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 ◽  
...  

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.

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2005-2005
Author(s):  
Betul Oran ◽  
Rima M Saliba ◽  
Yudith Carmazzi ◽  
Elizabeth J. Shpall ◽  
Katayoun Rezvani ◽  
...  

Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 486-486
Author(s):  
Katherine Tarlock ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  

Abstract CD33 is variably expressed on most acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO), a calicheamicin-conjugated anti-CD33 monoclonal antibody. COG studies AAML03P1 and AAML0531 evaluated the safety and efficacy of GO combined with conventional chemotherapy to determine the impact of GO on treatment outcomes. We have previously demonstrated that those with high CD33 expression are more susceptible to GO. As FLT3-ITD is associated with high levels of CD33 expression, this group of patients represents a subgroup of particular interest for this therapeutic approach. Patients with high-allelic ratio (HAR) FLT3-ITD have poor outcomes with conventional chemotherapy alone and experience improvement with allogeneic hematopoietic stem cell transplant (HCT). Thus, COG AAML0531 allocated HAR FLT3-ITD+ patients enrolled after April 14, 2008 to consolidation allogeneic HCT with the best available donor. In combined evaluation of COG AAML0531 and its preceding pilot study AAML03P1, 479 patients received conventional MRC based induction chemotherapy (0531 Arm A) and 735 patients received conventional chemotherapy + GO (03P1 and 0531 Arm B). A total of 183 FLT3-ITD+ patients were treated on 0531 Arm A (n=71) and on 03P1/0531 Arm B (n=112). Overall, patients with FLT3-ITD had significantly lower rates of complete remission (CR) compared to FLT3-ITD negative patients, 64% v. 77% respectively (p<0.001). Among FLT3-ITD+ patients, CR rates were identical in those with or without induction GO exposure of 64% vs. 64% respectively (p=0.98). Analysis of 5-year outcomes for FLT3-ITD+ patients treated with GO compared to no GO demonstrated no difference in overall survival (OS) (50% v 49% respectively, p=0.74). Importantly, cumulative incidence of relapse (CIR) at 5 years from CR for patients treated with GO was 37% vs. 59% in those who did not receive GO (p=0.018). This GO-associated improvement in relapse was offset by higher treatment related mortality (TRM) among GO compared to no GO recipients (16% v 0% respectively, p=0.008), leading to similar DFS of 47% vs. 41% respectively (p=0.45). The benefit of decreased relpase risk (RR) was most significant for patients receiving GO in addition to HCT. Among FLT3-ITD+ patients who underwent HCT, those who received GO (n=33) had a 5-yr RR of 22% compared to 56% for the no GO cohort (n=25, p=0.003). There was a trend towards increased TRM among patients receiving GO compared to no GO (22% v. 4% respectively, p=0.078), with a corresponding DFS in GO recipients of 56% vs. 40% for the no GO cohort (p=0.09). Evaluation of the 8 GO recipients who died at HCT revealed that 3 (38%) were the result of complications from transplant-associated sinusoidal obstructive syndrome. Patients with HAR FLT3-ITD, who experience poor outcomes with conventional chemotherapy alone, were analyzed separately to evaluate the impact of induction GO on outcomes. Among HAR FLT3-ITD+ patients who underwent HCT, those treated with GO (n=26) had a significantly lower RR of 15% compared to 53% among no GO recipients (n=15, p=0.007). Additionally, patients receiving GO had a trend towards higher DFS of 65% compared to 40% for no GO group, (p=0.079). In this cohort, TRM in GO vs. no GO recipients was 19% vs. 7% respectively (p=0.297). Among HAR FLT3-ITD+ patients who did not receive HCT, there were no significant differences in DFS, RR, and TRM among the GO versus no GO recipients. Data from the two consecutive COG studies AAML03P1 and AAML0531 suggest that FLT3-ITD+ patients may benefit from the addition of GO to intensive chemotherapy. There is further evidence that HCT may augment the therapeutic impact of induction GO by further reducing the risk of relapse. However, clinical impact of GO was tempered by higher incidence of TRM in GO recipients. CD33 targeting represents an attractive approach in FLT3-ITD+ patients as they often have elevated blast CD33 expression. Further understanding of the toxicity profile of GO, especially when used in conjunction with intensive chemotherapy and HCT, is needed to enhance its therapeutic benefit. Additionally, its impact may be most significant in certain biologic subsets of AML. Our findings demonstrate that CD33 targeting is an important treatment strategy in AML that warrants further investigation in FLT3-ITD+ patients. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
pp. JCO.20.03048
Author(s):  
Jessica A. Pollard ◽  
Erin Guest ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Mike R. Loken ◽  
...  

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 799-799
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  

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.


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 ◽  
...  

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 800-800
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Yi-Cheng Wang ◽  
Jason Joaquin ◽  
...  

Abstract Mutations of KIT (KIT +) occur in children and adults with core binding factor (CBF) acute myeloid leukemia (AML) and cluster within exons 8 and 17. We previously reported a 19% prevalence of KIT mutations in pediatric CBF AML and lack of prognostic significance in serial pediatric cooperative trials. We also determined that gemtuzumab ozogamicin (GO) improves outcomes for a subset of CBF AML patients with higher CD33 expression enrolled on AAML0531, a randomized trial of conventional chemotherapy with or without GO. Thus, in this study, we determined whether the clinical outcome of patients with KIT + CBF AML is affected by GO treatment. COG AAML0531 enrolled 1022 eligible pediatric de novo AML patients of which 247 had CBF AML [137 t(8;21) and 110 inv(16)/t(16;16)] based on central cytogenetic review. Of these 247 patients, 218 had evaluable samples for KIT mutational analysis. Analysis included PCR amplification of exons 8 and 17 and fragment length analysis and direct sequencing to identify all missense and size mutations. Mutations were detected in 55 patient samples (25%); 27 (49%) involved exon 8, 26 (47%) involved exon 17 and 2 (4%) involved both exons. Breakdown by exon and CBF translocation type demonstrated exon 8 mutations in 12/121 (10%) t(8;21) samples and 17/97 (18%) inv(16)/t(16;16)patient samples. Exon 17 mutations were found in 18/121 (15%) t(8;21) and 10/97 (10%) inv(16)/t(16;16) patient samples. Overall outcome analysis among the 218 CBF AML samples analyzed for KIT mutations revealed similar complete remission (CR) rates after induction I for KIT + vs. KIT- patients (83% vs. 82%, p=0.796). Five-year event-free survival (EFS) from study entry for KIT + vs. KIT- was 54% and 70%, respectively (p=0.029) with a corresponding overall survival (OS) of 76% vs. 83% (p=0.380). Notably, KIT + patients who achieved CR had a relapse risk (RR) of 45% vs. 23% for KIT- patients (p=0.010). Disease-free survival (DFS) for KIT + vs. KIT- was 51% and 72%, respectively (p=0.021). We also compared the clinical impact of exon 8 vs. exon 17 mutations. Outcomes of CBF AML patients with exon 8 mutations were similar to CBF AML patients without these mutations (OS 90% vs. 80%, p=0.277, EFS 55% vs. 68%, p=0.224, DFS 58% vs. 68%, p= 0.419, RR 42% vs. 26%, p= 0.112). In contrast, outcomes of patients with exon 17 mutations were inferior to those CBF AML patients without exon 17 mutations [OS 64% vs. 84%, p=0.035; DFS 43% vs. 70%, p=0.016) and higher RR was observed (48% vs. 26%, p=0.057). The impact of GO treatment on outcome was subsequently evaluated. KIT + CBF AML patients who did not receive GO had inferior OS and EFS from study entry compared to KIT-patients (OS 64% vs. 86%, p= 0.034, EFS: 46% vs. 69%, p=0.037). Higher RR (55% vs. 31%, p= 0.046) and inferior DFS (45% vs. 66%, p= 0.094) were also observed. In contrast, KIT + and KIT-patients receiving GO treatment had comparable outcomes (OS 88% vs. 80%, p=0.393; EFS 62% vs. 72%, p=0.438) as well as RR (33% vs. 15%, p=0.103) and DFS (57% vs. 77%, p=0.109). Analysis by mutation subtype revealed that outcomes of patients with exon 8 mutations were similar to exon 8 wild-type (WT) patients when treatment did not include GO (OS 81% vs. 80%, p=0.910; EFS 50% vs. 65%, p= 0.185). DFS and RR were also similar (DFS 57% vs. 62%, p= 0.752, RR 43% vs. 36%, p= 0.632). Treatment of exon 8 mutations with GO resulted in significant improvement in OS at 5 years from study entry compared to those without exon 8 mutations (100% vs. 80%, landmark p value <0.001) but other outcome parameters were not significantly improved (EFS 62% vs. 71%, p= 0.707; DFS 58% vs. 75%, p=0.382; RR 42% vs. 16%, p=0.056). For patients with exon 17 mutations, treatment without GO resulted in inferior outcomes when compared to CBF AML patients without exon 17 mutations (OS 56% vs. 85%, p= 0.019; EFS 44% vs. 66%, p=0.154; DFS 33% vs. 65%, p=0.049; RR 67% vs. 32%, p=0.031). Adding GO abrogated this negative impact. Specifically, OS, EFS, DFS and RR for patients with exon 17 mutations were comparable to that of CBF AML patients with WT exon 17 when treated with GO (OS 77% vs. 83%, p= 0.542; EFS 62% vs. 71%, p=0.516; DFS: 56% vs. 74%, p=0.195; RR 22% vs.19%, p=0.898). This analysis suggests that pediatric KIT + CBF AML has negative prognostic impact within the context of AAML0531. This effect was abrogated, particularly for patients with exon 17 mutations, with GO treatment. CD33-targeted agents may be beneficial, at least for a subset of these patients, in future clinical trials. Disclosures Aplenc: Sigma Tau: Honoraria.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 119-119 ◽  
Author(s):  
Katherine Tarlock ◽  
Jessica A. Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Yi-Cheng Wang ◽  
...  

FLT3/ITD mutations are among the most common in AML and are associated with adverse outcome. The addition of FLT3 inhibitors (FLT3-I) to cytotoxic therapy has provided improvements in outcome. We have previously shown that co-occurring mutations impact the clinical implications of FLT3/ITD, where those with NUP98-NSD1 fusions and/or WT1 mutations do particularly poorly (Figure 1A), regardless of ITD allelic ratio (AR). FLT3-I act on mutated and aberrantly activated FLT3, thus may be most effective in AML that is primarily driven by overactive FLT3 signaling. Given the significant overlap between FLT3/ITD and WT1 and NUP98-NSD1, we questioned whether response to FLT3-I may be modulated by these co-occurring variants. The Children's Oncology Group phase III trial AAML1031 treatment arm for patients with high AR (HAR; &gt;0.4) FLT3/ITD mutations evaluated the safety and efficacy of the FLT3-I sorafenib in combination with chemotherapy and hematopoietic stem cell transplant (HSCT). A total of 136 patients with HAR ITD were enrolled, 92 patients treated on the sorafenib arm (+SOR) with complete clinical and biologic (n=88) data available. An additional 42 patients were included in the primary randomization of +/- bortezomib and consolidation HSCT without sorafenib (w/o SOR). As equivalent outcomes were observed in the primary randomization, this cohort was combined for further analysis to serve as a control to evaluate outcomes of patients not receiving sorafenib. In addition to conventional karyotyping and mutational profiling (determination of the FLT3/ITD and respective AR by fragment length analysis), all patients were evaluated for NUP98-NDS1 by RNAseq and WT1 profiling by NGS or, hotspot sequencing of exons 7 and 9. Response to sorafenib was measured by 3-year overall survival (OS), event-free survival (EFS), and relapse risk (RR). We compared outcomes for patients +SOR to w/o-SOR to according to co-occurring mutations, specifically NUP98-NSD1, WT1, and triple positive (TP; ITD/NUP98-NSD1/WT1). Patients treated +SOR experienced a combined OS of 62% vs. 68% w/o-SOR (p=0.562). Patients with ITD+/NUP98-NSD1+ disease (WT1+ patients excluded) treated +SOR and w/o-SOR had similar poor outcomes with 3-year EFS of 22% and 20% respectively (p=0.912; Figure 1B). Among patients treated w/o SOR, NUP98-NSD1+ had significantly inferior outcomes compared to NUP98-NSD1-negative (neg) patients (EFS: 20% vs. 65%, p=0.02). NUP98-NSD1+ patients had similar dismal outcomes +SOR treatment, and inferior to NUP98-NSD1-neg patients treated +SOR (p=0.015; Figure 1B). Thus, sorafenib treatment did not improve outcomes of HAR ITD+/NUP98-NSD1+ patients. Analysis of the impact of co-occurring WT1 mutations (NUP98-NSD1+ patients excluded) demonstrated that ITD+/WT1+ patients had an adverse outcome w/o-SOR (EFS 0% and RR 100%), which was significantly inferior to WT1-neg patients treated w/o-SOR (p=0.002 and p=0.003 respectively; Figure 1C). However, WT1+ patients treated +SOR had much improved outcomes with an EFS of 50% and corresponding RR of 27%, which was comparable to WT1-neg patients treated +SOR (Figure 1C). Thus, sorafenib treatment resulted improved outcomes for ITD+/WT1+ patients. Combining all NUP98-NSD1+ patients, TP patients experienced poor EFS of 23%, similar to 21% for ITD+/NUP98-NSD1+/WT1-neg. Thus, we show that NU98-NSD1 fusions drive the dismal prognosis, as ITD+/NUP98-NSD1+ patients, regardless of additional mutations, experienced significantly inferior outcomes compared to other ITD+ patients, including WT1+, that was not improved by treatment with sorafenib in combination with chemotherapy and HSCT (Figure 1D). We show that sorafenib improved outcomes among the HAR ITD+/WT1+ patients, as this group of patients who did not receive sorafenib had very inferior outcomes, in line with previous findings for this poor risk cohort, while patients treated with sorafenib did much better with outcomes similar to other ITD+ patients. However, sorafenib failed to improve outcomes for NUP98-NSD1+ patients, further highlighting that novel therapeutic strategies will be needed for this group of patients. As the addition of FLT3-I is investigated in HAR FLT3/ITD+ patients, evaluation of its impact across patients with additional oncogenic mutations will be critical to determine which patients will derive the most benefit from this strategy. Disclosures No relevant conflicts of interest to declare. Off Label Disclosure: Sorafenib in FLT3/ITD-positive AML


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2778-2778 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Antonio Palumbo ◽  
Paul Richardson ◽  
Rudolf Schlag ◽  
Meletios A Dimopoulos ◽  
...  

Abstract Complete response (CR) has been shown to be prognostic for improved long-term outcomes, including progression-free survival and overall survival (OS), in previously untreated multiple myeloma (MM) patients receiving high-dose therapy and stem cell transplant (SCT; Harousseau et al, IMW 2007; van de Velde et al, Haematologica 2007). However, there is limited evidence of such a correlation in the non-transplant setting. In the large, international phase III VISTA study in previously untreated MM patients ineligible for SCT, bortezomib plus melphalan–prednisone (VMP) demonstrated superiority to MP across all efficacy end points, including response rates, time to progression (TTP), and OS. Here, we assess the differential prognostic impact of best response on time-to-event parameters in VISTA, and evaluate the impact of timing of CR on outcome in patients receiving VMP. A total of 682 patients (median age 71 years) were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2, days 1–4, cycles 1–9) or MP (N=338). The primary end point was TTP. Response and progression were determined using European Group for Blood and Marrow Transplantation (EBMT) criteria; in a post-hoc analysis, response was determined using International Myeloma Working Group (IMWG) uniform criteria. Associations between long-term outcomes and response were examined in the intent-to-treat population by multivariate Cox regression analysis with time-dependent covariates, adjusted for stratification factors (baseline β2-microglobulin and albumin; region), with age, sex, race, MM type, baseline Karnofsky Performance Status, and number of bone lesions as covariates. Among evaluable patients, response rates to VMP vs MP were 71% vs 35%, including 30% vs 4% CR, by EBMT criteria, and 74% vs 39%, including 33% vs 4% CR and 8% vs 4% VGPR, by IMWG criteria. Median TTP was 24.0 vs 16.6 months. CR by EBMT criteria was associated with significantly longer TTP (hazard ratio [HR] 0.45, p=0.004; Figure), time to next therapy (TNT; HR 0.44, p=0.014), and treatment-free interval (TFI; HR 0.37, p=0.004) vs PR, plus improved OS (medians not reached; clear separation between the curves; HR=0.59, p=0.265; statistical significance not seen likely due to a small number of deaths). Significant benefit was seen for CR and PR vs no response by EBMT criteria for all four parameters, including OS. Findings were similar for CR vs VGPR+PR vs no response by IMWG criteria. Importantly, CR was associated with significantly longer TTP (HR 0.45, p=0.019) and TFI (HR 0.39, p=0.026) vs VGPR, with a trend towards longer TNT (HR 0.54, p=0.126); no significant differences for these parameters were seen for VGPR vs PR. However, these findings should be interpreted with caution due to the small number of patients achieving VGPR. Among patients achieving CR (EBMT criteria) with VMP, there were no clear differences in clinical benefit associated with achieving CR early (cycles 1–4, within 24 weeks) vs later (cycle 5 onwards, after 24 weeks), although TTP and overall duration of response appeared slightly longer with later CRs, possibly due to the inherent slightly longer duration of therapy (mean 7.4 vs 8.5 cycles). In conclusion, this analysis demonstrates the prognostic significance of CR on long-term outcomes in the setting of non-intensive therapy. The data show that CR is associated with improved outcomes vs VGPR by IMWG criteria, and indicate that the clinical benefit of CR with VMP is similar regardless of time to achieve CR, supporting continuation of therapy to achieve maximal response. Figure: TTP in patients achieving CR vs PR (EBMT criteria) with VMP Figure:. TTP in patients achieving CR vs PR (EBMT criteria) with VMP


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2070-2070 ◽  
Author(s):  
Brittany Knick Ragon ◽  
Carey Clifton ◽  
Bipin N. Savani ◽  
Brian Engelhardt ◽  
Adetola A Kassim ◽  
...  

Abstract Abstract 2070 Introduction: The optimal healthcare model for follow-up of allogeneic stem cell transplant (allo-SCT) recipients after day-100 is not clear. Most centers reintegrate patients into primary hematology clinics, with a few centers having dedicated long term follow-up infrastructure. Long term transplant clinic (LTTC) was established at Vanderbilt University Medical Center in 2006. We have previously shown that LTTC longitudinal follow-up is associated with superior overall survival (OS) (Jagasia et al, BBMT, 289a, 2008). Recent data suggests that a long driving time to transplant center is associated with worse OS (Abou-Nassar et al, BBMT 2012). We hypothesized that geographic distance would not be associated with inferior outcome if patients are followed in a dedicated transplant clinic. Methods: Since 2006 all patients beyond day-100, who were medically stable (n=381) for discharge from the transplant center, were transitioned to LTTC and followed in a systematic manner. Some patients who were transplanted at other institutes established care in LTTC for geographic, insurance or social support reasons, and transitioned at later time points. Patients who could not return to the center for follow-up as per protocol were contacted through telephone, and all patients were encouraged to use an electronic communication system ([email protected]). The LTTC team coordinated multidisciplinary care with dedicated consultants in endocrinology, lipid, dermatology, pulmonary, infectious disease, orthopedics, and ophthalmology. Only patients with more than 1 LTTC visit (n=375) were included in the study cohort. Results: Pre-transplant characteristics: age (median-48 y, range 18–70); recipient gender (male-207, 55.2%; female-168, 44.8%); regimen (ablative-212, 56.5%; other-163, 43.5%); donor (related-204, 54.4%; unrelated-170, 45.3%); diagnosis (acute leukemia-179, 47.8%; lymphoid malignancies-90, 23.9%; other-106, 28.3%); and CIBMTR disease risk (low-191, 50.9%; intermediate-97, 25.9%; high-84, 22.4%). The median distance from the transplant center was 113 miles (range, 0.6–562.5). The 75th percentile (163 miles) was used as the cut off to analyze the impact of distance from the center on outcome (279 patients ≤ 75th percentile; 96 patients > 75th percentile). The two cohorts were balanced for pre-transplant characteristics (data not shown). The median day post-SCT for transition to LTTC was 114 d (range, 83–5844), with 70% transitioning by day 130. OS was calculated from transition to LTTC until last follow-up or death. Of the 375 patients, 78 are dead (relapse-52, 66.7%; non-relapse-26, 33.3%). Two-year OS for the entire cohort was 79.9% (±0.024 SE). In univariate analyses, age, regimen, donor, and diagnosis did not impact survival. Two-year survival for patients ≤ 163 miles and > 163 miles was 78.5% (±0.028 SE) and 82.4% (±0.045 SE), respectively (P=0.127). In multivariate analyses, adjusted for donor type, CIBMTR disease risk, time of transition to LTTC (cut off day 130), distance from transplant center (cut off 75th percentile), did not impact outcome. Conclusion: Contrary to previous reports, our study suggests that geographic distance from the transplant center is not associated with inferior outcome when follow-up care is delivered via a dedicated long-term transplant follow up clinic incorporating well orchestrated multidisciplinary care. Systematic care in LTTC to monitor, prevent, and treat chronic GVHD and late effects after allo-SCT will be increasingly important to optimize outcomes and should be considered an integral part of a transplant program. Disclosures: No relevant conflicts of interest to declare.


Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.


Sign in / Sign up

Export Citation Format

Share Document