Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531

2021 ◽  
pp. JCO.20.03048
Author(s):  
Jessica A. Pollard ◽  
Erin Guest ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Mike R. Loken ◽  
...  
Keyword(s):  
High Risk ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Cell Transplant ◽  
Oncology Group ◽  
Event Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Impact ◽  
Group Trial

PURPOSE We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with KMT2A-rearranged ( KMT2A-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 ( NCT01407757 ). METHODS Patients with KMT2A-r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners. GO's impact on response was determined and outcomes based on consolidation approach (hematopoietic stem cell transplant [HSCT] v chemotherapy) described. RESULTS Two hundred fifteen (21%) of 1,022 patients enrolled had KMT2A-r AML. Five-year EFS and OS from study entry were 38% and 58%, respectively. EFS was superior with GO treatment (EFS 48% with GO v 29% without, P = .003), although OS was comparable (63% v 53%, P = .054). For patients with KMT2A-r AML who achieved complete remission, GO was associated with lower RR (40% GO v 66% patients who did not receive GO [No-GO], P = .001) and improved 5-year DFS (GO 57% v No-GO 33%, P = .002). GO benefit was observed in both higher-risk and not high-risk KMT2A-r subsets. For patients who underwent HSCT, prior GO exposure was associated with decreased relapse (5-year RR: 28% GO and HSCT v 73% No-GO and HSCT, P = .006). In multivariable analysis, GO was independently associated with improved EFS, improved DFS, and reduced RR. CONCLUSION GO added to conventional chemotherapy improved outcomes for KMT2A-r AML; consolidation with HSCT may further enhance outcomes. Future clinical trials should study CD33-targeted agents in combination with HSCT for pediatric KMT2A-r AML.

Treatment of 11q23/MLL + AML with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 799-799
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Study Entry ◽  
Cell Transplant ◽  
Event Free Survival ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Pediatric Aml ◽  
To Receive

Abstract CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO). We previously demonstrated the clinical benefit of GO treatment in children with AML treated on COG AAML0531 in which patients were randomized to receive standard Medical Research Council-based chemotherapy with or without GO. We also demonstrated that CD33 expression is highly variable in pediatric AML and that children with 11q23 translocations involving the KMT2A gene, previously known as the mixed lineage leukemia gene and referred to here as MLL+, have significantly higher CD33 expression, as defined by mean fluorescent intensity (MFI) values, than patients without 11q23/MLL + leukemia (MLL-) [median CD33 MFI: MLL + 229.13 (range 6-1351) vs. MLL-129 (range 2.68-1225.87) P <0.001.] Given significantly elevated levels of CD33 expression in MLL + AML and our previous findings showing an association between high CD33 expression and improved response to GO, we evaluated MLL + AML patients treated on COG AAML0531 to determine whether GO treatment improved their clinical outcomes. COG AAML0531 included 1022 eligible patients ages 1 month-29.99 years of which 215 harbored a 11q23/MLL rearrangement that was confirmed by central cytogenetic review (including G-banding and FISH). Analysis of overall outcomes revealed similar complete remission (CR) rates after Induction I for MLL + and MLL-patients (71% vs. 73%, P = 0.494). However, MLL + patients had lower 5-year overall survival (OS) and event-free survival (EFS) than MLL-patients (OS 58% vs. 66%, P =0.012, EFS 38% vs. 51%, P =<0.001) as well as higher rates of relapse (RR) (52% vs. 36%, P =<0.001) and lower disease-free survival (DFS) (46% vs. 58%, P =0.002). Of the 215 MLL + patients, 107 were treated with conventional chemotherapy only (No-GO) and 108 with chemotherapy and GO (GO). CD33 expression data from flow cytometry analysis were available for 170 MLL + patients. The median CD33 MFI was similar for MLL + patients on both treatment arms [No-GO: 226.5 (range 6-911), GO 237.345 (range 7.6-1351), P = 0.648]. CR rate was higher for MLL + patients treated with GO vs. No-GO (77% vs. 64%; P =0.035). Evaluation of clinical outcomes for patients in the MLL + cohort by treatment arm revealed a superior outcome for GO recipients. EFS at 5 years from study entry was 48% for patients in the GO group vs. 28% for those in the No-GO group (P =0.002) with a corresponding OS of 64% vs. 53% (P =0.053). MLL-patients had similar EFS and OS regardless of GO exposure (P =0.435 and P =0.861, respectively, Figure 1). In MLL + patients who achieved CR, GO exposure translated to lower RR (40% vs. 66% No-GO, P =0.001) and improved DFS (57% vs. 33% No-GO, P =0.002) demonstrating that MLL + patients receiving GO treatment have improved outcomes. In COG AAML0531 a subset of patients was allocated to receive allogeneic hematopoietic stem cell transplant (HSCT) in 1st CR based on donor availability and risk status. This allowed us to evaluate the effect of HSCT in MLL+ patients in the context of GO exposure as any MLL+ patient with a matched family donor or poor induction response (>15% blasts) underwent HSCT. HSCT was conducted in 19 of 83 MLL+ patients (23%) in the GO group after one course of intensification therapy and in 11 of 73 (15%) patients in the No-GO group. Patients in the GO group who received HSCT consolidation had better outcomes than those not receiving HSCT. Specifically, MLL+ patients who received HSCT after prior treatment with GO had a RR of 28% at 5 years from HSCT compared with a RR of 73% for MLL + patients who received HSCT without GO prior (P =0.006). The corresponding DFS at 5 years from HSCT for patients in the GO and No-GO groups was 72% vs. 27% (P =0.004) respectively. These results highlight that the clinical impact of induction GO maintains clinical significance in the post-HSCT setting. Our analysis of data from AAML0531 suggests that pediatric MLL + AML might benefit from the addition of GO to conventional chemotherapy. HSCT might further enhance GO benefit in this subset of patients. Future studies, utilizing GO or other novel CD33 targeted agents, should be considered for MLL + pediatric AML given the superior outcomes observed. Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Disclosures Aplenc: Sigma Tau: Honoraria. Loken:Hematologics Inc.: Equity Ownership.

Negative Prognostic Impact Of High CD33 Expression Is Negated With The Use Of Gemtuzumab Ozogamicin: A Report From The Children’s Oncology Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 491-491 ◽  
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C Raimondi ◽  
Betsy Hirsch ◽  
...  
Keyword(s):  
Disease Risk ◽  
Risk Group ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Study Cohort ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem ◽  
The Impact

Abstract CD33 is expressed on leukemic blasts of most patients with acute myeloid leukemia (AML) and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 monoclonal antibody. CD33 expression of leukemic blasts was prospectively quantified within the context of COG AAML0531, a phase III randomized study for de novo AML in which patients were randomized to receive conventional chemotherapy (Arm A) vs. GO + conventional chemotherapy (Arm B) to determine the impact of CD33 expression on outcome within the context of this GO randomization. CD33 mean fluorescent intensity (MFI) of leukemic blasts was prospectively quantified in 825 diagnostic specimens. Patients were divided into quartiles (Q1-Q4) based on CD33 expression values and these levels were correlated with disease characteristics and outcome by treatment arm for the total study cohort and by cytogenetic/molecular disease risk-group. Analysis of 3 year outcome by treatment arm (N= 412 for Arm A vs. N=414 for Arm B) demonstrated that patients with high CD33 expression (Q4) in Arm A (no GO) had an overall survival (OS) from diagnosis of 55% vs. 70% for those with lower CD33 expression (Q1-3, P=.014) with a corresponding disease-free survival (DFS) from complete remission (CR) of 41% and 57%, respectively (P=.010). In contrast, for the patients in Arm B (receiving GO therapy) those with and without high CD33 expression had a similar OS from diagnosis (67% vs. 72%, P=.290) with a corresponding DFS from CR of 57% vs. 64%, respectively (P=.255). Comparison of the patients with the highest CD33 expression (Q4) who were treated with (N=105) and without (N=101) GO demonstrated that those who received GO had an OS from diagnosis of 67% versus 55% (P=.196) with a corresponding DFS from CR of 57% vs. 41% (P=.052). Analysis by cytogenetic/molecular disease risk group also showed that the effect of CD33 expression levels on outcome differed by treatment arm. Among intermediate risk (IR) patients on Arm A (N=200), those with high CD33 expression (Q4) had an OS from diagnosis of 52% vs. 62% for those with lower CD33 expression (P=0.194) with a corresponding DFS from CR of 28% vs. 53% respectively (P=.012). Conversely, for IR patients treated with GO (N=197), outcomes were similar for patients with high (Q4) and low (Q1-3) CD33 expression (OS from diagnosis of 65% vs. 64%, P=.923, DFS from CR of 50% vs. 53%, P=.687). The loss of prognostic impact of high CD33 expression for patients in Arm B may be due to improved response to GO in those with high CD33 expression (OS of IR patients in Q4 from study entry: Arm A (N=65) 52% vs. Arm B (N=70) 65%, P= .234, DFS from CR of IR patients in Q4: Arm A 28% vs. Arm B 50%, P=.033). Accurate sub analysis of the high-risk (HR) group was not feasible due to the very small number of HR patients with high CD33 expression (Q4) in Arm A (N=9) and Arm B (N=16). Similar trends were, however, observed in the low-risk (LR) group. LR patients with high (Q4) CD33 expression treated on Arm A (no GO) had an OS from diagnosis of 69% vs. 84% for those with lower CD33 expression (P=.092) with a corresponding DFS from CR of 68% vs. 64% respectively (P=0.803). For patients in Arm B (GO) those with and without high CD33 expression had an OS from diagnosis of 94% vs. 86%, respectively (P=.316) with a corresponding DFS from CR of 85% vs. 76% (P=.344). Like IR patients, those LR patients with high CD33 expression (Q4) who received GO trended towards improved outcome compared to Q4 patients treated without GO (LR OS from diagnosis: Arm A 69% vs. Arm B 94%, P= .069, LR DFS from CR: Arm A 68% vs. Arm B 85%, P=.195). However, given the small number of LR patients in Q4 (N= 27 Arm A, N=17 Arm B) we cannot state the significance of this finding with certainty. Taken together our results suggest that, for patients enrolled on AAML0531, high CD33 expression was associated with adverse outcome for those who received standard therapy and GO treatment negated the negative effect of high CD33 expression on clinical outcome for the entire study cohort and in IR and LR patients. This finding may reflect GO’s CD33 dependent mechanism of targeting and the potential for more efficient targeting in the setting of high antigen expression.It is also plausible that repeated exposure to GO, as seen within the context of treatment for all LR and some IR patients (e.g. those that did not undergo hematopoietic stem cell transplant), may also contribute therapeutic benefit within the context of high CD33 expression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Significant Improvements in Survival for Patients with t(6;9)(p23;q34)/DEK-NUP214 in Contemporary Trials with Intensification of Therapy: A Report from the Children's Oncology Group

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 519-519
Author(s):  
Katherine Tarlock ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Yi-Cheng Wang ◽  
Rhonda E. Ries ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Intensive Therapy ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Oncology Group ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Poor Outcomes

Abstract The occurrence of t(6;9)(p22;q34)/DEK-NUP214 is a rare subtype of pediatric AML that commonly co-occurs with FLT3-ITD mutations and is associated with poor outcomes, regardless of FLT3-ITD status. With increased recognition of the inferior prognostic impact of FLT3-ITD and to a lesser degree t(6;9), and with early identification of these lesions, these patients have been allocated to high risk intensive therapy on more contemporary clinical trials. Therefore we sought to interrogate the outcome of children with t(6;9) AML to determine if intensification of therapy, specifically the use of hematopoietic stem cell transplant (HSCT) in CR1, and FLT3 inhibitors for ITD+ patients, may have improved outcomes for this high risk group of patients. We evaluated the outcomes of all patients with t(6;9) detected by karyotype analysis on pediatric patients with de novo AML enrolled on the previous 7 Children's Oncology Group (COG) or its predecessor (POG or CCG) trials over 31 years (1988-2017). A total of 66 cases of t(6;9) AML were identified from CCG-2861 (n=2), CCG-2891 (n=5), POG-9421 (n=7), CCG-2961 (n=10), AAML03P1 (n=7), AAML0531 (n=17), and AAML1031 (n=18). For all studies prior to 2005 (CCG-2861, CCG-2891, POG-9421, CCG-2961) neither t(6;9) nor FLT3-ITD was used as a prognostic factor to adjust treatment, while on AAML0531 post an amendment in 2008 all patients on AAML1031 with high allelic ratio (HAR; &gt;0.4) FLT3-ITD were allocated to HSCT in CR1, which continued on AAML1031 and this group of patients also received sorafenib. Among all 66 t(6;9) patients identified, 45 (68%) had known data for ITD. Among these, 69% (n=31) harbored a co-occurring FLT3-ITD mutation (AR range 0.07-13.35), while 31% (n=14) were FLT3-ITD negative. In the early phase of trials prior to recognition of FLT3-ITD (1988-2002; CCG-2861, CCG-2891, POG-9421, and CCG-2961), the 5-year event-free survival (EFS) and overall survival (OS) for all t(6;9) patients was dismal at 14% and 18%, respectively (Figure 1). Trials from 2006-2010 (AAML03P1, AAML0531), evaluated the addition of gemtuzumab ozogamicin (GO) to chemotherapy as well as the use of HSCT in CR1 for patients with matched related donors, and the 5-year EFS and OS for patients with t(6;9) improved to 48% and 58% (p&lt;0.001 compared to 1998-2002, Figure 1). Among this group of patients, only 16% received HSCT in CR1. The prevalence and clinical implications of FLT3-ITD in childhood AML was reported early and was incorporated as a risk stratifying biomarker following an amendment to 0531 and for all FLT3-ITD patients with HAR disease on AAML1031; this cohort was considered high risk and allocated to intensified therapy, which in many cases significantly impacted the treatment of patients t(6;9) given the significant overlap. In the most recent trial (AAML1031, 2011-2017), the 5-yr EFS and OS for patients with t(6;9) was excellent at 71% and 94%, which was significantly improved compared to other trials (p&lt;0.001; Figure 1). Among the 18 t(6;9) patients on 1031, 72% (n=13) were allocated to HSCT in CR1, the indication for 7 was HAR FLT3-ITD and they also received sorafenib and for 6 was presence of residual disease after induction 1 (4 with LAR FLT3-ITD, 2 ITD negative). The EFS and OS for the t(6;9)/FLT3-ITD HAR and t(6;9)/FLT3-ITD LAR/neg ITD groups who both received HSCT in CR1 were comparable and very good (EFS: 87.5% vs 100%, OS: 87.5% vs 100%, p=NS for both). We show that over the past 3 decades, outcomes of patients with t(6;9) AML have improved significantly on upfront trials. While general improvements in AML treatment and supportive care are an important aspect, our data with excellent EFS on AAML1031 suggest that the intensification of upfront therapy with HSCT, which occurred for many t(6;9) patients due to their co-occurrence with FLT3-ITD, was critical to these improvements. On the current COG phase III AAML1831 trial, all patients with t(6;9) regardless of ITD status are considered high risk and allocated to HSCT in CR1, while those with a FLT3 mutation also receive gilteritinib. Evaluation of the outcome of t(6;9) patients with this therapy will be important as while FLT3-ITD patients have been an example of a group whose poor outcomes have been shown to be abrogated with intensified therapy, it appears that t(6;9) patients may have benefitted from their co-occurrence pattern and are also a group whose outcomes can be significantly improved with an intensified upfront therapeutic approach. Figure 1 Figure 1. Disclosures Pollard: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531

2014 ◽  
Vol 32 (27) ◽  
pp. 3021-3032 ◽  
Author(s):  
Alan S. Gamis ◽  
Todd A. Alonzo ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Group Trial ◽  
Acute Myeloid

Purpose To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and Methods Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). Results There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P = .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). Conclusion GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

scholarly journals CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III Children’s Oncology Group Trial AAML0531

2016 ◽  
Vol 34 (7) ◽  
pp. 747-755 ◽  
Author(s):  
Jessica A. Pollard ◽  
Michael Loken ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Risk Groups ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Limited Data ◽  
Oncology Group ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Pediatric Aml ◽  
Group Trial

Purpose CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level. Patients and Methods CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children’s Oncology Group AAML0531 and correlated with response to GO. Results Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, P = .731; event-free survival [EFS]: GO 53% v No-GO 58%, P = .456). However, patients with higher CD33 expression (Q2 to Q4) had significantly reduced RR (GO 32% v No-GO 49%, P < .001) and improved EFS (GO 53% v No-GO 41%, P = .005). This differential effect was observed in all risk groups. Specifically, low-risk (LR), intermediate-risk (IR), and high-risk (HR) patients with low CD33 expression had similar outcomes regardless of GO exposure, whereas the addition of GO to conventional chemotherapy resulted in a significant decrease in RR and disease-free survival (DFS) for patients with higher CD33 expression (LR RR, GO 13% v No-GO 35%, P = .001; LR DFS, GO 79% v No-GO 59%, P = .007; IR RR, GO 44% v No-GO 57%, P = .044; IR DFS, GO 51% v No-GO 40%, P = .078; HR RR, GO 40% v No-GO 73%, P = .016; HR DFS, GO 47% v No-GO 28%, P = .135). Conclusion We demonstrate that GO lacks clinical benefit in patients with low CD33 expression but significantly reduces RR and improves EFS in patients with high CD33 expression, which suggests a role for CD33-targeted therapeutics in subsets of pediatric AML.

scholarly journals Treatment of Childhood Nasopharyngeal Carcinoma With Induction Chemotherapy and Concurrent Chemoradiotherapy: Results of the Children’s Oncology Group ARAR0331 Study

2019 ◽  
Vol 37 (35) ◽  
pp. 3369-3376 ◽  
Author(s):  
Carlos Rodriguez-Galindo ◽  
Mark D. Krailo ◽  
Matthew J. Krasin ◽  
Li Huang ◽  
M. Beth McCarville ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Induction Chemotherapy ◽  
Concurrent Chemoradiotherapy ◽  
Advanced Disease ◽  
Black Children ◽  
Oncology Group ◽  
Event Free Survival ◽  
Free Survival ◽  
The Impact ◽  
To Receive

PURPOSE The treatment of childhood nasopharyngeal carcinoma has been adapted from adult regimens; pediatric-specific studies are limited. The ARAR0331 study sought to evaluate the impact of induction chemotherapy (IC) and concurrent chemoradiotherapy (CCR). PATIENTS AND METHODS Patients with American Joint Committee on Cancer stages IIb to IV were scheduled to receive three cycles of IC with cisplatin and fluorouracil, followed by CCR with three cycles of cisplatin. Patients with complete or partial response to IC received 61.2 Gy to the nasopharynx and neck, and patients with stable disease received 71.2 Gy. RESULTS Between February 2006 and January 2012, 111 patients (75 male) were enrolled. Median age was 15 years, and 46.8% of the patients were African American. After a feasibility analysis, the study was amended to reduce cisplatin to two cycles during CCR. The 5-year event-free survival (EFS) and overall survival estimates were 84.3% and 89.2%, respectively. The 5-year EFS for stages IIb, III, and IV were 100%, 82.8%, and 82.7%, respectively. The 5-year cumulative incidence estimates of local, distant, and combined relapse were 3.7%, 8.7%, and 1.8%, respectively. Patients treated with three versus two CCR cycles of cisplatin had improved 5-year postinduction EFS (90.7% v 81.2%, P = .14). CONCLUSION Patients in ARAR0331 were characterized by advanced disease and by a high proportion of black children and adolescents. Treatment with IC and CRT resulted in excellent outcomes. A radiation dose reduction is possible for patients responding to IC. Although the outcomes are comparable, we observed a trend toward decreased EFS for patients assigned to receive fewer doses of cisplatin during CCR.

scholarly journals Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial

2020 ◽  
Vol 38 (33) ◽  
pp. 3925-3936 ◽  
Author(s):  
Alexander M. M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandala ◽  
Georgina V. Long ◽  
Victoria G. Atkinson ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Stage Iii Melanoma ◽  
The Impact

PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 526-526 ◽  
Author(s):  
Edward A Stadtmauer ◽  
Amrita Krishnan ◽  
Marcelo C Pasquini ◽  
Marian Ewell ◽  
Edwin P Alyea ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Cell Transplant ◽  
Primary Analysis ◽  
Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

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