Enzyme markers in leukaemia.
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Biomarkers, Tumor↗
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Results for “Leukemia, Myeloid, Chronic-Phase”
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Terminal deoxynucleotidyl-transferase levels and membrane phenotypes in diagnosis of acute leukaemia.
Terminal deoxynucleotidyl transferase (T.D.T.) has been measured in the cells of 112 leukaemia patients whose cells were characterised by membrane markers as well as by standard haematological and cytochemical criteria. The concentration of enzyme ranged from 0.1 to 1.4 units/10(8) cells in the bone-marrows of 20 patients with normal marrow or benign marrow hyperplasia. The enzyme level was raised in 30 of 31 patients with untreated acute lymphoblastic leukaemia (A.L.L.) whose cells reacted positively with an anti-A.L.L. serum (range 0.9-197, mean 59, units/10(8) cells) and in all 9 patients with thymic A.L.L. (Thy-A.L.L.) (range 1.5-95, mean 36, units/10(8) cells). All but 1 of 17 patients with acute myeloblastic leukaemia gave negative results (range 0-1.5, mean 0.60, units/10(8) cells), and T.D.T. was also normal in all 7 bone-marrow samples from patients with chronic granulocytic leukaemia (C.G.L.) in the chronic phase. The T.D.T. assay gave a clear distinction between 11 patients with C.G.L. in lymphoid transformation, anti-A.L.L.-serum positive (range 15-226, mean 83, units/10(8) cells), and 12 patients with C.G.L. in myeloblastic transformation, anti-A.L.L.-serum negative (range 0-1.9, mean 0.7, units/10(8) cells). Among 17 patients with otherwise unclassifiable acute leukaemia, 10 gave raised values (range 1.6-113 units/10(8) cells) and 7 gave normal values. It is concluded that the assay of T.D.T. in the peripheral blood or bone-marrow of patients with acute leukaemia is of value in differentiating lymphoid (including non-T non-B and Thy-A.L.L.) from myeloid leukaemia.
Biomarkers, Tumor↗
Expression of the ETS2 and transferrin receptor genes in Philadelphia-positive chronic myeloid leukemia patients with a reciprocal t(3;21).
The translocation t(3;21)(q26;q22) is a rare recurring clonal abnormality, either preceding or associated with blast crisis in Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients. We previously localized the chromosomal breakpoints at 3q26.2 and 21q22.2, using high resolution chromosomal analysis. Two genes of interest are localized near the breakpoints, the transferrin receptor gene and the ETS2 proto-oncogene. Their chromosomal localizations, determined by in situ hybridization on normal metaphase cells, were 3q29 and 21q22.3, respectively. They underwent a reciprocal translocation in patients with t(3;21). Their structures were not altered by the translocation, and both were expressed to varying levels in t(3;21) patients. Southern blotting investigations showed that the structure of other single-copy genes, including FIM3, localized near the breakpoints, were not affected by the translocation. An analysis of ETS2 expression performed on CML patients without t(3;21) showed the presence of the transcript in 100% of the blast crises, but only in 20% of the chronic-phase patients. Thus ETS2 expression may either be linked to or play a role in CML progression.
Blast Crisis↗
Successful pregnancy in a patient with chronic myeloid leukemia following therapy with cytotoxic drugs.
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Acetaminophen↗
Complex translocation involving Ph chromosome in a patient with typical chronic myelogenous leukemia.
We report a cytogenetic study of a patient with chronic myelogenous leukemia (CML) who, while displaying a Philadelphia (Ph) chromosome, resulting from a standard t(9;22) at diagnosis, during the chronic phase (CP) showed disappearance of the Ph and occurrence of new chromosome changes, including a marker probably arising from a translocation involving chromosome 17 and the Ph. In situ hybridization confirmed the cytogenetic appearance and demonstrated that the breakpoint on the Ph marker occurred below the BCR-ABL fusion gene.
Chromosome Deletion↗
Initial cytoreduction by mitoxantrone and cytarabine has no impact on the outcome of interferon-alfa-2b therapy in chronic myelogenous leukemia.
Eleven previously untreated patients with chronic-phase Philadelphia-chromosome-positive chronic myelogenous leukemia were treated with cytotoxic chemotherapy followed by interferon-alfa-2b (IFN-alpha) maintenance. Initial chemotherapy consisted of three cycles of mitoxantrone 10 mg/m2 on day 1 and 2, and cytarabine 100 mg/m2 daily for 5 d. Complete hematological response was obtained in 9 (82%) patients with moderately associated toxicity. However, cytogenetic responses after three cycles were poor and transient (1 partial suppression and 2 minor suppression of Ph chromosome). Maintenance therapy with IFN-alpha was started in 10 patients at 5 x 10(6) U/m2 daily with dose reduction if hematologic toxicity or severe side-effects occurred. Of 9 evaluable patients treated for more than 3 months, 6 patients maintained a complete hematological response, whereas 1 patient remained in partial remission and 2 patients showed progressive disease. Cytogenetic evaluation showed partial suppression of Ph chromosome in 1 patient, whereas 1 patient had a minor response and 5 patients had no change or evolution of new chromosome abnormalities. As the results are not superior to IFN-alpha treatment alone, it is concluded that initial cytoreduction by mitoxantrone and cytarabine has no impact on the outcome of therapy in CML.
Adult↗
[Cause of death, survival, and prognostic factors in a series of 98 patients with chronic myeloid leukemia].
PURPOSE: To analyse the survival from diagnosis to blastic crisis, as well as the causes of death and the significance of different features in patients diagnosed of chronic myelogenous leukaemia (CML). MATERIAL AND METHODS: The series includes 98 patients who died of CML in Asturias Central Hospital and other nearby hospital between 1970 and 1990. The CML diagnosis had been established according to conventional criteria. The blastic crisis was diagnosed in accordance with morphologic and cytochemical studies, complemented in some cases with the assay of TdT or other markers. The Kaplan-Meier curves and long-rank test were applied to the statistical analysis of survival. The prognostic factors were evaluated by univariate correlation. RESULTS: The series' mean age was 48.57 years (range: 6-90) and the M/F ratio was 56/42. Cytogenetic study had been performed in 35 patients, of whom 33 had the Ph' chromosome. Death occurred in the blastic crisis in 67 cases (72%), in the accelerated phase in 14 cases (15%) and in the chronic phase in 12 cases (13%). The cause of death could be determined in 47 cases; of them, 24 (51%) died of infection, 11 (23.4%) of haemorrhage, and the remaining 12 (25.6%) of different complications. The median survival of the group as a whole was 32 months (range: 4-137). For the blastic crisis this figure was reduced to 2.5 months (range: 1-14), the lymphoid forms doing better, 5 months, than the non-lymphoid ones; 1.5 months (p < 0.03). Out of the data evaluated at diagnosis, only haemoglobin and the percentage of blast cells in peripheral blood showed any correlation with survival (r = +0.28, p < 0.05 for haemoglobin, and r = -0.30, p < 0.01 for blast cells). CONCLUSIONS: (1) Although most patients die from infection or haemorrhage during the blast crisis, CML increases the risk of death in the accelerated and chronic stages as well. (2) Non-lymphoid blastic crisis has poorer prognosis than the lymphoid form. (3) The concentration of blast cells and haemoglobin in peripheral blood at diagnosis acquire prognostic significance in the present study.
Adolescent↗
[Treatment with interferon alfa-2a in the chronic phase of Philadelphia-positive chronic myeloid leukemia].
PURPOSE: To evaluate the cytologic and cytogenetic response attained with interferon alpha-2a (IFN, Roferon*A) in patients with Ph '-positive chronic myelogenous leukaemia (CML) in the chronic phase. MATERIAL AND METHODS: A prospective study was carried out on 22 CML patients diagnosed in the Haematology Service at the Princesa Hospital in Madrid. The therapeutic regime consisted of two phases: A) Hydroxyurea was given until the white-cell count was reduced to 15-20 x 10(9)/L. B) Roferon*A was then given subcutaneously at a doses of 5 MU/m2 per day. The follow-up was performed weekly, and monthly once the leucocyte count had stabilized. The cytologic and cytogenetic response was assessed by bone marrow aspiration performed after 6, 9, 12 and 18 months. The toxicity was evaluated in accordance with the WHO recommendations. RESULTS: The median follow-up is 263 days (21-930). Thirteen patients (65%) had initial complete haematological response and 3 (15%) had partial response. The mean time to achieve response was 42 days (0-321). In the last evaluation, 69% of the patients were in sustained haematological remission (53% complete and 16% partial) with median follow-up of 232 days (21-930). The cytogenetic response was evaluable in 13 patients (follow up > or = 6 months): three attained complete response (23%) and three others partial response (23%). The commonest untoward effects were hypertriglyceridaemia (100%) and myelosuppression (86%). Grade-III thrombocytopenia was seen in 19% of the patients and grade-III anaemia or leucopenia in 5%. No infectious or haemorrhagic complications have appeared. Therapy was discontinued in 3 patients (14%), two due to severe flu-like syndrome and one for parkinsonism after 809 days of treatment. At the moment of evaluation two patients had died, one in lymphoid blastic crisis on day 217 and the other in the immediate post-BMT period. CONCLUSION: Treatment with interferon-alpha 2A is useful in the chronic phase of CML. An important number of responses can be attained, even in patients in the late chronic phase, and the toxicity seems acceptable.
Adolescent↗
Dual infection with Pneumocystis carinii and respiratory viruses complicating bone marrow transplantation.
Pneumonia due to dual infection with Pneumocystis carinii and respiratory viruses is a rare but formidable complication of bone marrow transplantation. We report here two cases of viral infections complicating P. carinii pneumonia in bone marrow transplant recipients who, at the time of infection, were not taking P. carinii prophylaxis. Both patients died following the pneumonia. Potential factors contributing to the dual infection included graft-versus-host disease, high-dose steroids and cyclosporin A. P. carinii prophylaxis should be continued for 12 months, or longer in bone marrow transplant recipients requiring prolonged immunosuppressive therapy. As specific antiviral therapy becomes available for some respiratory viral infections, performing regular viral surveillance cultures and responding with active early treatment may help improve the outcome in these immunocompromised patients.
Adenovirus Infections, Human↗
Analysis of late graft failure after allogeneic bone marrow transplantation: detection of residual host cells using amplification of variable number of tandem repeats loci.
In an attempt to gain insight into the etiology of late graft failure, we analysed the origin of bone marrow mononuclear cells (BMMC) and peripheral blood leukocytes in patients with this syndrome by taking advantage of DNA fragment length polymorphisms in variable number of tandem repeats (VNTR) loci. Amplification of the VNTR loci in DNA from BMMC using the polymerase chain reaction revealed the persistence of host cells in two of four patients studied. One of the patients, whose cultured lymphocytes inhibited in vitro growth of donor-derived hemopoietic progenitor cells, responded to immunosuppressive therapy and donor-derived hemopoiesis was restored. In the other patient, host-derived polymorphonuclear leukocytes (PMN) appeared together with donor-derived PMN from the early post-transplant period, and he proceeded to relapse with myelodysplastic syndrome. In the other two patients in whom host cells were not detectable, the marrow hypoplasia was associated with chronic graft-versus-host disease (GVHD). The hypoplasia improved significantly as the chronic GVHD improved in response to immunosuppressive therapy. We conclude that detecting minimal residual host cells by means of amplification of VNTR loci is valuable for understanding the etiology of late graft failure in marrow transplant recipients, and could prove helpful for choosing appropriate therapy for this syndrome.
Adolescent↗
Maintenance of Philadelphia-chromosome-positive progenitors in long-term marrow cultures from patients with advanced chronic myeloid leukemia.
We investigated the marrows of 19 patients with advanced Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in long-term marrow culture (LTMC) to determine the frequency of loss of clonogenic leukemic cells in vitro. Sixteen patients were in first chronic phase at a median of 24 months from diagnosis and had received prior therapy with busulphan and/or hydroxyurea. The effect of interferon therapy on loss of Ph+ clonogenic cells in LTMC was also investigated. Of 16 patients who had not previously received interferon, complete loss of Ph+ progenitors was documented by 4-5 weeks in the LTMCs from two (12.5%). Ph+ progenitors persisted at 4-5 weeks in the LTMC derived from 12 patients. Marrows from nine patients treated with interferon were also established in LTMC. Cultures from four patients did not yield colonies with detectable metaphases at 3-5 weeks, while Ph+ clones were present in the cultures initiated with marrows from five patients. Mean hematopoietic colony yields from the adherent layer at 2-4 weeks, and from the supernatant layer at 1-3 weeks, of cultures derived from interferon-treated patients were significantly lower than in LTMCs of patients not treated with interferon (p less than 0.05). The results indicate that in previously treated patients with late chronic phase CML there is a low frequency of conversion of Ph-negative hematopoiesis in long-term culture. Interferon therapy is associated with impaired progenitor yields in LTMC and does not improve selective loss of Ph+ progenitors.
Bone Marrow↗
Acute leukostasis pulmonary distress syndrome.
A 75-year-old woman in accelerated-phase chronic myeloid leukemia with hyperleukocytosis presented with acute respiratory distress syndrome. Despite early and aggressive pulmonary support and cytoreductive chemotherapy, the patient died. Autopsy confirmed the presence of the leukostasis syndrome. The clinical, radiologic, pathophysiologic, and therapeutic aspects of this entity are reviewed.
Acute Disease↗
Fractionated TBI and methotrexate-cyclosporin do not seem to increase relapses in BMT for first chronic phase CML patients: results of a single centre study.
Fractionated total body irradiation (FTBI) and methotrexate-cyclosporin A(MTX-CSA) have been found useful in reducing interstitial pneumonia (IP) and acute graft-versus-host-disease (GVHD) in bone marrow transplantation patients, but an increase in relapse rate has been observed by some authors when these strategies are used. To evaluate this relapse risk, we performed a retrospective analysis in 24 consecutive first chronic phase chronic myeloid leukemia patients who received an HLA-identical non-T cell-depleted graft in a single institution. All were conditioned with cyclophosphamide plus FTBI (12 Gy in six fractions delivered twice daily for 3 days) (CY-FTBI) and received MTX-CSA as GVHD prophylaxis. Serial hematologic and cytogenetic bone marrow analysis were performed at least three times (days +30, +100, +360) and at variable intervals thereafter in long-term survivors. Actuarial probabilities of developing IP and acute GVHD greater than or equal to II were respectively 5.9% and 44.2%, with a GVHD-associated mortality of 33%. Four-year actuarial relapse and disease-free survival rates were 7.7% and 48.2% respectively. No exclusively cytogenetic relapses were observed. Our results suggest that CY-FTBI and MTX-CSA are not associated with an increase in relapse rate in 1CP-CML patients.
Adolescent↗
Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation.
We report a patient who underwent two allogeneic bone marrow transplants for chronic myelogenous leukemia, initially in 1984 and again after relapse in 1990, who developed an identical pulmonary syndrome at a similar interval following each transplant. The patient presented with a non-productive cough, bilateral inspiratory crackles, and multiple patchy infiltrates on chest X-ray. Pulmonary function testing revealed a restrictive abnormality but no obstructive defects. The appearance of this pulmonary disorder after each transplant coincided with the development of chronic graft-versus-host disease. In both instances, this pulmonary syndrome completely reversed with corticosteroid therapy. The patient's chest computed tomographic scan and lung biopsy specimens were consistent with the diagnosis of bronchiolitis obliterans with organizing pneumonia (BOOP). While bronchiolitis obliterans has been reported following allogeneic transplant, BOOP has not previously been reported in this setting.
Adult↗
Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia.
The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4-hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.
Antigens, CD↗
Use of cell-free retroviral vector preparations for transduction of cells from the marrow of chronic phase and blast crisis chronic myelogenous leukemia patients and from normal individuals.
Marrow cells were exposed to the LNL6 or G1N safety-modified variants of the N2 retrovirus, which contain the G418 bacterial resistance gene neo. The frequency of acquisition of the G418 resistance phenotype following exposure to LNL6 or G1N was compared among hematopoietic progenitor cells from the marrow of patients with chronic phase chronic myelogenous leukemia (CML), blast crisis CML, or from nonleukemic individuals. Under the conditions of our experiments, the myeloid committed progenitor cells from 3 of 6 nonleukemic individuals, 9 of 18 chronic-phase CML patients, and 2 of 4 blast crisis CML patients acquired resistance to at least 1 mg/ml G418 following incubation with cell-free supernatants from the PA317 LNL6 or PA317 G1N producer cell lines. Ten of the 32 colonies growing up in 0.8 mg/ml G418 from chronic-phase marrow exposed to LNL6 were shown to contain the neo gene by polymerase chain reaction (PCR) assay of DNA. These results were consistent with estimates of the transduction frequency based on acquisition of resistance to G418 as the number of colonies growing under G418 selection was always greater at 0.8 mg/ml G418 than at higher concentrations of G418 (1.0-1.4 mg/ml). The average transduction frequency at each G418 concentration (1.0, 1.2, and 1.4 mg/ml) in cells from blast crisis CML cells ranged from 2 to 14%, as measured by acquisition of G418 resistance. Chronic-phase CML showed slightly lower average frequencies of transduction (0.6-2.8% of the colonies are G418 resistant). The average transduction frequency of cells from nonleukemic marrow was as high as that seen from the marrow of chronic-phase CML individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Cryopreserved peripheral blood cells functioning as autografts in patients with chronic granulocytic leukaemia in transformation.
Six patients with chronic granulocytic leukaemia (CGL) in transformation were treated with cytotoxic drugs or cytotoxic drugs plus total body irradiation, followed by infusion of reconstituted autologous peripheral blood cells that had been collected from them at diagnosis and stored in liquid nitrogen for up to 58 months. In four cases the blood and bone-marrow appearances were rapidly restored to those of typical chronic-phase disease. In three of these patients transformation recurred at 74, 32, and 26 weeks respectively. One patient was still in second chronic phase at eight weeks. One of the patients who entered a second transformation was restored to a third chronic phase by further treatment with cytotoxic drugs and a second autograft. Cryopreserved autologous blood cells may thus restore some patients with CGL in transformation to chronic-phase disease and so may help to prolong life.
Adult↗
Ultrastructural, cytochemical and surface marker analysis of cells during blast crisis of chronic granulocytic leukaemia.
The blast cells of 19 patients with Ph1-positive chronic granulocytic leukaemia (CGL) in blast crisis (BC) were studied by means of several techniques: morphology, cytochemistry, ultrastructure, surface markers and the enzyme terminal transferase. Cells of BC were, in most case, extremely undifferentiated by morphology and cytochemistry. Our data showed that in 80% of cases the cells in BC were myeloid and in 20% they were "lymphoblastic". The M1, M2 and M3 forms (FAB classification) were rare in CGL BC compared with acute myeloid leukaemia (AML). A megakaryoblastic type was seen in 15% of BC cases; the existence of this form could only be demonstrated by electron microscopy. The limphoblastic BC cells were, as in acute lymphoblastic leukaemia (ALL), positive with Greaves' anti-ALL serum and had elevated levels of terminal transferase. A case of a 17-year old boy presenting as ALL, reverting to chronic-phase CGL after complete remission and developing terminally a myeloid BC is described in detail. This case helps to illustrate a new form of natural history of CGL unveiled by the present study.
Adolescent↗