Purpose: Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification. Experimental Design: We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols. Results: ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, PgpÀITDÀ group), mutually exclusive in 73 of 171 (43%, PgpÀITD+ and Pgp+ITDÀ groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P < 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P < 0.0001),WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITDÀ (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus PgpÀ patients. In the PgpÀITDÀ group (41 of 95), CR rates were 70 % versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P < 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-PgpÀITDÀ group were not significantly different from the favorable cytogenetic group. Conclusion: Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.
Adult ALL still have poor outcome compared with childhood ALL, with an expected OS of less than 40%. Recent retrospective studies have shown that adolescents and young adults (<30 yo) treated with pediatric protocol have a better prognosis than those treated with adult protocols. The aim of this pilot study was to assess the feasibility and efficacy of the French pediatric protocol FRALLE 2000 to treat 28 oldest adult ALL aged from 16 to 57 years. Methods: 28 consecutive adults Philadelphia negative ALL aged from 16 to 57 years, with a median follow-up of alive patients of 35 months, received treatment courses according to FRALLE 2000 from 2001 to 2007. After a prednisone prephase and a four-drugs induction (prednisone, daunorubicin, vincristine and 9 infusions of L-asparaginase), patients in CR received a consolidation course, two delayed intensifications with L-asparaginase separated by an interphase, and a maintenance chemotherapy during two years. Results were compared with the outcome from 20 consecutive patients treated in our institution with the historic EORTC ALL-4 adults protocol from 1998 to 2001. Results: All the clinical (age, WHO performance status, gender) and biological (WBC, phenotype, cytogenetic) parameters of patients treated in FRALLE protocol were statistically similar with those of patients treated in ALL-4 adults protocol. CR rate was achieved in 82% of patients after FRALLE induction, and 100% after a salvage therapy with high doses cytarabine. The good early response was evaluated by cortico-sensitivity and chemo-sensitivity (after 14 days of chemotherapy). All patients who achieved cortico and chemo-sensitivity were alive in persistant CR, with a better survival than other patients (p=0.008) (fig1). When we compared patients treated by FRALLE or ALL-4 protocol, the 4-years DFS and OS are 90% +/−6% vs 47%+/−12%, (p= 0,01) and 83%+/−9% vs 35%+/−16%, (p=0,05) respectively (figures 2 and 3). This better outcome is not explained by significant differences in patients characteristics nor by a better CR rate but rather by a lower relapse rate in the pediatric treatment group. This indicates a major role of the dose intensity, especially for L-asparaginase, corticosteroid, methotrexate, and purinethol. No treatment related mortality and no severe side effect, except one pulmonary embolism, were observed during treatment with supportive cares including parenteral nutrition, granular growth factor, infectious prophylaxis, and antithrombine III infusions. This pilot study shows that adults up to 57 years with Ph negative-ALL have a dramatically better outcome when there are treated with childhood ALL protocol without any major side effect. This therapeutic strategy has to be confirmed by the current prospective study performed by the EORTC/HOVON group. Figure Figure
IGH PCR alone is not good enough for BMTB assessment, especially in FL. On the other hand, the PCR study for BCL2 is more sensitive than morphology, without any false negative results in this series, suggesting that BCL2-MBR PCR on MA can be used as an alternative and more sensitive examination for disease evaluation, providing that there is careful analysis of data, adequate knowledge of PCR pitfalls and absence of other haematological disorders.
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