RESUMEN
Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.
Asunto(s)
Acenaftenos/farmacología , Acenaftenos/farmacocinética , Apoptosis/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ribonucleótidos/farmacología , Ribonucleótidos/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Pronóstico , Distribución Tisular , Células Tumorales Cultivadas , Adulto JovenRESUMEN
BACKGROUND: After the World Health Organization (WHO) changed the definition of acute myeloid leukemia (AML) to ≥ 20% blasts, the International Working Group (IWG) response criteria for myelodysplasia were updated. This retrospective analysis evaluated response to decitabine using updated IWG criteria in patients pooled from 2 decitabine trials. PATIENTS AND METHODS: Outcomes for patients with myelodysplastic syndrome (MDS) with baseline marrow blasts ≥ 20% and < 30% (RAEB-t group) and < 20% (MDS group) were compared. RESULTS: Patients with RAEB-t (n = 26) had a significantly shorter time from diagnosis to study treatment (7.3 vs. 18.3 months), a higher International Prognostic Scoring System (IPSS) risk (77% vs. 16% high-risk patients), and lower median baseline platelet count (62.3 vs. 112.7 × 10(3)/µL) vs. patients with MDS (n = 157), yet no significant difference in overall response rate (ORR) (15.4% vs. 28.0%). Patients with MDS had better duration of response (9.9 vs. 5 months; P = .024) and overall survival (OS) (16.6 vs. 9.0 months; P = .021) compared with patients with RAEB-t. CONCLUSION: Decitabine is active in and may benefit patients with > 20% blasts (RAEB-t).
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/análogos & derivados , Médula Ósea/patología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Anciano , Anciano de 80 o más Años , Azacitidina/uso terapéutico , Decitabina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Treatment of fludarabine-refractory disease in patients with chronic lymphocytic leukemia (CLL) remains a challenge. Because a recent genome-wide methylation analysis of CLL cells suggested that demethylation therapy might be beneficial in CLL, we conducted a phase II trial with the hypomethylating agent azacitidine in patients with recurrent fludarabine-refractory CLL. PATIENTS AND METHODS: Nine patients with recurrent fludarabine-refractory Rai stage IV CLL (median age, 74 years; range, 49-81 years) were enrolled. Azacitidine (75 mg/m(2)) was administered by subcutaneous injection daily for 7 consecutive days every 3 to 8 weeks, and the data were analyzed at a median follow-up of 9 months (range 3-47 months). RESULTS: The trial was prematurely discontinued because of lack of response and slow accrual. The number of cycles administered ranged from 1 to 6. Three patients received 1 cycle, 3 patients received 2 cycles, and the remaining 3 patients received 4, 5, or 6 cycles. Side effects included grade 2 or 3 infectious episodes (resulting from immunosuppression and drug-induced neutropenia), diarrhea, rash, vomiting, anemia, and thrombocytopenia. One patient experienced reduction of hepatosplenomegaly and a substantial increase in platelet count after 4 cycles of therapy. However this response did not qualify as a partial response according to the National Cancer Institute International Workshop on CLL (NCI-IWCLL) criteria. At a median follow-up of 9 months after the start of azacitidine treatment, 3 patients (33%) who went on to receive other treatments were alive. CONCLUSIONS: Although no partial or complete responses occurred in these heavily pretreated patients, the encouraging response in 1 of these patients may warrant further studies to investigate the effects of azacitidine in CLL.