Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase I study of busulfan, cyclophosphamide, and timed sequential escalating doses of cytarabine followed by bone marrow transplantation. 154 48

Residual disease remains a major problem in the treatment of human neoplasia. To effectively monitor minimal leukemic activity after bone marrow transplantation (BMT), we used a competitive polymerase chain reaction (PCR) amplification technique to quantify expression of the characteristic bcr-abl fusion message in patients with chronic myelogenous leukemia (CML). Quantitative results were obtained between the 0.001% and 0.1% level in control experiments. This represents a significant advantage over cytogenetic and Southern blotting techniques routinely used to diagnose CML, which may not be sensitive below the 1% level. To illustrate the potential clinical usefulness of the quantitative PCR strategy, we compared results of bcr-abl messenger RNA expression with those obtained using cytogenetic and Southern blotting techniques, in a study of consecutive BM and peripheral blood (PB) samples from two CML patients at high risk for relapse after BMT. One patient received a syngeneic transplant during the chronic phase of the disease and relapse was apparent at the molecular level 4.5 months after BMT, while the patient was in complete clinical remission. The second patient was treated with an allogeneic BMT during the accelerated phase of the disease. A slow, but progressive decrease in bcr-abl expression was observed during the first 12 months after BMT, and expression was undetectable thereafter. Our results indicate that the competitive PCR technique can be used to monitor disease activity in patients at high risk of relapse, while the patients are in complete clinical remission, which should facilitate the early detection of relapse or the identification of progressive disappearance of leukemic activity. The approach used may serve as a model for the study of residual disease in an increasing number of other hematologic malignancies that express cancer-specific RNAs.
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PMID:Molecular quantification of residual disease in chronic myelogenous leukemia after bone marrow transplantation. 154 52

The polymerase chain reaction (PCR) has become a standard method for highly sensitive detection of the bcr/abl rearrangement in patients with chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). The exquisite sensitivity of the PCR facilitates the detection of residual leukemic cells after chemotherapy or after bone marrow transplantation. However, the detection of minimal residual disease does not yield any information on the malignant potential of the bcr/abl-rearranged cells. Qualitative PCR is therefore of limited prognostic value in the monitoring of residual leukemia. We have adapted the PCR for quantitative evaluation of cells carrying the bcr/abl rearrangement and by means of two exemplary cases of CML patients after bone marrow transplantation and under treatment with alpha-interferon, respectively, we show that this new technique is suitable for the long term follow-up of the activity of the residual bcr/abl rearranged clone. Longitudinal monitoring of residual disease by the technique presented provides a novel tool for detection of incipient relapse at a very early stage.
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PMID:Monitoring of residual disease in chronic myelogenous leukemia by quantitative polymerase chain reaction. 160 87

In vitro amplification of genomic or cDNA sequences by polymerase chain reaction (PCR) is one of the most powerful tools in recent molecular biology. More than 10(5) copies of DNA sequence ranging from 50 bp to 7 kb can be synthesized in a couple of hours. Ever since its development, PCR has attracted much attention because this strategy would allow the detection of minimal residual disease (MRD) at a very low level. The first successful application of this ultra-sensitive technique was the detection of residual tumor cells carrying a 14;18 translocation in follicular lymphoma. The abnormal transcripts caused by 9;22 translocation in chronic myelocytic leukemia (CML) was also exploited for the amplification to detect the MRD. These techniques have successfully shown the detection of one leukemic cell in 100,000 normal cells. Besides leukemic specific sequences caused by chromosome and gene translocations, unique sequences caused by rearrangements in IgH or TCR gamma, delta chain genes have been used as clonal markers for tumor cells. By targetting these sequences for PCR amplification, almost all ALL patients can be analyzed for MRD. The successive measurement of MRD might contribute to improvement of treatments for leukemic patients.
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PMID:[The detection of minimal residual disease in leukemia by in vitro DNA amplification]. 177 67

In chronic myelogenous leukemia (CML), amplification of a segment of bcr-abl messenger RNA (mRNA) by polymerase chain reaction (PCR) can be used to detect minimal residual disease after bone marrow transplantation (BMT). Previous studies have shown that this sensitive technique can often detect small numbers of leukemia cells in patients who are otherwise in complete remission. Nevertheless, the clinical significance of PCR positivity remains unclear because the majority of patients with PCR-detectable bcr-abl mRNA can remain disease-free for prolonged periods after allogeneic BMT. In the present studies, we applied PCR to detect bcr-abl-positive cells in 100 serial blood or BM samples from 24 patients with CML who underwent CD6 T-cell-depleted allogeneic BMT. After BMT, bcr-abl mRNA could be detected in 20 patients (83.3%) during complete cytogenetic or clinical remission. Patients in whom PCR positivity was sustained over time had a higher probability of CML relapse than patients in whom PCR was intermittently negative (P = .0095, log rank test). PCR detection of bcr-abl transcript between 2 and 10 weeks post-BMT also was associated with a high probability of subsequent relapse (P = .023, log rank test). In eight selected patients, we used a titration assay of the PCR-amplified product to estimate the number of residual tumor cells in each clinical sample post-BMT. PCR results in four patients showed a continuing increase in the number of tumor cells from early posttransplant until either cytogenetic or clinical relapse could be detected by conventional methods 1 to 2 years later. In contrast, PCR detected either no leukemia cells or relatively low and stable numbers of residual tumor cells throughout the follow-up period in four patients who remained in clinical remission. These results show that detection of the bcr-abl transcript by PCR after allogeneic BMT in patients with CML has important prognostic value. Estimation of the number of tumor cells in serial analyses can also be used to detect proliferation of the residual leukemic population. Sensitive detection of minimal residual disease can be used to assess the effectiveness of the transplant preparative regimen and to direct and evaluate further therapy post-BMT, before the development of overt relapse.
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PMID:Clinical significance of bcr-abl gene rearrangement detected by polymerase chain reaction after allogeneic bone marrow transplantation in chronic myelogenous leukemia. 182 68

In ALL the majority of cases possess clonal rearrangements of the Ig or TCR gene loci. Detection of these clonal markers by Southern blot analysis over a disease course has provided information on the fate and origin of leukaemic clones during treatment. Detection of these gene rearrangements has been used to detect residual disease during treatment. More recently, methods have been developed for the detection of Ig and TCR gene rearrangements using the polymerase chain reaction (PCR). This amplification technique allows for the rapid detection of gene rearrangements with a greater sensitivity than more conventional methods. The full impact and usefulness of this technique in residual disease detection has yet to be determined. The presence of the Philadelphia chromosome t(9;22) in ALL is associated with poor prognosis. Its detection by Southern blot is technically complicated due to the heterogeneity of chromosome breakpoints involved. The development of PCR-based methods for the detection of the bcr/abl mRNA associated with the Philadelphia chromosome has improved our understanding of the significance and incidence of this disease marker in ALL, emphasizing the importance of establishing Philadelphia status on all patients at diagnosis. Although longitudinal studies in CML have shown the presence of bcr/abl mRNA to be associated with residual disease, and its absence associated with long-term remission, these studies have yet to be reported for ALL. The usefulness of detection of residual disease using bcr/abl has yet to be determined.
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PMID:The molecular genetic analysis of gene rearrangements in acute lymphoblastic leukaemia. 195 87

In this study, cytogenetic and molecular analyses were employed to assess the response to therapy in 29 chronic myeloid leukemia patients undergoing high dose chemotherapy followed by autologous stem cell infusion. Of these, 11 had previously achieved hematologic remission and cytogenetic improvement after alpha-2b interferon (IFN) treatment, whereas 18 underwent autografting in an early phase of the disease. In each case bone marrow samples were examined pre-treatment and at +2, +6 and +12 months in order to verify the degree of Ph1 suppression. In addition, the position of the breakpoint within the BCR region was mapped with multiple restriction enzymes. In 17 cases (59%) a significant Ph1 reduction was observed at +60 days (0-57% residual Ph1+ cells). In three of these cases, a complete cytogenetic response was confirmed at the DNA level by Southern blotting, but specific amplification of the BCR/ABL junction by the polymerase chain reaction (PCR), performed in two cases, still showed residual disease. The remaining 12 patients (41%) revealed a substantial persistence of Ph1+ metaphases (90-100%). Nine of 17 responding patients (53%) showed an increase of Ph1+ cells at 6 months, and five of 20 evaluated had a further increase at 12 months. With the exception of the results seen by PCR, comparison of molecular and cytogenetic techniques did not show significant differences. The variable degrees of Ph1 suppression observed did not appear to be associated with the position of BCR breakpoints. The factors predicting cytogenetic response to IFN and stem cell autograft and long-term durability of cytoconversion should be elucidated in further studies and with longer follow-up.
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PMID:Therapy-induced Ph1 suppression in chronic myeloid leukemia: molecular and cytogenetic studies in patients treated with alpha-2b IFN, high-dose chemotherapy and autologous stem cell infusion. 208

The remission state of 13 Philadelphia positive chronic myeloid leukemia patients was studied after bone marrow transplantation (BMT) by cytogenetic and Southern blot analysis of the breakpoint cluster region (BCR) gene. Eight of 13 patients showed neither clinical nor genetic evidence of residual disease. In two patients hematological relapse was confirmed by cytogenetic and molecular analysis. Evidence for residual leukemic cells in otherwise complete remission was obtained genetically in three patients. One of the latter cases revealed BCR rearrangement despite negative cytogenetic findings, while in another patient cytogenetic relapse was observed without demonstrable rearrangement within the major BCR. Our results may indicate that cytogenetic and molecular genetic methods complement rather than replace each other for the detection of residual CML cells after BMT.
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PMID:Evaluation of remission state in chronic myeloid leukemia patients after bone marrow transplantation using cytogenetic and molecular genetic approaches. 250 80

Intensive cytoreductive therapy may be curative in certain hematopoietic malignancies, but its administration is limited by lethal marrow toxicity. Bone marrow transplantation (BMT) provides a way of rescue from this toxicity. The donor may be a human leukocyte antigen (HLA) "matched" sibling (allogeneic), an identical twin (syngeneic), or the patient (autologous). Long remissions and possible cures of 50% to 60% have been reported in acute leukemia after intensive treatment with chemotherapy, with and without total body irradiation, followed by allogeneic BMT. A similar approach has been used in chronic myelocytic leukemia (CML) and in non-Hodgkin's lymphoma with encouraging results. Results are best in younger patients and those transplanted early in their disease (i.e., in the first remission for acute leukemia and in the chronic phase of the disease in CML). Solutions to major problems associated with allogeneic BMT, such as graft-versus-host disease and viral infections, are being actively pursued. Syngeneic BMT avoids some of the above problems, but relapses appear to be greater. Nevertheless, this approach has produced a significant number of cures. Autologous BMT is the newest approach, and the demonstration that marrow may be purged of residual tumor cells by immunologic or pharmacologic means has engendered enthusiasm for this area of clinical therapeutic investigation.
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PMID:Bone marrow transplantation in leukemia. Current status. 638 15

Interferons (INF) are glycoproteins with protean antiviral, immunomodulator, and antiproliferative actions. In Haematology, IFN-alpha is the most widely used. Diffusion into the spleen, bone marrow and liver is good. Hairy cell leukemia is probably the malignant blood disorder which responds best to IFN. At some time during their treatment, nearly 90% of the patients require IFN. Treatment initiation is indicated when pancytopenia (polynuclear neutrophils below 1 x 10(9)/L) develops or in case of a very voluminous spleen. IFN-alpha 2a, 2b and 2c are active (leukocyte IFN is used less often, as is IFN-beta; IFN-gamma is ineffective). The standard dose is 3 x 10(6) U, three times a week for 12 weeks. Smaller doses and maintenance treatment is sometimes proposed. Haematological remission occurs in almost all cases, if not a misdiagnosis must be considered (villous lymphocyte lymphoma). Relapse usually occurs at the end of treatment, but sensitivity to IFN is not altered and final survival is improved. Nearly 90% of the patients are alive at 4 years. Although IFN is active in chronic myeloid leukemia, research in this area continues. Clinical trials have reported haematologic relapse in 90% and complete cytogenetic response in 15 to 35% of the patients. The effect on Ph+ cells is not observed with classical chemotherapies. Initial dose is generally 5 x 10(6) U/m2/day. High doses are not always well tolerated, but cytogenetic response is only seen in patients in haematologic and cytopenic remission. IFN therapy improves survival over classical treatments (median 62 versus 39 months). Survival is better after good cytogenetic response or complete remission. Combined chemo-IFN therapy is currently under study in an attempt to improve cytogenetic response. In terms of the molecular biology however, residual disease is almost always present and relapse is frequent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Interferons. Treatment of malignant hemopathies with interferons]. 751 80


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