Treating acute nonlymphocytic leukemia

Acute leukemia is no longer an uncommon disease among the middle-aged and elderly. In recent years, treatment programs available for acute nonlymphocytic leukemia have improved dramatically. While remission rates in patients over age 50 are not as high as in younger age groups, combination chemotherapy is effective in a significant number of older patients, and complete remissions can be obtained in 20 to 50%. Recent years have also witnessed much progress in the ability to provide essential supportive therapy during periods of marrow hypoplasia. Because acute leukemia is uniformly fatal if untreated, aggressive therapy should be made available to all these patients, regardless of age.     

Syndromes of acute nonlymphocytic leukemia

The marriage of cytogenetics and molecular biology has resulted in major advances in our understanding of acute nonlymphocytic leukemia. These technologies reveal a number of clearly recognizable syndromes of acute nonlymphocytic leukemia. This review describes the salient features of several of these syndromes: acute myelomonocytic leukemia with abnormal eosinophils; acute nonlymphocytic leukemia with 11q abnormalities [biphenotypic leukemia with t(4;11); and acute monocytic leukemia with t(9;11)]; acute nonlymphocytic leukemia with t(8;21); acute promyelocytic leukemia; acute nonlymphocytic leukemia with normal or elevated platelet counts and rearranged 3q21 and 3q26; and acute nonlymphocytic leukemia with increased basophils and t(6;9). The pathogenesis of therapy-related leukemias is discussed also.     

Differences in cell cycle characteristics among patients with acute nonlymphocytic leukemia

The proliferative characteristics of myeloid leukemias were defined in vivo after intravenous infusions of bromodeoxyuridine (BrdU) in 40 patients. The percentage of S-phase cells obtained from the biopsies (mean, 20%) were significantly higher (P = .00003) than those determined from the bone marrow (BM) aspirates (mean, 9%). The post- BrdU infusion BM aspirates from 40 patients were incubated with tritiated thymidine in vitro. These double-labeled slides were utilized to determine the duration of S-phase (Ts) in myeloblasts and their total cell cycle time (Tc). The Ts varied from four to 49 hours (mean, 19 hours; median, 17 hours). Similarly, there were wide variations in Tc of individual patients ranging from 16 to 292 hours (mean, 93 hours; median, 76 hours). There was no relationship between Tc and the percentage of S-phase cells, but there was a good correlation between Tc and Ts (r = .8). Patients with relapsed acute nonlymphocytic leukemia (ANLL) appeared to have a longer Ts and Tc than those studied at initial diagnosis. A subgroup of patients at either extreme of Tc were identified who demonstrated clinically documented resistance in response to multiple courses of chemotherapy. We conclude that Ts and Tc provide additional biologic information that may be valuable in understanding the variations observed in the natural history of ANLL.     

Effectiveness of acute nonlymphocytic leukemia induction chemotherapy in acute lymphocytic leukemia

Twelve adults with newly diagnosed acute lymphocytic leukemia (ALL) received a combination of daunorubicin, cytarabine, and 6-thioguanine (DAT) as induction chemotherapy. Eleven patients (91%) gained complete remission (ten patients after a single course of treatment). Because DAT alone seems effective in ALL, the combination of vincristine, prednisone, and DAT could improve the complete remission rate. Moreover, the resulting early leukemic cytoreduction could enhance remission duration in adults with ALL.     

Hepatitis in patients with acute nonlymphocytic leukemia

Three consecutive groups (University of Maryland Cancer Center protocols 7110, 7405, and 7802) of patients with acute nonlymphocytic leukemia who achieved a complete hematologic remission with similar antileukemic therapy were reviewed for the development of hepatitis. Ninety-four (73 percent) experienced viral hepatitis; eight had type B hepatitis and 86 had non-A/non-B hepatitis. The hepatitis was mild in all patients. Hepatitis secondary to cytomegalovirus, herpes simplex virus, Epstein-Barr virus, or Toxoplasma gondii was not observed. Antibody to type A hepatitis was common, but acute infection could not be substantiated. All cases of type B hepatitis in which the surface antigen could be serotyped were found to have the less frequently observed ayw marker, suggesting a common donor as the source of infection. The median duration of complete remission was longer (p = 0.03) for patients in Group II (protocol 7405) who contracted hepatitis (247 days) compared with patients without hepatitis (125 days). Median overall survival was also longer (p = 0.01) for these patients in whom hepatitis developed (672 days versus 372 days, respectively). No prolongation of complete remission duration or survival could be demonstrated for patients from Group I (protocol 7110) or Group III (protocol 7802) who contracted hepatitis. In patients with hepatitis, the height of transaminase serum bilirubin levels or duration of abnormal results of liver function tests did not correlate with the duration of complete remission or survival. Hepatitis, a common infection in those patients with acute nonlymphocytic leukemia who undergo induction therapy, had an inconsistent effect on the duration of complete remission interval and overall survival.     

Long-term disease-free survival in acute nonlymphocytic leukemia

Twenty-six of 45 adults (58%) with acute nonlymphocytic leukemia who were treated with intensive induction chemotherapy over 5 yr ago entered complete remission. All patients entering remission were placed on weekly maintenance chemotherapy consisting of cytosine arabinoside and 6-thioguanine. The median duration of complete remission was 17 mo and 7 patients (27%) remained in their initial remission for 62 + to 102 + mo. All but one of the patients in complete remission over 5 yr have had treatment discontinued. Only 1 of 7 patients in remission for more than 5 yr has relapsed. Median survival is 26.5 mo, and 8 patients (31%) currently remain alive without evidence of leukemia 63--105 mo from diagnosis. It is possible to achieve long-term disease-free survival with chemotherapy alone in acute nonlymphocytic leukemia.     

Aryl sulfatase A in acute nonlymphocytic leukemia

To ascertain whether estimation of urinary aryl sulfatase A (ASA) is a reliable noninvasive technique for monitoring disease activity in adult acute nonlymphocytic leukemia, we studied the excretion pattern of this enzyme during active disease, partial remission, and complete remission in ten patients and compared the results with those of ten healthy volunteers. There was no significant difference in enzyme excretion between complete remission cases and the control group. Patients with partial remission and active disease had significantly different urinary enzyme levels from each other and from the control and complete remission groups. Estimation of urinary ASA is a useful noninvasive method of monitoring disease activity in adult acute nonlymphocytic leukemia.     

Central nervous system involvement in acute nonlymphocytic leukemia. A prospective study of adults in remission

To identify adults with acute nonlymphocytic leukemia at risk for the development of central nervous system involvement, we performed periodic cerebrospinal fluid examinations on patients in remission. Among 58 consecutive patients monitored during first remission, central nervous system leukemia developed in nine (16 percent). Four patients, including one who was symptomatic, had central nervous system leukemia detected simultaneously with marrow relapse. Five additional patients were asymptomatic and continue to have bone marrow remission. Following central nervous system and systemic treatment, two of these five patients have never had relapse, and three had relapse in the bone marrow five, 10, and 21 months later. Factors at diagnosis associated with the subsequent development of central nervous system leukemia were elevated leukocyte count, serum lysozyme and lactate dehydrogenase, extramedullary infiltration including splenomegaly, and monocytic (FAB M4 or M5a) morphology. In six of 17 patients (35 percent) with monocytic morphology, central nervous system leukemia developed compared with only three of 41 patients (7 percent) with other subtypes (p = 0.02). Discriminant analysis identified leukocyte count, splenomegaly, and M4 or M5a morphology as the most important risk factors and led to a mathematical formula that correctly identified 90 percent of the patients. Although the risk of central nervous system leukemia in adults with acute nonlymphocytic leukemia is too low to justify routine prophylaxis, those patients recognized to be at a greater risk should receive prophylaxis or be monitored closely with periodic lumbar punctures.     

Proliferative characteristics of acute nonlymphocytic leukemia in vivo

The proliferative characteristics of myeloid leukemias were defined in vivo following intravenous bromodeoxyuridine (BrdU). Fifteen patients received a 2-hour infusion of BrdU. A monoclonal anti-BrdU antibody was used to detect the in vivo incorporation of BrdU by S-phase cells. The percentage of S-phase cells obtained from the biopsies (mean 17.3%) was significantly higher (p = 0.00001) than the percentage determined from the aspirates (7.8%). It is concluded that the true estimate of S-phase cells can only be obtained from biopsies following in vivo labeling of cells synthesizing DNA. The persistence of BrdU-labeled cells in follow-up studies can be used to recognize 'residual leukemia', and the subsequent fate of these cells can be defined in vivo.     

Spontaneous differentiation from myeloperoxidase-negative acute nonlymphocytic leukemia to acute myelomonocytic leukemia

We reported a 68-year-old woman with acute nonlymphocytic leukemia, in whom the leukemia transformed from poorly differentiated myeloperoxidase (MPO)-negative type into myelomonocytic type during the observation without chemotherapy. Hematological findings on admission revealed a leukocyte count of 3,500/microliters with 48% blasts and a platelet count of 9.2 x 10(4)/microliters. Bone marrow aspiration showed 68.2% infiltration of blasts negative for MPO. Sudan black B and esterase stains. By electron microscopy MPO was detected in the endoplasmic reticulum and nucleoenvelope of the blasts. Large vacuole-like granules were MPO-negative. She was observed without administration of any antileukemic agent or an immunopotentiator. The leukocyte count rose gradually, in association with increases in the relative and absolute counts of mature neutrophils and monocytic cells, and the platelet count. Twenty-six months after the initial diagnosis, a blood examination showed a leukocyte count of 74,300/microliters with 20.5% mature neutrophils and 15.5% monocytic and a platelet count of 31.4 x 10(4)/microliters. Cytological, cytochemical, ultrastructural and immunological studies of the bone marrow cells showed features compatible with acute myelomonocytic leukemia (FAB M4). This case is unusual in respect that poorly differentiated ANLL transformed spontaneously into moderately differentiated ANLL.     

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.     

High-dose cytosine arabinoside for acute nonlymphocytic leukemia

Eighteen patients with acute nonlymphocytic leukemia (ANLL), aged 17-73 years, were treated with high-dose cytosine arabinoside (HD-Ara-C) using 3 g/m2 IV q 12 hours X 12 doses. Seven patients were treated for relapse and four (57%) obtained a complete remission with a median duration of 19.5 weeks. In nine patients, refractory to conventional chemotherapy, no complete responders were observed. Treatment failure was most commonly due to drug resistance. Two elderly patients with ANLL not previously exposed to chemotherapy died during the initial induction. Recent data on the HD-Ara-C experience in ANLL are presented and compared with this study.     

The curative treatment of adult acute nonlymphocytic leukemia

Based on bone marrow findings and bone marrow stem cell kinetics and response to treatment, we have developed individualization of intensive induction and postremission chemotherapy for adult acute nonlymphocytic leukemia (ANLL). Thirty-four consecutive adults with ANLL were treated with an intensified induction regimen and a high dose sequential postremission therapy consisting of daunomycin, Ara-C, 6-MP and prednisolone (DCMP). The first course of remission induction was continued till achievement of a complete marrow aplasia which resulted in a decrease of leukocyte count less than 0.6-0.8 X 10(9)/L, a decrease of marrow nucleated cell count to less than 8 X 10(9)/L, and a decrease of marrow leukemic cell to less than 5%. Postremission therapy consisted of 4 courses of DCMP and a course of high-dose Ara-C. The first postremission course was initiated within 2-3 weeks subsequent to the last induction course. Twenty-eight of 34 patients (82.4%) achieved complete remission. The 4 year disease free survival rate was 64.4 +/- 14.0%. The results convinced us that individualized intensive induction and postremission therapy of adult ANLL given at the time of minimal residual leukemic disease in early remission might be sufficiently effective to produce long-term DFS to be considered potential cured.     

Heavy chain immunoglobulin gene rearrangement in acute nonlymphocytic leukemia

Samples of leukemic cell DNA from 14 children with acute nonlymphocytic leukemia (ANLL) and 4 human myeloid leukemia cell lines were analyzed for rearrangement in the heavy chain region of the immunoglobulin gene. The diagnosis of ANLL was confirmed in all patients by morphological, cytochemical, and immunologic studies. By restriction endonuclease digestion and hybridization with cloned heavy chain immunoglobulin gene probes for the constant (Cmu) and joining (JH) regions, the DNA of 2 patients and 1 cell line (ML-1) was found to contain rearrangements. The DNA from the remaining 12 patients and 3 cell lines was not rearranged (germline configuration). Both patients with apparent immunoglobulin gene rearrangement achieved complete remission on therapy for ANLL. Immunoglobulin gene rearrangement in phenotypically defined ANLL suggests (1) that such changes may not be limited to lymphoid leukemia of B cell lineage, or (2) that, in some patients, the leukemic transforming event may involve stem cells capable of both B cell and myeloid differentiation.     

Ubenimex in the treatment of acute nonlymphocytic leukemia in adults

Summary A multi-institutional randomized study for the evaluation of ubenimex (Bestatin) in the treatment of adult acute nonlymphocytic leukemia was performed. One hundred and ninety-five patients were registered from February 1988 to December 1990. Patients who had reached complete remission by one or two courses of remission induction chemotherapy were divided into the ubenimex group or the control group by randomization. Patients of the ubenimex group started to receive 30 mg ubenimex orally once a day when maintenance therapy began and continued as long as possible. Remission duration and survival were analyzed based on the data as of August 31, 1991. Remission duration of the ubenimex group was superior to that of the control group (generalized Wilcoxon test:-p=0.0338). Fifty percent remission duration was 508 days in the ubenimex group and 386 days in the control group. There has been no statistical difference in survival between the two groups as yet.     

11;13 translocation in acute nonlymphocytic leukemia.

In this paper, we report on a 9-year-old girl with acute nonlymphocytic leukemia (FAB-M5) with a rare chromosome abnormality, t(11;23)(q21;p11). Peripheral blood showed Hb 7.5 g/dl, WBC 3,600 cells/microliters (10% blasts), and platelet count 110 x 10(3) cells/microliters. The bone marrow aspirates showed normal cellularity with 36.7% blasts. On morphological characteristics, micromegakaryocytes were observed, and on chromosome examination the karyotype was shown to be 46,XX,t(11;13)(q21;p11) in all metaphases.