Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.

The leukemia from which the human cell line HL-60 was derived was classified in 1976 as acute progranulocytic leukemia (APL), although it was recognized to show a number of atypical features. In the ensuing 10 years, the concept of APL and its integral association with t(15;17) has evolved, and the concept of APL as a morphologically recognizable entity has become embodied in the term French-American-British classification M3 (FAB-M3). It is now recognized that not every case of leukemia with a high proportion of progranulocytes can be classified as FAB-M3. We reviewed the light and ultrastructural morphology of the original diagnostic material from this case, and we report that the leukemia from which HL-60 was derived does not conform to the currently recognized entity of FAB-M3 and is more appropriately classified as an acute myeloblastic leukemia with maturation, FAB-M2.

One-hundred and sixty-one of 378 previously untreated patients with acute myelogenous leukemia (AML) failed to enter complete remission with a combination of anthracycline, cytosine arabinoside, vincristine, and prednisone between 1973 and 1979. Thirty-six of the failing patients (22%) were considered chemotherapy failures. As in the past, the remainder failed largely because of death from infection. However, despite the routine use of prophylactic platelet transfusions, hemorrhage was a major cause of death in 33%. Thirty-seven percent of the fatal infections were due to fungi and the incidence of fungal infection was as high during the second week of treatment as later. Age greater than 50 yr predisposed to fatal infection but not chemotherapy failure, while the presence of an antecedent hematologic disorder increased the risk of both fatal fungal infection and resistance to chemotherapy. Patients with an initial white blood cell count of greater than or equal to 25000/microliter were more likely to die of hemorrhage at all times during treatment. Improvement in supportive care remains crucial if improved complete rates are to be forthcoming in previously untreated patients.

We investigated the antiproliferative effect of partially purified human leukocyte interferon (HuIFN-alpha) given in a dose of 9–15 X 10(6) U daily by intramuscular injection to 7 patients with chronic myelogenous leukemia (CML). Hematologic remission of the disease was obtained in 5 patients. Among the responding patients, the mean white blood cell count decreased from 97.4 X 10(3)/cu mm (range from 35 X 10(3)/cu mm to 239 X 10(3)/cu mm) to 4.2 X 10(2)/cu mm (range from 3.0 X 10(3) to 7.9 X 10(3) cu/mm). Parallel reduction occurred in serum B12, from a mean of 1,435 pg/ml to a mean of 726 pg/ml, and lactate dehydrogenase levels, from a mean of 325 mU/ml to 112 mU/ml. Enlarged spleens decreased in 3 of 3 patients. The 5 responding patients have been maintained on HuIFN-alpha, 3 X 10(6) U daily or every other day, for 6+-35+ wk.

Previous studies showed that downregulation of pyrimidine salvage underlies resistance against 5-azacytidine (AZA), indicating an important role for de novo pyrimidine synthesis in AZA resistance. Because de novo pyrimidine synthesis is inhibited by the immunomodulator teriflunomide and its pro-drug leflunomide, we examined the effect of combined treatment with AZA and teriflunomide on AZA resistance to develop a novel strategy to cancel and prevent AZA resistance. Teriflunomide markedly inhibited the growth of AZA-resistant human leukemia cell lines (R-U937 and R-HL-60) in comparison with their AZA-sensitive counterparts (U937 and HL-60). In the presence of a non-toxic concentration of teriflunomide (1 μM), AZA induced apoptosis in AZA-resistant cells and leukemia cells from AZA-resistant patients. AZA acted as a DNA methyltransferase 3A inhibitor in AZA-resistant cells in the presence of 1 μM teriflunomide. Although AZA-sensitive cells acquired AZA resistance after continuous treatment with AZA for 42 days, the growth of AZA-sensitive cells continuously treated with the combination of AZA and teriflunomide was significantly inhibited in the presence of AZA, demonstrating that the combined treatment prevented AZA resistance. These results suggest that combined treatment with AZA and teriflunomide can be a novel strategy to overcome AZA resistance.