Gemtuzumab Ozogamicin Arm Research Articles

Multicenter Retrospective Evaluation of Treatment of High-Risk Acute Promyelocytic Leukemia (APL): Results from the Hematology Research Outcomes (HERO) Consortium

Background: Regimens employing all-trans retinoid acid and arsenic (ATRA+ATO) are the backbone of high-risk APL treatment. The APML4 regimen consists of a three-phase treatment approach: induction with ATRA, ATO, and idarubicin; two cycles of consolidation with ATRA+ATO; and maintenance with ATRA, methotrexate, and mercaptopurine. 1 MD Anderson Cancer Center (MDACC) developed a regimen incorporating gemtuzumab ozogamicin (GO) in addition to ATRA+ATO. 2 Differences in tolerability and efficacy between these two approaches are unknown as no comparative data exists. We aimed to describe real-world treatment outcomes for high-risk APL, comparing toxicity between APML4 and ATRA+ATO+GO. Methods We conducted a multicenter, retrospective cohort study including patients treated among six US centers participating in the pharmacist-led collaborative research consortium, HERO. Adults (>18 years) with newly diagnosed high-risk APL (t(15;17)(q24.1;q21.2)) according to the Sanz risk model 3 between April 2014 and June 2022, who received at least one dose of an induction regimen under the institution's high-risk protocol were compared based on induction regimen received. Patients with incomplete records were excluded. The primary endpoint was a composite of mortality, ICU admission, or confirmed infection during induction. Secondary endpoints included individual components of the primary endpoint, other induction-related toxicities, and complete response (CR) rate after induction. Analyses were performed as intent-to-treat which included all patients who received APML4 and ATRA+ATO+GO inductions regardless of consolidation strategies. Chi-square or Fisher's exact tests were utilized to evaluate dichotomous variables. Continuous variables were analyzed via Student's t-test or Mann-Whitney U test. Kaplan-Meier analysis with log-rank test was performed to estimate progression-free survival (PFS) and overall survival (OS). Results Fifty-seven patients with high-risk APL who started either APML4 (n=41) or ATRA+ATO+GO (n=16) as induction treatment met inclusion criteria. Baseline characteristics were balanced (Table 1) except for race and ethnicity, with a higher percentage of non-Hispanic white patients in the APML4 cohort (p=0.020) and a higher percentage of Hispanic/LatinX in the ATRA+ATO+GO cohort (p=0.011). Of evaluated molecular abnormalities, FLT3-ITD was most common (76%). Steroid prophylaxis was more common in the ATRA+ATO+GO cohort (p=0.015). Additional cytoreductive therapy was frequent in both arms: hydroxyurea used more often in the APML4 cohort (p=0.033) and idarubicin in the ATRA+ATO+GO cohort (p<0.001) (Table 1). Induction mortality was 7%, including 3 deaths in the APML4 cohort and 1 in the ATRA+ATO+GO (Table 2; p=1.000). Time to platelet recovery was longer with APML4 than ATRA+ATO+GO (median 27 vs 23 days, p=0.021) as was time to ANC recovery (median 38 vs. 29 days, p=0.020). No additional significant differences in individual safety outcomes were observed. Of note, there was no difference in differentiation syndrome that required dose changes or holds between the two cohorts. There were no detectable differences in treatment effectiveness, with 92.7% of patients in the APML4 arm and 93.8% of patients in the ATRA+ATO/GO arm achieving a CR at end of induction (Table 2). With a median follow-up of 35 months, neither group reached the median for overall survival and the estimated 36-month survival was similar between cohorts; 92.5% (95%CI 84.3-100) for APML4 and 94.1% (95%CI 83.1-100) for ATRA+ATO+GO. Conclusion ATRA+ATO-based regimens yield similar short- and long-term efficacy in a high-risk APL population, though hematologic recovery occurred earlier in the ATRA+ATO+GO cohort. No clinically significant differences in acute toxicities exist between APML4 and ATRA+ATO+GO induction strategies as demonstrated by this real-world multicenter analysis.

A ten-gene DNA-damage response pathway gene expression signature predicts gemtuzumab ozogamicin response in pediatric AML patients treated on COGAAML0531 and AAML03P1 trials.

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.

Gemtuzumab Ozogamicin (GO) In Children With De Novo Acute Myeloid Leukemia (AML) Improves Event-Free Survival (EFS) By Reducing Relapse Risk – Results From The Randomized Phase III Children's Oncology Group (COG) Trial, AAML0531

▪ BackgroundEscalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic alternatives. ObjectiveTo determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML. MethodsPatients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD). ResultsBetween 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in Table 1. Median follow-up was 3.6 (range 0-6.4) years for those alive.Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age <2yr, initial WBC>100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). Table 2 illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). Table 1 shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, Table 2 shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm. ConclusionGO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission. Disclosures:No relevant conflicts of interest to declare.

Drug Transporter ABCB1 SNP Predicts Outcome in Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozagamicin: A Report from Children's Oncology Group AAML0531 Trial

Background: Gemtuzumab Ozogamicin (GO), is first ever approved immunotherapy for relapsed AML patients. GO is a humanized anti-CD33 antibody linked with the toxin calicheamicin gamma. Calicheamicin induces DNA damage and cell death once the linked CD33 antibody facilitates its uptake. Previous studies have shown that the drug efflux transporter PgP1, which is encoded by gene ABCB1, influences the cellular accumulation of calicheamicin. PgP1 activity in leukemic cells is also inversely correlated with GO response in patients with AML. Although GO was withdrawn from market due to lack of benefit and increase in early mortality observed in SWOG-S0106 study subsequent multiple randomized studies have shown benefit of GO with significant improvement observed in patients with favorable cytogenetic risk features. In light of these results and recent favorable voting by FDA oncology drug advisory committee based on results of ALFA-0701 trail demonstrating a favorable risk:benefit profile for GO there is increased enthusiasm among AML investigators. Given the potential comeback of GO, it is very timely to focus efforts on identifying genetic biomarkers that can improve our ability to develop personalized treatment with GO. In this study evaluate whether single nucleotide polymorphisms (SNPs) in ABCB1 gene are predictive of GO response in patients with AML.Method: Genomic DNA samples from 942 patients enrolled in the COG trial AAML0531 who gave consent for the study were genotyped for 12 SNPs in the ABCB1 gene . Since AAML0531 was designed to test the benefit of GO in a randomized manner, we analyzed the effect of ABCB1 genotypes on outcomes and risk of relapse (RR) between patients treated with or without addition of GO (GO vs. No-GO respectively).Results: The ABCB1 SNP C3435T (rs1045642) was significantly associated with outcome when analyzed by GO vs. No-GO arm. Presence of C3435T change has been previously associated with lower PgP1 expression. For AML patients in the GO arm, presence of variant allele (CT and TT genotype) was significantly associated with lower risk of relapse (RR) from the end of course 1 (GO vs. No-GO arm: RR: 30 ± 6%, n = 259 vs. 46 ± 7%, n= 235; P < 0.0001) and better 5-year event free survival (EFS) from study than for those in the No-GO arm (GO vs. No-GO arm: 55 ± 6%, n = 340 vs. 45 ± 5%, n= 337; P= 0.006). However, patients with the CC genotype showed no differences in RR (GO and No-GO arms: 45 ± 10%, n = 97 vs. 40 ± 11%, n= 91; P= 0.514) and EFS (GO and No-GO arms: 44 ± 9%, n = 128 vs. 50 ± 9%, n= 132; P= 0.425) between the GO and No-GO arms (Fig 1). Further the rs1045642 genotype was significantly associated with EFS (CC vs. CT/TT: 44 ± 9% vs. 55 ± 6%; P=0.022) and RR (CC vs. CT/TT 45 ± 10% vs. 30 ± 6%, P=0.007) for patients in the GO arm but for those in the No-GO arm no difference in outcome between the genotypes was observed (RR: P=0.278; EFS P=0.466).Conclusion: Our results show that for the nonsynonymous SNP rs1045642 (C>T) in an drug efflux transporter ABCB1, the presence of T allele is associated with better response in patients treated with GO based as compared to standard arm. Since ABCB1 is involved in efflux of calicheamicin the presence of a low expression T allele might result in higher intracellular accumulation of calicheamicin and thus better response in patients treated with GO. [Display omitted] DisclosuresLoken:Hematologics Inc: Employment, Equity Ownership. Walter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding.

Comparative Efficacy and Safety of Gemtuzumab Ozogamicin (GO) Plus Daunorubicin-Cytarabine Combination and Comparators As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia

Comparative Efficacy and Safety of Gemtuzumab Ozogamicin (GO) Plus Daunorubicin-Cytarabine Combination and Comparators As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

CD33_PGx6_Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

The US Food and Drug Administration recently announced reapproval of gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to develop strategies for effective use of GO. In light of our recent report showing prognostic significance of CD33 splicing single nucleotide polymorphisms (SNPs), the objective of this study was to comprehensively evaluate CD33 SNPs for accurate prediction of patients with AML who are more or less likely to respond to GO. We investigated the five new CD33 SNPs (rs2455069, rs35112940, rs61736475, rs1803254, and rs201074739) for association with CD33 leukemic cell surface expression and clinical response in pediatric patients with AML enrolled in the Children's Oncology Group AAML0531 trial. We further developed a composite CD33 pharmacogenetics (PGx) score using six CD33 SNPs (CD33_PGx6_score) for association with clinical outcome. Four CD33 SNPs were associated with cell surface CD33 levels and clinical response in the GO versus no-GO arms. Therefore, the CD33_PGx6_score was built using directional genotype scores for the previously reported splicing SNP and five new SNPs. Patients with a CD33_PGx6_score of 0 or higher had higher CD33 expression levels compared with patients with a score of less than 0 (P < .001). In addition, patients with a score of 0 or higher demonstrated an improved disease-free survival in the GO versus no-GO arms (62.5% ± 7.8% v 46.8% ± 8.3%, respectively; P = .008) and a reduced risk of relapse (28.3% ± 7.2% v 49.9% ± 8.4%, respectively; P < .001). No improvement from GO was observed in patients with a CD33-PGx6_score of less than 0. Consistent results were observed across the risk groups. In this study, we report a composite CD33_PGx6_score using directional genotype scores of CD33 SNPs. Once validated, our findings hold promise for use of the CD33_PGx6_score to guide efficient use of GO in patients with AML. In addition, because the CD33_PGx6_score considers SNPs with varying abundance in different ethnic groups, it has potential for global application.

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children\u2019s Oncology Group AAML0531 Trial

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.

Outcomes Following Hematopoietic Stem Cell Transplantation in Patients Treated with Chemotherapy with or without Gemtuzumab Ozogamicin for Acute Myeloid Leukemia

▪Introduction: The randomized phase 3 ALFA-0701 study demonstrated improved outcomes with the addition of gemtuzumab ozogamicin (GO) to standard 7+3 chemotherapy in patients with de novo acute myeloid leukemia (AML; Castaigne et al, Lancet 2012). 85 of 271 patients in the study received hematopoietic stem cell transplantation (HSCT) at any time during study. Here we describe transplant characteristics and compare survival and veno-occlusive disease (VOD) outcomes in these patients.Methods: Patients aged 50-70 years with de novo AML who received standard chemotherapy treatment (daunorubicin and cytarabine) with the addition of GO (GO arm) or alone (control arm) and underwent HSCT as part of the open-label, randomized phase 3 ALFA-0701 study were included in this analysis. Patients who experienced complete remission could be considered for allogeneic HSCT according to performance status, age, the existence or not of a related donor, and cytogenetic and molecular risk categories. Allogeneic HSCT was considered for patients in the European LeukemiaNet (ELN) intermediate 2 or adverse risk group. The type of pre-transplant conditioning regimen was left to the discretion of the transplant center. An interval of 2 months between the last dose of GO and HSCT was recommended. Post-transplant survival was defined as the time from HSCT to death due to any cause. Data on VOD events were extensively collected from screening up to the patient's death or the data collection cutoff date (November 1, 2013), whichever occurred first.Results: A total of 32 patients in the GO arm and 53 patients in the control arm underwent HSCT (Table). All patients received allogeneic HSCT except for 1 patient in the control arm who received autologous HSCT. In the GO arm, 17 patients received HSCT in first remission, 2 after induction failure, and 13 after relapse. In the control arm, 22 patients received HSCT in first remission, 9 after induction failure, and 22 after relapse. Median (range) age was 60 (51-67) years in the GO arm and 59 (50-69) years in the control arm, and 47% and 45% were male, respectively. The distribution of ELN risk classification was similar for the GO vs control arm, respectively (favorable/intermediate: 63% vs 72%; adverse: 28% vs 25%). Only 1 patient in the control arm who received GO as follow-up therapy received transplant <2 months after the last GO dose.As of April 30, 2013, 18 (56%) patients in the GO arm and 28 (53%) in the control arm had died: 7 and 16 of these deaths were attributed to disease progression/relapse, and 4 and 7 were attributed to graft versus host disease, respectively. Median post-transplant survival was 21.4 months in the GO arm vs 17.1 months in the control arm, with 3-year survival probability (95% confidence interval [CI]) of 39% (22-57) vs 45% (31-58), respectively (hazard ratio [HR]=0.97). Median post-transplant survival was not yet reached in the GO arm vs 19.2 months in the control arm for patients who received HSCT while in first remission, with 3-year survival probability (95% CI) of 53% (28-73) vs 46% (24-64), respectively (HR=0.71; Figure). In patients who received HSCT after relapse or induction failure, median post-transplant survival was 14.5 vs 10.5 months in the GO vs control arm, with 3-year survival probability (95% CI) of 21% (4-48) vs 44% (26-61), respectively (HR=1.42).In all, 3 patients in the GO arm and 2 in the control arm (both of whom received GO as follow-up therapy) developed VOD; 3 of these cases (2 in GO arm; 1 in control arm) occurred post-transplant. All but 1 patient fully recovered.Conclusions: Similar post-transplant outcomes were observed in patients with AML treated with standard chemotherapy with and without GO. The use of GO was not associated with an excess of VOD events after HSCT. The results suggest that the administration of GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant mortality and thus does not preclude the use of transplant as consolidation treatment following induction or salvage treatment. [Display omitted] DisclosuresBenner:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Castaigne:Pfizer: Honoraria, Research Funding.

CD33 Splicing Polymorphism Is a Strong Predictor of Therapeutic Efficacy of Gemtuzumab Ozogamicin in De Novo AML: Report from COG-AAML0531 Study

▪Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging as therapeutic for AML. We have previously discovered polymorphisms in CD33 coding region that might be associated with outcome in patients treated with GO. One particular coding polymorphism, CD33-SNP rs12459419-C>T (Ala14Val), is located within the splice enhancer region of exon-2, leading to expression of an alternate splice isoform lacking exon-2. This alternate splice isoform (D2-CD33), would encode a protein product lacking the IgV domain, which is the binding site for GO and most if not all CD33 antibodies used for diagnostic immunophenotyping. We therefore hypothesized that the SNP rs12459419 genotype would be associated with differential expression of the D2-CD33 transcript levels and differential cell surface CD33 expression leading to genotype determined differential response to GO.We evaluated the genotype frequency and functional significance of rs12459419, its association with CD33 cell-surface expression on leukemic blasts, and clinical response in 816 children and young adults with AML randomized to GO vs. No-GO in the COG trial AAML0531.The CD33 SNP rs12459419 genotype frequency was-CC=51%, CT=39% and TT=10% in patients, similar to the observed frequency in the general population. Correlation of SNP allele frequency with CD33 transcript levels and surface CD33 expression (as determined by p67.6 antibody) demonstrated that the T-allele was significantly associated with higher levels of D2-CD33 transcript (P=4.7e-11, Figure 1) and with lower diagnostic leukemic cell CD33 surface intensity (P=1.93e-29).Clinical outcome based on the SNP genotype demonstrated that patients with CC-genotype had significantly lower RR of 26%±7% in the GO arm whereas those in the No-GO arm had a RR of 49%±9% (HR=0.468, P<0.001). The corresponding DFS for CC genotype patients in the GO and No-GO arms was 65%±7% and 46%±9%, respectively (HR=0.597, P=0.004; Figure 1). In contrast, in those with heterozygous CT or homozygous TT genotype, GO exposure provided no clinical benefit in RR (CT: 38%±9% vs. 37±10%, P=0.975; TT: 46%±20% vs. 46%±20%, P=0.798) nor DFS (CT: 56%±9% vs. 60%±10% GO vs. No-GO, P=0.821; TT: 51%±20% vs. 54%±18%, GO vs. No-GO, P=0.972, Figure 1).We further evaluated the impact of the CD33 genotype on the efficacy of GO in different risk groups as well as in high vs. low CD33 expression cohorts. Patients in the low-risk (LR) group with the CC genotype treated with GO had a RR of 10%±8% vs. 37%±13% (P< 0.001) from remission. Standard-risk patients with CC genotype had a RR of 41±12% vs. 59±12% (P=0.056) and high-risk patients had a RR of 36%±27% vs. 70%±32% (P=0.073) for the GO and No-GO arms. In contrast there was no benefit of addition of GO in patients with the CT or TT genotypes within each risk group.Since CD33 expression has been recently associated with GO efficacy, we evaluated the association of rs12459419 genotypes in patients with low (N=153) and high CD33 (N=436) cell surface expression quartile-1 and quartiles-2-4, respectively. Significant improvement in RR was observed in patients with the CC genotype in the GO arm over those in the No-GO arm (P=0.001) within quartiles 2-4, but not with the CT/TT genotype (P=0.112). Within lower CD33 expression (quartile-1) cohort, a similar trend towards improvement in RR compared with those in the No-GO arm (P=0.055) was observed although the CC genotype was less frequent.Multivariate cox regression analysis that included genotype, risk status, and CD33 expression demonstrated that CD33 CC genotype was an independent predictor of response to GO (HR= 0.45, P<0.001 for RR and HR=0.57, P=0.003 for DFS).The rs12459419 genotype mediates expression of the GO binding site and informs on which patients should receive GO. The knowledge of CD33 genotype and prediction of response to GO provides opportunities to use patient genotypes for selecting CD33-targeted therapies. Given only half of the patients are expected to have a response to GO, we propose that all prior GO containing studies be re-evaluated for response based on patient CD33 genotype. The efficacy of GO in patients with an appropriate antibody binding domain also raises the possibility of developing next-generation CD33 immunoconjugates with epitopes targeted to regions not affected by alternative splicing and SNPs. [Display omitted] DisclosuresLoken:Hematologics: Employment, Equity Ownership.

ABCA3 Expression Predicts Response to Gemtuzumab Ozogamicin in AML

Background. The ATP binding cassette transporter 3 (ABCA3) has been recently found to induce a significant reduction in cytotoxicity following exposure to anthracyclines, mitoxantrone, etoposide, Ara-C, vincristine, and rituximab. ABCA3 acts through the modulation of multivesicular bodies (MVB) and contributes to drug sequestration in late endosomal organelles, i.e. MVB and lysosomes. Studies having investigated the prognostic impact of ABCA3 expression in AML have yielded conflicting results as ABCA3 expression has both been reported to exert unfavorable or neutral effects on patient outcomes. In addition, the small sample size of these studies precluded the use of multivariate analyses.Methods. Our goal was to investigate the prognostic impact of ABCA3 expression in adult patients with AML treated with IC with or without gemtuzumab ozogamicin (GO). To this end we investigated the relationship between ABCA3 expression and EFS in a representative series of 221 AML homogeneously treated in the ALFA-0701 trial. qRTPCR amplification of conserved ABCA3 mRNA sequences, as identified with FasterDB database, was performed with GUS and ABL as reference genes. Primer sets were complementary to conserved ABCA3 exons 6-7 and exon 19-20 junctions. Patients were given a 3+7 induction course without (control group, n=110) or with fractionated intravenous GO (n=111) (Castaigne S, Lancet 2012; 379:1508-1516).Results. Among the 278 randomized patients, 221 had available bone-marrow diagnostic samples with high-quality RNA. The same benefits associated with GO were observed in the 221 patients from the present study as in the entire trial population. Overall, median age, CR rate, relapse rate, median follow-up, 3-years EFS were 62.1 years, 76.5%, 66%, 47.45 months, 28±3%, respectively. There was no significant difference in the level of ABCA3 expression between responders and non-responders. In the 169 responders, ABCA3 expression at diagnosis was more than 3-fold higher in the 111 remitters who subsequently relapsed than in the 58 patients who remained in persistent CR (p=0.033). The level of ABCA3 expression was significantly lower in ELN favorable group than in intermediate and adverse risk AML (p= 0.004) and negatively correlated with CD33 expression (R=-0.272, p<10-4). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±3 vs 45±7 % p=0.002). Multivariate analysis identified age, treatment arm, and ELN risk group as independent prognostic factors for EFS. In the control group, there was no significant association between ABCA3 expression and CR rate, relapse rate, and EFS. In the 111 patients within the GO arm, there was no significant difference in the level of ABCA3 expression between responders and non-responder whereas in the 89 responders, ABCA3 expression at diagnosis was more than 7-fold higher in the 53 remitters who subsequently relapsed than in the 36 patients who remained in persistent CR (p=0.006). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±5 vs 64±9 % p=0.0002). Multivariate analysis identified ABCA3 expression, cytogenetics, CD33 expression, and ECOG as independent prognostic factors for EFS (Figure 1).Conclusion. WhileABCB1 has been previously found to attenuate GO-induced cytotoxicity in AML cells (Walter RB, Blood 2003; 102:1466-1473), present results indicate that higher ABCA3 expression independently predicts poor outcome in AML patients treated with fractionated GO and intensive chemotherapy (IC). GO is an anti-CD33 antibody carrying a toxic calicheamicin derivative that, after hydrolytic release within lysosomal vesicles, induces DNA strand breaks, apoptosis, and cell death. Whether the clinical effect of ABCA3 expression relies on the modulation of CD33 internalization, calicheamicin release or combination thereof is under investigation. Finally our results encourage inhibiting ABCA3, such as with indomethacin, in order to overcome drug resistance in AML treated with GO-IC. [Display omitted] DisclosuresThomas:Pfizer: Consultancy.

HFE Gene Mutation Status Predicts Response to Gemtuzumab Ozogamicin in AML

BACKROUND: The protein defective in type 1 hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins, associates with beta2-microglobulin and is implicated in membranous protein recycling. Gemtuzumab ozogamicin (GO), a monoclonal antibody directed against CD33 linked to a cytotoxic agent, has been used with controversial effects in acute myeloid leukemia (AML). Internalization of GO is required for its anti-leukemic effect. Therefore, we hypothesized that H63D or C282Y HFE gene mutations may impair GO activity by preventing its internalization.METHODS: Wild type, C282Y and H63D HFE leukemic cells and primary cell were used to assess effects of GO alone or in combination with cytarabine on cell proliferation and apoptosis. Flow cytometry, confocal and AMNIS stream analysis were used to evaluate GO internalization. HFE mutations were analyzed by PCR analysis on DNA from patients included in clinical studies. Post-hoc subgroup analysis was performed to assess in vivo the role of HFE status on GO efficacy and toxicity among the 280 patients of the ALFA-0701 study as a study cohort (patients aged 50-70 years; GO 3mg/m² on days 1, 4, and 7 of chemotherapy and on day 1 of the first and second induction ; total dose 15 mg/m² ) and then on the GOELAMS-LAM 2006 IR study (patients aged 18-60 years; GO 6 mg/m² on day 4 of chemotherapy during the induction and the first consolidation; total dose 12 mg/m²) and UK NCRI AML17 study (patients aged 18-81 years; GO 3 vs 6 mg/m² on day 1 of chemotherapy but not during consolidation) as validating cohorts.RESULTS: GO induced cell death by apoptosis in AML cell lines and primary cells in a dose-dependent manner and synergistically in combination with cytarabine. However, the IC5O of GO was significantly higher in HFE mutated cells (125 vs 10 ng/mL p<0.001). To further understand this phenomenon, the CD33 internalization was analyzed upon GO or anti-CD33 antibody exposure. In line with the cytotoxic effect, CD33 was significantly less internalized in HFE mutant cells (17.4% vs 65.1% after 1 hour, p<0.01).HFE mutations were screened in 242 of the 280 ALFA-0701 patients with DNA available. There were 155 non-mutated patients (64%), 68 (28%) heterozygous for H63D, 11 (5%) heterozygous for C282Y, and 8 (3%) homozygous for H63D, which is consistent with the prevalence of the various mutations in the French population. Median age was 62 years (50-71) and the M/F ratio was 0.5, equally distributed among the different groups. No significant difference was observed with respect to the diagnosis of various hematological parameters, including white blood cell count, blasts number, cytogenetic subgroups, molecular mutation incidences (FLT3, NPM1, CEBPA, IDH, DNMT3A).In the ALFA-0701 study cohort, HFE wild-type (WT) patients had a higher overall survival (OS) when treated in the GO arm (median, not reached vs 19.5 months, p=0.0193). In contrast, OS was similar among patients with heterozygotes HFE mutations treated in the GO and the control arm (median, 19.9 vs 21.9, p=0.9675).In confirmatory cohorts, GO treatment led to a trend to increased OS in the GOELAMS-LAM 2006 IR cohort only in HFE WT patients (4-year OS with GO 62% vs 48%, p=0.08) but not in mutated patients (4-year OS with GO 73% vs 64%, p=0.45). Furthermore, in this cohort in the FLT3 WT patients subgroup, GO further improve OS in WT patients (4-year OS with GO 72% vs 50%, p=0.017), but not in patients with heterozygous HFE mutation (4-year OS with GO 80% vs 65%, p=0.23) In the UK NCRI AML17 cohort, which used GO only during induction, 245 patients were randomized between GO at 3mg/m2 and 6mg/m2 and evaluated for HFE status. Overall there was no effect of GO dose on outcomes, and no evidence of either any heterogeneity by HFE, nor any subgroup, which showed a differential effect of GO dose.CONCLUSIONS: Future studies should focus on optimising the fractionated schedule for GO at the 3mg/m2. Fractionated high doses (3x3mg/m2) during induction and single dose during consolidation seems to be the best schedule. Most importantly, the effect of GO treatment differed between HFE WT and heterozygote mutated AML patients. GO only increased OS among HFE WT patients. This is likely related to impaired internalization of the CD33 target. Our data suggest that HFE status should be used as a companion test to predict outcome of AML treated with GO. DisclosuresNo relevant conflicts of interest to declare.

Final Analysis of the ALFA 0701 Study

▪Aim:The first analysis of the ALFA-0701 study, testing the addition of gemtuzumab ozogamicin (GO) to standard treatment in de novo AML patients aged 50 to 70 years, was presented at ASH 2011 and showed a benefit in 2-year estimated EFS (primary endpoint of the study) (P=0.0018), RFS (P=0.0009) and OS (p=0.03). With a longer median follow up for alive patients of 43 months (reference date: 04/30/2013), we present here the final analysis of this study.Methods:Patients were randomized to receive induction therapy with daunorubicin (DNR) 60 mg/m2 for 3 days and cytarabine 200 mg/m2 for 7 days ± fractionated doses of GO (3mg/m2 on days 1, 4, 7). Patients in CR/CRi received 2 consolidations courses of intermediate doses of cytarabine ± one dose of GO (3mg/m2on day 1, maximum dose: 5mg), according to initial randomization. From March 2008 to November 2010, 278 patients were included.Results:CR+CRi was observed in 215/278 patients, 103/139 in control and 112/139 in GO arm (p=0.25). Primary resistant patients were 30/139 in control and 18/139 in GO arm (p=0.08). There were 6/139 (4%) induction deaths in control and 9/139 (6%) in GO arm (P=0.41).In this final analysis, with follow-up ranging from 30 up to 63.5 months in alive patients, the EFS and RFS benefits associated with GO were still observed, with estimated 3-year EFS at 19% in control versus 31% in GO arm (HR=0.66, 95%CI: 0.50-0.87; median: 9.7 vs. 15.6 months; p=0.0026) and 3-year RFS at 25% versus 38% (p=0.006). However, OS data did not confirm benefit with 3-year OS at 36% in control and 44% in GO arm (HR=0.82, 95%CI: 0.60-1.10; median: 20.8 vs 25.4 months; p=0.18). At the reference date, 132 patients had relapsed (69 control, 63 GO). After relapse, most patients received either intensive salvage with idarubicin and cytarabine (28 control, 42 GO) or GO as a single agent or in combination (20 control, 1 GO). A minority of patients received azacytidine (10 control, 8 GO) or supportive care (11 control, 12 GO). Second CR rate was 66% after intensive salvage, 47% after GO-containing salvage, and 5% after azacytidine. Cumulative incidence of second CR (42% in control and 51% in GO arm) did not differ according to the randomization group (p=0.38). Overall survival after relapse did not differ according to the randomization group. There was no evidence of difference in survival after relapse among those patients who received intensive or GO-containing salvage (2-year post-relapse OS, 31% and 37% respectively).Overall throughout the study, 47 patients in control and 33 in GO arm received an allogeneic stem cell transplant (SCT) either as primary resistant patients (6 and 3, respectively) or in CR1 (23 and 17, respectively) or after relapse (18 and 13, respectively). The cumulative incidence of SCT did not differ significantly between the two arms (p=0.29). Post-SCT survival did not differ between the two arms.Prognostic analyses were performed including age, gender, baseline WBC, ECOG, cytogenetics and the following gene mutations: NPM1, FLT3-ITD, IDH1, IDH2, RUNX1 and DNMT3A. Univariate prognostic analyses for EFS showed that besides treatment arm, cytogenetic and DNMT3Amutation were the only prognostic factors identified. After adjustment on these factors, GO arm remained significantly associated with longer EFS (p=0.013).The effect of treatment arm was then analyzed in the patient subsets: age (60-year cutoff), cytogenetics, FLT3-ITD, NPM1 and DNMT3Amutations. No significant heterogeneities were observed across these subsets for EFS or OS and the tests for interaction were negative, though the effect of GO was not observed in patients with unfavorable cytogenetics.In terms of safety, 68 and 101 SAEs were reported in 60 (43%) and 79 (57%) patients, in control and GO arm respectively. More patients from GO arm experienced more than one SAE (P= 0.031). Persistent thrombocytopenia (<50.10.9/L) by day 45 after induction or consolidation were reported in 21 patients (15%) in the GO arm compared to 4 patients (2%) in the control arm (P= 0.0001).Conclusion. Final analysis of the ALFA 0701 study with a longer follow up confirms the efficacy of adding GO to standard chemotherapy in AML treatment on primary endpoint EFS and on RFS. However, the gain in OS was no longer observed. After relapse, a similar number of patients reached second CR and were transplanted in second CR in the two arms. Of note, one third of patients from the control arm received GO at the time of relapse. [Display omitted] DisclosuresCastaigne:Pfizer Inc: Consultancy, Honoraria. Off Label Use: Gemtuzumab Ozogamicin is not authorized for previously untreated AML..

Improved Overall Survival with Gemtuzumab Ozogamicin (GO) Compared with Best Supportive Care (BSC) in Elderly Patients with Untreated Acute Myeloid Leukemia (AML) Not Considered Fit for Intensive Chemotherapy: Final Results from the Randomized Phase III Study (AML-19) of the EORTC and Gimema Leukemia Groups

▪Background: An unmet medical need persists for elderly patients (pts) with AML who are deemed not to be fit for intensive chemotherapy. Such pts are usually treated with BSC and hydroxyurea or low-dose cytarabine, but outcomes are dismal. The immunoconjugate GO has shown single agent efficacy and tolerability in older pts with relapsed AML. The AML-19 study was designed as a sequential phase II/III trial comparing GO monotherapy to BSC (including hydroxyurea if clinically indicated) in pts age ≥ 61 yrs with previously untreated AML who were considered unfit for intensive chemotherapy (or refused it). Of the two induction schedules of GO (total dose 9 mg/m2 delivered in 2 or 3 fractions over one week) under comparison in the phase II part of the study, the 2-fraction regimen was found to have the best efficacy profile to warrant phase III comparison with BSC (BJH 2010; 149:376). We herein report the final results of the phase III part of the study.Methods: Untreated pts with de novo or secondary AML, adequate renal and hepatic function, and WBC count <30x109/L at baseline (a short course of hydroxyurea permitted) were centrally randomized 1:1 (stratified by age, WHO PS, CD33 expression on marrow blasts, WBC at diagnosis, and center) to receive either a single induction course of GO (6 mg/m2 day 1 and 3 mg/m2 day 8) or BSC. Pts with no evidence of disease progression following GO induction could receive up to 8 monthly infusions of the drug at 2 mg/m2. The primary objective of the study was to compare overall survival (OS) in the two groups. A total of 210 deaths was required in order to detect a hazard ratio (HR) of 0.63 for OS, with 90% power and 2-sided alpha=5%.Results: Between 11/2004 and 03/2013, 237 pts were randomized from 35 European sites. The intention-to-treat population comprised 118 pts in the GO arm and 119 in the BSC arm. The median age was 77 years (range 62-88) with 64% of pts over 75 years. Baseline characteristics were well balanced between arms. At the final analysis (05/2014 cutoff), 228 deaths occurred: 113/118 (95.8%) in the GO arm, and 115/119 (96.6%) in the BSC arm. GO significantly improved OS (median 4.9 vs 3.6 months; 45.9% vs 29% alive at 6 months; 24.3% vs 9.7% alive at 1 year; 10.3% vs 6.9% alive at 1.5 year; HR, 0.69; 95% CI, 0.53-0.90; P=0.005) compared with BSC. Subgroup analyses based on stratification factors and other baseline characteristics showed that the OS benefit was generally consistent among subgroups, with a greater effect seen in pts with good/intermediate cytogenetics (median 7.3 vs 3.8 months; HR, 0.48; 99% CI, 0.31-0.75), in those with high CD33 expression (≥81% positive blasts; median 5.5 vs 3.8 months; HR, 0.47; 99% CI, 0.30-0.74), as well as in those with secondary AML (median 7 vs 4 months; HR, 0.55; 99% CI, 0.33-0.91). Among 111 pts who received at least the first dose of GO, the overall complete response rate was 27% (CR 15.3%, CRi 11.7%), and the overall disease control rate (including PR in 5.4% and stable disease for >30 days in 24.3%) was 56.7%. Of the 30 pts who achieved CR/CRi, 28 later relapsed or died in remission (1 infection, 2 general physical deterioration, 2 unknown cause), and the median disease-free survival (DFS) was 5.3 months with a 1-year DFS of 20%. CR/CRi pts had a median survival from remission of 8.2 months, with 40% alive at 1 year. The 30-day all-cause mortality from randomization was comparable in the GO (10.8%) and BSC (13.5%) arms. Most frequent grade 3+ non-hematologic adverse events (AEs) for GO vs BSC were infection (35.1% vs 34.3%), febrile neutropenia (18% vs 23.7%), bleeding (12.6% vs 12.3%), fatigue (11.7% vs 21%), and cardiac toxicity (6.3% vs 14%). Severe liver dysfunction occurred infrequently (2.7% vs 1.8% for GO vs BSC), and no episodes of VOD were reported. Overall, AEs led to GO discontinuation or death in 27 pts (24.3%).Conclusions: Compared with BSC including hydroxyurea as necessary, single agent GO in the dose/schedule chosen significantly improved OS in elderly AML pts not considered fit for intensive chemotherapy, with an acceptable safety profile. Of note, estimates of the benefit of GO were greater in pts presenting with better-risk cytogenetics, high CD33 expression on blast cells, or secondary disease. DisclosuresOff Label Use: Gemtuzumab Ozogamicin in AML.

MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin.

We analysed the prognostic significance of minimal residual disease (MRD) level in adult patients with acute myeloid leukemia (AML) treated in the randomized gemtuzumab ozogamicin (GO) ALFA-0701 trial. Levels of WT1 and NPM1 gene transcripts were assessed using cDNA-based real-time quantitative PCR in 183 patients with WT1 overexpression and in 77 patients with NMP1 mutation (NPM1mut) at diagnosis. Positive WT1 MRD (defined as > 0.5% in the peripheral blood) after induction and at the end of treatment were both significantly associated with a higher risk of relapse and a shorter overall survival (OS). Positive NPM1mut MRD (defined as > 0.1% in the bone marrow) after induction and at the end of treatment also predicted a higher risk of relapse, but did not influence OS. Interestingly, the achievement of a negative NPM1mut MRD was significantly more frequent in patients treated in the GO arm compared to those treated in control arm (39 % versus 7% (p=0.006) after induction and 91% versus 61% (p=0.028) at the end of treatment). However, GO did not influence WT1 MRD levels. Our study supports the prognostic significance of MRD assessed by WT1 and NPM1mut transcript levels and show that NPM1 MRD is decreased by GO treatment.

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.

Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials

Gemtuzumab ozogamicin (GO) is a targeted antineoplastic agent comprised of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Previous trials have showed conflicting results concerning the efficacy and toxicity of adding GO to induction chemotherapy for newly diagnosed acute myeloid leukemia (AML). A systematic review and meta-analysis was conducted to resolve this controversial issue. Summary data from five randomized phase III trials compared adding GO to induction chemotherapy with induction chemotherapy alone for newly diagnosed AML were meta-analyzed. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and relapse-free survival (RFS), and pooled odds ratios (ORs) and 95% CIs for complete remission (CR) rate, incidences of resistance disease, relapse and toxicity were calculated. Data of 3596 patients (1798 GO and 1798 controls) from five randomized phase III trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, 95% CI 0.86-1.00, P=0.05) and RFS (HR 0.87, 95% CI 0.79-0.95, P=0.003), decreased the incidences of resistant disease (OR 0.71, 95% CI 0.55-0.93, P=0.01) and relapse (OR 0.75, 95% CI 0.63-0.90, P=0.002), but had no effect on CR rate (OR 1.15, 95% CI 0.91-1.46, P=0.24). Sensitivity analysis yielded similar results. Subgroup analysis identified that cytogenetics might be an influencing factor for the effect of adding GO. In addition, the risks of grade 3-4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in GO arm. Adding GO to induction chemotherapy for newly diagnosed AML can significantly prolong OS and RFS, decrease incidences of resistant disease and relapse, but may increase risks of grade 3-4 nausea/vomiting, diarrhea and liver AST elevation.

The Addition Of Gemtuzumab Ozogamicin (GO) To Induction Chemotherapy Reduces Relapse and Improves Survival In Patients Without Adverse Risk Karyotype: Results Of An Individual Patient Meta-Analysis Of The Five Randomised Trials

IntroductionGemtuzumab ozogamicin (GO, Mylotarg) in AML treatment remains controversial: some studies report significant survival benefits either overall or in patient subgroups, but one study showed no, with an excess of early mortality in the GO arm. The five trials so far reported had the common aim of augmenting standard induction chemotherapy which lends itself to a meta-analysis, to determine whether the totality of the evidence demonstrates any benefit for GO, and/or in which specific subgroups of patients. We therefore performed an individual patient data (IPD) meta-analysis of these trials. An IPD meta-analysis has considerable advantages over a published data meta-analysis. Analyses can take into account updated data, unpublished trials, and also look at stratified analyses to identify subgroups of patients. Methods and MaterialsThe 5 trials combining GO with the first course of standard induction chemotherapy were identified, the SWOG-0106 study (ClinicalTrials.gov Identifier: NCT00085709), the ALFA-0701 trial, the UK MRC/NCRI AML15 & 16 trials, and the GOELAMS AML2006IR trial. The last of these is so far unpublished. Updated datasets were requested from all trialists. A total of 3339 patients, ranging in age from 0 to 84 were recruited. Information was requested on age, sex, de Novo/Secondary disease, performance status, cytogenetics, FLT-3 ITD, NPM1 status, survival, relapse, remission, and stem cell transplant. Outcomes were assessed using standard meta-analytic techniques, where patients within the same trial were compared and then summary statistics combined to obtain overall estimates. Heterogeneity between trials, and interactions between treatment and baseline covariates were explored using standard heterogeneity and trend statistics. ResultsThe addition of GO did not change remission rate (OR 0.91, 95% CI 0.77-1.07, p=0.3). However, there was a suggestion of slightly greater early mortality (30-day mortality HR 1.28 (0.97-1.70) p=0.08. Overall survival was improved (HR 0.89 (0.82-0.97) p=0.01), due to a significant reduction is relapse (HR 0.80 (0.72-0.89) p=0.00006), leading to significantly improved survival from remission (HR 0.84 (0.76-0.94). p=0.001). In all cases there was no significant heterogeneity between trials, although there was a suggestion that the excess early mortality was greater in patients given higher dose of GO. In analyses stratified by baseline covariates, there was no evidence of significant interaction between either age or FLT-3 ITD status and the effect of GO on survival (p=0.9 for trend by age, p=0.9 for heterogeneity by ITD mutation status). However, there was a highly significant interaction between cytogenetic risk group, as defined by each cooperative group, and treatment (p=0.003 for trend, p=0.006 for heterogeneity). There was highly significant benefit for patients with favourable (HR 0.50 (0.33-0.77) p=0.001) and intermediate (HR 0.85 (0.76-0.96) p=0.007) risk patients, but no evidence of benefit for patients with adverse risk cytogenetics (HR 1.04 (0.86-1.25) p=0.7). ConclusionsThe combined evidence from 5 randomised trials of GO given with course 1 of induction chemotherapy shows a significant benefit in survival which more than outweighs any possible increase in early mortality. However, the benefit appears to be restricted to patients who have favourable or intermediate risk cytogenetics, with the greatest benefit in patients with a core binding factor leukaemia, although survival is still highly significantly improved in intermediate risk patients. On the basis of this IPD meta-analysis, adding GO to induction improves survival in the majority of patients with AML with no restriction by age of FLT3 ITD mutation status.On behalf of the GO trialists collaborative group.The SWOG-0106 Study was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926 and in part by Pfizer Pharmaceuticals. Disclosures:Off Label Use: Gemtuzumab Ozogamicin in AML.

Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)

This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS). The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

Minimal Residual Disease Assessed by WT1 Expression and NPM1 Mutations Specific RQ-PCR Assays Identifies Patients with Distinct Outcomes in the ALFA 0701 Trial and Is Decreased by Treatment with Gemtuzumab Ozogamicin

AbstractAbstract ▪659▪This icon denotes a clinically relevant abstract Background:NPM1 mutations and WT1 expression are frequently identified in acute myeloid leukemia (AML). Both markers have been reported as suitable molecular target for minimal residual disease (MRD) monitoring. Recently, Gemtuzumab Ozogamicin (GO) has been shown to improve event free survival and overall survival in adult AML. Aims:To follow MRD in AML patients with NPM1 mutations (NPM1mut) and/or WT1 expression (WT1+) and treated in the randomized ALFA 0701 GO trial conducted by the Acute Leukemia French Association (Castaigne et al, Lancet 2012), in order to validate their prognostic significance and to evaluate the effect of GO on MRD response. Methods:The ALFA 0701 trial included 278 patients aged 50–70 years with newly-diagnosed de novo AML, randomized to receive or not five doses of 3 mg/m2 GO, on day 1, 4 and 7 of standard induction chemotherapy and on day 1 of two consolidation chemotherapy courses, respectively. A total of 77 NPM1mut (35 in control arm, 42 in GO arm) and 178 WT1+ (87 in control arm, 91 in GO arm) AML patients were studied. WT1 + at diagnosis was defined as a ratio WT1/ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples. PB and BM samples were collected at diagnosis, after induction and after each consolidation course. MRD levels were assessed using cDNA-based real-time quantitative PCR (RQ-PCR) and reported as the ratio NPM1mut or WT1 transcript/100 ABL transcript. Occurrence of a MRD level below the threshold (NPM1mut <0.1% and WT1 transcript < 0.5% in PB) was defined here as a good MRD response. The prognostic value of MRD was assessed by comparing the outcome of good versus poor MRD responders after induction in terms of cumulative incidence of relapse (CIR) at 18 months. Effect of GO was then evaluated by comparing MRD response in both treatment arms. Results:178 patients (favorable cytogenetics: 4%, intermediate: 69%, unfavorable: 27%) were WT1+. WT1 transcript levels at diagnosis had no prognostic impact on complete remission (CR) rate or CIR. In the 104 patients who achieved CR, post-induction WT1 MRD level was predictive of relapse: 18-month CIR was 70% (95%CI: [49% - 84%]) in poor responders (n=31) versus 38% [26% - 50%] in good responders (n=73) (p=0.0001). When adjusted on cytogenetics, randomization arm and FLT3-ITD status, WT1 MRD remained independently associated with relapse (HR: 2.43, [1.25 – 4.75], p=0.009).Similarly, NPM1mut transcript levels at diagnosis had no prognostic impact on CR rate or CIR. Among the 67 NPM1mut patients who achieved CR, post-induction NPM1mut MRD level was predictive of relapse: 18-month CIR was 64% [45% – 70%] in poor responders (n=50) versus 25% [10% – 42%] in good responders (n=17) (p=0.0007). When adjusted on randomization arm and FLT3-ITD status, NPM1 MRD remained independently associated with relapse (HR: 4.2, [1.2 – 14.3], p=0.02).We were able to evaluate both MRD markers in 53 patients after induction (NPM1+/WT1+ n=16, NPM1+/WT1- n=24, NPM1-/WT1- n= 13). 18-month CIR was significantly different in the 3 groups (respectively 69% [38% - 87%], 40% [19% - 60%] and 25% [5% - 51%], p=0.008). In patients with poor MRD response assessed by NPM1mut, the presence of a positive WT1 MRD level was associated with a higher CIR.NPM1 MRD good response was more frequently observed in GO arm as compared to control arm (OR: 4.38 [2.12 – 9.03], p<0.0001). The rate of good NPM1 MRD response was 41% versus 7% after induction, 76% versus 35% and 93% versus 62% after first and second consolidation in GO and control arms respectively. WT1 MRD good response was more frequently observed in GO arm, although not reaching statistical significance (OR: 1.84 [0.89 – 3.77] p=0.098). The rate of good WT1 MRD response was 76% versus 65% after induction, 87% versus 66% and 87% versus 80% after first and second consolidation, respectively in GO and in control arms (figure 1). Conclusion:Our study confirms the predictive value of MRD based on NPM1 mutations and WT1 expression in patients treated in the ALFA 0701 randomized trial. In multivariate analysis, WT1 and NPM1 MRD levels remained independent prognostic factors for relapse. We showed that treatment with GO significantly improved MRD response in adult AML. [Display omitted] Disclosures:Castaigne:Wyeth: Consultancy.