA levels. Three receive intravenous immunoglobulin; for one of
these, it is less than one year since BMT. Nine are above the 2nd
centile, and 10 of 12 old enough to be assessed have normal neurodevelopment.
results are better than those published for in utero BMT for SCID.
Early postnatal BMT should be the preferred option in neonatal SCID.
Hematopoietic stem cell transplant patients are susceptible to infection despite cellular reconstitution. In a murine model of syngeneic bone marrow transplantation (BMT), we previously reported that BMT mice have impaired host defense against Pseudomonas aeruginosa pneumonia due to overproduction of (PG)E2 in lung. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an effector in the PGE2 signaling pathway that negatively regulates alveolar macrophage (AM) phagocytosis and bacterial killing. Therefore, examined whether overproduction of PGE2 after BMT inhibits AM host defense by up-regulating PTEN phosphatase activity. We found that PTEN activity is elevated in BMT AMs in response to increased PGE2 signaling and that pharmacological inhibition of PTEN activity in BMT AMs fully restores phagocytosis of serum-opsonized P. aeruginosa but only partially restores phagocytosis of nonopsonized P. aeruginosa. In wild-type mice transplanted with myeloid-specific conditional PTEN knockout (PTEN CKO) bone marrow, bacterial clearance is improved after challenge with P. aeruginosa pneumonia. Furthermore, PTEN CKO BMT AMs display improved TNF-α production and enhanced phagocytosis and killing of serum-opsonized P. aeruginosa despite overproduction of PGE2. However, AM phagocytosis of nonopsonized P. aeruginosa is only partially restored in the absence of PTEN after BMT. This may be related to elevated AM expression of IL-1 receptor–associated kinase (IRAK)-M, a molecule previously identified in the PGE2 signaling pathway to inhibit AM phagocytosis of nonopsonized bacteria. These data suggest that PGE2 signaling up-regulates IRAK-M independently of PTEN and that these molecules differentially inhibit opsonized and nonopsonized phagocytosis of P. aeruginosa.
pneumonia; lung; neutrophil; eicosanoids; bacteria
Although delirium is a common medical comorbidity with altered cognition as its defining feature, few publications have addressed the neuropsychological prodrome, profile, and recovery of patients tested during delirium. We characterize neuropsychological performance in 54 hemapoietic stem cell/bone marrow transplantation (BMT) patients shortly before, during, and after delirium and in BMT patients without delirium and 10 healthy adults. Patients were assessed prospectively before and after transplantation using a brief battery. BMT patients with delirium performed more poorly than comparisons and those without delirium on cross-sectional and trend analyses. Deficits were in expected areas of attention and memory, but also in psychomotor speed and learning. The patients with delirium did not return to normative “average” on any test during observation. Most tests showed a mild decline in the visit before delirium, a sharp decline with delirium onset, and variable performance in the following days. This study adds to the few investigations of neuropsychological performance surrounding delirium and provides targets for monitoring and early detection; Trails A and B, RBANS Coding, and List Recall may be useful for delirium assessment.
Bone marrow transplantation; Cognition; Cancer; Attention; Delirium
The kinetics of T and B cell immune recovery after bone marrow transplantation (BMT) is affected by many pre- and post-transplant factors. Because of the profoundly depleted baseline T and B cell immunity in recombination activating gene 2 (RAG-2)-deficient severe combined immunodeficiency (SCID) patients, some of these factors are eliminated, and the immune recovery after BMT can then be clearly assessed. This process was followed in ten SCID patients in parallel to their associated transplant-related complications. Early peripheral presence of T and B cells was observed in 8 and 4 patients, respectively. The latter correlated with pre-transplant conditioning therapy. Cells from these patients carried mainly signal joint DNA episomes, indicative of newly derived B and T cells. They were present before the normalization of the T cell receptor (TCR) and the B cell receptor (BCR) repertoire. Early presentation of the ordered TCR gene rearrangements after BMT occurred simultaneously, but this pattern was heterogeneous over time, suggesting different and individual thymic recovery processes. Our findings early after transplant could suggest the long-term patients' clinical outcome. Early peripheral presence of newly produced B and T lymphocytes from their production and maturation sites after BMT suggests donor stem cell origin rather than peripheral expansion, and is indicative of successful outcome. Peripheral detection of TCR excision circles and kappa-deleting recombination excision circles in RAG-2-deficient SCID post-BMT are early markers of T and B cell reconstitution, and can be used to monitor outcome and tailor specific therapy for patients undergoing BMT.
α-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic α-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.
The effects of allogeneic bone marrow transplantation (BMT) on non- insulin-dependent diabetes mellitus (NIDDM) were examined using KK-Ay mice. KK-Ay mice reconstituted with KK-Ay bone marrow cells showed glycosuria, hyperinsulinemia, and hyperlipidemia. However, KK-Ay mice (H-2b) that had been lethally irradiated (9.0 Gy) and then reconstituted with T cell-depleted bone marrow cells from normal BALB/c mice (H-2d) showed negative urine sugar with decreases in serum insulin and lipid levels 4 mo after BMT. Morphological recovery of islets and glomeruli was also noted after allogeneic BMT. These findings suggest that BMT can be used to treat not only a certain type of NIDDM but also its complications such as hyperlipidemia and diabetic nephropathy.
Plasma concentrations of beta 2 microglobulin (B2M), the light chain of the class I major histocompatibility complex, were measured serially in 26 patients undergoing allogeneic bone marrow transplantation (BMT). The concentrations fell after conditioning treatment, and recovered when the marrow was transplanted. Bacterial infection did not influence B2M concentration, but nine of 22 episodes of acute graft versus host disease were associated with raised concentrations. Increased plasma B2M concentrations were also a feature of eight episodes of chronic graft versus host disease, and these fell after treatment. Reactivation of herpes simplex, varicella zoster, or cytomegalovirus infections were also accompanied by raised B2M concentrations. Three patients with cytomegalovirus pneumonitis had high concentrations of plasma B2M, the rise starting between five and 22 days before onset of symptoms. Although it is non-specific, serial measurement of plasma B2M in patients undergoing BMT may be clinically useful in monitoring chronic graft versus host disease.
Bone marrow transplant (BMT) is a common treatment option for adolescents with various diseases; however, the aggressive therapy often causes significant side effects that can lead to poor eating. There is little documentation of eating experiences and necessary support needed after the initial BMT hospitalization. This phenomenological study, guided by Martin Heidegger’s philosophical influences, revealed the meaning of adolescents’ eating experiences, eating strategies, and the impact of eating on the adolescents’ quality of life during the first 100 days post-BMT. Individual interviews were conducted at 50 and 100 days post-BMT. Data analysis used the hermeneutic circle and revealed 5 themes. Adolescents discussed the slow return of eating, barriers that affected their eating, personal eating strategies, significance of eating, and feelings regarding eating. Eating issues do not end when a BMT patient is discharged from the hospital, and caregivers need to have a better understanding of the ongoing issues affecting adolescents throughout the BMT recovery phase.
bone marrow transplant; eating; adolescents; phenomenology
There is considerable variation in the use of HLA-matched related bone marrow transplantation (BMT) for the treatment of pediatric patients with newly diagnosed acute myeloid leukemia (AML). Some oncologists have argued that BMT should be offered to most patients in first complete remission (CR). Others have maintained that transplantation in first remission should be reserved for patients with high-risk disease. We performed this study to determine how disease risk influences the efficacy of BMT.
We combined data from four cooperative group clinical trials: Pediatric Oncology Group 8821, Children's Cancer Group (CCG) 2891, CCG 2961, and Medical Research Council 10. Using cytogenetics and the percentage of marrow blasts after the first course of chemotherapy, patients were stratified into favorable, intermediate, and poor-risk disease groups. Patients who could not be risk classified were analyzed separately. Outcomes for patients assigned to BMT and for patients assigned to chemotherapy alone were compared.
The data set included 1,373 pediatric patients with AML in first CR. In the intermediate-risk group, the estimated disease-free survival at 8 years for patients who did not undergo transplantation was 39% ± 5% (2 SE), whereas it was 58% ± 7% for BMT patients. The estimated overall survival for patients who did not undergo transplantation was 51% ± 5%, whereas it was 62% ± 7% for BMT patients. Both differences were significant (P < .01). There were no significant differences for survival in the other two risk groups or in the non–risk-stratified patients.
Our study indicates that HLA-matched related BMT is an effective treatment for pediatric patients with intermediate-risk AML in first CR.
Beta-thalassemia and sickle cell anemia (SCD) represent the most common hemoglobinopathies caused, respectively, by deficient production or alteration of the beta chain of hemoglobin (Hb). Patients affected by the most severe form of thalassemia suffer from profound anemia that requires chronic blood transfusions and chelation therapies to prevent iron overload. However, patients affected by beta-thalassemia intermedia, a milder form of the disease that does not require chronic blood transfusions, eventually also show elevated body iron content due to increased gastrointestinal iron absorption. Even SCD patients might require blood transfusions and iron chelation to prevent deleterious and painful vaso-occlusive crises and complications due to iron overload. Although definitive cures are presently available, such as bone marrow transplantation (BMT), or are in development, such as correction of the disease through hematopoietic stem cell beta-globin gene transfer, they are potentially hazardous procedures or too experimental to provide consistently safe and predictive clinical outcomes. Therefore, studies that aim to better understand the pathophysiology of the hemoglobinopathies might provide further insight and new drugs to dramatically improve the understanding and current treatment of these diseases. This review will describe how recent discoveries on iron metabolism and erythropoiesis could lead to new therapeutic strategies and better clinical care of these diseases, thereby yielding a much better quality of life for the patients.
Hemoglobinopathies; iron metabolism; erythropoiesis; mouse models; hemochromatosis; hepcidin; ferroportin
We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11 can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell–depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic B6 donors. Animals also received host-type P815 mastocytoma cells at the time of BMT. Recipients were injected subcutaneously with recombinant human IL-11 or control diluent twice daily, from 2 days before BMT to 7 days after BMT. TCD recipients all died from leukemia by day 23. All control- and IL-11–treated allogeneic animals effectively rejected their leukemia, but IL-11 also reduced GVHD-related mortality. Examination of the cellular mechanisms of GVL and GVHD in this system showed that IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. In addition, IL-11 treatment did not affect cytolytic effector functions of T cells after BMT either in vivo or in vitro. Studies with perforin-deficient donor T cells demonstrated that the GVL effect was perforin dependent. These data demonstrated that IL-11 can significantly reduce CD4-dependent GVHD without impairing cytolytic function or subsequent GVL activity of CD8+ T cells. Brief treatment with IL-11 shortly after BMT may therefore represent a novel strategy for separating GVHD and GVL.