High-dose methotrexate in acute lymphocytic leukemia.

A pharmacokinetic study of methotrexate (MTX) was performed in 60 patients who received high-dose MTX at 500 mg/m2 infused over 24 hours. MTX levels reached 1.2 X 10(-7) M in the cerebrospinal fluid (CSF) within 10 minutes and remained constant at that level for 24 hours. Forty of these 60 patients were children with acute lymphocytic leukemia. In these 40 patients, simultaneous intrathecal MTX was given along with high-dose MTX. The resultant CSF levels (lumbar area) were higher than those obtained with either high-dose MTX alone or simultaneous intrathecal MTX alone. To date, there have been one systemic and one central nervous system relapse in these 40 children, and the treatment program appears safe to administer.     

Immunogenetic determinants of familial acute lymphocytic leukemia.

Acute lymphocytic leukemia developed almost simultaneously in two adolescent brothers, and another brother and both parents had rheumatoid arthritis. Laboratory studies uncovered no evidence for an underlying immunodeficiency state in the family. Immunogenetic evaluation showed the leukemic siblings to be HLA- and mixed-leukocyte-culture identical and homozygous for a recessively inherited locus dictating the presence of antigens on the surface of B-cells. This Ia antigen, as detected by sera from mothers of leukemic children, appeared to be mapped within the major histocompatibility region and may be a human analogue to murine immune-response antigens associated with susceptibility to leukemia.     

Actinomycin D in childhood acute lymphocytic leukemia.

Eighteen evaluable children who relapsed with acute lymphocytic leukemia (ALL) were treated with intermittent, high-dose actinomycin D. Objective responses occurred in four of 11 children who had relapsed with chemotherapy which did not contain an anthracycline. The major toxic effects included thrombocytopenia and granulocytopenia. Minor toxic effects included nausea, vomiting, skin rash, and stomatitis. The onset of the maculopapular skin rash coincided with the platelet count nadir. These data suggested that actinomycin D is active in ALL.     

Adenovirus-mediated cytotoxicity of chronic lymphocytic leukemia cells.

We have studied adenovirus-mediated cytotoxicity after infection of malignant cells obtained from patients with chronic lymphocytic leukemia (CLL). Our studies indicate that adenoviruses can infect primary CLL cells and that infection of CLL cells with a replication-competent strain of human adenovirus 5 (Ad5dl309) results in cytotoxicity. Adenovirus-mediated cytotoxicity was also seen after infection of CLL cells with a variety of viruses attenuated by mutations in the adenovirus early region 1 (E1) or early region 2 (E2). Even viruses attenuated by deletion of the entire E1 region resulted in cytotoxicity after infection of the CLL cells obtained from some patients. Although there was variability in the degree of cytotoxicity induced by different viruses in different patients cells, a virus with a mutation in the E1B 19K gene resulted in the greatest degree of cytotoxicity in most of the CLL samples tested. These studies demonstrate that infection of CLL cells by attenuated adenoviruses with specific mutations in the E1 or E2 region results in cell death. Attenuated adenoviruses should be developed further as therapeutic agents for patients with CLL.     

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.     

Monocyte markers and the common acute lymphoblastic leukemia antigen on chronic lymphocytic leukemia cells

The mononuclear cells from 42 patients with chronic lymphocytic leukemia (CLL) were analyzed for surface markers using monoclonal antibodies and flow cytofluorimetry. All 42 CLLs were Ig+HLA.DR+OKT3-OKT4-OKT6-OKT8- and monoclonal with respect to light chain type. Thirty of the 42 tumors expressed the common acute lymphocytic leukemia antigen, and cells from 18 leukemias stained with the antibodies OKM1 and 63D3, which are specific for different antigens characteristic of myeloid cells. Eight of the leukemias failed to stain with PI153, which has been reported to recognize all B-cell CLLs.     

Philadelphia chromosome-positive adult acute lymphocytic leukemia

The CML-specific Philadelphia (Ph1) chromosome is relatively common cytogenetic abnormality of ALL, which has been shown 20% of adult ALL and 5% of child ALL. We analysed here the 12 patients of Ph1-positive ALL, aged 35 to 69-years old, who were experienced in our hospital for latest eight years. In comparison with Ph1-negative ALL, these 12 patients were elder and showed high peripheral and bone marrow leukemic cell counts. Of these, seven patients had 100% Ph1 abnormality in the bone marrow and another five patients showed mosaic marrow patterns of Ph1 and normal chromosomes. Remissioned eight cases had no more Ph1 abnormalities in their bone marrows. Our Ph1-positive ALL revealed B-cell lineage leukemia, since their surface phenotype were Ia+ and CD10+ and they have rearranged immunoglobulin JH genes. Four out of these nine patients had such gene rearrangement in the 5.8kb bcr (major BCR: M-BCR) as CML's patient had. Eight out of twelve Ph1-positive ALL patients (66.7%) achieved complete remission, but the prognosis was so bad since they had shorter remission duration (median 6.7 mos) and survival months (median 11.9 mos) than those of Ph1-negatives.     

Comparison of techniques for detecting T-cell acute lymphocytic leukemia.

Three versions of the E-rosette test, one using untreated sheep erythrocytes at 37 degrees C, another using such cells at 4 degrees C, and a third using sheep erythrocytes treated with S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET), were applied to each of 72 bone marrow specimens from as many unselected patients with untreated acute lymphocytic leukemia (ALL). The same specimens were also examined for T-cell antigens, based on reactivity with an antithymocyte serum. Lymphoblasts in eight ALL specimens formed E rosettes at 37 degrees C; no other E-positive specimens were identified when the assay was done at 4 degrees C. With AET-treated erythrocytes, lymphoblasts from these eight specimens and six additional specimens readily formed rosettes. T-cell antigens were detectable in all specimens positive for rosette formation withe untreated erythrocytes, in four of the six specimens positive for rosette formation with AET-treated erythrocytes, and in four specimens that showed no rosette formation under any of the experimental conditions used. Altogether, 18 specimens contained lymphoblasts with one or more surface markers characteristic of T-cell leukemia. These findings indicate that more specimens are likely to be identified at T-cell luekemias when E-rosette tests of increasing sensitivity and assayss for T-cell antigens are used. Some leukemic blasts do not possess the full array of membrane receptors and antigens usually associated with T cells. A combination of E-rosette tests and serologic tests is necessary to determine reliably the relationship of the test specimen to either T-cell ALL or common ALL and to establish the clinical significance of blasts that express membrane properties intermediate between those of T-cell ALL and common ALL.     

Treatment of acute lymphocytic leukemia in adult

Since April, 1978 to October, 1988, 66 acute lymphocytic leukemia (ALL) patients aged 15 to 79 (21 L1, 43 L2, 2 L3/6 Ph1+) were treated with 3 different therapeutic protocols. The drugs used for induction were VCR (VDS) + Pred, followed by DNR + VCR (VDS) + 6MP + Pred and VCR (VDS) + L-asp + Pred in protocol I, Ad + VCR + Pred in protocol II and DNR + VCR + Pred in protocol III. Complete remission (CR) was attained in 72.7% of 66 patients. The CR rate of each group as followings; 71.4% in protocol I and 75.0% in protocol II and III, respectively. The median duration of remission was 10.2 months + and the probability of being in continuous CR at 3 years was 21.9%. For the 48 patients in remission the median survival was 17.8 months and the probability of being alive at 3 years was 24.3%. The intensified induction and consolidation therapy is expected in the cure oriented treatment of adult ALL.     

T cell acute lymphocytic leukemia terminating as malignant histiocytosis.

Less than 200 cases of malignant histiocytosis (histiocytic medullary reticulosis) have been reported in the literature. Five previously reported cases and the case reported in this article have been preceded by acute lymphocytic leukemia. All of these cases have had similar courses characterized by prompt response of the leukemia to chemotherapy followed in three to six months by the onset of rapidly fatal malignant histiocytosis. The leukemic lymphoblasts in the two cases studied for lymphocyte surface markers had T cell markers. No residual leukemia was identified at autopsy in four of the six cases.     

Terminal deoxyribonucleotidyl transferase activity in B-cell acute lymphocytic leukemia.

Moderately high levels of activity of the enzyme terminal deoxyribonucleotidyl transferase (TdT) were found in the leukemic cells of a patient with acute lymphyocytic leukemia. The proliferating cells were B lymphocytes bearing IgG antibody, and the disease was associated with an IgG monoclonal spike and a mediastinal mass. The observations in this case suggest that TdT is related more to the immaturity and proliferation of certain lymphoid stem cells than to their progress toward B- or T-cell differentiation.     

Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias.

The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2,000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL-7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3,280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells, and that this effect is not restricted to the lymphoid lineage.     

Donor leukocyte infusions in acute lymphocytic leukemia

Donor leukocyte infusion (DLI) has well-documented activity in CML but the role of DLI in other diseases is less well defined. To evaluate the strategy in acute lymphocytic leukemia (ALL) we evaluated 44 ALL patients from 27 centers who were treated with DLI. Patients with persistent or recurrent disease received DLI from the original marrow donor (30 matched related, four mismatched family, and 10 matched unrelated). Chemotherapy was given before DLI to 28 patients. Of 15 patients who received no pre-DLI chemotherapy, two achieved complete remissions, lasting 1112 and 764+ days. In four patients who received DLI as consolidation of remission induced by chemotherapy or immunosuppression-withdrawal, duration of remission post DLI was 65, 99, 195 and 672+ days. Of 25 patients who received DLI in the nadir after chemotherapy, 13 survived > or =30 days post DLI but did not achieve remission, seven died within less than 30 days post DLI, and five entered remissions that lasted 42, 68, 83, 90, 193 days. Seven patients who did not respond to the initial DLI received a second DLI; none of these patients attained durable remission. Eighteen of 37 evaluable patients developed acute GVHD and five of 20 evaluable patients developed chronic GVHD. Overall actuarial survival is 13% at 3 years. In conclusion, DLI has limited benefit in ALL. New approaches are needed in this group of patients.     

B-cell acute lymphocytic leukemia in HIV-antibody-positive patients

B-cell non-Hodgkin lymphoma (NHL) has been well described in association with human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS). Many of these lymphomas are of the diffuse, aggressive, subtype B-cell NHL, including Burkitt and Burkitt-like lymphoma. Recently, there have been reports of B-cell acute lymphocytic leukemia (ALL), Burkitt type, in patients who were either HIV antibody-positive or at high risk for AIDS. We have seen three cases of B-cell ALL, Burkitt type, and herein describe their clinical and laboratory characteristics. All patients were HIV antibody-positive. Since stage IV Burkitt lymphoma in blood phase and B-cell ALL, Burkitt type, represent a continuum of the same disease, and since it is also an aggressive B-cell malignancy, we suggest that B-cell ALL, Burkitt type, in HIV antibody-positive patients should support the diagnosis of AIDS.