Assessment of ST2 and Reg3a levels in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Background/aim: Graft-versus-host disease (GVHD) is a crucial complication leading to significant morbidity and mortality allogeneic hematopoietic stem cell transplantation which occurs in approximately half of the transplant recipients. Suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha(Reg3a) might be important biomarkers to predict acute GVHD. Materials and methods: In the present study, blood samples were collected from 17 patients with acute GVHD and 12 control patients after allogeneic stem cell transplantation. ST2 and Reg3a were measured in plasma samples compared in patients with acute GVHD and the controls. Results: Median age of the study population was 42 years (range 19­49). When compared to controls, the mean ST2 levels was significant higher in acute GVHD (9794 ng/dL vs. 2646 ng/dL, P = 0.008). Mean Reg3a level did not show significant difference between control and acute GVHD group (8848 ng/dL vs. 5632 ng/dL, respectively, P = 0.190). Conclusion: The ST2 level might be used as a significant biomarker for predicting acute GVHD.

Flexible semi-parametric regression of state occupational probabilities in a multistate model with right-censored data.

Inference for the state occupation probabilities, given a set of baseline covariates, is an important problem in survival analysis and time to event multistate data. We introduce an inverse censoring probability re-weighted semi-parametric single index model based approach to estimate conditional state occupation probabilities of a given individual in a multistate model under right-censoring. Besides obtaining a temporal regression function, we also test the potential time varying effect of a baseline covariate on future state occupation. We show that the proposed technique has desirable finite sample performances and its performance is competitive when compared with three other existing approaches. We illustrate the proposed methodology using two different data sets. First, we re-examine a well-known data set dealing with leukemia patients undergoing bone marrow transplant with various state transitions. Our second illustration is based on data from a study involving functional status of a set of spinal cord injured patients undergoing a rehabilitation program.

The burden of care and quality of life of caregivers of leukemia and lymphoma patients following peripheric stem cell transplantation.

This study was conducted to identify the burden of care and quality of life of caregivers of leukemia and lymphoma patients who had undergone peripheric stem cell transplantation. The sample consisted of 123 patient caregivers, all of whom were relatives. Data were collected using a survey, the Burden Interview, and the Caregiver Quality of Life Index Cancer Scale. Data evaluation was done using correlation analysis, Kruskall Wallis, and Mann-Whitney U tests. Factors that were significantly associated with quality of life and care burden perception included caring for an older patient, patient dependence for daily activities, and having low economic status.

Individual physician practice variation in hematopoietic cell transplantation.

PURPOSE: Previous studies have evaluated practice variation in hematopoietic cell transplantation (HCT) among transplant centers and countries. There are no studies investigating individual physician practice variation in HCT. METHODS: An international Internet-based survey of transplant physicians collected data on medical decisions made by adult and pediatric HCT physicians. Multivariable analyses identified practitioner and transplant center characteristics predictive of medical decision making. RESULTS: Analysis of 526 assessable respondents showed a wide variation in management approaches to specific clinical scenarios. Pediatric and adult transplant physicians differed significantly in their management strategies for chronic myeloid leukemia, acute and chronic graft-versus-host disease, and choice of graft source for patients with aplastic anemia. Among adult transplant physicians, there was little agreement on the patient factors favoring reduced intensity conditioning or myeloablative conditioning. CONCLUSION: These results emphasize the heterogeneity of worldwide transplant practices. Local preferences or biases likely result in similar patients being offered different transplant and treatment procedures. The degree of practice variation also highlights the need for clinical trials to clarify areas of controversy. Where clinical trials are not feasible, data from observational studies may be the best available evidence to guide practice.

Patterns of T-cell reconstitution by assessment of T-cell receptor excision circle and T-cell receptor clonal repertoire after allogeneic hematopoietic stem cell transplantation in leukemia patients--a study in Chinese patients.

OBJECTIVE: Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution normal T-cell immunity. Measurement of T-cell receptor excision circles (TRECs) and T-cell receptor beta (TCRBV) CDR3 repertoire is a means of quantifying recent thymic T-cell production and reflecting antigen-specific T-cell clones proliferation. METHODS: We used real-time quantitative PCR to detect TRECs from 43 Chinese patients who underwent three kind of allo-HSCT without T-cell depletion. RT-PCR was performed to amplify 24 subfamily genes of TCRBV in 24 patients of them. RESULTS: For haploidentical-D group, the TRECs numbers were lower up to 24 months. For matched-sibling donor (MSD) group, the recovery of TRECs was faster than those of other two groups. TRECs values in matched-unrelated donor (MUD) were in the middle. During 2-19 months after transplantation, there were 6-16 BV subfamilies expressed and 33-48% of them were polyclones. The usage rate of TCRBV and percentage of polyclones in haploidentical-D were less than those of other two groups. Twenty-three CDR3 molecules were obtained from nine patients who were potentially associated with GVHD or CMV infection. CONCLUSIONS: Analyzing the changes of TCRBV repertoire and measuring TRECs during immune reconstitution would be useful to determine the host's current immune status and ability of T-cell immune reconstitution and also to find antigen-specific T-cell clones in the three kinds of HSCT.

The cost-effectiveness of stem cell transplantations from unrelated donors in adult patients with acute leukemia.

OBJECTIVE: Hematopoietic stem cell transplantation is an accepted treatment of hematological malignancies, but the cost-effectiveness of this technology has not been fully explored. This study aims to assess the cost-effectiveness of stem cell transplantation from either cord blood or bone marrow/peripheral blood compared with no transplantation in adult patients with acute leukemias not expected to be cured with chemotherapy. METHODS: A systematic review was performed to estimate the efficacy of unrelated cord blood and bone marrow/peripheral blood stem cells (BM/PBSC) transplantations in adults with acute leukemia. A Markov decision analysis model using Monte Carlo simulations was used to calculate the incremental cost-effectiveness ratio (ICER) and 95% confidence intervals (CIs). RESULTS: The estimated cumulative survival at 1 and 10 years were 27.9% and 14%, respectively, for cord blood recipients and 47% and 17.7%, respectively, for BM/PBSC recipients. Using conservative assumptions, the cost per life-year gained compared with no transplantation was US 16,346 dollars (95% CI 8695 dollars, 38,006 dollars) for BM/PBSC transplantation and US 34,360 dollars (95% CI 23,101 dollars, 89,417 dollars) for cord blood transplantation. CONCLUSIONS: Although both types of stem cell transplantations are associated with a high short-term mortality and high cost, the cumulative gains in life-years of survivors can be substantial, resulting in ICERs compared with no transplantation that are usually considered acceptable. However there is less certainty about this conclusion with cord blood transplantation.

Second allogeneic peripheral blood stem cell transplants with reduced-intensity conditioning.

In two institutions in México, twelve patients were given a second allogeneic stem cell transplantation, using the "Mexican" non-myeloablative preparative regimen. Eight had a malignant condition (six acute leukemias, one myelofibrosis and one myelodysplasia), eleven individuals were allografted twice from the same donor and in one case, cells from two different umbilical cords were used. The median time to conduct the second allograft after the first one was 6 months (range 1-41). The five patients who failed to engraft after the first transplant failed also to engraft after the second one; all of them had been heavily transfused. Only three patients were successfully rescued with the second transplant, two with acute leukemia and one with aplastic anemia. Seven patients are alive 10-41 months (median 35) after the second transplant, but only three (25%) remain disease-free. The 52-month overall survival (SV) of the patients is 58%, whereas the median overall SV has not been reached, being above 52 months. Conducting a second allograft may be useful to rescue some individuals relapsing after a first hematopoietic allotransplant.

Second allogeneic peripheral blood stem cell transplants with reduced-intensity conditioning / Segundos trasplantes hematopoyéticos con esquemas de acondicionamiento de intensidad reducida

In two institutions in México, twelve patients were given a second allogeneic stem cell transplantation, using the "Mexican" non-myeloablative preparative regimen. Eight had a malignant condition (six acute leukemias, one myelofibrosis and one myelodysplasia), eleven individuals were allografted twice from the same donor and in one case, cells from two different umbilical cords were used. The median time to conduct the second allograft after the first one was 6 months (range 1-41). The five patients who failed to engraft after the first transplant failed also to engraft after the second one; all of them had been heavily transfused. Only three patients were successfully rescued with the second transplant, two with acute leukemia and one with aplastic anemia. Seven patients are alive 10-41 months (median 35) after the second transplant, but only three (25%) remain disease-free. The 52-month overall survival (SV) of the patients is 58%, whereas the median overall SV has not been reached, being above 52 months. Conducting a second allograft may be useful to rescue some individuals relapsing after a first hematopoietic allotransplant.

En dos instituciones en México se llevaron a cabo doce segundos trasplantes de células hematopoyéticas usando el "método mexicano" de acondicionamiento no mieloablativo. Ocho pacientes tenían una enfermedad maligna (seis leucemias agudas, una mielofibrosis y una mielodisplasia). Once sujetos se retrasplantaron del mismo donador y en un caso se emplearon células hematopoyéticas de dos diferentes cordones umbilicales. La mediana del tiempo transcurrido entre los dos trasplantes fue de seis meses (rango 1 a 41). Los cinco pacientes que no se injertaron con el primer trasplante tampoco se injertaron con el segundo; todos ellos habían sido multitransfundidos antes de los trasplantes. Sólo tres pacientes se pudieron rescatar con el segundo trasplante, dos con leucemia aguda y uno con anemia aplástica. Siete pacientes están vivos 10 a 41 meses (mediana 35) después del segundo trasplante, pero sólo tres (25%) se encuentran libres de enfermedad. La supervivencia (SV) global a 52 meses es de 58%, en tanto que la mediana de SV no se ha alcanzado y es mayor de 52 meses. Hacer un segundo trasplante hematopoyético puede rescatar a algunos pacientes quienes recaen después de un trasplante de médula ósea.

[First report on assessment of the status of engraftment after allogeneic hematopoietic stem cell transplantation by using denaturing high-performance liquid chromatography].

Monitoring engraftment of donor cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is supposed to be important for the early diagnosis of graft failure or relapse of malignancy. Several techniques have been reported for this purpose. PCR-based assays analyzing polymorphic short tandem repeats (STR) as markers are attractive because they are sensitive and can be performed rapidly. The intent of this study was to test a novel approach for assessment of donor engraftment using denaturing high-performance liquid chromatography (DHPLC) combined with STR-PCR. The feasibility of this assay and the accuracy of semi-quantitative results were tested in-vitro by using serial DNA mixtures from unrelated individuals. The results showed that dilution experiments of the mock chimerism sample revealed a clear correlation between the percentage of donor or recipient DNA and the proportion of allele peak areas, with the limit of detection for a minor DNA percentage being 5%. Discrimination between donor and recipient was possible in all patients analyzed (n = 51) except for 5 patients whose pre-transplant samples were not available and identical twins in one case. STR results were the same as values obtained by capillary electrophoresis combined with fluorescence labeling multiply PCR. Results were also compared with data obtained with FISH analysis in a subgroup of patients receiving grafts from sex-mismatched donors or with PCR-detectable disease-specific gene products analysis. The results of the microsatellite analysis correlated well with the corresponding clinical findings. Full donor chimerism (FDC) were detected in all patients; decreasing values of donor chimerism were detected concomitantly with the appearance of relapse of disease in 3 patients. Samples from eight patients receiving HLA mismatched-haploidentical transplants from related donors together with cord blood transplants from unrelated donors were analyzed by this method. The results showed all 8 patients achieved FDC derived from related donors. It is concluded that this novel approach allows a rapid, sensitive, economical, auto-mated and non-isotopic STR-PCR testing, thus provides a reliable alternative for assessment of the status of engraftment after allo-HSCT.

Hematopoietic stem cell transplantation among patients with leukemia of all ages in Texas.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective but expensive medical procedure to which some ethnic minorities, the elderly, and those without insurance have been shown to have limited access. The purpose of the current study was to determine whether socioeconomic factors were associated with HSCT usage rates in patients with leukemia. METHODS: The authors identified 6574 patients with acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, or other leukemias from the 1999 Texas Hospital Inpatient Discharge Public Use Data File. Of these patients, 1604 received an autologous or allogeneic HSCT. The authors assessed patients' ethnicity, payer status, age, gender, and comorbid medical conditions. Logistic regression was used to control for patient characteristics and to evaluate associations among payer status, ethnicity, and HSCT use. P < or = 0.05 indicated statistical significance. RESULTS: Patients who self-paid had the highest rate of HSCT use in all age groups (32%; P < or = 0.01) and in the adult group (36%; P = 0.11). Elderly patients with Medicare had a low rate of HSCT use (17%; P = 0.13). Logistic regression showed no statistically significant associations between payer status or ethnicity and HSCT use. However, elderly women were significantly less likely to undergo HSCT than elderly men (odds ratio, 0.34; P < or = 0.01). CONCLUSIONS: The lack of statistically significant differences in HSCT use among adult patients with leukemia was surprising because previous studies had shown differences in HSCT by ethnicity and insurance.

Flow cytometric assessment of bone marrow transplant patient.

Flow cytometry laboratory plays an integral part in the evaluation of a BMT patient. Its role starts at the time of clinical presentation to assure most accurate and reproducible disease diagnosis and subclassification. This can only be achieved if the flow cytometrist is fully qualified in the diagnosis of hematolymphoid neoplasia and is able to correlate each and every case with morphologic data. Flow cytometric report, therefore, includes a standing diagnosis and goes beyond the sole description of an abnormal/atypical population. Following initial diagnosis, generated data are carefully stored and are retrieved for review whenever needed particularly during the evaluation of the remission status, response to chemotherapy, relapse, staging and detection of residual disease in marrow and apheresis product. Our laboratory performs leukemia/lymphoma assessment of approximately 150-200 samples a month in addition to 3-8 weekly apheresis procedures, 25-30 post-BMT immune monitoring samples and other isoteric assessments including CD4 counts for HIV population, HLA B27 evaluation, platelet/leukocyte antibodies, reticulated platelets, immunodeficiency disorders etc. This multidisciplinary center allowed us to develop a substantial expertise in the field, which hopefully benefits our patient, clinicians and fellow cytometrists. We are please to share our expertise at this distinguished forum.

Prognostic importance of histological and immunopathological assessment of skin and rectal biopsies in patients with GVHD.

Skin and rectal biopsies from patients with GVHD were examined histologically and immunopathologically before and after treatment for the disease. The patients were divided into two groups: those showing a good response to treatment and those showing a poor or no response. The aims of the study were to assess the possibility of predicting the response to treatment and to compare good and poor responders after treatment. The results show that there are no features on either skin or rectal biopsy that could identify those patients with early GVHD who would respond to treatment. Following treatment with steroids there was no change histologically in the grading of the skin biopsy whereas the rectal biopsy showed improvement in six of nine good responders and no improvement in the poor responders. There was an increase in infiltrating lymphocytes in both the skin and rectum of patients showing a poor response and this is most likely due to the ongoing immune reaction. The pre-treatment biopsy did not show any features that would predict this development and was therefore of no prognostic value. However, examination of skin and rectal biopsies may aid in determining whether patients are responding to the treatment given for GVHD.

Quantitative assessment of posttransplant host-specific interleukin-2-secreting T-helper cell precursors in patients with and without acute graft-versus-host disease after allogeneic HLA-identical sibling bone marrow transplantation.

Recent studies in mice and humans have emphasized an important contribution of host-reactive minor histocompatibility antigen (mH)-specific lymphokine-secreting donor T-helper cells (Th) for the induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). By using limiting dilution (LD) and clonal specificity analyses, we investigated in 14 patients with and without acute GVHD after non-T-depleted HLA-identical sibling BMT whether posttransplant host-reactive mH-specific interleukin-2 (IL-2)-secreting Th are involved in the development of clinically significant acute GVHD and the establishment of tolerance. At different time intervals posttransplant (I, days 0 through 45; II, days 45 through 90; III, days 90 through 180), host-specific IL-2-secreting Th-precursors (Th-p) were quantitatively assessed in six patients during clinically apparent grade II-III acute GVHD. Frequencies of responding Th-p ranged from 1/13,000 to 1 4,000. The presence of host-specific Th-p was significantly correlated with the development of grade II-III acute GVHD (P = .0003 by Fisher's exact test). The detectability of host-specific Th-p preceded the clinical onset of grade II-III acute GVHD. Host-specific Th-p were no longer detectable after the clinical resolution of grade II-III acute GVHD. No subsequent chronic GVHD was observed in these patients. However, prolonged occurrence of host-specific Th-p was accompanied by clinically persisting acute GVHD and the onset of secondary chronic GVHD. In patients with no acute GVHD (grade 0) (n = 7) and grade I (n = 1) acute GVHD, host-specific Th-p were not detectable at all. We conclude that host-reactive Th are critically involved in the development and maintenance of acute GVHD and may contribute to the establishment of tolerance after genotypically HLA-identical sibling BMT.

Costs of bone marrow transplants using unrelated donors.

Bone marrow transplantation is an expensive treatment, rationed primarily by the availability of donors. Recruiting potential unrelated bone marrow donors to a register would add not only to the cost, but also to the volume, of transplantation. Proposals to establish such registries have thus been subject to rigorous financial scrutiny. In Australia, 3 alternative estimates suggest that approximately 200 patients, otherwise suitable for bone marrow transplantation, do not receive transplants because they have no suitable related donor. The population of Australia is approximately 16 million. The alternatives for these patients are thus chemotherapy or unrelated bone marrow transplantation. The costs of chemotherapy and transplantation have been directly compared in 1 trial of treatment for acute nonlymphoblastic leukaemia. The cost per year of life saved was approximately the same for the 2 treatments, with better patient survival from transplantation. The estimated cost difference in both the United States and Australia, between the policy extremes of no patients transplanted, and all transplanted, was between 1.3-2.4% of the total costs of managing these patients. The cost of searching existing registers for unrelated donors for Australian patients, averages A$24,000-28,000 to the point of a successful donor procedure. The cost of establishing and maintaining an Australian Register of a size predicted to find donors for half of the potential recipients, has been estimated at A$ 10,000 per donor procedure. The decision to proceed with unrelated bone marrow transplantation commits resources that are currently used by the alternative therapies. It is thus important to monitor both the costs and effects of the new approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Total parenteral nutrition and nutritional assessment and leukaemic children undergoing bone marrow transplantation.

The aggressive radiotherapy and chemotherapy used in conditioning regimens for children with leukaemia undergoing bone marrow transplantation (BMT) cause a severe catabolic state. Total parenteral nutrition (TPN) is indispensable in the management of these patients. 25 children with leukaemia undergoing BMT were studied to evaluate the efficacy of TPN and the value of anthropometric parameters and biochemical variables (albumin, retinol-binding protein and prealbumin) in monitoring nutritional status in the critical post-BMT phase. The complications of TPN were mainly metabolic, generally mild and easily controlled. The hyperalimentation solution and infusion line were not responsible for infection in any patient. The marked variations in anthropometric parameters and albumin expected in such patients were not observed in our children due to the nutritional support given. Prealbumin and retinol-binding protein showed statistically significant, positive variations (P less than 0.01), thus proving sensitive indices of the response to nutritional repletion.

Psychosocial correlates of physician-patient communication at time of informed consent for bone marrow transplantation.

In obtaining informed consent for bone marrow transplantation (BMT) oncologist-investigators may feel that they engender emotional distress in patients due to the disclosure of potentially lethal complications associated with BMT. However, little is known regarding the psychological profile of BMT patients at the time of informed consent or what impact the consent process has upon the physician-patient relationship. The purpose of this study was to assess (1) the psychological symptom profile of patients consenting to BMT and (2) the relationship of behavioral and psychological factors to patients' perceptions of the quality of communication between physician and patient. The results indicated that adult BMT patients experienced significant psychological distress at the time at which they provided written consent for BMT. Two factors were positively related to perceived quality of communication between physician and patient: problem-focused coping style and perceived autonomy in decision making. These findings are interpreted in relation to the goals of informed consent and its implications for the physician-patient relationship.

[DNA polymorphisms as implant markers in allogeneic bone marrow transplantation. Preliminary evaluation]. / Los polimorfismos del DNA como marcadores de implante en el trasplante alogénico de medula ósea. Valoración preliminar.

After allogeneic bone marrow transplantation (BMT), patient hematopoietic and lymphoid cells are replaced by cells derived from the donor marrow. To document and characterize successful engraftment, host and donor cells must be distinguished from each other. We have used DNA sequence polymorphism analysis in 6 patients, at times varying, to determine reliably the host or donor origin of posttransplant cell populations and to compare these results with those obtained using red blood cell antigens and cytogenetics. Initially full engraftment was documented in all patients. In 1 patient a mixed lymphohematopoietic chimerism was documented 6 months after BMT and it reverted to donor hematopoiesis at 1 year post BMT. Posttransplant leukemic relapse was studied in two patients and shown to be of host origin in both cases. The DNA restriction fragment length polymorphisms (RFLP), are a powerful tool for the documentation of engraftment after BMT, to document mixed lymphohematopoietic chimerism and for the evaluation of leukemic relapse.