Related Acute Myeloid Leukemia Research Articles

AML-234 Prognostic Value of FLT3-ITD Residual Disease in Acute Myeloid Leukemia

FLT3-internal tandem duplications (FLT3-ITD) are among the most common genetic molecular abnormalities in acute myeloid leukemia (AML) patients. Here, the prognostic impact of the presence of minimal residual disease (MRD) of FLT3-ITD in AML patients is assessed by next-generation sequencing (NGS). The prognostic significance of FLT3-ITD in AML in relation to other concurrent gene mutations and allelic mutational burden has remained a subject of scientific controversy. Detection of FLT3-ITD MRD by RQ-PCR is restricted by patient-specific variables, such as sequence, position, and length. However, systematic studies analyzing the applicability of FLT3-ITD MRD detection with NGS techniques are currently lacking. Here, we evaluate the impact of the presence of FLT3-ITD MRD detected by NGS on treatment outcome in the context of current prognostic factors at diagnosis and MRD status measured by multiparameter flow cytometry (MFC) and mutant NPM1. In 161 de novo AML patients with an FLT3-ITD enrolled in the HOVON-SAKK clinical trials, NGS was performed at diagnosis and ultra-deep in CR after induction chemotherapy. Presence of FLT3-ITD MRD was correlated to incidence of relapse and overall survival (OS). NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) AML patients. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year CIR, 75% FLT3-ITD MRD vs. 33% no FLT3-ITD MRD; P<0.001) and inferior OS (4-year OS, 31% FLT3-ITD MRD vs. 57% no FLT3-ITD MRD; P<0.001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P<0.001) and OS (hazard ratio 2.51; P<0.001). Presence of FLT3-ITD MRD exceeds the prognostic value of most of the generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD status of mutant NPM1 and MFC. Presence of FLT3-ITD MRD in CR detected by NGS after induction chemotherapy identifies AML patients with an increased risk of relapse and inferior OS that outweighs the significance of currently accepted prognostic factors. This finding offers support for the use of FLT3-ITD MRD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

NK-cell dysfunction of acute myeloid leukemia in relation to the renin-angiotensin system and neurotransmitter genes.

Acute myeloid leukemia (AML) is the most heterogeneous hematological disorder and blast cells need to fight against immune system. Natural killer (NK) cells can elicit fast anti-tumor responses in response to surface receptors of tumor cells. NK-cell activity is often impaired in the disease, and there is a risk of insufficient tumor suppression and progression. The aim of this study is to assess the dysfunction of NK cells in AML patients via focusing on two important pathways. We obtained single-cell RNA-sequencing data from NK cells obtained from healthy donors and AML patients. The data were used to perform a wide variety of approaches, including DESeq2 (version 3.9), limma (version 3.26.8) power differential expression analyses, hierarchical clustering, gene set enrichment, and pathway analysis. ATP6AP2, LNPEP, PREP, IGF2R, CTSA, and THOP1 genes were found to be related to the renin–angiotensin system (RAS) family, while DPP3, GLRA3, CRCP, CHRNA5, CHRNE, and CHRNB1 genes were associated with the neurotransmitter pathways. The determined genes are expressed within different patterns in the AML and healthy groups. The relevant molecular pathways and clusters of genes were identified, as well. The cross-talks of NK-cell dysfunction in relation to the RAS and neurotransmitters seem to be important in the genesis of AML.

AML with inv(16)/t(16;16) and high-risk cytogenetic abnormalities: atypical features and unfavorable outcome

ABSTRACT Objectives Acute myeloid leukemia (AML) with inv(16)/t(16;16) is among the most frequent AML subtypes. It is recognized by the detection of the CBFB-MYH11 fusion which confers a favorable prognosis, irrespective of the presence of secondary cytogenetic abnormalities. However, the effect of additional genetic anomalies on the behavior of inv(16) AML is debatable. Recent case reports describe an unfavorable prognosis for those patients, characterized by early relapse and death. In this study, we present a series of patients with CBFB-MYH11 fusion and high-risk rearrangements to increase knowledge about this potentially distinct subgroup. Methods All cases with inv(16)/ t(16;16) and one or more high risk abnormalities were reviewed at two tertiary healthcare centers between years 2006 and 2020 in terms of demographics, biological and clinical data. Results Among the total 1447 and 1283 AML cases, the frequency was found to be 0,2% and 0.3%. Clinical data could be retrieved for 5 patients. Detected high-risk abnormalities included TP53 and 5q deletion, complex and monosomal karyotype. The median age was 67 years, with a majority of females (M:F = 1:1.5). Two out of 5 patients presented with therapy related AML, with short latency periods. All patients presented with thrombocytopenia and/or leukocytopenia. Bone marrow aspirates revealed atypical morphology and the detection of rare CBFB-MYH11 fusion transcripts. All 5 patients died, with a short mean overall survival of 5.8 months. Discussion and Conclusion Our series suggests that the presence of high risk abnormalities confers distinct biological features and poor prognosis to inv(16) AML.

Hydrophilic Realgar Nanocrystals Prolong the Survival of Refractory Acute Myeloid Leukemia Mice Through Inducing Multi-Lineage Differentiation and Apoptosis.

IntroductionAcute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and the AML cells are differentiation retarded which results in the hyperproliferation of those malignant tumor cells. To stop the uncontrollable proliferation, inducing the AML cell differentiation is one highly expected therapy because it can bring relatively low systematic side effects compared to conventional chemotherapies; however, there are few options of inductive therapeutics in the clinical applications so far. This study aims to investigate the differentiation-induction effects of lab-developed hydrophilic nanocrystals of As4S4 (ee-As4S4).MethodsIn this work, ee-As4S4 was applied upon a refractory mouse model co-expressing AML1-ETO and HyC-KITD816V as well as a related human AML cell line, Kasumi-1, to investigate whether the nanocrystals can break the retardation of differentiation and drive the cells undergo apoptosis.ResultsIt was shown that ee-As4S4 induced the upregulation of surface markers CD11b, CD235a, and CD41a, which indicate granulocytic, erythroid, and megakaryocytic differentiation respectively, leading to the multiple-lineage differentiation and post-differentiation apoptosis, and the inhibition of histone deacetylase activity was largely involved with the differentiation-induction effects. In the AML mice, orally administered ee-As4S4 increased the level of Ter119, CD11b, and CD41 in bone marrow-derived leukemia cells while reducing the percentage of leukemic cells in the bone marrow. Also, ee-As4S4 improved the hemogram and relieved the hepatomegaly and splenomegaly of the AML mice. As a result, the survival of the AML mice was significantly prolonged. Importantly, ee-As4S4 did not cause acute or chronic toxicity in healthy mice.ConclusionIn conclusion, ee-As4S4 induced effective and multiple-lineage differentiation and apoptosis of AML cells in the refractory AML mouse model and cell line, suggesting that it holds promising potential as a novel inductive agent in differentiation therapy of AML.

Therapy related acute myeloid leukemia single centre experience

Therapy related acute myeloid leukemia single centre experience

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification

Outcomes of Patients with AML Treated with CPX-351 Based on the 2017 ELN Risk Stratification

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission after 5-Azacitidine and Venetoclax: A Multicenter Retrospective Study

The therapeutic landscape for acute myeloid leukemia (AML) has evolved in recent years with the introduction of hypomethylating agents (HMA) and venetoclax in patients previously deemed unfit for curative - intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT), yet there are scarce data regarding transplantation outcomes.We conducted a multicenter nationwide retrospective cohort study to evaluate outcomes of patients with AML who underwent alloHCT in first CR (CR1) after frontline treatment with 5-azacitidine plus venetoclax (aza-ven group). In addition, we collected a historical control group of patients who achieved CR1 following first line intensive chemotherapy followed by alloHCT (intensive group).24 patients in the aza-ven group were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years, p <0.001), had higher incidence of therapy related AML and AML with antecedent hematologic disorder (p <0.001) and had more often adverse cytogenetics (p=0.022). They had a higher percentage of allografts from matched unrelated donors, and reduced intensity conditioning was more commonly used (Table 1).Median follow up was 8 (range, 0 to 25) months in the aza-ven group and 23 (range, 4 to 56) months in the intensive group. Estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group (p=0.492). The estimated median relapse free survival (RFS) was not reached in the aza-ven group and was 19.3 months (CI 95% 1-38) in the intensive group. There was no difference between the two groups in 12 months RFS (58% and 54% in the aza-ven group and intensive group, respectively, p = 0.892). The estimated median survival of the aza-ven group was not reached and the 12 months overall survival (OS) rate was 63.2%. The estimated median survival of the intensive group was 50 months (CI 95% 5 - 96) and the 12 months OS rate was 70.8%. There was no statistical differences between the two groups regarding OS (p = 0.58).In a subgroup Cox regression analysis of the aza-ven group, adverse ELN 2017 risk category and HCT-CI score ≥3 were predictive of decreased RFS, both in univariate analysis (UVA) and in multivariate analysis (MVA) (HR 10.56, CI 95%1.64-68.1, p=0.013 and HR 6.43, CR 95% 1.34-30.75, p=0,02, respectively). Graft source (alternative vs. matched donor) and HCT-CI score ≥3 were predictive of decreased OS in UVA (HR 19.45, CI 95% 1.66-228.13, p= 0.018 and HR 5.93, CI 95% 1.13-31.05, p=0.03], yet in MVA neither of these factors retained their predictive value.The cumulative incidence of acute GVHD at 6 months was similar between groups: 58% in the aza-ven group vs. 62% in the intensive group (p=0.39). Likewise, there was no difference in the cumulative incidence of chronic GVHD at 12 months: 40% vs 42%, respectively (p=0.747)In conclusion, our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short term post-transplant outcomes comparable to those expected after traditional intensive chemotherapy. Our results were collected in the real world setting, and patients in the aza-ven group were older and had inherently worse leukemia characteristics, including more secondary AML and more adverse cytogenetic features. Future research is warranted to decipher the true spectrum of AML patients who could benefit from remission induction with this less intensive regimen prior to alloHCT. [Display omitted] DisclosuresRam: Gilead: Honoraria; Novartis: Honoraria. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy. Yeshurun: Astellas: Consultancy; Janssen: Consultancy.

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Frontline Venetoclax (ven) Based Combination Therapy in Older Adults with Acute Myeloid Leukemia Treated in the Real-World Setting; A Multi-Institutional Retrospective Study

Introduction: Acute myeloid leukemia (AML) is a disease of the older population, with a median age at diagnosis of 68 years. Outcomes remain poor for patients (pts) older than 60 years of age who are unfit to receive intensive chemotherapy. Ven based combination therapy has become the standard of care based on the results of the Viale-A and Viale-C in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), respectively. This combination therapy is myelosuppressive leading to multiple dose adjustments in the real-world setting, which may impact the validity of the trial responses and overall survival (OS) in a community-based practice. We therefore sought to investigate the outcomes of pts treated with ven based combination therapy in the real-world setting to better understand efficacy and patterns of adverse events.Methods: Pts 65 years of age or older, diagnosed with AML on or after January 1, 2019, and who received frontline ven based combination therapy with azacitidine (aza), decitabine (dac) or LDAC were identified in the COTA real-world database. The COTA database is a USA-based dataset comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of pts with cancer. Clinical outcomes, including real-world overall response rate (rwORR), OS and adverse events were calculated by treatment group. Responses were defined per treating physician as complete response (CR) or partial (PR) or progressive disease (PD). Categorical variables and rwORR were compared using Fisher's exact test. Survival outcomes were calculated using the Kaplan-Meier method and compared amongst groups using log-rank test.Results: A cohort of 112 pts were treated with ven based combination: ven/aza (n=54), ven/dac (n=52) and ven/LDAC (n=6). Across all treatment groups, the majority (91.1%) of pts were treated in the community setting. The median age at diagnosis was 77 yrs (IQR: 71-81 yrs). Per ELN risk, 6.2% had favorable, 19.6% had intermediate and 62.5% had high-risk AML. Five of the 6 pts receiving ven/LDAC had secondary AML (Table 1). The most common molecular abnormalities across the cohort were TP53 (38.4%), TET2 (26.8%), ASXL1 (27.7%), and DNMT3A (20.5%). The rwORR by treatment was 57.7% for ven/dac, 55.6% for ven/aza and 33.3% for ven/LDAC (ven/dac vs. ven/aza, p=0.85). Median OS (mOS) was similar for ven/dac with a longest mOS of 13.9 mo, followed by ven/aza with a mOS of 11.3 mo, and ven/LDAC mOS of 6.5 mo (ven/dac vs. ven/aza, p=0.77). The most common reasons for treatment discontinuation were toxicity (32.1%) followed by progression/inadequate response (10.7%). The most common toxicities were related to myelosuppression/cytopenias (Table 3). In this cohort, only 6 pts underwent an allogeneic stem cell transplant in first remission and no pts underwent an allogeneic transplant in second remission.Conclusions: To our knowledge, this dataset represents the largest cohort of pts treated with ven based combination therapy in the real world setting across multiple community practices. As less intense regimens are used to treat AML, more pts are receiving induction in the community setting, making these findings relevant in clinical practice. Although ven/dac combination had the longest OS, this was not significantly different from ven/aza. The ven/HMA response rates were lower and survival outcomes were shorter than those reported in the Viale-A trial, which raises concerns about early discontinuation of therapy in the real world setting due to myelosuppression. Ven/LDAC combination had the shortest OS, though most of these patients had sAML. Despite this enriched population for targeted therapies, the outcomes remained poor overall.There are drawbacks to interpreting retrospective outcomes data. First, there were no treatment related AML cases in this dataset, which would be highly unusual in an elderly population of 112 cases of AML. It is more plausible that the diagnosis of treatment related AML was not utilized in the patient's chart. Other data points that were not adequately captured were cause of death and International Working Group response criteria. Mutational panel testing remains underutilized for AML patients in a community-based practice setting. However, this dataset highlights the need for larger datasets to compare the outcomes of AML therapy by practice setting. [Display omitted] DisclosuresMadanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Hansen: COTA, Inc.: Current Employment. Foss: COTA, Inc.: Current Employment. Schulte: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

A Retrospective Comparison of Hypomethylating Agent in Combination with Venetoclax Versus Liposomal Daunorubicin and Cytarabine in Frontline Treatment of Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis in the adult population, despite recent advancements in treatment paradigm. Induction with the liposomal formulation of cytarabine and daunorubicin (CPX-351) which has been shown in phase III trials to improve the median overall survival (OS) compared to standard induction (9.6 versus 5.9 months, respectively) and is FDA approved for patients therapy related AML or AML with myelodysplasia-related changes. Hypomethylating agents (HMA) (azacitidine and decitabine) have recently garnered renewed attention in combination with the BCL-2 inhibitor venetoclax (VEN). Azacitidine with venetoclax demonstrated a median overall survival of 16.9 months in those that were deemed ineligible for intensive induction. While these trials were inherently different patient populations, in clinical practice, physicians must often choose between these two therapies in the frontline setting. Thus, we aimed to examine patient characteristics and respective outcomes with these two treatment approaches.Methods: This was a retrospective cohort studies of patients diagnosed with AML and treated at Virginia Commonwealth University/Massey Cancer Center as identified by our data analytics core between June of 2018 and December of 2020. Data was extracted and manually verified from the electronic medical record into an AML database instrument created in RedCap. Statistical analysis was then performed using GraphPad Prism. Descriptive analyses were conducted for demographics and baseline clinical characteristics, and OS rates were evaluated using Kaplan-Meier analyses and compared using log-rank test.Results: A total of 160 patients with AML were identified. Of those, 58 were treated with either HMA/VEN (N = 43) or CPX-351 (N = 15) in the frontline setting. Median age of patients treated with HMA/VEN was 72 (range: 37 - 85) compared to the median age of 69 (range: 44 - 72) for the CPX-351 group, which was statistically significant (p = 0.002). There was no statistical difference in other demographic characteristics such as sex (p = 0.380), race (p = 0.323), Charleston Comorbidity Index (p = 0.097), or ECOG score (p = 0.126). AML risk stratification based on molecular and cytogenetic data per ELN 2017 also did not differ between the two groups (p = 0.230), with both groups having numerically similar adverse-risk patients (86.7% in the CPX-351 cohort and 70.7% in the VEN cohort). Figure 1 demonstrates a Kaplan-Meier analysis, which revealed a median OS in the VEN group of 281 days (9.23 months) compared to a median OS in the CPX-351 group of 713 days (23.4 months), which was not significant (p = 0.109). Additionally, there was no difference in the OS when only the adverse cytogenetic categories were analyzed from each cohort (Figure 2, p = 0.058). There was one (6.7%) death within 30 days in the CPX-351 group and no deaths within 60 days, compared to one (2.3%) death within 30 days and 9 (20.9%) deaths within 60 days in the VEN group, which was not significantly different (p = 0.257). Allogeneic stem cell transplant was more common in the CPX-351 group (40%) than the VEN group (4.7%) (p = 0.0007).Conclusion: Although these regimens were intended for diverging populations of induction versus non-induction candidates, there is clinical overlap in physician discretion regarding both regimens. Our data shows similar baseline characteristics between these two groups, though the VEN cohort was slightly older. Our data demonstrated that in the CPX-351 cohort, the OS was longer, there appeared to be fewer deaths during induction, and more patients proceeded to transplant - though the former approached statistical significance, particularly when matched with adverse cytogenetic risk (p = 0.058). This argues for continued use of intensive regimen for those who are candidates, especially those in whom allogeneic hematopoietic stem cell transplant is being considered. Prospective studies between these regimens is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Sequential Fludarabine, Ara-C, Etoposide (FLAV) Followed By Fludarabine/ Busulfan Reduced Toxicity Conditioning Is Safe and Effective Salvage for Adult Patients with Refractory Acute Myeloid Leukemia and High Risk Myelodysplasia

BackgroundA significant proportion of patients with acute myeloid leukemia (AML) will either be refractory to initial chemotherapy or will suffer refractory relapse. The role of allogeneic transplantation (SCT) in active disease is contentious. There is a growing body of literature that sequential chemotherapy, pioneered by the German FLAMSA regimen, followed by RIC SCT is a safe and efficacious modality in these patients, and there have been numerous modifications of this regimen, especially as amsacrineis not widely available. Fludarabine, cytarabineand and etoposide (VP16) (FLAV) have been reported as an effective salvage regimen. Here we report on single center outcomes of a variation of the FLAMSA regimen, substituting amsacrine for etoposide with mainly myeloablative conditioning.MethodsPatients were offered this regimen if fit for allogenic HSCT and had AML which is refractory to two cycles of chemotherapy or refractory to one cycle and considered at high risk for complication with second cycles. Patients with MDS received this regimens if eligible for transplant with high or very high risk cytogenetics. All patients received cytoreductive chemotherapy consisted of fludarabine 30mg/m2/day x 4 days, Cytarabine 2g/m2/day x 4 days, etoposide 100mg/m2/day x 3days, commenced simultaneously. After 3 days of rest, conditioning chemotherapy consisted of fludarabine 30mg/m2 x 2 days and and IV busulfan 0.8mg/m2 q 6 hours; the number of busulfan doses varied between 8 - 12, depending on patient comorbidity. All patients received 2 doses of ATG at 2.5mg/m2/day on day -3 and -2. All patients received GCSF mobilized peripheral blood hematopoietic cells. Post-transplant GVHD prophylaxis consist of CsA and MMF. CsA was tapered from day+60 and stopped at day +90 in the absence of GVHD. MMF was discontinued between day +30 and day +40. Donor lymphocyte infusions were collected for planned prophylactic DLI.ResultsTwenty six patients received FLAV-SCT between March 2014 and July 2019. The median age was 38 (14-60); 16 (62%) female. Overall 12 (46%) pts had de novo AML, 10 (39%) pts had secondary or therapy related AML and 4 (15%) pts had MDS. Fourteen (54%) pts had adverse risk cytogenetics include 8 (31%) pts had complex or monosomal karyotype. Patients' characteristics are summarized in Table 1.All patients had active disease prior to FLAV-SCT. The median time for ANC and platelet engraftment was 14 (10 - 42) days and 17 (10 - 52) days respectively. Day 30 assessment shows CR in 16 (61%) pts and CR/CRi in 17 (65%) pts. Outcomes are summarized in Table 2. Three patients (12%) developed veno-occlusive disease. Acute GVHD grade II-IV and III-IV occurred in 9 (35%) pts and 2 (8%) pts respectively. Three (12%) patients developed chronic GVHD. Cumulative incidence of NRM at 100 days and 2 years was 8% and 12% respectively. The median OS for all pts was 5.2 months with 2 years rate of 32% (15 - 50). Among responders, the median OS and RFS were 19.2 months and 8.7 months, 2y-OS and RFS were 47% and 25%, respectively (Figure 1).ConclusionOur result demonstrates that transplant is an effective therapeutic modality in this very high risk refractory AML/MDS patients. Sequential chemotherapy (FLAV) followed by SCT with busulfan at myeloablative dose is tolerable with an acceptable toxicities and encouraging results. [Display omitted] DisclosuresChaudhri: Novartis: Honoraria; Abbvie: Honoraria; Astra Zeneca: Honoraria. Alzahrani: King Faisal Specialist Hospital and Research Centre: Current Employment; Novartis: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Induction Mortality in Acute Myeloid Leukemia: A 9 Year Retrospective Study from a Tertiary Care Centre in a Low-Middle Income Country Setting

INTRODUCTION: Literature on acute myeloid Leukemia (AML) from low and middle income countries (LMIC) like India indicate lower uptake of intensive treatment (29%) and higher induction mortality (25%) (Philip C, BJH 2015). This is attributable to delayed presentation, higher infection burden, multi-drug resistant organism (MDRO) infections, poor nutritional status, access to care, and high costs driven by ‘out-of-pocket expenditures’, among other reasons.AIM: To determine the clinical profile, cause and costs of care of patients who die during Induction therapy of newly diagnosed AML.METHODOLOGY: This is a retrospective chart review of newly diagnosed AML patients who died during Induction therapy. Induction mortality was defined as death within 60 days from the date of initiation of therapy for newly diagnosed AML. Secondary and therapy related AML were excluded from the study. Demographic and clinical profiling and analyses of the cause of death was undertaken.RESULTs: Between May 2011-Dec 2019, 825 adult patients were registered with newly diagnosed AML. 455 (55.2%) patients discontinued care primarily due to financial constraints, and 370 (44.8%) continued treatment here. Among these (n=370), 275 (74.3%) chose to receive standard or abbreviated intensive therapy (Group A), 58 (15.7%) chose disease control only with continuous less-intensive regimens like hypomethylating agents (Group B) and 37 (10%) chose palliation and best supportive care (Group C). Median age was 55y (20-84) overall, and 39.5y, 67.5y and 69y respectively in groups A, B and C. Females were 59% of the cohort. The overall induction mortality was 13.78% (n=51). Independently, induction mortality was 9.4% (26/275) in Group A, 24.13% (14/58) in Group B and 29.72% (11/37) in Group C, with a yearly trend suggesting a decrease in Group A (Fig 1) in the last 3 years. The most common cause of death was sepsis, 92.1% (n=47), with or without a bleeding episode. Isolated bleeding episodes were accountable for 4% (n=2) of overall deaths, and disease progression in the rest (n=2). Disease burden at presentation (% blasts in peripheral blood and marrow respectively, median values): 40% & 55% in Group A, 47% & 55% Group B, and 60% & 61% in group C. ELN 2017 risk grouping: 16% standard risk (n=8), 51% intermediate risk (n=26) & 33% high risk (n=17). 33% (n=17) had a lung infection at baseline and this was the commonest source of sepsis. Stool and throat surveillance cultures revealed MDRO (carbapenem resistant enterobacteriaceae) in 47% (n=15/32 tests) and 33% (n=7/21 tests) patients, respectively. 74.5% (n=38/51) developed blood culture positive infections during induction therapy. The median number of days to culture positivity was 11 days overall, 13 days in Group A (n=22), 3 in group B (n=13) and 1 day in Group C (n=3). The most common blood culture-detected organism was MDRO Carbapenem resistant Klebsiella (n=12). Imaging detected fungal infection was observed in 47% (n=24). The common antibiotic regimens included meropenem and colistin, with voriconazole being the most common antifungal used. The median ICU stay was 3.5 days (range of 0-24 days) in Group A and 1.5 days (range 0-13) in Group B. The median direct hospital costs in these patients were $6999 in Group A, $7923 in Group B and $2655 in Group C [per-capita GDP of India in 2019: $2099.6].CONCLUSIONS: The induction mortality in AML varies with age and the intent of treatment. Younger patients undergoing intensive curative therapies have lesser induction mortality. Sepsis is the most common cause of induction deaths, primarily due to a high disease burden and higher infection burden at presentation, and the presence of MDRO bacteremia. Costs of care are very high and contribute to the high drop out rate from curative therapy of newly diagnosed AML. [Display omitted] DisclosuresRadhakrishnan: Novartis India: Membership on an entity's Board of Directors or advisory committees; NATCO Pharmaceuticals: Research Funding; Janssen India: Honoraria; Intas Pharmaceuticals: Research Funding; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca India: Honoraria, Speakers Bureau; Aurigene: Speakers Bureau; Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cipla Pharmaceuticals India: Research Funding; Emcure Pharmaceuticals: Research Funding. Garg: Dr Reddys Laboratories: Honoraria, Speakers Bureau. Nair: Intas pharmaceuticals: Honoraria, Speakers Bureau; Fresenius Kabi India: Honoraria; Janssen India: Honoraria, Speakers Bureau; Cipla Pharmaceuticals: Honoraria, Speakers Bureau; Novartis India: Honoraria; Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mylan pharmaceuticals: Honoraria. Chandy: Intas Pharmaceuticals: Research Funding; Pfizer: Honoraria; Janssen: Honoraria.

TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

ObjectivesTP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients.MethodsPatients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA).ResultsA total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients.DiscussionIn this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

TP53 in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation.

Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5–10% of de novo AML, and in 30% of therapy related AML (t-AML). TP53 mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of TP53 mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of TP53 on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.

Secondary Acute Myeloid Leukemia (sAML): Similarly Dismal Outcomes of AML After an Antecedent Hematologic Disorder and Therapy Related AML

Therapy related acute myeloid leukemia (tAML) and secondary AML after an antecedent hematologic disorder (sAML-AHD) are often addressed together, blurring any clinical and prognostic differences. Among 516 AML patients, we compared characteristics and outcomes of 149 patients with “sAML” (sAML-AHD: 104, tAML: 45), uniformly and intensively treated during the last 2 decades at 1 center. Clinical outcomes of the whole “sAML” cohort were significantly inferior compared to de novo AML and in both intermediate and poor cytogenetic risk groups. Adverse karyotype had no effect on survival in tAML, while it was a negative predictor in sAML-AHD. Both groups showed similarly dismal outcome, with low complete remission rates (CR 44% vs. 41%) and median overall survival (OS 7 vs. 10.5 months). Allogeneic hematopoietic cell transplantation (alloHCT) recipients in CR1 had superior median OS (24 vs. 8 months). By multivariate analysis, alloHCT was an independent predictor of outcome, while karyotype was for sAML-AHD only. In conclusion, both “sAML” groups have inferior outcomes after chemotherapy, with adverse karyotype affecting primarily sAML-AHD. Until new treatment approaches are available, only alloHCT offers a survival advantage.

Prognostic significance of chromosomal abnormalities at relapse in children with relapsed acute myeloid leukemia: A retrospective cohort study of the Relapsed AML 2001/01 Study.

In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.

Presence of Rare Germline Variants in Fanconi Anaemia Pathway Genes Confers a Poor Prognosis Comparable to TP53 Mutations in Therapy-Related Myeloid Neoplasms

Introduction: T-MN inclusive of therapy related myelodysplastic syndrome (T-MDS) and acute myeloid leukemia (T-AML) are aggressive neoplasms occurring after exposure to chemo (CT) and/or radiotherapy (RT) and are characterized by high frequency of complex cytogenetics and poor prognosis. TP53 and other genes involved in DNA repair such as Fanconi Anaemia(FANC) pathway are critical in maintaining genomic stability. TP53 mutations are associated with complex karyotype and poor prognosis in myeloid malignancies. Further, variants in the FANC pathway are a risk factor for malignancies, but remain less well studied in T-MN. Churpek et al . (Cancer 2016) reported germline mutations in BRCA1, BRCA2, TP53, CHEK2 and PALB2 in 8/43 (19%) treated breast cancer patients who developed T-MN. However, their interaction with TP53 mutations and impact on survival is unknown. Here we investigate the genomic architecture of T-MN patients from the South Australian Myelodysplastic Syndrome (SA-MDS) registry.Methods: Demographic, clinical and laboratory data including cytogenetic profile of 147 T-MN patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 63 genes (43 myeloid neoplasms associated genes & 20 FANC; all coding regions) was performed on diagnosis bone marrow samples from 101 T-MN samples. Rare FANC variants were selected based ExAC MAF <0.2% and variants only with VAL ≥20% were selected for further analysis. FANC variants were called deleterious if predicted to be deleterious by atleast two in-silico prediction model (e.g. CADD, SIFT, POLYPHEN and Mutation taster) and/or reported in COSMIC, gene specific databases or in literature.Results: Median age of T-MN was 71 (20-91) years and the most frequent primary neoplasms were lymphoproliferative neoplasms (n=56, 38%) and prostate cancer (n=22, 15%). Sixty-three (43%), 34 (23%) and 48(33%) patients received CT, RT and CT plus RT respectively. The T-MN group consisted of 104 T-MDS (71%) and 43 T-AML (29%). Poor risk cytogenetics were more frequent in T-MN cases following CT than after RT alone.Somatic mutations in myeloid genes were detected in 95/101 (94%) of T-MN cases. Notably, all normal karyotype T-MN (29/29, 100%) were mutated. Mutations were most frequently seen in transcriptional factors (35%), TP53 (32%) and splicing factors (26%). Significantly higher proportion of TP53mut T-MN patients had complex karyotype (22/32, 84%) compared to TP53wt (5/69; 7%, p<0.0001).Examination of 20 FANC pathway genes identified 38 rare variants in 31(31%) T-MN at a variant allele frequency (VAF) of ≥20% and most of the variants were missense (35/38; 92%). These were mostly seen in BRCA1, FANCA, FANCM, BRCA2, FANCL and SLX4 genes. Of patients with FANC variants, 42% (13/31) had concomitant TP53 mutations. The median VAF was 49% (range 20-100%) with no significant difference between the deleterious (n=13; 34%) and non-deleterious variants (n=25). Out of 13 deleterious variants (including 2 BRCA1 variants previously reported pathogenic on BIC database), ten variants were seen in nine TP53wt patients. We compared the disease characteristics, prior chemotherapy and survival outcome in patients with TP53mut (n=32), TP53wt harbouring predicted deleterious FANC variants (TP53wt /FANCdel var; n=9), TP53wt harbouring predicted non-deleterious FANC variants (TP53wt /FANCnon-del var; n=9) and TP53wt /FANCwt (n=51). There was no difference in bone marrow blast %, type of prior malignancy, prior therapy (CT vs RT vs combination), proportion of T-AML and treatment for T-MN between the groups. Interestingly, median number of mutations were significantly lower in TP53mut group (1; range 0-11) compared to TP53wt /FANCdel var, TP53wt /FANCnon-del var (both groups - 3; range 0-6) and TP53wt /FANCwt (3; range 0-9) (p=0.0005). Importantly, median OS of TP53wt /FANCdel var and TP53wt /FANCnon-del var groups was identical and significantly shorter than TP53wt /FANCwt (9.7 vs. 9.9 vs. 19.1 months; p=0.00485), and similar to TP53mut group (8.9 months).Conclusions: In our cohort, somatic mutations were seen in 90% of T-MN patients, comparable to primary MDS, contrary to previously published literature. Somatic TP53 mutations and FANC variants are seen in 32% and 31% of cases respectively and 13% harboring both. This study demonstrating that rare FANC variants are associated with significantly poor survival comparable to TP53 mutated T-MN patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia with Deletion 13q: Prognostic Predictors and Outcome after Treatment with Fludarabine, Cyclophosphamide and Rituximab (FCR)

INTRODUCTIONChronic lymphocytic leukemia (CLL) with deletion 13q (del13q) has historically better outcome after chemotherapy. However a sizeable number of such patients do progress with a decreased progression free survival (PFS) and overall survival (OS). We analyzed this group of patients treated with FCR to characterize the relationship between clinico-biological parameters and outcome. METHODSWe retrospectively analyzed 134 CLL patients with del(13q) treated with FCR from March 2004 to August 2014 in our institution. The association between base line characteristics, 12 month minimal residual disease (MRD) status as detected by flow cytometry with PFS and OS was assessed using univariate Cox proportional hazards model on all patients. RESULTSOf 134 patients 63% (n=84) were male and 37% (n=50) female, and median age was 60 (range 35-83) yrs. Median follow up was 70.3 mths (5.9 yrs). Median WBC was 39.3 K/μL (3.2-666.5) and Hb 13.6 (g/dL) (7.1-16.4). Seventy three (54%) were IGVH mutated and 51(38%) unmutated. Eighty nine (66%) had beta-2 microglobulin (β2M) <4 and 44 (33%) > 4 μg/mL. Karyotype was diploid in 107 (80%) patients and abnormal in 16 (12%) patients. By fluorescence in situ hybridization (FISH), %age of cells having del(13q) ranged from 8-98% with median of 55.75%. One locus was involved in 110 (82%) and both loci in 20 (15%) patients. Splenomegaly was present in 55 (41%) and absent in 76 (57%). Ninety six percent (n=129) patients had non bulky disease and only 4 (3%) had bulky disease. After FCR therapy, 83 patients (62%) achieved complete response (CR), 26 (20%) nodular partial response (nPR), 21 (16%) partial response (PR) and 4 (3%) treatment failure. Overall 38% (n=51) patients experienced disease progression. Thirteen percent (n=17) patients died after FCR treatment, of which 8 had progressed and 9 had not progressed. There were 12 malignancies detected after diagnosis of CLL: 4 basal cell carcinomas, 4 squamous cell carcinomas, 1 breast carcinoma, 1 colon carcinoma, 1 small bowel carcinoma, 1 therapy related acute myeloid leukemia, 1 therapy related myelodysplastic syndrome, 1 B-acute lymphoblastic leukemia. Median PFS was 83.1 mths (6.9 years), OS at 5 years was 89.9%, and at 10 years was 79.1%. Median OS was not reached. Of 51 patients who experienced disease progression, there were 8 observed deaths. Due to small number of observed events, estimated survival rates could not be ascertained meaningfully. β2M >4 (HR 1.85, p=0.02), high WBC count (HR 1.55, p<0.01), Hb <10 gm/dL (p=0.01), unmated IGVH (HR 2.78, p=0.001), abnormal karyotype (HR 2.01, p=0.04), splenomegaly (HR 2.45, p=0.001), MRD positivity at 12 months (HR 2.87, p=0.01) had a significant negative impact on PFS. Platelet count <50,000/μl, bi-allelic del(13q) while showing a negative impact on PFS was not statistically significant. Percentage of del(13q) >50% had no impact on PFS. Except for Hb <10 gm/dl (p=0.001), none of other parameters had statistically significant impact on OS. This could be explained by the limited statistical power for detecting OS due to small number of observed patient deaths. CONCLUSIONIn CLL with del(13q), a subset of patients progress after FCR therapy and have poor PFS. β2M, WBC count, Hb, unmated IGVH, abnormal karyotype, splenomegaly, MRD positivity at 12 months have a significant impact on PFS. [Display omitted] DisclosuresKantarjian:Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Wierda:The University of Texas MD Anderson Cancer Center: Employment; Sanofi: Consultancy, Honoraria; Kite: Research Funding; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Merck: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Juno: Research Funding. Burger:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Hypometilating Agents (HMA) As Salvage Therapy in Relapsed or Refractory AML: A 5-Center Retrospective Study

Introduction: 5-azacytidine and decitabine have been widely studied as first line chemotherapy in acute myeloid leukemia (AML) patients not eligible for allogenic stem cell transplantation, but data on their use as salvage chemotherapy are limited. We tried to define efficacy and feasibility of hypometilating agents (HMA) as salvage chemotherapy in patients without previous allogenic stem cell transplantation.Methods: We retrospectively reviewed clinical records of 35 patients treated with HMA as salvage therapy in our 5 institutions since their introduction in clinical practice for AML patients.Results: Median age was 68 years. 22 patients were men and 13 women. One patient was AML with t(9;11), 18 were AML MRC, 4 were therapy related AML, 12 were AML NOS. Two patients were favorable risk sec ELN 2017, 20 were intermediate, 11 were adverse risk. Cytogenetic risk was not available for 2 patients. 66% of patients received HMA as second line therapy for their disease, 23% as third line and 11% were beyond the third line. 29 patients were treated with azacitidine and 6 with decitabine. Six patients reached CR or morphologic leukemia free state (MLFS) or PR after HMA. All patients underwent intensive chemotherapy (i.e. FLAI or 3+7 like) as first line induction, and we excluded patients who had an HMA as first line chemotherapy and another one as second line. Median number of hospitalization days during HMA therapy was 11(1-78); median number of HMA cycles was 3 (range 1-31). 7 episodes of sepsis demonstrated by positive blood cultures and 3 fungal infections were recorded during HMA therapy. Median OS was 197 days from the starting of HMA and median EFS was 125 days. Median EFS in patients with adverse cytogenetic risk was 68 days, while median EFS in patient with favorable and intermediate risk was 207 days (p=0,0124). Median OS in patients with adverse cytogenetic risk was 181 days, while median OS in patient with favorable and intermediate risk was 307 days (p=0,0401).We did not find significant difference between median OS ed EFS in patients with refractory disease compared to relapsed patients. 31% of patients with adverse cytogenetic risk reached a stable disease with HMA therapy while 64% of patients with favorable/intermediate cytogenetic risk reached a response (CR, PR; MLFS) or a stable disease. We did not find significant differences between transfusion needs before and after salvage therapy but this could be due to the small size of our sample.Conclusion: HMA showed efficacy and a considerable OS in our patients. OS was significantly better in favorable/intermediate risk patients than adverse risk patients. Hospitalization was limited, and we can argue that this could lead to improved costs and quality of life, but further studies are needed. So HMA could be a good clinical option in a selected population of relapsed patients, especially in those not suitable for allogenic bone marrow transplantation, in whom the prognosis is generally extremely poor. Further studies are needed to define if there is a survival or quality of life advantage over other therapies. DisclosuresNo relevant conflicts of interest to declare.