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MK-0457, an Aurora kinase and BCR-ABL inhibitor, was studied on a Phase I/II study in 77 patients with refractory hematologic malignancies. The average number of cycles per patient was 3 (range 1-21). Maximum tolerated doses for a 5-day short infusion and continuous infusion regimens were 40 mg/m(2)/h and 144 mg/m(2)/h, respectively. Drug-related adverse events (AEs) included transient mucositis and alopecia. Eight of 18 patients with BCR-ABL T315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission. MK-0457 has important activity in patients with leukemias expressing the highly resistant T315I BCR-ABL mutation.

It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) +/- idarubicin are superior to regimens containing idarubicin + ara-C (IA) without either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m(2)/d, given by continuous infusion in IA, and over 2 to 4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95% confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were not randomized, and patients with worse prognoses were disproportionately given the FA and TA regimens. Nonetheless, after accounting for prognosis the FA and TA regimens remained highly significantly associated with lower CR rates, shorter EFS in CR, and shorter survival. Accounting for possible effects of individual trials within each of the IA, FA, and TA groups did not alter these findings. It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments.

Daunorubicin and doxorubicin are anthracyclines that have efficacy against malignancies such as breast cancer, lung cancer, lymphoma, and leukemia. Their adverse effects are similar. The most serious is cardiotoxicity, which often limits the total cumulative dose that can be administered. Introduction of a liposomal formulation for both agents allows tumor selectivity by accumulating the drug in tumor tissue, thus increasing the tolerated dose. Liposomal doxorubicin is commonly associated with palmar-plantar erythrodysesthesia syndrome (PPES), although no reports of PPES were found in the literature related to liposomal daunorubicin (L-DNR). Two patients developed PPES while receiving high-dose L-DNR. The symptoms were self-limiting and resolved within a few weeks.

Background: Interleukin-2 (IL-2) has immunomodulatory effects, including stimulating the activity of cytotoxic T cells and natural killer cells, and inducing the generation of lymphokine-activated killer cells. The authors investigated whether IL-2 may improve the duration of complete remission (CR) and survival in acute myelogenous leukemia (AML) patients in first CR., Methods: Eighteen patients were included after achieving a CR and receiving at least two courses of consolidation chemotherapy. Therapy was comprised of IL-2 4.5 x 10(5) U/m2 daily by continuous infusion (CI) for 12 weeks, plus boluses of 1 x 10(6) U/m2 on Day 8 and weekly thereafter while continuing the CI. No further chemotherapy was given after the administration of IL-2 was started., Results: The median age of the patients was 50 years (range, 18-73 years), and 7 patients (39%) had an antecedent hematologic disorder (AHD). The median CR duration was 12 months, with 6 patients still alive in CR at a median follow-up of 64 months (range, 50-82 months). Long term CR by cytogenetics occurred in 2 of 5 patients with a normal karyotype (CR duration of 68+ months and 72+ months, respectively), 1 of 3 patients with t(8;21) (CR duration of 82+ months), 1 patient with inv(16) (CR duration of 67+ months), none of 2 patients with -5/-7 (1 patient died in CR after 10 months), 1 of 2 patients with abnormalities in chromosome 11 (CR duration of 60+ months), and 1 of 4 patients with miscellaneous abnormalities (CR duration of 74+ months). The median survival was 47 months. To assess the significance of these results, the authors selected two historic controls receiving long term postremission chemotherapy per each IL-2 case. The controls had remained in CR for at least as long as the cases when the latter underwent treatment initiation with IL-2 and were matched for the number of induction courses required to achieve CR, AHD, cytogenetic abnormalities, and age. Six of 18 IL-2 patients (33%) were alive in CR at 3 years compared with 7 of 36 controls (19%) (P = 0.31). Nine IL-2 patients (50%) were alive at 3 years compared with 10 controls (28%) (P = 0.13)., Conclusions: These results suggest that IL-2 is tolerable in AML patients in first CR and should be studied further in future studies as a therapeutic strategy to prolong remission duration.

Trisomy 21 is the second most common trisomy in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). However, its clinical and prognostic significance is not known. We analyzed the records of 1187 consecutive patients with untreated AML or MDS. Thirty-seven (3.3%) had trisomy 21: four (0.3%) as the only cytogenetic abnormality and 33 (2.7%) with other cytogenetic abnormalities (-5 and/or -7 in 15, +8 in nine, t(15;17) in three, inv(16) in three, t(8;21) in one, and hyperdiploid with several other additional chromosomes in two). Twenty-eight patients had AML and nine MDS. No patients had megakaryocytic phenotype (M7), common in patients with constitutional trisomy 21 (Down's syndrome) and AML. Overall, 57% achieved complete remission (CR), with median CR duration of 39 weeks, and median survival of 31 weeks. When patients with additional cytogenetic abnormalities were compared to patients with similar abnormalities but no trisomy 21, their clinical features as well as their CR rate, CR duration and survival were similar, with or without trisomy 21. We conclude that trisomy 21 in AML typically presents in conjunction with other cytogenetic abnormalities, especially -5/-7 and +8 whose presence rather than the presence of +21 dictates the clinical outcome.