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At least 595 records · Page 33Linked to original sources
PubMed2003

The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients.

Fludarabine in addition to cytosine-arabinoside (ARA-C) increases the accumulation of ARA-C-5'-triphosphate (ARA-CTP), which is responsible for the cytotoxic effect in leukemic blasts. In a randomized phase 3 trial, patients with high-risk myelodysplastic syndrome (MDS) (n = 91) or elderly patients with acute myeloid leukemia (AML) (n = 43) were randomized to receive 2 induction courses consisting of ARA-C (2 g/m2 days 1 through 5) and granulocyte colony-stimulating factor (G-CSF) (filgrastim, 5 microg/kg) during and after chemotherapy with or without fludarabine (25 mg/m2, days 1 through 5) (FLAG versus AG). Consolidation consisted of daunorubicin (45 mg/m2, days 1 through 3) and ARA-C (200 mg/m2, days 1 through 7). Complete remission (CR) rate following AG was 65% versus 71% with FLAG (P =.49). Overall survival (OS) at 24 months was 24% for AG treatment and 39% for FLAG (P =.32). Event-free survival (EFS) at 2 years was 10% and 19% (P =.31) for the AG and FLAG treatments, respectively. Platelet and granulocyte recovery times after the second cycle were prolonged in the FLAG treatment group. Grades 3 to 4 neurotoxicities were more often reported in the FLAG arm (14% versus 3%, P =.03), whereas no significant differences in other toxicities were observed. In a cohort of patients, the in vivo accumulation of ARA-CTP in leukemic cells was determined. Although ARA-CTP accumulation in leukemic cells after FLAG was enhanced, clinical outcome in terms of CR rate, OS, EFS, and disease-free survival (DFS) was not significantly improved by combining fludarabine with ARA-C.

Adult↗
PubMed2002

Timed sequential chemotherapy with concomitant granulocyte colony-stimulating factor for high-risk acute myelogenous leukemia: a single arm clinical trial.

BACKGROUND: The timed-sequential chemotherapy regimen consisting of etoposide, mitoxantrone and cytarabine (EMA) is an effective therapy for relapsed or refractory acute myelogenous leukemia (AML). We postulated that granulocyte colony-stimulating factor (G-CSF) might enhance the cytotoxicity of EMA by increasing the proportion of leukemic blasts in S-phase. We added G-CSF to EMA (EMA-G) for therapy of advanced high-risk AML patients. METHODS: High-risk AML was defined as refractory, relapsed or secondary to either an antecedent hematologic disorder or exposure to cytotoxic agents. The patients were treated with one course of EMA-G consisting of mitoxantrone and cytarabine on days 1-3, and etoposide and cytarabine on days 8-10. G-CSF was started on day 4 and continued until absolute neutrophil count recovered. RESULTS: Thirty patients were enrolled. The median age was 51 years (range, 25-75). Seventeen (61%) patients had unfavorable cytogenetic karyotypes. Twenty (69%) patients had secondary AML. Ten (34%) had relapsed disease. Four (14%) had refractory AML. Three (10%) patients died from febrile neutropenia and sepsis. Major non-hematologic toxicity included hyperbilirubimenia, renal insufficiency, mucositis, diarrhea, nausea and vomiting, skin rash. A complete remission was achieved in 13 (46%) patients. Median overall survival was 9 months (range, 0.5-66). Median relapse-free survival (RFS) for those who had a CR was 3 months (range, 0.5-63) with RFS censored at the time of allogeneic bone marrow transplantation or peripheral stem cell transplantation for 6 of the patients. CONCLUSIONS: EMA-G is a safe and efficacious option for induction chemotherapy in advanced, high-risk AML patients. The activity of EMA may be increased if applied in patients with less advanced disease.

Acute Disease↗
PubMed2002

Gleevec for the treatment of chronic myelogenous leukemia: US. Food and Drug Administration regulatory mechanisms, accelerated approval, and orphan drug status.

Gleevec (imatinib mesylate), a highly promising new drug for the treatment of chronic myelogenous leukemia in blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance, received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001. The purpose of this report is to summarize FDA regulatory mechanisms, i.e., accelerated approval and orphan drug regulations, that have permitted patients to receive this drug as rapidly as possible.

Antineoplastic Agents↗
PubMed1987

Adoptive transfer of insulitis and diabetes in neonates of diabetes-prone and -resistant rats. Tissue localization of injected blasts.

Intravenous transfusion of concanavalin A-activated splenic cells from acutely diabetic BB or diabetic BB/hooded hybrid donor rats into 6- to 36-h-old neonate recipients of diabetes-prone and -resistant rat lines induced insulitis and in some severe diabetes. These effects were observed 10-20 days after the injection of the blasts. Focal lesions of insulitis were absent in neonates killed 1 and 3 days after the blast injection but were observed in neonates killed on the 5th and 8th day. As determined by autoradiography after the injection of [3H]thymidine-labeled blasts, numerous blast cells migrated and settled in various immature lymph nodes and in the spleen within 24 h after injection. Focal mononuclear infiltrations in the islets containing labeled and unlabeled cells were again observed on the 5th and 8th day but not on the 1st and 3rd day after injection. These experiments indicate that target-specific blasts undergo a short phase of proliferation and maturation in lymphoid organs of the recipients, before initiating the autoimmune process in the pancreatic islets. They further suggest that specific immune cells rather than humoral anti-islet antibodies are more likely to play the major role in this autoimmune animal model of diabetes.

Animals↗
PubMed1979

The proliferative activity of leukaemic myeloblasts following the intravenous infusion of cytarabine.

Serial bone marrow aspirates were obtained from 16 adults with acute myeloid leukaemia (AML) before and after a single infusion of cytarabine (5.0 mg/kg i.v. over 30 min). Changes in the proliferative activity of the leukaemic myeloblasts were monitored by determination of the labelling index (LI) and the mitotic index (MI). There was a significant fall in both LI and MI within a few hours of the administration of cytarabine (P = 0.005). In 14 of the 16 cases the LI subsequently rose to observed maxima 0.3% to 14.1% (mean 5.0%) above the preinfusion LI, 11 to 77 hours (mean 40.8 h) after the infusion (P less than 0.05). The MI returned to the mean pretreatment level within the period of observation in 11 of the 16 cases. In general, the changes in MI followed those in LI; the results are consistent with cytarabine-induced arrest or death of leukaemic blast cells in S phase. Because of the variability in timing of kinetic changes in leukaemic myeloblasts following cytarabine, it is not possible to institute remission induction therapy consistently at the time of maximum synchronization with any fixed chemotherapeutic schedule. Furthermore, the degree of synchronization attained is, in general, small, limiting the prospect of exploiting synchronization with cytarabine as a means of improving the remission rate for AML.

Adolescent↗
PubMed1996

High-dose cytarabine and recombinant human granulocyte colony-stimulating factor for the treatment of resistant acute myelogenous leukemia.

Few salvage treatments are successful for patients with relapsed acute myelogenous leukemia after a short first remission, multiple relapses, or for patients with disease refractory to initial induction chemotherapy. To improve the results of salvage therapy we studied the efficacy and toxicity of a combination of G-CSF (5 mu tg/kg IV q day) used as a priming agent followed by continued exposure to G-CSF and high-dose cyatarabine (2 gm/m(2) IV q 12 hours x 12 doses) in fifteen adult patients with relapsed or refractory acute myelogenous leukemia. Nine of fourteen (64%; 95% confidence interval 35 to 87%) achieved complete remission, four failed to enter remission and one died of multiorgan system failure after progressive leukemia cutis despite chemotherapy-induced bone marrow aplasia. Median disease-free survival is 148 days and median survival from study entry for responding patient is 174 days. Three patients who achieved complete remission subsequently relapsed with a median time to relapse of 147 days. Median time to granulocyte >0.5 x 10(9)/L was 22 days (19 to 34 days) and the median time to platelet recovery >20 x 10(9)/L was 30 days (23 to 214 days). Although gastrointestinal toxicity was common, no patient developed severe cardiac, hepatic, pulmonary, or neurologic complications. An elevation in the percent of bone marrow blasts in S-phase after 48 hours of treatment with G-CSF was identified in 7 of 12 evaluable patients. These results demonstrate that the combination of G-CSF and high-dose cytarabine may be used as an effective salvage treatment for patients with resistant acute myelogenous leukemia.

Acute Disease↗
PubMed1975

Kinetic studies of circulating lymphocytes in malignant lymphatic disease using the impulse cytophotometer.

Measurements of the DNA content of mononuclear cells in the blood of patients with malignant lymphatic disease were made. In one case of acute lymphoblastic leukaemia, a large fraction of large type of blasts were in S phase. In the blood of a patient with leukaemic transformation of lymphosarcoma, a population of aneuploid tumour cells with a high percentage of cells in S phase was recognized. The increase of DNA synthesizing cells in the blood of patients with malignant lymphoma was associated with activity of the disease. The fraction of DNA synthesizing cells was raised sharply during chemotherapy.

Antineoplastic Agents↗
PubMed2000

BCR-ABL positive essential thrombocythaemia: a variant of chronic myelogerous leukaemia or a distinct clinical entity: a special case report.

A 37-year-old Malay man presented initially with the clinical picture of essential thrombocythaemia (ET) without the extreme leukocytosis, marked splenomegaly and low neutrophil alkaline phosphatase characteristic of chronic myelogenous leukaemia (CML). Bone marrow examination showed massive megakaryocytic hyperplasia; cytogenetic studies showed the presence of Philadelphia chromosome. The patient was treated with hydroxyurea that resulted in reduction in the platelet count. Seventeen months later, he presented with fever associated with tender massive splenomegaly. Bone marrow finding was consistent with chronic phase CML. The presence of a rearrangement involving the major breakpoint cluster region (M-bcr) on chromosome 22 was confirmed by reverse transcriptase-polymerase chain reaction. The clinical importance of finding the Philadelphia chromosome in patients who seem to have ET is in assessing prognosis. ET generally follows a chronic, indolent course. However, this patient who had Philadelphia chromosome underwent clinical transition to chronic phase CML17 months and blast crisis 29 months after presentation.

Adult↗
PubMed1999

[Allogeneic bone marrow transplantation for chronic myeloid leukemia: 118 cases analysis].

OBJECTIVE: To analyze the outcome of allogeneic bone marrow transplantation (allo-BMT) performed for chronic myeloid leukemia (CML) patients. METHODS: One hundred and eighteen CML patients received allo-BMT with conditioning regimens of TBI or modified BU/CY. The pre-BMT situations were, 91 cases in first chronic phase (CP1), 19 in accelerating phase (AP), 2 in blast crisis (BC) and 6 in advanced CP (> CP2). RESULTS: One hundred and nine patients were successfully engrafted. The probabilities of 5 year survival for CP1 and AP patients were 69.6% and 51.0%, and 5 year relapse rates were 3.2% and 12.5%, respectively. CONCLUSIONS: Disease stage, conditioning regimen and splenomegaly did not affect the time for engraftment. For patients in CP1, splenomegaly was positively correlated with relapse. There was no difference between the effect of the two conditioning regimens on the prognosis.

Adolescent↗
PubMed2002

Imatinib mesylate for chronic myeloid leukemia: what do we really know?

Imatinib mesylate (GleevecTM) is a tyrosine kinase inhibitor, one of a new class of anticancer drugs called signal transduction inhibitors. A systematic review of case-series reports shows imatinib, when indirectly compared to conventional therapy, improves overall 12-month survival, but not surrogate outcomes, in individuals with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in myeloid-blast crisis, and accelerated phase. Surrogate outcomes, but not overall survival, were improved in chronic phase disease. Preliminary data from one randomized controlled trial suggest imatinib has a greater impact on surrogate outcomes compared to the combination of interferonalpha and cytarabine in patients undergoing treatment for chronic phase Ph+CML, however, it is not yet known whether it prolongs or improves quality of life.

Canada↗
PubMed2002

Cytogenetic profile of chronic myeloid leukemias.

Chronic Myeloid leukemia is a clonal disease of multipotent haematopoietic cells associated with specific cytogenetic changes involving a translocation t(9;22) (q34:q11), more commonly known as Philadelphia Chromosome (Ph1). A total of 525 patients with CML (480 adults and 45 children) diagnosed at the Nizam's Institute of Medical Sciences, Hyderabad, formed the subjects of this study. Hematological investigations were carried out using standard methods. Unstimulated peripheral blood samples and/or bone marrow aspirates were used for cytogenetic analysis. Hematological evaluation at presentation showed that 435 were in chronic phase, 36 in accelerated phase and 54 in blast crisis. Chromosomal analysis revealed that 86.3% were Ph1 positive and 13.7% Ph1 negative. Additional chromosome changes observed during blast crisis included an extra Ph1 chromosome, Trisomy 8 and Trisomy 19. The results were correlated with survival pattern and prognosis of patients following certain treatment protocols.

Adolescent↗
PubMed1991

p53 gene alterations in human hematological malignancies: a review.

Mutations of the tumor suppressor gene p53 are found in a wide variety of human tumors. In hematological malignancies, p53 alterations are involved in the evolution of chronic phase CML to myeloid blast crisis. p53 mutations were also found associated with Burkitt lymphoma (35%) and its leukemic counterpart, L3 type B-cell acute lymphoblastic leukemia (60%). These observations suggest that several common mechanisms are involved in the transformation process of these two hematological disorders.

Gene Rearrangement↗
PubMed1990

Update on therapeutic options for chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder triggered by a chromosomally induced mutation in a pluripotent stem cell. Its progressive clinical course consists of a chronic or benign phase, which terminates in blast crisis. Historically, treatment has been limited: conventional chemotherapy yields a median survival of approximately 36 to 42 months, and bone marrow transplantation, while achieving success in more than half of patients treated, is limited to younger patients with HLA-matched siblings. Treatment with interferon alfa in CML was initiated in 1981. The first studies were performed using partially pure interferon alfa; these studies were followed by treatment regimens employing interferon alfa-2a.

Bone Marrow Transplantation↗
PubMed1989

[The prognostic significance of parameters of bone marrow blast cell proliferation in patients with acute leukemia].

Percentage of bone marrow blasts in S-phase (S%) in acute leukemia patients was evaluated by 3H-thymidine autoradiography or Feulgen cytophotometry at the initial acute period before chemotherapy. In acute lymphoid leukemia (ALL) patients who showed complete remission (CR) S% was 8.6 +/- 1.8% versus 2.1 +/- 0.4% in cases without CR (p less than 0.001). In acute non-lymphoid leukemia (ANLL) the corresponding values were 11.4 +/- 1.4% and 8.3 +/- 1.8%, p greater than 0.05. A negative correlation was observed between S% and the duration of CR in ALL: S% was 13.0 +/- 0.7% in CR, more than 12 months, and 6.9 +/- 1.1% in CR less than 12 months (p less than 0.01). The duration of life also correlated negatively with S%. In ALL S% was 9.5 +/- 1.5% for patients with survival less than 12 months versus 6.2 +/- 0.6% for patients with survival more than 12 months (p less than 0.05). In ANLL the difference (10.3 +/- 1.6% and 6.8 +/- 1.2, respectively) was not significant (p greater than 0.05). Thus in ALL the correlations between S% and the probability to achieve CR is positive, while the correlations between S% and survival and remission duration are negative. In ANLL these correlations are statistically insignificant.

Biopsy, Needle↗
PubMed1994

Expression of the c-kit proto-oncogene in myeloproliferative disorders and myelodysplastic syndromes.

The c-kit proto-oncogene is the receptor gene for the stem cell growth factor. Little is known about the distribution and role of this gene product in malignant hematopoiesis. We analysed here the expression of c-kit in myeloproliferative disorders (MPDs), including chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis (IMF) and in the myelodysplastic syndromes (MDS). The c-kit expression of peripheral blood mononuclear cells was measured both at the messenger RNA level using Northern analysis, the RNA dot blot technique with densitometric quantification, the sensitive reverse transcription polymerase chain reaction, and at the protein level using immunofluorescence with monoclonal antibodies. There was a statistically significant increase in c-kit messenger levels in CML, ET, PV, IMF, and MDS as compared with controls (healthy volunteers). The percentage of c-kit protein expressing cells was also higher than in the controls in these disorders. There was a significant correlation of the c-kit protein expression with the CD34 antigen of the cells. Expression correlated with the phase of the disease, being highest in the blast crisis of CML and in the RAEB/RAEBt phases of MDS. The data suggest that increased amounts of circulating stem/progenitor cells with c-kit receptor are found in MPDs and MDS. It is possible that elevated c-kit expression could maintain the affected clone in MPDs and MDS.

Adult↗
PubMed1994

Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis.

We previously reported the cloning, and characterization of a receptor tyrosine kinase, axl, from two patients with chronic myelogenous leukemia. Herein, we describe the expression pattern of axl in normal and malignant hematopoietic tissue axl message is detected in normal human bone marrow but not significantly in normal blood leukocytes. Cell separation experiments showed that axl is expressed in hematopoietic CD34+ progenitor and marrow stromal cells, at low levels in peripheral monocytes, but not in lymphocytes or granulocytes. Consistent with the normal pattern of axl expression, axl RNA was found predominantly in diseases of the myeloid lineage: 39 of 66 (59%) patients with myeloproliferative disorders (acute myeloid leukemia, chronic myeloid leukemia (CML) in chronic phase, CML in myeloid blast crisis, and myelodysplasia) showed significant axl transcription, as compared with 1 of 45 (2%) lymphoid leukemias (chronic lymphocytic leukemia, acute lymphocytic leukemia, and CML in lymphoid blast crisis). Treatment of K562 cells with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), administration of interferon alpha (IFN alpha) to normal monocytes, and treatment of U937 cells with TPA and IFN tau significantly induced axl expression, supporting a role for this kinase in the intracellular signaling of myeloid cells through a variety of biochemical pathways. These results suggest that the axl kinase may be operative in normal and malignant myeloid biology.

Base Sequence↗
PubMed1996

CD56+bright and CD56+dim natural killer cells in patients with chronic myelogenous leukemia progressively decrease in number, respond less to stimuli that recruit clonogenic natural killer cells, and exhibit decreased proliferation on a per cell basis.

Human natural killer cells (NK) require accessory cell-derived contact and soluble factors for maximal expansion. However, it is unclear whether increased recruitment of clonogenic NK, increased proliferation on a per cell basis, or a combination of both is responsible for the increased expansion. We show that expansion of both CD56+dim and CD56+bright NK from normal donors is increased in the presence of M2-10B4 accessory cell-soluble factors. In contrast, the addition of M2-10B4 stromal ligands further augments only the expansion of CD56+bright NK. Using single-cell sorting of CD56+bright NK, M2-10B4-soluble and contact factors independently increase both recruitment of clonogenic NK and proliferation on a per cell basis. This well-defined M2-10B4 accessory cell system was used to investigate potential defects in NK from patients with CML. Although we have previously shown diminished interleukin-2 (IL-2)-activated NK outgrowth and function from patients with chronic myelogenous leukemia (CML) as their disease progresses, it has been unclear if this is due to a defect in an accessory cell function or an inherent abnormality of CML NK themselves. CD56+/CD3- NK purified by fluorescence-activated cell sorting from 21 patients (7 early chronic phase [ECP] patients, 10 late chronic and accelerated phase [LCP/AP], and 4 blast crisis [BC] patients) were studied. The proliferative capacity, clonogenic frequency, and cytotoxic capacity of CML NK were compared with NK from normal donors. The absolute number of circulating NK per milliliter of peripheral blood is significantly decreased in patients with CML compared with normal donors (normal, 63,700 +/- 6,400; ECP, 40,700 +/- 6,700; LCP/AP, 31,900 +/- 6,000; BC, 10,700 +/- 5,200). Additionally, the unique CD56+bright NK subset, analyzed as a percentage of the total circulating NK pool, is significantly reduced in all patients with CML (normal, 5.7% +/- 0.8% v CML [all stages combined], 2.5% +/- 0.5%, P = .001]. After purification of NK to correct for differences in circulating NK number, resting NK cytotoxicity against K562 tumor targets is significantly reduced in patients with CML on or recently on hydroxyurea therapy. However, this reduced cytotoxicity can be corrected by 18 hours of incubation with 1,000 U/mL recombinant IL-2. When plated in limiting dilution on viable M2-10B4, which maximally stimulates NK from normal donors, we show that both NK clonogenic frequency and proliferative capacity are significantly reduced as CML progresses, demonstrating an inherent defect in their ability to respond to normal NK stimuli. Although NK cloning efficiency between normal donors and ECP CML patients was the same, significant differences were observed in (1) the absolute number of circulating CD56+/CD3- NK, (2) the absolute number of circulating CD56+bright NK, and (3) proliferation on a per cell basis. Unlike resting NK function, prior cytotoxic therapy alone did not account for these observed abnormalities. These data suggest that, although NK are not derived from the malignant clone, they are inherently affected by their malignant microenvironment.

Adolescent↗