Time Of Acute Myeloid Leukemia Diagnosis Research Articles

A Prognostic Score Model for Relapsed/Refractory Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Patients with acute myeloid leukemia (AML) can achieve complete remission (CR) after receiving initial therapy, while some patients will develop relapsed/refractory AML (R/R-AML), which has a poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been shown to be effective in improving the prognosis of R/R-AML patients. It is necessary to evaluate the factors that can affect the prognosis of patients receiving allo-HSCT for R/R-AML, including leukemia-free survival (LFS) and overall survival (OS). In previous studies, such prognostic evaluation factors included cytogenetics, response to salvage induction therapy before transplantation, time from diagnosis to transplantation, and acute graft-versus-host disease (aGVHD). However, there is still a lack of a prognostic model that can systematically predict prognosis at an early stage after transplantation. In this study, a prognostic model was established to predict the 2-year prognosis of R/R-AML patients receiving allo-HSCT. Method Refractory AML is defined as no CR after 2 courses of intensive induction treatment, while relapsed AML is defined as ≥ 5% bone marrow blasts, reappearance of blasts in the blood or development of extramedullary AML after CR. In this retrospective study, patients receiving allo-HSCT for R/R-AML from January 1, 2015, to June 30, 2021 at Peking University People's Hospital were identified and divided into a derivation cohort and an external validation cohort according to the time of transplantation. Detailed data of all patients were collected from medical records. Categorical variables were analyzed using the 2-tailed Fisher's exact test. Continuous variables were analyzed using the Mann‒Whitney U test. Factors with a P value < 0.10 were included in the multivariate Cox analysis. Factors that were identified as independent prognostic factors in the multivariate Cox analysis were included in the score model. Results A total of 200 patients who received allo-HSCT for relapsed/refractory AML were identified. The median age of diagnosis of AML was 39.5 years (range, 18-68 years), and the median age of transplantation was 40 years (range, 20-68 years). In the overall survival analysis, age at diagnosis, age at transplantation, sex, white blood cell (WBC) count at diagnosis, WBC engraftment time and duration from AML diagnosis to allo-HSCT were identified as potential prognostic factors. In the multivariate Cox analysis, age > 55 years (HR, 3.587; 95% CI, 1.099 to 11.702; P =.034), WBC level at AML diagnosis < 4.0×10^9/L (HR, 4.548; 95% CI, 1.209 to 17.104; P =.009) and duration from AML diagnosis to HSCT > 250 days (HR, 6.541; 95% CI, 0.941 to 5.488; P =.058) were identified as independent prognostic factors. A model for the survival rate of R/R AML patients receiving allo-HSCT was developed according to the regression coefficients of the multivariate analysis. Patients who met the criteria of age > 55 years, WBC level at AML diagnosis < 4.0×10^9/L or duration from AML diagnosis to HSCT > 250 days received 1 point for each variable. Points 0, 1-2, and 3 were defined as low, median and high risk, respectively. This prognostic score model performed well in the external cohort (AuROC =.783; 95% confidence interval,.599 to.966). In the LFS analysis, WBC count at AML diagnosis < 4.0×10^9/L (HR, 3.120; 95% CI, 1.198 to 8.122; P =.020) and female sex (HR, 2.778; 95% CI, 1.013 to 7.617; P =.047) were related to poor LFS . Conclusion In this study, we developed a prognostic score model of 2-year OS for R/R‒AML patients after receiving allo-HSCT. Independent prognostic factors included age at transplantation (> 55 years), WBC count at AML diagnosis (< 4.0×10^9/L) and duration from AML diagnosis to HSCT (> 250 days). This model can effectively evaluate the 2-year mortality of R/R-AML patients after receiving allo-HSCT and help improve the prognosis of patients. There was a higher mortality for patients with R/R‒AML after receiving allo-HSCT when the WBC count at the time of AML diagnosis was lower than the normal range. Considering that the main cause of death of patients in this study was infection, this correlation may be related to the destruction and reconstruction of the immune system.

Outcomes of Acute Myeloid Leukemia Patients Suffering from an Additional Active Malignancy Treated with Venetoclax and Azacitidine: A Single Center Experience

Introduction: Venetoclax (ven) and azacitidine (aza) has become the standard of care for the treatment of patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy on the basis of the phase III VIALE-A trial, which showed prolonged overall survival with ven-aza vs. placebo-aza. Pts with active additional malignancies (AM) at the time of AML diagnosis are often unfit for intensive chemotherapy but are excluded from clinical trials, including VIALE-A. We aim to compare the characteristics and outcomes of AML patients with AM vs without AM (non-AM), all treated in a real world setting. Methods: A retrospective analysis including all AML pts diagnosed between Jan 2019 and Apr 2023 and treated with ven-aza in Tel Aviv Sourasky Medical Center. We defined active malignancy as any malignancy additional to AML that was diagnosed within 2 years prior to or concomitantly with the diagnosis of AML, or receiving active treatment at the time of the diagnosis of AML. We excluded prior MDS, MPN and basal cell or localized squamous cell carcinomas of the skin. We defined patients eligible for registration trial (RTE) as pts meeting the inclusion criteria for the VIALE-A trial. We compared categorical and continuous variables as appropriate, and examined survival outcomes by a Kaplan Meier and Log-Rank test. Event free survival (EFS) was defined as time until treatment failure (2 courses of ven-aza without achievement of response), relapse, or death. Results: We analyzed 113 pts diagnosed with AML and treated with ven-aza. 17 patients had an additional AM; 11 solid and 6 hematological, at the time of AML diagnosis. Six pts had more than one additional malignancy. Six patients had newly diagnosed AM, 6 had AM in remission and were treated with maintenance therapy at the time of AML diagnosis, and 5 had an active relapsed / progressive AM. Five patients received treatment for AM concomitantly or alternating with ven-aza, including surgery, letrozole, olaparib, arabiterone acetate, pazopanib, and trabectedin. We compared the baseline characteristics and outcomes of AML pts with AM to AML pts treated with ven-aza who did not have AM (96 pts, non-AM) and pts who met inclusion criteria for the registration VIALE-A trial (57 pts, RTE). Pts with AM were younger than non-AM pts or RTE pts (11.8% over the age of 75 vs. 67% and 68%; respectively, p<0.001), and had a slightly higher baseline creatinine level than RTE pts (median=1.1 range 0.6-1.4 mg/dL vs. median=0.9 range 0.5-1.3 mg/dL; p=0.01). ECOG functional status, ELN risk category, and baseline cell counts were similar between all groups. Treatment with ven-aza was initiated within a median of 6 days from diagnosis in AM pts (range 1-20). 58.2% of AM pts achieved CR/CRi vs. 57% of non-AM pts and 68% of RTE pts (p=0.9 and p=0.46, respectively). The 30 day mortality rate for AM pts was 17.6% vs 7.3% for non-AM pts (p=0.17) and 3.5% for RTE pts (p=0.07). Causes of early mortality among AM patients were non-responsive/progressive AML (2 pts) and sepsis (1 pt). Overall, 13 of 17 AM pts died, 7 from progressive AML, 3 from progressive additional malignancy and 3 from treatment complications. Six of the AM pts underwent allogeneic stem cell transplant (35%) vs. 14 non-AM pts (14.5%, p=0.07) and 11 RTE pts (19.2%, p=0.19). Median length of follow-up was 23.8 months (95% CI, 12.9-34.7). Overall survival (OS) EFS, and relapse free survival (RFS) were similar between AM and non-AM pts. (Figure 1A). ECOG score other than 0 (p=0.009, HR=2.2 95% CI 1.2-4.1) and secondary AML type (p=0.049, HR=1.8, 95% CI 1.001-3.124) but not AM (p=0.354, HR=1.42, 95% CI 0.67-3.03) were associated with reduced overall survival in a multivariate analysis which included age, sex and ELN risk category. A trend for worse survival outcomes in AM vs. RTE pts was noted (HR=1.82, CI 0.95-3.46 p = 0.068) (Figure 1B). EFS and RFS were similar between AM and RTE pts. Conclusions: Among pts diagnosed with AML and an additional active malignancy, treatment with ven-aza in the real world setting resulted in similar response and survival rates as in patients without active malignancies, but with a trend for worse overall survival and higher early mortality than pts who meet the eligibility criteria of the VIALE-A trial. 21.8% of AM pts were alive at 24 months. These results imply that treatment for AML for pts with active malignancy with ven-aza is feasible, and should not be withheld from these pts.

Frail and Pre-Frail Older Adults with Acute Myeloid Leukemia Have Inferior Survival Due to Higher Rates of Disease-Related Deaths

Introduction: The intensity of initial remission-inducing therapy for patients with newly diagnosed acute myeloid leukemia (AML) may be high (anthracycline and cytarabine-based), intermediate (venetoclax combinations), or low (single hypomethylating agent or targeted therapy). In older adults, it is important to consider “fitness” when selecting initial therapy. Current methods to determine “fitness” in AML include subjective measures such as physician assessment (“clinician gestalt, CG”) semi-subjective measures such Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status (KPS), and those based on clinical comorbidity data like the hematopoietic cell transplantation-comorbidity index (HCT-CI). Geriatric assessments in older adults with cancer may improve therapy selection and decision-making, but whether unfit patients have better outcomes with lower intensity compared to higher intensity therapies is unknown. Freid's Frailty Phenotype (FP) combines subjective (self-reported exhaustion, weight loss >5%, activity level) and objective (4-meter walk speed and grip strength) measures to categorize patients into fit, pre-frail, and frail. We hypothesized that being frail by FP is associated with higher overall mortality (OM) and inferior overall survival (OS) and may inform decision-making for older adults. Methods: Eighty-fivepatients 60 years or older admitted to the Hospital of the University of Pennsylvania at the time of AML diagnosis or electively admitted for AML chemotherapy initiation were prospectively enrolled from September, 2018 to May, 2023 on an IRB approved study. FP, HCT-CI, KPS, ECOG, gait speed, and recorded CG (fit or unfit) were performed prior to initiation of disease-directed therapy. Results: Themedian age of the cohort was 71 (range60-91). Patients in our cohort had high-risk disease features: 64% were adverse risk by European LeukemiaNet (ELN) 2017 with 73% of patients harboring mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) (Table 1). 39% of patients received IC, 52% received HMA/ven, 6% received HMA alone or targeted therapy, and 2% received best supportive care. By FP, 18% of patients were fit, 38% were pre-frail, and 45% were frail. Higher ECOG, KPS, CG, and HCT-CI were associated with frail phenotypes (Table 1). For the entire population, 60-day and 100-day OM rates were 18% and 33%, respectively. For fit, pre-frail, and frail patients 60-day OM was 7%, 13%, and 24% and 100-day OM was 13%, 22%, and 42%, respectively. Two-year OS was 65% for patients aged 60-69 years old and 15% for patients ≥70 years old (p=0.002). FP was significantly associated with OS (Figure 1; p=0.0474): 2-year OS was 57%, 42%, and 21% in fit, pre-frail, and frail patients, respectively. Of the individual components of FP, self-reported exhaustion and slower gait speed were both associated with inferior OS (p=0.0015 and p=0.0005). Neither activity level, (p=.0864), weight loss (p=0.1988), or grip strength (p= 0.7136) were associated with OS. Of the total population 19% went on to hematopoietic cell transplant (HCT) with 8% of frail patients receiving HCT compared to 27% of fit and 28% of pre-frail patients. ECOG, HCT-CI, CG, and gait speed ≤8 meters/sec were all significantly associated with OS, but KPS was not. The 6-month OS for frail patients receiving IC was 75% compared with 49.7% for those receiving HMA/Ven, although not significant due to small sample size. Cause of death was leukemia-related for 40% of fit patients, 76% of pre-frail patients, 77% of frail patients. Conclusions: FP was associated with a doubling of early mortality and inferior 2-year OS. Pre-frail and frail patients had increased disease-related deaths. This work supports that most geriatric assessments, including FP and clinician intuition, can be utilized to risk-stratify newly diagnosed older adults with AML. Future work is needed to evaluate whether we can integrate geriatric assessments, such as individual components of FP or gait speed, with molecular features to improve risk stratification of older adults with AML. Given frailty's association with disease-related deaths, further study is warranted to determine whether this is due to adverse disease biology or whether frail patients are undertreated.

Successful Bridging to Allogeneic Hematopoietic Stem Cell Transplantation by Azacitidine and Venetoclax in a Case of Acute Myeloid Leukemia With t(3;3)(q21.3;q26.2) Developed Early After Orthotopic Heart Transplantation

A 48-year-old male patient developed acute myeloid leukemia (AML) with t(3;3)(q21.3;q26.2) chromosomal mutation 8 months after orthotopic heart transplantation from a human leukocyte antigen-unmatched brain-dead donor for cardiac sarcoidosis. He had sequelae of stroke and chronic renal failure at the time of AML diagnosis. He received 3 cycles of azacitidine and venetoclax induction therapy and achieved complete hematological remission with incomplete count recovery without causing severe complications, including infection. He sequentially underwent allogeneic peripheral blood stem cell transplantation from a HLA-8/8 matched, ABO-blood matched, unrelated female donor and successfully achieved donor cell engraftment. His transplanted heart was viable, and the coronary vessels were not damaged even after allogeneic peripheral blood stem cell transplantation. Although AML relapsed afterward, azacytidine/venetoclax was a tolerable bridging therapy even for early-onset AML after heart transplantation.

Targeting IDH1-Mutated Pre-Leukemic Hematopoietic Stem Cells in Myeloid Disease, Including CCUS and AML

Introduction: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been reported in clonal hematopoiesis and are recurrent, early events in the development of acute myeloid leukemia (AML). A subsequent stepwise acquisition of additional genetic aberrations leads to the development of frank leukemia. At the time of AML diagnosis, rare pre-leukemic hematopoietic stem cells (pHSC) can be detected containing some, but not all, of the mutations in the corresponding leukemia, although these pHSCs are phenotypically indistinguishable from residual wildtype hematopoietic stem cells (HSC). The frequency of pHSCs at the time of diagnosis is known to correlate to overall survival in AML patients (Corces et al, Nat Genet 2016), indicating the potential relevance of therapeutically targeting these cells to prevent relapse. Methods: To model these rare pre-leukemic cells, we introduced IDH1 R132H and IDH2 R140Q mutants or their wildtype counterparts into human CD34+ hematopoietic stem and progenitor cells (HSPC) using CRISPR/Cas9 and AAV6-mediated homology directed repair (HDR). Successfully edited cells were then sorted by FACS based on GFP expression for subsequent analyses including 2HG quantification, colony formation, differentiation capacity, RNA sequencing, and metabolic assays. Additionally, primary pHSCs from diagnostic bone marrow aspirates from AML patients were also isolated by FACS and subjected to treatment, colony formation assays, and genotyping by ddPCR. Results: Human CD34+ HSPCs engineered to express either IDH1 R132H or IDH2 R140Q produced 2HG and showed a striking reduction in colony formation and differentiation capacity, recapitulating the cytopenic phenotype observed in IDH-mutated clonal cytopenia of undetermined significance (CCUS). RNA-seq of these cells revealed large transcriptomic changes shared between IDH1 R132H and IDH2 R140Q mutations, but gene set enrichment analyses revealed the specific and significant downregulation of oxidative phosphorylation-related genes in R132H-mutated cells. These R132H cells were further confirmed to have lower basal metabolic activity coupled to a higher mitochondrial dependency as determined by SCENITH (Argüello et al, Cell Metab 2021). These metabolic alterations suggested that it might be possible to selectively therapeutically target R132H mutated cells. To evaluate this, we treated HSPCs engineered to express GFP, IDH1 wildtype, or IDH1 R132H, with the known mutant-specific inhibitor ivosidenib, the OXPHOS-inhibitor IACS-010759, or DMSO as a control. Strikingly, ivosidenib restored the defect in colony formation conferred by R132H and increased the total number of colonies whereas IACS-010759 effectively inhibited R132H colony formation (Figure 1A). To further investigate this vulnerability, we sorted pHSCs from diagnostic bone marrow samples from primary IDH1 and IDH2-mutated AML samples according to the phenotype CD45dimCD3-CD19-CD20-CD34+CD38-CD99-TIM3-. These cells were subjected to treatment with DMSO, ivosidenib, enasidenib, or IACS-010759 and subsequently plated for colony formation. Because the sorted cell population contained a mixture of mutant pHSCs and residual wildtype HSCs, all colonies were picked and genotyped for IDH mutations using ddPCR, revealing that only IDH1 wildtype colonies grew out after IACS-010759 treatment whereas all other conditions resulted in a mixture of wildtype and mutant colonies (Figure 1B). Conclusions: The OXPHOS-inhibitor IACS-010759 can eradicate IDH1-mutated pHSCs whereas ivosidenib cannot. This effect is specific for IDH1 mutations and the same effect is not seen in IDH2-mutated pHSCs. These results have potential clinical implications when considering therapeutic options in AML as well as IDH1-mutated pre-leukemic conditions such as CCUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Secondary Neoplasms in AML Long-Term Survivors: Even More Cancer to Come?

Introduction: As outcomes of patients with acute myeloid leukemia (AML) have improved, the fraction of patients surviving long-term is increasing. Information on somatic and psycho-social health consequences of AML and its treatment is sparse. The aim of our study was to perform a multi- dimensional analysis of health outcomes in AML long-term survivors (AML-LTS). This report focuses on secondary neoplasms (SN) after AML. Data on psychosocial outcomes and clonal hematopoiesis are presented by Telzerow et al., Görlich et al. and Krauss et al. Methods: We conducted a cross-sectional study including AML survivors who had been enrolled in clinical trials or the patient registry of the AML-CG study group, and were alive ≥5 years after initial diagnosis. Data concerning somatic health status were collected through patient questionnaires, assessments by the patients' physicians, and medical and laboratory reports. (DRKS00023991) Results: Data on somatic health status is available for 355 AML-LTS, 58% female, aged 28 to 93 years [y] (median 60y), 5 to 19y after initial diagnosis (median, 11.6y). Sixteen percent were initially diagnosed with secondary AML (sAML) or therapy-related AML (tAML) and 38% were treated with chemotherapy only while 62% had undergone allogeneic stem cell transplantation (alloHSCT). Fifty-five AML-LTS (15.5%) had developed SN after AML, that manifested 3 months to 18y after initial diagnosis (median, 12.4y), at age 31 to 83y (median 59y). Forty-two percent of AML-LTS with SN were female, 66% had undergone alloHSCT and 24% were initially diagnosed with sAML or tAML. At the time of study participation, 96% percent of all AML-LTS and 90 % of those diagnosed with SN fulfilled CR criteria (neutrophils >1G/L and thrombocytes >100G/L). Most common tumor types were non-melanoma skin cancers (30%), breast cancer (11%, all female, 25% of female AML-LTS with SN), head and neck cancers (7%) and, in 5% each, cancers of the esophagus, lung, bladder and prostate (9.4% of male AML-LTS with SN). Kaplan-Meier-Analyses show a 20%-risk of AML-LTS to develop SN 15 years after initial diagnosis, with no significant difference between patients treated by alloHSCT or chemotherapy only (log-rank p=.26; Fig. 1). However, 10y-risk was 5.6% and 15y-risk was 18.5% for AML-LTS treated with chemotherapy only, whereas for AML-LTS treated with alloHSCT 10y-risk was 12% and 15y-risk was 21%. AML-LTS >60y at the time of AML diagnosis had a significantly higher risk to develop secondary cancer, with a 10y-risk of 17.7% compared to 7.9% for AML-LTS aged 30-60y and 6.6% aged <30y at initial diagnosis (Fig. 2). Using Cox regression models, we analyzed the influence of age at AML diagnosis, sex, smoking status, sAML/tAML vs. de novo-AML, AML relapse (as time-dependent covariable) and treatment with alloHSCT vs. chemotherapy only on the risk of developing secondary malignancies after AML. Only older age at initial diagnosis (OR=1.03 per year, 95% CI: 1.01 - 1.05, p=.01) and male sex (OR=1.93, 95%-CI: 1.12 - 3.37, p=.02), but none of the diagnosis- and treatment-related factors significantly associated with higher risks for secondary malignancies. However, AML-LTS diagnosed with sAML/tAML tended to develop SN earlier after initial diagnosis than those diagnosed with de novo AML. Ten-years-risk was 9% and 15y-risk was 20% for AML-LTS diagnosed with de-novo-AML, whereas for AML-LTS diagnosed with sAML/tAML 10y-risk was 14% and 15y-risk was 23% (log-rank p=.08). Conclusion: Our study includes a large cohort of AML-LTS representing a wide age range, a long follow-up period of 5 to nearly 20 years, and heterogeneous therapy regimens (chemotherapy + autoHSCT vs. alloHSCT), close to real-life clinical settings. We found that the 15y-risk to develop a SN after AML is ~20%, with men having a 2-fold higher risk, and older age at the time of diagnosis being a negative predictor. We did not identify diagnosis- or treatment-related factors associated with increased risks for SN, although SN tended to occur earlier in patients who received alloHSCT compared to those treated with chemo only. We hope that our results may guide future recommendations for risk-adapted follow-up of AML-LTS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of induction approach on post-stem cell transplant (SCT) outcomes in older adults with newly diagnosed acute myeloid leukemia (AML).

7038 Background: The optimal induction regimen for older patients (pts) with AML who are eligible for SCT is not well-established. Methods: This is a retrospective analysis of 127 pts age ≥60 years with newly diagnosed AML who underwent allogeneic SCT in first remission between 9/2012 and 7/2021 at our institution. Pts with previously treated secondary AML were excluded. Pts were divided according to induction therapy received: intensive chemotherapy (IC) (n = 44), lower-intensity therapy (LIT) without venetoclax (VEN) (n = 36), and LIT with VEN (n = 47). We compared overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) according to the induction regimen received. Results: Pts who received IC were younger than those who received LIT with or without VEN (median age: 63 vs. 68 years; P &lt; 0.0001) and were more likely to have an ECOG performance status of 0 at time of AML diagnosis (34% vs. 14%; P = 0.02). Cytomolecular risk was well-balanced between the 3 arms; the rates of adverse cytomolecular features in the IC, LIT without VEN and LIT with VEN groups were 43%, 50%, and 55%, respectively. Donor sources and degree of HLA matching were similar in the 3 groups. Most pts (92%) in the LIT with VEN group received reduced-intensity conditioning prior to SCT, compared with 54% and 58% in the IC and LIT without VEN groups, respectively. The majority of pts achieved CR/CRi prior to SCT (IC cohort:100%, LIT without VEN: 94%, LIT with VEN: 92%); the rest had MLFS as best response. The rate of measurable residual disease (MRD) negativity by flow cytometry prior to SCT was higher in the LIT with VEN group (69%), compared with IC (58%) and LIT without VEN (49%) (P = 0.14). The median number of cycles of chemotherapy prior to SCT was 3 in all groups. The median post-SCT follow-up was 37 months. The 2-year CIR was similar in pts who received IC or LIT with VEN (18% and 19%, respectively) and was highest in pts who received LIT without VEN (36%). The 2-year NRM was lowest in pts with LIT with VEN (11%), as compared with IC or LIT without VEN (27% and 22%, respectively) (P = 0.02 for IC vs. LIT with VEN). The 1-year post-SCT RFS for pts who received IC, LIT without VEN and LIT with VEN was 58%, 50%, and 75%, respectively, and the 2-year RFS was 54%, 42% and 62%. The 1-year post-SCT OS was 63%, 58%, and 84%, respectively, and the 2-year OS was 58%, 44% and 73%. OS was statistically superior for LIT with VEN compared with LIT without VEN (P = 0.02) and there was a trend towards superior OS with LIT with VEN compared to IC (P = 0.17). Conclusions: LIT with VEN was associated with similar rates of CIR and lower NRM compared with IC. Despite the older age of pts in the LIT with VEN cohort, their post-SCT survival outcomes were noninferior, and possibly superior, to those who received IC. These results suggest that LIT with VEN is a valid induction strategy for older SCT-eligible pts with newly diagnosed AML.

Impact of treatment intensity on infectious complications in patients with acute myeloid leukemia

BackgroundInfectious complications reflect a major challenge in the treatment of patients with acute myeloid leukemia (AML). Both induction chemotherapy and epigenetic treatment with hypomethylating agents (HMA) are associated with severe infections, while neutropenia represents a common risk factor. Here, 220 consecutive and newly diagnosed AML patients were analyzed with respect to infectious complications dependent on treatment intensity and antifungal prophylaxis applied to these patients.Patients and methodsWe retrospectively analyzed 220 patients with newly diagnosed AML at a tertiary care hospital between August 2016 and December 2020. The median age of AML patients undergoing induction chemotherapy (n = 102) was 61 years (25–76 years). Patients receiving palliative AML treatment (n = 118) had a median age of 75 years (53–91 years). We assessed the occurrence of infectious complication including the classification of pulmonary invasive fungal disease (IFD) according to the EORTC/MSG criteria at diagnosis and until day 100 after initiation of AML treatment. Furthermore, admission to intensive care unit (ICU) and subsequent outcome was analyzed for both groups of AML patients, respectively.ResultsAML patients subsequently allocated to palliative AML treatment have a significantly higher risk of pneumonia at diagnosis compared to patients undergoing induction chemotherapy (37.3% vs. 13.7%, P < 0.001) including a higher probability of atypical pneumonia (22.0% vs. 10.8%, P = 0.026). Furthermore, urinary tract infections are more frequent in the palliative subgroup at the time of AML diagnosis (5.1% vs. 0%, P = 0.021). Surprisingly, the incidence of pulmonary IFD is significantly lower after initiation of palliative AML treatment compared to the occurrence after induction chemotherapy (8.4% vs. 33.3%, P < 0.001) despite only few patients of the palliative treatment group received Aspergillus spp.-directed antifungal prophylaxis. The overall risk for infectious complications at AML diagnosis is significantly higher for palliative AML patients at diagnosis while patients undergoing induction chemotherapy have a significantly higher risk of infections after initiation of AML treatment. In addition, there is a strong correlation between the occurrence of pneumonia including atypical pneumonia and pulmonary IFD and the ECOG performance status at diagnosis in the palliative AML patient group. Analysis of intensive care unit (ICU) treatment (e.g. in case of sepsis or pneumonia) for both subgroups reveals a positive outcome in 10 of 15 patients (66.7%) with palliative AML treatment and in 15 of 18 patients (83.3%) receiving induction chemotherapy. Importantly, the presence of infections and the ECOG performance status at diagnosis significantly correlate with the overall survival (OS) of palliative AML patients (315 days w/o infection vs. 69 days with infection, P 0.0049 and 353 days for ECOG < 1 vs. 50 days for ECOG > 2, P < 0.001, respectively) in this intent-to-treat analysis.ConclusionThe risk and the pattern of infectious complications at diagnosis and after initiation of AML therapy depends on age, ECOG performance status and subsequent treatment intensity. A comprehensive diagnostic work-up for identification of pulmonary IFD is indispensable for effective treatment of pneumonia in AML patients. The presence of infectious complications at diagnosis contributes to an inferior outcome in elderly AML patients.

The Associations between Coping Strategy Use and Patient-Reported Outcomes in Patients with Acute Myeloid Leukemia

Background: Patients with acute myeloid leukemia (AML) who receive intensive chemotherapy must cope with immense physical and psychological symptoms associated with a variety of patient-reported outcomes (PROs) such as quality of life (QOL). Although coping is critical to the management of an AML diagnosis and its treatment, data characterizing the use of coping strategies and its associations with PROs in the AML population are limited. Hence, we characterize coping strategy use among patients with AML and examine the associations between coping strategy use, psychological distress, and QOL.Methods: We used cross-sectional secondary data analyses to describe coping in 160 patients with newly diagnosed high-risk AML enrolled in a multi-site randomized supportive care trial. We used the Brief COPE, Hospital Anxiety and Depression Scale (HADS), PTSD Checklist-Civilian Version (PCL-C), and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) within 72 hours of patient initiation of chemotherapy, to measure coping strategies, psychological distress and QOL, respectively. We grouped coping strategies into two higher-order domains of coping based on prior literature: approach-oriented coping (i.e., use of emotional support, active coping, positive reframing, acceptance) or avoidant coping (i.e., self-blame, denial, behavioral disengagement). We used the median split method for the distribution of coping domains. We used multivariate regression models adjusting for age, gender and diagnosis type (newly diagnosed vs. relapsed/refractory AML) to assess the relationship between coping and PROs.Results: Participants (median age of 64.4 years) were mostly non-Hispanic White (86.3%), male (60.0%), and married (73.8%). Most (51.9%) reported high utilization of approach-oriented coping strategies (e.g., emotional support) whereas 38.8% reported high utilization of avoidant coping strategies (e.g., denial) (Figure 1). At the time of AML diagnosis, use of approach-oriented coping was associated with less psychological distress and better QOL (Table 1). Use of avoidant coping was associated with more psychological distress and worse QOL. Additionally, patients who used multiple approach-oriented coping strategies had less psychological distress and better QOL (Table 2). In contrast, patients who used multiple avoidant coping strategies had more psychological distress, and worse QOL.Conclusions: Our study illustrates that most patients with high-risk AML utilize both approach-oriented and avoidant coping strategies. Our results also reveal links between approach-oriented coping strategies, less psychological distress, and better QOL. These findings underscore the need for early integration of supportive oncology interventions that help patients to cultivate approach-oriented coping strategies. [Display omitted] DisclosuresBrunner: Novartis: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Acceleron: Consultancy; Agios: Consultancy; Keros Therapeutics: Consultancy; GSK: Research Funding; Aprea: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding. Fathi: AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. LeBlanc: Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Pfizer: Consultancy, Other: Advisory Board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; UpToDate: Patents & Royalties; American Cancer Society: Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; Flatiron: Consultancy, Other: Advisory board; Astellas: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other; Jazz Pharmaceuticals: Research Funding; Duke University: Research Funding; Helsinn: Consultancy, Research Funding; Heron: Consultancy, Honoraria, Other: advisory board; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; Amgen: Consultancy, Other: travel.

Acute Myeloid Leukemia in the Context of Previous History of Cancer with or without Exposure to Chemotherapy or Radiotherapy

Background: Therapy-related acute myeloid leukemia (AML) is a well-described entity and known to carry a worse prognosis, compared to de novo AML. In the current study, we sought to describe the presenting features and outcome of patients with AML, in the setting of previous history of cancer with or without exposure to chemotherapy or radiotherapy.Methods: A Mayo Clinic database of patients with AML was queried to identify patients with a previous history of cancer, both hematologic and solid tumors. A comparative analysis of presenting features, treatment details and survival were performed between patients with therapy-related AML (Group A) and those with AML and a history of cancer that had been managed with surgery alone (Group B).Results: A total of 250 patients (median age 68 years, range 19-90; 60% males) with AML and a previous history of cancer (both hematologic and solid) were identified; 182 (73%) cases were determined to be therapy-related AML (Group A) while the remaining 68 (27%) did not receive chemotherapy or radiotherapy for their antecedent cancer (Group B) (Table). Among group A patients 106 (58%) were exposed to chemotherapy, 37 (20%) to radiotherapy and 39 (22%) to combination chemotherapy and radiotherapy for their cancer.At the time of AML diagnosis, adverse karyotype was noted in 91 (51%) group A and 12 (19%) group B patients (p<0.0001); the incidence of adverse karyotype in patients exposed to chemotherapy vs radiotherapy alone vs combined chemoradiotherapy was 54% (57/106), 30% (11/37), and 59% (23/39) respectively (p=0.04). Group A patients, compared to those in group B, included more females (46% vs 24%; p=0.001), and more preceding hematologic malignancies (p=<0.0001). Next generation sequencing was performed in 74 patients and the results showed no significant difference between groups A and B (Table).Treatment and outcome in Groups A and B: Intensive and less intensive AML-directed chemotherapy were given to 100 (55%) and 44 (24%) patients in group A and 38 (56%) and 14 (21%) patients in group B (P=0.8). 79 (65%) remissions (complete remission (CR) 42 (29%) and CR with incomplete count recovery (CRi) 37 (26%) were documented in Group A and 37 (71%) remissions (CR: 21 (40%) and CRi=16 (31%) in Group B (P=0.2). After a median follow-up of 8.4 months (range: 0.9-217), 184 deaths were documented: 132 (72.5%) in Group A and 52 (76.5%) in Group B (P=0.5). 52 (36%) patients from Group A and 25 (48%) from Group B relapsed (P=0.1).The median (range) overall survival (OS) rates of patients from Group A was 13 (9-17) months and that of Group B was 14 (10-35) months (P=0.6). The 1-, 3- and 5-year OS rates were 52%, 28%, and 24% in Group A; and 62%, 33%, and 24% in Group B patients (Fig 1). Multivariable analysis identified relapse (HR 2.8, 95% CI 1.7-4.7) and failure to achieve CR/CRi (HR 2.8 95% CI 1.9-4.7) as risk factors for inferior survival (Fig 2a and 2b). The median (range) relapse free survival of patients in Group A was 28 (17 -81) and that of Group B was 27 (14 - 76) months (P=0.9) (Fig 2c). 28 patients underwent allogenic stem-cell transplant (25 in CR1 and 3 in CR2), 23 in Group A and 5 in Group B; the 1-, 3-, and 5-year OS of patients who underwent allogenic stem cell transplant were 88%, 72%, and 72% regardless of the group (Fig 2d).Conclusion: The current study did not find significant differences between AML patients with previous history of cancer with or without exposure to chemo/radiotherapy, in terms of either response to AML-directed therapy or overall or relapse-free survival, despite a higher prevalence of adverse karyotype in therapy-related AML. [Display omitted] DisclosuresPatnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee.

IDH1/2 Mutations Are Maintained in a Subset of Patients with Acute Myeloid Leukemia in Complete Remission and Do Not Correlate with Residual Disease

Rationale: Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations may be the nearest signal to in vivo leukemogenesis that we are able to see in overt acute myeloid leukemia (AML). Without immediate transforming activity and slow, metabolism-related effect, IDH1/2 mutations may be considered within the early events that made a myeloid stem cell a malignant one.Methods: With the aim to investigate the behavior of IDH1/2 mutation in AML patients, we prospectively and longitudinally collected clinical data and samples of DNA extracted from bone marrow of consecutive patients. The study was approved by local Ethical Authority (012/2009/U/Tess, 01/2011/U/Tess, 10/2011/U/Tess and 253/2013/O/Tess). Droplet digital polymerase chain reaction (DdPCR) was performed with Bio-Rad's Qx200 DdPCR System© according manufacture instructions. DdPCR for all the samples were performed in duplicate. Serial dilutions were used to identify sensitivity limit of the method for each mutation included in the study.Results: We analyzed 106 samples from 23 patients (median of 5 samples per patient). At database cut-off, 19th September 2020, median follow-up was 23.8 months (IQR 19.5 - 38.8). Fourteen patients were female. Median age at AML diagnosis was 59 years (IQR: 47.5 - 66). Most of the patients had normal karyotype (15/23, 65%) and 1 patient (4%) received diagnosis of AML after a previous myelodysplastic syndrome. Five out of 22 patients tested (23%) harbored FLT3 ITD, 8/21 (38%) had a NPM1 mutation. Almost the entire population (20/23, 87%) received intensive chemotherapy as induction regimen and 55% of these patients obtained complete remission (CR) after induction. Ten out of 23 patients (45%) harbored an IDH1 mutation, 2/23 (9%) R132G and 8/23 (35%) R132H; 13/23 patients (57%) harbored an IDH2 mutation, 7/23 R172K, 1/23 (4%) R172S and 5/23 (22%) R140Q.Most of the samples were collected in complete remission (CR) (54.5%). Other samples were collected at the time of AML diagnosis (15.1%) or relapse/stable disease (37.3%). Median IDH1/2 fractional abundance was 45.3% (IQR 28.6 - 46.8) at diagnosis, 39.5% (IQR 29.5 - 48.0) at relapse/refractory, and .10 % (IQR: .05 - 17.24) in CR. Few cases showed a fractional abundance below 20% at relapse and only one case was IDH1 negative (during an extramedullary relapse).The fractional abundance of IDH1/2 mutation in CR present a bi-modal trend, allowing us to define 2 groups by k-means stratification. Patients in group 1 (42 samples) tend to have a mutation specific fractional abundance that varies with disease burden (figure B, blue box). On the contrary, at the different time points patients in group 2 (group center 45.58%, 12 samples) have fractional abundance values over 30%, comparable to the levels at diagnosis, even in the absence of any other evidence of AML (figure B, orange box).For NPM1, IDH1/2 positive patients, in 18 timepoints, NPM1 qPCR minimal residual disease (MRD) was compared with IDH1/2 fractional abundance selecting the best possible threshold (best possible threshold .083, predicted sensitivity 75%, predicted specificity 60%; R2= .763, 95% C.I.: .521 - .1.00; asymptotic significance = .062).Finally, we selected 15 patients in which we were able to determine IDH1/2 mutation fractional abundance after induction therapy. Our results indicate that IDH1/2 ddPCR positivity does not impact on prognosis in our patient set.Conclusion: Our study shows that IDH1/2 mutations are maintained throughout time in a subset of patients with IDH1/2 positive AML in CR and that they do not univocally correlate with levels of residual disease. In these AML patients, the persistence of IDH1/2 mutations may be part of a more complex process involving clonal hematopoiesis. In such setting, further studies on the biological and clinical significance of IDH1/2 mutations persistence are warranted. [Display omitted] DisclosuresMartinelli: Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Daichii Sankyo: Consultancy; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Incyte: Consultancy; Stemline Therapeutics: Consultancy. Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Impact of Transfusion Dependence on Outcomes of Patients with Acute Myeloid Leukemia (AML) Evolving from Myeloproliferative Neoplasms (MPNs)

Introduction: Secondary acute myeloid leukemia (AML) evolving in a patient who had a prior myeloproliferative neoplasm (MPN) is a challenging entity to treat, and associated with poor patient outcomes. The optimal approach to these patients is uncertain. In this study, we retrospectively assessed the outcomes of patients with an MPN evolving into AML, to determine factors that contribute to improved survival.Methods: We retrospectively identified adult patients at Massachusetts General Hospital and Icahn School of Medicine at Mount Sinai, who had a preceding Ph-negative MPN diagnosis (polycythemia vera, PV; essential thrombocythemia, ET; myelofibrosis, MF) and who subsequently developed AML. We collected information about baseline characteristics, mutational data, treatment history, and transplant status. Overall survival (OS) was from the time of AML diagnosis until death; patients were otherwise censored at last known alive. Patient characteristics were reported descriptively and compared using the Fisher and log rank tests; OS was estimated by the method of Kaplan and Meier.Results: We identified a total of 58 patients with an underlying MPN (PV n=14, ET n=26, MF n=13, other n=5) and subsequently diagnosed with AML between 2006-2016. The median age at the time of MPN diagnosis was 58 years, while the median age at AML diagnosis was 68 years (range 40-92). The median time from MPN diagnosis to AML was 9.1 years (range 0.3-36). More patients were male (59%), except those with prior ET (46% of subgroup). JAK2 status during MPN diagnosis was reported for 40 patients; 63% had a JAK2 V616F mutation (n=24) or exon 13 mutation (n=1). A total of 17 of 55 (31%) patients with transfusion history were transfusion dependent during their MPN diagnosis. Treatments for MPNs included hydroxyurea (n=38), anagrelide (n=9), lenalidomide (n=4), HMA (n=8), and ruxolitinib (n=11). A total of 2 patients underwent transplant for their MPN before progression to AML.At the time of AML transformation, 2 of 33 tested patients had FLT3-ITD mutations, both with prior ET. Patients had intermediate (37%) and poor risk (63%) karyotype at AML diagnosis. 2 patients had mutated NPM1 and 1 had mutated CEBPA . Of 44 patients with mutated JAK2 testing at AML diagnosis, 64% had a JAK2 V617F (n=27) or exon 13 (n=1) mutation. For patients with testing at both MPN and AML diagnosis (n=34), 1 patient had a newly identified JAK2 V617F mutation at AML diagnosis, while 2 patients with a JAK2- mutated MPN were wildtype at AML diagnosis. Upon transformation to AML, patients received induction chemotherapy (n=14), HMA (n=27), other therapy (n=5), went direct to transplant (n=2) or received supportive care alone (n=9); 1 patient did not have AML treatment history available. More patients achieved remission with induction (64%) than HMA (15%). Median OS from AML transformation was 5.8 months for the entire group, and of the 14 patients achieving CR, PFS was 14.9 months. Median OS varied per AML therapy: induction (8.3 mo), HMA (6.6), other therapy (8.8) and supportive care (1.4). There was no impact on whether a patient had received ruxolitinib previously for their MPN and on survival outcomes (p=0.28). Patients with TP53 mutations (n=3) had worse survival compared to WT (n=14, p=0.0279). Among all patients, median OS was better for those who achieved CR (not reached, p=0.0016). Patients with transfusion dependence were less likely to achieve CR (6% CR) and had worse OS compared to non-transfusion-dependent (median 7.3 vs 3.7 mo, p=0.033). Among patients not undergoing HCT, OS at 1 year post-AML transformation was 21% and median OS was 3.8 months.A total of 19 patients underwent transplant for AML, including 10/13 patients who achieved CR. At 1-y post-HCT, 54% of patients were alive. Patients who were in CR prior to transplant did not have a significantly improved OS compared to those without CR (p=0.30); however, those patients who were transfusion dependent prior to HCT had worse OS compared to non-transfusion dependent patients (Figure 1; median OS not reached vs. 4.mo, p=0.0010).Discussion: AML progression from a prior MPN represents an unmet clinical need. Survival is improved among patients who achieve a CR to AML therapy and those receiving transplant. In this study we also find that prior transfusion dependence during the MPN diagnosis is associated with poor OS among patients undergoing transplant, and may be a consideration in the pre-HCT evaluation. [Display omitted] DisclosuresBrunner:Celgene: Research Funding; Takeda: Research Funding. Mascarenhas:CTI Biopharma: Research Funding; Merck: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Novartis: Other: DSMB member , Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding.

A Single Arm, Phase II Study of Eltrombopag to Enhance Platelet Count Recovery in Older Patients with Acute Myeloid Leukemia (AML) Undergoing Remission Induction Therapy

A Single Arm, Phase II Study of Eltrombopag to Enhance Platelet Count Recovery in Older Patients with Acute Myeloid Leukemia (AML) Undergoing Remission Induction Therapy

Prevalence and Effects of Polypharmacy on Overall Survival (OS) of Acute Myeloid Leukemia (AML)

Introduction Polypharmacy, commonly defined as taking ≥5 prescribed medications, is a major issue in adults, especially those ≥60 years of age. Drug-drug interactions can significantly increase toxicities while undergoing chemotherapy, and may affect OS in AML. Polypharmacy can also increase treatment costs. We aimed to evaluate the effects of polypharmacy on OS in AML. Methods We included adult AML patients diagnosed from 2000-2016 at University of Nebraska Medical Center. Based on the number of prescribed medications at the time of AML diagnosis, patients were divided into 2 groups: patients with (≥5 medications) versus without polypharmacy (&lt;5 medications). Fisher's exact test was used to identify the association of polypharmacy with baseline characteristics. OS, defined as the time from diagnosis of AML to death from any cause, was determined by the Kaplan-Meier method, and comparisons of survival curves was done using the log-rank test. Cox proportional hazard model was used to determine the effect of polypharmacy on OS adjusting for other covariates for the entire cohort, and separately for &lt;60 years and ≥60 years old. Results We included a total of 399 patients in the study- 59% were ≥60 years, 52% were male, 96% were white, and 34% had adverse cytogenetics (Table 1). Median number of medications was 4 (range 0-39). Forty-nine percent of patients received ≥5 medications. In patients with polypharmacy, median number of medications was 8 (range 5-39) vs. 2 (range 0-4) among patients without polypharmacy. Patients with polypharmacy, compared to those without polypharmacy, were more likely to be ≥60 years (77% vs 42%, p&lt;0.0001), had Karnofsky performance status (KPS) of ≤80 (53% vs.26%, p&lt;0.0001) and adverse cytogenetics (41% vs 27%, p=0.01). Median hematopoietic cell transplant (HCT) comorbidity index (HCT-CI) was 2 (range 1-4) in the polypharmacy group vs 1 (range 1-4) in the group without polypharmacy (p&lt;0.0001). Patients with polypharmacy were less likely to receive intensive chemotherapy (56% vs 81%, p&lt;0.0001) and undergo HCT (17% vs 37%, p&lt;0.0001). Patients with polypharmacy had worse OS compared to those without polypharmacy (hazard ratio [HR] 2.1, (95% confidence interval [CI] 1.6-2.6], p=0.03) (Figure 1). One-year OS of patients with polypharmacy vs. those without polypharmacy was 29% vs 49% (p&lt;0.001) (Table 1). OS was significantly lower with polypharmacy in patients &lt;60 years of age (37% vs 65% at 1-year, p&lt;0.001) but similar in patients ≥60 years (26% vs 27% at 1-year, p=0.09) (Figure 2 and 3). In polypharmacy group, 1-year OS for patients ≥60 years was 26% compared to 37% for patients &lt;60 years (p=0.02). In two separate multivariate analyses, polypharmacy conferred worse OS in patients &lt;60 years of age (HR 1.9, 95% CI 1.2-3.1) but not in patients ≥60 years (HR 1.1, 95% CI 0.8-1.6). Conclusion Patients with polypharmacy were older and had greater incidence of adverse cytogenetics, and were less likely to receive intensive chemotherapy and HCT. While HCT CI was slightly greater in the polypharmacy group, the difference in HCT CI does not seem to be clinically remarkable for the degree of difference in the median number of medicines between groups. AML patients with polypharmacy, when adjusted for age, had worse OS than those without polypharmacy. In multivariate analysis based on the age cutoff of 60 years, polypharmacy had negative impact on OS of patients aged &lt;60 years but not on patients aged ≥60 years. While traditionally older adults are considered to be at a greater risk of polypharmacy, our study highlights that the effect of polypharmacy may be even more important in younger adults with AML. Given the impact of polypharmacy on OS, patients with newly diagnosed AML should be assessed for appropriateness of prescribed and over the counter medication. Disclosures Al-Kadhimi: Celldex Biotech: Other: Stocks; Seattle Genetics: Other: Stocks. Gundabolu:Pfizer: Consultancy; Novartis: Consultancy; Jazz pharmaceuticals: Consultancy; Samus Therapeutics: Research Funding. Bhatt:National Marrow Donor Program: Consultancy; Tolero Pharmaceuticals: Research Funding; Incyte: Consultancy, Research Funding; Partner therapeutics: Consultancy; Abbvie: Consultancy; Agios: Consultancy; CSL Behring: Consultancy; Pfizer: Consultancy.

Validation of the Khorana score in acute myeloid leukemia patients: a single-institution experience

BackgroundAlthough patients with acute myeloid leukemia (AML) were shown to have an increased risk of thrombosis, no thrombosis risk assessment scoring system has been developed for AML patients. The Khorana Risk Score (KRS), which has been widely used for thrombosis risk assessment in the clinical setting, was developed on the basis of solid tumor data and has not been validated among AML patients. This study aims to validate the use of the KRS as a thrombosis risk-scoring system among patients with AML.MethodsUsing data from H. Lee Moffitt Cancer Center and Research Institution’s Total Cancer Care Research Study, we retrospectively identified patients who were histologically confirmed with AML from 2000 to 2018. Clinical and laboratory variables at the time of AML diagnosis were characterized and analyzed. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using the log-rank test.ResultsA total of 867 AML patients were included in the analysis. The median age at AML diagnosis was 75 years (range, 51–96), and the majority were male (65%, n = 565). A total of 22% (n = 191), 51% (n = 445), 24% (n = 207), and 3% (n = 24) of patients had a KRS of 0, 1, 2, and 3, respectively. A total of 42 thrombotic events (3% [n = 6/191] with a KRS of 1; 5% [n = 23/445] with a KRS of 2; 6.3% [n = 13/207] with a KRS of 3) were observed, with a median follow-up of 3 months (range, 0.1–307). There was no statistical difference in the risk of thrombosis between these groups (P = .1949).ConclusionsAlthough there was an increased risk of thrombosis associated with a higher KRS among AML patients with a KRS of 1 to 3, the difference was not statistically significant. Furthermore, only a few patients were found to have a KRS > 3, and this was largely due to pancytopenia, which is commonly associated with AML. These results indicate the need for a better thrombotic risk-scoring system for AML patients.

Effects of obesity on overall survival (OS) of patients with acute myeloid leukemia (AML).

e18510 Background: The relationship between obesity and prognosis of AML has not been established. Our retrospective study aimed to determine the effect of obesity on OS of AML. Methods: AML patients diagnosed from 2000-2016 at University of Nebraska Medical Center were included. Body mass index (BMI) at the time of AML diagnosis was divided into 3 groups: normal (18.5≤25 kg/m2) or underweight (&lt;18.5 kg/m2); over-weight (25-30 kg/m2); and obese (≥30 kg/m2). Chi-square test, Kruskal-Wallis test and ANOVA were used to look at the association of different BMI groups with other patient characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplant (HCT) co-morbidity index and Bonferroni correction was used to adjust p-values. OS, defined as time from diagnosis to death from any cause, was determined by Kaplan-Meier method and comparisons were done using log-rank test. Cox Regression was performed to detect survival effect of BMI (as continuous variable). P&lt;0.05 was considered statistically significant. Results: A total of 314 patients were included in the study (Table): 46% were female, 35% had adverse cytogenetics, 15% had FLT3-ITD mutation, 68% received intensive chemotherapy and 30% underwent HCT. 38% of total patients were obese. Baseline characteristics were similar in all 3 BMI groups except co-morbidity index (p=0.04). OS for normal/underweight, overweight and obese groups at 1 year was 85%, 92%, and 94% respectively (p=0.84). BMI, as a continuous variable, was not a significant risk factor for death (HR 1.00, 95% CI 0.98-1.03). Conclusions: Obese patients, compared to non-obese patients, did not differ in baseline characteristics other than increased comorbidity burden. Obesity, when adjusted for other characteristics, did not have any effect on OS of patients with AML. Patient characteristics. [Table: see text]

Validation of the Khorana Score in Acute Myeloid Leukemia Patients: A Single Institution Experience

INTRODUCTION: Both solid and hematologic malignancies are associated with an increased risk of thromboembolic events, according to previous studies. One of the most common risk scoring systems was developed based on type of non-hematologic cancer, body mass index (BMI), WBC, hemoglobin, and platelet counts. However, compared to other solid tumors, acute leukemia patients commonly present with pancytopenia at the time of diagnosis and the Khorana Risk Score (KRS) has not been validated in patients with acute myeloid leukemia (AML). The goal of our study was to validate the KRS in AML patients.METHODS: Using Total Cancer Care (TCC), we retrospectively identified histologically confirmed AML patients from 2000 to 2018. Clinical and laboratory variables including age, gender, previous cancer history, use of growth factors, underlying coagulopathy, white blood cell counts, hemoglobin, and platelet counts were characterized at the time of AML diagnosis and annotated using descriptive statistics. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using log-rank test. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7.RESULTS: A total of 867 AML patients were included in this study. The median age at AML diagnosis was 75 (51-96) years and male patients were 65% (n=565). A total of 28% (n=241) patients had prior cancer history (hematologic malignancies, n=34; solid tumor, n=207). A total of 12% (n=101), 7% (n=58), and 1% (n=8) patients had EPO, G-CSF, GM-CSF treatment prior to AML diagnosis and 84% (n=728) patient were treated with any typed of growth factors after AML diagnosis. The median BMI was 27.1 (14.8-103) and 5% (n=47) patients had BMI higher than 35. A total of 26% (n=229) patients had WBC ≥11 x109/L (median 3.165 (0.08-413.74) x109/L), 67% (n=584) patients had hemoglobin <10 g/L (median 9.3 (5.6-15.2) g/L, 1% (n=10) patients had platelet >350 x109/L (median 46 (1-800) x109/L). A total of 22% (n=191) patients had Khorana score 0, 51% (n=445) patients had score 1, 24% (n=207) patients had score 2, and 3% (n=24) patients had score 3, respectively. A total of 42 thrombotic events were observed in the median follow up of 3 (0.1-307) months. Among these, a total of 3% (n=6/191), 5% (n=23/445), 6.3% (n=13/207), and 0% (n=0/24) thrombotic events occurred in patients with Khorana sore 0, 1, 2, and 3, respectively. Log-rank (Mantel-Cox) test showed no statistical difference between individual subgroup (p=0.1949).CONCLUSIONS: In AML patients, there was a higher incidence of thrombotic events in patients with higher Khorana score though the difference was not statistically significant. The proportion of patients with Khorana score ≥3 was relatively low, which could be due to pancytopenia, a common presentation in AML patients. These results suggest that the development of better thrombotic risk scoring system is warranted in patients with AML. [Display omitted] DisclosuresKomrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

P53 protein overexpression in de novo acute myeloid leukemia patients with normal diploid karyotype correlates with FLT3 internal tandem duplication and worse relapse-free survival.

Although ~50% of acute myeloid leukemia (AML) patients have a normal diploid karyotype by conventional cytogenetics at diagnosis, this patient subset has a variable disease course and outcome. Aberrant overexpression of the p53 protein is usually associated with TP53 alterations and a complex karyotype, but the prevalence and impact of p53 overexpression in AML with diploid cytogenetics is unknown. We examined 100 newly diagnosed AML patients to evaluate the impact of p53 expression status quantified in bone marrow core biopsy samples using immunohistochemistry and computer-assisted image analysis. A total of 24 patients had p53 overexpression defined as 3+ staining intensity in ≥5% of cells; this finding correlated with lower platelet counts (P = .002), absence of CD34 expression in blasts (P = .009), higher bone marrow blast counts (P = .04), and a higher frequency of FLT3 internal tandem duplication (P = .007). Overexpression of p53 independently predicted for shorter leukemia-free survival in patients who underwent allogeneic stem cell transplantation by univariate (P = .021) and multivariate analyses (P = .004). There was no correlation between MDM2 and p53 protein expression in this cohort. We conclude that p53 expression evaluated by immunohistochemistry in bone marrow biopsy specimens at the time of AML diagnosis may indicate distinct clinical characteristics in patients with normal diploid cytogenetics and is a potentially valuable tool that can enhance risk-stratification.

Novel Risk Factors for Predicting the Development of Invasive Fungal Infections in Acute Myeloid Leukemia Patients Undergoing Induction and Re-Induction Chemotherapy

BACKGROUNDInvasive fungal infections (IFI) occur in 5% to 40% of patients with hematologic malignancies, most commonly in patients with acute myeloid leukemia (AML). Historically, at the University of Virginia (UVA), antifungal prophylaxis was not routinely used in patient undergoing induction chemotherapy for AML. With an antifungal treatment naïve patient cohort, this study had the unique opportunity to examine if specific patient characteristics, comorbidities, or diagnostic criteria were predictive for the development of an IFI. METHODSA retrospective chart review of 126 consecutive patients undergoing induction or re-induction chemotherapy for AML at UVA from July 2011 to December 2015 was conducted. The primary endpoint was to determine the rate of probable or biopsy proven IFIs within ninety days of chemotherapy initiation as characterized by the European Organization for Research and Treatment of Cancer/Invasive Fungal Cooperative Group and the National Institute of Allergy and Infectious Disease Mycoses Study Group criteria. Secondary endpoints include patient comorbidity and disease specific indices associated with IFI. Each induction or re-induction regimen was counted as a distinct event. Statistical methods include pairwise Wilcoxon tests, univariate analyses, and Kruskal-Wallis tests. Statistical significance was defined as a p-value <0.05. RESULTSOf 126 patients, there were a total of 176 distinct induction or re-induction events. Thirty-eight patient events (22%) received antifungal prophylaxis with fluconazole per attending physician preference. In patients (n=102, 81%) who did not receive antifungal prophylaxis during induction, there were a total of 19 (19%) patients with probable/proven IFI. There was a significant association with probable/proven IFI in regards to decreased bone marrow cellularity (p-value 0.018). There were no correlations between probable/proven IFI and body mass index, age of diagnosis, gender, nicotine abuse, length of neutropenia, cytogenetics, and bone marrow blast percentage. In the antifungal prophylaxis cohort, 3 patients (8%) had probable/proven IFI.Another aspect reviewed is the potential concept of an immune reserve ratio (IRR). The IRR is the percentage of the bone marrow core cellularity divided by blasts - representing the bone marrow functionality at the time of leukemia diagnosis or relapse. IRR was 1.9 vs 1.4 vs 1.2 (p-value 0.038) for none vs possible vs probable/proven IFI cohorts. DISCUSSIONThis study reveals that decreased bone marrow cellularity and decreased IRR may be used to predict which AML patients undergoing induction chemotherapy are at higher risk of developing an IFI. Traditional risk factors, such as tobacco use, length and degree of neutropenia, were not found to be significant in this review. Other patient co-morbidities, such as hypertension, COPD, and chronic kidney disease, and AML disease specific characteristics, such as cytogenetic and bone marrow blasts, also did not demonstrate clinical significance.To date, studies have not developed a method to quantify a patient's immune reserve at the time of AML diagnosis and risk of IFI. The IRR attempts to use the ratio of bone marrow cellularity and blasts as a surrogate marker of functional immune activity. This review suggests that the IRR is highly correlative of IFI development. Future studies need to be performed to validate this prospectively. UVA is currently conducting a prospective clinical trial examining the utility of IRR to predict IFI in adults with AML induction chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Impact of the Difference in Body Mass Index at Transplantation from That at Diagnosis for Graft-Versus-Host Disease-Free, Relapse-Free Survival in Acute Myeloid Leukemia

Introduction: Consistent with more direct measures of body fat, body mass index (BMI), defined as a personfs weight in kilograms divided by the square of his height in meters (kg/m2), is strongly correlated with various adverse health outcomes. Recent studies have reported the prognostic benefits of higher BMI at diagnosis in acute myeloid leukemia (AML). However, there are few reports on the prognostic impact of BMI classification and post-remission therapy, including hematopoietic stem cell transplantation (HSCT). Although some studies have reported worse outcomes related to lower BMI at transplant, there are no studies on the prognostic impact of the difference-BMI (d-BMI) between time of transplant and time of AML diagnosis. We hypothesized that lower BMI at transplant and reductions in BMI from diagnosis are associated with worse survival outcomes, including graft-versus-host disease-free survival, relapse-free survival (GRFS), which is currently defined as a novel composite endpoint in the first post-HSCT year.Patients and Methods: We identified 369 patients from January 2000 to March 2015 newly diagnosed with adult AML who had been administered daunorubicin or idarubicin in combination with cytarabine as induction chemotherapy (IC) at any of the seven Japanese hospitals that collaborate to form the Yokohama Cooperative Study Group for Hematology. Patients with acute promyelocytic leukemia, myeloid sarcoma, and aged 66 years or more were excluded from this study. For adjustment treatment intensification, patients who had over 20% reduction in actual dosage of IC were also excluded. In this study model, 184 patients were eligible for HSCT. According to the classification of obesity by the World Health Organization, underweight patients were characterized by BMI of <18.5 kg/m2, normal weight by BMI of 18.5-25 kg/m2, overweight by BMI of 25-30 kg/m2 and obese by BMI of >30 kg/m2. d-BMI was calculated as BMI at the time of transplant subtracted from BMI at the time of diagnosis, which reflects constructive changes in body structure due to intensive chemotherapy. Based on the ranges of d-BMI, patients were divided into three groups: under −2, between −2 and +2, and over +2. We analyzed overall survival (OS), disease-free survival (DFS), and GRFS in different BMI groups at transplant and in d-BMI groups.Results: This study included 115 males and 69 females, with median age of 43 years (range, 17-65 years) at diagnosis. In BMI classification at transplant, 29 patients were underweight, 116 were normal weight, 30 were overweight, and nine were obese. At transplant, median BMI was 22.1 kg/m2 (range, 14.8-33.2 kg/m2) and median d-BMI was −0.39 (range, −7.9-+10.0). There were no significant differences in basement characteristics of patients at transplant and in each BMI and d-BMI group. Survival outcomes were observed with a median follow-up period of 1081 days (range, 8-5230 days). At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). There was no significant association between BMI at transplant and survival outcomes. GRFS at 1 year for the d-BMI groups under −2, between −2 and +2, and over +2 was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067) (Figure 1). Multivariate analysis showed that a worse GRFS was associated with lower BMI at transplant than that at diagnosis (d-BMI < −2) (HR 2.72, 95% CI, 1.47-5.03, P = 0.015) and the other prognostic factors of performance status (PS) and disease risk.Conclusions: Our results showed that among 184 AML patients who underwent HSCT for the first time, those with d-BMI < −2 had worse GRFS. [Display omitted] DisclosuresFujita:Chugai Pharmaceutical Co.,LTD: Honoraria.