Introduction:
Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML ...have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy.
Methods:
We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality.
Results:
Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached.
Conclusion:
In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen.
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Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.
Background: Tumor protein 53 (TP53), located on the short arm of chromosome 17, is an important tumor suppressor gene responsible for critical regulatory functions. There is existing controversy ...regarding the role of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a TP53 mutation. While most studies report increased relapse and poor survival after allo-SCT with TP53 mutated AML or MDS, (Bajar et al., JCO 2014; Lindsley et al., 2017) others found no influence of TP53 mutation on allo-SCT outcomes (Aldoss et al., 2017). Notably, previous studies have predominantly evaluated the prognostic impact of TP53 mutation at the time of diagnosis and not serially in response to treatment. In this study, we aim to clarify the prognostic impact of TP53 mutation clearance prior to allo-SCT in patients with TP53 mutated AML or MDS.
Methods: Data was obtained and analyzed on MDS or AML patients who received allo-SCT at the Moffitt Cancer Center (2013-2018) and had presence of TP53 at least once after diagnosis and prior to allo-SCT. TP53 clearance was defined by last next-generation sequencing (NGS) test prior to allo-SCT demonstrating no TP53 mutation with a variant allele frequency (VAF) greater than 5%. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and median overall survival (OS) from the time of allo-SCT. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were performed as defined by the Fine and Gray model.
Results: We identified 47 patients (29 males/18 females) with TP53 mutation prior to allo-SCT with primary diagnosis of AML (55.3%) or MDS (44.7%) (Table 1). The median follow-up was 25.4 months with 2-year OS of 32.8% for the entire cohort. The median age at diagnosis was similar between TP53-cleared and TP53-persistent groups with 68% of the patients >= 60 years at the time of allo-SCT. Only 26% (n=12) had clearance of their TP53 mutation prior to allo-SCT. The majority of the patients had complex cytogenetics at diagnosis (85%) with deletion 5q being the most common coexisting aberration (75% in TP53-cleared and 68.6% in TP53-persistent, p=NS). Patients with TP53 clearance received hypomethylating agent (HMA) as frontline treatment more frequently compared to those with persistent TP53 (66.7% vs. 45.7%, p=NS). They also had fewer lines of therapy (83.3% with 1 line vs. 62.9%, p=NS), and a higher rate of complete response prior to allo-SCT (83.3% vs. 57.1%, p=NS). Amongst patients receiving HMA as frontline therapy (n=24), we observed significantly better survival in TP53-cleared patients compared to those with persisted TP53 (median OS of 21.73 months vs. 6.44 months, p=0.042) (Figure 1). Myeloablative conditioning (MAC) regimen was used in 33.3% of TP53-cleared in comparison to 42.9% in TP53-persistent cohort (p=NS). Median OS was 21.7 months for patients with clearance of TP53 vs. 8.1 months for those with persistent TP53 at allo-SCT; although it did not meet statistical significance (p=0.106). MAC compared to reduced intensity conditioning (RIC) regimen resulted in significantly worse RFS (HR 2.06, 95% CI 1.04-4.12, p=0.040) and OS (HR 2.70, 95% CI 1.30-5.60, p=0.008). Conditioning intensity was the only factor that significantly influenced RFS and OS outcomes (Table 2). When repeating these analyses separately on the TP53-cleared and TP53-persistent groups, only the latter remained significant for conditioning (MAC, univariate OS: HR 2.6, 95% CI 1.14-5.92, p=0.023).
Conclusions: TP53 clearance at the time of allo-SCT is predictive of better outcomes in patients who had frontline HMA therapy. For patients with persistent TP53 at the time of allo-SCT, those received MAC experienced worse outcomes compared to RIC in this cohort. The OS at 2-year for TP53-persistent patients is over 30% suggesting even these patients can potentially benefit from transplantation.
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Talati:Celgene: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bejanyan:Kiadis Pharma: Other: advisory board. Kuykendall:Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria. Padron:Incyte: Research Funding. Komrokji:Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; celgene: Consultancy; DSI: Consultancy; pfizer: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees.
Background: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoiesis, and aberrant expression of this gene can facilitate leukemogenesis. RUNX1 mutations (RUNX1mut) are thought ...to carry a poor prognosis and have been recently incorporated into the risk stratification systems for acute myeloid leukemia (AML) by European LeukemiaNet (ELN) (Dohner et al. 2017) and National Comprehensive Cancer Network (NCCN et al. 2019). However, the clinical significance of this mutation after allogeneic stem cell transplantation (allo-SCT) is controversial with a recent study suggesting that allo-SCT may reverse the unfavorable influence of RUNX1mut (Qin et al. 2017). In this study, we describe the prognostic impact of RUNX1mut in patients with AML undergoing allo-SCT and compare the outcomes to ELN-defined adverse risk, RUNX1wt AML patients and patients with intermediate risk AML.
Methods: We retrospectively reviewed our database of 407 patients who received allo-SCT at the Moffitt Cancer Center between 2013 and 2018. Only AML patients undergoing allo-SCT during first complete remission that had molecular information prior to transplant were included. This cohort was divided into three subgroups: 1) RUNX1mut AML 2) ELN-defined adverse risk, RUNX1wt AML and 3) ELN-defined intermediate risk AML. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Cumulative incidence function was performed as defined by the Fine and Gray model. Kaplan-Meier analysis with log-rank test was used to estimate median overall survival (mOS) from the time of diagnosis.
Results: Among 407 AML patients reviewed, we identified 28 patients with RUNX1mut, 71 adverse risk RUNX1wt patients, and 69 intermediate risk patients. Of the 28 patients (18 males/10 females) with RUNX1mut, 53.6% were under age 60, two-thirds had de novo AML (dAML), and 92.9% had intermediate risk cytogenetics as defined by ELN 2017 at diagnosis. Baseline characteristics are described in Table 1.
Univariate analysis identified RUNX1mut to be predictive of inferior OS compared to the intermediate risk cohort (HR 2.29, 95% CI 1.12-4.64, p=0.022). Subsequent multivariate regression using covariates of age, sex, AML type, lines of therapy prior to allo-SCT, and conditioning regimen confirmed RUNX1mut as an independent covariate for reduced OS (HR 2.51, 95% CI: 1.18-5.33, p=0.016). At a median follow-up of 29.3 months for the entire cohort, Kaplan-Meier analysis confirmed an inferior mOS in patients with RUNX1mut compared to the intermediate risk group (25.7 months vs. 59.8 months, p=0.029) and was not different from RUNX1wt adverse risk group (25.7 months vs. 45.7 months, p=0.872) (Figure 1A).
Cumulative incidence of relapse after allo-SCT for patients with RUNX1mut is significantly higher than intermediate risk patients (p=0.005, Figure 1B); however, there was no difference compared to RUNXwt adverse risk AML (p=0.295). There was no difference in non-relapse mortality (NRM) between RUNX1mut and intermediate risk patients (p=0.789, Figure 1B) or RUNX1mut and RUNX1wt adverse risk AML (p=0.323).
When impact of concomitant somatic mutations on disease recurrence in RUNX1mut cohort was assessed, no discernible trends were identified. RUNX1mut was mutually exclusive with NPM1 and frequently co-occurred with DNMT3A (21.4%), IDH2 (17.9%), and SRSF2 (17.9%) (Figure 2). Interestingly, 92.9% of the patients with RUNX1mut had ELN-defined intermediate risk cytogenetics and only 7.1% of the cohort had ELN-defined adverse risk cytogenetics.
Conclusions: Our findings indicate that allo-SCT AML patients with RUNX1mut have poor outcomes analogous to RUNX1wt adverse risk AML.
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Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Agios: Honoraria. Kuykendall:Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Background:
Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline ...therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML.
Methods:
We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided.
Results:
Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009).
At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97).
The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07).
Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted.
Conclusion:
Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML.
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Padron:Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria.
Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.
Background
The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML ...and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351.
Methods
We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided.
Results
Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3.
Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24).
We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT.
Conclusion
Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified.
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Kuykendall:Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.
Background
Role of somatic mutations in Chronic Myeloid Leukemia (CML) is fairly underexplored. We hypothesize that clonal evolution of chronic phase CML (CP-CML) to blast phase CML (BP-CML) is ...molecularly driven thus augmenting on previous findings of ASXL1 being a commonly recurrent mutation in CML. Therefore, early detection of specific somatic mutations can predict progression of disease.
Methods
We performed a retrospective chart review of clinically and molecularly annotated 60 cases of CML from Moffitt Cancer Center. Genotyping was performed using next generation targeted DNA sequencing detecting for common recurrent mutations in hematological malignancies. Fisher's Exact and Student T-test were used to determine statistical significance (p-value of <0.05). All calculated p values were two sided.
Results
Total 48 patients with CP-CML and 12 patients with BP-CML were included. Median age was 56 and 53.5 years in CP-CML and BP-CML cohort, respectively. Among CP-CML cohort, 37.5% (n=18) had at least 1 mutation with ASXL1 being the most frequently mutated gene (27.7%, n=5) where 80% (n=4) were isolated and only 20% (n=1) had comutation in RUNX1 (Figure 1A). In BP-CML patients, at least 1 mutation was detected in 100% of the cases (n=12) with ASXL1 being the most frequently mutated gene (67%, n=8) (Figure 1B). In contrast to the CP-CML cohort, ASXL1 mutation co-occurred with other mutations in 87.5% of the cases (n=7). The most frequent co-occurring mutations were TET2 (37.5%, n=3) and CUX1 (37.5%, n=3) followed by RUNX1 (25%, n=2), SETBP1 (25%, n=2), TP53 (25%, n=2) and PHF6 (12.5%, n=1). Majority of the BP-CML comprised of myeloid BP (83%) where ASXL1 mutations were exclusively found. Lymphoid BP (16%, n=2) cases revealed lymphoid specific mutations in CDKN2A and IKZF1 genes.
In BP-CML compared to CP-CML, presence of ASXL1 mutation was more frequent (OR 17.2, 95% CI 3.77-78.32, p=0.002) with increased frequency of co-occurrence with at least one other mutation (OR 28.0, 95% CI 1.35-580.0, p=0.032). In BP-CML cohort, 83% (n=10) of the patients had additional cytogenetic abnormalities (ACAs) and only 16.5% (n=2) had isolated standard Philadelphia chromosome. In contrast to BP-CML, there was no correlation between presence of ACAs and presence of mutations in CP-CML cohort.
Conclusions
Although this study is comprised of a small sample size, the findings suggest that the presence of ASXL1 in CP-CML may represent an early event or “first hit”, which then acquires an additional mutation or “second hit”, contributing to progression to advanced phase CML. These findings need to be validated in a large prospective cohort study.
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Chavez:Abbvie: Speakers Bureau; Janssen: Speakers Bureau; Kite: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Pinilla-Ibarz:Pfizer: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria; BMS: Honoraria, Speakers Bureau.
Introduction
The identification of somatic genomic alterations in cancer has brought forth a paradigm change in the personalized management of patients with acute myeloid leukemia (AML). This is ...exemplified by the recent FDA approvals with the targeted small molecule inhibitors of mutant IDH1 (ivosidenib) and IDH2 (enasidenib) for patients with relapsed/refractory AML. IDH1/2 mutations have been reported to occur in approximately 16-20% of patients with AML based on the largest published cohorts to date (Dinardo et al., Am J Hematol, 2015; Papaemmanuil et al., NEJM, 2016). However, there remains a paucity of data on the frequency of IDH1/2 and other targetable mutations in extramedullary manifestations of AML (i.e. myeloid sarcoma and leukemia cutis; EM-AML). We sought to characterize the mutational landscape of EM-AML, with a focus on determining the frequency of IDH1/2 mutations.
Methods
This is a multi-institutional retrospective analysis of patients diagnosed with EM-AML, who were treated at Moffitt Cancer Center or Memorial Healthcare System and underwent next-generation sequencing (NGS). All patients were evaluated for IDH1/2 mutations and up to 435 additional genes. Clinical variables and outcomes of EM-AML patients were characterized at the time of sample procurement. Additionally, we acquired additional de-identified NGS data on EM-AML patients who underwent sequencing of the EM site at Genoptix. We describe the mutational landscape of patients and compared the frequency of IDH1/2 mutations to historical controls in AML from the published literature using Fisher's exact test. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of mutation identification.
Results
Thirty-five patients with EM-AML were identified (22 in the clinical cohort and 13 in the Genoptix cohort) and are included in this analysis. The distribution of EM-AML diagnoses were myeloid sarcoma in 71% of cases (n=25) and leukemia cutis in 29% (n=10). The sequenced samples were from an extramedullary site for 63% (n=22) of the cases. The median age of the cohort was 64 (IQR 52 - 72) with a male predominance (55%). Of the clinical cohort, 68% (n=15) were non-Hispanic White, 23% (n=5) were Hispanic, and 9% (n=2) were Black. The molecular landscape of the cohort is shown in Figure 1. The frequency of IDH1/2 mutations was 31% (11/35), with IDH1 and IDH2 mutations reported in 17% (n=6) and 14% (n=5) of cases, respectively. All IDH1 mutations were at position R132 (4 R132H and 2 R132C) and all IDH2 mutations were at R140 (4 R140Q and 1 R140G). The other most frequent genomic alterations were DNMT3A (29%), NPM1 (26%), FLT3 (23%; ITD in 18% and TKD in 5%; 11% in IDH wildtype), NRAS (21%), TET2 (17%), and ASXL1 (17%). Mutations in DNA methylation occurred in 54% of patients (n=19). Co-occurring NRAS/KRAS mutations were more frequent in IDH mutant patients (45%; 5/11) compared to 12% (3/24) of IDH wild type patients (P=0.01). DNMT3A mutations were reported in 45% (5/11) of IDH mutant cases compared to 21% (5/24) of IDH wildtype cases, although this was not statistically significant (P=0.23). In comparison to a historical frequency of IDH1/2 mutations in AML patients of 17.4% (n=2366), EM-AML patients had an increased frequency of 31% (P=0.04). The median OS of the cohort was 13.6 months. Within the clinical cohort 50% (4/8) of the IDH1/2 mutant patients were treated with an IDH inhibitor with CR in 1 patient, CRi in 1 patient, and stable disease in 2 patients. The patient who achieved CR developed widespread leukemia cutis during cycle 1 of enasidenib which resolved over 6 months and is in durable CR for 15 months.
Conclusion
Overall, EM-AML patients had targetable mutations (i.e. IDH1/IDH2/FLT3) in 40% of cases with an increased frequency of IDH1/2 mutations (31%) in comparison to the general AML population. IDH mutant EM-AML patients achieved clinical benefit to specific inhibitors. These data support mutational analysis of EM-AML patients in order to personalize therapeutic options for our patients.
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Bhagat:Genoptix: Employment. Watts:Takeda: Research Funding; Jazz Pharma: Consultancy, Speakers Bureau. Sweet:Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; Agios: Consultancy; Phizer: Consultancy; Phizer: Consultancy; BMS: Honoraria. Komrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau.
Background Hypomethylating agent (HMA) therapy represents the standard of care for patients with higher risk myelodysplastic syndromes (MDS) although only 50% of patients respond to treatment. Recent ...evidence from molecular profiling through next-generation sequencing (NGS) in myeloid diseases has been conflicting as to the value of somatic mutations as a biomarker for response to HMA. In particular, there have been conflicting data on response rates and outcomes in TP53 mutant (MT) MDS and acute myeloid leukemia (AML) based on azacitidine versus decitabine (Welch et al., NEJM 2016; Garcia-Manero et al., NEJM 2017). However, the TP53 mutant cohorts in these studies were small (median 23 patients, range 13-39) and heterogeneous based on treatment status (treatment naïve versus relapse/refractory). Therefore, our goal was to characterize outcomes of TP53 mutant MDS patients who received frontline HMA therapy.
Patients and MethodsTP53 MT MDS and oligoblastic AML (20-30% blasts) cases were retrospectively identified from the Moffitt Cancer Center MDS database. All patients had NGS of TP53 and up to 53 additional genes performed prior to the initiation of HMA. The lower limit of VAF detection was set at 5% and the minimum depth of coverage at each position was 500X. Clinical variables and outcomes of MDS patients were characterized at the time of sample procurement. Fisher's exact tests were used for comparative analyses. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of HMA initiation. Response rates and outcomes of TP53 MT patients were compared to a cohort of wildtype (WT) patients (n=63).
Results From May 2013 to May 2018, a total of 71 patients with TP53 mutant MDS were identified with a median age of 68 years (39-82) and male predominance (66%). Fourteen patients (20%) had multiple mutations in TP53. Of the cohort, 82% of patients (n=58) were treated with azacitidine (88% (n=51) with AZA monotherapy; 12% (n=7) with AZA in combination (2 pts with lenalidomide and 5 pts with investigational agents)) with 18% (n=13) receiving decitabine. The median # of HMA cycles was 4 (range 1-33). Thirteen pts (18%) proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Of the cohort, 18% (n=13) obtained complete remission (CR) with 39% (n=28) overall response rate (ORR). There was no difference in CR or ORR in pts treated with AZA vs DAC (P=0.24 and P=0.2, respectively). At a median follow up 20 months, the median OS of the entire cohort was 9.7 months. There was no difference in median OS between AZA vs AZA combo vs DAC (7.6 vs 15.2 vs 12.5 months; P = 0.44; Figure 1A). TP53 variant allele frequency (VAF > 20% vs ≤ 20%) was not predictive of outcomes to HMA (7.8 vs 10.4 months, P = 0.36).
However, TP53 MT patients who had clonal response to HMA (i.e. VAF < 5%; n=19 (27%)) had improved OS (14.5 vs 7.5 months; HR 0.33, 95% CI 0.18 to 0.59; P = 0.001; Figure 1B). In multivariable analysis incorporating age, revised international prognostic scoring system (IPSS-R) category, HSCT status, or type of HMA, TP53 clonal clearance remained an independent covariate for improved OS (HR 0.34, 95% CI 0.16 to 0.72; P = 0.005). Pts who underwent HSCT (n=13) had a trend for improved OS (14.5 months vs 7.9 months; P = 0.09). Notably in transplanted pts who had serial TP53 NGS (n=7), pts who achieved a VAF < 5% had significant improved OS (16.3 months vs 8.9 months; P=0.03). Compared to higher risk MDS/AML TP53 WT patients treated with HMA, there was no difference in CR (18% vs 14% (P = 0.64) or ORR rates (39% vs 40%). In contrast, TP53 MT patients had significantly inferior OS with HMA therapy (9.7 vs 15.4 months; HR 2.14, 95% CI 1.32. to 3.27; P = 0.001; Figure 1C).
Conclusion In this large cohort of higher risk MDS and oligoblastic AML pts who received frontline HMA therapy, TP53 MT patients have significantly inferior OS with no significant differences in response rates or outcomes by HMA. TP53 MT patients who achieve maximum clonal suppression with HMA treatment (i.e. VAF < 5%) have improved OS as well as improved outcome with HSCT. Novel therapy targeting TP53 mutation is needed to improve outcomes.
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Sallman:Celgene: Research Funding, Speakers Bureau. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.
INTRODUCTION: Treatment outcomes of secondary Acute Myeloid Leukemia (sAML) including AML with myelodysplasia related changes (AML-MRC) and therapy related AML (tAML) are dismal compared to de novo ...AML patients, where long term disease free survival (DFS) remains less than 40%. Studies in pediatric AML identified frequent MYC somatic mutation and gene amplification, and although MYC somatic mutations are rare in adult AML, a recent study showed de novo AML patients expressing high levels of the MYC oncoprotein have inferior survival outcomes versus low levels of MYC. Compared to other AML subtypes, AML-MRC patients were shown to have dynamic range of MYC protein expression, yet the clinical significance of MYC levels in these patients group is unknown. Here we report the prognostic impact of MYC protein levels on survival outcomes in AML-MRC patients.
METHODS: Using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases, we retrospectively identified histologically confirmed AML-MRC patients from 2011 to 2018. MYC protein expression was assessed by immunohistochemistry (IHC) staining. TP53 mutation was tested by 54 myeloid targeted gene sequencing. We used 5% as cut-off (calculated as MYC positive cells out of total counted blasts in the selected area with sheets of blasts) as previously reported (Ohanian et al. 2018). Clinical variables and disease-related prognostic factors including age, gender, cytogenetics and somatic mutations were characterized at the time of AML-MRC diagnosis and were annotated using descriptive statistics. The overall survival (OS) were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7.
RESULTS: A total of 132 AML-MRC patients were included in this study. The median age at AML-MRC diagnosis was 67 (22-86) years and 64% of patients were male (n=84). A total of 49% (n=65) patients had chromosome 17p deletion del(17p) based on cytogenetic analyses or/and fluorescence in situ hybridization (FISH) assays. A total of 42% (n=55) patients had TP53 mutation and 29% (n=38) patients had both del(17p) and TP53 mutation. Additional chromosomal abnormalities including deletion 5q, trisomy 8, deletion 7q, deletion 20q, and complex karyotypes were observed in 28% (n=37), 17% (n=23), 20% (n=27), 7% (n=9), and 31% (n=41) of patients, respectively. A total of 55% (n=73) of patients were treated with intensive chemotherapy, 18% (n=24) were treated with hypomethylating agents and 20% (n=27) patients underwent allogeneic stem cell transplant. A total of 39% (n=51) patients had high MYC expression and 61% (n=81) patients had low MYC expression. Notably, the median OS was significantly longer in low MYC patients compared to high MYC patients (median OS 33.1 vs. 15.2 months, p=0.0222). Further, when considering only TP53 wild type patients without del(17p), low MYC patients had even longer median OS (median OS 58.6 vs. 17.7 months, p=0.0224). In AML-MRC patients with either TP53 mutation and/or del(17p), the median OS was not statistically different between low and high MYC groups (median OS 21.0 vs. 15.1 months, p=0.3101). Finally, multivariate analysis including TP53 mutation status, del(17p), transplantation status, gender, and age, revealed that high MYC expression is a poor prognostic factor (HR 2.08, 95%CI=1.136-3.807, p=0.018).
CONCLUSIONS: AML-MRC patients with high MYC expression have inferior OS outcome compared to low MYC patients. Further, multivariate analysis established that high MYC level is a poor prognostic factor in AML-MRC patients. These findings warrant further study of the prognostic impact of MYC expression in addition to MYC gene amplification or/and somatic mutations in AML patients, with larger numbers of patients having other somatic mutations or chromosomal abnormalities that have adverse outcomes.
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Sallman:Celgene: Research Funding, Speakers Bureau. Sweet:BMS: Honoraria; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Phizer: Consultancy. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. List:Celgene: Research Funding.
Background: CPX-351 (Vyxeos) is a liposomal combination of daunorubicin and cytarabine that was FDA approved in 2017 for treatment of adults with newly diagnosed therapy-related acute myeloid ...leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Genomic predictors of response to CPX-351 have not been described. TP53 mutations are uncommon in de novo AML, but relatively enriched in the t-AML and AML-MRC populations for which CPX-351 is approved (Christiansen DH et al. JCO 2001; Devillier R et al. Oncotarget 2015). As TP53 mutations confer resistance to conventional daunorubicin and cytarabine chemotherapy, we sought to determine whether TP53 mutations confer resistance to CPX-351.
Methods: This is a retrospective, multi-center review of patients who received at least 1 cycle of induction chemotherapy with CPX-351 at Memorial Sloan Kettering Cancer Center (MSKCC), Moffitt Cancer Center (MCC), and Weill Cornell Medical College (WCMC). 101 patients were identified at MSKCC (n=22), MCC (n=44), and WCMC (n=35). Responses to CPX-351 were graded using European Leukemia Net (ELN) response criteria. (Döhner H et al Blood 2017) Immunophenotypic minimal residual disease (MRD) was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry in 43 patients (MSKCC n=22, WCMC n=21). Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by next-generation sequencing using 21, 32, 49, or 400 gene panels, all of which included TP53. Cytogenetics/FISH were performed using standard techniques. Fisher's exact tests were used to determine significance and are two-tailed. Kaplan-Meier (KM) analysis with log-rank test was performed to estimate overall survival (OS).
Results: Patient characteristics are in Table 1. 84/101 (83.1%) had baseline molecular profiling prior to CPX-351. TP53 mutations were identified in 18/84 (21.4% of patients). Analysis of additional co-mutations and responses will be presented by our collaborators (Talati et al., ASH 2018 submitted). TP53 mutations (19/20 distinct mutations) clustered in the DNA binding domain (Figure 1A). TP53 mutations are significantly associated with complex or monosomal karyotypes (p<0.001, see Table 1). Following 1-2 cycles of CPX-351 induction, complete responses (CR) combined with complete responses with incomplete blood count recovery (CRi) were significantly higher in TP53 wild-type (WT) patients compared to TP53 mutant patients. 62% WT (41/66) achieved CR/CRi, in comparison to 33% (6/18) TP53 mutant CR/CRi, p=0.0353, odds ratio=0.3049 (95 % CI:0.1016 to 0.9150). (Figure 1B). Responses for CR alone also trended in favor of TP53 WT patients. 45.5% (30/66) WT achieved CR, while 27.8% TP53 mutant (5/18) achieved CR, P=0.2806. Responses for MRD negative CR also favored WT patients, 36% MRD-CR WT (9/25), 8.3% MRD-CR TP53 mutant (1/12), although these results were not statistically significant likely due to low numbers of (n=37) who underwent molecular profiling and later MRD analysis. OS was not significantly different (Figure 3B, p=0.093), but also trended towards favoring WT over TP53 mutant patients. Additional data with longer-term follow-up will be presented.
Conclusion: Our data demonstrate that AML patients with TP53 mutations have lower rates of CR/CRi than WT patients after 1-2 cycles of CPX-351. While our study is retrospective and limited by small numbers, our data overall support the hypothesis that resistance to liposomal daunorubicin and cytarabine chemotherapy is common in AML patients with TP53 mutations. Future clinical studies are needed to determine optimal therapy for these patients.
Figure 1. A) Map of TP53 mutations in patients treated with CPX-351. Black circles represent truncating mutations; purple circles represent non-synonymous single nucleotide variants or splice site mutations. B) Rates of CR/CRi (left), CR (middle), and MRD negative CR in WT (n=66) and TP53 mutant (n=18) patients treated with CPX-351. C) OS for WT and TP53 mutant patients treated with CPX-351. Table 1. Patient Characteristics.
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Goldberg:AROG: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Sallman:Celgene: Research Funding, Speakers Bureau. Roboz:Novartis: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Eisai: Consultancy; Sandoz: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy; Aphivena Therapeutics: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Roche/Genentech: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Aphivena Therapeutics: Consultancy. Sweet:Celgene: Honoraria, Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Consultancy; Phizer: Consultancy; Jazz: Speakers Bureau. Tallman:Cellerant: Research Funding; AROG: Research Funding; Orsenix: Other: Advisory board; AbbVie: Research Funding; ADC Therapeutics: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board.
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