Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy ...(CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10
/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission ...induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.
The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.
At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.
HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of ...patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.
Rhodococcus equi is an uncommon Gram positive, variably acid-fast pathogen, that appears as hard to treat mostly owing to the establishment of intracellular niches. Lack of interpretive criteria for ...susceptibility testing may lead to under-reporting or overestimation of resistances, whereas knowledge about this pathogen's clinical impact may be affected by erroneous phenotype-based characterization at a genus and species level.We present the case of a bacteraemia with a concomitant lung mass in a lymphoma patient, that further highlights the emergence of rhodococcal diseases as a matter for concern in the fields of infectious diseases and haematology.
*The 2 first authors contributed equally to the work.
Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients has remained controversial (Cornelissen JJ ...&Blaise D, Blood 2016, 127, 62-70) and there is paucity of studies comparing intensive chemotherapy to autologous (auto) or allogeneic (allo) bone marrow transplantation (BMT).
Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the pivotal EORTC/GIMEMA AML-8A (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223).
Methods. The EORTC/GIMEMA AML-8A prospectively assessed the impact of 3 post-remission treatments on disease-free survival (DFS) and overall survival (OS) in younger (<60 years of age) AML patients who reached a complete remission (CR) after induction with cytarabine and daunorubicin. All patients received a consolidation chemotherapy course (ICT1) including intermediate-dose cytarabine and amsacrine. Patients who had an HLA-identical sibling donor were then allocated to allo-BMT while remaining patients, at the start of ICT1, were randomized to receive auto-BMT or a second course of intensive chemotherapy consisting of high-dose cytarabine and daunorubicin (ICT2 group) after recovery of ICT1. At the time of the publication of the results (Zittoun et al., New England Journal of Medicine 1995, 332, 217-223), the median follow-up from inclusion was 3.3 years.
Results. In the current report, median follow-up was 11.1 (range, 0-28) years. For the whole population (n=422), the 5-, 10 and 15-year OS rates from inclusion were 35%, 32% and 31%, respectively. After the completion of ICT1, 168 patients were allocated to theallo-BMT arm, while 254 patients were randomized to auto-BMT (n=128) or ICT2 (n=126). DFS from CR was longer afterallo-BMT than auto-BMT and DFS from CR was longer after auto-BMT than ICT2, due to a lower relapse incidence (P<0.001). Details are provided in table 1. Patients randomized to the auto-BMT arm had still a longer DFS from CR than patients in the ICT2 group (P=0.11) due to a lower incidence of relapse (P=0.047). Regarding OS, the differences between the 3 groups was no longer significant. In the ICT2, the improved outcome regarding OS as compared to DFS was due to a higher proportion of ICT2 patients who received a salvage auto-BMT.
Conclusions. This long-term follow-up of the EORTC/GIMEMA AML-8A study confirms a better DFS with allo-BMT or auto-BMT when compared to ICT2 for AML patients in first CR. Further, this long-term follow-up study revealed that the vast majority of patients alive in first CR at 5-year remains disease-free survivors 5 years later. Although indications of allogeneic hematopoietic stem cell transplantation (allo-HCT) are nowadays largely driven by cytogenetic/molecular AML profile, long-term results of AML8A study demonstrate that auto-BMT remained superior to ICT2 in younger AML patients not candidate for an allo-HSCT.
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Efficace:TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; Lundbeck: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau.
Summary
This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML ...patients were randomized to receive DNR (45 mg/m2 days 1–3) or DNX (80 mg/m2 days 1–3) plus cytarabine (AraC; 100 mg/m2 days 1–7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51·0%) achieved CR, 55 (35·9%) were resistant and 20 (13·1%) died during induction. Among 148 patients in the DNX arm, 73 (49·3%) achieved CR, 47 (31·8%) were resistant and 28 (18·9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12·5% vs. 2·6% at 6 months, P = 0·053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0·064), with a cross in overall survival (OS) and disease‐free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long‐term follow‐up, because of a reduction in late relapses.
Summary
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 ...>60 years, 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 17·5 months 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.
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Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line ...management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013.
Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10x109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally developed by the MD Anderson Cancer Center group, or the Italian AIDA2000 protocol (Estey et al., Blood 2006 and Lo-Coco et al., Blood 2010). Patients in the ATRA-ATO arm received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in the ATRA-CHT arm received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based consolidation together with ATRA and low dose CHT and ATRA for maintenance. The primary study objective was EFS at 2 years.
Results: A total of 254 patients were evaluable for response to induction. CR was achieved in 122/122 (100%) in the ATRA-ATO versus 128/132 (97%) in the ATRA-CHT arm (P=0.12). Four patients died during induction in the ATRA-CHT arm. After a median follow-up of 36 months (range 1-75 months), the 2-year EFS was 98% and 84.9% in the ATRA-ATO and ATRA-CHT groups respectively (P= 0.0002), The 2-year cumulative incidence of relapse (CIR) rate was 1.1% and 9.4%, respectively (P=0.005) and, finally, the 2-year overall survival (OS) rate was 99.1% vs. 94.4% (P=0.01) for ATRA-ATO vs ATRA-CHT, respectively.
Conclusions: The data on this extended cohort demonstrate a significantly augmented survival benefit coupled to a higher antileukemic efficacy provided by ATRA-ATO as compared to ATRA-CHT, in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting.
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Platzbecker:Teva: Honoraria. Off Label Use: Presentation includes off-label use of arsenic trioxide (ATO) in front-line management of APL. ATO is currently approved in treatment of relapsed APL in the US and Europe. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Lübbert:Cephalon / TEVA: Travel support Other. Link:TEVA: Consultancy, Speakers Bureau. Radsak:Celgene: Research Funding. Döhner:TEVA: Research Funding. Schlenk:TEVA: Research Funding, Speakers Bureau. Lo-Coco:TEVA: Honoraria; Lundbeck: Honoraria.
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