Treatment Of Adult Acute Leukemia Research Articles

Effect of Rutin on Cytarabine-Associated Pulmonary Oedema and Oxidative Stress in Rats.

Cytarabine is effectively used in the treatment of adult acute leukemia, but it has a dose-limiting side effect of fatal pulmonary oedema because it increases the vascular permeability of the alveolar capillaries. The aim of the present study was to conduct a radiological, biochemical and histopathological investigation of the effect of rutin on cytarabine-associated pulmonary oedema in rats. Rats were treated with a combination of rutin+cytarabine by administering oral rutin at a dose of 50 mg/kg; other rat groups were orally administered the same volume of physiological saline. One hour after administration of rutin or saline, the rutin+cytarabine and cytarabine groups received an intraperitoneal injection of cytarabine (200 mg/kg). This administration procedure was repeated once a day for 14 days. Radiologically, 50% of the animals given cytarabine alone showed lung oedema, but the rutin+cytarabine group showed no oedema. The inclusion of rutin decreased the amounts of cytarabine-associated malondialdehyde, tumour necrosis factor-α, and nuclear factor-κB in the lung tissue. Rutin also inhibited the reduction of total glutathione by nitric oxide. These findings suggest that rutin may be a beneficial adjunct that can minimise the development of cytarabine-associated pulmonary oedema.

Chemotherapy of acute leukemia in adults

Background: General therapeutic options for adult patients with acute leukemia are reviewed and specific new treatment strategies are described. Objective: Treatment results and controversial issues on current and future antileukemic strategies are discussed. Methods: Data in this review came from the published literature. Results/conclusion: In the past years, striking new developments have been noticeable in the treatment of adult acute leukemia. However, the overall outcome of adult acute leukemia remains poor, particularly in older patients. Intensive chemotherapy remains the standard for leukemia treatment but several approaches using new cytotoxic agents seem promising. Therapeutic targeting of specific biologic abnormalities present in the leukemia cell population might, in a near future, improve outcome of adult leukemia patients.

Treatment of adult acute leukemia.

In 1996 progress has been made toward a better understanding of acute leukemias, their biology, the effects of different intensity or subtype-specific chemotherapy, and the contribution of bone marrow transplantation. In acute lymphoblastic leukemia, high-dose cytarabine in induction and in postremission treatment improves the cure rate, whereas dose reduction of daunorubicin in older patients worsens response and increases mortality. After acute promyelocytic leukemia has been successfully treated by retinoids, another subtype-specific chemotherapy containing high-dose methotrexate has overcome the primarily poor prognosis of B-cell acute lymphoblastic leukemia. The leukemic stem cell of acute myeloid leukemia representing minimal residual disease, producing disease progression in the patients, and initiating long-term growth in cultures or immunodeficient mice appears as a primitive multipotent cell. Leukemic transformation is reflected either by the specific balanced chromosome translocations or by chromosome deletions or losses. They are associated with histories of cytotoxic drugs such as epipodophylotoxins and anthracyclines or alkylating agents. Alternatively, both kinds of aberrations develop spontaneously with ethnic differences in special subtypes. Cytogenetics also determine favorable and unfavorable prognosis both for chemotherapy and bone marrow transplantation. In acute lymphoblastic leukemia high-risk and nonstandard-risk patients seem to benefit from allogeneic transplantation, whereas in acute myeloid leukemia there is no adequate basis for risk-adapted stratification between treatment modalities. New prospects lie in a more successful use of the effects of treatment intensification possibly supported by autologous blood stem cell transplantation. On the basis of standardized treatment, future clinical research can address the role of biologic features of the individual leukemia such as specific chromosome aberrations, fusion genes, expression of oncogenes, and monitoring of minimal residual disease.

RHuGM-CSF after high-dose chemotherapy in post-remission acute leukemia.

Post-remission high-dose chemotherapy has been an important advance in the treatment of adult acute leukemia (AAL). Without the use of colony-stimulating factors (CSFs) in this program, the mortality rate varies from 5 to 17%, and infectious complications arise in more than 50%. These findings limit the widespread use of such forms of therapy. The use of high-dose ara-C (HIDAC) alone or in combination with other drugs is the most common regimen studied, however neither other drug combinations nor the addition of supporting CSFs have been extensively explored. For this reason we studied the effect of high-dose cyclosphosphamide-etoposide (CECY) plus recombinant human granulocyte-macrophage (rHuGM)-CSF with the intention of decreasing morbimortality and prolonging disease-free survival (DFS). Since 1992 we have included 51 complete remission patients with AAL in the CECY plus rHuGM-CSF protocol. The maximal myelosuppression occurred in a mean of 6.4 days, and the mean days required for absolute neutrophil count recovery was 13 days and for platelets 21 days (p < 0.0001). No toxic deaths occurred and only two serious infectious complications were seen. After two years of follow-up, 50% of de novo acute myelogenous leukemia patients had relapsed at 13 months, and 50% of de novo adult acute lymphocytic leukemia patients had relapsed at 15 months. In a recent update, we have not seen a significant difference when compared to historic groups. The CECY protocol does not appear to be superior in prolonging DFS compared to HIDAC as a post-remission strategy for newly diagnosed AAL. The main difference was the absence of toxic deaths and minimal serious infectious complications in the CECY protocol. Therefore, we suggest that the use of rHuGM-CSF in post-remission programs should be included in future studies.

Acute leukemia in adults: recent developments in diagnosis and treatment.

Major advances in the diagnosis, classification, and treatment of adult acute leukemias have resulted in significant increases in the number of complete remissions and long-term disease-free survivors. Despite these improvements, most adult patients with acute leukemias still eventually die from their disease or complications of its treatment. New experimental and clinical approaches used to diagnose, monitor, and treat these diseases hold promise for further increased cure rates in the future. This article reviews the classification, immunobiology, cytogenetics, diagnosis, and treatment of adult acute leukemias and describes new directions being taken toward their cure.

Current Progress in the Treatment of Adult Acute Leukemia in Japan

Current Progress in the Treatment of Adult Acute Leukemia in Japan

Allogeneic Bone Marrow Transplantation for the Treatment of Adult Acute Leukemias

Allogeneic BMT has been shown to be a highly effective therapy for both AML and ALL. With the availability of unrelated donors, continuing advances in the development of new and more effective transplant regimens, and the identification of agents such as the hematopoietic growth factors, alprostadil, and pentoxifylline to decrease the regimen related toxicities, BMT will become a viable option for a greater number of adults with acute leukemia. The optimal timing for BMT will continue to evolve, but based upon the currently available information, patients age 55 or less with AML with a high probability of relapse based upon cytogenetic abnormalities should be considered for transplantation in first remission if a related or unrelated donor can be identified. For patients at low risk for relapse (e.g., age 25 or less who have received high-dose intensification), transplantation can be delayed until documentation of early relapse. For patients with Ph1+ ALL or t(4;11), transplantation in first remission should be considered if a suitable related or unrelated donor is identified. Adults with ALL without adverse prognostic characteristics should be considered for transplantation at relapse or in second remission.

Diagnosis and treatment of adult acute leukemia

L EUKEMIA has received a great deal of attention since first described in 1845 by Virchow. He described a condition in which the relationship between red and colorless corpuscles was the reverse of normal, coining the term weisses blut or white blood. ~ In 1889, Ebstein introduced leukemia as a distinct clinical entity. Early reports described a rapidly fatal disease and, as late as 1966, the median survival for adults with acute myelogenous leukemia (AML) was only 4 or 5 months. 2 The past 2 decades have shown advances in remission induction rates as well as survival. This progress has occurred as a result of more effective chemotherapeutic agents, improved blood product and antimicrobial support, and specialized nursing care. 3 Although therapeutic questions continue to be central to leukemia research, nontherapeutic studies are rapidly expanding our understanding of the biology of this disease. Epidemiologic, cytogenetic, immunologic, and pharmacologic studies are providing a better appreciation for the great heterogeneity of this disease, as well as a more comprehensive understanding of the biology and clinical behavior of the leukemia subtypes. This report will discuss the epidemiology of acute leukemia, review the diagnostic evaluation, provide a historical background for today's therapeutic treatment strategies, and explore the impact of nontherapeutic studies on treatment and prognosis.

Experience with combinations containing mitoxantrone in the treatment of adult acute leukemias.

Thirty cases of acute leukemia in patients over 15 years of age (18 males and 12 females) were treated with combinations containing mitoxantrone between January 1986 and August 1987 at the Kuwait Cancer Control Center. Acute nonlymphoblastic leukemia (ANLL) cases received mitoxantrone 10 mg/m2/day, days 1-3, cytosine arabinoside (Ara-C) 100 mg/m2 continuous daily infusion, days 1-5, and 6-thioguanine 100 mg/m2/day, days 1-5. Cases of acute lymphoblastic leukemia (ALL) received mitoxantrone 10 mg/m2/day, days 1-3, vincristine 1.4 mg/m2 days 1, 8, 15 and 22 and prednisone 40 mg/m2/day, days 1-22, then tapered down over one week. There were 16 cases of newly diagnosed ANLL, 9 cases of newly diagnosed ALL and 5 cases of relapsing leukemias. The 30 patients received 59 courses of therapy. The main toxicity was pancytopenia which occurred following all courses. It started following 75% of courses on day 8, lasted between 8-10 days and then rapidly recovered. In cases of ALL, the platelet count was much less affected in subsequent courses. Nausea and vomiting was a minor problem and occurred following 19% of courses, and in the majority was mild. Mucositis occurred following 30% of courses, and was mainly of moderate degree starting one week following the start of the course, and lasted about one week. Alopecia in the 25 newly diagnosed cases occurred in 18 cases (9 partial and 9 complete).(ABSTRACT TRUNCATED AT 250 WORDS)

Our experience in the treatment of adult acute leukemias in the past 5 years

Our experience in the treatment of adult acute leukemias in the past 5 years

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse.

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.

The hematologic malignancies. Leukemia, lymphoma, and myeloma.

Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4'-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.

Rubidazone in combination with Ara-C, vincristine and prednisone (ROAP) in the treatment of adult acute leukemia A Southwest Oncology Group Study

In an 18-month period, 340 consecutive adult patients with acute leukemia were treated using a 7-day continuous infusion of Ara-C in combination with rubidazone, vincristine and prednisone (ROAP). Of 334 (96%) evaluable cases, 77% were 50 years of age or older. The complete remission (CR) rate was 51% with a standard error of 3%. After adjustment for known prognostic factors this overall CR rate is 10% higher than the predicted CR rate when compared to the last completed SWOG study which used adriamycin in combination with a similar regimen of Ara-C, vincristine, and prednisone. The CR rate in patients over 50 years of age was particularly noteworthy. Using rubidazone, the CR rate was 46.1% (116/256) compared to 37.4% (91/243) for the adriamycin study in this poorly responding age group. The median survival time achieved was 27 weeks. However, in the age groups 40-49 years and 50-59 years the median survival was 70 and 44 weeks, respectively.

Etoposide in the treatment of acute leukemia in adults

Summary The value of etoposide in the treatment of adult acute leukemia is as yet poorly defined. It has a distinct activity in ANLL, but there is no evidence as yet based on experience with adults to indicate its effective use in ALL. A clear activity has been demonstrated for etoposide used as a single agent for all ANLL forms. Although the existing data are as yet fragmentary, the best results seem to have been obtained with acute monocytic leukemia. In this form, Bernasconi obtained remission rates through primary induction with etoposide alone that were similar to the results obtained with combination chemotherapy; moreover, the durations were comparable (1, 2). This fact is all the more important for the treatment of older patients who poorly tolerate an aplasia-producing induction therapy. Further investigations in this area are desirable. In the light of the preliminary Zurich data especially, incorporation of etoposide in the treatment of relapses of all ANLL forms seems to be quite promising and should be systematically further investigated. The question of a synergism between ara-C and etoposide has not yet been answered clinically.

Treatment of Acute Leukaemia in Adults

Although progress in the treatment of adult acute leukaemia has been much less dramatic than that which has occurred in the management of children with ALL, it should be clear from this progress report that significant strides have recently been made in the treatment of both adult ANLL and ALL that are of real benefit to the individual patient. This improvement is equally the result of improved supportive care and antileukaemia treatment. The progress has been of sufficient magnitude to clearly justify the optimism expressed in several recent reviews of leukaemia treatment (Freireich et al, 1976; Holland et al, 1976; Wiernik, 1976).

Cytosine arabinoside modulation of the mitotic index in treatment of adult acute leukemia.

Twenty-three unselected adult acute leukemic patients were treated with an initial intravenous pulse of cytosine arabinoside (Ara-C) 5 mg/kg. The mean mitotic index dropped from 7.7/1,000 to 2.8/1,000 at 4 hours after Ara-C pulse and rebounded to 6.7/1,000 at 18 hours. Infusions of Ara-C 7--10 mg/kg were given for 9 or 12 hours, depending on changes in the mitotic index. The group of responders (M1 or M2 marrows) could be predicted by the initial blast count in the marrow and the change in the mitotic index 18 hours after the Ara-C pulse. There were 9 (39%) complete and partial remissions. Six patients remained in remission more than 200 days. Since the changes in the mitotic indices induced by Ara-C were indistinguishable from those of another more successful trial, we infer that factors other than modulation of the cell cycle are critical to the success of this mode of therapy.

Adult Acute Leukemia

A ten-year retrospective study of adult acute leukemia was performed in nonieukemia-specialized centers to determine prognostic factors, length and quality of survival, cause of death, and response to different modes of therapy. Of 200 patients, 9.5% achieved complete remission, 14.0% obtained partial remission, and no response was present in 76.5%. Patients who were 50 years old or more (64.5%) had a significantly lower response rate (P less than .005) and survival (P less than .05) than the younger age group. Aggressive chemotherapy significantly improved the response rate, as well as survival (P less than .001). Quality of life was similar for responders and nonresponders, both spending only one fourth of their survival time in the hospital. Infection as the leading cause of death. The overall ten-year response rate of 23.5% represents a realistic rate in nonleukemia-specialized centers in which the treatment of adult acute leukemia is variable.

The treatment of adult acute leukaemia with modified VAMP therapy.

The treatment of adult acute leukaemia with modified VAMP therapy.

Treatment of Adult Acute Leukemia with a Combination of Cytosine Arabinoside, Vincristine, 6-Mercaptopurine, Prednisolone, and L-Asparaginase.

Treatment of Adult Acute Leukemia with a Combination of Cytosine Arabinoside, Vincristine, 6-Mercaptopurine, Prednisolone, and L-Asparaginase.

Treatment of adult acute leukemia with arabinosylcytosine and thioguanine.

Forty unselected adults with acute leukemia were treated with CA (2–3 mg/kg) by daily rapid intravenous injection and TG (2.5 mg/kg) orally. Two patients were judged to have had an inadequate trial, having died after 3 and 4 days. Of 38 adequately treated patients, 2 had acute lymphoblastic and 36 acute myeloblastic, monoblastic, or myelomonoblastic leukemia. Twenty-eight patients had had previous chemotherapy (19 with either CA or 6-MP alone) but had failed to respond or had relapsed and were refractory. The 38 adequately treated patients had 1 or more courses of CA and TG of 8–32 days each as limited by individual tolerance. The drugs caused moderate or severe pancytopenia and marrow hypoplasia in all but 3 patients treated. Twenty-one of 38 patients had remission with M-1 marrows lasting an average 6 (1.5–13) months with 6 patients still in remission. Seventeen of 21 patients had H-1 peripheral blood ratings (normal platelet, leukocyte and hemoglobin values) and 4 had H-2 ratings, all because of low hemoglobin. Twenty patients in remission were given maintenance therapy; the dosage varied but is currently TG 2.5 mg/kg 4–5x/wk + CA 2–3 mg/kg 1-2x/wk.