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PubMed1993

Idarubicin in the initial treatment of adults with acute lymphoblastic leukemia: the effect of drug schedule on outcome.

Fifty two adults (aged 15 to 66 years) with newly diagnosed acute lymphoblastic leukemia (ALL, n = 47) or lymphoid blast phase chronic myelogenous leukemia (Ly-CML, n = 5) were managed with three distinct protocols containing idarubicin at a cumulative dose of 36, 20, and 10 mg/m2, respectively, plus vincristine, L-asparaginase, and prednisolone (IVAP-1, -2, -3). IVAP-1 was highly toxic and gave a low complete remission (CR) rate (7/17, 41%). Nine patients died of complications while severely neutropenic, and one had resistant disease. In contrast, 24 of 28 patients subsequently treated with IVAP-2 achieved a CR (86%, p 0.005), the rate of both hematological and extrahematological toxicity being significantly reduced compared with IVAP-1 (p < 0.05). With IVAP-3, 6/7 patients aged > 60 years achieved CR. IVAP-2 with total idarubicin 20 mg/m2 is a very effective and well tolerated regimen for the initial treatment of adults with ALL.

Adolescent↗
PubMed2006

Clinico-pathologic features of chronic myeloid leukemia and risk stratification according to Sokal score.

OBJECTIVE: To compile the clinical and haematological parameters of chronic myeloid leukemia (CML) and risk stratification according to Sokal score in our population. DESIGN: A descriptive analysis. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, during the period from August 1997 to August 2005. SUBJECTS AND METHODS: All patients with diagnosis of chronic myeloid leukemia treated as outpatient in haematology clinic, or admitted in haem-oncology wards in The Aga Khan University Hospital were included. Records were retrospectively analyzed for clinicopathologic features. Risk groups were assigned as per Sokal scoring. RESULTS: During the 8 years study period, 245 patients with chronic myeloid leukemia were analyzed, the median age of presentation was 35 years (range 11-73); with male to female ratio 1.69:1. At the time of diagnosis, 178 patients (72.6%), 48 (19.7%) and 17 (7.8%) of patients were in chronic, accelerated and blast phase of the disease respectively. Abdominal fullness was the frequent clinical presentation followed by fever. Laboratory parameters revealed mean hemoglobin 10.0 g/dl (range 4.6-15), mean total leukocyte count 168 x 10(9)/L (35-959) and mean platelets 408 x 10(9)/L (range 30-2335). The mean size of spleen at the time of presentation was 9.2 cm below the left subcostal margin. A large number of patients (46.2%) were in high risk group according to Sokal score i.e. > 1.2. CONCLUSION: CML occurred more commonly at younger age in this series. Most of these patients were in high risk group according to Sokal score.

Adolescent↗
PubMedDate not supplied

Hypotheses on the role of chromosomal changes in leukemias. Application of the Weibull distribution function.

Investigations were carried out in 38 patients with acute leukemias or with chronic myeloid leukemias in the blast phase and a correlation was made between the cytogenetic aspect and the survival time. The interpretation of results was made by the Weibull distribution function. It was mathematically demonstrated that in the leukemic patients with chromosomal aberrations there is a preclinical period of over 40 months necessary for the formation of these anomalies. Chromosomal aberrations, the absence of mitoses and age over 70 proved to be aggravating factors in the diseases investigated.

Adolescent↗
PubMed1998

[Study on nuclear matrix protein in leukemia cells].

OBJECTIVE: To compare the composition of nuclear matrix proteins (NMP) between leukemia cells and normal bone marrow cells. METHODS: NMP was isolated by high-salt extration and identified by SDS-PAGE and western blotting. RESULTS: Increase in NMP was demonstrated in acute and chronic myelogenous leukemic cells as well as in the blast phase of chronic leukemia. On SDS-PAGE, NMPs with molecular weight different from what were seen in normal bone marrow cells were present in both acute and chronic myelogenous leukemias. CONCLUSION: Marked changes of NMP, not only in contents but also in compositions, exist in leukemic cells compared with normal bone marrow cells. NMP may serve as a target of chemotherapeutic drugs against leukemia.

Antigens, Nuclear↗
PubMed1976

Chromosomal banding patterns in acute nonlymphocytic leukemia.

Bone marrow chromosomes obtained from 50 of 55 consecutive adult patients with acute nonlymphocytic leukemia were analyzed with quinacrine fluorescence. Twenty-five patients showed a normal karyotype and 25 an abnormal karyotype on the initial samples available for analysis. Among the 25 patients with abnormalities, the marrow cells contained 48 chromosomes in one case, 47 in two, 46 in ten, 45 in nine, 43 in two, and 42 chromosomes in one case. Seven of the ten patients with 46 chromosomes had abnormalities, primarily balanced translocations, that were not detected with the standard Giemsa stains. The analysis of all of the data available revealed the presence of nonrandom chromosome changes such as the addition of No. 8, the loss of No. 7, and a gain or loss of one No. 21. the most frequent structural rearrangement was the translocation between the long arm of No. 8 and No. 21, which may also be associated with the loss of a sex chromosome. Chromosomal abnormalities decreased or disappeared during remission; the same abnormality recurred in relapse. Chemotherapy did not appear to produce a stable clone of aberrant cells. Evolution of the karyotype occurred in eight patients, in five of whom an additional No. 8 was observed. This pattern of chromosomal evolution in patients with acute leukemia was very similar to that observed in patients with chronic myelogenous leukemia in the blast phase.

Acute Disease↗
PubMed1992

[The expression of C-myc oncogene in leukemia and its relationship to clinical symptoms].

The expression of C-myc proto-oncogene were studied at the levels of protein in bone marrow cells obtained from patients with AML and CML. It was found that the expression of C-myc in florid AML and during blast phase of CML were much higher than that in remission of AML and in chronic phase of CML. In 7 cases of AML diagnosed for the first time, 2 cases with high C-myc expression had no remission after 3-6 months, while 5 with rare C-myc expression had remission after 3-6 months. This results suggest that the expression of C-myc proto-oncogene are possibly sensitive indicator of the prognosis of leukemia.

Acute Disease↗
PubMedDate not supplied

[Prognostic significance of additional chromosomal abnormalities in Ph positive bone marrow cells in chronic myeloid leukemia].

We studied the prognostic significance of combination of different chromosomal abnormalities and genomic mutations in Ph+ chronic myeloid leukemia patients. In general 49 cytogenetic analyses of bone marrow aspirate from 35 patients (11 of these observed in dynamics) have been carried out. The additional chromosome changes were found in 25.07% cases and approximately 80% of anomalies appeared in the blast phase. Among the secondary chromosomal abnormalities extra Ph-chromosome appeared mostly in different combinations with trisomy of chromosomes 8 and 19. Appearance of clonal differences of cells, high rate of genome mutations and of microchromosomes had negative prognostic significance on disease proceeding.

Bone Marrow Cells↗
PubMed2006

Dasatinib: BMS 354825.

Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. These mechanisms include insufficient potency at therapeutic doses, activation of alternate oncogenic pathways, and overexpression of the multidrug-resistant gene. One of the possible causes of imatinib-acquired resistance is associated with increased expression of the SRC-related kinase Lyn and loss of BCR-ABL dependence arising from sequence mutations. In December 2005, Bristol-Myers Squibb announced that it has completed the rolling NDA submission to the US FDA for dasatinib in the treatment of CML in chronic, accelerated or blast phases, as well as Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in patients with resistance or intolerance to prior treatment. At the Bristol-Myers Squibb R&D Day in May 2005, the company stated that it plans to evaluate dasatinib in solid tumours. In in vitro assays, dasatinib induced apoptosis and had potent activity in the imatinib-resistant tumour cells lines and CML patient specimens. It effectively inhibited the proliferation of cells expressing nearly all imatinib-resistant isoforms. In vivo, dasatinib has shown efficacy, with no apparent toxicity, when administered orally in SCID mice with xenografts of imatinib-sensitive and resistant human CML cells lines. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020.

Animals↗
PubMed2006

[Monitoring bcr-abl mRNA levels by real-time quantitative RT-PCR in chronic myeloid leukemia patients after hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the value of real time quantitative RT-PCR (Q-PCR) for monitoring bcr-abl mRNA levels in chronic myeloid leukemia (CML) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Quantification of bcr-abl mRNA was performed on 316 bone marrow samples from 112 patients with CML after HSCT by Q-PCR using the TaqMan probe system. The bcr-abl mRNA level was normalized by control gene abl. Cytogenetic response was evaluated with fluorescent in-situ hybridization (FISH). RESULTS: The reproducible sensitivity of Q-PCR was 5 copies. The coefficients C(T) of interassay and intraassay variation for abl and bcr-abl were all below 2.0%. 289 bone marrow samples were collected from 101 CML patients who achieved a sustained complete cytogenetic response (CCyR) one month post allo-HSCT in a period of 6 - 60 months (median 12 months) at different intervals. In general, the median bcr-abl levels gradually decreased with the prolongation of time after HSCT: the median bcr-abl levels were 0.035% (0 - 0.406%) at 1 month post allo-HSCT (+ 1 month), 0.006% (0 - 0.683%) at +3 month, 0% (0 - 0.225%) at +6 month and remained 0% till +24 months. The highest level in CCyR patients detected at + 6 month was 0.068%. The bcr-abl mRNA level was decreased by 3 log in sustained CCyR patients at + 1 month compared with the newly diagnosed CML-CP patients (33.0%, data unpublished). On the contrary, Q-PCR results ranged from 0.12% to 13.45% in 8 cytogenetic non-responders or relapsed patients post allo-HSCT. Among them, 5 patients' samples were collected 1 - 2 months before cytogenetic relapse, the results were ranged from 0.09% to 3.42%. If 0.09% was assumed 0.09% as a threshold, 9 sustained CCyR patients (8.9%) were tested once higher than that within 6 month after HSCT but decreased to 0% eventually. 2 blast crisis patients achieved CCyR within 1.6 and 3 months after HSCT, but hematological relapse occurred after 1 and 1.5 months, and their bcr-abl mRNA levels increased dramatically from 0% and 0.14% to 46.9% and 75.9% respectively. CONCLUSIONS: Q- PCR is a sensitive, precise and reliable technique, and can be used to monitor CML patients post allo-HSCT regularly. Patients in blast phase of CML should be monitored more frequently.

Adolescent↗
PubMed1990

Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders.

Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by "stem cell-derived" malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, "dim SIg" CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders ("bright SIg" CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). "High-grade" B-cell non-Hodgkin's lymphomas (B-NHL) express in general a higher level of CD54 than "low-grade" ones. This finding in conjunction with the expression of CD54 in all 17 patients with "bright SIg" CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.

Antigens, Surface↗
PubMed1991

Inhibition of hydroxymethylglutaryl coenzyme A reductase activity induces a paradoxical increase in DNA synthesis in myeloid leukemia cells.

The effects of competitive inhibition of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase by compactin on the in vitro proliferation of peripheral blood myeloid leukemia cells were studied using the cells from 45 patients with acute myeloid leukemia or chronic myelogenous leukemia in blast phase. The cells from 58% of these patients showed a dose-related inhibition of DNA synthesis when incubated with compactin. Unexpectedly, cells from 18% of the patients were resistant to the inhibitory effects of compactin on DNA synthesis and responded to the HMG CoA reductase inhibition with an actual increase in the incorporation of 14C-labeled thymidine into DNA. Another 18% of the patients studied displayed both inhibition and stimulation of DNA synthesis in a biphasic response depending on the particular concentration of compactin used. The maximum enhanced rates of cellular DNA synthesis were observed with lower compactin concentrations (5 x 10(-7) mol/L) than were required for maximum inhibition of DNA synthesis (10(-5) mol/L). Leukemia cells displaying a stimulated response to compactin had a significantly lower baseline DNA synthetic rate than did cells that showed an inhibitory response of DNA synthesis to compactin. There was no correlation between these cells' varying DNA synthetic response to compactin and measures of baseline HMG CoA reductase activity or acetate conversion to cholesterol. Whereas the observation of cellular DNA synthesis stimulation by HMG CoA reductase inhibition has not been observed in other mammalian cells and seems paradoxical, explanations may emerge in light of our growing knowledge concerning the importance of isoprenylation for the function of certain cell regulatory proteins.

Cell Cycle↗
PubMed1990

Chronic myelogenous leukemia as a model for the genetic basis of cancer.

CML has provided a model for the genetic basis of human neoplasia. Since 1960 with the discovery of the Ph chromosome, study of this disease has provided a conceptual basis for viewing cancer as a clonal disorder occurring at the stem cell level and associated with intrinsic genetic defects which contribute to abnormal growth regulation. Although several oncogenes have been identified through the study of tumor-producing retroviruses in animals, discovery of the BCR/ABL translocation, the altered 8.5 kb BCR/ABL transcript, and the hybrid BCR/ABL P210 protein with enhanced tyrosine kinase activity has provided one of the first examples of a human neoplasm in which structural alterations in a normal cellular gene might lead to malignant transformation. However, it is likely that P210 is necessary but not sufficient for the full spectrum of malignant behavior observed in this disease. Investigation of the molecular events that are associated with the additional cytogenetic abnormalities of blast phase will most likely reveal alterations of other important growth regulatory genes which contribute to the multistep nature of malignant transformation in CML.

Chromosomes, Human, Pair 22↗
PubMed1989

Temporal relationships between the major complications of bone marrow transplantation for leukemia.

Data from 3113 patients receiving HLA-identical sibling bone marrow transplants for leukemia were analysed to determine the time course of the major causes of treatment failure. The median interval from transplant to onset of acute graft-versus-host disease (GVHD) was 17 days, interstitial pneumonitis 63 days, and chronic GVHD 111 days. The median interval from transplant to relapse was 3.3 months for patients transplanted in relapse of acute leukemia or blast phase of chronic myelogenous leukemia (CML), 6.4 months when transplants were performed in second or subsequent remission of acute leukemia or accelerated phase of CML, and 7.8 months for patients transplanted during first remission of acute leukemia or while in the first chronic phase of CML. Shorter intervals from transplant to onset of interstitial pneumonitis or chronic GVHD were associated with a significantly lower probability of 2-year survival. The temporal relationships between these complications are displayed graphically and demonstrate the overlapping and competing causes of death following allogeneic bone marrow transplantation.

Adolescent↗
PubMed1988

Further evidence of the involvement of the c-abl oncogene in chronic myelogenous leukemia and acute lymphocytic leukemia.

In an attempt to further substantiate the involvement of the c-abl oncogene in the genesis of chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL), we performed in-situ hybridization with the c-abl probe on metaphase chromosomes of a healthy control, a karyotypically normal non-CML leukemia, three cases of CML with t(9;22), t(13;22) and t(3;9;22), one blast phase CML with t(9;22), Ph, + Ph, and one ALL with t(9;22), Ph, + Ph. The aberrant 9q could be cytogenetically identified in all cases except t(13;22). The molecular data clearly demonstrated the involvement of the c-abl in t(13;22) and the karyotype was revised to t(9;13;22). All patients, except the control, showed the altered c-able/bcr rearrangement that has been demonstrated in the Ph-chromosome from the standard t(9;22) translocation. These findings suggest that genomic diversities have important clinical differences in these two diseases. The amalgamation of information from cytogenetic and molecular data on cases where translocations are not precise or difficult to identify, will lead towards a deeper understanding of leukemias.

Chromosomes, Human, Pair 22↗
PubMed1986

Interferon alfa-2b in the treatment of chronic granulocytic leukemia.

Studies of the effect of interferon on the growth of colonies of myeloid leukemic blast cells, myeloma colony-forming cells, and normal hemopoietic precursor cells have demonstrated that interferon shows no specificity in inhibiting the growth of these cells in culture (ie, growth of the malignant and normal precursor cells is equally inhibited). However, interferon markedly reduces the self-renewal capacity of acute myeloid leukemic blast cells and myeloma cells. This observation suggested that interferon's ability to prolong rather than induce remissions should be tested. We have studied the ability of interferon alfa-2b (Intron A) to prolong remissions induced by busulfan (Myleran) in patients with chronic granulocytic leukemia (CGL). The leukocyte doubling time and remission duration among patients receiving no therapy was compared with the values observed during interferon alfa-2b maintenance therapy. Nine patients have begun the study; five have completed 3 months of interferon alfa-2b therapy. In four (80%) of the five patients, there has been a significant slowing of the leukocyte doubling time and prolongation of the remission duration. A larger study, with longer follow-up, will be required to determine whether interferon alfa-2b therapy will slow progression of CGL to the blast phase and prolong survival.

Adult↗
PubMed1994

[Study on correlation and clinical significance of superoxide dismutase (SOD) activity and content in 102 patients with leukemia].

Serum superoxide dismutase (SOD) activity and blood Cu/Zn SOD content were examined in 102 cases of leukemia. The results showed that the total SOD activities, Cu/Zn SOD activities and contents declined significantly in blast phase of acute leukemia, yet increased to normal levels in remission. There was a positive correlation between SOD and blood hemoglobin concentration as well as leucocyte count. It declined again when leukemia recurred and in dying patients. There was a dissociation between Cu/Zn SOD activities and contents in patients with chronic granulocytic leukemia. In chronic lymphocytic leukemia, both activity and contents of SOD were normal. It was suggested that SOD plays a protective role during the occurrence and development of leukemia. SOD is a useful parameter in the differential diagnosis of leukemias and monitoring clinical course of leukemias.

Adolescent↗
PubMed1993

Ubiquitous expression of cytokines in diverse leukemias of lymphoid and myeloid lineage.

It has recently been suggested that autocrine production of hematopoietic regulatory molecules can modulate the cardinal features of many leukemic states: excessive proliferation of the neoplastic cells and suppression of the normal elements. We therefore analyzed samples obtained from 57 patients with a variety of hematologic malignancies (21, acute myelogenous leukemia; 14, acute lymphoblastic leukemia; 12, Philadelphia chromosome-positive chronic myelogenous leukemia [blast phase] or acute leukemia; 5, chronic lymphocytic leukemia; and 5, chronic myelomonocytic leukemia) for expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) transcripts on Northern blots. TNF-alpha mRNA was discerned in almost half of the samples (47%), and was expressed in some patients with every type of leukemia, except T-cell acute lymphoblastic leukemia (ALL). Expression occurred with great frequency in samples (12 of 15 [80%]) from monocytic (acute or chronic) leukemias, and from advanced chronic lymphocytic leukemia (4 of 5 samples [80%]). IL-1 beta transcripts were detected in 20 of 57 samples (35%). Its presence, like that of TNF-alpha, was ubiquitous, and only chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia cells consistently failed to produce IL-1 beta message. Therefore it appears that TNF-alpha and/or IL-1 beta mRNA can be found in the leukemic cells from a substantial subset of patients with B cell-derived acute lymphoblastic leukemia as well as with chronic and acute myeloid, monocytic or lymphocytic leukemias. Because these cytokines have potent direct and indirect effects on normal and malignant hematopoiesis, their widespread constitutive expression by neoplastic blood cells may play a fundamental role in driving the leukemic process.

Blotting, Northern↗