bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and prognosis of BRCAm, homologous recombination repair mutation (HRRm) or HR deficiency positive (HRD+) across tumor types.
Authors: Shao Changxia , Ren Yixin , Zhou Heng , Chen Cai , Dettman Elisha , Cristescu Razvan , Gozman Alexander , Jin Fan , Zhou Wei
Published: June 2022

e18802

Background: BRCAm, HRRm, or HRD+ may be predictive of response to poly (ADP-ribose) polymerase inhibitors (PARPi) with/without immunotherapy (IO). However, there is limited data on the prevalence of these biomarkers and their impact on overall survival (OS) among patients who are not treated with PARPi or IO. Methods: This is a retrospective observational study across 15 available tumor types, using data from the de-identified Flatiron Health - Foundation Medicine (FMI) clinicogenomic database collected up to Dec 31, 2020. The de-identified data originated from ̃280 US cancer clinics (̃800 sites of care). Eligible patients were aged ≥ 18 years, diagnosed with advanced/metastatic solid tumors in 2018-2019. BRCAm, HRRm, and HRD were assessed by FMI F1CDx. HRD+ was defined as genomic loss of heterozygosity (gLOH) ≥16. OS analysis from second line therapy initiation (2L, primary index date) was performed as primary analysis since this population had high unmet medical need, and most patients were sequenced after 1L. Patients were excluded if PARPi/IO started on the index date or earlier or if patients died before the index date; and patients were censored as of PARPi/IO initiation if PARPi/IO was started later than the index date. OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusted for age, sex, and tumor type. Results: A total of 9,462 patients with advanced/metastatic solid tumors were included, with 52% women and mean age of 66 years. The top five tumor types represented more than 75% of the patients, including non-small cell lung cancer (27%), colorectal (19%), breast (13%), pancreatic (8%) and gastric (8%) cancers. Known or suspected deleterious BRCAm was observed in 4.6% of patients across tumors and varied by tumor type, with the highest prevalence in ovarian cancer (13.0%). Total HRRm prevalence was 13.2% across tumor types with prostate cancer (25.9%) as the highest, and the prevalence of HRD+ was 20.6% cross tumor types with breast cancer (34.4%) as the highest. The adjusted hazard ratio (aHR) for OS from initiation of 2L therapy for patients with BRCAm vs BRCA wild type (BRCAwt) was 0.81 (95%CI, 0.61-1.07). Comparable results were observed when calculating OS from 1L or 3L therapy. The aHR of OS from 2L therapy with HRRm vs HRRwt was 0.92 (0.78-1.09) and 1.20 (1.01-1.43) for patients with HRD+ vs HRD negative (HRD-). Conclusions: The prevalence of BRCAm, HRRm, and HRD+ varies widely by tumor type. There was no association between BRCA/HRRm status and OS, yet HRD+ might be associated with shorter OS among patients who were not treated with PARPi or IO across the evaluated tumor types.[Table: see text]
Breakthrough COVID-19 cases and hospitalization risk: ASCO COVID-19 registry.
Authors: Bruinooge Suanna Steeby , Kurbegov Dax , Kaltenbaugh Melinda , Hanley Williams Jen Hanley , Gralow Julie R. , Garrett-Mayer Elizabeth
Published: June 2022

e18807

Background: The ASCO Registry was created to analyze the impact of COVID-19 (COVID) on treatment (Tx) and outcomes of patients (pts) with cancer. Vaccination questions were added in 2021, enabling examination of breakthrough cases  i.e., SARS-CoV-2 infection after vaccination. Methods: The Registry includes pts who test positive for SARS-CoV-2 and have clinically evident cancer receiving Tx or resected cancer on adjuvant Tx <12 months since surgery at the time of the positive test. Practices report data on COVID vaccine type and dates, positive SARS-CoV-2 test date, and subsequent Tx. Breakthrough cases were defined as 1) > 35 days after 1st Pfizer dose, 2) > 42 days after 1st Moderna dose, 3) > 14 days after 1st Janssen dose, or 4) > 42 days after 1st unknown vaccine dose. Data submission cutoff for all practices was February 2, 2022. Summary statistics and exact binomial 95% confidence intervals (CIs) were calculated. Results: This analysis reports on 231 pts with breakthrough cases. Median age is 68 years and 57% of pts are over age 65. Of 73 pts with non-metastatic solid tumors, 19% were hospitalized. Of 74 with metastatic solid tumors, 39% were hospitalized. Of 75 with B-cell malignancies, 32% were hospitalized. Of 9 with other hematologic malignancies, 56% were hospitalized. While the fraction of patients in the ASCO registry with breakthrough cases who were hospitalized remained fairly constant throughout 2021 (approximately 40%), those with breakthrough cases occurring in the last month of 2021 and early 2022 had a lower hospitalization rate (approximately 20%), which is consistent with less severe cases of COVID-19 in patients infected with the omicron variant (the predominant variant in the US in Dec 2021- Jan 2022) (Table). The majority of breakthrough cases occurred more than 6 months after initial vaccination (71%) and the median time to breakthrough infection from initial vaccination was 7.3 months (IQR: 5.6  9.9). The Registry continues to accrue cases and additional vaccine data; analysis will be updated with most current vaccination data for possible Annual Meeting presentation. Conclusions: Hospitalizations among patients with cancer and breakthrough COVID in the ASCO Registry occur at a high rate, particularly among patients with advanced cancers and hematologic malignancies. This decrease in recent months is likely due to increased incidence of the Omicron variant that resulted in milder COVID symptoms among those infected. A majority of SARS-CoV-2 infections occurring six months or more after vaccination suggests waning vaccine efficacy over time that could be impacted by additional doses.[Table: see text]
Real-world healthcare resource utilization and costs among patients with multiple myeloma in the United States.
Authors: Gupta Niodita , Tai Ming-Hui , Kaila Shuchita , Thompson-Leduc Philippe , Ghelerter Isabelle , Kurteva Siyana , Lefebvre Patrick , Lafeuille Marie-Hélène
Published: June 2022

e18811

Background: The economic burden of multiple myeloma (MM) has been shown to increase with more advanced lines of therapy (LOTs). Given the rapidly evolving treatment landscape of MM, this study aimed to describe the current real-world healthcare resource use (HRU) and costs among patients with MM across LOTs. Methods: A commercial insurance claims database was used to identify patients with ≥2 MM diagnoses who initiated a LOT containing an antineoplastic agent for MM between 1/2016 and 2/2021, had continuous insurance coverage ≥6 months before and ≥60 days after first line (1L) initiation, and never received stem cell transplant. LOTs were defined based on agents used within a 60-day period. End of LOT was defined when patients switched treatment, or after a treatment gap of 90 days. HRU and costs (in 2021 USD) were reported for the duration of each LOT (from initiation of LOT to initiation of a subsequent LOT or end of coverage). Results: 1492 patients initiated 1L, 681 initiated 2L, 359 initiated 3L and 188 initiated 4L. Mean age at 1L initiation was 66.6 years. Mean duration of LOT (10.7, 9.4, 8.1 and 10.2 months in 1L, 2L, 3L and 4L, respectively) was longer in 1L than in subsequent LOTs. All-cause monthly outpatient (OP) and inpatient (IP) visits were stable across LOTs (5.0-5.6 OP visits; 0.21-0.32 IP visits). However, mean monthly all-cause costs were lowest in 1L (15.9% - 34.9% lower) as compared to subsequent LOTs ($23.6K in 1L, $29.7K in 2L, $27.3K in 3L and $31.8K in 4L; Table). Conclusions: In this study, the duration of LOT was the longest among 1L patients. Total all-cause healthcare costs were the lowest in 1L than in more advanced LOTs. This suggests that selection of 1L best treatment regimen upfront that prolongs time to disease progression could reduce the overall economic burden of MM.[Table: see text]
Impact of preauthorization review on oncology drug and radiation costs.
Authors: Talcott James Austin , Salmon-Gardell Megan , Kozlovsky Vlad , Yedwab Erik , Boehringer Traci , Avery Tiffany P.
Published: June 2022

e18829

Background: Preauthorization review (PR) is designed to ensure that patients receive evidence-based medicine (EBM) treatment but also affects costs. We estimated changes in chemotherapy and radiation costs when PR found treatments to deviate from EBM. Methods: We identified chemotherapy and radiation treatment plans reviewed by Eviti Connect in 2020 found to contain medically unjustified deviations from EBM after a request for peer-to-peer discussion. We calculated the cost difference in antineoplastic and supportive drugs and radiation procedures between deviating plans and any approved replacements. We assumed completion of curative drug regimens and 4 months duration for non-curative treatments. Results: We report net change in treatment costs for all patients with plans reviewed. Of 13,370 patients with reviewed plans, 1-4 deviating plans were identified for 1899 patients (14.2%), or 2160 deviating plans. Mean savings were $38,242 (95%CI $35,354 - $41,118) per patient with a deviating plan, $33,097 (95%CI $30,851- $35,343) per deviating plan, and $5,348 per patient with a plan reviewed. Inflation-adjusted per patient savings were 27% greater than we reported in 2012. Total savings were $71,497,374. Applying these results to a covered population of 1 million, assuming 0.3% undergo PR annually, would save $16,041,000. Provider appeals were submitted for 2.2% of cases found deviating and 0.3% were upheld. Conclusions: PR directly ensures EBM cancer care by identifying deviating treatments and reduces treatment costs. This analysis likely underestimates realized savings because it includes only drug and radiation procedure costs; noncurative treatments often extend beyond 4 months; and provider experience with PR may deter submitting treatments previously determined to be deviating.
Treatment patterns and medical costs of metastatic breast cancer care in the United States.
Authors: Jaber Chehayeb Rachel , Hood Annette , Mougalian Sarah Schellhorn , Lustberg Maryam B. , Wang Shi-Yi , Greenup Rachel Adams , Pusztai Lajos , Kunst Natalia
Published: June 2022

e18834

Background: Substantial advances in treatment of metastatic breast cancer (mBC) have led to changes in clinical practice and treatment costs in the United States in the past decade. We aimed to identify treatment patterns in mBC patients by subgroup and year after mBC diagnosis and associated costs from payer and societal perspectives. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database (1/2011-5/2021). We excluded cases that were male, had < 6 months of follow up, no treatment data, no structured data within 90 days of diagnosis, participated in clinical trials, had non-breast invasive cancers, received therapies not used in mBC, had no data on human epidermal growth factor (HER2) and hormone receptor (HR) status. We classified patients into four subgroups: HER2-HR+, HER2+HR+, HER2+HR-, and Triple Negative (TNBC). We calculated anti-cancer and supportive drug costs at the patient level and mean costs by year after diagnosis for each subgroup. We used average wholesale prices (AWP, from McKesson Corporation) for payer perspective and Medicare prices (part B payment limit data, Part D Drug Spending Dashboard) for societal perspective. We estimated costs up to year 5 after diagnosis of mBC (< 8% received treatment after year 5). Results: 15,215 patients met the criteria (64.41% non-Hispanic White, 66.85% HER2-HR+, 18.30% HER2+HR+, 5.27% HER2+HR-, 9.58% TNBC). AWP and Medicare cost estimates by year after diagnosis and subgroup are shown in Table. 334,812 for HER2+HR+, $284,609 for HER2+HR-, $104,774 for HER2-HR+, and $54,355 for the TNBC. We observed an increase in annual costs between years 2011-2021 in most subgroups. This increase was most substantial for HER2-HR+ patients. From 2011 to 2019 (most recent complete year 1 data is for patients diagnosed in 2019), annual Medicare treatment costs in year 1 increased from $12,986 to $80,563 for HER2-HR+, $99,997 to $156,712 for HER2+HR+, and $31,397 to $53,775 for TNBC. There was no increase in costs of treating HER2+HR- in year 1, but an increase in year 2 (from $90,427 to $129,690 between 2011-2019). Conclusions: mBC treatment costs vary significantly by receptor subtype and years after diagnosis. Annual costs increased over time. Costs were greatest for HER2+ and lowest for TNBC.[Table: see text]
Determination of direct treatment costs of patients with metastatic and nonmetastatic castration-resistant (mCRPC, nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in Colombia.
Authors: Niño Rafael , Restrepo-Miranda Diego , Amezquita Miguel Alberto , Lancheros Jeisson , Corredor Lina Maria , Medina Yudy , Aguirre Andres
Published: June 2022

e18838

Background: The purpose of this study was to determine the direct costs associated with the management of patients with metastatic castration resistant (mCRPC), non-metastatic (nmCRPC) and metastatic hormone-sensitive (mHSPC) prostate cancer in the Colombian healthcare system. Methods: First, a literature review was carried out to identify the main clinical recommendations for the treatment and follow-up of patients with prostate cancer at local and international levels. Subsequently, a participation process was developed with clinical experts, through a modified Delphi panel, to validate the natural history of the disease, and identify treatment options, skeletal-related events management, resource utilization, and distribution of patients within stages. Based on the above, a cost analysis model was performed, using Colombian health technology assessment agency recommendations, to calculate direct cost of treatment for mCRPC, nmCRPC and mHSPC from payer’s perspective. Exchange rate used was USD $1 = COP $4,000. Finally, the results were estimated considering the cost per patient per year. Results: According to the cost analysis of each stage, in the non-metastatic castration resistant stage (nmCRPC) the associated yearly cost of a patient was lower than in the metastatic castration resistant stage (mCRPC) (USD $8,581 versus $24,590, respectively), with a difference of USD $16,008. The metastatic hormone-sensitive stage (mHSPC) had a lower yearly cost than the metastatic castration-resistant stage (mCRPC) (USD $15,030 versus $24,590, respectively), with a difference of USD $ 9,559. The event that generated the greatest impact on the cost is the incidence of skeletal-related events associated with disease metastasis (55%). The deterministic sensitivity analysis on key variables, such as the percentage of patients who responded to treatment and the incidence of skeletal-related events, showed consistency of results. Conclusions: Delaying or stopping disease progression to mCRPC could more than halve annual treatment costs for patients. Given the findings, advanced metastatic castration resistant stages demand more resource utilization associated with disease management. The Colombian healthcare system would benefit from risk management strategies that implement timely interventions associated with early diagnosis and screening. In this way, the resource utilization in health sector's institutions would be directly impacted through budget optimization, obtaining better results focused on the national follow-up indicators of the prostate cancer patient cohort.
Cyclin-dependent kinase 6 body methylation and association with prognosis of patients with acute myeloid leukemia.
Authors: Zhang Lei , Ma Rui , Yu Qingxiang , Sun Lihua
Published: June 2022

e19000

Background: Cyclin-dependent kinase 6 (CDK6) plays critical roles in leukemogenesis and leukemia stem cells activation, and its inhibition has emerged as a novel therapeutic strategy in acute myeloid leukemia (AML) management. However, association between CDK6 methylation and prognosis in patients with AML remains unclear. Methods: Methylation profile, somatic alterations, and CDK6 gene expression data of 200 clinically annotated patients with de novo AML were retrieved from the TCGA Pan-Cancer Atlas project deposited in the UCSC Xena database. Specifically, methylation levels of all 64 CpGs across CDK6 were extracted, and then methylation abundances of promoter and gene body regions were calculated as average levels of CpGs located in the respective regions. Patients were categorized into two subgroups (hypo- and hyper-methylated) as per the median methylation level for either region or single CpG site. Log-rank tests were conducted to compare overall survival (OS) of patients stratified by methylation status. A Cox proportional hazards model was fitted to control confounding factors, including age, white blood cell count, cytogenetic risk classification (favorable, intermediate, and poor risk), and TP53 mutations, as reported previously. Associations of methylation status with cytogenetic risk and somatic alterations were examined using the Wilcoxon and Kruskal-Wallis rank sum tests, respectively. Spearman rank correlation coefficient ( R) was used to evaluate correlations between methylation and expression. Results: Of the 200 patients, 109 (54.5%) were men, and median (interquartile range [IQR]) age was 57.5 (44.75-67) years. Median (IQR) methylations of promoter and body were 5.2% (4.8%-5.7%) and 55.6% (53.7%-57.9%), respectively. Body methylation was observed to correlate with gene expression ( R, -0.22; P = .005), but not promoter methylation. In Kaplan-Meier analysis, low methylation of body rather than promoter predicted prolonged OS (median, 27.4 vs 9.2 months; hazard ratio [HR], 0.43; 95% CI, 0.29-0.63; P < .001). Notably, the OS improvement persisted with multivariable Cox model adopted (HR, 0.64; 95% CI, 0.42-0.98; P = .038). In addition, the body hypomethylation was strongly associated with early age, favorable cytogenetic risk, mutations in TP53, NPM1, and IDH1/ 2, as well as PML- RARA and MYH11- CBFB fusions (all P < .05). Further analysis identified that cg08300570, cg09653641, cg10481072, and cg13590558 in the body were all prognostic for OS (all P < .05). Intriguingly, all these CpGs resides in the enhancer. Conclusions: This is the first study to unravel clinical significance of CDK6 body methylation in AML, and it may serve as an independent prognostic marker. Given that azacitidine and decitabine are widely used, our findings may have implications for combination therapy of CDK4/6 inhibitors with hypomethylating agents in AML. Prospective studies are warranted.
Clinicopathologic characteristics and treatment outcomes of de novo myeloid sarcoma.
Authors: Kuhlman Justin J. , McCormick Benjamin J. , Badar Talha , Foran James M. , Abdel Rahman Zaid H. , Murthy Hemant S.
Published: June 2022

e19002

Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p < 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]
Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia.
Authors: Sumbly Vikram , Landry Ian , Iqbal Qamar , Rehman Mohammad Ebad Ur , Chattaraj Asmi , Aijaz Zobia , Khattak Zoia Ehsan , Anwer Faiz
Published: June 2022

e19006

Background: Acute myeloid leukemia (AML) is a neoplasm that is defined by the uncontrolled growth of myeloid progenitor cells. It is the most common form of acute leukemia in adults and is associated with poor outcomes in patients ≥ 75 years. Multiple antibody-drug conjugates (ADCs) are being investigating for their benefits in AML. Methods: A search was performed on PubMed, Cochrane, Scopus, Web of Science and ClinicalTrials.gov using the PRISMA guidelines. After screening 1,806 articles, a total of eight studies were included for this review. Results: Montesinos et al. gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm. Uy et al. studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose. Ho et al. noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine. Feldman et al. observed that the ORR was higher in the lintuzumab (anti-CD33 antibody) + chemotherapy arm than control arm (36% vs 28%). Daver et al. and Vey et al. both studied lirilumab (anti-KIR antibody), but Daver et al. reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm. In a separate study, Daver et al. administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70). Zeidan et al. reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%). A summary of the adverse events was provided below (Table). Conclusions: Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.[Table: see text]
Racial disparities in patients with TP53 mutated acute myeloid leukemia.
Authors: Badar Talha , Litzow Mark Robert , Shallis Rory , Stahl Maximilian , Bewersdorf Jan Philipp , Saliba Antoine N , Sacchi de Camargo Correia Guilherme , Patel Anand Ashwin , Abaza Yasmin , Guru Murthy Guru Subramanian , Duvall Adam , Burkart Madelyn , Al-Kali Aref , Palmisiano Neil , Dinner Shira , Goldberg Aaron David , Atallah Ehab L.
Published: June 2022

e19007

Background: While clinical outcomes of patients (pts) with TP53 mutated (m) acute myeloid leukemia (AML) are dismal, subsets of pts with eligibility to curative intent therapies can do better. As racial disparities are known to impact outcome in hematological malignancies, we sought to explore disparities in TP53m AML. Methods: We conducted a multicenter study of 304 TP53m AML pts, divided into 2 groups, White (n= 240) and Black/Hispanic (n=64), to compare difference in disease characteristics and clinical outcome. We grouped Black and Hispanic together as the number of pts were small in each group and our aim was to evaluate outcome in under-represented races/ethnicities. Results: Baseline characteristics are summarized in Table. The median age of the pts was comparable between White and Black/Hispanic (p= 0.97). A significantly higher proportion of Black/Hispanic pts (23%) had diabetes mellitus when compared with White (14%) pts (p= 0.02). A higher proportion of Black/Hispanic pts had therapy-related AML (33% vs. 20%, p= 0.03), complex cytogenetics (98% vs. 87%, p= 0.003) and co-mutations (70% vs. 57%, p= 0.02). The proportion of pts who received hypomethylating agent + venetoclax (29% vs 20%, p= 0.20) or CPX-351 (22% vs 20%, p= 0.13) were comparable between White and Black/Hispanic, respectively. A higher proportion of Black/Hispanic pts received supportive care (17% vs. 4%, p= 0.002). White pts had higher rates of complete remission with or without count recovery (25% vs. 19%, p= 0.07). Only 6% of Black/Hispanic pts received allogeneic stem cell transplantation (alloHCT) compared to 16% for White pts (p= 0.01). The median event free survival was 2 months (mo) (95% CI;1.52-2.41) and 2.5 mo (95% CI:1.62-3.31) in White and Black/Hispanic pts, respectively (p= 0.71). The median overall OS was shorter for Black/Hispanic (6.37 mo [95% CI:2.88-9.85]) than for White (6.90 mo [95% CI:5.55-8.24] [p= 0.009]). Conclusions: Our study demonstrates poorer OS in Black/Hispanic pts with TP53m AML. Potential drivers of this disparity include lower alloHCT rates, higher rates of pts receiving supportive care, and higher-risk disease in Black/Hispanic pts.[Table: see text]
Tracking C-type lectin-like receptor positive leukemic stem cells to determine therapeutic efficacy in acute myeloid leukemia.
Authors: Liu Suhu , Lin Hong , Lan Fengshou
Published: June 2022

e19011

Background: Although the importance of leukemia stem cells (LSC) in disease course of acute myeloid leukemia (AML) is well established in basic research, detecting and tracking LSC is seldom adopted in routine clinical practice. This is partly due to difficulty in tracking LSC in routine clinical practice and the paucity of evidence to support the benefit of detecting LSC in guiding clinical practice. Recently, a functional LSC population has been methodically characterized immunophenotypically, and the C-type lectin-like receptor (CLL1; aka CD371) has been shown to be widely expressed on LSC but not on normal hematopoietic stem cells (HSC). We postulate that CLL1 can be used to track LSC in a clinical setting and by analyzing changes in the LSC Compartment, we may be better able to assess response to therapy. Methods: Bone marrow samples from non-M3 CD34+ AML patients that were positive for CLL1 expression were included. Flow cytometry data were retrospectively analyzed for CLL1 percent positivity in the HSC compartment, which was defined as the CD34+CD38low/- fraction. A chart review was conducted to determine correlation between CLL1 positive LSC compartment change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: From 12/2018 to 12/2021, 49 AML cases with both pre- and post-treatment data from a single institution, were identified for the study. Among them, fourteen patients with CLL1 positivity higher than 50% were analyzed for CLL1+/HSC fractional change between pre- and post-treatment. We found that 6 of these 14 patients with significant reduction in CLL1+/HSC achieved longer remission, while the other 8 patients with no significant decrease in the CLL1+/HSC fraction demonstrated no or only a temporary remission. Importantly, several cases of patients with significant reduction in CLL1 positive cells will be presented to highlight the fact that LSC fractional change was more accurate in evaluating therapeutic effects and more predictive of clinical outcome than traditional morphology and flow cytometric analysis. This may even alter interpretation of specific treatment outcomes by predicting, for example, the brief nature that can be expected from certain remissions. Lastly, the CLL1+/HSC compartment in the peripheral blood is highly correlated with that of the bone marrow, indicating future feasibility of tracking LSC fractional change non-invasively to guide therapeutic decisions. Conclusions: CLL1 as a LSC marker is readily applicable to the clinical setting. Tracking LSC before and after AML treatment provides critical information regarding therapeutic effects that can sometimes be missed by traditional morphological and flow cytometric analysis. Thus, measuring changes in the LSC compartment using CLL1 analysis should be incorporated routinely in clinical practice to guide therapy decisions.
Predicting early mortality and overall survival (OS) in acute promyelocytic leukemia (APL) based on Charlson comorbidity index (CCI).
Authors: Dhakal Prajwal , Lyden Elizabeth , Pyakuryal Avantika , Bhatt Vijaya Raj
Published: June 2022

e19017

Background: CCI is an established tool used to measure the comorbidity burden in patients, with higher CCI signifying a greater comorbidity burden. We performed a large database analysis to evaluate CCI as a predictor of one-month mortality and OS in patients < 60 years with APL. Methods: Using the National Cancer Database, we identified a total of 4969 patients < 60 years diagnosed with APL between 2004 and 2015. We divided patients into 3 groups with CCI of 0, 1, and ≥2. Multiple regression analysis was used to evaluate the effects of CCI on one-month mortality. Cox regression model determined the impact of CCI on OS. Results: Seventy-eight percent of patients had CCI of 0; 16% had CCI 1, and 6% had CCI ≥2. Median age was 42 years (range 0-59), and patients 41-59 years comprised 53% of the total cohort. Fifty-one percent were female, 32% were treated at academic centers, and 67% had private insurance. One-month mortality was 5%, 14%, and 25% for patients with CCI 0, 1 and ≥2, respectively. After adjusting for other co-variates, one-month mortality was worse for patients with CCI 1 (Odds ratio 2.6, 95% confidence interval [CI] 2.0-3.4, p < 0.001) and CCI ≥2 (Odds ratio 5.3, 95% CI 3.9-7.4, p < 0.001) compared to patients with CCI 0. Median 5-year OS was 85%, 71%, and 60% for patients with CCI 0, 1, and ≥2, respectively. After adjusting for other co-variates, OS was worse for patients with CCI 1 (Hazard ratio [HR] 1.8, 95% CI 1.5-2.1, p < 0.001), and CCI ≥2 (HR 2.7, 95% CI 2.2-3.3, p < 0.001) compared to patients with CCI 0. Patients 41-59 years had worse OS than 0-18 years (HR 2.4, 95% CI 1.3-4.5, p = 0.003). Private insurance was associated with better OS than Medicare (HR 2.1, 95% CI 1.7-2.6, p < 0.001) and Medicaid/other government insurance (HR 1.3, 95% CI 1.1-1.6, p < 0.001). Conclusions: This is one of the first and the largest database analyses examining the prognostic association of comorbidity burden in younger patients with APL. CCI independently predicted both one-month mortality and OS. Compared to CCI of 0, one-month mortality increased by 2.5-fold with CCI 1 and more than five-fold with CCI ≥2. The higher chances of one-month mortality in patients with greater comorbidity burden may reflect the risks associated with initial APL diagnosis and treatment such as coagulopathy, infection, and differentiation syndrome. One-month mortality was the key driver for OS. OS was also worse among patients with higher CCI. Our results indicate CCI as an important predictor of one-month mortality and OS in APL. CCI should be taken into consideration while interpreting clinical trial results.
Induction mortality (IM) of acute myeloid leukemia (AML) patients treated with purine analogues-cytarabine-anthracycline at a general hospital.
Authors: Rios Adan , Yohannan Binoy , Cervoni-Curet Frances Natalia
Published: June 2022

e19019

Background: Cytarabine-anthracyclines (7+3) induction chemotherapy (IC)) has been the mainstay therapy for over four decades and it remains the standard AML IC regimen internationally. Triplet IC using purine analogues (fludarabine/cladribine) in combination with cytarabine and idarubicin (FIA/CLIA) is superior to the standard 7+3 regimen, but challenging to administer in general hospital settings due to myelosuppression. We reviewed AML IM rate in patients induced with (fludarabine/cladribine) combined with cytarabine and idarubicin (FIA/CLIA) at Memorial Hermann Hospital, Texas Medical Center (MHH at TMC). Patients and Methods: Of 44 AML reviewed records from January 2013 to January 2022, 40 received 5 days FIA/CLIA IC, and four 3-4 days due to age and comorbidities. For clinical characteristics see Table. Results: Median age was 51.5 years (range: 18-68). Three died before assessment. After 1 cycle the composite CR (CR+ CR i) was 82.9% (34/41) and 87.8% (36/41) after 2 cycles. MRD negative composite CR was 92%. Four patients had adverse risk cytogenetics and primary induction failure (modified FIA). 37% had febrile neutropenia. 25% had bacteremia with 15% requiring ICU admission and 4% mechanical ventilation. The 30-day induction mortality was 9%. Conclusions: FIA/CLIA has a higher CR rate than ‘3+7’ (which historically is 60%). The 30-day induction mortality in non-academic centers is about 30%. Given the fact that in AML achieving a CR is the most important factor to improve survival, with adequate treatment expertise, triplet IC regimen can be safely administered with a low induction mortality. [Table: see text]
Re-induction with venetoclax in combination with hypomethylating agents (HMAs) versus FLAG-IDA in relapsed or refractory AML.
Authors: Bouligny Ian Michael , Maher Keri Renee
Published: June 2022

e19030

Background: The optimal selection and sequence of salvage regimens during treatment of acute myeloid leukemia (AML) remains unclear. While venetoclax augmentation of a hypomethylating agent backbone is now routinely used as salvage following impressive performance in the front-line setting, little is known about outcomes in relapsed or refractory AML, especially when compared to re-inductions with anthracycline-based regimens. Thus, the aim of this study was to compare outcomes of venetoclax-based regimens versus FLAG-IDA in patients under 70 years. Methods: We retrospectively analyzed 47 patients with AML that were younger than 70 years in the relapsed and refractory setting treated with either FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin) or venetoclax in combination with decitabine or azacitidine from July 2017 to December 2020. Two cohorts were created: a FLAG-IDA cohort and a matched venetoclax cohort for age, ECOG score, and comorbidities. Cytogenetic risk and molecular profiling (through next-generation sequencing [NGS]) at diagnosis and throughout treatment, dates and doses of induction, toxicity, responses, and measurable residual disease (MRD) analysis were recorded and analyzed. Results: In the venetoclax cohort of 32 patients, the median age was 60 years, the median ECOG score was 1, and the median Charlson Comorbidity Index (CCI) score was 4. Six out of 22 evaluable patients achieved either a CR or CRi for a composite response rate (CRR) of 27.3%. Out of three evaluable patients that responded, none were MRD-negative by NGS. The overall survival (OS) of the venetoclax cohort was 8.2 months. In the FLAG-IDA cohort of 15 patients, there were no statistical differences between age (p = .114), ECOG score (p = .249), or CCI score (p = .137) compared to the venetoclax cohort. The CRR of the FLAG-IDA cohort was 85.7%, a significant difference from the venetoclax cohort (p = .011), and 50% were negative for MRD by either NGS or PCR. The overall survival was not reached at a median follow-up time of 15.5 months, significantly different compared to the venetoclax cohort by the log-rank test (p = .001). A Cox proportional hazards model was used to investigate the effects of commonly mutated genes ( NPM1, ASXL1, FLT3, IDH1/2, RAS, TP53, TET2) on OS in venetoclax-based re-induction, and identified IDH1/2 mutations as having a favorable impact in the relapsed/refractory setting (HR 0.01, 95% CI 0.0001-0.7214). Conclusions: Our results highlight the efficacy of FLAG-IDA compared to venetoclax-based regimens with respect to CRR and survival, significantly favoring FLAG-IDA at the time of relapsed or refractory disease. Although limited by sample size, IDH1/2 mutations may convey a better prognosis in the relapsed/refractory setting when treated with venetoclax + HMAs. Larger studies are needed to confirm these findings.
Molecular stratification of response and survival of venetoclax in combination with hypomethylating agents in AML.
Authors: Maher Keri Renee , Bouligny Ian Michael
Published: June 2022

e19033

Background: The use of venetoclax, a BCL-2 antagonist, in combination with decitabine or azacitidine has become routine for the upfront treatment of patients with acute myeloid leukemia (AML) not eligible for intensive induction. The impact of the addition of venetoclax to hypomethylating agents (HMAs) on outcomes with respect to various gene mutations is currently unclear. The aim of this study was to investigate response and survival of patients with AML receiving venetoclax-based induction with respect to specific molecular aberrations. Methods: We retrospectively analyzed 41 patients with AML treated with upfront venetoclax + HMAs from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including molecular profiling either through PCR or NGS at the time of induction, alongside cytogenetic risk, doses of induction regimens, response including MRD analysis, and survival. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Nine patients were identified with NPM1mut and 66.6% were ELN adverse risk. The composite response rate (CRR = CR + CRi) was 44.4% and the OS was 8.2 months. Seven patients had either DNMT3Amut or DNMT3Bmut and 57.1% were classified as adverse risk. The CRR was 28.6% and the mOS was not reached after a median follow-up time of 15.1 months. Eleven patients had FLT3-ITDmut or FLT3-TKDmut and 81.8% were classified as adverse risk. The CRR was 45.6% and the OS was 6.3 months. Six patients had either NRASmut or KRASmut. The CRR was 16.7% and the OS was 8.9 months. Seven patients had ASXL1mut, the CRR was 28.5% with the OS not reached at a median follow-up time of 8.9 months. Six patients with RUNX1mut demonstrated a CRR of 50.0% and the OS was not reached at a follow-up time of 12.8 months. Nine patients had TP53mut with a CRR of 33.3% and OS 12.6 months. Conclusions: Survival with venetoclax + HMA appears to numerically favor TP53mut AML when compared to more intensive strategies, consistent with prior literature reporting favorable responses to HMA monotherapy in this subset of disease. FLT3mut appeared to have a relatively lower OS, though not significantly different from either NPM1mut or TP53mut at the time of this analysis. DNMT3mut AML may preferentially respond to venetoclax + HMAs given the 15.1 month duration of follow-up, though longer follow-up with larger cohorts are needed to further identify subsets of molecularly stratified preferential responders to venetoclax-based strategies.[Table: see text]
Trends of leukemia mortality in the United States, 1999-2018.
Authors: Bakhati Bibek , Chamarti Karthik , Sibi Victoria , Dang Thao , Bajaj Kelash
Published: June 2022

e19034

Background: Malignant neoplasms are the second leading cause of mortality in the United States. Among the cancer sites, leukemia is the seventh most common cause of deaths. It accounts for 3.2% of all new cases of cancer and 3.9% of all cancer deaths. The Mortality-to-Incidence Ratio (MIR) has previously been applied as a measure to examine health disparities and outcomes of cancer therapy. In this study, we aim to analyze leukemia incidence, mortality, and trends of MIR for gender and race over the previous two decades. Methods: We conducted a retrospective population-based study using Cancer Statistics from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research system (CDC WONDER). Subjects with leukemia as the cancer site were selected. Age-adjusted mortality and age-adjusted incidence rates for race and gender were obtained and reported over 100,000 people. Negative binomial regression analysis using age-adjusted rates was subsequently used to analyze mortality, incidence, and trends of MIR. Results: 448,893 deaths were reported to be associated with leukemia between 1999 and 2018, of which males accounted for 56.85%. A total of 894,726 incident cases of leukemia were recorded during the same period. Males had a higher age-adjusted mortality rate than females (9.3 vs 5.2, OR: 1.70 [1.48-1.95]). Compared to Native Americans, African Americans and White cohorts had substantially higher age-adjusted mortality rates (3.5, 6.0, 7.2, OR: reference, 1.74, 2.05), whereas Asians had a non-significantly higher rate (3.8, OR: 1.09 [0.87-1.36]). In males, incidence rates were significantly higher (17.9, OR: 1.61 [1.58-1.64]). Against White population, Asian and African American race had a significantly lower age-adjusted incidence rate (14.4, 7.9, 10.6, OR: reference, 0.60, 0.79), while Native American race had a significantly higher rate (8.2, OR: 1.15 [1.06-1.24]. The mortality-to-incidence ratio has decreased significantly over time in both male and female populations (22.82% and 27.62%, respectively), as well as in African American and White cohorts (24.36% and 23.24%, respectively). Conclusions: Over the last 20 years, the mortality-to-incidence rate ratio significantly declined, possibly suggesting the effectiveness of cancer treatment outcomes in the United States. Yet, the reduction in mortality was not observed in all races. More efforts and further research are needed to guide the policy change.
Outcomes stratified by molecular aberration following induction with daunorubicin 60 mg/m2 versus daunorubicin 90 mg/m2 in AML.
Authors: Maher Keri Renee , Bouligny Ian Michael
Published: June 2022

e19035

Background: Prior work investigating the optimal dose of daunorubicin in combination with cytarabine for upfront treatment of AML has resulted in several studies suggesting differential responses following daunorubicin dose optimization when analyzed by molecular cohort (such as NPM1, FLT3-ITD, or DNMT3A). While some studies advocated for a dose of 90 mg/m2 in younger patients with NPM1mut (following induction with either daunorubicin 45 mg/m2 versus 90 mg/m2), little is known regarding outcomes stratified by molecular lesion between daunorubicin 60 mg/m2 and daunorubicin 90 mg/m2. Methods: We retrospectively analyzed 92 patients with AML treated with upfront daunorubicin 60 mg/m2 or 90 mg/m2 from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including cytogenetic risk, molecular profiling either through PCR or NGS at the time of induction, doses of induction regimens, response including MRD analysis (when available), and survival. Results: In the 60 mg/m2 cohort, 10 patients had NPM1mut, the CRR (CR+CRi) was 60.0% and the OS was 1.7 y. Four patients with DNMT3mut had a CRR of 25.0% and a 4.1 m. OS. Nine patients with FLT3-ITD or FLT3-TKD all treated with FLT3 inhibitors achieved a CRR of 22.2% with a 4.9 m. OS. Ten patients with NRASmut or KRASmut had a CRR of 50.0% and a 20.7 m. OS. In the adverse category, five with ASXL1mut had a 20.0% CRR and a 6.4 m. OS; 7 with RUNX1mut had a CRR of 42.9% and a 14.5 m. OS; and 6 with TP53mut demonstrated a CRR of 0% and an 13.1 m. OS. In the 90 mg/m2 cohort, 8 patients had NPM1mut with a CRR of 75.0% and an 18.8 m. OS. Two patients with DNMT3mut both achieved CR and the OS was not reached. Three of 5 patients with FLT3mut treated with midostaurin achieved CR or CRi and a 16.2 m. OS. Four of 5 patients with RASmut achieved CR and the OS was not reached at a 15.8 m. follow-up time. In the adverse category, there were no patients treated with a dose of 90 mg/m2 with ASXL1mut and one with RUNX1mut with non-evaluable response. Two out of 4 patients achieved CR or CRi with TP53mut and the OS was not reached. Conclusions: Response rates appear numerically higher across molecular subtypes favoring daunorubicin 90 mg/m2, although no significant differences in survival were appreciated, likely due to limited sample size. This may argue for intensification of anthracycline doses in carefully selected patients regardless of molecular profiling. Toxicity with high-dose daunorubicin must be weighed against any potential response or survival benefit, particularly for TP53mut and ASXL1mut – especially in the setting of alternative induction strategies such as CPX-351 and venetoclax with a hypomethylating agent. Larger prospective studies analyzing outcomes with regards to molecular profiling and treatment strategies are warranted.
Phase II study of cladribine, idarubicin, cytarabine (CLIA) plus gilteritinib in patients (pts) with FLT3 mutated acute myeloid leukemia (AML).
Authors: Abuasab Tareq , Kantarjian Hagop M. , Garcia-Manero Guillermo , Bravo Guillermo Montalban , Alvarado Valero Yesid , Daver Naval Guastad , Yilmaz Musa , Pemmaraju Naveen , Chien Kelly Sharon , Kornblau Steven Mitchell , Burger Jan Andreas , Jain Nitin , Islam Rabiul , Dinardo Courtney Denton , Borthakur Gautam , Jabbour Elias , Ravandi Farhad , Kadia Tapan M.
Published: June 2022

e19036

Background: The addition of multi-kinase inhibitors of FLT3 such as midostaurin and sorafenib to chemotherapy have demonstrated improved outcomes in patients with newly diagnosed FLT3 mutated AML Gilteritinib (gilt) is a second generation FLT3 inhibitor approved for pts with relapsed/refractory (R/R) FLT3-mutated AML. We studied to the combination of gilt with the CLIA regimen in FLT3 mutated AML. Methods: Eligible pts were between 18-65 years (yrs) with FLT3-mutated AML. Induction was: Cladribine 5 mg/m2 IV on D1-5, Cytarabine 1.5-2.0 g/m2 IV on D1-5, Idarubicin 10 mg/m2 IV on D1-3 and gilt 120 mg on D1-14. Consolidation was cladribine 5 mg/m2 IV for 3d, Cytarabine 750 mg/m2 IV for 3 d, and idarubicin 8 mg/m2 IV for 2 d, with gilt 120 mg continuously during cycle two onward. A historical cohort combining sorafenib (400 mg PO BID) with idarubicin + cytarabine (1.5 g/m2) backbone was used as comparison. Results: Twenty-four pts were enrolled with a median age of 53 yrs (range, 28-63). 21 pts (88%) had FLT3-ITD, 6 pts (25%) had FLT3-D835, and 3 pts (13%) had both. Nineteen pts (79%) had diploid cytogenetics, and 4 pts (18%) had trisomy 8. The most commonly co-occurring mutations were: NPM1 (46%), ASXL1 (29%), DNMT3A (29%), TET2 (25%), and KDM6A (20%). 16 pts (67%) achieved complete remission (CR), 2 (8%) had CR with incomplete recovery (CRi), for a CR/CRi rate of 75%. 13 responding pts (54%) underwent to allogeneic SCT. The median overall survival for the entire cohort was not reached. We compared these outcomes to our historical cohort of 107 pts treated with sorafenib combined with high-dose cytarabine-based chemotherapy. Other than older age and greater anemia for the gilt, there was not significant difference in baseline characteristics between the two groups. The CR/CRi rate was similar (75% gilt vs. 71% sorafenib; P = > 0.999) between the 2 cohorts; while there was a trend, there was no significant difference in OS with CLIA + Gilt (median NR vs. 17.3 months for sorafenib; P = 0.533). Conclusions: The combination of the FLT3 inhibitor gilteritinib to CLIA produced high rates of complete remission in pts diagnosed with FLT3-mutated AML. These results were similar for Sorafenib when combined with intensive chemotherapy with OS rates favoring gilteritinib. Further study of intensive chemotherapy with different FLT3 inhibitors is warranted. Clinical trial information: NCT02115295.