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PubMed1997

[The importance of studies of the glycosaminoglycans in the peripheral blood leukocytes of patients in the diagnosis of the phases of chronic myeloleukemia].

To elucidate new diagnostic markers of chronic myeloid leukemia (CML) phases, we investigated quantitative and qualitative composition of glycosaminoglycans (GAG) of leukocytes from peripheral blood of 72 patients. Chronic CML phase was characterized by elevated GAG levels (2 times compared to normal values), weakening of anionic properties of chondroitin sulfate (CS) and high amount of heparan sulfate (HS). In CML transformation in the progressive phase overall concentration of GAG grew still higher, GAG fraction composition changed. In the blast crisis there was a sharp fall in the overall GAG, new electrophoretic fractions emerged. In the myeloid variant of the crisis an additional GAG component appeared (GAG-m), whereas in the lymphoid variant another component was found (GAG-1). It is suggested that the number and composition of GAG in peripheral blood leukocytes may serve markers of CML phase.

Biomarkers↗
PubMed2003

[Successful attainment of the third chronic phase by autologous peripheral blood stem cell transplantation and imatinib in a patient with chronic myeloid leukemia].

Chronic myeloid leukemia in a 61-year-old man progressed into the accelerated phase 8 months after the initial evaluation (Ph chromosome [20/20], FISH 93.5%), although the major cytogenetic response (Ph chromosome [0/20], FISH 9.7%) had been achieved 6 months after the initiation of the treatment with interferon and hydroxyurea. The Peripheral blood stem cells (Ph chromosome [0/20], FISH 5.8%, PCR 2.7 x 10(2) copies/microgram RNA) were harvested simultaneously with the attempt to induce the second chronic phase using the mini-ICE (idarubicin, cytosine arabinoside and etoposide) therapy. However, 2 months later, the disease progressed into blast crisis with the additional chromosomal abnormalities, and did not respond to the re-induction therapy with idarubicin and cytosine arabinoside. Autologous stem cell transplantation was then performed using the preparatory regimen with busulfan and cyclophosphamide. The third chronic phase was successfully achieved, and has been well maintained with imatinib for more than 13 months (Ph chromosome [0/20], FISH 0.0%, PCR < 10(2) copies/microgram RNA). This may be a rare case in which normal hematopoietic stem cells could be enriched in the peripheral blood in the accelerated phase, and that cytogenetic remission was achieved using these cells in the blast crisis. Flexible use of peripheral blood stem cells and imatinib could be an additional strategy for the better treatment of chronic myeloid leukemia.

Antineoplastic Agents↗
PubMed1981

Terminal deoxynucleotidyl transferase-positive lymphadenopathy in acute-phase chronic granulocytic leukemia.

A patient who had Philadelphia chromosome-positive chronic granulocytic leukemia had generalized lymphadenopathy. The lymph node biopsy revealed blast cells with small numbers of eosinophilic myelocytes indicative of granulocytic differentiation. In addition, the blast cells were found to have Philadelphia (Ph1) chromosome and extremely high levels of terminal deoxynucleotidyl transferase (TdT). The patient's peripheral blood and bone marrow reverted to the chronic phase, and the lymphadenopathy disappeared on two occasions with vincristine and prednisone therapy. The extramedullary proliferation of blastic chronic granulocytic leukemia, therefore, seems to share the histologic, cytogenetic biochemical, and chemotherapeutic sensitivity features of the basic disease process. TdT assay of enlarged lymph nodes in acute-phase chronic granulocytic leukemia might be used to identify the patients responsive to vincristine and prednisone despite the granulocytic histologic features of their lymph nodes.

Adult↗
PubMed1984

Burn injury to the face with associated fracture caused by a flare gun: a case report.

A case is presented of a child who sustained a full-thickness burn to the glabella and nose area, associated with an underlying fracture and cerebrospinal fluid leakage. This first reported case of a flare gun injury illustrates some important principles of facial management and soft tissue cover, in both the acute and the reconstructive phases.

Blast Injuries↗
PubMed1990

Autologous bone marrow or blood stem cell transplantation in chronic myeloid leukemia. France Auto Greffe Group.

Forty-seven patients with Ph1-positive chronic myeloid leukemia in transformation (CML) underwent autologous transplantation of peripheral blood stem cells (ABSCT) collected at the original diagnosis before any treatment. They were treated according to 3 consecutive strategies: single transplant (Group I = 17 patients), double transplant (Group II = 13 patients), double transplant followed by recombinant alpha interferon (IFN) (Group III = 17 patients). The actuarial median duration of second chronic phase was 3 months, 10 months and 18 months for Group I, Group II and Group III patients (p less than 0.0001). The encouraging results observed for Group III patients prompted us to propose ABSCT for patients in chronic phase with initial prognostic factors (high-risk CML) suggesting that IFN will not be effective if administered as front-line therapy. To date, 13 patients with high-risk CML underwent ABSCT followed by IFN therapy. Ten patients achieved a complete hematological response following transplantation. Two of 6 evaluable patients had a cytogenetical response 6 months after ABSCT. A longer follow-up is needed to see if the duration of chronic phase may be prolonged.

Adult↗
PubMed1996

Different methylation patterns of the M-BCR gene in myeloblastic and lymphoblastic crisis of chronic myelocytic leukemia.

OBJECTIVE: To investigate the relationship between methylation status of M-bcr gene and transformation of chronic myelocytic leukemia (CML) from chronic to blastic phase. MATERIAL AND METHODS: The methylation patterns of M-bcr in 23 patients with Ph' positive CML were studied. DNAs extracted from mononuclear cells of both chronic and blastic phases (20 cases) or blastic phases only (3 cases), were doubly digested with restriction enzymes HpaII and BglII, hybridized with a 5'M-bcr probe labeled with 32p-deoxycytidine triphosphate, and autoradiographed. RESULTS: In all the patients with myeloblastic crisis, DNAs from both chronic and blastic cells of each patient showed identical methylation patterns. There was substantial heterogeneity in methylation patterns in the patients with lymphoblastic crisis. All the lymphoblastic patterns were distinct from the chronic patterns as well as the patterns shown in myeloblastic crisis. Moreover, in four out of six patients with lymphoblastic crisis, the chronic patterns were different from those in cases with myeloblastic crisis. CONCLUSIONS: The methylation status of M-bcr was stable during evolution of CML from chronic to myeloblastic phase. Analysis of M-bcr methylation status may be of clinical use in distinguishing lymphoblastic from myeloblastic crisis and predicting the cell lineage of crisis when the disease is still in its chronic phase.

Blast Crisis↗
PubMed1990

Continuous infusion diaziquone and etoposide: a phase I study in adult patients with acute leukemia.

Diaziquone (AZQ) and etoposide (VP-16) were administered as simultaneous 5-day continuous infusions to 27 patients with acute leukemia (22 with acute myeloid leukemia (AML), three with chronic myeloid leukemia in blast crisis (CML-B), and two with acute lymphocytic leukemia) at four different doses in a phase I trial. Gastrointestinal toxicity, primarily stomatitis, was dose limiting, occurring in six of 10 patients at the highest dose level. Diarrhea was the only other grade 3 toxicity noted (three of 10 at the highest dose level). The duration of bone marrow aplasia was excessive at the highest dose (median 48 days to granulocytes greater than 500/mm3, range 33-67) but acceptable (31 days) at the maximum tolerated dose: AZQ 28 mg/m2/day x 5 days, VP-16 150 mg/m2/day x 5 days. Complete remissions were seen in seven patients (six AML, one CML-B) and a partial remission in one patient with AML. The median duration of unmaintained complete remission was 3 months (range 1.5-26+).

Adult↗
PubMed1994

Red cell ferritin and iron stores in chronic granulocytic leukemia.

Basic red cell ferritin was investigated in 28 patients with different phases of chronic granulocytic leukemia (CGL). Red cell ferritin was significantly decreased in remission after busulphan treatment and significantly elevated in the blast crisis as compared to healthy controls. Bone marrow stainable iron was decreased or absent in 86% of patients in the initial phase at the time of diagnosis and in 92% of those in remission. Red cell ferritin correlated with serum ferritin, however, serum ferritin level remained above normal range during all phases of the disease. A negative correlation between red cell ferritin and hemoglobin (Hb) (r = -0.605, p < 0.001) suggested that red cell ferritin level reflected the rate of iron utilization for heme synthesis. Decreased red cell iron stores observed in the remission may be explained by regression of dyserythropoiesis and by restoration of normal Hb synthesis after busulphan treatment. A progressive dyserythropoiesis in the blast crisis may lead to an increased red cell ferritin level.

Biopsy↗
PubMed2000

Accelerated and blastic phase of chronic myeloid leukemia.

There is currently no standard treatment for the blastic phase of chronic myeloid leukemia (CML-BC), which is a chemoresistant form of acute leukemia. Current approaches include using standard acute myeloid leukemia (AML) regimens in an effort to induce remission, variations of these approaches with drugs that seem more active in this specific leukemia, and the direct entry of patients into studies of investigational agents. Although the likelihood of achieving remission is small, immediate bone marrow transplantation in remission should be considered because it provides the only opportunity for long-term survival at this time. Allogeneic transplantation is preferred, but autologous transplantation of an early chronic phase marrow may provide benefit. Often, however, the duration of chemotherapy-induced remission of blast crisis is very short and may preclude entry into a transplant program. In addition, the patient may not be a candidate due to donor issues, age, or medical problems. If transplant is not an option, maintenance interferon is often used, although its benefit is uncertain. For patients in the accelerated phase of the disease, which is characterized by a variety of clinical presentations and cytogenetic abnormalities, the possibility of favorably manipulating the disease is greater. Again, there is no standard treatment, and clinical trials are recommended as first-line therapy. Treatment in the accelerated phase includes standard AML chemotherapy regimens, combinations of new agents, and the combination of cytostatic agents with interferon. Patients whose accelerated phase reverts to chronic phase after treatment may become candidates for bone marrow transplantation. However, current new approaches to the chronic phase applied in accelerated phase as well as new approaches directed specifically toward accelerated phase may lead to prolonged stabilization without bone marrow transplantation. In view of a median age of 55 at diagnosis of chronic phase, nontransplant regimens for accelerated phase that produce long-term benefit are urgently needed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Destructive bone lesions in chronic granulocytic leukemia.

Bone involvement in Chronic Granulocytic Leukemia (CGL) is rare. We describe here five such patients who presented with severe localized bone pain with involvement of femur neck, skull, tibia-upper end and spine. Lesions were osteolytic in three of them. Blast crisis was present in four of them. Survival was poor in all except one who presented in chronic phase. Bone involvement in CGL carries a poor prognosis.

Adult↗
PubMed1994

A randomized phase II study of low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in myelodysplastic syndromes (MDS) with a high risk of developing leukemia. EORTC Leukemia Cooperative Group.

In a randomized phase II study, patients with myelodysplastic syndromes (MDS) with 10-30% blasts in the bone marrow and hematopoietic failure were treated with low-dose Ara C (2 x 10 mg/m2 subcutaneously (s.c.) days 1-14) and rhGM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day s.c.) given either following Ara C (days 15-21) or simultaneously (days 8-14) for 1-5 cycles. 108 patients with a median age of 65 years, range 17-80 years and refractory anemia with an excess of blasts (RAEB, n = 54), RAEB with transformation (RAEBt, n = 50) or with chronic myelomonocytic leukemia (CMML, n = 4) were evaluable. Complete remission was achieved in 15 cases (14%), 11 had a partial response (10%), and 16 a minor response (15%). Stable disease was reached in 35 cases (32%). There were 16 cases of toxic death (15%), progression occurred in 15 patients (14%). No differences existed between the two treatment arms with respect to response and duration of response. Prognostic factors for poor response included the presence of cytogenetic abnormalities and a history of previous blood transfusions. Major adverse events during treatment were hemorrhage (55%), infections (54%), and fever associated with GM-CSF administration (40%). The overall response rate ws 39%, median duration was 12.5 months from start of treatment which allowed responding patients to lead good quality life without further therapy. The question whether the combination is indeed superior to LD-Ara C alone is not settled but will be evaluated in an ongoing clinical trial.

Acute Disease↗
PubMed1987

Chromosome abnormalities in CML.

The Ph chromosome is the hallmark of CML, where it is found in more than 90% of the cases. Cytogenetically, it usually results from a t(9;22)(q34;q11). The Ph arises in a stem cell and in chronic phase is found in all haematopoietic cell lineages, although it causes only increased granulopoiesis, and sometimes increased thrombopoiesis; furthermore blast crisis may occur in all differentiative patterns of the pluripotent stem cell. Recently, molecular investigations of Ph positive CML cases have revealed a consistent genomic recombination between two genes, BCR on chromosome 22 and the ABL oncogene. The latter is translocated from 9q34, its normal site, to the 22q- or Ph chromosome. This molecular rearrangement expresses a unique 8.5 kb BCR-ABL hybrid mRNA transcript, that encodes an altered BCR-ABL protein of approximately 210 kD with enhanced in vitro tyrosine kinase activity. The breakpoints on chromosome 22q- are clustered in a 5 kb DNA fragment, allowing their study using Southern blot analysis. Cytogenetic variant forms of the Ph translocation involving three or more chromosomes are found in about 5% of the cases. Southern blot and in situ hybridization studies have demonstrated that these variants are cytogenetically more complex than the standard t(9;22) but molecularly they show the same essential genomic recombination. This is also true for a small number of cases of Ph negative CML. Clonal progression, indicated by the presence of clonal, non-random chromosome abnormalities, in addition to the Ph is rare during chronic phase but is found in 80% of blast crisis. These additional aberrations may precede BC by weeks or months and have therefore a clear prognostic value. Ph is not restricted to CML, since it is also found in ALL (20% of adult cases) and rarely in AML. Ph in acute leukaemia is cytogenetically indistinguishable from Ph in CML, but molecular studies have shown that in 50% of the cases the breakpoint on chromosome 22 is different from the very consistent and characteristic breakpoint in CML. Nevertheless genomic recombination takes place that results in a novel ABL protein at least in some of the cases. Despite extensive cytogenetic and molecular investigations, the mechanisms underlying the formation of the Ph as well as the pathogenesis of Ph positive CML are still unknown but are now the object of intensive research.

Blast Crisis↗
PubMed1978

Terminal deoxynucleotidyl transferase in the diagnosis of leukemia and malignant lymphoma.

Neoplastic cells from 253 patients with leukemia and 46 patients with malignant lymphoma were studied for the presence of terminal deoxynucleotidyl transferase (TdT) by biochemical and fluorescent antibody technics. TdT was detected in circulating blast cells from 73 of 77 patients with acute lymphoblastic leukemia, 24 of 72 patients with chronic myelogenous leukemia examined during the blastic phase of the disorder and in cell suspensions of lymph nodes from nine of nine patients with diffuse lymphoblastic lymphoma. Blast cells from six of 10 patients with acute undifferentiated leukemia were TdT positive, but the enzyme was found in only two of 55 patients with acute myeloblastic leukemia. TdT was not detected in other lymphocytic or granulocytic leukemias or in other types of malignant lymphomas. The fluorescent antibody assay for TdT permits rapid and specific identification of the enzyme in single cells. The TdT assay is clinically useful in confirming the diagnosis of acute lymphoblastic leukemia, evaluating patients with blastic chronic myelogenous leukemia, and distinguishing patients with lymphoblastic lymphoma, whose natural history includes rapid extranodal dissemination, from patients with other poorly differentiated malignant lymphomas.

Adolescent↗
PubMed1977

[Detection of an antigen, associated with cells during the blast crisis of chronic myeloleukemia, in a cytotoxic test using xenogenic antibodies].

The immune antimyeloblast serum (AMS) was obtained from horses immunized with white blood cells from patients suffering from chronic myeloid leukemia (CML) at the blast crisis stage; the serum was completely absorbed with normal red blood cells and white blood cells (WBC). The absorbed antiserum remained cytotoxic to blast cells from 20 of 42 patients with CML at the blast crisis stage. AMS failed to react with the WBC from patients with CML in its chronic phase, and from patients with other types of leukemia Morphological studies indicated a possibility of identification of the antigen associated with myeloblasts from the blood of patients with CML blast crisis, by means to AMS.

Animals↗
PubMed1990

A study of prognostic factors in blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia.

In 80 patients with Ph-positive chronic myelogenous leukaemia the main clinical, haematological and cytogenetical data were recorded at diagnosis of blast crisis and evaluated for prognostic significance. At the time of the analysis 73 patients had died, with a median survival of 4-8 months from diagnosis of blast crisis for the whole series. When analysed as a time-dependent variable, the achievement of a favourable response to chemotherapy resulted in a longer patient's survival. On the other hand, the univariate analysis identified six pretreatment characteristics associated with a poorer prognosis: a longer chronic phase, presence of extramedullary blastic involvement, a platelet count below 200 x 10(9)/l, a less marked leucocytosis, a blood blast cell percentage higher than 10%, and presence of trisomy 8. The latter parameters were included in a multiple regression model together with the blast cell phenotype (lymphoid versus non-lymphoid), and only four of them (trisomy 8, duration of chronic phase, platelet count, and leucocyte count) retained their prognostic influence. When the therapeutical response was also included in the regression model, it proved to be the most important prognostic variable, followed by trisomy 8, length of chronic phase, extramedullary disease, and platelet count, whereas the leukocyte count lost its predictive value. Thus, in spite of the short overall survival of blast crisis patients, the identification of prognostic factors in such a haematological condition may be of interest, especially in the interpretation of new therapeutical approaches.

Adult↗
PubMed1988

Blast crisis of Philadelphia chromosome-positive chronic myelocytic leukemia (CML). Treatment results of 69 patients.

We have studied the clinical courses of 69 patients with blastic crises of Philadelphia chromosome positive CML to identify parameters that were associated with an increased response rate or survival. Cytogenetic analysis at the time of blastic transformation revealed additional chromosome changes in 70% of the patients tested. Bone marrow fibrosis was detected in 58% of evaluable patients. Lymphoblastic transformation was seen in 28% of the patients tested with cell surface marker analysis. The value of 5'-nucleotidase as a marker for distinguishing lymphoid from non-lymphoid blast crisis was confirmed. Of 57 evaluable patients, 23 (40%) responded to therapy (CR/PR longer than 14 days). Median survival was 75 days. Longer survival was related to the following factors: Ph1-chromosome as the only detectable cytogenetic abnormality; lymphoblastic transformation; no bone marrow fibrosis; high percentage of blasts and promyelocytes in the bone marrow, and response to therapy. No prognostic significance was associated with age, sex, Tdt, LDH, spleen size, duration of the chronic phase of the disease, white blood cell count, Hb, platelet count and percentages of basophils, eosinophils, erythroblasts and blasts and promyelocytes in the peripheral blood. These data confirm the poor prognosis of patients with blastic crisis of CML treated by conventional chemotherapy.

Adult↗
PubMed1995

[A "primitive" variant of the blast crisis in chronic myeloleukemia].

While immunotyping blast cells from 45 patients with CML blast crisis, we detected 5 cases with immunologically primitive blast cells. The immunological phenotype of these cells corresponded to that of primitive stem cells which are characterized by expression of CD34 and HLA-DR antigens in the absence of other immunological markers. We suggest that blast cells from these patients may undergo differentiation similar to that of primitive stem cells that implies the existence of a new immunological variant of CML blast crisis, a primitive variant. Morphologically, blast cells in 3 cases could be classified as myeloid, in 2 cases precise identification was impossible. Cytochemically, this type of cells can be defined as mixed. The patients with CD34+ phenotype do not differ clinically or hematologically from those with CML blast crisis. Blast cells with membrane marker CD34 are likely to arise in any CML phase either as a component of overall leukemic population or predominant, single subclone.

Adult↗