2nd Randomization Research Articles

ALL-REZ BFM 2002 Is Associated with Improved Outcome as Compared to ALL-R3 Strategy in Children with Standard Risk Isolated CNS Relapse of Acute Lymphoblastic Leukemia, while Maintaining Comparable Efficacy in Patients with Bone Marrow Relapse. Results of the Multi-National, Multi-Center Trial IntReALL SR 2010

Background: Around 15% of children with acute lymphoblastic leukemia (ALL) experience disease relapse. The prognosis of these patients largely depends on the site of recurrence, time to relapse and leukemia immunophenotype. The ALL-REZ BFM 2002 and the ALL R3 trials have proved to be effective in previous trials. The IntReALL SR 2010 trial, conducted under the umbrella of the I-BFM SG, aimed at investigating feasibility, toxicity and efficacy of both treatment strategies in a large multi-national, multi-center prospective randomized trial. Methods: Patients with a first standard-risk (SR) ALL relapse aged 1 - 17 years were recruited to the trial from 23/Oct/2014 to 31/Jul/2020 in 17 countries (210 centers). SR relapse criteria were: late (≥ 6 months after end of initial therapy) isolated bone marrow (BM) relapse, late or early (< 6 months after end of initial therapy and ≥ 18 months after initial diagnosis) combined BCP-ALL BM relapse, any late/early isolated extramedullary (IEM) relapse. They were randomized at a 1:1 rate to receive either arm A (ALL-REZ BFM 2002) or B (ALL R3). During consolidation, patients were randomized to receive the CD22-directed monoclonal antibody epratuzumab in addition to backbone chemotherapy. Results of this 2nd randomization will be communicated separately. Patients with late BM relapse were allocated to consolidation and maintenance chemotherapy or to allogeneic hematopoietic stem-cell transplantation (HSCT), depending on their minimal residual disease (MRD, cut-off arm A 10e-3 and arm B 10e-4) assessed after induction therapy. Patients with early either combined BM or IEM relapse were allocated to receive allogeneic HSCT. Results: Overall, 620 patients were randomized to receive arm A (n=304) or Arm B (n=316). Patient's characteristics were equally distributed among both groups (table 1). Induction death, 2nd remission rate, death in remission (5-years cumulative incidence (CI) 4.1 vs 7.4%, p=0.10), and subsequent relapse rates by arm A and B (CI 23.8 vs 22.8, p=0.80) did not differ between both groups. The MRD response rate with < 10e-4 post induction was significantly higher in Arm B (p=0.015), but not significantly different based on the arm specific cut-off, leading to comparable rates of allogeneic HSCT. The probability of 5-years event-free survival (pEFS) with arm A versus arm B was 70.2±3.1 SE versus 68.5±3.1 (p=0.61, figure 1) and that of overall survival (pOS) was 86.7±2.3 versus 87.1±2.0 (p=0.8). Subgroup analyses revealed a significantly higher pEFS in patients with isolated CNS relapse when treated with arm A (81.6±6.3, n=40) compared to arm B (43.3±8.3, n=45, p=0.001), whereas in patients with BM involvement or those with non-CNS IEM relapse, no significant difference was found (p=0.41). However, patients with isolated BM relapse experienced a higher CI of subsequent relapse with arm A (12.5±2.1, n=146) as compared to arm B (6.5±1.6, n=153, p=0.008). Patients with late BM relapse and MRD poor response after induction had comparable pDFS (arm A 65.8±6.4, n=74; arm B 68.8±6.2, n=75; p=0.71), which also did not differ from that of patients with MRD good response (arm A 67.7±5.6, n=100; arm B 68.9±5.6, n=113; p=0.77). Patients with late IEM relapse achieved a pEFS of 86.7±4.6 whereas those with early relapse and HSCT indication achieved a pEFS 61.8±5.4 (p=0.0004). Rates of reported severe adverse events (SAEs) per treatment phase did not differ between arms except nervous system disorders occurring more frequently in arm A (p=0.03, table 1). Conclusion: Both arm A and B were effective in this large multi-national trial. EFS and OS probabilities compare favorably to results recently published by other cooperative groups. In particular, the outcome of patients with early IEM relapse or with late BM relapse and MRD poor response is encouraging confirming the benefit of allo HSCT in these subgroups. Due to superior outcome of isolated CNS relapse with arm A, patients without BM involvement will receive that arm as backbone in future trials. Since arm B showed a better MRD response rate after induction and a lower relapse rate in patients with BM relapse, it will be implemented as backbone for future trials in patients with BM involvement. Toxicity (TRM and SAE rates) is substantial in both arms demonstrating the urgent medical need of replacing toxic chemotherapy elements with equally effective, but less toxic targeted immunotherapy strategies in future trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Neutrophil count and efficacy of chemoradiation in patients with locally advanced unresectable pancreatic carcinoma: An ancillary study of in the LAP 07 trial.

4120 Background: Predictive biomarkers of Overall Survival (OS) and Progression Free Survival (PFS) in locally advanced pancreatic cancer (LAPC) pts are mandatory. Baseline leukocyte, neutrophil and monocyte counts in addition to lymphocyte ratio (NLR) may predict OS in LAPC pts. Efficacy of chemoradiation (CRT) depending on neutrophil count was retrospectively analyzed in the largest Phase III cohort of LAPC. Methods: The international multicenter randomized LAP07 phase III trial (NCT00634725) has recruited 442 LAPC pts. We have studied the predictive and prognostic value of systemic inflammation, as defined: (i) baseline neutrophilia (neutrophil count &gt; 7 G/L at first randomization) or (ii)increased absolute neutrophil count (IANC) after induction chemotherapy vs baseline. Univariate and multivariate Cox analysis evaluated the benefit of CRT for OS, PFS and Local Control (LC) in pts without systemic inflammation. Results: Patients with baseline neutrophilia (11%) had a worse OS (median 8.9 vs 13.3 months, p = 0.01). At 2nd randomization, 9% and 29% pts had baseline neutrophilia or IANC, respectively. Both neutrophilia (median OS 10.6 vs 16.1 months, p = 0.03) and IANC (median OS 14.6 vs 17.4 months, p = 0.02) predicted poor OS. Systemic inflammation predicted local resistance to CRT (p = 0.02, interaction = 0.015). After excluding pts with systemic inflammation, 1-year local control was 80% in CRT vs 54% in chemotherapy arms (p &lt; 0.001). Pts without systemic inflammation in CRT arm had improved PFS vs chemotherapy arm (median 10.3 vs 8.3 months, p = 0.04). In multivariate analysis in this population, CRT increased PFS (HR = 0.66, 95%CI: 0.45 - 0.97, p = 0.03), after adjusting on age, tumor size, pain at enrollment, albumin, and CA 19.9 according to PROLAP nomogram parameters. Conclusions: In LAPC pts with tumor controlled after induction chemotherapy, systemic inflammation may help to better predict those who will benefit from CRT. This result may impact clinical management and the design of future clinical trials for LAPC. An external validation with a cohort from the ARCAD pancreas meta-analysis is under consideration. Clinical trial information: NCT00634725.

Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial

Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial

A randomized clinical trial comparing adjuvant radiation versus chemo-RT versus chemotherapy alone after radical cystectomy for locally advanced bladder cancer.

356 Background: There is growing interest in using adjuvant radiation therapy (RT) to reduce local failures (LF) after radical cystectomy (RC) for locally advanced bladder cancer. A previous RCT demonstrated significantly improved LF &amp; OS with adjuvant RT vs. RC alone. An RCT was performed to compare the efficacy of adjuvant RT vs chemo-RT vs chemo alone after RC. The primary endpoint was disease-free survival (DFS). Secondary endpoints were OS, LRFS, DMFS and toxicity. Methods: Patients ≤ 70 yrs with ECOG PS ≤ 2 with locally advanced bladder cancer and ≥ 1 high-risk feature who underwent RC with negative margins at the Egyptian National Cancer Institute from 2002 – 2008 were enrolled. High risk features included stage ≥ pT3b, grade 3, or positive nodes. Patients were randomized following RC to RT (45 Gy in 1.5 Gy/fx given BID with 3D-conformal RT), chemo-RT with 2 cycles of gemcitabine/cisplatin before and after RT, or 4 cycles of chemo alone. The chemo alone arm was added as a 2nd randomization in 2007. Patients were followed regularly with CT scans q 6 months in the first 2 years &amp; then yearly. Results: 198 patients were enrolled. 78 received RT, 75 chemo-RT and 45 received chemo alone. Median age was 54 (range 27 – 70) and the M:F ratio was 4:1. 53% had urothelial carcinoma, 41% had SCC and 6% other. Median follow-up was 19 mo (range 1 – 127 mo). The RT, chemo-RT and chemo alone arms had similar characteristics except for age (median 55, 52 and 55, respectively, p = 0.03) and tumor size (p = 0.02). There was no significant difference in DFS, DMFS or OS, although there was a trend toward improved DFS favoring the RT-containing arms with 3 yr rates of 63%, 68% and 56% in the RT, chemo-RT and chemo arms (p = 0.25). LRFS was significantly improved for the RT arms vs. chemo alone, with 3 yr rates of 87%, 96% and 69% (p &lt; 0.01), regardless of histology. Treatment was reasonably well-tolerated with late grade ≥ 3 GI toxicity of 8%, 7% &amp; 2%, respectively. Conclusions: This is the first RCT comparing adjuvant RT (+/- chemo) vs. adjuvant chemo following cystectomy for bladder cancer. RT was associated with significantly improved local control compared to chemo alone. There was no significant difference in DFS, DMFS, or OS. Clinical trial information: NCT01734798.

Ofatumumab (OFA) Vs. Physician’s Choice (PC) of Therapy in Patients (pts) with Bulky Fludarabine Refractory (BFR) Chronic Lymphocytic Leukaemia (CLL): Results of the Phase III Study OMB114242

OFA was approved for the treatment of fludarabine and alemtuzumab refractory CLL on the basis of a single-arm study which also included pts with BFR CLL. This open label, randomized, Phase III study of OFA or PC treatment in pts with CLL refractory to fludarabine and with bulky lymphadenopathy (at least one lymph node > 5 cm) was conducted to confirm the results of OFA in BFR pts and also through a 2nd randomization to compare extended OFA (12 months) vs. approved regimen of OFA (6 months). PC was considered an appropriate comparator for these pts given the lack of a consensus around standard of care treatment for this difficult-to-treat population.Pts were randomized 2:1 to receive either the approved regimen of 8 weekly infusions of OFA followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2000 mg) or PC of non-OFA containing therapy, including treatments approved for CLL and well established standards of care for up to 6 months. Pts in the OFA arm who had an investigator-assessed CR, PR or SD underwent a 2nd 2:1 randomization to 6 additional OFA infusions 2000 mg every 4 weeks (OFA Ext), or observation (Obs). Pts in the PC arm who developed disease progression during the study could receive OFA salvage therapy for up to 12 months of treatment. Premedication for OFA infusions consisted of glucocorticoid, paracetamol, and antihistamine.The primary objective of this study was to evaluate progression-free survival (PFS) with OFA treatment versus PC as assessed by an Independent Review Committee (IRC). Response assessments were performed using the 2008 Update of the NCI-WG CLL Guidelines [Hallek, 2008]. Secondary endpoints included overall response rate (ORR), time to next therapy (TNT), overall survival (OS), and safety.122 pts were randomized (79 OFA, 43 PC). Pts completed a median of 12 OFA infusions and 3 months PC therapy. The median PFS (mPFS) as measured by IRC was 5.4 months for OFA and 3.6 months for PC (hazard ratio [HR] 0.79, p=0.27, stratified log rank test; Fig 1). Median PFS as assessed by the investigator (INV) was 7.0 months for OFA and 4.5 months for PC (HR 0.56, p=0.003). The median time to start of next anti-CLL treatment was 11.5 months for OFA and 6.5 months for PC (p=0.0004, stratified log rank test). The ORR (95% CI) by IRC evaluation was 38% (27%, 50%) for OFA and 16% (7%, 31%) for PC (p=0.02). 37 pts underwent a 2nd randomization to either OFA Ext (n=24) or Obs (n=13). From 2nd randomization, mPFS (INV) was 5.6 months for OFA Ext and 3.5 months for Obs (HR: 0.49, p=0.026, stratified log rank test) (Fig 2). Grade ³3 infusion reactions occurred in 5% of pts in the OFA arm with no fatal reactions in either arm. Grade ≥3 cytopenias in the OFA arm included neutropenia (24%, no prolonged neutropenia and 1 patient with late onset neutropenia), thrombocytopenia (8%), anemia (8%). Of the 43 PC pts, 22 received OFA Salvage with an ORR of 50% and mPFS of 5.4 months.Table of Response and Time to event EndpointsOFA (N=79)PC (N=43)CharacteristicsMedian (range)Age, years61.5 (46 – 82)63 (40 – 76)No. prior therapies4 (2 – 16)3 (2 – 11)No. of infusions12 (1 – 18)3 (1 – 6)IRCInvestigatorEfficacy endpointsOFAPCp-valueOFAPCp-valueResponders, %38%16%0.01949%37%0.415mPFS, months5.363.610.26774.50.003OFAPCTNT, months11.56.5p=0.0004OS, months19.214.5p=0.13 [Display omitted] [Display omitted] Conclusions: Although the study did not meet its primary endpoint of demonstrating statistically significant superior PFS by IRC, the ORR, PFS by investigator, TNT, and OS favor OFA and were consistent with previously reported results in BFR pts. There was also a longer PFS in pts who underwent the 2nd randomization to receive OFA Ext vs. the approved OFA treatment regimen of 6 months treatment. DisclosuresÖsterborg:GSK: Research Funding. Off Label Use: Discussion of extended ofatumumab dosing (12 months) in addition to the approved 6 month dosing of ofatumumab in refractory CLL. Zaritskey:Novartis: Consultancy, Honoraria. Kaplan:GSK: Honoraria. Steurer:GSK: Consultancy, Honoraria, Research Funding. Schuh:GSK: Honoraria; Roche: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Napp: Honoraria. Montillo:GSK: Honoraria. Kulyaba:GSK: Honoraria. Gorczyca:GSK: Employment. Daly:GSK: Employment. Chai-Ni:GSK: Employment. Lisby:Genmab: Employment. Gupta:GSK: Employment.

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML): Final Report of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups on the Value of Low Dose IL-2 Maintenance,

Abstract 3612The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) combined with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm/d for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU/d s.c. for 5 days per month) during one year. A total of 577 pts were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done in eligible pts. From 9/1999 till 1/2008, 2005 pts were randomized (891 by EORTC-LG and 1114 by GIMEMA). In addition 104 pts (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. Due to insufficient reporting, 3 centers, who recruited 63 pts, have been excluded from the analysis. After 1 or 2 courses of induction, CR was achieved in 1500 pts. Between 4/2000 and 5/2008 544 pts have been randomized for the IL-2 question, of whom 528 (222 EORTC, 306 GIMEMA) met the eligibility criteria and were included in the analysis: 263 in IL-2, 265 in Observation (Obs) arm; the remaining pts have not been randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The two groups were well balanced with respect to the above mentioned stratification factors. Due to prolonged pancytopenia after auto-SCT, severe organ damage or infection after auto-SCT, early relapse or patient refusal, 165 pts actually received IL-2 and 197 pts were adequately documented in the Obs arm. During the first 4 months 82% of the pts in the IL-2 arm received a mean daily dose of 6 × 106 IU and 62% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (22%) or toxicity (16%). During the second 4 months, out of 103 pts 82% in the IL-2 arm received a mean daily dose of 6 × 106 IU and 76% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (15%), toxicity/refusal (6%) or other reasons (2%). During the third 4 months, among 79 of the pts in the IL-2 arm 80% received a mean daily dose of 6 × 106 IU and 85% of the pts received the maximally required 20 s.c. injections. Grade 3–4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (3% vs 0%), fatigue (7.9% vs 1%), rigor/chills (6.1% vs 0%), arthralgia/myalgia (3.6% vs 0%).For the total of 528 pts, the median follow-up from the 2nd randomization was 6 years. As of July 2011, a total of 308 events were reported: 150 (IL-2 arm) vs 158 (Obs arm); among them 277 relapses (137 vs 140) and 31 deaths without relapses (13 vs 18). The DFS from 2nd randomization was similar in the 2 groups: the 5-yr DFS rate was 44.2% (IL-2) vs 40.4% (Obs), hazard ratio (HR)=0.95, 95% CI (0.76,1.19), p=0.66. A total of 259 pts died: 128 (IL-2 arm) vs 131 (Obs. arm). The 5-yr overall survival rate was 52.2% (IL-2) vs 50.9% (Obs), HR=0.98, 95% CI (0.77,1.26), p=0.9. The initial remission induction treatment (received/randomized) did not have impact on the results after the 2nd randomization. Conclusion:This study shows that, with a median follow-up of 6 years, low dose IL-2 maintenance does not lead to a prolonged DFS and overall survival in pts with AML in first complete remission treated in the EORTC-GIMEMA AML12 trial. Disclosures:Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML): Final Report of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups on the Value of High Dose AraC

Abstract 257The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age (<46 vs > 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died. Results:After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC>SD-AraC. CR rates for pts<46 yrs were 74.7% (SD-AraC) and 81.4% (HD-AraC) and for pts>45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts<46 yrs 284 pts had an HLA identical sibling (<46D) and 481 did not or had not been typed (<46NoD). Among 665 CR-pts>45 yrs 225 pts had an HLA identical sibling (>45D) and 440 did not or had not been typed (>45NoD). In the <46D group 211 underwent an allo-SCT and 11 an auto-SCT. In the <46NoD group 274 underwent an auto-SCT and 29 a MUD-SCT; in the >45D group 147 underwent an allo-SCT and 14 an auto-SCT. In the >45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table.EndpointAll patientsAge < 46Age >45SD-Ara-CHD-Ara-CSD-Ara-CHD-Ara-CSD-Ara-CHD-Ara-COS: 6-yr rate38.7%42.5%43.4%51.9%33.9%32.9%OS: HR (CI)*0.89 (0.79–1.00)0.79 (0.63–1.00)0.99 (0.81–1.22)OS: p-value**0.060.0090.91DFS: 6-yr rate41.5%44.7%46.4%52.8%35.7%35.6%DFS: HR (CI)*0.92 (0.80–1.06)0.83 (0.64–1.08)1.02 (0.80–1.32)DFS: p-value**0.250.070.80S from CR: 6-yr rate50.2%51.8%55.2%60.7%44.4%41.7%S from CR: HR (CI)*0.95 (0.81–1.10)0.85 (0.63–1.14)1.05 (0.80–1.37)S from CR: p-value**0.480.150.66*: CI = confidence interval; 95% CI – all patients – and 99% CI – by age -;**logrank testThe impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts >45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%). Conclusion:The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years. Disclosures:Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Study AML-BFM 2004: Improved Survival In Childhood Acute Myeloid Leukemia without Increased Toxicity

AbstractAbstract 181Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML TherapyStudy AML-BFM 2004 was designed to improve outcome of children and adolescents with AML without increasing toxicity. Patients were stratified into a standard- (SR)* or high-risk (HR)** group according to morphology, cyto-/molecular genetics including FLT3-ITD, and therapy response on day 15. Notably, reclassification of SR patients to the HR group in case of FLT3-ITD positivity was newly established in this study. Improvement of prognosis was attempted by intensification of chemotherapy: (1) Randomized introduction of liposomal daunorubicin (L-DNR) in a higher equivalent dose than idarubicin during induction in both risk groups (L-DNR 80mg/m2/day/3x) in comparison to standard induction using idarubicin 12mg/m2/day/3x, each combined with cytarabine and etoposide (L-DNR may offer an increased therapeutic window due to lower cardiotoxicity) and (2) randomised introduction of 2-chloro-2-deoxyadenosine (2-CDA, 2×6mg/m2) as intensification during the cytarabine/idarubicin (AI) consolidation in HR patients only.Overall results improved compared to the previous study AML-BFM 98: Survival estimates at 5 year (pOS) in patients (excluding Myeloid leukemia in Down syndrome) were 72% + 3% vs. 64% + 2% (AML-BFM 04 n=566 vs. AML-BFM 98 n=472), plogrank=0.02; the 5-year event-free survival (pEFS): was 54% + 3% vs. 50% + 2%, plogrank=.40. Results in the 197 SR patients were excellent: pOS 88% + 3% vs. 78% + 3% (n=182), plogrank=.01, EFS 69%, + 4% vs. 64% + 4%, plogrank=.40. Results in the 368 HR patients also improved: pOS 63% + 4% vs. 56% + 3% (n=290), plogrank=.07, EFS 46%, + 3% vs. 41% + 3%, plogrank=.43. OS improvement was partly due to better results after treatment of relapse or nonresponse (3-year pOS after nonresponse/relapse in 171 patients of study 2004 40% + 5% vs. 32% + 4% in 198 patients in AML-BFM 98, plogrank=.017).Results for the 1st randomization L-DNR vs. idarubicin during induction were similar (pOS 78% + 4% vs. 70% + 4%, plogrank=.15, pEFS 60% + 4% vs. 54% + 4%, plogrank=.17). There were less early deaths (4 vs. 8 patients) and less treatment related deaths in remission in the L-DNR group (2 vs. 5 patients). The rate of severe infection was slightly lower with L-DNR (pFisher 0.15). Two L-DNR vs. 6 idarubicin patients showed grade III/IV cardiotoxicity after induction. Results of the 2nd randomization in HR patients (AI/2-CDA vs. AI) were also similar: p=OS 75% + 5% vs. 65% + 5%, plogrank=.18, pEFS 51% + 5% vs. 51% + 5%, plogrank=.98. Toxicity rates of the intensification with 2-CDA were tolerable.In conclusion, compared to the previous study AML-BFM 98, results of study AML-BFM 2004 show significant improvement in both risk groups. This appears attributable to a combination of factors including therapy intensification, better supportive care and improved treatment of patients with relapse or nonresponse. Given the reduced toxicity of L-DNR and a trend towards better survival rates by adding L-DNR during induction and 2-CDA during HR consolidation, these agents will be further used in the forthcoming AML-BFM study.*Standard risk group definition: FAB M1/M2 with Auer rods, FAB M4eo or favorable cytogenetics [t(8;21) or inv(16)] and blasts in the bone marrow on day 15 <5%, and FAB M3 (all patients)**High-risk group definition: all others. Disclosures:Off Label Use: liposomal daunorubicin is used, which is off label for pediatric AML. It was used because it offers a possibility to increase cumulative dosages of anthracyclines with lower cardiotoxicity.

Value of Low Dose IL-2 as Maintenance Following Consolidation Treatment or Autologous Transplantation in Acute Myelogenous Leukemia (AML) Patients Aged 15-60 Years Who Reached CR After High Dose (HD-AraC) Vs Standard Dose (SD-AraC) Cytosine Arabinoside During Induction: Results of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups.

Abstract 791The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, were randomized (891 by EORTC-LG and 1114 by GIMEMA) and 104 (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. After 1 or 2 courses of induction, CR was achieved in 1377 patients. Between 4/2000 and 5/2008 550 (230 EORTC, 320 GIMEMA) were randomized for the IL-2 question: 276 in IL-2, 274 Observation (Obs) arm; the remaining patients were not randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The 2 groups were well balanced with respect to the stratification factors, age, sex, WBC counts and history of the disease. Currently, maintenance/observation period has been documented for 144 IL-2 and 144 Obs patients. The patients received a median of 30 s.c. injections (range 3-60) of IL-2. In more than 75% of patients, the mean dose was 6 × 106 IU per injection. Grade 3-4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (4.2% vs 0%), fatigue (9% vs 1.4%), rigor/chills (4.2% vs 0%), arthralgia/myalgia (3.5% vs 0%). A total of 32 patients (22.2%) out of 144 stopped IL-2 prematurely based on patient refusal or medical decision due to toxicity. In the Obs arm, 4 (2.8%) patients out of 144 went off study due to toxicity. Maintenance/observation period has not yet been documented for 132 IL-2 and 130 Obs patients. Among them 28 (21.2%) vs 13 (10%) respectively went off-study due to toxicity of the previous treatment (autoSCT or consolidation), 41 vs 45 due to early relapse, 9 vs 11 due to protocol violation, 9 vs 5 due to other reason. For the total of 550 patients, the median follow-up from the 2nd randomization was 3.6 years. As of July 2009, a total of 269 DFS events were reported: 132 (IL-2 arm) vs 137 (Obs arm); among them 242 relapses (121 vs 121) and 27 deaths without relapses (11 vs 16). The DFS from 2nd randomization was similar in the 2 groups: the 3-yr DFS rate was 44.1% (IL-2) vs 42.0% (Obs), hazard ratio (HR)=0.93 (95% CI 0.74-1.19), p=0.57. A total of 106 patients died in each treatment group. The 3-yr overall survival rate was 54.1% (IL-2) vs 55.9% (Obs), HR=1.01 (95% CI 0.77-1.32), p=0.94. The initial treatment received/randomized did not impact the treatment outcome after the 2nd randomization. This evaluation of the second randomization (IL-2 vs Obs) of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3.6 years, low dose IL-2 maintenance does not lead to a higher DFS and overall survival. Disclosures:Muus:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Worry Exposure versus Applied Relaxation in the Treatment of Generalized Anxiety Disorder

Background: Worry exposure (WE) is a core element of cognitive-behavioral treatment for generalized anxiety disorder (GAD). Its efficacy as a stand-alone treatment method (without further cognitive-behavioral therapy interventions) has never been tested.We aimed to examine whether WE alone is as efficacious as the empirically supported stand-alone treatment for GAD, applied relaxation (AR). Methods: In a randomized controlled study, 73 outpatients meeting DSM-IV criteria for GAD as primary diagnosis were allocated to either WE or AR or a waiting list control group; in a 2nd randomization procedure the waiting list subjects were reallocated to WE or AR. The treatment was manualized (15 sessions with WE or AR), included 6-month and 1-year follow-ups, as well as last observation carried forward and completer analyses, and was controlled for allegiance effects.The Hamilton Anxiety Rating Scale and the State-Trait Anxiety Scale were used as primary outcome measures. Self-report scales of anxiety, worrying and depression including negative metacognition about worrying and thought suppression served as secondary outcome measures. Results: The dropout rate was moderate. The pre-/posttreatment effects were high for the Hamilton Anxiety Rating Scale (standardized mean difference >1) and for the State-Trait Anxiety Inventory (standardized mean difference >0.87). The proportion of patients reaching high end state functioning was 48% (WE) and 56% (AR). WE and AR did not differ with regard to dropout rate or treatment effects. The treatment effects were stable at 6 month and 1 year follow-up. Conclusion: This is the first study to show that a stand-alone exposure in sensu technique – WE – is efficacious in the treatment of GAD. Both AR and WE seem to represent effective principles of change in GAD.

High-Dose Methotrexate Seems to Benefit Only to Standard-Risk BCP-ALL Patients with Good Early Response to Chemotherapy: Final Analysis of the FRALLE93B Study

From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC< 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLL rearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2 × 2) vs idarubicin (IDA: 8 mg/m2 × 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2 at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (< 5%): n=555, M2 (6–25%): n=71 and M3 (> 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1st or 2nd randomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1st and 2nd randomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2nd randomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows:5-yr EFSRelapses CIiBM relapses CIOther relapses CI5-yr OSHD-MTX87.82±1.99%0.12±0.047.01±0.025.17±0.0295.20±1.30LD-MTX79.92±2.47%0.20±0.0610.6±0.039.10±0.0388.64±1.95Testlog-rankGrayGrayGraylog-rankp value0.0280.0370.160.180.07(EFS: event-free survival, CI: cumulative incidence, iBM: isolated bone-marrow, OS: overall survival)At the contrary, among M2 pts there is no difference in EFS for pts treated with HD-MTX (61±7%) and LD-MTX (65±9%)Conclusion:HD-MTX seems to benefit to pts with standard-risk BCP-ALL and good early response to chemotherapy, and the benefit is associated with a reduction in the number of relapses.No benefit is demonstrated in M2 pts with SER who have a very poor outcome and do require a more intensive treatment; the better EFS of M3 patients treated with double delayed intensification is in favour of this hypothesis.

Azacytidine as a Maintenance Therapy in Elderly AML Progressively Demethylates CpG Sites within the p16 Gene

Acute myeloid leukemia (AML) accounts for ~30% of adult leukaemia cases and is expected to increase as the population ages, due to median age of onset at ~60 years old. Recent evidence suggests that DNA methylation is actively involved in AML and myelodysplastic syndrome (MDS). Tumor suppressor genes, such as p16, have been shown to be silenced by methylation in AML. However, epigenetic events such as DNA methylation are reversible and therefore targets for chemotherapeutic intervention. It has been reported that ~30% of MDS patients with an abnormal karyotype show normalization of their methylation status after receiving a demethylating drug during early stages of their therapy.The UK NCRI AML16 programme for elderly patients (>60 years old at diagnosis) with AML and high risk MDS has several therapeutic questions for patients considered fit for intensive treatment, one of which is to compare the use of azacytidine demethylation maintenance treatment with no maintenance therapy.Samples were obtained from patients entered into the AML16 trial, at diagnosis and from patients entered into the intensive arm of the trial who were randomized to receive azacytidine maintenance therapy were analyzed for the alterations for genomic methylation.Pyrosequencing was used to determine methylation within 17 CpG sites within p16, MLH1, and MGMT whilst LINE1 was used as a measure of global methylation. To date, approximately 714 patients have been entered into AML16. Of these 195 diagnostic samples have been analyzed, of which 103 were in the intensive arm of the trial. At the second randomization stage, 34 patient samples were analyzed and a further 26 samples were obtained following 3, 6 or 9 courses of azacytidine therapy.Statistical comparison of the methylation levels at each individual CpG or for the averaged CpG in each gene studies indicated that there was no difference whether the sample was derived from bone marrow or peripheral blood. This allowed the direct comparison of peripheral blood samples obtained at 2nd randomization and during azacytidine maintenance courses. Differential levels of methylation at individual CpG within the gene were seen at diagnosis. Higher levels of average p16 methylation were observed in the AML patients when compared to a small cohort of “well elderly” individuals.No difference was noted in the individual or averaged CpG methylation status for MGMT or LINE1 during the maintenance course of azacytidine. However, the methylation status of the CpG sites within the p16 and MLH1 genes reduced during maintenance by a median of 19% and 25% respectively. However, the number of patients completing three courses of azacytidine was only about 20% of those entering the intensive arm of AML16, however sequential samples from the same individual also showed demethylation of the CpG sites in p16 and MLH1. This study shows that azacytidine maintenance therapy in elderly AML patients does reduce the methylation status of some genes whilst others genes show no response. This is being investigated further using arrays containing 12,000 CpG sites which will be correlated with gene expression microarrays on the diagnostic samples from AML16.

High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SDAraC) during Induction and Value of IL-2 during Maintenance in Acute Myelogenous Leukemia (AML): Impact of AraC Dose on Complete Remission Rate and Toxicity (Results on the first 1700 randomized patients of the AML-12 trial of EORTC and GIMEMA Leukemia Groups)

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, (891 by EORTCLG and 1114 by GIMEMA) were randomized. Currently for 1700 pts (857 in SD-AraC vs 843 in HD-AraC arm) sufficient information on remission induction response is available. The median follow up is 3 years. After 1 or 2 courses of induction, CR was achieved in 631 (73.6%) pts (SD-AraC group) vs 680 (80.7%) pts (HD-AraC group): p=0.001. Partial remission or resistance was documented in 161 (18.8%) vs 114 (13.5%) pts, and death in induction in 65 (7.6%) vs 49 (5.8%). Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: 0.1% (SD-AraC) vs 4.4% (HD-AraC). Currently in 909 pts cytogenetic information is not yet available and in 791 pts cytogenetic information is known. Comparison of SD-AraC vs HD-AraC according to cytogenetic subgroups is shown in the Table.No cytogeneticsGoodIntermediateBadVery badNo pts448 vs 46155 vs 50215 vs 20089 vs 9050 vs 42CR (%)71.2 vs 82.490.9 vs 84.078.6 vs 82.568.5 vs 77.864.0 vs 54.8PR/Resistance (%)20.3 vs 12.60 vs 6.015.3 vs 10.527.0 vs 16.726.0 vs 40.5Induction death (%)8.5 vs 5.09.1 vs 10.06.0 vs 7.04.5 vs 5.610.0 vs 4.8In pts who reached CR, the DFS was similar in the 2 treatment groups: the 3-yr DFS rate was 43.4% (SD-Ara-C) vs 44.6% (HD-Ara-C), hazard ratio (HR)=0.96 (p=0.66). A total of 291 vs 313 DFS-events were reported in the 2 treatment groups: 230 (36.5%) vs 236 (34.7%) relapsed and 61 (9.7%) vs 77 (11.3%) died in CR. Among pts who reached CR, 451 pts had an HLA identical sibling and 860 did not or have not been typed. In the first group, 120/200 (60.0%) SD-AraC vs 134/251 (53.4%) HD-AraC pts underwent an allo-SCT. In the 2nd one, 211/431 (49.0%) SD AraC pts vs 211/429 (49.2%) HD AraC pts underwent an auto-SCT. In pts with a donor, the 3-yr DFS rate was 51.8% (SD-Ara-C) vs 47.6% (HD-Ara-C), HR=1.13, p=0.41, whereas in those without a donor the 3-yr DFS rate was 39.6% (SD-Ara-C) vs 42.9% (HD-Ara-C), HR=0.91, p=0.31. Evaluation of the first 1700 patients of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C without improving the DFS.

High Dose (HD-AraC) vs Standard Dose Cytosine Arabinoside (SD-AraC) during Induction in Acute Myelogenous Leukemia (AML): Impact on Stem Cell Mobilization after Consolidation and on Autologous Transplantation (Second Report of the EORTC-Leukemia Group (LG) - GIMEMA AML-12 Trial.

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation (Co) consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after Co in pts without a donor: auto-SCT followed or not by low dose IL-2. From 9 1999 till 7 2006, 1675 AML pts (APL excluded), age <61 years, from 67 centers (23 EORTC-LG and 44 GIMEMA) entered. Currently 1571 pts have been randomized for induction and 429 pts post-Co. During the induction toxicity was similar in the 2 arms except for conjunctivitis: 6% (HD-AraC) vs 0% (SD-AraC). HD-AraC given in the induction had no impact on the organ toxicity during Co but platelet recovery (> 50x109/l) was longer (median 4.0 vs 3.3 weeks; P=0.01). Among 886 pts randomized until 7 2005 by EORTC centers and 6 large GIMEMA centers, median follow-up of 2.5 years, 815 were evaluable for response. Out of 643 pts who reached CR, 57 went off study (toxicity, early progression). Among the remaining 586 who received Co, 37 could not be evaluated (early death/relapse, too early) and 549 were still CR after Co: 297 pts had no donor/no sibling, 197 had a donor and 55 were not typed. In these 3 groups the present estimates of the SCT rates are: 63% (auto-SCT), 71% (allo-SCT) and 69% (auto-SCT), resp. The 2.5-yr DFS rates (SE%) were 45% (3%), 61% (4%), and 67% (7%), resp. In pts < 50 yrs, 216 pts had no donor/no sibling, 135 had a donor and 14 have not been typed. For the first 2 groups, the 2.5 yr DFS rates (SE%) were 50% (4%) vs 68% (4.5%), hazard ratio=0.64, 95% CI (0.44, 0.93), P=0.02. In pts without a donor/a sibling successful mobilization of blood stem cells (b-SC) after Co was in HD-Ara-C vs SD-Ara-C arm 53 vs 69%, of failure/postponement 37 vs 24%, and other 9.5 vs 7%. The rate of auto-SCT was similar (65 vs 64%), but harvest of BM cells was more often required in the HD-AraC group (15 vs 4.5%). Pts with an insufficient/delayed b-SC harvest had a longer (P<0.001) platelet recovery (> 50x109/l) after Co than those with a successful harvest: median = 6.7 vs 3.3 wks. Among 393 pts with information on cytogenetics, 14% had good risk, 50% normal, 23% other and 13% poor risk (-5/5q-, -7/7q-, complex). The 2.5-year EFS (no CR, time to relapse or death in CR) rates (SE%) were 68% (7%), 42% (4%), 32% (5%) and 14% (5%), resp. So far: toxicity of HD-Ara-C was acceptable; in those who received HD-AraC in induction platelet recovery after Co was longer and the rate of successful b-SC collection was lower; SCT rates are high and similar in the 2 randomized arms; pts <50 yrs with a donor do have a longer DFS; pts with poor risk cytogenetics continue to have a poor prognosis.

Long Term Follow-Up of the Gimema GSI 103 AMLE Randomized Trial: Daunoxome Seems To Improve Disease-Free Survival (DFS) of Elderly Patients with Acute Myelogenous Leukemia (AML).

The GSI 103 AMLE was a randomized phase III clinical trial to explore the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) standard treatment in AML elderly patients. From 10/2001 to 2/2004, 301 patients aged 61 to 75 years with a diagnosis of AML according to WHO classification and eligible for intensive chemotherapy were enrolled in this trial by 39 GIMEMA Centers. Patients were randomized to receive induction treatment with DNR (45 mg/sqm day 1 to 3) or DNX (80 mg/sqm day 1 to 3) plus AraC (100 mg/sqm day 1 to 7 by continuous infusion): as consolidation therapy, patients in CR received a further course of the assigned induction treatment. After the consolidation course, patients in CR underwent a 2nd randomization independently from the 1st random, to receive as maintenance therapy either AraC (20 mg twice daily day 1 to 10) plus all-trans retinoic acid (ATRA) (45 mg/sqm day 1 to 10) every 28 days for a maximum of 12 cycles (Arm A) or no further treatment (Arm B). 153 patients were enrolled in the DNR arm and 148 in the DNX arm: the two arms were comparable as to relevant patient characteristics, including karyotype. In the DNR arm, 77 patients (50.3%) achieved CR, 56 (36.6%) were resistant and 20 (13.1%) died during induction (ID). In the DNX arm, 73 patients (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Differences between the two arms at univariate analysis were not statistically significant either considering the 3 different types of response or considering ID versus other (Chi-square 0.34 and 0.17 respectively). After CR, the effect of DNX seems to be time-related, due to higher incidence of early deaths in CR (11% vs 3%, p=0.053) and lower incidence of relapse beyond 6 months (at 24 months 60% vs 80%, p=0.064). This translates in a cross of the OS and DFS curves between the two arms, with initial advantage for the DNR arm followed by an advantage for DNX arm after 12 months from diagnosis. A time-dependent covariate Cox model and a landmark analysis on patients in CR after 6 months revealed a better outcome of DNX patients (p= 0.029 and p=0.092, respectively) in the long term DFS follow-up. No difference has been observed in the DFS curves according to maintenance randomization. In conclusion, DNX is as effective as DNR in the induction phase of AML elderly patients, with a trend of increased early toxicity (ID + deaths in CR): however, DNX seems to improve the OS and DFS in the long-term follow-up of these patients, due to a reduction of late relapses. Further trials in more selected elderly patients or in younger patients will be helpful to define the exact role of DNX in AML.

No Benefit of Adding High-Dose Melphalan (HDM) Suppported by Autologous Stem Cell Transplantation (SCT) over Treatment with Conventional Induction, HD ARAC Consolidation, and Auto SCT (Busulfan + HDM) for Acute Myelogenous Leukemia (AML) under 60: First Results of the Randomized AML 2001 Trial.

From 11/2001 until 04/2005, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were 1st randomized to received induction with continuous IV ARAC (200 mg/m2, x 7d) and Daunorubicin (D: 60 mg/m2 x 3d) OR Idarubicin (I: 8 mg/m2 x 5d). If marrow blasts > 5% on D15, 2nd induction course was applied (D: 35 mg/m2 x 2d OR I: 8 mg/m2 x 2d plus ARAC 1 g/m2 x 4 doses over 2d). After achieving CR, all patients received low dose consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus SC ARAC 100 mg/m2 x 7d). Patients with HLA-identical sibling receive a T-replete alloSCT: either conventional (bone marrow graft, TBI-cyclophosphamide, ciclosporin-methotrexate) if age ≤ 50 = arm M; or non myeloablative (NST: peripheral blood, Busulfan (Bu)-Fludarabin-Thymoglobulin®, ciclosporin alone), AFTER intensive consolidation (idem below) if age 51–60 = arm m. A small subgroup of patients (3 % patients in CR) with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction) did not receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered for relapse = arm C. Other patients proceed to 2nd randomization: intensive consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus ARAC 3 g/m2 x 8 doses over 4d) PLUS 1 autoSCT (Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm A; or intensive consolidation PLUS 2 autoSCT (HDM 200 mg/m2 THEN Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm B.After 1st randomization (D vs I), no difference was observed between 2 arms regarding age, leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: D = I 13%), intermediate (D 66%, I 59%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; D 21%, I 28%). Use of both anthracyclins results in same CR rate (D 83% vs I 85%); early death (3%); projected EFS (D 46% vs I 50%, p = 0,28) and OS (D 61% vs I 64%) at 2 years. Noteworthy was the more frequent use of 2nd induction course to obtain CR with D (30%) as compared with I (22%).78% of all patients in CR proceeded to 2nd randomization or were assigned to alloSCT arms (33 % of them). Actual results concern 550 patients with 15 months follow-up. No benefit was observed with addition of HDM 200 for 2y projected DFS (A 53% vs B 49%) or OS (A = B 68%). Toxic death rate was higher in arm B, accounting for 18% total deaths vs 6% in arm A. Conventional alloSCT results in better 2y DFS than combined arms A+B (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06). No significant difference was observed between conventional and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50 : 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). In conclusion:conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1;NST after intensive consolidation seems promising for older patients and may extend use of alternative sources of alloSCT;HDM course adds no benefit for these patients. Data with more than 2 years follow-up will be presented.