Chronic myelogenous leukemia in nonlymphoid blastic phase

Abstract

BACKGROUND The prognoses of patients with chronic myelogenous leukemia in blastic phase (CML‐BP) are extremely poor. Treatment of patients with nonlymphoid CML‐BP is associated with very low response rates, a median survival of 2–3 months, and significant toxicities. The aim of this study was to evaluate the results of therapy in CML‐BP with different treatments in relation to response rate, survival, and toxicity. METHODS A total of 162 adults patients with a diagnosis of nonlymphoid CML‐BP referred from 1986 to 1997 were included in this analysis. Only first salvage therapy was considered for the purpose of this analysis. The blastic phase of CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Ninety patients were treated with intensive chemotherapy, 31 with decitabine, and 41 with other single agents. RESULTS Thirty‐six patients (22%) had an objective response. Response rates were similar among patients treated with intensive chemotherapy (28%) or with decitabine (26%). In aggregate, other single agents showed objective response rates of 7%. The median duration of remission for all patients was 29 weeks and the median overall survival 22 weeks. Patients treated with decitabine showed a trend toward better survival, despite a higher percentage of older patients (P < 0.004). The median survival times were 29 weeks with decitabine, 21 weeks with intensive chemotherapy, and 22 weeks with other agents. When only older patients were considered, survival was significantly better with decitabine versus other treatments (P < 0.01). A multivariate analysis of prognostic factors for survival confirmed the independent, significant favorable effect of decitabine therapy (P = 0.047). In all groups complications of myelosuppression were the most significant side effects. Severe nonhematologic toxicities were not observed in patients treated with decitabine; they occurred in 20% and 17% of patients treated with intensive chemotherapy or other single agents, respectively. CONCLUSIONS Compared with intensive chemotherapy, decitabine showed favorable results, with similar objective response rates, a better nonhematologic toxicity profile, and a trend for better survival, particularly among older patients. Studies will now attempt to combine decitabine with other promising approaches, such as homoharringtonine, low dose cytarabine, and interferon‐α, in all CML phases. Cancer 1999;86:2632–41. © 1999 American Cancer Society.

5-Aza-2′-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation

“…Although there is insufficient data to show a relationship between p53 status and efficacy of 5-aza-CdR in patients, several studies suggest that p53 status may be a key predictive factor for the efficacy of 5-aza-CdR treatments (10, 24, 56). For example, 5-aza-CdR appears to be very effective in the treatment of adult human chronic myelogenous leukemias, which generally have wildtype p53 (56,57) but is less demonstrably effective in the treatment of solid tumors, such as human lung cancers, which typically have mutant p53 (24,58). Our data suggest that the future clinical development of 5-aza-CdR may depend on genetic factors such as the p53 status of the treated tumor.…”

Reactivating the expression of methylation silenced genes in human cancer

“…Our results raise the possibility that p53 activation may affect both the efficacy and toxicity of 5-aza-CdR treatments in vivo. Consistent with this hypothesis are observations that 5-aza-CdR treatment has, up until now, shown the greatest benefit for chronic myelogenous leukemia, a malignancy in which functional p53 is retained (Peller et al, 1998;Sacchi et al, 1999;Wang et al, 1998).…”

“…Additionally, 5-aza-CdR itself may act as a mutagen as the result of interactions between 5-aza-cytosine and DNMT1 (Jackson-Grusby et al, 1997). Despite these concerns, 5-aza-CdR treatment appears to be well tolerated in both mice and humans (Laird et al, 1995;Sacchi et al, 1999;Thibault et al, 1998). As mentioned earlier, part of this tolerance may be accounted for by physiological feedback systems that serve to quickly re-methylate DNA following 5-aza-CdR treatment.…”

Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

“…The rate of response to standard induction chemotherapy in patients with myeloid blast crisis is approximately 20%, and the rate of complete remission is less than 10%. In patients with lymphoid blast crisis, the rate of response is approximately 50%, but remissions are short-lived (Sacchi et al, 1999;Talpaz et al, 1987). AlloBMT during blast crisis induces fiveyear survival in only 6% of patients (Clift and Storb, 1996;Gratwohl and Hermans, 1996).…”