Allogeneic Bone Marrow Transplant Recipients Research Articles

Self-concept as a “BMT patient”, illness intrusiveness, and engulfment in allogeneic bone marrow transplant recipients

Objective The experience of cancer and its treatment by bone marrow transplantation (BMT) can enhance the salience of one's status as a patient in the evolution of self-concept. Illness and the patient role can come to dominate the sense of self, resulting in feelings of hopelessness, helplessness, and distress (“engulfment”). Illness-induced lifestyle disruptions (“illness intrusiveness”) introduce adaptive demands, challenging preexisting conceptions of self. Illness intrusiveness and engulfment may interact, leading affected individuals to construe themselves as highly similar to a prototypical “BMT patient”. Methods Ninety allogeneic BMT outpatients completed the Illness Intrusiveness Ratings Scale, Modified Engulfment Scale, and a semantic differential measure of self-concept as a BMT patient in an interview context. Results Illness intrusiveness correlated significantly with engulfment ( r=.58, P<.0001) and with self-concept as a BMT patient ( r=.27, P<.016). Engulfment did not correlate significantly with self-concept as a BMT patient ( r=.15). Multiple regression analysis, controlling for relevant covariates, indicated a significant Illness Intrusiveness×Engulfment interaction effect on self-concept as a BMT patient [ F(1,84)=4.93, P<.029]. Conclusions Self-concept as a BMT patient increases as cancer and its treatment introduce increasing lifestyle disruptions (illness intrusiveness). These effects are amplified when self-experience is dominated by disease and treatment and patients feel helpless, hopeless, and distressed (engulfment).

Constitution and telomere dynamics of bone marrow stromal cells in patients undergoing allogeneic bone marrow transplantation.

We evaluated the genotypic origin of mesenchymal stem cells (MSC) following sex-mismatched allogeneic bone marrow transplantation (BMT), and investigated the telomere dynamics in MSC in normal individuals and patients after BMT. The study population consisted of 11 patients with hematologic disorders who showed complete chimerism after BMT. Telomere length was measured in MSC using Southern blotting analysis in eight patients and 18 healthy subjects as a control group. Following culture, MSC were identified by the expression of SH2 and SH4, and lack of CD14, CD34, and CD45. All MSC showed the recipient genotype, based on the results of fluorescent in situ hybridization analysis using X-chromosome satellite probes or microsatellite DNA polymorphism analysis. The mean telomere length in MSC from normal controls was 7.2+/-0.53 kb (range, 6.12-7.78), and progressive telomere shortening was seen with age. There was no significant difference in MSC telomere length between the BMT group and age-matched controls. This study confirmed that the MSC isolated from the recipients of allogeneic BMT did not have the donor genotype, despite complete chimerism. Moreover, MSC were demonstrated to show progressive loss of telomere length with age, but the telomeres in MSC were not affected by BMT.

Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes

Bronchiolitis obliterans (BrOb), a late complication of bone marrow transplantation (BMT), is associated with chronic graft-versus-host disease (GVHD) and is frequently fatal. To identify the risk factors associated with BrOb, the factors affecting survival, treatment outcomes, and causes of death of patients with BrOb, we retrospectively analyzed 2859 BMT recipients. No cases of BrOb occurred among 1070 autologous BMT recipients. Among 1789 allogeneic BMT recipients, we identified 47 patients with BrOb. In multivariate analysis, older recipients or donors and acute GVHD were significantly associated with the development of BrOb. Among patients with BrOb, 5-year survival from the time of transplantation was only 10%, versus 40% among allogeneic BMT recipients without BrOb. The clinical course of BrOb had a significant effect on survival: 79% survived 5 years from the time of BrOb diagnosis if BrOb improved versus 13% if there was no improvement after the first-line therapy. Predictors of response included older donors and recipients, a previous diagnosis of chronic GVHD, and diagnosis of BrOb 6 months after transplantation; each of these significantly increased the likelihood of a favorable response to treatment. BrOb had high mortality rate of 55%, and pulmonary failure was the leading cause of death. More effective BrOb therapy is needed, especially for patients with unfavorable presentation.

Repifermin (keratinocyte growth factor-2) reduces the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect

Graft-versus-host disease (GVHD) is the principal complication after allogeneic bone marrow transplantation (BMT). Reductions in systemic GVHD are frequently associated with a corresponding diminishment of the graft-versus-leukemia (GVL) response. In this study, we tested the effects of a novel recombinant human keratinocyte growth factor, repifermin (keratinocyte growth factor-2), on the induction of GVHD in a well-defined murine BMT model (B6 → B6D2F1). Administration of repifermin (5 mg/kg/d) to allogeneic BMT recipients resulted in a significant decrease in both systemic GVHD and target organ histopathology. Repifermin treatment also reduced serum levels of tumor necrosis factor α and lipopolysaccharide compared with control mice. In contrast, repifermin did not affect T-cell proliferation, cytokine production, or cytotoxic responses to host antigens. When 2000 host-derived P815 (H-2 d) leukemia cells were added to the bone marrow inoculum, repifermin preserved GVL effects and resulted in significantly delayed mortality compared with control-treated allogeneic BMT recipients. Collectively, these data suggest that repifermin administration may represent a novel strategy to separate the toxicity of GVHD from the beneficial GVL effects after allogeneic BMT.

Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia

AbstractActivating mutations of receptor tyrosine kinases (RTKs) and their downstream affectors are common in acute myeloid leukemia (AML). We performed mutational analysis of FLT3, c-kit, c-fms, vascular endothelial growth factor (VEGF) receptors (Flt-1, KDR [kinase domain receptor]), and ras genes in a group of 91 pediatric patients with AML treated on Children’s Cancer Group clinical trial CCG-2891. Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes. Mutation-positive patients had a higher median diagnostic white blood cell (WBC) count (71.5 vs 19.6 × 109/L; P = .005) and lower complete remission rate (55% versus 76%; P = .046) than mutation-negative patients. The Kaplan-Meier estimate of overall survival (OS) for patients with and without an activating mutation was 34% versus 57%, respectively (P = .035). However, within this group, patients with FLT3/ALM (activation loop mutation) had good outcomes (OS, 86%). Exclusion of the FLT3/ALM from analysis decreased the OS for the remaining mutation-positive patients to 26% (P = .003). Ten of the 23 mutation-positive and 11 of the 34 mutation-negative patients received an allogeneic bone marrow transplant (BMT) in first complete remission (CR). In the mutation-positive group, the disease-free survival (DFS) for the allogeneic BMT recipients was 72% versus 23% for the 13 patients who received chemotherapy or autologous BMT (P = .01). DFS for the mutation-free patients with and without allogeneic BM transplantation was 55% and 40%, respectively (P = .38). Activating mutations in the RTK/ras signaling pathway are common in pediatric AML, and their presence may identify a population at higher risk of poor outcome who may benefit from allogeneic BM transplantation.

Fulminant adenovirus hepatitis following bone marrow transplantation. A case report and brief review of the literature.

Adenovirus infections are frequently encountered in immunocompromised patients and transplant recipients. However, fulminant hepatic failure due to adenovirus infection as a fatal complication in bone marrow transplant recipients is extremely rare. We report a case of fulminant adenovirus hepatitis in a 21-year-old allogeneic bone marrow transplant recipient who subsequently died of the disease. The diagnosis was established by histologic and immunohistochemical examination of a liver biopsy and was confirmed by liver tissue and blood cultures.

Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients

OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40(-/-) donor or OX40L(-/-) recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4(+) and CD8(+) T cells isolated during GVHD, the major effects of OX40 ligation were on CD4(+) and not CD8(+) T-cell-mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription-6(-/-) (Stat-6(-/-)) (Th2-defective) or Stat-4(-/-) (Th1-defective) major histocompatibility complex (MHC)-disparate splenocytes, indicating that the GVHD-ameliorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L(-/-) versus OX40L(+/+) T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD.

Hypophosphatemia and hypouricemia in pediatric allogeneic bone marrow transplant recipients.

Increased phosphate (P) uptake by the replicating neutrophils during engraftment syndrome has been described to play a role in the development of hypophosphatemia (HP) in bone marrow transplantation patients, and suggested as a measure of neutrophil recovery. Here, the relationship of serum P with engraftment was determined in 56 children who underwent allogeneic bone marrow transplantation (BMT). Uric acid (UA) levels were also analyzed to study the contribution of cytolysis on P levels. HP and hypouricemia (HU) developed at least once in 63 and 57% of patients respectively, before and until day +20 after transplantation. The minimal values of P and UA were observed at day +10 and were significantly lower than the baseline values (p < 0.01). The mean neutrophil engraftment was at day +13, following the P and UA nadir by 3 days. In addition there was a significant correlation between P and UA levels (p = 0.01). The levels of of both P and UA returned to pretransplant values at day +20. A significant correlation (p < 0.05) between platelet engraftment and P levels was also demonstrated. HP and HU seen in pediatric patients undergoing BMT reflects a combination of pathophysiologic mechanisms.

Systemic nocardiosis following allogeneic bone marrow transplantation

Five cases of systemic Nocardia infection were diagnosed among 301 allogeneic bone marrow transplant recipients. A sixth case included in this report received her transplant at another institution. The cumulative annual incidence rate of this infection was 1.75%. All patients had been treated previously for acute graft-versus-host disease (GVHD). At the time of diagnosis of systemic Nocardia infection, a median of 198 (range 148-1121) days after transplantation, all patients had extensive chronic GVHD and were taking 2 to 3 immunosuppressive medications. Prior to diagnosis of Nocardia infection patients had experienced multiple opportunistic infections, including infections with Mycobacterium avium-intracellulare, Pneumocystis carinii, and cytomegalovirus antigenemia. Treatment with trimethoprim-sulfamethoxazole (TMP-SMX), ceftriaxone, or carbapenem antibiotics resulted in a median survival of 219 days from the time of diagnosis and an actuarial 1-year survival of 40%. All patients who received more than 2 weeks of therapy were cured of their infections. Notably, 5/6 patients in this cohort were unable to take TMP-SMX because of myelosuppression. In comparison with randomly selected control patients, the use of pentamidine for prevention of P. carinii infection was associated with a marginal increase in the risk of Nocardia infection. We postulate that the use of TMP-SMX may be of benefit in the prophylaxis of infections other than P. carinii in patients with chronic GVHD.

Pretransfusion incubation of apheresis platelets at 37 degrees C improves posttransfusion recovery.

The effect of brief 37 degrees C pretransfusion incubation of apheresis platelets (n = 25) was studied in 14 allogenic bone marrow transplant recipients (5 children, 9 adults). Apheresis platelets were collected on a cell separator, divided in two aliquots, and stored 1 to 5 days at 22 degrees C during agitation. One aliquot was incubated at 37 degrees C for 1 hour before transfusion, and the other was transfused as a paired control. When the patient's peripheral platelet count fell below 30 x 10(9) per L, one aliquot was transfused. The other aliquot was transfused the following day. Each patient received the two aliquots in random order. Corrected count increment (CCI) at 1 hour after transfusion of 37 degrees C incubated platelets was 12.2 +/- 9.5 (mean +/- SD) compared to 7.5 +/- 5.4 for paired control platelets (p < 0.05). CCIs the next day were 4.4 +/- 6.1 and 2.4 +/- 2.7, respectively (not significant). It can be concluded that 37 degrees C incubation of apheresis platelets improves posttransfusion CCI.

Analysis of sepsis in allogeneic bone marrow transplant recipients: a single-center study.

We reviewed the records of 235 consecutive recipients of allogeneic bone marrow transplantation (allo-BMT) at our center between February 1983 and October 2000. Sepsis occurred in 25 patients (10.6%) at a median of 10 days (range, 1-280 days) after BMT. Five of the 25 patients (20%) died of sepsis. Pathogens isolated from blood culture were gram-positive cocci in 19 patients, gram-negative rods in 7, fungi in 2, and others in 1 patient. Two pathogens were detected concomitantly in 4 patients. Univariate analysis revealed that risk factors for sepsis were selective gut decontamination using lomefloxacin hydrochloride and nystatin, an unrelated donor, HLA mismatched BMT, and stomatitis. Multivariate logistic regression analysis revealed that an unrelated donor was the only significant independent risk factor, with a relative risk of 5.432. In 12 of 25 patients with sepsis, the pathogens of sepsis were sensitive to antibiotics used for gut decontamination. Selective gut decontamination significantly increased the incidence of sepsis, especially that with gram-positive cocci, but not the mortality rate of sepsis, compared with total gut decontamination using vancomycin. We also found a significant relationship between pathogens isolated from blood culture and those isolated from surveillance cultures of stool, urine, and gargled water in the period before sepsis occurred. The present study revealed an independent risk factor for sepsis (unrelated donor), the feasibility of selective gut decontamination, and the importance of surveillance culture.

Risk Factors for Bronchiolitis Obliterans in Allogeneic Bone Marrow Transplant Recipients for Leukemi

Risk Factors for Bronchiolitis Obliterans in Allogeneic Bone Marrow Transplant Recipients for Leukemi

Prevention and treatment of epstein–barr virus‐associated lymphoproliferative disorders in recipients of bone marrow and solid organ transplants

Prevention and treatment of epstein–barr virus‐associated lymphoproliferative disorders in recipients of bone marrow and solid organ transplants

Naevi in allogeneic bone marrow transplantation recipients: the effect of graft-versus-host disease on naevi.

Non-melanoma skin carcinoma is more common in transplant recipients, probably because of immunosuppression. An increased risk of developing melanoma could be a late effect of transplantation. The number of naevi, which is a risk marker for melanoma, is increased in renal transplant recipients of all ages and may be related to immunosuppression. The risk of melanoma has been suspected to be particularly high after bone marrow transplantation. Cutaneous graft-versus-host disease (GVHD) might be an interesting model for the study of interactions between naevi and the immune system. To assess whether aBMT exposes an individual to a particularly high risk of melanoma, using naevi as a surrogate measure of the risk. To improve our knowledge of the effect of the immune system on naevi, using GVHD as a model. We carried out an epidemiological case-control study with two age-, sex- and hair colour-matched controls for each case. The results were analysed with analysis of variance, a general linear model analysis and multivariate analysis. The number of naevi was not significantly increased in aBMT patients, as compared with controls, although there was a significant excess on the palms and legs. In exploratory subgroup case-control comparisons and with the general linear model, patients who were conditioned with a combination of two alkylating drugs at high doses, and patients who had an aBMT before the age of 20 years tended to have a higher count of naevi (P = 0.002 and P = 0.06, respectively). Conversely, there was a trend in favour of a lower count of naevi in patients with diffuse skin lesions of chronic GVHD (P = 0.01). These data were corroborated by multivariate analysis, which showed that conditioning with high-dose chemotherapy, the absence of severe chronic cutaneous GVHD and a young age at transplantation were the main variables that independently predicted an excess of naevi. This study of aBMT patients confirms that chemotherapy stimulates naevus growth. It also suggests for the first time that diffuse lesions of chronic cutaneous GVHD are associated with a decreased number of naevi. Whether allo-immunity, chronic skin inflammation or the masking of naevi by pigmentation and fibrosis is responsible for the decreased number of naevi requires further investigation. With respect to the long-term risk of melanoma in aBMT recipients, our results support an increased risk particularly when aBMT is performed at a young age, and when conditioning is with high doses of alkylating drugs.

Telomere length analysis on cord blood cells by the flow-FISH method

Telomerase is the enzyme responsible for synthesizing telomeric repeats at the ends of chromosomes to maintain telomere length. Recent studies have suggested that telomere shortening may serve as a surrogate marker of the progression of malignant disorders and seems to be accelerated in allogeneic bone marrow transplant recipients. In this study, the results of the telomere length of nine cord blood mononuclear cell samples are presented. Telomere length was measured by the flow-FISH method, using a peptide nucleic acid probe. The proportion of cord blood cell subsets (CD19/CD34/CD3) was also evaluated. The telomere length of the internal control 1301 cell line was estimated to be 100%. The mean telomere length of cord blood cells was 18.5 +/- 3.9%, compared with the internal control. The progenitor CD34+ cells were detected as 2.6 +/- 0.7% in the lymphoid gate measured. Linear correlation analysis did not find any connection between the cell subsets (CD3+, CD34+, CD19+) and the telomere length. The findings confirm that the telomere flow-FISH method is sufficient for estimation of the telomere length. Assessment of the current procedures of collection, manipulation, and ex vivo expansion of cord blood cells in terms of their effect on telomere shortening might be important.

Non-endocrine late complications of bone marrow transplantation in childhood: part II.

Non-endocrine late complications of bone marrow transplantation in childhood: part II.

Human leucocyte antigen alloimmunization after bone marrow transplantation: an association with chronic myelogenous leukaemia

Platelet refractoriness due to human leucocyte antigen (HLA) alloimmunization is a significant risk to allogeneic bone marrow transplant recipients. To identify factors contributing to this risk, we reviewed the records of 317 consecutive, paediatric, allogeneic bone marrow transplant recipients at a single institution. The 6-year estimated cumulative incidence of platelet refractoriness due to HLA alloimmunization was 2.6% +/- 0.9%. The incidence among patients with chronic myelogenous leukaemia (CML) 12.5% +/- 5.3% was significantly greater than that of other patients (1.1% +/- 0.6%, P < 0.001). Graft rejection (P = 0.003) and the number of platelet transfusions during the first 90 d after bone marrow transplantation (BMT) (P = 0.0025) were also significantly associated with alloimmunization. The association with CML and with graft rejection was not seen among patients alloimmunized before transplantation. Eight patients developed alloimmunization, of whom three had mismatched grafts and four had unrelated grafts. Alloantibody specificities, identified in seven patients, were unrelated to host or graft major histocompatibility complex (MHC). Host recognition of alloantigens in transfused blood products, not graft-host recognition, therefore seems predominantly responsible for the alloimmunization. These results show that paediatric CML patients have a significantly increased risk of platelet refractoriness due to HLA alloimmunization after BMT. Identifying the mechanism for the increased alloimmunization risk may assist in the development of therapies to prevent platelet refractoriness.

Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants

AbstractOral valacyclovir for cytomegalovirus (CMV) prophylaxis in bone marrow transplantation (BMT) was investigated in a randomized, double-blind, acyclovir-controlled, multicenter clinical trial in recipients of allogeneic BMT who were CMV seropositive (or donor positive) before transplantation and were aged 13 years or older. Patients were randomized before BMT. All initially received intravenous acyclovir (500 mg/m2) 3 times daily until day 28 after transplantation or after discharge, then oral valacyclovir (2 g) or acyclovir (800 mg) 4 times daily until week 18 after transplantation. Evidence of CMV infection, CMV disease, and death were documented for 22 weeks. Primary end points were time to CMV infection (detection of CMV in blood, broncho-alveolar lavage) or CMV disease and survival. Preemptive CMV therapy was permitted. Seven hundred twenty-seven patients were evaluable for efficacy. After the administration of intravenous acyclovir, valacyclovir was significantly more effective than oral acyclovir in reducing the incidence of CMV infection. CMV infection or disease developed in 102 (28%) valacyclovir patients, compared with 143 (40%) acyclovir patients (HR, 0.59; 95% CI, 0.46-0.76; P < .0001). Survival did not differ between treatments (76% and 75% in the valacyclovir and acyclovir groups, respectively). The safety of oral valacyclovir was similar to that of high-dose oral acyclovir. Valacyclovir was more effective than acyclovir in preventing CMV reactivation in BMT recipients and showed a similar safety profile. CMV disease incidence was low, and no differences were observed between oral valacyclovir and acyclovir. Survival was similar in each group. Valacyclovir prophylaxis provides a clinically valuable intervention but must be part of an overall strategy for CMV prevention in BMT.

Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors.

Human herpesvirus 6 (HHV-6) infection was studied in 82 bone marrow transplant (BMT) recipients (72 allogeneic, 10 autologous). All recipients and 30 donors were seropositive for HHV-6 antibody at the time of bone marrow transplantation. Thirty-one recipients (37.8%) had HHV-6 viremia 2-4 weeks after transplantation. The incidence of HHV-6 viremia was significantly higher among allogeneic BMT recipients than in autologous BMT recipients (P=.011). Therefore, the following analyses of allogeneic BMT recipients were carried out (n=72). Geometric mean antibody titers (log(10)) were significantly higher in recipients without viremia than in those with viremia (1.84+/-0.39 vs. 1.61+/-0.42; P=.022). Logistic regression analysis demonstrated that leukemia or lymphoma is an independent risk factor (P=.031) for HHV-6 viremia. Rash occurring within 1 month after transplantation was observed in 17 (54.8%) of 31 recipients with HHV-6 viremia but in only 8 (19.5%) of 41 recipients without HHV-6 viremia (P=.001).

Cataract surgery in allogeneic bone marrow transplant recipients with graft-versus-host disease

Purpose To study the outcomes of cataract surgery in allogeneic bone marrow transplant recipients with documented graft-versus-host disease (GVHD) and to elucidate the concomitant ocular surface problems often encountered in these patients. Setting W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. Methods This retrospective study comprised 12 cataract surgeries in 7 patients with GVHD) after allogeneic bone marrow transplantation. In particular, visual acuity improvement, surgical complications, and problems associated with concomitant ocular surface disease were reviewed. Results The mean visual acuity improved significantly from 20/46 (logMAR 0.32) preoperatively to 20/21 (logMAR 0.02) postoperatively ( P < .005). The mean postoperative follow-up was 23 months (range 3 to 48 months). All patients had dry eyes, and 3 had conjunctival cicatrization with mild keratinization. No patient had postoperative corneal breakdown. Conclusion With aggressive management of dry eyes and other ocular surface problems, cataract surgery had excellent outcomes in patients with GVHD.