High HSP70-membrane expression on leukemic cells from patients with acute myeloid leukemia is associated with a worse prognosis.
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Acute Disease↗
Biomedical subjects
H-J Kolb
Publications and source records attributed to H-J Kolb.
Kinetics of dendritic cell chimerism and T cell chimerism in allogeneic hematopoietic stem cell recipients.
Dendritic cells (DC) as potent antigen-presenting cells (APC) and T cells as effector cells play an essential role in the pathophysiology of both graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactions after transplantation. Therefore, we determined the kinetics of DC and T-cell chimerism establishment after allogeneic hematopoietic cell transplantation (AHCT) in a group of 144 patients, using fluorescence-activated cell sorting (FACS) or magnetic cell sorting (MACS) followed by FISH or STR-PCR analysis for chimerism evaluation. In all, three cell lines investigated (CD3(+) T cells, CD11c(+) DC1 and CD123(+) DC2), we found a rapid and consistent establishment of complete donor chimerism (CDC) in over 70% of all patients during the first 6 weeks after AHCT. The rate of patients with CDC increased significantly over time within the first year after transplantation. A related donor (P=0.004) as well as an underlying lymphatic leukemia (P=0.03) were found to be significantly associated with development of MC in T cells. No significant correlation between DC or T cell chimerism and GvHD or relapse was detected. Our results thus demonstrate a fast and stable CDC in DC1, DC2 and T cells after AHCT that continuously increases over time in nearly all patients.
Adolescent↗
Cytogenetic response to prior treatment with interferon-alpha is predictive for survival after allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia.
We investigated the impact of a cytogenetic response (CyR) to IFN prior to and at the time of allogeneic hematopoietic stem cell transplantation (HSCT) on transplant-related mortality (TRM), relapse rate and survival probability after HSCT in 162 transplanted patients with chronic myeloid leukemia. One-hundred-one patients (62.3%) achieved a CyR prior to HSCT. Survival probabilities were higher in patients, who achieved any CyR prior to HSCT than in patients without CyR (63.6 vs 49.2%: P = 0.019). Survival probabilities in patients, who achieved a major CyR were better than in patients with minimal and minor CyR or in patients with no CyR (69.4 vs 58.8% vs 49.2%: P = 0.040). TRM and survival of chronic phase patients without CyR at the time of HSCT were similar to that of patients transplanted in advanced phase. Both groups combined had an outcome inferior to patients with at least minimal CyR (TRM, Gray test: P = 0.016, survival, log-rank test: P = 0.002). Univariate and multivariate analyses identified CyR prior to or at HSCT as a strong and independently favorable prognostic factor. We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups.
Hematopoietic Stem Cell Transplantation↗
The diallelic locus encoding the minor histocompatibility antigen HA-1 is evolutionarily conserved.
The polymorphic minor histocompatibility antigen HA-1 induces powerful T-cell alloreactivities with important consequences for graft-vs-tumor activity and development of graft-vs-host disease in patients after human leukocyte antigen-matched stem-cell transplantation (SCT). In view of possible translational animal studies, we analyzed the evolutionary conservation of the diallelic HA-1 locus in four mammalian species. Our results show that rodents do not encode the HA-1(H) allele, neither show polymorphism in this position on the HA-1 gene. Contrariwise, the HA-1(H) allele is present in non-human primate species and dogs. Interestingly, both the HA-1(H) T-cell epitope and its non-immunogenic counterpart HA-1(R) are present in the latter species. Thus, the HA-1 allelic polymorphism is conserved in evolution in primates and dogs.
Alleles↗
Protein C and procollagen III peptide levels in patients with hepatic dysfunction after allogeneic hematopoietic stem cell transplantation.
Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versus-host disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, P<0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, P<0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.
Adolescent↗
OKT3 muromonab as second-line and subsequent treatment in recipients of stem cell allografts with steroid-resistant acute graft-versus-host disease.
We retrospectively evaluated response to monoclonal antibody directed against CD3 (OKT3) treatment in 43 patients with steroid-resistant acute graft-versus-host disease (aGvHD) following allogeneic hematopoietic cell transplantation. Median duration of OKT3 therapy was 9 (range, 1-20) days. In all, 20 cycles were administered as second-line and 28 as third-plus line treatment. Side effects were mild to moderate. Overall response rate was 69 with 12% complete remissions and best response in skin involvement. Proportional reduction of concomitant steroids was higher in responding patients. Five patients (12%) achieved durable responses. Pharmacokinetic studies of OKT3 showed adequate plasma levels (> or = 1000 ng/ml) in 13 of 17 evaluable patients after a median of 6 (1-11) days on treatment. OKT3 became undetectable shortly after discontinuation of therapy. Median survival for all patients was 80 (2 to 2474+) days. There was a trend for better survival for patients on second-line vs third-plus line treatment (146 vs 46 days; P=0.07) and significant longer survival for patients with grade II when compared to those with grade III/IV aGvHD (206 vs 47 days; P=0.039). We conclude that salvage treatment with OKT3 shows considerable efficiency, however, sometimes of transient nature, and is well tolerated in patients with corticosteroid-resistant aGvHD.
Adolescent↗
Gender aspects in chronic myeloid leukemia: long-term results from randomized studies.
Gender-related aspects in chronic myeloid leukemia (CML) have not been studied well. We therefore analyzed 856 patients with Ph/BCR-ABL-positive CML from the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan) and II (IFN+HU vs HU alone). The median observation time was 8.6 years. A total of 503 patients (59%) were male. Female patients were older (51 vs 46 years; P<0.0001), presented with lower hemoglobin (11.7 vs 12.5 g/dl; P<0.0001), higher platelet counts (459 vs 355 x 10(9)/l; P<0.0001), smaller spleen size (3 vs 4 cm below costal margin; P=0.0097), a lower rate of additional cytogenetic aberrations (9 vs 15%; P=0.018) and a less favorable risk profile (P=0.036). The transplantation rate was 14% for female (n=48) and 22% for male patients (n=113). Median survival was longer in female patients (58 vs 49 months; P=0.035) mainly attributable to better survival in the low- and intermediate-risk groups and, independent from risk groups, in the HU group. These results were confirmed by matched-pair analyses based on German population data (n=496, 59 vs 45 months; P=0.0006). This is the first analysis of gender aspects in CML using randomized trials. It demonstrates the relevance of analyses of gender differences in CML and in malignant disease at large.
Adult↗
Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT).
Results of reduced intensity conditioning regimen (RIC) in the HLA identical haematopoietic stem cell transplantation (HSCT) setting have not been compared to those after myeloablative (MA) regimen HSCT in patients with acute myeloblastic leukaemia (AML) over 50 years of age. With this aim, outcomes of 315 RIC were compared with 407 MA HSCT recipients. The majority of RIC was fludarabine-based regimen associated to busulphan (BU) (53%) or low-dose total body irradiation (24%). Multivariate analyses of outcomes were used adjusting for differences between both groups. The median follow-up was 13 months. Cytogenetics, FAB classification, WBC count at diagnosis and status of the disease at transplant were not statistically different between the two groups. However, RIC patients were older, transplanted more recently, and more frequently with peripheral blood allogeneic stem cells as compared to MA recipients. In multivariate analysis, acute GVHD (II-IV) and transplant-related mortality were significantly decreased (P=0.01 and P<10(-4), respectively) and relapse incidence was significantly higher (P=0.003) after RIC transplantation. Leukaemia-free survival was not statistically different between the two groups. These results may set the grounds for prospective trials comparing RIC with other strategies of treatment in elderly AML.
Aged↗
Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy.
Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1 kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible alternative for patients with no suitable donor, but hampered by the risk of relapse due to the persistence of leukaemia cells in the transplant. To study the effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from eight CML patients (one at diagnosis, three in chronic and four in accelerated phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from healthy donors as measured by colony-forming unit (CFU) assays. BMCs from patients in accelerated phase showed selective, but incomplete elimination of Ph1 chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors interfered with DNA synthesis, but not with viability. In summary, our results indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone marrow of patients with CML and certain other forms of leukaemias.
8-Bromo Cyclic Adenosine Monophosphate↗
Adoption of long-term cultures to evaluate the cryoprotective potential of trehalose for freezing hematopoietic stem cells.
Dimethylsulfoxide (DMSO), which is widely used as a cryoprotectant for hematopoietic stem cells (HSC), has considerable toxicity for both the thawed cells and the patient. The aim of this study was to evaluate the cryoprotective potential of trehalose in comparison to DMSO for human HSC. Human bone marrow (BM) and peripheral blood stem cells (PBSC) of volunteer donors were cryopreserved in the presence of different concentrations of trehalose with and without insulin, as well as with DMSO 10%. After thawing to 37 degrees C colony-forming unit (CFU) assays were performed. Long-term marrow-cultures (LTMC) were established and used for the detection of long-term culture-initiating cells (LTCIC). The total amount of CFUs detected was 104+/-134 (mean+/-s.d.) in DMSO-preserved cells and 179+/-34 in trehalose-protected cells. For LTMC the best feeder layer proved to be fresh human BM and the most useful concentration of trehalose was 0.5 M. Using these culture conditions we could detect after 5 weeks LTMC a total of 172+/-28 CFUs for trehalose-protected cells and 170+/-52 for DMSO-preserved cells. In conclusion, trehalose exerts a similar cryoprotective potential for hematopoietic progenitor and stem cells like DMSO and could possibly replace DMSO at least in part as cryoprotectant in the setting of hematopoietic cell transplantation.
Bone Marrow Cells↗
Low-dose ARAC, donor cells, and GM-CSF for treatment of recurrent acute myeloid leukemia after allogeneic stem cell transplantation.
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Acute Disease↗
Prospective evaluation of neurological complications after allogeneic bone marrow transplantation.
OBJECTIVE: To determine the spectrum and frequency of neurologic sequelae after allogeneic bone marrow transplantation (BMT) and to define a risk profile of the patients. METHODS: A prospective follow-up of 71 allogeneic bone marrow recipients 14 +/- 3 months after transplantation. Patients underwent a neurologic examination, a neuropsychological test battery, and cranial MRI before and after BMT. RESULTS: A large proportion of patients (65%) developed sequelae after BMT. Acute complications of defined etiology occurred in 18% of the patients and led to death in 9% of the study population. A total of 47% of the patients developed new neurologic abnormalities of undefined origin that were mild and subacute and predominantly affected the peripheral nervous system. The cognitive and neuroradiologic outcome was favorable in a majority of these patients, but a small subgroup exhibited cognitive deterioration and white matter lesions. Risk factor analysis identified acute graft-versus-host disease (GvHD) and other variables partly related to GvHD such as long-lasting immunosuppression as the main predictors of sequelae after allogeneic BMT. The authors have established an association with various factors but, owing to the observational character of this study, conclusions about the etiology of the findings are unclear. CONCLUSION: Neurologic complications significantly contribute to the morbidity and mortality of patients receiving allogeneic BMT. Subclinical abnormalities, cognitive deficits, and white matter lesions detected 1 year after BMT in a subgroup of patients may be related to more extensive CNS changes observed after transplantation in an earlier retrospective study and may be associated with the risk factor chronic GvHD/immunosuppression.
Adolescent↗
[Neuromuscular complications after allogeneic bone marrow transplantation].
Neuromuscular syndromes following allogeneic bone marrow transplantation (BMT), although occasionally described,were not the focus of studies concerning neurologic complications following bone marrow transplantation. In this study,we summarize different polyneuropathy syndromes following BMT and report on patients with myasthenia gravis and inflammatory neuromuscular disorders such as myositis or fasciitis. Concerning the etiology of neuropathies, a neurotoxicity of immunosuppressants,a preexisting disorder due to the underlying disease as well as an association with graft-versus-host disease (GVHD) is discussed.GVHD-associated polyneuropathies as well as muscular complications have been found to occur during the early BMT phase, while myasthenia gravis is a late neurologic complication of GVHD.
Adult↗
Dose-dependent effects of in vivo antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML.
We conducted a dose-escalation study with antithymocyte globulin (ATG) in patients undergoing unrelated donor bone marrow transplantation (URD-BMT). This study analyzes the results for 97 patients with chronic myelogenous leukemia (CML) in first chronic phase. Median age was 36 years (16-51). In all, 40 patients were transplanted within 2 years after diagnosis and 57 later during disease. ATG-S (Fresenius) 20-120 mg/kg body weight (b.w.) was given prior to transplantation. A total of 31 patients received less than 60 mg/kg b.w. and 66 patients received 60 mg/kg b.w. or more. All patients except one were grafted with bone marrow, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Graft failure did occur in one patient. Grade II-IV acute GVHD developed in 56.7% and extensive chronic GVHD in 11.3% of the patients. The relapse rate was 13.4%. With a median follow-up of 5.8 years (1.5-12.1), 5-year disease-free and overall survival for all patients were 56 and 66%, and for patients transplanted within 2 years of diagnosis it was 72 and 82%. A lower dose of ATG was a significant risk factor for poor outcome. In summary, URD-BMT remains an excellent treatment option for patients with early phase CML, if a sufficient amount of ATG is included in the preparative regimen.
Adolescent↗
ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML).
Matched unrelated donor transplants have an increased risk of severe graft-versus-host disease and transplant-related mortality (TRM). ATG has been introduced to decrease GvHD and to facilitate engraftment. We conducted a retrospective analysis of 333 patients with chronic myelogenous leukemia, who were treated with Fresenius ATG (n=145, average=90 mg/kg bw, range 40-90 mg/kg bw) or standard immunosuppression without ATG (n=188). Both groups were comparable regarding distribution of age, sex, HLA-matched vs mismatched donors. ATG Fresenius led to a faster leukocyte engraftment, decreased the incidence of acute GvHD and TRM (P=0.01 and P=0.03) and led to a significant better overall survival (70 vs 57%, P=0.03). We concluded that a prospective randomized study is needed to evaluate the definite role of ATG in hemopoietic stem cell transplantation.
Acute Disease↗
Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.
The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.
Adolescent↗
Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha.
Chronic myeloid leukemia (CML) in older patients has not been studied well. To assess the long-term outcome of older patients with Philadelphia- and/or BCR-ABL-positive CML, 199 patients aged >/=60 years representing 23% of 856 patients enrolled in the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan (BU) and II (IFN+HU vs HU alone) were analyzed after a median observation time of 7 years. In all, 45 patients were treated with Bu, 63 with HU, and 91 with IFN. The 5-year survival was 38% in patients >/=60 years and 47% in patients <60 years (P<0.001). Whereas 5-year survival in chemotherapy-treated older patients was inferior to that in younger patients (33 vs 46%, P=0.006 for HU and 29 vs 38%, P=0.042 for Bu), no significant survival difference could be verified in IFN-treated patients (46 vs 53%, P=0.077). Calculation of age-adjusted, relative survival confirmed these results. Adverse effects of IFN were similar in both age groups, but IFN dosage to achieve treatment goals was lower in older patients. We conclude that the course of CML is not different in the elderly. They require lower IFN doses, achieve the same hematologic and cytogenetic response rates and the same survival advantage at comparable toxicity.
Adolescent↗
The long-term psychosocial effects of haematopoetic stem cell transplantation.
The purpose of this study was to identify long-term psychosocial effects of allogenic, syngenic and autologous haematopoetic stem cell transplantation (HSCT) on relevant parameters (physical performance, role and sexual functioning, intimate relationships, professional and social rehabilitation). A total of 163 patients, who had undergone an autologous (11.6%), syngenic (3.1%) or allogenic (85.3%) HSCT at the Department of Internal Medicine III, Ludwig-Maximilians-University, during a preceding 16-year period, were asked to complete the Herschbach Questionnaire on Stress in Cancer Patients in order to evaluate their current psychosocial distress status. An additional questionnaire for demographic data was used. Reduced quality of life as a result of HSCT is restored to its pre-HSCT level by most patients within 2 years after transplantation (no differences between groups transplanted 2-5, 6-9 or >10 years ago). The majority of patients had serious problems with "fitness" (24%), followed by problems with "pain" (17.2%) and "fear/emotional stress" (14.1%). Professional reintegration is an important factor in patients' well-being. However, 30.7% of these patients did not return to work at all. Unemployed patients had significantly higher scores for pain, anxiety, sleep disorders, depression, impairments in social functioning, partnership and family life. Only 9.8% of all patients took part in a psychotherapeutic programme and 39.3% in a rehabilitation programme. Identifying strategies for risk patients (e.g. lower education and married) need to be developed in order to optimize support for this group. Although some patients show a higher distress score in anxiety/fear and psychophysical performance, only 9.8% of all patients took advantage of available psychotherapy.
Adult↗