Treatment with CPX-351 Induces Deep Responses and TP53 Mutation Clearance in Patients with t-AML and AML MRC, Including Younger Patients and Those with Pre-Existing MPNs: A Real-World Experience

Background Patients with secondary acute myeloid leukemia (sAML) have poor outcomes compared to those with de novo AML. In 2017, liposomal daunorubicin and cytarabine (CPX-351) was FDA approved for the treatment of adults with newly diagnosed AML with myelodysplasia-related change (AML-MRC) or therapy-related AML (t-AML). In its landmark trial, CPX-351 has displayed significant improvement in overall survival (OS) compared to conventional 7+3 in patients 60-75 years of age with sAML. Gaps remain in the literature regarding the clinical use of CPX-351 in context of the FDA approved label. Here we evaluate real-world outcomes with disease response and molecular monitoring in patients treated with CPX-351. Methods Adults who received CPX-351 between September 2017 and December 2019 were identified. The primary endpoint was overall response rate (ORR), defined by complete remission (CR) and CR with incomplete hematologic recovery (CRi) according to the Revised IWG criteria. Additional outcomes of interest included molecular minimal residual disease (MRD) status post induction as measured by next-generation sequencing (NGS), ORR in patients with baseline TP53, and progression-free survival (PFS) in patients with CR/CRi, with and without MRD after induction. Mutations associated with clonal hematopoiesis (TET2, ASXL1, DNMT3A) were excluded from analysis of molecular MRD. Results Fifty-four patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was elderly with the median age of 64 [IQR: 60-68], and 13 patients were younger than 60 years old. Six patients developed AML in the setting of a pre-existing myeloproliferative neoplasm (MPN). The most common indication for treatment with CPX-351 was antecedent MDS (42.6%), followed by de novo AML with MDS karyotype (24.1%), therapy-related AML (13%), and antecedent MPN (11.1%). NGS was performed prior to treatment with CPX-351 in all but one patient, and 88.7% had at least one molecular marker that is not identified as one of the mutations associated with clonal hematopoiesis. Most commonly identified molecular markers were TP53 (16/53, 30.2%), RUNX1 (10/53, 18.9%), SRSF2 (8/53, 15.1%), NRAS (7/53, 13.2%), and IDH2 and JAK2 (6/53, 11.3%, each). Most patients were hospitalized until hematologic recovery. However, 5 patients received induction in the outpatient setting, and an additional 6 patients were discharged early before hematologic recovery. Among the patients who were discharged early or underwent outpatient induction, 81.8% (9/11) were admitted for a complication. There were no deaths associated with outpatient induction. Overall, 46 patients (85.2%) experienced febrile neutropenia and 17 patients (31.5%) had bacteremia. Thirty-day and 60-day mortality were 9.3% and 14.8%, respectively. The ORR was 54%, and the response rates observed in patients who were younger vs older than 60 years were similar (41.7% vs. 57.9%, p=0.508). In patients who achieved a remission after induction, 56% (14/25) were MRD positive by NGS. Among those who had TP53 mutation at baseline, 14 were available for response assessment after induction. The ORR in this subgroup was 57% (8/14) and all but 3 (63%) were MRD negative by NGS. Consolidation with allogeneic transplant was performed in 18 patients (33%). Median OS was 10.4 mos. Median OS was similar for patients older or younger than 60 years (p=0.76). For patients achieving a CR/CRi, median OS had not been reached at the time of analysis but was significantly improved compared to those with refractory disease (6.1 mos, p=0.0007). Median OS or PFS did not differ significantly (p=0.68) based on MRD negativity (Figure 1). Conclusion This analysis demonstrates comparable response rates to the landmark trial (54% in our analysis vs. 47.7%). Outpatient induction and/or early discharge was safe and feasible in appropriately selected patients. While this analysis is limited by the small sample size, CPX-351 appeared effective in populations that were not included in the published randomized studies, such as patients below the age of 60 years old and those with antecedent MPN. Remission rates and MRD clearance was high among TP53 mutants. A considerable number of patients who achieved a remission remained MRD positive by NGS, but this did not impact PFS. Future studies should evaluate the impact of molecular MRD and allele frequency to further guide treatment. Disclosures Koprivnikar: Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. McCloskey:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau.

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Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles

Blood ◽

10.1182/blood.v112.11.4027.4027 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4027-4027

Author(s):

Melissa L. Larson ◽

Ann M. Thomas ◽

Nitin Goyal ◽

Jamile M. Shammo ◽

John J. Maciejewski ◽

...

Keyword(s):

Cell Cycle ◽

Complete Remission ◽

De Novo ◽

Response Rates ◽

High Dose ◽

Bone Marrow Biopsies ◽

Secondary Aml ◽

Number Of Patients ◽

Induction Regimen ◽

De Novo Aml

Abstract Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile. Patients and Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc21: 4642, 2003). Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively. Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%. Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.

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Real-World Study of CPX-351 Treatment Outcomes for Acute Myeloid Leukemia (AML) in England

Blood ◽

10.1182/blood-2021-148450 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2310-2310

Author(s):

Alex Legg ◽

Pesheya Doubleday ◽

Adam Reich ◽

Alexandrina Lambova ◽

Greg Medalla

Keyword(s):

Real World ◽

Salvage Therapy ◽

Group Performance ◽

De Novo ◽

Cell Transplant ◽

Publicly Traded ◽

Probability Of Survival ◽

De Novo Aml ◽

The Impact

Abstract Introduction: CPX-351 (US: Vyxeos ®; Europe: Vyxeos ® Liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Since November 2018, the National Institute for Health and Care Excellence (NICE) has recommended its use for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) due to either prior myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) or de novo AML with myelodysplasia-related cytogenetic changes. The key aims of this study were to utilize the Cancer Analysis System (CAS) database available through the National Cancer Registration and Analysis Service (NCRAS) to describe the demographics and clinical characteristics of adults with AML in England who have received CPX-351, as well as to estimate overall survival (OS) and survival within stratifications of interest. Methods: The NCRAS systematically collects and curates population-level data about cancer diagnoses, treatments, and outcomes across England. Adults (aged ≥18 years) diagnosed with AML and treated with CPX-351 were included in this study. A diagnosis of t-AML or AML-MRC between January 2013 and March 2020 was determined either directly using International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes or indirectly using non-specific ICD-O-2, ICD-O-3, or ICD-10 AML codes in combination with either prior systemic anticancer therapy or radiotherapy (t-AML) or a prior diagnosis of MDS or CMML (AML-MRC; other AML-MRC subtypes could not be specifically identified and are included within the de novo AML subgroup). OS was measured from the date of diagnosis; a separate analysis of OS landmarked from the date of hematopoietic cell transplant (HCT) was also performed. Within this preliminary analysis, no OS adjustments have been made to account for any COVID-19-related deaths. Results: A total of 172 patients with AML who were treated with CPX-351 were identified: 37 (22%) had t-AML, 57 (33%) had AML-MRC, and 78 (45%) had de novo AML. At diagnosis, the mean (standard deviation) age was 62.8 years (10.1), with 49/172 (28%) patients aged <60 years; 66% of patients were male; 87% were white; and most had an Eastern Cooperative Oncology Group performance status of 0 or 1 (68%). Six (3%) patients had received azacitidine treatment for a prior malignancy. To date, 43/172 (25%) patients had undergone HCT overall, including 43/97 (44%) patients with ≥3 months of follow-up. The cut-off date for OS was December 31, 2020, giving a median (interquartile range) follow-up of 11.2 months (3.6, 16.9). Overall, 91 patients had died, with an estimated median OS (95% confidence interval [CI]) of 16.6 months (11.0, not estimable) and probability of survival (95% CI) at 1 and 2 years of 0.54 (0.47, 0.62) and 0.39 (0.30, 0.50), respectively (Figure 1). Early mortality rates were 7% at 30 days and 15% at 60 days. When OS was landmarked from the date of HCT, median OS was not reached, with a probability of survival (95% CI) at 1 year of 0.74 (0.62, 0.89; Figure 2). When stratified by age, estimated median OS (95% CI) was not reached for patients aged <60 years and 12.8 months (8.9, 17.6) for patients aged ≥60 years. In a treatment patterns analysis that evaluated second-line treatments after CPX-351, 68 patients died without salvage therapy and 64 were alive without receiving subsequent therapy by the end of the study period. The most common salvage treatments were fludarabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor (FLAG-Ida; n = 15), daunorubicin plus cytarabine (DA)-based therapy (n = 6), and azacitidine alone (n = 7). Of the 43 patients who received an HCT, 6 (14%) underwent HCT following salvage therapy. Conclusions: This is the largest study to date examining the real-world outcomes for patients with AML who were treated with CPX-351. The estimated median OS of 16.6 months is consistent with reported real-world outcomes for CPX-351 in French and Italian studies. Median OS has not been reached in patients aged <60 years or when landmarked from the date of HCT. Once the CAS database has been updated, these analyses will be repeated to increase follow-up and patient numbers and to determine the impact of COVID-19 on OS following CPX-351 treatment. Figure 1 Figure 1. Disclosures Legg: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Doubleday: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Reich: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Lambova: IQVIA Inc., which was contracted by Jazz Pharmaceuticals for the conduct of this analysis: Current Employment. Medalla: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

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The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽

10.1182/blood-2010-08-301713 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2137-2145 ◽

Cited By ~ 216

Author(s):

Sabine Kayser ◽

Konstanze Döhner ◽

Jürgen Krauter ◽

Claus-Henning Köhne ◽

Heinz A. Horst ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Topoisomerase Ii ◽

De Novo ◽

Negative Impact ◽

Primary Malignancy ◽

De Novo Aml ◽

The Impact ◽

Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

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Impact of Cytogenetics and Cytogenetic Response On Outcome in MDS Treated with Azacitidine (AZA).

Blood ◽

10.1182/blood.v120.21.2807.2807 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2807-2807 ◽

Cited By ~ 1

Author(s):

Marie Sebert ◽

Valérie Vidal ◽

Virginie Eclache ◽

Sylvain Thepot ◽

Thorsten Braun ◽

...

Keyword(s):

Research Funding ◽

Response Rates ◽

Risk Groups ◽

Cytogenetic Response ◽

Risk Category ◽

Complex Karyotype ◽

Cytogenetic Abnormalities ◽

Hematological Response ◽

Number Of Patients ◽

The Impact

Abstract Abstract 2807 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the prognostic value of baseline cytogenetics on response to AZA, and the impact of cytogenetic response (CyR) on outcome in responders remain uncertain. Methods: Between Jan 2005 and Nov 2011, we treated at our center155 consecutive MDS patients (pts), including FAB RAEB-T / WHO AML with 20–30% blasts, with AZA (75 mg/m2/d x7 d every 4 weeks, for a median of 6 cycles). Karyotype at onset of AZA was evaluable in 143 pts, and abnormal in 95 (66%) pts. Median age was 74 years and IPSS high: 51, int2: 58, int 1: 14, NA: 20. 65 (42%) pts achieved hematological IWG 2006 response, including 28 (18%) CR, 8 (5%) PR, 13 (8%) Marrow CR, 16 (10%) stable with HI. With a median follow up of 28 months, median OS was 16 months. Results: Of the 95 pts with abnormal karyotype, 47 had −7/del(7q) including 9 isolated −7/del (7q), 37 had del(5q)/-5 including only 3 isolated del(5q)/-5,26 had +8 including 9 isolated +8, 9 had abnormalities leading to del (17p)(6 of them had complex karyotype), 16 had del (20q)and 44 had complex karyotype (>= 3 abnormalities). Response and OS according to cytogenetics are summarized in table 1. None of the cytogenetic abnormalities studied (complex, normal, del20q, 17p, del5q/-5,7/del (7q) or +8) had a significant impact on response to AZA. Presence of del (17p) (median 7 vs 18 mo, p= 0.0001), del5q/-5 (12.5 vs 20 mo, p= 0.0008), −7/del (7q) (9.7 vs 20 mo, p=0.02) or complex karyotype (12 v 20 mo, p=0.002) was associated with significantly shorter OS. Among pts with complex karyotype, there was a trend for shorter OS for pts when 17p abn (median 6.7 vs 12.5 mo, p=0.12) del (5q)/-5 (9 v 21 mo, p=0.16) or −7/del (7q) (7 v 17 mo, p=0.06) abnormality was part of the complex karyotype. By contrast, isolated −7/del (7q) (21 vs 16 mo, p=0.3) and +8 (all+8:20 vs 14 mo, p=0.48; isolated +8:23 vs 16 mo, p=0.92) had no significant impact on OS. According to IPSS cytogenetic risk, response rates and CR rates were similar across the 3 groups, but OS was significantly longer in the good risk category (p=0.04) (table 1). Cytogenetics could be reclassified using new IPSS-R cytogenetic groups in 138 pts (Shanz, JCO, 2011) in 1 very good, 52 (38%) good, 24 (17%) int, 30 (22%) poor and 31 (23%) very poor. According to this IPSS-R cytogenetic classification, response rates and CR rates were similar across the 4 main groups. Median OS was 20.6 mo, 23 mo, 14 mo and 12 mo in the good, int, poor and very poor risk groups respectively (p= 0.037). 66 of the pts with baseline cytogenetic abnormalities had cytogenetic analysis at treatment evaluation, after 4 to 6 cycles of AZA, of whom 32 had achieved hematological response. In those 32 pts, 34% achieved complete CyR(CCyR), none partial CyR, 37% had stable cytogenetics (and the remaining pts had cytogenetic failure). In those 32 pts, achievement of CCyR had no significant impact on OS (p=0.36) but the number of pts was relatively small. In a landmark analysis performed at D100 in pts with baseline cytogenetic abn, achieving CCyR was not associated with an OS advantage compared to stable cytogenetics (median 22 vs 17 mo, p=0.82). Of note, only 1 patient with baseline cytogenetic abn (+8) who did not achieve hematological response achieved CCyR, of 6 months duration, before disease progression. Conclusion: Baseline cytogenetic findings were strong predictors of survival in patients with MDS treated with AZA, while impact on response was limited. In hematological responders with baseline cytogenetic abnormalities, achieving cytogenetic response was not was associated with an OS advantage, butthe number of patients analyzed may have been insufficient to conclude. Disclosures: Gardin: celgene: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.4971.4971 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4971-4971

Author(s):

Simon B. Zeichner ◽

Sarah Alghamdi ◽

Gina Elhammady ◽

Robert Poppiti ◽

Amilcar Castellano-Sanchez

Keyword(s):

Myeloid Leukemia ◽

Tp53 Mutation ◽

De Novo ◽

Performance Status ◽

Nucleotide Polymorphisms ◽

Complex Karyotype ◽

Single Nucleotide ◽

Tp53 Mutations ◽

Significant Difference ◽

De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

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Changes in liver function following real-world transarterial chemoembolization (TACE) in US patients (pts) with hepatocellular carcinoma (HCC): The LiverT study.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.441 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 441-441

Author(s):

Rebecca A. Miksad ◽

Sadahisa Ogasawara ◽

Fang Xia ◽

Marc Mardoche Fellous ◽

Fabio Piscaglia

Keyword(s):

Liver Function ◽

Real World ◽

Small Sample Size ◽

Small Sample ◽

Chronic Liver ◽

Diagnostic Code ◽

Chronic Liver Damage ◽

Vein Thrombosis ◽

Diabetes Status ◽

The Impact

441 Background: Acute elevations of serum transaminases and bilirubin after TACE are commonly observed in pts with HCC. However, real-world incidence of chronic liver damage after TACE is unclear. LiverT is a retrospective, observational study to assess potential chronic deterioration of liver function of HCC pts after a single TACE in US real-world practice. Methods: Eligible HCC pts underwent index TACE between Jan 1, 2010 and Mar 31, 2016 and did not undergo repeat/additional HCC treatment in the subsequent 90 days. Pts were identified from Optum’s integrated database using standard codes. At least one laboratory value was required within 30 days prior to index TACE (baseline = latest value within period) and 30–90 days after TACE (chronic period = latest value within period). Due to lack of universally accepted liver function deterioration criteria, clinically meaningful changes in laboratory parameters were predefined by experts (Table). Subgroup analyses explored the impact of HCC etiology, diabetes status, anticoagulation use, and presence of portal vein thrombosis. Results: Of 5142 Optum TACE pts, 572 (11%) were eligible; exclusions were primarily due to lack of HCC diagnostic code and laboratory availability; 411 (72%) were male and median age was 62 yrs. Although lower than acute liver deterioration (0–29 days post-TACE), 30–90 day chronic liver deterioration varied by parameter and ranged from 15% to 31% (Table). Overall, sub-groups showed similar patterns. Conclusions: We report real-world chronic deterioration of liver function 30–90 days after a single TACE in a cohort of HCC pts. Limitations include missing data, small sample size, and difficulty establishing causation. Subsequent HCC treatments may be limited by liver function; therefore, further characterization of post-TACE chronic deterioration of liver function for HCC is important. [Table: see text]

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Retrospective, observational study to see the effect of evogliptin on continuous glucose monitoring (CGM) in T2DM Indian patients: A real-world experience

Indian Journal of Pharmacy and Pharmacology ◽

10.18231/j.ijpp.2021.048 ◽

2022 ◽

Vol 8 (4) ◽

pp. 267-269

Author(s):

Abhijit Trailokya ◽

Suhas Erande ◽

Amol Aiwale

Keyword(s):

Blood Glucose ◽

Treatment Regimen ◽

Real World ◽

Glucose Monitoring ◽

Small Sample ◽

Target Range ◽

Percentage Time ◽

Number Of Patients ◽

Mean Blood Glucose ◽

Time In Target Range

This study aimed to assess effectiveness of Evogliptin 5 mg through continues glucose monitoring (CGM) in patients with T2DM in retrospective observational real world settings. Overall 6 patients who received Evogliptin as routine clinical practice in management of T2DM were analyzed retrospectively from single center. Data collected from past medical records. FreeStyle Librepro 1.0.6 was used for CGM. CGM was done 15 days prior to adding Evogliptin and repeated immediately after that for next 15 days. Mean BG level, Percentage time in target range (80-140mg/dl), Percentage time above target and Percentage time below target were assessed prior and after adding Evogliptin in existing treatment regimen. Significant reduction in Mean blood glucose level seen after adding Evogliptin in existing treatment regimen from 215 mg/dl to 138 mg/dl (-77 mg/dl P=0.006). Significant improvement seen in Percentage time in target range (80-140mg/dl) from 17% to 44% (27% P value 0.007) and in Percentage time above target from 81% to 43% (- 38%, P valve 0.003). 13.5 % of the patients seen below target. Evogliptin was found to be effective when added to the patients who were uncontrolled on other oral anti-diabetic medications. It effectively showed improvement in continues glucose monitoring (CGM) parameters like Mean blood glucose, more number of patients were in Time in Target range i.e (80-140mg/dl) after adding Evogliptin to existing anti-diabetic medications & well tolerated. Small sample size and retrospective study

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Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven)

Blood ◽

10.1182/blood-2021-147886 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1216-1216

Author(s):

Irena Tan ◽

Matthew Schwede ◽

Paul Phan ◽

Raymond Yin ◽

Tian Y Zhang ◽

...

Keyword(s):

Real World ◽

Proportional Hazards ◽

De Novo ◽

Hematologic Malignancy ◽

Cox Proportional Hazards ◽

Secondary Mutation ◽

Mutation Profile ◽

Significant Difference ◽

De Novo Aml

Abstract Background: The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML. Methods: Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression. Results: 82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS. There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10). Conclusions: Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. Figure 1 Figure 1. Disclosures Mannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

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Prognostic Impact of MYC Oncoprotein Expression on Survival Outcome in Secondary AML Patients

Blood ◽

10.1182/blood-2018-99-120048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2756-2756

Author(s):

Seongseok Yun ◽

Rohit Sharma ◽

David A Sallman ◽

Nicole D. Vincelette ◽

Kendra L. Sweet ◽

...

Keyword(s):

Multivariate Analysis ◽

Research Funding ◽

Tp53 Mutation ◽

Somatic Mutations ◽

De Novo ◽

Chromosomal Abnormalities ◽

Survival Outcomes ◽

Prognostic Impact ◽

Poor Prognostic Factor ◽

De Novo Aml

Abstract 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. Figure. Figure. Disclosures 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.

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Retrospective Analysis of Adults with Acute Myeloid Leukemia Treated with Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center

Blood ◽

10.1182/blood-2018-99-119593 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1424-1424 ◽

Cited By ~ 1

Author(s):

Matthew Tenold ◽

Benjamin Moskoff ◽

David Benjamin ◽

Brian A. Jonas

Keyword(s):

Research Funding ◽

De Novo ◽

Response Rates ◽

Median Number ◽

Adult Patients ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Hypomethylating Agents ◽

De Novo Aml

Abstract Introduction Venetoclax (VEN) is a potent B-cell lymphoma 2 (BCL-2) inhibitor and demonstrates synergistic anti-AML activity when used in combination with hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC). This regimen has demonstrated high response rates and durable activity in treatment naïve (TN) older patients; however, the efficacy in relapsed and/or refractory (R/R) AML is less well characterized, with one study showing a response rate of 21%. To further characterize VEN plus HMA activity in these populations, we retrospectively reviewed the outcomes of both TN and R/R AML patients treated with VEN plus HMA at the University of California Davis Comprehensive Cancer Center (UCDCCC). Methods Adult patients (≥18 years) with an acute leukemia treated with VEN off protocol between January 1, 2014 through June 22, 2018 were included. Under an IRB-approved protocol, patients were retrospectively reviewed using an electronic medical record generated report. Baseline data included patient demographics, performance status, disease characteristics, prior chemotherapy, bone marrow biopsy studies and labs. Regimen data included other chemotherapy agents received, VEN dose and modifications, antifungal prophylaxis (ppx), and granulocyte colony stimulating factor (GCSF) use. Efficacy outcomes included complete remission (CR), CR with incomplete count recovery (CRi), composite CR (cCR, defined as CR + CRi), morphologic leukemia free state (MLFS), overall leukemia response (OLR, defined as cCR + MLFS), overall survival (OS), and relapse free survival (RFS). Toxicity outcomes were reviewed, including tumor lysis syndrome (TLS), febrile neutropenia (FN), and prolonged pancytopenia. All follow-up clinic visits, hospitalizations and deaths were reviewed. Results Forty-two patients were included (AML, n=41; acute undifferentiated leukemia, n=1). Median age was 67 years [25-88] and 67% were male. Eighteen (43%) had de novo AML, 17 (40%) had preceding myelodysplastic syndrome (MDS), 4 had MDS/myeloproliferative neoplasm (MPN) (10%) and 3 (7%) had primary myelofibrosis. Sixteen were TN (38%), thirteen (31%) had relapsed disease, and 13 (31%) had refractory disease. Median number of prior regimens was 1 [0-6]. Thirty-seven (88%) had an ECOG of 0 to 1 [0-3]. ELN genetic risk classification was intermediate in 19 (45%) and adverse in 22 (52%). VEN was combined with AZA in 12 (29%) and DEC in 30 (71%). Median VEN dose was 400 mg [50-800 mg]. Median follow-up was 17.2 months. For the entire study, the cCR was 43% and the OLR was 57%. See table 1 for cCR and OLR for subgroups including previously untreated, R/R, de novo, secondary AML (sAML), and various molecular and cytogenetic subgroups. Median OS was 6.2 months (Figure 1). For patients with cCR, OLR, and MLFS, median survival was 21.6, 15.1, and 4.9 months respectively (Figure 2). Median OS and median OS in responders for patients with de novo AML, sAML, untreated patients, and R/R patients is shown in Figure 3, Figure 4, and Table 1. Median number of cycles for cCR was 1 [1-6]. Of patients who obtained cCR, 6 (33%) experienced relapse of AML. Median time to relapse was 6.6 [3.4-13.9] months. Eight (19%) patients were bridged to allotransplant. Lab TLS occurred in 1 patient. Seventeen (40%) experienced prolonged pancytopenia. Eighteen (43%) had FN and 4 (22%) received GCSF. Antifungal ppx was used in 41 (98%) patients: micafungin in 17 (40%) and a non-fluconazole azole in 24 (57%). Seven (17%), of which 5 (71%) had R/R AML, were diagnosed with a fungal infection; 5 (71%) were receiving ppx azoles and 2 (29%) micafungin. Three and 6 died within 30 and 60 days of therapy initiation, respectively; all 3 patients who died within 30 days had R/R AML. The most common cause of death was refractory AML at 14 (52%) followed by infection in 9 (33%). Conclusion At UCDCCC, VEN in combination with an HMA is well tolerated and produces high rates of response in adult patients with AML. Response rates for TN AML, sAML and multiple molecular subgroups are consistent with prior reports, while higher than expected response rates and survival were seen in R/R AML. Responses were also seen in post-MDS/MPN and post-MF patients. In extended follow-up, survival has been durable in patients with cCR, but not MLFS. The use of VEN plus HMA combinations in adults with AML represents a viable treatment option for both TN and R/R AML. Disclosures Jonas: AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Pharmacyclics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Kalobios: Research Funding; Accelerated Medical Diagnostics: Research Funding; LP Therapeutics: Research Funding.

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