Post-consolidation Treatment Research Articles

Efficacy and safety of the use of dinutuximab in newly diagnosed or relapse high risk neuroblastoma: Single arm systematic review and meta-analysis.

10044 Background: Patients with high-risk Neuroblastoma have a poor prognosis, with 43% experiencing a 3-year survival rate in newly diagnosed cases and a 21% 1-year event-free survival in relapsed patients. Dinutuximab, an immunotherapy targeting anti-disialoganglioside (GD2), emerges as a promising treatment for high-risk Neuroblastoma. This single arm meta-analysis aims to assess the efficacy and safety of dinutuximab, providing insights into its impact on survival rates among neuroblastoma patients. Methods: We systematically searched Pubmed, Cochrane and EMBASE for clinical trials between 1988 to 2023 utilizing Dinutuximab (ch14.18 or ch14.18/CHO) in patients with newly diagnosed or relapsed/refractory high-risk neuroblastoma. We pooled the prevalence and the 95% confidence intervals (CI) for the outcomes of interest: overall survival (OS), event-free survival (EFS) and progression-free survival (PFS), objective response rate (ORR), and treatment-emergent adverse events (TEAE). Heterogeneity was assessed using I² analysis and all statistical analyses were employed using R software version 4.3.2 and a random-effects model. Results: The analysis included 2214 patients from 13 clinical trials, comprising four phase III trials and six phase II. Six studies included Interleukin 2 (IL-2). Among the patients, 364 (16.5%) had relapsed or refractory disease. Dinutuximab was applied as post-consolidation treatment in 1809 patients (81.1%). The age of patients ranged from 1 to 21 years. In a pooled analysis, the 3-year OS rate was 69% (CI 0.62-0.76; I² = 85%), and the 3-year EFS rate was 61% (CI 0.52-0.69; I² = 77%). In the group of newly diagnosed patients, the 3-year EFS rate was 62% (CI 0.58-0.66; I² = 52%) and 3-year OS rate of 74% (CI 0.69-0.79; I² = 71%). Among patients with relapse, there was a 3-year OS rate of 57% (CI 0.50-0.64; I² = 0%). The overall ORR was 47% (CI 0.37-0.57; I² = 69%), of which 38 newly diagnosed patients using Dinutuximab during induction chemotherapy showed an ORR of 86%. TEAEs of grade ≥ 3 were 70% (CI 0.44-0.88; I² = 94%), and in the subgroup without IL-2 use, it was 43% (CI 0.29-0.57; I² = 85%). Conclusions: This single-arm meta-analysis suggests that both newly diagnosed or relapsed/refractory high-risk Neuroblastoma patients benefit from Dinutuximab, with a promising impact on 3-year OS and EFS. Dinutuximab appears to be a safer option; however, concomitant use of IL2 is associated with a higher rate of adverse effects.

LONG-TERM Results of the Frontline Dasatinib/Blinatumomabprotocol (D-ALBA, GIMEMA LAL2116) for Adult Ph+ Acutelymphoblastic Leukemia

Introduction. The prognosis of Ph+ acute lymphoblastic leukemia (ALL) has changed profoundly following the advent of tyrosine kinase inhibitors (TKIs). Since 2000, the GIMEMA frontline studies for adult Ph+ ALL patients have been based on a TKI plus steroids in induction without systemic chemotherapy. This has allowed complete hematologic remission (CHR) rates of 94-100%, irrespective of age, with virtually no deaths in induction 1-5. We then designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA). The preliminary results 6,7 showed a CHR rate of 98% with 60% of molecular responses at the primary endpoint of the study (after 2 blinatumomab cycles); the OS and DFS were 95% and 88% at 18 months. Here we present the final long-term results of the study. Methods. Post-consolidation treatment was left to the treating physicians and all the information has been collected in the GIMEMA LAL2217 ancillary study. Sixty-three patients were enrolled (median age 54 years, range 24-82); 2 patients withdrew from the trial, 1 died in CHR and 1 relapsed after induction due to a major protocol violation 6,7. Results. After the primary endpoint, molecular responses increased further following additional blinatumomab cycles, being 75, 77, 70, 85, 90 and 93% at 2, 4, 6, 8, 10 and 12 months from the last blinatumomab cycle. At a prolonged follow-up, a persistent molecular negativity was found with 78.3, 73.1, 85, 87.4, 94.2, 90.2, 86.6 and 86.7% of responders at 16, 20, 24, 28, 32, 36, 42 and 48 months in the evaluable population. At a median follow-up of 53 months, DFS and OS are 75.8% and 80.7% (Figure 1). A significantly better DFS and OS was observed in the 17 patients in molecular response at the end of induction (EOI) (100%) vs cases who were not (42) (68.6%) (p=0.016 and 0.036, respectively). These patients have so far not relapsed. After 2 blinatumomab cycles, DFS and OS did not differ between molecular (33) and non-molecular (22) responders: 82.9% and 89.4% vs 75.7% and 84.2%, underlying the effect of blinatumomab. A worse DFS from the EOI was recorded for IKZF1 pluspatients (11; 45.5%) compared to those without IKZF1 deletion (25; 82.3%) or with IKZF1 only deletions (13; 74%) (p=0.029). Similar results were observed also for OS. A similar trend was observed also when DFS was calculated from the primary endpoint of the study (62.5% vs 84.8% vs 74%). The 4 patients with a concomitant IKZF1 plus signature and T315I mutation had the worse outcome. After induction/consolidation, 29 patients continued treatment only with a TKI; 27 (93.1%) had obtained a deep molecular response after dasatinib/blinatumomab. Overall, 28 patients (96.5%) who did not receive systemic chemotherapy/transplant are in persistent CHR at a median follow-up of 48 months. Of the 24 patients transplanted in 1 st CHR, 13 (54.2%) were non-molecular responders at the primary endpoint and only 2 became molecularly negative after further blinatumomab. Twenty patients (83.3%) are alive in CHR at a median follow-up of 49 months, 1 has relapsed 1 month after the transplant and 3 have died of complications. Three/6 patients transplanted in 2 nd CHR are alive at 30, 40 and 52 months. The transplant-related mortality was 12.5% for patients transplanted in 1 st CHR and 13.7% overall. Nine relapses have occurred: 4 hematologic, 4 involving the CNS and 1 nodal. The median time to relapse was 4.4 months (1.9-25.8). A IKZF1 plus signature, evaluated at diagnosis, was present in 4/8 evaluable cases. ABL1 mutations, evaluated on BM samples at relapse or at a concomitant MRD increase in extra-hematologic recurrences, were found in 7 cases. Treatment was well tolerated with no unexpected long-term toxicities. Conclusions. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen based on a targeted strategy and immunotherapy is feasible and effective in inducing durable long-term hematologic and molecular responses in Ph+ ALL patients of all ages. Half of the patients remained only on a TKI and never underwent systemic chemotherapy or a transplant. These results pave the way for a new era in the treatment of adult Ph+ ALL patients. 1. Vignetti et al, Blood 2007 2.Foà et al, Blood 2011 3. Chiaretti et al, Haematologica 2016 4. Chiaretti et al, Haematologica 2021 5. Martinelli et al, Blood Advances 2022 6. Foà et al, N Engl J Med 2020 7. Foà & Chiaretti, N Engl J Med 2022

Patterns of relapse after immunotherapy in patients with high-risk neuroblastoma.

10043 Background: While the addition of anti-GD2 immunotherapy led to improvement in outcomes in patients on the Children’s Oncology Group (COG) ANBL0032 study, relapse remains a concern. Prior studies demonstrated the prognostic importance of time to first relapse, however, the effect of immunotherapy on timing and patterns of relapse in neuroblastoma (NBL) have yet to be evaluated. The purpose of this exploratory analysis was to describe the impact of immunotherapy on patterns of relapse in patients with high-risk NBL, including a descriptive comparison of sites of relapse based on post-consolidation treatment received [dinutuximab with cytokines and isotretinoin (DIN) vs isotretinoin alone (ISO)]. Methods: A retrospective, descriptive analysis of patients on ANBL0032 was performed, including patients randomized to DIN or ISO and those non-randomly assigned to DIN after ISO arm closure. Pt characteristics including age, stage, MYCN amplification status, tumor grade, mitosis-karyorrhexis index (MKI) and ploidy were summarized descriptively and relapse sites were tabulated. For DIN patients who subsequently relapsed, overall survival (OS) was calculated starting from the time of first relapse after enrollment on ANBL0032 (“post-relapse OS”). Kaplan-Meier OS curves were generated based on site of relapse. Results: The analytic cohort included 1,431 (DIN = 1,327; ISO = 104) patients. Among DIN patients, 492 relapsed, many in > 1 site. In the randomized cohort (n = 248), 122 relapsed (DIN = 68/144; ISO = 54/104). The frequencies (DIN; ISO) by site of relapse in the randomized cohort were: bone (53%; 54%), CNS (16%; 11%), lymph node (13%; 17%), abdominal (10%; 17%), paraspinal (6%; 2%), liver (3%; 4%), other soft tissue (22%; 7%). A higher proportion of ISO patients had marrow relapse (29.4% DIN; 48.2% ISO); however, the proportion of DIN patients with lung relapses appeared higher (9% vs 2%). Among all relapsed patients, the proportion with bone relapse did not appear to differ between treatment groups, regardless of MYCN status. Among patients with MYCN amplified disease, the proportion with marrow relapse did not appear to differ based on treatment [21/149 (14.1%) DIN; 3/20 (15.0%) ISO]; however, among patients with MYCN non-amplified disease, the proportion with marrow relapse appeared higher in the ISO group [16/23; 69.6%] vs the DIN group [52/193 (26.9%)]. Conclusions: In this exploratory analysis of patients on COG ANBL0032, the pattern for site of relapse appears to differ between patients treated with DIN vs ISO. While immunotherapy remains the treatment of choice in this population, the findings from this retrospective exploratory analysis warrant further investigation to decrease the risk for post-immunotherapy relapse. Clinical trial information: NCT00026312.

Hypercalcemia is a frequent side effect of 13-cis-retinoic acid treatment in patients with high-risk neuroblastoma.

13-cis-Retinoic acid (13-cisRA) is used as a postconsolidation treatment in patients with high-risk neuroblastoma. Hypercalcemia is a known side effect of retinoids. Frequency, symptoms, treatment, and risk factors for hypercalcemia were analyzed. Data were retrospectively analyzed for 350 patients registered in the German Neuroblastoma trials NB97 and NB04 who were treated with high-risk protocols-including myeloablative chemotherapy with autologous stem cell transplantation (SCT) or maintenance therapy-and had received 13-cisRA between January 1, 2000 and December 31, 2010. Hypercalcemia was reported in 78 patients (22.3%), and 37 patients (10.6%) developed Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 hypercalcemia. The calcium levels were 2.5-4.6mmol/L (median 3.1mmol/L). Patients with a single kidney were at a higher risk of developing hypercalcemia (p=.001). Regarding postinduction treatment, 69 of 280 patients with SCT (24.6%) and nine of 70 patients without SCT (12.9%) developed hypercalcemia during 13-cisRA treatment (p=.037). Most patients developed hypercalcemia in the first cycle of 13-cisRA, and only in a single cycle. Hypercalcemia symptoms were frequent but moderate. In most patients, treatment with 13-cisRA was continued without dose reduction in subsequent cycles. In this cohort, grades 3 and 4 hypercalcemia were observed more often than previously reported. A single kidney and pretreatment with myeloablative chemotherapy with stem cell transplantation were identified as potential risk factors for the development of hypercalcemia.

Understanding processing parameter effects for carbon fibre reinforced thermoplastic composites manufactured by laser-assisted automated fibre placement (AFP)

In this study, experimental investigations were performed to gain insights into the processing parameter effects of laser-assisted automated fibre placement (AFP) on the mechanical properties of carbon fibre (CF)/polyphenylene sulphide (PPS) composites from the perspective of void content and crystallinity. First, thermal characterisation was carried out to obtain the processing window for the PPS/CF composites. The temperature histories at the nip point during an AFP process were measured using an in-house temperature measurement system and the desired ranges of laser power and placement rate were determined based on the measured temperatures. The placement rate was ranging from 6 to 60 m/min, and the range of the used laser power was 1–6 kW. Then, the effects of tool temperature ranging from 30 to 120 °C on the interlaminar shear strength and compression strength of the CF/PPS composites were examined. It was found that the interlaminar void content dominated the mechanical properties of the composite rather than the crystallinity. Finally, the composites produced by the AFP were further treated by an autoclave. It was shown that the interlaminar shear strength of the composites was significantly improved after the autoclave post-consolidation treatment due to the reduction in void content and the improvement of crystallinity. The interlaminar shear strength of the composites after the autoclave treatment was found to be independent of the placement rate, indicating elimination of the AFP thermal history due to sufficient heating and compaction time in the autoclave.

Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial

Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial

Estimand Framework in AML Based on a Randomized, Placebo-Controlled, Phase 3 Study Investigating the Effect of Adding Midostaurin to Standard Chemotherapy in Patients with Newly Diagnosed AML without a FLT3 Mutation

In the ongoing randomized, placebo-controlled, phase 3 study in patients with newly diagnosed FLT3-mutation-negative acute myeloid leukemia (AML; NCT03512197) investigating the effect of adding midostaurin to standard chemotherapy, event-free survival (EFS) is the primary endpoint. EFS is a standard endpoint in clinical studies in AML. In a recent FDA submission, EFS was confirmed by an advisory committee to be clinically meaningful in AML (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM570800.pdf. Accessed August 1, 2018). With the release of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E9 draft addendum, we describe EFS in the estimand framework to address the scientific question of interest and illustrate the power of this concept to transparently define the relevant population, the variable of interest, and the management of relevant incidents that can occur in a clinical trial (“intercurrent events”).The objective is to determine the benefit of adding midostaurin to the whole standard chemotherapy sequence, consisting of induction, consolidation therapy, hematopoietic stem cell transplant (HSCT; if applicable), and postconsolidation therapy, in patients with newly diagnosed AML without a FLT3 mutation. The main interest is the interventional effect of the whole treatment sequence and not the contribution of an individual part of it.The study population includes all randomized patients following the treatment policy approach. Patients can be randomized only if there is confirmation from the central laboratory that there is no FLT3 mutation.EFS is a composite endpoint defined as the time from randomization until death, relapse, or induction failure. Induction failure is defined as no achievement of remission until end of the induction period. The definition of induction failure also includes instances in which HSCT is conducted as salvage therapy in nonresponding patients. Per convention, the EFS event date of induction failure is set to the randomization date.The option to receive HSCT can be an outcome of the treatment. Therefore, clinical benefit is assessed regardless of whether patients received HSCT. This treatment policy approach mandates collection of disease assessments after HSCT has been completed. In the same consideration, the option to receive consolidation and postconsolidation treatment is also an outcome of the induction treatment as only patients achieving remission with induction qualify to continue with consolidation and postconsolidation treatment. As such, the benefit is assessed regardless of treatment duration.The analysis plan defines a supportive estimand to assess the treatment effect of midostaurin, excluding potential benefit from HSCT. Another supportive estimand assesses the effect of discontinuation of induction treatment due to toxicities. This approach addresses a hypothetical scenario in which patients did not receive HSCT, for instance, to estimate the midostaurin-only effect. However, the outcome of the treatment is not limited to the direct effect of an experimental compound but also includes which new treatment option the compound allows for the patients (eg, HSCT).The estimand framework is an efficient tool to ensure consistency between the scientific question and the definition of the study objectives. It ensures transparency in unfavorable yet unavoidable situations in clinical trials (“intercurrent events”). It facilitates communication within the clinical team and with health authorities. The outcome of studies that are following the estimand framework can be interpreted in a consistent manner. DisclosuresBengoudifa:Novartis: Employment. Weber:Novartis: Employment. Gathmann:Novartis: Employment. Hoenekopp:Novartis: Employment. Berkowitz:Novartis: Employment.

Clinical Impact of an Accurate Genetic Characterization of Older Acute Myeloid Leukemia Patients: A Report from the Northern Italy Leukemia Group (NILG) Randomized Trial 02/06

IntroductionIn acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287).Patients and MethodsFive hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation.ResultsThe characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P<0.0001), while 3-years DFS was 73%, 28% and 13% (P<0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P<0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002).ConclusionsOlder AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. [Display omitted] DisclosuresCattaneo:GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

Dinutuximab: A Review in High-Risk Neuroblastoma.

Dinutuximab (ch14.18; Unituxin™) is a chimeric human-mouse monoclonal antibody that binds to the glycolipid antigen disialoganglioside, which is highly expressed on the surface of neuroblastoma cells. This intravenous drug is approved in the EU and USA as combination therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and isotretinoin for the postconsolidation treatment of patients with high-risk neuroblastoma. In a multinational, phase III study in this patient population, event-free survival (EFS) benefits with the dinutuximab-containing regimen versus isotretinoin alone were observed at the time of the primary (p = 0.0115) and confirmatory (p = 0.0330) efficacy analyses, although the observed p-value for the between-group difference in EFS for the primary efficacy analysis did not cross the prespecified boundary for statistical significance (p < 0.0108). Significant and sustained (5years) overall survival benefits were seen with the dinutuximab-containing regimen versus isotretinoin alone. Despite pretreatment with analgesics, antihistamines and antipyretics, serious adverse reactions have been reported with the dinutuximab-containing regimen, with infusion reactions and neuropathy prompting the US FDA to issue boxed warnings. Dinutuximab administered in combination with GM-CSF, IL-2 and isotretinoin represents an important advance in the postconsolidation treatment of patients with high-risk neuroblastoma, with its benefits outweighing its risks in a patient population with a poor prognosis and limited therapeutic options.

Post Induction WT1 MRD Analysis Significantly Predicts Early Relapse in Acute Myeloid Leukemia (AML) Patients

AML patients early relapsing within 12 months, still represents an extremely poor prognosis setting. Cytogenetic and molecular data are not diagnostic in 20-25% of AML patients and intermediate 2 ELN risk category has still an undefined prognosis. Post induction and consolidation MRD might represent a new prognostic factor besides patients and disease characteristics. We have evaluated post induction and consolidation bone marrow mimimal residual disease (MRD) in 126 AML patients (median age: 61.5 years, range: 17-89) with 20 months median follow-up (range 2-79.9). We analysed abnormal leukemia immunophenotype (ALIP) by multiparameter flow cytometry (MPFC) and WT1 by RT-PCR as described by Buccisano et al and Cilloni et al. Cytogenetic, NPM and FLT3 status were performed in 111, 97 and 119 patients respectively, defining the molecular cytogenetic risk in 96 patients. WT1 was +ve in 91/114 patients (70%) at diagnosis (median 1,231.5; range: 2-268,784), in 11/71 (15.5%) post induction (median 1216; range:260-134,633) and in 8/66 (12,1%) post consolidation (median 627.8; range:258-45,338). MPFC MRD was +ve in 33/66 (50%) patients after induction and in 18/48 (37.5%) after consolidation. We analysed 12 month Cumulative Incidence of Relapse (CIR) adjusted by MRD status, patients and disease characteristics. 82/99 patients achieved CR, 40 relapsed in a median of 8 months (1-52 months) 29 within 12 months with 37.5% 1 yr CIR. Patients receiving chemotherapy (38), Autologous (14) and Allogeneic Transplant (39) as post consolidation treatment had 45%, 35% and 30% 1 yr CIR respectively. NPM+FLT3- patients had 25% 1 yr CIR, compared to 25% in NPM-FLT3-, 50% in NPM+FLT3+ and 47% in NPM-FLT3+. Patients with WT1 positive post induction and consolidation had 1 year CIR of 90% and 72.5% respectively. Patients with MPFC positive post induction and consolidation had a 1 year CIR of 48.6% and 44.5% respectively. Multivariate analysis identified post induction WT1 positive status as the main predictor of 1 year CIR. Patients with WT1 positive after induction had a a 15.8 RR of 1 year CIR(p<0.0001) in comparison to WT1 negative patients. Hyperleukocytosis (WBC count >50,000/ml at diagnosis) and age>60 yrs also significantly predicted 1 year CIR with a RR of 7.22 (p=0.002) and 9.1 (p=0.001) respectively. In conclusion WT1 post induction status confirmed its prognostic significance in our series targeting a subset of early relapsing patients with an extremely poor outcome deserving experimental approaches. DisclosuresNo relevant conflicts of interest to declare.

Cost Analysis of Immunotherapy Using Dendritic Cells for Acute Myeloid Leukemia Patients

INTRODUCTIONTreatment for acute myeloid leukemia (AML) presents a significant economic burden to patients, health care insurers and society, and is expected to remain so in the near future. There are few studies describing the costs of AML in the literature. However, the high cost of treating AML and the demographic evolution of the world population, indicate that such studies are needed to support ongoing efforts to allocate resources efficiently in health care. OBJECTIVETo describe and compare the costs of AML therapies daily used at the Antwerp University Hospital in adult patients receiving chemotherapy with/without stem cell transplantation and in patients receiving immunotherapy using dendritic cell vaccination. DESIGN AND METHODSThis monocentric study compares direct hospital medical costs of treatment for AML between 2005 and 2010, allocated and charged according to the hospital analytic accounting system. Information on use of medical resources was collected from electronic medical records. Professional and facility charges associated with inpatient and outpatient management were collected using electronic billing information. Drug costs and drug administration costs were based on list prices published by the Belgian reimbursement authority (RIZIV/INAMI). The cost analysis distinguished between group 1, patients treated with induction and consolidation therapy alone; group 2, patients treated with induction and consolidation therapy plus allogeneic hematopoietic stem cell transplantation (HSCT) and group 3, patients treated with induction and consolidation therapy plus immunotherapy using dendritic cells engineered to express the Wilms’ tumor protein (Van Tendeloo et al. Proc Natl Acad Sci USA. 2010;107(31):13824-9). RESULTS AND DISCUSSION51 adult patients who were treated for newly diagnosed AML were included. Costs on medical and nursing care at the hematology ward, pharmaceutical prescriptions, transfer episodes to the intensive care ward, laboratory tests and medical imaging were analyzed. The cost of dendritic cell vaccine preparation was € 20 450 per patient. The median cost in group 1 (15 patients) was € 32,648 (range: € 4,759 - € 140,383). Only 1 patient in group 1 went into remission after induction therapy and received consolidation therapy. All patients in group 1 died within 5 year after diagnosis, 13 patients died within 1 year and 5 died within 1 month. The median cost in group 2 (26 patients) was € 184,554 (range: € 87,932 - € 449,155). The median post-consolidation treatment cost in group 2 was € 110,430 (range: € 31,364 - € 255,948). Five-year survival in group 2 was 19%. Seventeen patients in group 2 died within 1 year after HSCT. The median cost in group 3 (10 patients) was € 88,635 (range: € 23,392 - € 215,119). The median post-consolidation treatment cost in group 3 was € 40,748 (range: € 26,907- € 156,870). Five-year survival in group 3 was 30%. Four patients in group 3 died within 1 year after vaccination. CONCLUSIONThis study comparing different post-consolidation therapies confirmes the high cost of treating AML and suggests that savings to the healthcare system could be achieved by sustaining complete remission status for longer periods. Dendritic cell vaccination is one of the new therapeutic options to attain a long remission status. DisclosuresNo relevant conflicts of interest to declare.

Mobilization-Driven Postconsolidation Therapy in Elderly Patients with Acute Myeloid Leukemia: Feasibility and Efficacy of Autologous Stem Cell Transplantation versus Low-Dose Gemtuzumab Ozogamicin

We prospectively evaluated 2 postconsolidation strategies, administered according to the mobilization outcome, in 72 acute myeloid leukemia (AML) fit elderly patients, achieving complete remission after the first high-dose cytarabine-based induction. Autologous stem cell transplantation (ASCT) was performed in patients collecting ≥3 × 106 CD34+/kg and low-dose gemtuzumab ozogamicin (GO) was performed in poor mobilizers (collecting <3 × 106 CD34+/kg). Fifty-five patients (76.3%) underwent peripheral blood stem cell (PBSC) mobilization, after first consolidation, and 24 of 55 (44%) collected >3 × 106 CD34+ cells/kg. Among the 55 patients eligible for PBSC mobilization, 7 did not receive the planned treatment, 23 were allocated for ASCT, and 25 were allocated for GO on an intention-to-treat basis. With a median follow-up of 70 months (range, 24 to 124), 20 of 55 patients are alive, 18 of them in continuous complete remission. The 8-year overall survival (OS) and disease-free survival (DFS) are, respectively, 35.9% (95% confidence interval [CI] 24% to 49.8%) and 31.2% (95% CI, 21% to 43.8%), median OS and DFS were 22 and 16 months, respectively. In multivariate analysis, postconsolidation treatment and hyperleukocytosis (WBC > 50,000/μL) significantly predicted OS and DFS, whereas secondary AML was significantly associated with a higher relapse rate (83.4% versus 54% of de novo AML). Patients with hyperleukocytosis had 0% 3-year OS versus the 46% (at 8 years) in patients without hyperleukocytosis (P = .01); 57% of patients in the GO arm are alive at 8 years, compared with 25.4% of patients in the ASCT arm, who had an overall relative risk (RR) of death of 2.6 (95% CI, 1.2 to 5.8; P = .02). DFS at 8 years was 45.3% in patients receiving GO, compared with 26% in ASCT arm (RR, 2.1; 95% CI, 1 to 4.3; P = .05). Our study outlines low feasibility and efficacy of ASCT in elderly AML patients, whereas postconsolidation with GO appears safe and effective in this unfavorable setting. The study was registered at Umin Clinical Trial Registry (www.umin.ac.jp/ctr), number R000014052.

Geriatric Assessment Driven Treatment In 149 AML Elderly Patients

In elderly AML the prognosis still remains poor and unchanged in the last decades, with only 10% long term OS. Aging is often synonymous of frailty, traducing in difficulties of enrolment of older patients in experimental study. We explored feasibility and efficacy of an high dose Cytarabine regimen, the so called ‘Memorial', including Idarubicin plus Amifostine, in a cohort of 149 AML patients older than 59 years and prospectively evaluated by Multidimensional Geriatric Assessment, between 1999 and 2010. We estimated comorbidities by CIRSG, presence of geriatric syndromes and autonomy in daily life activities (ADL) score as described by Balducci et al, frail patients, candidate to best supportive care (BSC), have been identified as those with 1 grade III or more than 2 grade II comorbidities or a geriatric syndrome or ADL score<6. Ninetyone patients (61%) resulted fully fit or partially fit but with adequate cardiac function (50% EF by echocardiography) and therefore eligible to receive a Memorial based induction and consolidation. The 58 patients of the BSC group, compared with intensive chemotherapy group, had a higher incidence of unfavourable karyotype (64.5% vs 40.7%, p= 0.05), secondary AML (53.4% vs 39.6%, p=0.005), WHO PS>1 (44.4% vs 12.1%, p=0.003), age>69 years (82.7% vs 42.9%, p<0.001).In the 91 patients we observed 5 induction deaths (5.5%) and 76% CR rate (67/88, 3 too early) with 67 grade III-IV febrile episodes, 13% and 9% grade III-IV mucositis and liver toxicity. Neutrophils (>1,500/ml) and platelets (>20,000/ml) recovery was achieved on days +15 and +16 respectively, with a median duration of hospitalization of 30 days (range: 15-69). Sixty-one patients achieving CR received a consolidation, followed by Allogeneic Transplant in 4, Autologous Transplant in 22 and Gemtuzumab Ozogamycin in 23, according to the mobilization results and donor availability. The remaining patients went off the study because of early leukemia recurrence or poor tolerance.With a median follow-up of 70 months we observed a 20.4% 8 years OS with a median duration of 11.4 months. The 58 BSC patients had a significantly lower OS since all died within 18 months with a median OS of 1.5 months (p<0.001).The presence of poor risk cytogenetic was confirmed as the only factor significantly predictive of refractory disease with a RR of 3.26 (95% CI: 1.18-9.53) p=0.03. By the way we observed a 63,6% CR rate in this unfavourable setting, unusually high if compared to the results reported by the literature.Eight years OS was significantly reduced at univariate analysis in patients with secondary disease vs those with de novo AML (10.4% vs 27.1%; p= 0.04); in those with unfavourable cytogenetic risk vs other risk groups (11.4% vs 30.3% p= 0.01) and in those with WBC count> 50,000/ml vs < 50,000/ml (0% at 33 months vs 23.4%, p= 0.009). Multivariate Analysis selected only cytogenetic risk and hyperleukocytosis as predictors of Overall Survival. Patients with poor karyotype had a 2.1 relative risk to die and a 1.89 relative risk to die or relapse when compared with patients with other cytogenetic risk (p=0.005, 0.012), those with hyperleukocytosis ≥50,000/ml showed lower OS and EFS in comparison with patients with a WBC count <50,000/ml, with relative risks respectively of 3.53 and 3.45 (p=0.001).In conclusion Multidimensional Geriatric assessment allows a reproducible and accurated selection of AML elderly patients eligible for intensive chemotherapy treatment.Memorial plus Amifostine represents an intriguing approach in elderly AML patients with an acceptable haematological and extra-haematological tolerance, a transplant feasibility comparable to other studies; finally 8 yrs OS doubled than that reported by the literature. Disclosures:Off Label Use: Gemtuzumab Ozogamycin was administered as post consolidation treatment after September 2010 (when it has lost indication for AML elderly treatment after SWOG phase III study results) only after AIFA permission and approval by IRB. A written informed consent indicating the reasons for the withdrawal of Gemtuzumab from the market, was signed by patients receiving Gemtuzumab after that date.

Feasibility of the AMLprofiler™ (Skyline array) in Patient Risk-Stratification in a Multicenter Trial. Comparison with the Standard Approach

AbstractAbstract 4813Accurate cytogenetic and molecular diagnosis of acute myeloid leukemia help to establish the prognosis and to select the best postconsolidation treatments. This genetic characterization is currently being performed by means cytogenetic techniques and molecular methods mainly based in PCR, capillary electrophoresis and Sanger sequencing. Recently, large and homogeneous series of AML patients have been analyzed by means expression arrays. These studies have helped to standardize the method and they are becoming an alternative to traditional methods in terms of simplicity and time. ObjectivesTo assess the usefulness of the AMLprofiler™ in genetic stratification of de novo AML enrolled in a cooperative Group. To investigate the applicability of the array diagnostic platform in multicenter trials. To compare the AMLprofiler™ with the standard approach. Patients and methodsTwenty one consecutive de novo AML cases enrolled in the Spanish CETLAM protocol were included in the study. Patients were recruited during 2012. Cytogenetic analysis was performed in each participating center and the results were sent to the HSCSP. Complete immunophenotype and molecular studies were performed centrally at the HSCSP. Purified DNA was employed to test FLT3-ITD and TKD mutations, NPM1, CEBPa and MLL. For each FLT3-ITD positive case, the allelic ratio was calculated. Given that FLT3 mutations are not detected by the AML-profiler™, this determination was common to both approaches. Purified RNA was used to assess the presence of the AML1-ETO and CBFb-MYH11 rearrangements and to test RNA integrity. We used the AMLprofiler™ assay which detects chromosomal aberrations (t(8;21), t(15;17), inv(16), mutations (CEBPA dm, NPM1 A/B/D) and genetic expresion of BAALC and EVI1. Only those cases fulfilling the quality required by the manufacturer were hybridized the AMLprofiler™array. Based on this requirement one case was ruled out. ResultsTwenty cases were analyzed with the AMLprofiler™ and with the conventional methods (21 intended/20 hybridized). There were 4 cases with FLT3-ITD. One case had a t(8;21) and it has been succesfully detected by both methods. There were 4 inv(16), in one case the RNA quality was not satisfactory and was not hybridized, in the remaining 3 cases the AMLprofiler detected the genetic lesion including one case with a cryptical translocation and in one case with a typical inv(16) but with a complex CBFb-MYH11 transcript. In 8 cases a NPM1 mutation was detected by molecular methods, in all NPM1 A, B or D, the AMLprofiler™ gave concordant results, one case with a non-ABD mutation was not detected. When considering technician times, AMLprofiler™ compared favorably with the conventional molecular biology techniques (mean times: 2958 min vs 3422 min). This figure does not take into consideration the cytogenetic workload performed in each participating center. ConclusionsThe AMLprofiler™ could be easily used to stratify de novo AML patients enrolled in multicenter trials. It provides accurate results and requiring less time than the currently employed methods in the CETLAM group. The AMLprofiler™ seems to be specially useful in the core binding-factor leukemias. The most important limitations are related to the need of an excellent RNA sample and the presence of rare NPM1 mutations. Disclosures:No relevant conflicts of interest to declare.

MRD-Directed Post-Remissional Therapy Dramatically Improves Outcome of Adult Patients with High Risk AML by Implementing Allogeneic Transplant Option

AbstractAbstract 2702Despite improvements in supportive care and wider availability of novel drugs, the outcome of young adult with AML still remains unsatisfactory with a long term survival of 30–40%. Such a dismal outlook is due to the contribution of several reasons. Among these, we believe that risk-category allocation based on the sole definition of pre-treatment biological features (genetics/cytogenetics) may fail to distinguish some high-risk patients which consequently are not timely addressed to intensive treatments. Furthermore, proper treatment of patients with poor prognosis may be hampered by the limited availability of HLA full compatible sibling donors (30% of patients). For the same reasons, some low-risk patients may be misclassified and over-treated (e.g. by giving them allotransplant for the simple reason that they have a full related compatible donor) with an excessive rate of treatment related mortality. Minimal residual disease (MRD) detection promises to be a strong predictive factor in adult AML when measured after the [induction-consolidation] phase and in fact, we have demonstrated (Venditti Blood 2000, Maurillo JCO 2008, Buccisano Blood 2010) that it refines the upfront genetic/cytogenetic risk classification. Thus, we designed a risk-directed pilot study which took into account: 1) an adjusted risk-stratification based on pretreatment genetics/cytogenetics and MRD status at the end of consolidation; and 2) a fast prospective assignment of all high-risk patients to allogeneic stem cell transplantation (alloSCT) in the form of HLA full compatible sibling, matched unrelated donor, umbilical cord blood or full haploidentical donor transplant. By applying this adjusted risk-stratification, we were able to discriminate two discrete category of patients: 1) Low-risk: good and intermediate-risk karyotype (K) that were MRD negative after consolidation (MRDneg good/int-K); and 2) High-risk: adverse-risk K, FLT3-ITD mutated cases and good/intermediate-risk K that were MRD positive after consolidation (MRDpos good/int-K). We also analyzed the outcome of a matched historical cohort of high-risk patients whose post-consolidation treatment was oriented according to a “genetic randomization”: alloSCT for those with a HLA full compatible sibling and autologous stem cell transplant (auSCT) for those lacking this option. Results achieved in this retrospective cohort were compared with those generated in the analysis of the prospective one. The prospective cohort included 25 high risk patients (4 MRDpos good-K, 9 MRDpos int-K, 4 adverse-karyotype and 8 FLT3-ITD). Five of them relapsed early being 20 evaluable for this analysis. The retrospective cohort accounted for 52 high-risk patients (8 MRDpos good-K, 33 MRDpos int-K, 1 adverse-karyotype and 10 FLT3-ITD). Ten of them relapsed early being 42 evaluable for this analysis. Even though the median follow-up of the prospective cohort is still short (18 months) survival estimates were dramatically superior as compared to the retrospective one (DFS 70% vs. 20%, p=0.00047; OS 69% vs. 24%, p=0.046). Accordingly, the prospective cohort also showed a lower relapse rate (20% vs. 52%, p=0.003). The 2 cohorts were well balanced in terms of frequency of FLT3-ITD, adverse-K and treatment related mortality rate, therefore, we believe that the improvement in survival estimates is related to the higher percentage of patients who were able to receive alloSCT. In fact, in the prospective cohort 21/20 (95%) of patients entering the post-consolidation phase underwent alloSCT as compared to 12/42 (30%) in the retrospective cohort (p<0.001). Notably, in the prospective cohort, only 8/21 patients had an HLA full compatible sibling whereas in 6 and 7 an haploidentical or MUD/UCB donor was found, respectively. We conclude that: 1) risk-assessment combining upfront genetics/cytogenetics with post-consolidation MRD status improves identification of high-risk category of patients who share a very poor prognosis if not selectively submitted to alloSCT; 2) the actual risk of disease recurrence should guide alloSCT option according to a “transplant vs no transplant” rather than “donor versus no donor” approach. This implies that once high-risk patients are identified they should receive alloSCT whatever the source of stem cell and, in our experience, this is feasible in the large majority of patients. Disclosures:No relevant conflicts of interest to declare.

Post‐consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin‐2 in AML

The initial chemotherapy in acute myeloid leukaemia (AML) comprises a first phase of induction and a second phase of consolidation. In the majority of patients, the induction treatment leads to complete remission (CR), defined as microscopic disappearance of leukaemic disease along with the return of normal haematopoiesis. However, despite the introduction of more efficacious consolidation regimens, a worryingly large proportion of AML patients in CR will subsequently experience relapses with poor prospects of long-term survival. A relapse is assumed to be the result of expansion of residual leukaemic cells that have escaped the initial chemotherapy. The anti-leukaemic functions of T cells and natural killer (NK) cells has formed the background to the use of interleukin-2 (IL-2), a T- and NK cell-activating cytokine, with the aim to eliminate residual leukaemia and hence reduce the relapse rate in AML, but the clinical trials using IL-2 monotherapy have yielded disappointment. A recent phase III study has demonstrated that post-consolidation treatment with the combination of histamine dihydrochloride (HDC) and IL-2 significantly prevents relapse in AML patients. Here we account for the preclinical background to the use of HDC/IL-2 in AML along with a review of clinical results.

Histamine Dihydrochloride Maintains Cytotoxic Effector T Lymphocyte Function and Viability under Conditions of Oxidative Stress.

BACKGROUND: Malignant diseases are frequently accompanied by suppression of cytotoxic lymphocyte function, and a large body of circumstantial evidence suggests that lymphocyte suppression may have implications for disease-free survival in several hematopoietic cancers. In AML, a plethora of immunosuppressive mechanisms have been described including the production of T- and NK-cell-inhibitory factors by AML blasts, a deficient expression of activating receptors on natural killer (NK) cells, and an impaired stimulatory interaction between the CD28 antigen expressed by T cells and contact antigens on AML blasts. We and others have proposed that the production of oxygen radicals (including hydrogen peroxide and its derivatives) by normal and leukemic phagocytic cells may significantly contribute to the state of immunosuppression in AML. The phagocyte-derived oxygen radicals strongly suppress the anti-leukemic cytotoxicity of natural killer (NK) cells with ensuing NK cell death by apoptosis, and inhibitors of oxygen radical formation efficiently rescue NK cells from inhibition and apoptosis. These mechanisms may have implications for AML treatment, as exemplified by the use of the T and NK cell activator interleukin-2 (IL-2) in conjunction with the oxygen radical inhibitor histamine dihydrochloride (HDC) as relapse-protective therapy in AML (Blood 108: 88–96).METHODS and RESULTS: The question whether oxygen radical-induced activation apply to CD8+ T cells with spontaneous reactivity against human primary AML blasts has remained unresolved. Autoreactive T cells in AML were recently phenotypically defined as CD3+/8+/45RA+/CCR7 cells (CD8+/45RA+ cells; Blood 100:2132–7). We recovered these cells from human peripheral blood by FACS sorting (FACSAria) with high purity (>98%) and exposed them to exogenous hydrogen peroxide or oxygen radical-producing mononuclear phagocytes. CD8+/45RA+ T cells acquired features of apoptosis at low concentrations of hydrogen peroxide. Also, more than 60% of the CD8+/45RA+ cells acquired features of apoptosis when admixed with autologous mononuclear phagocytes (at a 1:1 phagocyte to T cell ratio, n=11, p<0.0001). HDC, an inhibitor of oxygen radical formation in phagocytes, completely prevented apoptosis in the CD8+/45RA+ T cell subset (n=8, p<0.0001). In the presence of mononuclear phagocytes, HDC synergized with IL-2 in promoting cell cycle proliferation (n=4, p=0.004) and activation (as measured by the acquisition of membrane CD69; n=9, p=0.017) in CD8+/45RA+ cells.CONCLUSIONS: The phenotype of T cells with spontaneous reactivity against AML blasts is highly sensitive to oxidants. By inhibiting oxygen radical formation, HDC efficiently protects these cytotoxic lymphocytes from apoptosis in an environment of oxidative stress. In addition, HDC synergizes with IL-2 to activate and expand CD8+/45RA+ T cells. These mechanisms of T cell activation may be relevant to the prevention of leukemic relapse reported for post-consolidation treatment with HDC/IL-2 in AML.

High Levels of Tumor Load Reduction after Intensive Chemotherapy Favorably Affect the Prognosis of BCR/ABL+ ALL Adult Patients Receiving Imatinib Mesylate Alone as a Post-Consolidation Treatment According to the Italian GIMEMA LAL 0201/A Protocol.

Thirty-six adult patients aged between 20 and 60 years (median age: 44) with BCR-ABL+ ALL were prospectively monitored by Q-RT-PCR between December 2001 to November 2005. All patients were treated according to the GIMEMA LAL 0201/A protocol, in which Imatinib alone, was administered as post-consolidation therapy, in responding patients after high-dose induction and consolidation treatment, at the dosage of 400 mg x 2 daily for at least six months and continued on the basis of the opinion of physicians. Twenty-three (64%) were p190+ and 13 (36%) p210+. At presentation, the median BCR-ABL/ABL ratio was 1.33 (range 0.23 to 7.8). Before Imatinib, all patients were in 1st CR (34 after the first induction and consolidation course; 2 after a salvage treatment). At this time point, the median reduction from baseline in BCR-ABL transcripts, calculated for each individual patients, was 2.1 log (range: 0 to 6.1). In particular, 18 of the 36 cases showing a log reduction of the BCR-ABL/ABL ratio > 2.1 (p190=14 cases; p210 = 4 cases) were considered as good responders to the antecedent chemotherapies, whereas 18 cases (p190=9; p210=9 cases) showing a log reduction ≤2.1 were considered as bad responders. The median reduction from baseline in BCR-ABL levels was 2.49 log (range: 0.00–6.1) and 1.45 log ( range: 0.19–5.34) in p190 and p210 positive cases, respectively (p=.16). During Imatinib treatment, 10 (56%) of the 18 poor responders patients presented a relapse of disease versus 5 (28%) ( 3 =BM; 2=CNS) of the 18 good responders.At last follow-up 16 patients were in first CR; of these patients, only 4 were allo-transplanted (2 good, 2 bad responders), therefore 12 (9 good, 3 bad responders) persisted in first CR maintained by Imatinib alone after a median follow-up of 24 months (range: 7–48). At 24 months, the cumulative incidence of relapse was 29% vs 44% for good and bad responders (p=.034), respectively, whereas, the DFS and OS rates were 65% vs 33% ( p=.0032) and 76% vs 32% (p=.0056) for good and poor responder patients, respectively. Monitoring of MRD was prospectively evaluated at the starting of Imatinib therapy and afterwards at the 3rd, 5th and 6th month. At these time points, the median BCR-BCR/ABL ratio were 0.015, −0.006, −0.008 and −0.009, respectively. In addition to the classification as good/ bad responders, the current variation of BCR-ABL ratio (used as time-dependent covariate in a Cox model), was associated with an increase of the hazard of failure (hazard ratio of an increase by 2 log of the BCR-ABL levels compared to a constant ratio equal to 2.1). In conclusion, Imatinib mesylate is a highly effective post-consolidation treatment for adult Ph+ ALL patients. However, the clinical outcome after Imatinib was significantly affected by the level of molecular response evaluated before the starting of Imatinib, resulting excellent for the good responders but remaining dismal for patients who responded poorly to the initial chemotherapy.

Improved Leukemia-Free Survival after Post-Consolidation Treatment with Histamine Dihydrochloride and Interleukin-2 in AML: A Randomized Phase III Trial.

Background: Histamine dihydrochloride (HDC) potentiates immune-based therapies by protecting pivotal anti-neoplastic lymphocytes from phagocyte-induced suppression. Previous results in AML indicated that post-consolidation treatment with HDC and low-dose interleukin-2 (IL-2) is safe and feasible, and that the combination may prolong leukemia-free survival (LFS).Aims: The primary objective was to determine if post-consolidation treatment with IL-2 and HDC could improve LFS for AML pts in complete remission (CR). Secondary objectives included overall survival (OS), LFS in CR1 and CR>1 subgroups, and safety.Methods: This international, randomized, open-label, phase III study was conducted at 92 centers. From June 1998 to October 2000, 320 AML pts [148 females, 172 males, median age 57 (18–84) yrs] were enrolled in CR after completion of standard consolidation therapy. Pts were stratified by CR1 or CR>1 and randomized to either treatment (n=160) or no treatment (control, n=160) arms. The treatment was self-administered at home and included 10 cycles of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg, sc bid plus HDC (Maxim Pharmaceuticals) 0.5 mg sc bid. For cycles 1–3, each cycle comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. The study arms were well balanced with respect to age, sex, karyotype-based risk, time from CR to inclusion and frequency of secondary leukemia. Pts were followed for relapse and survival using an identical assessment schedule until 3 yrs after last enrollment. All efficacy analyses were intent-to-treat.Results: The median follow-up of living pts was 46 months. For the primary endpoint, treatment with HDC/IL-2 increased LFS in the entire study population (CR1/CR>1, n=320, p=0.026 stratified log-rank test). There was no significant difference in OS (p=0.33). In the analysis of pre-stratified subgroups, one pt was excluded. For CR1 pts (n=262), HDC/IL-2 significantly improved LFS (p=0.011, log-rank test), with 3-year Kaplan-Meier estimates of 26% (control group) and 40% (treatment group). The difference in OS did not reach significance (p=0.16). For CR>1 pts (n=57), outcome was not affected by treatment. Side effects attributable to IL-2 included fever and local inflammatory reactions. HDC treatment induced symptoms of transient vasodilatation. Serious adverse events occurred in approximately 20% of pts in both groups. There were no treatment-related deaths.Conclusions: For AML pts in CR, post-consolidation therapy with HDC and IL-2 was safe and significantly improved LFS compared to standard of care. The benefit observed of HDC/IL-2 treatment appears to be explained by a reduction of relapses in CR1 pts.

Clinical Impact of Q-RT-PCR Monitoring of Minimal Residual Disease in Newly Diagnosed Adult Patients with BCR-ABL+ Acute Lymphoblastic Leukemia Receiving Imatinib Mesylate Alone as a Post-Consolidation Treatment According to the Italian GIMEMA LAL 0201/A Protocol.

Twenty-six adult patients (pts) aged between 22 and 60 years (median age: 46) with BCR-ABL+ acute lymphoblastic leukemia (ALL) were prospectively monitored by Q-RT-PCR between August 2001 and July 2004. All pts entered the GIMEMA LAL 0201/A protocol, in which Imatinib alone, at the dosage of 400 mg x 2 daily for at least six months, was administered as post-consolidation therapy in responding pts after intensive chemotherapy (CHT). Eighteen pts (69%) were p190+and 8 (31%) p210+ with/without the p190. In these two groups, the mean number of BCR-ABL copies at diagnosis (ie: BCR-ABL/ABL x 104) was 13,052 (range: 1,466–35,449) and 22,487 (range: 7,315–78,000) (p=ns), respectively. All pts were in 1st complete hematologic remission (25 pts after the first induction-consolidation course; 1 pt after a salvage treatment). Before Imatinib, 8 of the 18 p190+ pts (44%) showed a BCR-ABL copy reduction of ≥ 3 log compared to the levels at diagnosis, (mean BCR-ABL copies 3.6; range: 0–10), and they were defined as good responders to CHT. The remaining 10 pts (56%), defined as poor responders, showed a reduction of < 3 log (mean copies 2,825.8; range: 12 – 25,245). In the 10 poor responders, BCR-ABL copies constantly increased over time and this was predictive of an hematologic relapse in 8/10 patients. By contrast, 7 of the 8 good responder pts during Imatinib treatment persistently showed levels of BCR-ABL below 10. These 7 pts are in CCR maintained by Imatinib alone at 6, 9, 13, 13, 17, 21 and 23 months, respectively. In 1 pt, at 6 months from the start of Imatinib, a CNS relapse preceded a marked increase in the BCR-ABL copy numbers in BM cells. Therefore, after a median follow-up of 6 months (range 3 – 23), for poor responders, and of 13 months (range 6 – 30), for good responders, the actuarial probability of relapse was 100% and 12.5%, at 24 months (p=.027), respectively. p210+ pts achieved a molecular response rate slightly different respect to the p190+ cases. In fact, before starting Imatinib, only 2 of the 8 cases (25%) analyzed showed a reduction in BCR/ABL copies ≥ 3 log whereas in the remaining 6 pts, 1 relapsed at 6 months, but the other 5 showed a decrease of the BCR-ABL copies that in 2 cases fell below the 3 log reduction after 8 and 12 months, respectively. Altogether, after a median follow-up of 6 months (range: 2–28), 7/8 p210+ pts were in CCR maintained by Imatinib alone without transplant at 2, 4, 5, 6, 19, 24 and 28 months, respectively. In conclusion, Imatinib is a highly effective post-consolidation treatment for adult Ph+ ALL pts being able to maintain and/or to induce a minimum level of BCR-ABL expression, without the high morbidity and mortality relating to allografting procedures. In addition, in the p190+ cases an unsatisfactory molecular response rate after CHT was a powerful predictor of a subsequent clinical resistance to Imatinib.