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)

The reciprocal translocation (9;22)(q34;q11) is highly characteristic of chronic myeloid leukemia (CML) and the pericentric inversion inv(16)(p13q22) is almost only found in acute nonlymphocytic leukemia of the myelomonocytic subtype (ANLL M4). Only twice before have an inv(16) and a t(9;22) been found in the same cells, and both times the patients seemed to have de novo ANLL M4. We describe the case of a 21-year-old man who in July 1986 presented with a clinically and hematologically classic chronic phase CML. Treatment with busulfan led to no improvement; instead in September 1986 he developed blast crisis with ANLL M4Eo morphology. He was now cytogenetically examined and the karyotype 45,X,-Y,t(9;22)(q34;q11),inv(16)(p13q22) was found. Southern blot analysis of the bone marrow DNA sampled at this time revealed a standard rearrangement in the 3' end of the M-bcr. Intensive cytostatic treatment caused cytopenia followed by complete hematologic, clinical, and cytogenetic reversal to chronic phase CML, so that in January 1987 the bone marrow karyotype was 46,XY,t(9;22)(q34;q11). Persistent splenomegaly was treated with splenectomy, and a chloroma of the skin was removed by irradiation. In March 1987 he received an allogeneic bone marrow transplant. Since then his only medical problem has been mild graft-versus-host disease; he is well and is working full time as a blacksmith.
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PMID:Acute myelomonocytic leukemia with inv(16)(p13q22) complicating Philadelphia chromosome positive chronic myeloid leukemia. 155 89

Bone marrow transplantation is the only treatment that can result in long-term disease-free survival and possible cure in a significant number of patients with CML. Several prognostic features influence relapse and survival following allogeneic BMT for CML. The most important factor is treatment of patients during chronic phase. The timing of BMT in chronic phase CML remains controversial, because the Seattle findings that BMT done within a shorter interval from diagnosis to transplant was associated with improved survival has not been confirmed by the IBMTR. No factor can predict in the individual patient the timing of transformation, even in patients with low-risk chronic phase CML, but we believe that allogeneic BMT should be offered as soon as possible for newly diagnosed patients who have histocompatible siblings. More widespread application of BMT in CML is possible because of effective methods for preventing GVHD, the major cause of morbidity after allogeneic BMT. However, in vitro techniques for the depletion of donor marrow T cells have resulted in higher graft failure and relapse rates. More precise understanding of the immune mechanisms involved may permit more selective depletion techniques which not only abrogate GVHD but also permit sustained engraftment and preserve GVL effect. This may extend application of BMT for patients with mismatched related or histocompatible unrelated donors. It is of interest that cytogenetic relapse after BMT is not invariably followed by hematologic relapse. It is likely that the use of polymerase chain reaction techniques which detect the bcr-abl rearrangement at a very low level will identify the persistence of the malignant clone after allogeneic BMT in even more patients. At present, the significance of such findings is unclear, but further study of the kinetics of disappearance of the CML clone post-BMT may increase our understanding of the immune mechanisms involved in suppression of the malignant clone and determine whether in fact CML can be cured using BMT approaches.
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PMID:The evolving role of bone marrow transplantation in the treatment of chronic myelogenous leukemia. 218 97

BMT is the only curative therapy for CML, a uniformly lethal malignant disorder of the hematopoietic stem cell. Younger patient age and transplant in CP are associated with better outcome. Transplant within 1 year of diagnosis may provide a greater chance of survival than transplant at a longer interval from diagnosis. T-cell depletion of donor BM significantly reduces the incidence of acute and chronic GVHD, but is associated with an increased risk of graft failure and a marked increase in rate of relapse. Early results suggest that HLA-matched or partially HLA-mismatched unrelated donors may be used successfully in cases in which a suitably matched related donor is not available. Autologous transplantation of BM or PB stem cells can result in successful engraftment and possibly prolonged survival in some patients with CML. Following allogeneic BMT, some patients relapse cytogenetically without progressing to hematologic relapse. The use of PCR methodology to amplify bcr-abl transcripts has revealed persistence of the malignant clone in a substantial number of patients who are in hematologic and cytogenetic remission. The clinical significance and biologic mechanism(s) of this form of molecular relapse remain to be defined.
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PMID:Treatment of chronic myelogenous leukemia with bone marrow transplantation. 219 13

A case of acute myelocytic leukemia (AML-M2) with a late appearance of Philadelphia chromosome (Ph1) is presented. Chromosome analysis revealed a normal karyotype at the time of diagnosis and for 23 months, when hematological relapse occurred, accompanied by abnormal clones, 46, XX, t(9;22) (q34;q11) (78%) and 45,XX, -16, t(9;22) (q34;q11), del (5) (q13q31) (22%). The patient died of GVHD after bone marrow transplantation. Molecular analysis confirmed bcr gene rearrangement in the cells with Ph1 chromosome. Acquisition of Ph1 chromosome during the course of hematological malignancies other than CML is extremely rare. This case is undoubtedly important for the understanding of leukemogenesis and the evolution of leukemia clones. The authors discussed possible mechanisms of Ph1 acquisition in the late stages of AML.
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PMID:[Late appearance of Philadelphia chromosome with bcr gene rearrangement in an acute myelocytic leukemia patient]. 269 64

Fourteen patients treated by allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML) were evaluated by the polymerase chain reaction (PCR) for bcr-abl-specific transcripts. Nine patients were transplanted in the first chronic phase, three in the second chronic phase, and two in the accelerated phase. All patients achieved a complete cytogenetic and hematologic remission after bone marrow transplantation. Twelve patients are alive (median, 18 months; range, 5-54 months) and two patients died early. bcr-abl mRNA was persistently detectable for 6 to 54 months in four patients (patients 1, 3, 4, 6). From two of them, DNA fingerprint analysis showed only donor type DNA although bcr-abl mRNA was detectable. bcr-abl mRNA was never detectable posttransplant in three patients (patients 2, 5, 13). Six patients had detectable bcr-abl mRNA (patients 8-12, 14): by 6 months, all of these patients were bcr-abl mRNA negative. One patient (patient 7) had detectable full bcr-abl mRNA again at 12 months, but was then negative at 20 months. Ten patients (patients 2, 4-8, 10-13) had never detectable Philadelphia (Ph1) chromosome t(9.22) translocation, whereas four patients had detectable Ph1 (patient 1, 3, 9, 14); by 6 months, three of four cases were negative. One patient (patient 1) had detectable Ph1 at 44 months, but was negative at 50 months. Three of six patients who initially had bcr-abl mRNA detectable posttransplant (patient 7-9) became negative for bcr-abl mRNA at the time of development of chronic graft-versus-host disease (GVHD). These results suggest that the detection of subclinical Ph1 positive cells by PCR is not associated with imminent clinical or cytogenetic relapse. Moreover, graft-versus-leukemia (GVL) activity may contribute to the treatment of minimal residual disease in CML after allogeneic bone marrow transplantation.
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PMID:Predicting relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation by bcr-abl mRNA and DNA fingerprinting. 757 10

We studied 346 patients after bone marrow transplantation (BMT) for chronic myeloid leukemia (CML) for the presence of the bcr-abl transcript detected by the polymerase chain reaction (PCR) to understand the frequency and implication of a positive test. A total of 634 samples of BM and/or peripheral blood were obtained for PCR analysis between 3 and 192 months after BMT. A positive PCR test at 3 months post-BMT was not statistically significantly associated with an increased risk of relapse compared with PCR-negative patients. However, a positive PCR assay at 6 months and beyond was highly associated with subsequent relapse. The Kaplan-Meier estimate of relapse for patients testing PCR-positive at 6 to 12 months was 42% versus 3% for PCR-negative patients (P < .0001). The Kaplan-Meier estimate of survival at 4 years for the PCR-positive patients was 74% compared with 83% for the PCR-negative group (P = .002). Multivariable analysis indicated that a PCR-positive result at 6 to 12 months post-BMT, the type of BMT donor (allogeneic matched donor v mismatched or unrelated), and the presence of acute GVHD were independent risk factors for subsequent relapse. The relative risk (RR) for relapse for patients PCR-positive at 6 to 12 months post-BMT was 26.1 (95% confidence interval, 8.9 to 76.1, P < .0001). The outcome of long-term patients (> 36 months post-BMT) who tested PCR-positive was much better, as 15 of 59 (25%) tested positive for bcr-abl, but only one patient relapsed. There was a 91% concordance between PCR tests of simultaneously obtained BM and peripheral blood. These analyses show that the PCR assay of the bcr-abl fusion transcript 6 to 12 months post-BMT is an independent predictor of subsequent relapse which provides an opportunity for early therapeutic intervention.
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PMID:Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. 772 89

We performed a two-step polymerase chain reaction (PCR) to detect bcr-abl-specific mRNA in 440 peripheral blood and/or bone marrow samples of 30 chronic myeloid leukemia (CML) patients (mean 15, range 2-50 samples) following non T-cell-depleted allogeneic (n = 28) or syngeneic (n = 2) bone marrow transplantation (BMT). Median follow-up after BMT is 40 months (range 2-116 months), the median observation time 29 months (range 2-40 months). In 15 patients (50%), bcr-abl-specific mRNA could be detected following BMT. Bcr-abl positivity was rare in patients who were in hematological remission for at least 40 months (2/11). In five patients, PCR positivity was observed only once; all five patients are in complete hematological remission. Ten patients showed bcr-abl specific mRNA in two or more consecutive samples. Hematological relapse occurred in five of the latter patients. Bcr-abl positivity preceded hematological relapse in all cases. Bcr-abl positivity was detected more frequently in patients without graft-versus-host disease (GVHD) (11/15), than in patients with GVHD (4/15) (p < 0.02). Our data indicate that transient bcr-abl positivity is not usually followed by hematological relapse, while patients, who are positive in serial samples have a high risk of relapse.
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PMID:Frequent detection of BCR-ABL specific mRNA in patients with chronic myeloid leukemia (CML) following allogeneic and syngeneic bone marrow transplantation (BMT). 823 Dec 44

Although serial detection of bcr-abl positive cells by PCR appears able to identify distinct patient groups with different risks of relapse following BMT, there remain many unanswered questions regarding the clinical utility and biological significance of PCR detectable cells in this disease. Many of the studies summarized have conflicting results and the influence of various clinical parameters which are known to affect the risk of relapse post-BMT has not yet been consistently associated with the ability to detect bcr-abl positive cells by PCR. These clinical parameters include GVHD, T-cell depletion and intensity of immunosuppression following BMT. Prospective studies with larger patient numbers will be necessary to define the impact of these factors in PCR status and relapse. The answers to all these questions will increase our understanding of the biology of chronic myelogenous leukemia and help provide more effective therapies for the future.
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PMID:Clinical significance of bcr-abl gene rearrangement detected by the polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. 837 16

Chronic myelogenous leukemia is a lethal disease of the hematopoietic stem cell. Marrow transplant from an HLA-matched sibling donor can cure some patients with chronic myelogenous leukemia. Best results are observed when patients receive transplants early in chronic phase. The advantages of delaying marrow transplantation for a trial of interferon-alpha are questionable if a suitable matched related donor is available. The high incidence of relapse following T-lymphocyte-depleted marrow transplantation for chronic myelogenous leukemia emphasizes the existence of dormant, malignant clones that persist after ablative therapy. The presence of very small numbers of bcr-abl-positive hematopoietic cells after marrow transplantation can be detected by sensitive molecular genetic techniques and does not always predict hematologic relapse. Successful treatment of hematologic relapse after marrow transplantation can result from treatment with interferon-alpha, donor buffy coat cells, or second transplantation. HLA phenotypically matched and, in some cases, class I HLA antigen mismatched unrelated donors can be used successfully for marrow transplantation. Complications include an increased incidence of graft failure and graft-versus-host disease. Younger patients undergoing transplantation early in the disease course fare best. Preliminary results suggest that autologous marrow transplantation can induce complete hematologic and cytogenetic remission and may prolong survival in some cases. Strategies are being developed to obtain benign primitive progenitors suitable for autologous marrow transplantation by positive selection and to develop further posttransplantation antileukemic cell therapy to be used as an adjunct to autologous marrow transplantation for chronic myelogenous leukemia.
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PMID:Therapy for chronic myelogenous leukemia with marrow transplantation. 845 12

A 25-yr-old Caucasian man presented in 1988 with Philadelphia chromosome (Ph) negative, bcr-abl rearranged, chronic phase chronic myeloid leukemia (CML). He was treated with human leukocyte antigen matched sibling allogeneic bone marrow transplantation but relapsed 5 yrs later. At this time he was given donor leukocyte infusions from the original bone marrow donor, seeking an immune anti-leukemic effect. This treatment induced graft versus host disease and severe bone marrow aplasia, requiring immunosuppression and repeat donor marrow infusion (without prior conditioning). Graft versus host disease was controlled and full donor hematopoiesis was restored, resulting in complete eradication of the leukemic clone at a molecular level. The patient remains in complete clinical and molecular remission and off all immunosuppression 24 mths later. This emphasizes a potentially powerful graft versus leukemia effect in CML.
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PMID:Donor leukocyte infusions in the treatment of chronic myeloid leukemia in relapse post bone marrow transplantation. 871 72


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