Harvey D. Preisler

MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia

Summary. The expression of the MDR1 gene was studied by Northern blot analysis in leukaemic cell specimens obtained from 74 patients with acute myelogenous leukaemia (AML). No relationship was found between MDR1 RNA levels and FAB type of leukaemia or patient age. Transcript levels tended to be highest in the leukaemic cells of patients with a history of toxic exposure or preleukaemia compared with ‘standard risk’patients at diagnosis but the differences were not significant (P= 0.07). Patients whose leukaemic cells contained high MDR1 transcript levels were difficult to induce into remission and, if remission was induced, the remissions were short. Hence high levels of MDR1 expression may explain, at least in part, the ineffectiveness of anthracycline antibiotic containing treatment regimens in some patients with AML.

An autopsy study of 1206 acute and chronic leukemias (1958 to 1982).

Autopsy data on 1,206 children and adult patients with acute myelocytic leukemia (AML) (585), chronic granulocytic leukemia (CGL) (204), acute lymphocytic leukemia (ALL) (308), and chronic lymphocytic leukemia (CLL) (109) obtained from 1958 to 1982 were reviewed. This analysis has shown that, whereas the proportion of patients with residual AML at any anatomic site decreased significantly and uniformly over the entire study period, significant corresponding decreases in patients with CGL and ALL occurred only since 1976 and 1978, respectively. No significant corresponding decreases were noted in patients with CLL at any time. Significant decreases were also noted over time in the rates of extramedullary site involvement by AML, CGL, and ALL. Whereas the lymphoreticular organs, kidneys, adrenals, and pituitary were most often involved at autopsy by CLL, the testes, leptomeninges, dura mater, uterus, large bowel, and pancreas were most often involved by ALL. In general, patients with AML and CGL showed the lowest relative rates of involvement of the various organs by leukemia during the 24‐year period. Whereas patients with AML and ALL showed significant decreases in the rates of involvement of nearly all anatomic sites during the most recent study periods, those with CGL and CLL showed corresponding decreases in only a few organ sites. The lower rates of organ involvement in patients with AML and ALL attest to the more aggressive eradication of leukemic cells by therapeutic regimens in these diseases over time. In particular, the significant decrease in the rate of meningeal involvement by ALL during the most recent period is probably attributable to central nervous system prophylaxis.

Therapy of secondary acute nonlymphocytic leukemia with cytarabine.

ACUTE nonlymphocytic leukemia is an increasingly common complication of therapy with alkylating agents or ionizing radiation. Incidences as high as 5 per cent have been reported in patents with Hod...

Acute myelogenous leukemia with leukemia cutis. Eighteen cases seen between 1969 and 1986

Leukemia cutis was documented by biopsy in 18 of 877 patients (2%) with acute myelogenous leukemia (AML) seen at Roswell Park Memorial Institute (Buffalo, NY) between 1969 and 1986. French‐American‐British (FAB) types included four M2, one M3, ten M4, and three MS. Lysozyme was more consistently detectable in skin sections in our cases than Leu‐M1, α‐1‐antitrypsin, α‐1‐antichymotrypsin, or chloroacetate esterase activity. Additional extramedullary sites of involvement were present in 16 patients, including meningeal leukemia in six. Two patients had leukemia cutis preceding bone marrow leukemia. Skin was the initial site of relapse in 11 patients, without marrow relapse, occurring as late as 5.5 years after diagnosis. Most patients in this retrospective series were treated with radiation therapy and/or palliative chemotherapy, and did poorly, with prompt bone marrow relapses and serial skin relapses. Long‐term disease‐free survival was achieved in the one patient whose skin relapse was treated with whole‐body electron‐beam radiation therapy in conjunction with reinduction and consolidation chemotherapy. Severe skin toxicity was caused by administration of Adriamycin (doxorubicin) 12 days after electron‐beam irradiation in one patient, but was not seen when cytosine arabinoside was administered in doses up to 3 g/m2 in conjunction with radiation therapy. This retrospective review suggests that optimal management of AML involving skin might include whole‐body electron‐beam irradiation in conjunction with induction or reinduction chemotherapy without anthracyclines, followed by consolidation chemotherapy. Additionally, there should be ongoing surveillance for and treatment of extramedullary disease at other sites, including the meninges.

Intensive remission consolidation therapy in the treatment of acute nonlymphocytic leukemia.

A pilot study was conducted to determine the possible efficacy and the toxicities associated with the administration of four courses of intensive consolidation chemotherapy to patients with acute nonlymphocytic leukemia in remission. All therapy was completed within 6 months. The median duration of remission was 22 months, with 45+% of patients in remission at 3 years and few relapses to date thereafter. Sixty percent of patients experienced significant side effects after each course of therapy. The therapy appeared to be particularly efficacious for patients less than 45 years of age, since 65% are alive at 3 years and there is no projection for a median duration of remission as yet. The cytogenetic characteristics of the leukemic cells, the percentage of S phase cells, and the height of the WBC count were the most important prognostic characteristics at diagnosis.

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study.

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.

Gastrointestinal "sterilization" in the treatment of patients with acute leukemia.

In preliminary studies, a combination of gentamicin, vancomycin, and nystatin in conjunction with either sterile or reduced‐bacterial diets consistently resulted in bacterially “sterile” stools and an apparent reduction of infection in granulocytopenic patients receiving myelosuppressive chemotherapy. the ease and economy of the approach recommends it to chemotherapy centers which lack elaborate isolation facilities. Studies are in progress to more precisely compare the relative effectiveness of physical isolation, air filtration, diet, and prophylactic antibiotics in reducing the infectious complication of cancer chemotherapy.

Relationship between plasma adriamycin levels and the outcome of remission induction therapy for acute nonlymphocytic leukemia

SummaryPlasma adriamycin and adriamycinol levels were masured in 45 patients with acute nonlymphocytic leukemia 3 h after the drug was administered. A wide range of levels was found. Plasma levels increased after the administration of each of three daily doses of the drug. High plasma levels were associated with both death during remission induction therapy and, for patients who entered remission, long remissions.

Relationship between leukemic cell retention of cytosine arabinoside triphosphate and the duration of remission in patients with acute non-lymphocytic leukemia.

Bone marrow cells were obtained from patients with acute non-lymphocytic leukemia immediately prior to the administration of cytosine arabinoside/anthracycline antibiotic remission induction therapy. The ability of the leukemic cells to take up and phosphorylate cytosine arabinoside (araC) and to retain cytosine arabinoside triphosphate (araCTP) was measured and compared to the outcome of remission induction therapy and the duration of remission. While the outcome of remission induction therapy was unrelated to cellular metabolism of araC, the duration of remission was highly correlated with araCTP retention. A comparison of the remission durations of patients treated on successive chemotherapeutic protocols suggests that the benefits of intensive remission consolidation therapy may be limited to patients whose leukemic cell retention of araCTP is low and that aggressive consolidation chemotherapy may reduce the prognostic significance of araCTP retention.

Prediction of response of patients with acute nonlymphocytic leukaemia to remission induction therapy: use of clinical measurements

Two hundred patients with acute nonlymphocytic leukaemia received remission induction therapy consisting of cytosine arabinoside and an anthracycline antibiotic. Analysis of the pretherapy characteristics of the patients demonstrated that patient age was the most important factor in determining whether or not the patient would survive remission induction therapy. Assessment of the characteristics of the bone marrow after 6 d of therapy permitted the recognition of patients who were likely to fail to enter remission because of persistent leukaemia. Taken together, these observations demonstrate that it is possible to identify patients for whom conventional chemotherapy is not likely to be of benefit either because it is too intensive or because it is not intensive enough to produce a complete remission.