Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes.

PURPOSE: A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. PATIENTS AND METHODS: HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. RESULTS: Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, -9.3; 95% CI, -17.8 to -0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. CONCLUSION: Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL.

Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.

BACKGROUND: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. METHODS: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%. RESULTS: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity. CONCLUSIONS: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors.

To reduce toxicity in elderly patients with acute promyelocytic leukaemia, in 1997 the Gruppo Italiano Malattie Ematologiche Dell'Adulto (GIMEMA) started an amended protocol for patients aged >60years, with the same induction [all-trans retinoic acid (ATRA)+idarubicin] as in younger patients, followed by a single consolidation course (idarubicin+ cytarabine) and maintenance with intermittent ATRA. Among 60 enrolled patients, 54 (90%) achieved haematological remission and six died during induction. Four additional patients died in complete remission (CR) from haemorrhage (2) and infection (2) prior or during consolidation therapy. Eleven patients relapsed at a median time of 17·5months from CR. The 5-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) rates were 76·1%, 64·6% and 27·4%, respectively. Univariate analysis identified a performance score (PS)=2 as the only significant adverse prognostic factor for both OS (P=0·017) and DFS (P=0·0003). Male sex had an unfavourable impact on DFS (P=0·021) and on CIR (P=0·019), but not on OS (P=0·234). In multivariate analysis for DFS, only PS=2 retained prognostic significance (HR=4·5, P=0·0083). In conclusion, the amended GIMEMA protocol is effective, with similar relapse rate and inferior toxicity compared to the original AIDA 0493. However, considering the recent availability of effective new agents, a less aggressive approach should be tested in this setting.

AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance.

All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction-negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction-negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

A common 93-kb duplicated DNA sequence at 1q21.2 in acute lymphoblastic leukemia and Burkitt lymphoma.

In three patients with acute lymphoblastic leukemia (ALL) and in another with Burkitt lymphoma (BL), conventional cytogenetics and fluorescence in situ hybridization (FISH), applied singly or in combination, showed 1q duplication in two cases of ALL with hyperdiploid karyotypes, 1q duplication resulting from an unbalanced translocation in a third case of ALL, and inv dup(1)(q) in a patient with BL. Centromeric or telomeric breakpoints and extension of the 1q duplicons varied in each case. FISH defined a minimal, common duplicated region of 93kb at band 1q21.2 corresponding to clone RP11-212K13. In this region three putative oncogenes or tumor suppressor genes have been mapped: SF3B4 (splicing factor 3b, subunit 4), OTUD7B (OTU domain containing 7B), and MTMR11 (myotubularin related protein 11). For the first time, a minimal common 1q21.2 duplicated sequence has been identified in lymphoid malignancies in a region where putative oncogenes or suppressor genes have been mapped. This finding elucidates the genomic background of ALL and BL with 1q duplication and provides the basis for molecular studies investigating which genes are involved in leukemogenesis or disease progression in these cases.

Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol.

Between 1996 and 2000, 90 newly diagnosed adult patients with T-acute lymphoblastic leukemia (T-ALL) were registered in the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acuta Limfoide (LAL) 0496 protocol. Cases were centrally processed for morphology, immunophenotype, cytogenetics, molecular biology, and multidrug resistance (MDR). Twenty-two patients were females and 68 were males. Four percent of cases were pro-T, 47% pre-T, 39% cortical T, and 10% mature T-ALL. Fifty-six percent of patients with pro-T + pre-T-ALL achieved complete remission (CR) compared with 91% for cortical + mature cases (P = .002). CD34 expression was associated with a significantly lower CR rate: 54% versus 84% (P = .009). Thirty-one (36.5%) of 85 patients had an abnormal karyotype, the most common abnormality (15%) being a partial del(6q). The cytogenetic profile did not impact on CR achievement. MDR1 function, present in 26% of cases, correlated significantly with CR achievement (P = .004). A highly significant (P = .001) difference in CR rate was observed between patients who did not express the CD13/CD33/CD34 antigens and were MDR functionally negative (96%) compared with patients positive for at least one of these markers (57%). Multivariate analysis showed an impact on CR achievement for CD33 expression and MDR1 function. An extensive biologic workup of adult T-ALL cases at presentation is recommended in order to design tailored therapeutic strategies aimed at improving CR rates.

A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol.

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.