Age and treatment response in acute nonlymphoblastic leukemia.

Treatment of older acute leukemia patients has been the subject of recent debate. We treated 101 acute leukemia patients in a prospective randomized trial. Fifty-seven per cent of the population was over 50. Half were treated with a mild induction program (VAMP) and half with a vigorous program (CAT). The older patients who received vigorous treatment did better than those who received mild treatment. We suggest that patients over 50 should be regarded as a separate category in design of treatment protocols in order to further maximize the benefits of therapy.     

Expression of functional markers in acute nonlymphoblastic leukemia

Multidrug resistance parameters, tissue infiltration parameters, receptors for colony-stimulating factors (CSFr) and cell cycle parameters were analyzed using flow cytometry in 145, 109 initial and 36 relapsed or refractory, acute nonlymphoblastic leukemia (ANLL) patients to find out clinically more reliable functional parameters. Lung resistance-associated protein (LRP) was most frequently expressed in ANLL (44.1%) followed by P-glycoprotein (PGP) (35.9%) and multidrug resistance-associated protein (MRP) (8.3%). LRP and PGP were expressed more frequently in relapsed or refractory ANLL than initial ANLL cases. Complete remission rate after standard chemotherapy falls in PGP-positive cases (p = 0.001). CD44-positive ANLL cases relapsed more frequently. The organ tropism is different depending on the infiltration parameters, vascular cell adhesion molecule to splenomegaly, matrix metalloprotease-2 to hepatomegaly and to extramedullary infiltration other than spleen, liver or lymph node. The percentage of the granulocyte-macrophage-CSFr expression was high in M4 and M5, and granulocyte-CSFr-positive ANLL showed less extramedullary infiltration (p = 0.007) and more PGP expression. Ki-67 was expressed significantly less in refractory ANLL than initial ANLL and DNA topisomerase IIalpha was expressed significantly more in the surviving patients group. In conclusion, analysis of these new functional parameters could help to predict and overcome the clinical behavior of each ANLL at the time of diagnosis.     

Central nervous system leukemia in children with acute nonlymphoblastic leukemia

Factors contributing to the development of central nervous system (CNS) leukemia, and the impact of leukemic involvement of this site on subsequent remission length, were determined in 184 children with acute nonlymphoblastic leukemia who had been treated in two successive clinical trials. Preventive CNS therapy in both studies consisted of intrathecal methotrexate (12 mg/m2) given monthly during the first six months of therapy and then every three months until all treatment was stopped. Children with CNS leukemia at diagnosis or relapse were given intrathecal chemotherapy weekly for four weeks and then monthly throughout the remainder of the treatment course. Those continuing in complete remission received 2,400 rad cranial irradiation plus five doses of intrathecal methotrexate before cessation of therapy. The 38 children (20.7%) with CNS leukemia at diagnosis were more likely to have an initial leukocyte count greater than or equal to 25 X 10(9)/L (P = .01) and age less than 2 years (P = .03). The presence of CNS leukemia at diagnosis did not adversely affect the remission induction rate (P = .13) or the length of complete remissions (P = .73). CNS relapse ended initial remissions in 11 patients only and did not preclude subsequent long-term survival, as four of these children are off therapy and in second complete remission for 33+ to 78+ months. Three features at diagnosis were predictive of CNS relapse: monocytic or myelomonocytic leukemia (P = .002); age less than 2 years (P = .0001); and leukocyte count greater than or equal to 25 X 10(9)/L (P = .012). By stepwise Cox regression analysis, each factor was found to have independent predictive value. Despite the apparent effectiveness of intrathecal methotrexate as preventive CNS treatment, our findings indicate that more effective prophylaxis is needed for patients with features predisposing to CNS relapse.     

Phase I study of bisantrene in acute nonlymphoblastic leukemia

A phase I study of bisantrene using a daily injection for 5 days was undertaken in adult patients with relapsing acute nonlymphoblastic leukemia. Seventeen patients received 27 courses, with daily doses ranging from 75 to 250 mg/m2. Although gastrointestinal toxicity and alopecia were rare, hematological toxicity occurred in 85% of the patients. There was cholestasis unrelated to infectious events in 27% of the courses, as well as reversible renal failure in eight of 27 evaluable courses. Responses (complete + partial) were obtained in 35% +/- 10% of the patients. The recommended dose for phase II study is 200 mg/m2/day X 7.     

High-dose methylprednisolone for remission induction in children with acute nonlymphoblastic leukemia

The effectiveness of high-dose intravenous methylprednisolone (HIVMP) in inducing an initial remission was examined in a child with acute nonlymphoblastic leukemia (ANLL). Dramatic clinical and hematological improvement with 7% marrow blasts was obtained in 3 weeks with HIVMP treatment without giving any other antileukemic drugs. Based on the results of this preliminary observation we suggest that high-dose methylprednisolone (20-30 mg/kg) might be a useful approach when applied as an initial short treatment in childhood ANLL.     

Allogeneic marrow transplantation for acute nonlymphoblastic leukemia after first relapse

Sixty-two patients with acute nonlymphoblastic leukemia in first relapse or second remission were treated with allogeneic marrow transplantation from HLA-matched siblings. In 17 patients (group 1), no attempt at reinduction of remission was made prior to transplantation. In 20 patients (group 2), attempts at inducing a second remission prior to transplantation were unsuccessful; and in 25 patients (group 3), a second remission was achieved. Five of 17 patients (29%) in group 1, 2 of 20 (10%) in group 2, and 5 of 25 (20%) in group 3 are surviving disease-free 2-6 yr after grafting. Early mortality from nonleukemic causes was equal in the 3 groups, but the risk of recurrent leukemia after transplantation was less in patients transplanted without attempts at reinduction (group 1). Among patients transplanted in relapse, those in early relapse (less than 30% blast cells in the marrow) appeared to do better than patients in florid relapse. The results obtained in group 1 are as good as or better than those achieved in patients transplanted in second or subsequent remission. Thus, for patients with acute nonlymphoblastic leukemia not transplanted in first remission, the optimal time for transplantation would appear to be as soon as possible after the first relapse.     

Evaluation of hypercoagulability after remission induction chemotherapy of acute leukemia

Summary In 20 patients with acute leukemia the thrombin-mediated fibrin monomer complexes (SFMC) were determined before and after remission induction chemotherapy for several weeks to assess the extent of hypercoagulability. Increased levels of SFMC were observed in patients with high leukocyte cell counts after induction chemotherapy which may reflect the release of thromboplastic material from destructed leukemic cells. Patients with low leukocyte counts showed only a moderate increase in SFMC. A low concentration of antithrombin III (<20 mg/100 ml) or a drop from a previously normal value was a prognostic unfavorable sign. An elevated level of plasmin-mediated fibrin-split-products could not be related to the course of therapy.     

High plasma urokinase-type plasminogen activator levels are present in patients with acute nonlymphoblastic leukemia.

An exaggerated hemorrhagic syndrome is a characteristic in acute non-lymphoblastic leukemia (ANLL) and it determines the patient's outcome. Disseminated intravascular coagulation as a result of a procoagulant factor release and primary hyperfibrinolysis due to plasminogen activators also released by leukemic cells have been implicated in the development of this syndrome. The aim of this work was to evaluate urokinase-type plasminogen activator (u-PA) and related parameters of the fibrinolytic system in 14 ANLL patients. Our results showed an increased u-PA concentration in ANLL patients compared to controls [2.63 (1.61-4.62) vs. 0.95 (0.77-1.48) ng/ml, p < 0.01]. u-PA levels correlated positively with tissue-type plasminogen activator. The relevance of the enhancement of u-PA in this clinical setting was supported by the fact that it was the only analytical parameter positively correlated with patient mortality (p < 0.05). Though u-PA levels do not seem to be the determining factor in the development of the hemorrhagic syndrome of ANLL patients, a contributory role of this plasminogen activator is suggested from our results.     

Phenotypic and clinical heterogeneity of CD56-positive acute nonlymphoblastic leukemia

Summary The precise phenotype and clinical course are described of a subgroup of acute nonlymphoblastic leukemias (ANLL) expressing the NK-cell differentiation antigen CD56. As previously reported, CD56+ leukemias occurred in a frequency of about 20% of ANLL cases showing clinical and immunophenotypical heterogeneity. Carrying various myelomonocytic markers, all cases were diagnosed to be of nonlymphoid origin. Positive or negative expression of CD34 allowed us to distinguish two major subtypes of CD56+ leukemias representing immature and more differentiated cells carrying further differentiation antigens (CD14 and/or CD15) of the myelomonocytic lineages. These phenotypes correlated with the M0, M2, M4, and M5 leukemias of the FAB classification.     

Clinical significance of low levels of myeloperoxidase positivity in childhood acute nonlymphoblastic leukemia

The clinical significance of a low percentage of myeloperoxidase- positive blast cells in childhood acute nonlymphoblastic leukemia was determined. Of 155 consecutive cases studied by cytochemical staining methods, 14 were characterized by 4% to 15% (median 6%) myeloperoxidase- positive blasts. All 14 cases showed reactivity to Sudan black B stain, and 7 had Auer rods. The morphological subtypes of leukemia were M1 (8 cases), M2 (3), M4 (1), and M5 (2). Immunological marker studies disclosed the lymphoid-associated T11 antigen on cells from 8 of the 11 cases tested. Other lymphoid-related findings in these 8 cases included the T3 antigen and E rosette formation in 1 case each. Among cases that were prospectively studied for the expression of lymphoid-associated markers, 6 of 8 with low levels of myeloperoxidase positivity compared with only 1 of 44 with higher levels (greater than 15%) possessed such features (P less than 0.001). We conclude that low levels of myeloperoxidase reactivity distinguish cases of acute leukemia in which the blast cells coexpress lymphoid (T11 antigen) and myeloid markers.     

Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis.

To evaluate the clinical value of the expression of multidrug resistance P-glycoprotein (P-170) on the surface of acute nonlymphoblastic leukemia (ANLL) cells, we analyzed specimens from 150 newly diagnosed patients for staining with MRK16, a monoclonal antibody (MoAb) that binds to an external epitope of P-170. Other surface markers (CD13, CD14, CD15, and CD34) were studied by the same technique. A marker was considered positive when 20% or more cells were stained. Of 150 samples, 71 were P-170-positive. These cases did not differ from P-170-negative cases with regard to age, sex, initial white blood cell (WBC) counts, or French-American-British (FAB) type (except for M3 ANLL, which were more frequently negative). However, leukemias arising from previous myelodysplastic syndrome (MDS) and therapy-induced leukemias were more frequently P-170-positive. CD34 and P-170 expression were significantly associated. All patients were treated by intensive chemotherapy. Complete remission (CR) rates were significantly lower in P-170-positive (23/71, 32%) than in P-170-negative cases (64/79, 81%) (P less than 10(-5)). CD34 positivity was also associated with a low remission rate (P less than 10(-5)). Survival was shorter for P-170- and CD34-positive patients (P less than 10(-5)). The prognostic value of both markers was confirmed in multivariate analysis. CR duration was also shorter for P-170-positive cases, but the difference is less significant (P = .05). It is concluded that P-170 analysis may be an important tool for predicting the outcome of intensive chemotherapy in ANLL patients.     

Bone marrow transplantation or chemotherapy after remission induction for adults with acute nonlymphoblastic leukemia. A prospective comparison

We compared the outcome of marrow transplantation with that of continued chemotherapy for adults with acute nonlymphoblastic leukemia who achieve a first remission. From May 1977 to July 1982, 111 consecutive adults (ages 17 to 50) with newly diagnosed acute nonlymphoblastic leukemia were treated with induction chemotherapy. Ninety patients (81%) had a complete remission. Forty-four remission patients had available donors: 33 received a transplant and 11 did not. Forty-six patients in remission without matched donors were treated with continued chemotherapy. Kaplan-Meier estimates of 5-year, disease-free survival from complete remission are 49% +/- 18% for the transplant group and 20% +/- 13% for the chemotherapy group. When compared to the chemotherapy group, patients undergoing transplantation had a higher risk of dying during the first 6 months after remission induction but a lower risk of dying thereafter. Within the transplant group, only age influenced survival. Within the chemotherapy group, a leukocyte count of greater than 10 000 mm3 at diagnosis, a French-American-British (FAB) Cooperative Group morphologic status of M-4, M-5, or M-6, and the presence of infection at diagnosis were all associated with shorter survival.     

Marrow transplantation for children in first remission of acute nonlymphoblastic leukemia: an update

Thirty-eight children between the ages of 0.8 and 17 years with acute nonlymphoblastic leukemia in first remission induced by chemotherapy were given cyclophosphamide, total body irradiation, and bone marrow transplants from HLA-matched donors. Six patients died of pneumonia, one died of metabolic problems, and one died of chronic graft-v-host disease complications. Five patients relapsed between six months and 3.2 years after transplantation. Three of the five died of leukemia, one survives with leukemia three years after transplantation, and one survives in remission off treatment following chemotherapy for 22 months. Twenty-five survive in continuous remission from 1.7 to 8.4 years after transplantation, and the actuarial analysis shows a disease- free survival rate of 64%, with a plateau extending from 3.5 to 8.4 years. All lead normal lives.