Addition Of Gemtuzumab Ozogamicin Research Articles

Addition of single dose gemtuzumab ozogamicin to intensive induction chemotherapy in core-binding factor acute myeloid leukemia

In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3 mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Addition of Single Dose Gemtuzumab Ozogamicin to Intensive Induction Chemotherapy in Core-Binding Factor Acute Myeloid Leukemia

Background: In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). The survival benefit was observed with a lower dose or fractionated schedule of GO. Given the heterogenous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We report our outcomes of adding a single-dose of GO to intensive induction chemotherapy for patients with CBF-AML. Methods: We conducted a retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with and without GO, at the University of Alabama at Birmingham (UAB) between January 2010 and April 2023. Single-dose GO was given at 3mg/m 2 during induction only. Results: There were 87 patients included in the analysis (GO=32, control=55). The baseline characteristics are shown in Table 1. The median age of the GO and control groups was 50y (19-68y) and 47y (21-74y), respectively. There was an overrepresentation of white patients in the control group. In the GO group, more patients had t(8;21) (53% vs. 31%, p=0.02), KIT (28% vs. 12%, p&amp;lt;0.01), FLT3-ITD (16% vs. 7%, p=0.03) and NRAS/KRAS mutations (40% vs. 20%, p&amp;lt;0.01) compared to the control group. Induction chemotherapy consisted of 7+3 in 88% of patients receiving GO and all patients in the control group. Patients &amp;lt;65y received idarubicin 12mg/m 2 while older patients received daunorubicin 45mg/m 2. The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p&amp;lt;0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups (GO=62%, control=69%, p=0.5). There were no significant differences between the two groups in terms of time to neutrophil and platelet recovery, veno-occlusive disease, febrile neutropenia and length of hospital stay. GO was not administered during consolidation chemotherapy. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9) (Figure 1). Conclusion: In our report, we find that survival of patients with CBF-AML is favorable in the real-world setting. These outcomes are comparable to those reported in the meta-analysis leading to the approval of GO. The addition of single-dose GO did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. However, the analysis is limited by differences in baseline characteristics between the two groups with more patients in the GO group harboring high-risk features such as the presence of t(8;21), KIT, FLT3-ITD and KRAS/NRAS mutations. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.

During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.

Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09–09): a randomised, open-label, multicentre, phase 3 trial

Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. Pfizer and Amgen.

A Randomized Comparison of the Fractionated Versus Single Dose Schedule of Gemtuzumab Ozogamicin at Induction with Determinants of Benefit for Older AML Patients: UK NCRI AML18 Trial Results

The addition of Gemtuzumab Ozogamicin (GO) to induction chemotherapy has been demonstrated to improve outcomes in older adults with non-adverse cytogenetic risk acute myeloid leukemia (AML) but it is currently uncertain whether a higher dose, delivered as a fractionated schedule as per the ALFA0701 trial, provides a survival benefit over a single lower dose (GO 3mg/m2) as given in the NCRI AML16 trial. The AML18 trial evaluated this and we now report 5yr overall survival (OS) results together with information from response assessment by measurable residual disease (MRD) and molecular stratification. Methods The NCRI AML18 trial randomised older AML or high-risk MDS patients (>10% blasts) who were not known to have adverse cytogenetics at trial entry to receive course 1 DA induction (Daunorubicin 60mg/m2 d1, 3, 5, AraC 100mg/m2 bd d1-10) with either GO 3mg/m2 on day 1 (GO1), or fractionated GO on days 1 and 4, maximum 5mg per dose (GO2). Further courses did not include GO. Of 852 enrolled patients, 8 withdrew trial consent. Baseline cytogenetics and molecular profiling included a 95-gene targeted NGS panel. Following course 1 MRD response was assessed by flow cytometry (results available for 608 patients including 453 in remission [CR+CRi] post course 1) with any measurable level of MRD considered positive. Randomisations for course 2 were MRD directed and will be reported separately. Results Treatment arms (GO1, n=422; GO2, n=422) were balanced for baseline characteristics. Median age was 68 years. 79.7% had de novo AML, 10.6% clinical secondary AML, 9.7% high risk MDS. Of patients with cytogenetic data (n=782), 4.4% and 80.9% had favourable or intermediate risk cytogenetics respectively. 114 patients (14.6%) were found to have adverse risk cytogenetics after trial entry. Median follow-up was 50.2 months (quartiles: 44 to 60). GO1 and GO2 were comparable for day 30 mortality (7.6% vs 8.0%), time to count recovery (median 29 vs 29 days for neutrophils to 1 x 109, median 29 vs 30 days for platelets to 100 x 109/L), toxicity profiles and post course 1 response rates (56.6% vs 62.5% for CR, 63.5% vs 67.3% for CR+CRi). However lower post course 1 MRD levels (Figure A) and a higher MRD negative response rate were observed for the GO2 arm (57.3% GO2 vs 49.7% GO1 for MRD negative, 72.2% GO2 vs 62.4% GO1 for MRD <0.1%). This differential response for GO2 versus GO1 varied across molecular subtypes, greatest for IDH mutations (MRD <0.1%, 71% GO2 vs 47% GO1 for IDH2, 76% GO2 vs 62% GO1 for IDH1) and then NPM1 mutated patients (MRD <0.1%, 81% GO2 vs 73% GO1). 5yr OS rates were 29% for GO2 and 24% for GO1 patients (p=0.14). In a sensitivity analysis excluding patients with adverse cytogenetics / TP53 mutations, 5yr OS rates were 33% for GO2 and 26% for GO1 (p=0.045). Survival advantage from GO2 vs GO1 was most apparent for the subgroup of patients with DNA methylation-type mutations (including mutated IDH 1/2, DNMT3A) (HR 0.77, 95%CI 0.63-0.93). 27% of patients received a CR1 allogenic stem cell transplant (ASCT) (122 GO1, 106 GO2) with a survival advantage for transplant on Mantel-Byar analysis (HR 0.76, 95%CI 0.62-0.93, P=0.007). Survival was superior for transplanted patients on the GO2 arm compared to GO1 (HR 0.66, 95%CI 0.47-0.91, P=0.01) (Figure B). The overall survival benefit from GO2 was lost when patients were censored at ASCT. Additionally, GO2 did not provide a survival advantage for patients over 70yrs by age subgroup analyses (test for trend, P=0.019). Conclusions Compared to single dose GO, the fractionated schedule (GO2) was associated with greater reduction in MRD, and improved overall survival in older adults with non-adverse risk genetics; comparable differences by molecular subtype were observed for MRD response and survival. AML18 trial results suggest that the differential benefit from GO2 for older adults is dependent on delivery of ASCT in order to translate the better leukemia clearance from induction into a significantly higher 5yr survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of different treatment modalities for favorable risk acute myeloid leukemia: Standard-dose anthracycline versus high-dose anthracycline versus addition of gemtuzumab ozogamicin.

e19016 Background: The standard remission induction regimen for medically fit patients with AML consists of a backbone of cytarabine &amp; an anthracycline (“7+3” therapy). However, the choice &amp; dose of the anthracycline varies between institutions &amp; practitioner preference, particularly in patients with favorable risk cytogenetics. Gemtuzumab ozogamicin (GO) may improve outcomes in this patient population but is associated with increased toxicities. Methods: We performed a retrospective analysis on medically fit patients ≥ 18 yo with favorable risk AML from 2015-2020 treated with 7+3 at the University of Virginia. Patients were stratified based on standard dose (45 or 60 mg/m2 daunorubicin) (SD) vs higher dose (90 mg/m2 daunorubicin or 12 mg/m2 idarubicin) (HD) of anthracycline vs the addition of GO. Measures included rates of remission, EFS, RFS, and OS as well as rates of treatment-related complications. Results: In total, 58 patients were identified, of which 33 received induction with SD, 19 received HD, &amp; 6 received GO. The majority (75%) of patients were &lt; 60 years old &amp; 93% had de novo AML. The rates of complete remission in the SD, HD &amp; GO groups were 90.9%, 89.5% &amp; 100%, respectively (p = 0.57). EFS at 2-years was 43.9%, 36.7%, &amp; 66.7%, respectively (p = 0.85). RFS at 2-years was 53.0%, 39.0%, &amp; 100%, respectively (p = 0.18). OS at 2-years was similar between all groups (58.9%, 56.9%, &amp; 66.7%, p = 0.92). The rate &amp; duration of cytopenias after induction were similar among all groups (median duration 29 days), however cytopenias were more common in the GO group following consolidation. The rates of major bleeding, admission to the intensive care unit (ICU), and new onset cardiomyopathy (EF &lt; 50%) were higher in the GO group (major bleeding: 0% in SD, 5.3% in HD, 33.3% in GO; ICU admission: 12.1% in SD, 21.1% in HD, 33.3% in GO; cardiomyopathy: 12.1% in SD, 26.3% in HD, 33.3% in GO). The rate of infection, liver dysfunction, &amp; acute renal injury were similar among all groups. No patients developed veno-occlusive disease. Conclusions: Patients receiving GO had a trend toward improved EFS &amp; RFS, however with a similar OS at the expense of higher rates of cytopenias, major bleeding, ICU admission, &amp; cardiotoxicity. Patients receiving HD had a trend toward worse outcomes than those who received SD. A major limitation of our study is the small sample size &amp; single institution experience, however multi-institutional analysis is ongoing for further investigation.[Table: see text]

Efficacy and safety of adding gemtuzumab ozogamicin to conventional chemotherapy for adult acute myeloid leukemia: a systematic review and meta-analysis

ABSTRACT Introduction: Compared with the 3 + 7 regimen, the addition of gemtuzumab ozogamicin (GO) has improved survival in patients with acute myeloid leukemia (AML). We conducted a systematic review and meta-analysis to examine the overall efficacy and safety of GO in combination with conventional chemotherapy regimens in patients with AML. Methods: We searched several databases (MEDLINE, Embase, Web of Science and Cochrane Library). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS); odds ratios (ORs) with 95% CIs were calculated for the other outcomes. Results: Ten records involving 11 randomized controlled trials (RCTs) met the inclusion criteria. GO plus induction chemotherapy significantly increased RFS (HR: 0.84, 95% CI: 0.73–0.98), decreased the incidence of relapse (OR: 0.78, 95% CI: 0.68–0.91) and resistant disease (OR: 0.72, 95% CI: 0.61–0.84), and had no significant effect on the rate of complete remission (CR) with or without incomplete platelet recovery (OR: 1.21, 95% CI: 0.94–1.55), 30-day mortality (OR: 1.25, 95% CI: 0.99–1.57). Subgroup analysis showed significant OS benefits for patients with favorable cytogenetic (HR: 0.50, 95% CI: 0.28–0.89) or given GO at induction stage (HR: 0.91, 95% CI: 0.84–1.00). Compared with other dosing schedule groups, 3 mg/m2 fractionated schedule had a greater RFS benefit (HR: 0.52, 95% CI: 0.36–0.76) and lower relapse risk (OR: 0.48, 95% CI: 0.28–0.84). Conclusions: Adding low-dose GO to induction or both induction and post-remission chemotherapy has considerable efficacy and unequivocal safety for newly diagnosed adult AML.

Real World Data of Concurrent Arsenic Trioxide and All-Trans Retinoic Acid with Minimal Use of Anthracycline in the Treatment of Acute Promyelocytic Leukemia

▪In the setting of clinical trials, high cure rates have been reported for acute promyelocytic leukemia (APL) with the chemotherapy-free combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for low-intermediate risk disease, and with the addition of gemtuzumab ozogamicin or minimal anthracycline for high-risk disease. Despite clear in-vitro synergy between ATO and ATRA, most clinical trial protocols in APL have not used these drugs concurrently beyond induction. There is limited real world data on the use of chemotherapy-free combination of ATO and ATRA with minimal anthracycline use in the treatment of APL, especially in the high risk group. We did a retrospective analysis of the clinical outcomes of patients with newly diagnosed APL treated at our center from January 2015 to May 2020 using concurrent ATO, ATRA and minimal anthracycline in a risk stratified manner. The data was frozen and analyzed as on 1st June 2021. During the study period, 167 patients were diagnosed to have APL at our hospital. Of these, we excluded 5 patients who had presented with relapsed disease and 28 patients who were treated with single agent ATO. The remaining 134 patients were treated with a uniform protocol as summarized in Figure 1a. Figure 1b shows the KM plot for EFS (2 year: 90.8±2.5%) for these 134 patients. For analysis of regimen safety and efficacy, we excluded patients who wished to pursue treatment elsewhere within the first 1 week of treatment (n=7), and patients who had severe infections or life-threatening bleeding at presentation or before therapy initiation and subsequently died (n=4). Thus, a total of 123 patients with newly diagnosed APL were included for further analysis. The median age was 35 years (IQR: 24 to 45 years). Forty-six (37.4%) were females. The median duration of symptoms prior to admission was 14 days (IQR: 7 to 28 days). Sixty-one (49.6%) had high risk APL while the remaining 62 (50.4%) had low-intermediate risk APL. During induction, 28 (22.7%) patients had major bleeding while 5 (4%) patients developed major thrombosis. Sixty-seven (55%) patients had at least one documented infection during induction therapy. The median number of packed red cell concentrates, fresh frozen plasma, platelet rich concentrates and cryoprecipitates transfused during induction therapy was 5 (IQR: 3 to 6.5), 10 (IQR: 3 to 30), 40 (IQR: 23 to 55) and 6 (IQR: 0 to 18) respectively. Nineteen (15.4%) patients developed differentiation syndrome; all were treated with steroids, 8 required transient cessation of treatment and 6 required intensive care. Eight (6.5%) patients died during induction. During induction, grade 3 hepatotoxicity was noted in 8 (6.5%) patients, 10 (8.1%) patients had ATRA related headache or benign intracranial hypertension of which 5 required transient cessation of ATRA, while 11 (8.9%) patients had transient QTc prolongation of which 6 required transient cessation of ATO. Seventeen (13.8%) patients developed symptomatic sensory neuropathy requiring treatment. None required permanent discontinuation of therapy. At a median follow up of 854 days, there were 2 (1.6%) hematologic relapses and no deaths beyond induction therapy. The 2-year OS and EFS for the cohort (n=123) are 93.4% ± 2.3% and 91.6% ± 2.6% respectively (Figure 1c). Two (1.6%) patients have developed second malignancies. In a real world setting, concurrently administered ATO and ATRA with minimal anthracycline use results in excellent long term survival, even in the high risk group. Early deaths due to delayed presentation with infections and life threatening bleeding remain an unmet need for future research along with the need for strategies to reduce treatment-related toxicities. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All “Non-Adverse” Risk AML

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535)

AbstractHigh-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

CD117 Expression Is Associated with Cytogenetic and Molecular Profiles and Outcome in Pediatric Acute Myeloid Leukemia

Cell surface antigen expression in AML is becoming focus of investigation as it relates to prognostic impact as well as potential therapeutic implications. The CD117 (c-KIT) receptor tyrosine kinase is expressed on the cell surface of hematopoietic stem cells and its signaling is important in cell survival, proliferation and differentiation. CD117 is expressed in a majority of AML cases. In addition, mutations in c-KIT have been identified in a subset of patients, specifically those with CBF AML (inv(16)/t(16;16) and t(8;21)). As there is increasing interest in using tyrosine kinase inhibitors with anti-KIT activity based on surface CD117 expression as treatment in AML, we sought to evaluate the association of CD117 expression with biologic and clinical features in pediatric and young adult (YA) AML. A total of 1803 pediatric and YA patients (ages 0.01-29.2 years) treated on the Children's Oncology Group (COG) phase III trials AAML0531 (n=762) and AAML1031 (n=1041) with complete cyto/molecular and outcome data available were included in the analysis. The primary aim of AAML0531 evaluated the addition of gemtuzumab ozogamicin to a 5-course MRC-based backbone, while AAML1031 evaluated the addition of bortezomib to a similar 4-course backbone. Outcomes between the 2 primary randomized arms on each trial were similar and thus were included together for each trial. Multidimensional flow cytometry was used to determine the CD117 mean fluorescence intensity (MFI) of myeloid progenitor cells as defined by CD45 low and side scatter using a CD117-PE antibody with stable intensity detection since 2002. Patients were divided into quartiles based on CD117 expression and clinical characteristics and outcome were evaluated across the quartiles. CD117 MFI distribution was similar across both trials (Fig 1A). Analysis of CD117 expression with cytogenetics demonstrated that t(8;21) was significantly associated with higher CD117 (p&lt;0.001), with 72% of patients demonstrating expression above the median (Fig 1B). Similarly, inv(16) was associated with higher CD117 (p&lt;0.001), with 76% of patients with CD117 MFI above the median (Fig 1B). In contrast, CD117 expression was inversely associated with KMT2A rearrangements (p&lt;0.001), with 82% of patients with CD117 MFI below the median (Fig 1B). Evaluation of CD117 expression according to risk stratifying mutations demonstrated higher expression among patients with CEBPA mutations, with 76% of CEBPA-mutant patients with CD118 MFI above the median (Fig 1C). In contrast, CD117 expression was inversely associated with NPM1 mutations (p&lt;0.001) as 63% of patients had expression below the median (Fig 1B). Significant differences in CD117 expression across all the quartiles was seen among FLT3/ITD patients, with the majority of patients (63%) in Q2-Q3, with 18% and 19% in Q1 and Q4 respectively (0&lt;0.001; Fig 1C), and a similar pattern was seen among the HAR subset. Outcome analysis demonstrated that CD117 surface expression was not associated with CR, with similar CR rates across the quartiles (p=0.726). In a univariate analysis, overall survival (OS) was associated with higher CD117 expression (p&lt;0.001), with higher OS in Q3-Q4 (65% and 70% respectively) compared to Q1 and Q2 (61% and 58% respectively; Fig 1D). Similarly, improved disease free survival (DFS) was associated with higher CD117 expression, with higher DFS in Q3/Q4 (58% and 60% respectively) compared to 48% each in Q1 and Q2 (p&lt;0.001). This was driven by a higher relapse risk in Q1/2 (45% each) compared to Q3/4 (39% and 36% respectively; p=0.001). Analysis in the CBF cohort demonstrated no significant differences in outcome (p=NS in OS, DFS, and relapse risk) across the quartiles (Fig 1E). We show here that CD117 expression was higher in patients with favorable risk CBF AML and inversely associated with KMT2A rearrangements, which are generally considered to be neutral or unfavorable depending on the specific translocation partner. Higher CD117 expression was associated with improved outcomes, which may in part be explained by the association with CBF and inverse association with KMT2A. Although patients with higher CD117 MFI generally have favorable risk genomic alterations, the strategy of c-KIT inhibition warrants further investigation in AML given the potential for facilitating de-escalation of conventional therapeutics with significant toxicity in future clinical trials if found to be safe and effective. Disclosures Eidenschink Brodersen: Hematologics, Inc: Employment. Pardo:Hematologics, Inc: Employment. Dai:Hematologics, Inc: Employment. Loken:Hematologics, Inc: Employment, Equity Ownership.

Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia

Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia

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.

Abstract 368: Specific chromosomic alterations confer therapy resistance in a cohort of 49 patients with newly diagnosed acute myeloid leukemia treated with intensive chemotherapy

Abstract Introduction. Intensive induction chemotherapy in non-M3 young Acute Myeloid Leukemia (AML) patients is represented by the association of an antracycline and Cytarabine. Some treatment regimens including fludarabine or the addition of Gemtuzumab Ozogamicin (GO) as a third or fourth drug, proved to give a benefit in terms of CR rates. Aims of the study. In a group of 49 patients treated with intensive chemotherapy, we evaluated chromosomal abnormalities with SNP 6.0 and Cytoscan HD (Affymetrix) in order to improve conventional cytogenetic analysis and discover novel chromosomic aberrations related to clinical data and therapy response. Patients and Methods. From 2001 to 2014, 489 patients were treated in our Institution. Among those, in 49 newly diagnosed AML patients (median age 54 (range 19-71)), SNP microarray based-genotyping were performed and then analyzed by Nexus Copy Number™ v7.5 (BioDiscovery) and R Development Core Team. According to karyotype, FLT3 and NPM1 mutational status, 55.9% of the patients were considered at High Risk (HR) and 4.1% at low risk (LR). Ten patients had secondary AML. Patients were treated with induction schemes including MyFLAI, MyAIE, FLAI, FLAN, FLAG, 3+7 or DAE. Results. The CR rate after induction was 87.8% (43/49 patients). Deaths during induction (DDI), occurring in the first 50 days from 1st line therapy, were 1/49. The median OS was 135 months, the 5-years OS in our patients was 55,1%. Patients treated with GO showed a non-statistical trend toward a better OS than patients treated with other regimens (median OS not reached vs 133 months, respectively). We explored the alterations found by SNP array in our patients searching for novel markers of therapy resistance. We found a median of 192,5 total copy number aberrations (range 72- 1071): a median of 145,5 total copy number aberrations in responding patients group (RPG), and a median of 361 total copy number aberrations (p = ns) in non-responding patients group (NRPG). We compared the frequency of detected aberrations in RPG and in NRPG with Fisher's exact test. We found that PIK3CA, Gain chr3:178,927,088-178,929,550 (p = 0,0016), SMAD4, Gain chr18:48,573,154-48,573,255 (p = 0,0166) and several other gene's loci (CASC18, TCF12, UTY, GRB10, ZFY) are significant aberrations in NRPG compared with RPG. Conclusions. We identified a number of genes with significant aberrations in NRPG, particularly PIK3CA, a protein-coding gene involved in cell proliferation and metabolic pathway with interaction with HRAS/KRAS and EGF, and SMAD4, a transcription factor activated by TGF-beta. Those 2 genes were found overexpressed in other solid tumors. We suppose that those genes may be involved in a hyper-proliferative pathway that underlies a mechanism of chemo-resistance. Acknowledgments Work supported by ELN, AIL, AIRC, Progetto Regione-Universit⁁ 2010-12 (L.Bolondi), FP7 NGS-PTL project. Citation Format: Cristina Papayannidis, Maria Chiara Fontana, Giovanni Marconi, Viviana Guadagnuolo, Giorgia Simonetti, Antonella Padella, Simona Soverini, Stefania Paolini, Maria Chiara Abbenante, Sarah Parisi, Chiara Sartor, Silvia Lo Monaco, Marco Manfrini, Elisa Zuffa, Eugenia Franchini, Claudia Venturi, Maria Teresa Bochicchio, Andrea Ghelli Luserna di Rorà, Emanuela Ottaviani, Giovanni Martinelli. Specific chromosomic alterations confer therapy resistance in a cohort of 49 patients with newly diagnosed acute myeloid leukemia treated with intensive chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 368.

The addition of gemtuzumab ozogamicin to chemotherapy in adult patients with acute myeloid leukemia

ABSTRACTThe treatment of acute myeloid leukaemia has remained largely unchanged for the last 30 years since the advent of combination chemotherapy with cytarabine arabinoside and daunorubicin with remission rates around 70% but with long term survival still only around 40% in young adults. Doses of chemotherapy have been pushed to the limit of toxicity. Gemtuzumab ozogamicin allows additional chemotherapy to be delivered to the leukaemic cells without significantly adding to toxicity since the active agent is coupled to a monoclonal anti-CD33 antibody. It was approved by the FDA in 2000 for the treatment of elderly patients with relapsed CD33 positive AML at a dose of 9mg/m2 on two days two weeks apart. Almost at once, questions were raised about its safety, with a particular liver signal, and it was voluntarily withdrawn from practice in 2010. Many groups have been examining the role of gemtuzumab ozogamicin in combination with chemotherapy, usually at lower doses than originally recommended, with varying degrees of success and toxicity and gemtuzumab ozogamicin is now entering a period of rehabilitation. Currently it is only commercially available in Japan although it is currently also available in the UK Bloodwise AML18 study.

Gemtuzumab-Ozogamicin Containing Regimens As Induction Therapy Give the Highest Complete Remission Rate and the Longest Overall Survival Compared with Other Induction Regimens in Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction. Conventional induction treatment in young non APL-Acute Myeloid Leukemia (AML) patients is still represented by the association of an antracycline and Cytarabine, which offers a complete remission (CR) rate not inferior to 60%. The addition of Gemtuzumab Ozogamicin (GO) as a third or fourth drug, already demonstrated to improve clinical outcome, in terms of CR rates.Aims of the study. We retrospectively evaluated and compared the efficacy of different induction schedules, in terms of CR rates and Overall Survival (OS), administered to two groups of AML patients. Group 1 (n=139) was treated with a GO containing course (MyFLAI or MyAIE schedules); Group 2 (n=270) received a non-GO based regimen including or not Fludarabine (FLAI, FLAN, FLAG, 3+7 or DAE).Patients and Methods. From 1997 to 2014,409 newly diagnosed AML patients were treated in 3 Italian Institutions. Their median age was 53 (range 19-74) and 52 (range 17-75) years, respectively.According to karyotype (performed in 392/409 patients), FLT3 (available for 244/409 patients), and NPM1 mutational status (available for 157/409 patients), based on the NCCN-2013 risk stratification criteria, 35.2% of the patients were considered at High Risk (HR) (31.6% and 36.4% in the two groups, respectively) and 7.6% at low risk (LR) (7.8% and 7.0%, respectively).Results. The complete remission (CR) rate after induction was 81.4% and 70.4% for Group 1 and 2, respectively (p=0.01). Deaths during induction (DDI), occurring in the first 50 days from 1st line therapy, were 4/139 (2.9%) in Group 1 and 22/270 (8.1%) in Group 2 (p=0.003).Patients treated with GO showed a better OS than patients of Group 2 (Figure 1); the 5-years OS in the two groups was 54.01% and 34.9%, respectively, and different according to age (54.0% and 34.9% respectively (p=0.0003) in patients <60 years, 30.2% and 13.5% respectively (p=0.001) in patients ³60 years). The 5-years Event Free Survival (EFS) in the two groups was 45.6% and 30.8% respectively (p=0.0003) (Figure 2).Then, with a logistic univariate regression analysis.,we explored the impact of GO therapy in terms of CR rate. The use of GO was identified as a strong predictor of the achievement of a 1st CR (p=0.008). Moreover, a logistic multivariate regression analysis (risk and age) confirmed the role of the compound as a predictor of higher CR rate (p=0.013).We also performed a Cox Regression analysis, to investigate the impact of GO therapy, age and risk on OS: the use of GO was confirmed to be an independent predictor of better OS (p<0.0001) with a Hazard Ratio of 1.966 (p<0.0001).In a sub-analysis performed on HR patients, we observed a significantly better outcome in Group 1 than in Group 2 in terms of OS (p=0.0074, 5-year OS 47.7%; in group 2 OS 21.0% respectively, Figure 3) and EFS (p=0.001). However, there was no difference in terms of CR rate (p=ns). In particular, HR patients with adverse karyotype, may benefit from GO induction therapy in terms of OS (5-years OS 42.9% and 12.8% in Group 1 and 2, respectively, p=0.02); nevertheless FLT3 mutations negative impact canÕt be overcome by the drug administration (5-years OS 66.6% and 61.3% in Group 1 and 2, respectively).In SR AML, GO offered a better OS (p=0.036, 5-years OS 51.4% and 41.9% respectively).Comparing with Fisher's exact test the rate of increment in 5-years OS between Group1 and Group2 in HR and SR AML, we demonstrate that treatment with GO gave the higher benefit in HR AML (p=0.0005).Conclusions. These data showed that a four-drugs intensified induction therapy is a feasible approach in AML patients: adding GO at any induction regimen is an independent and strong predictor of better OS and higher CR rates. In our population, GO was not associated with a higher incidence of DDI.This approach, could be strongly recommended in SR and HR AML patients, due to karyotype abnormalities, in which showed an advantage in term of OS if compared with other standard regimens. On the contrary, we donÕt suggest the same schedule in FLT3 mutated patients, in which no benefits have been observed.Acknowledgments Work supported by ELN, AIL, AIRC, Progetto Regione-Universitˆ 2010-12 (L.Bolondi), FP7 NGS-PTL project. [Display omitted] [Display omitted] [Display omitted] DisclosuresSoverini:Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Fanin:Novartis Farma: Speakers Bureau. Cavo:BMS: Honoraria; Millenium Pharmaceuticals: Honoraria; Jansenn: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Onyx: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ROCHE: Consultancy; MSD: Consultancy; AMGEN: Consultancy; Ariad: Consultancy.

Gemtuzumab Ozogamicin (GO) in Infants with Acute Myeloid Leukemia (AML) – Combined Results from the Children’s Oncology Group (COG) Trials, AAML03P1 and AAML0531

Background: Infants <1 year of age with AML are at high risk of early death during induction, pulmonary and infectious toxicities, and treatment related mortality (TRM). Compared with older children, infants are more likely to have higher risk clinical and cytogenetic features. Targeted therapy is needed to improve the outcomes for infants with AML while minimizing toxicities.Objective: To determine if the addition of gemtuzumab ozogamicin (GO) to standard chemotherapy is safe, tolerable, and improves event free survival (EFS) in infants <1 year of age with AML.Methods: Infants >/= 1 month to <1 year of age with de novo AML or <1 month of age with progressive AML were eligible for enrollment on the COG trials AAML03P1 and AAML0531. Infants with acute promyelocytic leukemia, juvenile myelomonocytic leukemia, bone marrow failure syndromes, or Down syndrome were not eligible. The 5-course chemotherapy backbone was identical in both trials. GO 3 mg/m2/dose (0.1 mg/kg for patients with a body surface area <0.6 m2) was given on day 6 of Induction (Ind) I and day 7 of Intensification (Int) II to all patients on AAML03P1 and to randomized patients on the experimental arm of AAML0531. Patients on the control arm of AAML0531 were treated with standard therapy without GO (noGO). Stem cell transplant (SCT) was given following IntI to patients on AAML03P1 with a matched family donor (MFD) and to patients on AAML0531 with high risk (HR) disease or with intermediate risk (IR) disease and a MFD. SCT recipients only received one dose of GO. Patients were removed from protocol if the bone marrow had >/= 20% blasts after IndI on AAML03P1 or >/= 5% blasts after IndII on both studies. Early death (ED) was defined as death during IndI.Results: AAML03P1 enrolled 39 infants from 2003-2005 and AAML0531 enrolled 103 infants from 2006-2010 (Table 1). Median follow up was 5.02 years. The demographics and disease characteristics of infants enrolled on both studies were similar. Compared with enrolled children >/= 1 year of age, infants had higher frequencies of hepatomegaly (p<0.001), splenomegaly (p<0.001), hyperleukocytosis (WBC>100x103/µL, p=0.003) and French-American-British (FAB) M5 (p<0.001), and M7 (p<0.001) AML. Infants had less FAB M1 (p<0.001), M2 (p<0.001), and M4 (p=0.029) AML. There was no difference in CNS disease by age. The frequency of 11q23/MLL rearrangement was highest in infants 0-179 days of age (44%) and significantly decreased with increasing age (p<0.001). Favorable cytogenetics were rare in infants: t(8;21) was not found and inv(16)/t(16;16) was only found in 4 patients. FLT3-ITD HAR was absent in infants. The majority of infants (89%) fell into the IR group and infants were less likely to have had high (HR) or low risk (LR) disease when compared with children >/= 1 year. [Display omitted] The ED rate was higher in younger infants (7 ED, infants 0-179d) when compared with older infants (1 ED, infants 180-364d) (p=0.013). EDs were not increased in infants who received GO vs. noGO (5 vs. 3 ED, p=0.730). The complete remission (CR) rate for infants was 68% at the end of IndII. The 5 year EFS was lower in infants than children >/= 1 year (42 vs. 50%, p=0.001). The 5 year OS for infants was 62%, relapse risk (RR) was 44%, and TRM was 10%. Infants who received GO had improved OS, EFS, and RR, though the differences were not statistically significant (Table 2). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Combination treatment for acute myeloid leukaemia

Addition of gemtuzumab ozogamicin, an anti-CD33 antibody drug conjugate, to chemotherapy could reduce risk of relapse and improve survival in older patients with acute myeloid leukaemia, latest research suggests.