Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response to and survival following first salvage therapy regimens for 243 patients with acute myelogenous leukemia (AML) treated between 1974 and 1985 were evaluated. Eighty (33%) patients obtained a complete remission (CR), 24% died prior to achieving a response, and 43% were resistant on their first salvage regimen. The median survival was 18 weeks. Five percent overall and 16% of the CR patients are predicted to survive for more than 5 years. The factor most strongly associated with response and survival was the duration of the initial remission with 49 of 82 (60%) patients whose initial CR duration was at least 1 year in duration obtaining a second CR v 31 of 161 (19%) for patients with a shorter remission (P less than .01). Age, liver function, serum lactic dehydrogenase (LDH), karyotype, and the proportion of blasts plus promyelocytes present at the time of starting salvage therapy were strongly associated with probability of response and survival. Multivariate analysis was used to develop logistic regression and proportional hazard models to predict probability of response and survival, respectively. The major regimens used were conventional-dose cytarabine (ara-C) (combined with anthracyclines or amsacrine), high-dose ara-C, rubidazone, amsacrine (AMSA), other anthracyclines, and autologous or allogeneic transplant programs. After allowing for the prognostic factors in the models, specific treatment regimens were not strongly associated with prognosis.
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PMID:Response to salvage therapy and survival after relapse in acute myelogenous leukemia. 266 90

Since 1980, adults with acute myelocytic leukemia (AML) have been treated on two clinical studies using intensive timed sequential therapy. All patients ages 16 to 80, including those with secondary AML (SAML) and those with AML preceded by a hematologic disorder (AHD), were treated, regardless of medical complications at the time of diagnosis. The first study combined high doses of cytarabine (ara-C, AC) and daunorubicin (DRN, D) in sequence (Ac2-D-Ac) and resulted in a complete remission rate of 55%. A group of these patients selected by functional status was able to receive a second course of therapy in remission, which resulted in a disease-free survival (DFS) of greater than 40% at 7 years. Because of toxicity in that study, 114 patients were entered on a second trial initiated 4 years ago, using a less aggressive first course, with amsacrine, to achieve a stable remission (Ac2-D-Amsa). This first treatment was followed by a more intensive second course (Ac6-D-Ac). With this two-step approach, a higher complete remission (CR) rate (76% for de novo AML and 54% for SAML-AHD) was achieved, and more patients were able to receive the second course of therapy. At the current median follow-up of 26 months, the median duration of DFS and overall survival are 11 and 14 months for patients with de novo AML. Age less than or equal to 55 is the most significant prognostic factor for both prolonged DFS and overall survival, with median durations of 17 and 18 months, respectively, for these younger patients. Patients with SAML-AHD remain relatively refractory to treatment despite aggressive chemotherapy, with median durations of DFS and overall survival of 9 months and 5 months, respectively.
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PMID:A two-step timed sequential treatment for acute myelocytic leukemia. 267 14

On the basis of in vitro studies demonstrating marked synergy between mitoxantrone and high-dose cytosine arabinoside (ara-C) (HiDAC) against L5178Y murine leukemia and clinical studies showing usefulness of the combination in patients with refractory acute myeloid leukemia, a phase I study was initiated to find tolerable doses for use in patients with refractory solid tumors. Initial dose levels were mitoxantrone 2 mg/m2 infused over 30 minutes, followed by high-dose ara-C 750 mg/m2 infused over 3 hours repeated once at 24 hours (total dose 4 mg/m2 mitoxantrone and 1,500 mg/m2 HiDAC per 2-day course), with planned subsequent escalation of mitoxantrone. Moderate-to-severe myelosuppression, however, required sequential dose reduction of both agents. Nonhematologic toxicity was restricted to manageable nausea and vomiting in one-half the patients and a single episode of transient delirium of uncertain etiology. No responses were observed in 23 heavily pretreated patients with a wide variety of malignancies. On the basis of this study, doses of 187-375 mg/m2 ara-C given every 24 hours for two doses following mitoxantrone 1 mg/m2 every 24 hours for two doses would be tolerated by most patients with subsequent dose escalation in some as allowed by myelosuppression.
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PMID:Mitoxantrone and high-dose ara-C in refractory malignancies: a phase I trial. 270 36

Twenty nine consecutive patients (pts) with either relapsed (n = 23) or primary refractory AML (n = 6) were treated with 1 or 2 cycles of intermediate-dose (ID) ara-C (1g/m2 IV q 12 h days 1-6) and m-AMSA (120 mg/m2 IV days 5-7). Pts reaching complete remission (CR) were consolidated with 1 cycle of ara-C 3 g/m2 IV q 12 h days 1-4 and m-AMSA 120 mg/m2 IV day 5. The median duration of the preceding remission was 9.5 months, median time from last chemotherapy until relapse 3 months. 18/23 (78%) of relapsed pts achieved CR regardless of the type of prior intensive maintenance (HD-ara-C/m-AMSA/5-AZA or DNR/CD-ara-C). 3/23 (13%) pts died during hypoplasia, 2/23 (9%) pts were refractory to 2x ID-ara-C/m-AMSA. 3/23 pts died in CR during hypoplasia after intensive consolidation with HD-ara-C. Predictive factors for remission were the duration of preceding remission and the time from last chemotherapy to relapse. Three pts were transplanted in 2nd CR. 1/6 refractory pts reached CR, 2 pts remained refractory, and 3 died during hypoplasia. The median duration of disease-free survival (DFS) of relapsed pts was 3.3 months without further treatment, median survival of responding pts (18 replased pts, 1 refractory pt) was 4.6 months, the overall survival (n = 29) was 4.8 months. Pts receiving BMT were censured at the time of BMT. Seven pts experienced lung toxicity due to ara-C, four of whom died. The incidence of lung toxicity was clearly related to the extent of ara-C pretreatment during intensive maintenance. In conclusion, ID-ara-C/m-AMSA is a very effective reinduction treatment in these pts with acceptable toxicity; the impact of HD-ara-C during consolidation for DFS and survival is questionable.
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PMID:Intermediate-dose Ara-C/m-AMSA for remission induction and high-dose Ara-C/m-AMSA for intensive consolidation in relapsed and refractory adult acute myelogenous leukemia (AML). 270 39

We hypothesized that the steady-state concentration of intracellular cytarabine 5'-triphosphate (ara-CTPss) in leukemia cells is proportional to the dose rate of cytarabine (ara-C) during continuous infusion. To evaluate this possibility, patients with acute myelogenous leukemia in relapse were treated with two sequential schedules of serially increasing ara-C dose rates over a total of 36 hours. Schedule I consisted of serial infusions of 250, 500, and 750 mg/m2 each over 12 hours. Subsequently, patients entered on schedule II received 500, 1,000, and 1,500 mg/m2 serially, each over 12 hours. Steady-state levels of ara-CTP were achieved within four hours after beginning ara-C infusion and, in separate studies of a single ara-C dose rate, were shown to be maintained beyond 36 hours. Four patients treated with schedule I and two patients treated with schedule II showed a linear dose rate-dependent increase-of ara-CTPss at all three dose rates. The cells of one patient on schedule I and two patients on schedule II had a dose rate-dependent ara-CTPss increase only over the first two dose levels, while no increase or lower ara-CTPss was observed at the third dose rate. The ara-CTPss of one patient on schedule II did not change. These results suggest that there is a proportionality between the continuous infusion dose rate of ara-C and the ara-CTPss in circulating leukemia cells within the dose range of 250 to 1,000 mg/m2 over 12 hours. This opens the possibility that pharmacologic determinations may be used to redirect the ara-C dose rate to achieve a desired ara-CTPss level in leukemia blasts during therapy.
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PMID:Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. 270 90

A case of AML (M 4) with t(6; 11) showed recovery to myelodysplastic syndrome (MDS)-like bone marrow after one course of DCMP regimen. Dysplastic changes of three cell-lineages were observed and micromegakaryocytes were markedly increased in number. Recovering hematopoiesis was incomplete. During MDS-like phase, t(6; 11) disappeared, reverting to normal karyotypes. Low dose ara-C regimen did not show any effect. AML soon relapsed with reappearance of t(6; 11). MDS-like abnormal hematopoiesis has recently been reported to occur after remission induction therapy or at the time of relapse. G-6PD isozyme study revealed in a remission case of AML that hematopoiesis still consisted of abnormal clone in spite of karyotypic normalization. The abnormal hematopoiesis observed in our case can be referred to such a clonal disorder predominating after disappearance of blastic component of AML. It seems important to reveal what proportion of de novo AMLs shows such an abnormal hematopoiesis and to establish suitable therapeutic approach.
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PMID:[Marked dysmyelopoiesis after induction chemotherapy in a case of acute myelomonocytic leukemia (M 4) with t(6; 11)]. 274 77

Between January 1980 and March 1983, a study was conducted into the effects of postremission therapy on 20 patients with acute leukemia who had achieved complete remission through induction therapy. Postremission therapy consisted of cyclic administration of six combination therapies given at gradually longer intervals. Postremission therapy used DCMP (D, daunorubicin; C, cytosine arabinoside; M, 6-mercaptopurine; P, prednisolone), DCyMP (Cy, cyclocytidine), DCVP (V, vincristine), BHAC-DMP (BHAC, behenoyl-ara-c), BHAC-AMP (A, aclarubicin) and ACM-MP (ACM, aclacinomycin). Six combinations were given sequentially starting at one month interval, and then at 2, 3, 4, 5 and eventually 6 month intervals until 5 year survival was reached. The median remission duration was 38 months for acute myelogenous leukemia (AML), and 17 months for acute lymphoblastic leukemia (ALL). The median survival was 66 months for AML, and 33 months for ALL. The survival rate at 5 years was 60% for AML., 40% for ALL, and 50% in all 20 patients. Methotrexate and prednisolone were administered intrathecally for prophylaxis of CNS leukemia on Day 4 of each stage of postremission therapy. There was no CNS leukemia. This postremission therapy was shown to be effective in improving the prognosis of adults with acute leukemia.
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PMID:An eight year experience with gradually longer interval postremission therapy for adults with acute leukemia. 278 38

We have proposed that the blasts in acute myeloblastic leukemia (AML) are renewal populations maintained by a small subpopulation of stem cells. The balance between self-renewal and differentiation in blast stem cells may be an important attribute contributing to treatment outcome. Cytosine arabinoside (ara-C) is included in most chemotherapeutic regimens for the treatment of AML. When ara-C survival curves are constructed, the drug appears to be more toxic when an assay is used that detects principally self-renewing divisions, compared with a procedure that depends on terminal divisions. AML blasts usually respond in culture to myelopoietic growth factors; their response often includes a change in self-renewal, differentiation, or both. These features of the model for AML blasts led to the prediction that growth factors would alter ara-C survival curves in a way that depended on the effects of the culture conditions on self-renewal and differentiation. Four AML blast populations were chosen to test this prediction on the basis of our ability to manipulate them by adding or withholding one or more growth factors. Highly significant changes were seen in the ara-C survival curves, depending on the growth factors present in the cultures as was predicted by the observed effects of the factors on renewal and differentiation.
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PMID:Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. 278 97

Retinoic acid (RA) is a potent morphogen that has been shown to increase differentiation in some leukemic cell populations. RA has been used in treatment of some patients with acute myeloblastic leukemia (AML) and myelodysplastic syndromes. In previous experiments we had observed that RA may decrease the self-renewal of blast cells in established cell lines, and in our clinic RA has been tested as maintenance treatment in association with chemotherapeutic drugs. Accordingly, we asked if exposure of AML blast cells to RA affected their subsequent response to ara-C. We found that brief exposure to RA regularly increased the ara-C sensitivity of cells from two established AML cell lines. A similar, though less marked, effect was seen when the blast cells from one patient were tested directly; in a second instance, highly ara-C resistant blasts did not become sensitive when exposed to RA. Experiments using high specific activity tritiated thymidine did not disclose any changes in the proportion of AML cells in the DNA synthesis phase of the cycle at times when their responses to ara-C were changing. We interpret our findings as support for continuing efforts to integrate RA in the management of AML patients and suggest that the mechanism of ara-C sensitization may not depend on changes in the cell cycle.
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PMID:Interaction between retinoic acid and cytosine arabinoside affecting the blast cells of acute myeloblastic leukemia. 281 79

A predictable increase in the proliferative rate of malignant cells remaining after initial cytoreduction in vivo forms the rationale for timed sequential therapy (TST) with 1-B-D-arabinofuranosylcytosine (ara-C) for adult acute myelogenous leukemia (AML). The relationship between in vivo leukemic cell growth, intracellular ara-C metabolism, and clinical response to ara-C-containing TST was evaluated by comparing AML marrow cell growth kinetic and biochemical pharmacologic determinants obtained before therapy (day 0) and at the predicted peak of in vivo postdrug residual tumor proliferation (day 8). Serial measurements of DNA synthesis and net intracellular ara-C metabolism demonstrated marked increases in both determinants in day 8 residual tumor when compared with the pretreatment cells for newly diagnosed adults achieving complete remission but not for TST-refractory patients. The interrelationship of AML cell proliferation and biochemical pharmacology together quantitate cytotoxicity measured by both achievement and duration of remission and serve to predict eventual clinical outcome in response to TST with ara-C where both growth and favorable pharmacokinetics are intrinsic to the success of the drug schedule.
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PMID:In vivo cell growth and pharmacologic determinants of clinical response in acute myelogenous leukemia. 291 Mar 62


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