Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in the treatment of childhood acute lymphoblastic leukemia (ALL) have been striking while results have been less impressive in adults who develop this disease. Obvious differences in a patient's ability to withstand cytotoxic therapy may account, in part, for these findings, but the biologic behaviour of the disease in the two age groups appears to be different; relapses are more frequent and cures less common in adults. In fact, age alone appears to be the most important prognostic factor in ALL. The demonstration of the efficacy of bone marrow transplantation in advanced disease as well as the marked improvements in supportive care and the development of effective high-dose cytotoxic preparative regimens, especially those which use total body irradiation, however, have paved the way for transplantation in first complete remission. Formerly, most adult ALL patients who underwent bone marrow transplant did so in relapse, or in second or subsequent remission. In most studies 40-50% of first remission adult patients attain long-term disease-free survival after allogeneic and autologous bone marrow transplant. Relapses are considerably higher in the autologous transplant group when compared to the allogeneic group, but the latter population may experience increased morbidity and mortality due to graft-versus-host disease and opportunistic infection. These differences may reflect the beneficial graft-versus-leukemia effect in the allograft as well as infusion of autologous leukemia cells in the autograft but neither transplant subtype appears superior. Compared to more conventional approaches, however, transplantation may offer improved disease-free survival, although patient selection appears to be significantly influence outcome. These many inherent biases must be noted when comparing markedly different approaches, e.g. transplant versus conventional therapy. The challenge of demonstrating which therapy is superior for adult ALL patients can only be addressed in a well-designed, prospective, randomized trial.
 ...
PMID:Bone marrow transplantation for acute lymphoblastic leukemia (ALL). 785 Feb 67

Outcome of allogeneic BMT for childhood ALL performed at a national centre was evaluated for the period between 1985 and 1996. Sixty-seven patients representing all Danish children and adolescents (1-19 years) transplanted for ALL, were evaluated. Patients transplanted with a family donor (n = 51) had a 3-year probability of leukaemia-free survival (P-LFS) of 56% (95% confidence limits 41-69%) and patients receiving marrow from a matched unrelated donor (MUD) (n = 16) had a 3-year P-LFS of 67% (34-86%) (P = 0.38). Relapse was responsible for 48% of the deaths and occurred with increasing frequency among children transplanted with marrow from HLA-identical siblings. Patients transplanted with family donors from 1985-1989 had P-LFS of 72% (54-84%) compared to patients transplanted after 1990 who revealed a significantly reduced P-LFS of 28% (10-49%, P = 0.01). Furthermore, the risk of relapse was increased (65% (24-88%)) (P = 0.02) in the later period. In contrast, patients transplanted with marrow from a MUD (1990-1996) had a lower risk of relapse (11%, 5-20%) (P = 0.002) but a comparable risk of transplant-related mortality. Children who experience relapse after modern, intensive treatment for ALL may have an increased propensity for relapse even after BMT. Therefore, when performing BMT for childhood ALL, there may be a benefit in overall survival from the increased graft-versus-leukaemia effect that follows less intensive GVHD prophylaxis or transplantation with a MUD.
 ...
PMID:Outcome of acute lymphoblastic leukaemia in Danish children after allogeneic bone marrow transplantation. Superior survival following transplantation with matched unrelated donor grafts. 972 66

As cure rates in childhood acute lymphoblastic leukemia edge toward 80%, the focus of research is shifting to better means of identifying and treating resistant cases. This new emphasis has stimulated progress in several areas. Recent findings suggest that poor early responses to therapy and detection of minimal residual disease at the postremission induction period by immunologic methods are reliable indicators of an adverse prognosis warranting modification of treatment. In this regard, timely administration of intensified chemotherapy, including a second reinduction/intensification phase, may nullify the adverse prognosis conferred by a delayed response to induction therapy. Comparative analysis of survival outcomes in T-cell patients who received chemotherapy or cranial irradiation (12 Gy) to prevent overt leukemia in the central nervous system suggests that the latter modality should be retained for cases with leukocyte counts > 100 x 10(9)/L. Recent innovations in histocompatibility matching, prevention of graft-versus-host disease, and antiviral prophylaxis have enhanced the applicability of hematopoietic stem cell transplantation, making this procedure available to candidates lacking matched sibling donors. Finally, demonstration that acute lymphoblastic leukemia has an angiogenic phase in bone marrow raises the possibility of effective treatment with antiangiogenic agents, such as endostatin. Remaining challenges in the treatment of childhood leukemia include 1) the development of specific and more effective therapy for high-risk cases and 2) the reduction of long-term complications associated with intensive chemotherapy and cranial irradiation.
 ...
PMID:Recent advances in the biology and treatment of childhood acute lymphoblastic leukemia. 974 36

This multicenter study was designed to evaluate whether allo-PBPCT provides some advantages, if any, over BMT in terms of engraftment kinetics, acute and chronic GVHD incidence, TRM, relapse incidence and survival in acute lymphoblastic leukemia patients (ALL). From January 1995 to December 1999, 67 ALL patients (34 in the PBPCT group and 33 in the BMT group) were included in this study. Median age for both groups was 8 years (range, 1-18). There were 24 patients in first or second CR in the PBPCT group and 28 such patients in the BMT group. Preparatory regimens were TBI-based in 26/34 in the PBPC group and 25/33 in the BMT group. GVHD prophylaxis was CsA alone in 38 patients (18 PBPCT vs 20 BMT) and CsA plus short Mtx in 29 (16 PBPCT vs 13 BMT). Engraftment was achieved in all cases. Median days to neutrophil recovery was 10 (range, 7-18) after PBPCT vs 14 (range, 9-21) after BMT (P < 0.0001). Platelet engraftment (>50 x 10(9)/l) was also faster for PBPCT patients (median 13 days, range, 9-40 vs 23 days, range, 15-165) (P < 0.0001). Acute GVHD grade II-IV incidence was similar in both groups (46.4 +/- 8.8% vs 42.7 +/- 8.6%) (P = 0.45). Probability of chronic GVHD was 50.6 +/- 12.2% after PBPCT vs 27.8 +/- 9.2% after BMT (P = 0.1). Probability of relapse was similar (28.7 +/- 9.2% for PBPCT vs 27.1 +/- 8.2% for BMT) (P = 0.89). There were eight patients who died from transplant-related complications after PBPCT vs 5 after BMT (P, NS). With a median follow-up of 25 months the event-free survival probability was 53 +/- 8.9% for PBPCT vs 54.9 +/- 9.7% for BMT (P = 0.54). Using PBPC for allogeneic transplantation in childhood ALL results in faster hematopoietic recovery compared to BM, with a similar incidence of aGVHD, TRM, relapse and disease-free survival. However, the issue of cGVHD remains unresolved.
 ...
PMID:Matched-pair analysis comparing allogeneic PBPCT and BMT from HLA-identical relatives in childhood acute lymphoblastic leukemia. 1210 71

We have retrospectively investigated the relationship between the level of minimal residual disease (MRD) detected in bone marrow taken prior to conditioning therapy and outcome following stem cell transplantation for high risk childhood ALL. Forty-one patients, in whom both a molecular marker of MRD and sufficient archival material was available, were included in the study. All were in remission at BMT: eight in CR1, 32 in CR2 and five in greater than CR2. MRD was measured by PCR amplification of antigen receptor gene rearrangements and clone-specific oligoprobing, the median sensitivity of detection being one leukaemic cell in 10000 normals. Results were classified as high-level positive (if a clonal band was evident after electrophoresis), low-level positive (if MRD was detected only after oligoprobing) and negative. MRD was detected at high levels in 17 patients, at low levels in 10 patients and 14 patients were MRD negative at the time of transplant. The 5-year event-free survival for these groups was 23%, 48% and 78%, respectively (P = 0.022). Limited multivariate analysis confirmed the significance of MRD (P = 0.0095) vs CR status, donor type, sex, immunophenotype and acute GvHD. This study confirms the strong relationship between MRD level and outcome following allogeneic transplantation. In contrast to a previous study we observed that a minority of children with high-level pre-BMT MRD can enter long lasting remission. The possible role for acute GVHD coupled with a graft-versus-leukaemia effect in the clearance of high level MRD in patients with ALL is discussed.
 ...
PMID:Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. 1220 Jun 79

Haploidentical transplantation in childhood acute lymphoblastic leukemia (ALL) is a promising option for children lacking a suitable donor. We have updated our series of patients with ALL and report the results. Additionally, we reviewed the literature and try to embed our own experiences in the published results. We performed HLA-mismatched stem cell transplantations with megadoses of purified positively selected mobilized peripheral blood CD34+ progenitor cells (PBPC) from adult donors in 27 children with acute lymphoblastic leukemia (ALL) in first (CR1 n = 7), second (CR2 n = 10), or third (CR3 n = 4) complete remission, and in refractory state (NR n = 6). The patients received a mean number of 19.1+/-11.3 x 10(6)/kg purified CD34+ and a mean number of 15.5+/-24.2 x 10(3)/kg CD3+ T-cells. No additional graft-versus-host disease (GVHD) prophylaxis was used, except as short-term CSA in the first 3 patients. The myeloablative treatment was based on busulfan in 12 and on TBI in 14 patients. One patient was grafted with a non-myeloablative approach. Engraftment was rapid in 26 patients, with two patients suffering from a rejection. These two and one patient with initial non-engraftment had been successfully regrafted. The probability of survival of the total group is 0.34+/-0.09; the 12 patients transplanted in remission showed a probability of survival of 0.44+/-0.11. None of the patients transplanted in non-remission survived. There was no statistical difference in survival for patients with a 1, 2 or 3 antigen mismatched donor (out of 6 HLA antigens) or for patients in 1st, 2nd or 3rd remission. Causes of death were relapses in 10 patients, veno-occlusive disease (VOD) in 1, multi-organ failure (MOF) in 2 and infections in 4 patients. 3/24 evaluable patients without any additional GVHD-prophylaxis developed grade 1 or 2 GVHD. Ten patients were treated with additional donor lymphocyte infusion (DLI), from which 4 developed a maximum grade 3 GVHD. We conclude that the HLA barrier can be overcome by transplantation of megadoses of highly purified CD34+ PBPC and GVHD can effectively be prevented. This approach offers a promising treatment option for patients with acute lymphoblastic leukemia needing urgently transplantation but lacking a suitable donor.
 ...
PMID:Haploidentical transplantation for acute lymphoblastic leukemia in childhood. 1518 2

Acute lymphocytic leukemia (ALL) is a common indication for hematopoietic stem cell transplantation (HSCT) in children. Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased GVHD potential. Publications describing outcomes of children with leukemia who underwent UCB transplants have compared them to those having received unrelated donor marrow transplants. Results are similar. We compared our outcomes using UCB vs allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n=21) or in CR2 (n=28) with initial remission less than 36 months. Patients received myeloablation with fractionated total body irradiation, cyclophosphamide, and etoposide and GVHD prophylaxis with cyclosporine and methotrexate. Antithymocyte globulin was added for UCB recipients to address the HLA differences. In all, 23 patients underwent allogeneic -related HSCT and 26 underwent UCB transplantation. Other than increased time to engraftment for UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. UCB is a reasonable option for children with ALL who are referred for HSCT.
 ...
PMID:Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia. 1536 8

Experimental and clinical data demonstrate an antileukemia effect of acute graft-versus-host disease (aGVHD). In all, 58 pediatric patients with acute lymphoblastic leukemia (ALL) who had received an allogeneic bone marrow transplant (BMT) at our institution were retrospectively analyzed for a correlation between the development of aGVHD and leukemic relapse. Probability of relapse after 5 (3) years was 13% (7%) in patients developing grade II-IV aGVHD vs 30% in patients with grade 0 or I aGVHD. There was a trend for a difference of the point estimates at 3 years, but no overall significance because of an unusual late relapse. Moreover, we analyzed the impact of cyclosporin A (CsA) on aGVHD in a subgroup of 22 children who had received a matched sibling donor (MSD) BMT. An increased dose of CsA within the first 2 weeks after BMT led to decreased occurrence and severity of aGVHD (P=0.035). The cumulative CsA dose appeared to have more impact than the average CsA whole-blood levels within the first 2 weeks and than the CsA dose given from day 15 to 40. In this subgroup, no life-threatening aGVHD or death from aGVHD occurred. In all cases (6/22), leukemic relapse was the cause of death. We therefore suggest that there is a relation between dose of CsA and relapse rate in childhood ALL transplanted from a MSD.
 ...
PMID:The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia. 1590 76

The prognosis for childhood acute lymphoblastic leukemia (ALL) has improved dramatically over the past quarter of a century. Despite improvements in the treatment of childhood ALL, relapse still occurs in 20%-30% of patients. Although many of these relapses occur in the "standard-risk" patients, approximately 10% of these patients present at diagnosis with clinical and biological features that identify them as having a very high risk of relapse. Children (2 months to 21 years) with > or =1 ultra-high-risk feature (UHRF) of ALL in first remission treated on a frontline Children's Cancer Group (CCG) ALL study with a matched family allogeneic donor were eligible for study entry onto CCG-1921 and an allogeneic bone marrow transplant (AlloBMT). Each patient received fractionated total body irradiation (1200 cGy) and cyclophosphamide (120 mg/kg) conditioning therapy followed by unmobilized BM from a matched family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporin. Twenty-nine patients with a median age of 8.7 years with UHRF ALL in first complete remission (CR1) received an AlloBMT from a family member. The incidence of grade II-IV acute GVHD was 20.7% and the incidence of chronic GVHD was 3.7%. AlloBMT conditioning regimen was well tolerated and only 1 patient (3%) had treatment-related mortality. Ten patients (35%) died due to progressive disease. The 5-year event-free survival (EFS) for all patients was 58.6% and patients without cytogenetic abnormalities had a 5-year EFS of 77.8%. The 5-year EFS rates for infants and non-infants were 20.0% and 66.7% (log-rank test, P = .01), respectively. Patients with Philadelphia chromosome-positive ALL had a 5-year EFS of 66.7%. The children with UHRF of ALL may benefit from AlloBMT in CR1, especially patients with primary induction failure and Philadelphia chromosome-positive ALL. Randomized prospective cooperative group studies are required to establish the role of allogeneic hematopoietic stem cell transplantation versus intensive chemotherapy in children with UHRF ALL in CR1.
 ...
PMID:Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblastic leukemia: A children's oncology group study report. 1724 27

To study the effect of early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation (HSCT) on outcome in pediatric ALL, we reviewed 136 consecutive pediatric patients with ALL who received allogeneic HSCT between 1994 and 2005 at the Hospital for Sick Children, Toronto, Canada. Patients with an absolute lymphocyte count (ALC) <0.3 x 10(9) per liter at day 21 (n=104) had more than five times risk of relapse compared to those with ALC >0.3 x 10(9) per liter (n=32) (hazard ratio (HR) 5.3; P=0.002) and had inferior 3-year event-free survival, (EFS), 0.42 (95% confidence interval (CI) 0.32, 0.51) compared to 0.66 (95% CI 0.48, 0.82; P=0.02). Similarly, patients with an ALC <0.3 x 10(9) per liter (n=48) at day 30 were more than twice as likely to relapse compared to those with an ALC >0.3 x 10(9) per liter (n=88) (HR 2.2; P=0.01) and had an inferior 3-year EFS, 0.30 (95% CI 0.18, 0.45) compared to 0.57 (95% CI 0.46, 0.68; P=0.0001). Interestingly, increasing ALC at days 21 and 30 was not associated with increased incidence of acute or chronic GVHD or transplant-related mortality (TRM). Early lymphocyte recovery post-HSCT is associated with a significant GVL without increase in GVHD.
 ...
PMID:Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia. 1795 29


1 2 Next >>