bluuebunny/crossref_metadata_2025 huggingface dataset:
Breaking down cancer costs: Hospital charges for patients with melanoma.
Authors: Hundal Henna , Taneja Kamil , Patel Karan , Zhang Alex , Diaz Michael , Chandragiri Sahas , Cohen Jules A.
Published: June 2023

e18921

Background: 78,000 new melanoma cases are diagnosed every year in the US and many present to the emergency department (ED). Furthermore, the increasing cost of healthcare has been well established. However, there is little data on the annual trends of hospital charges and risk factors for a high charge for these patients. Methods: We utilized the 2006-2012 Nationwide Emergency Department Sample to analyze the charges of melanoma patients. Multivariate linear regressions were used to identify factors associated with higher ED and inpatient (IP) costs. The 20 most common primary diagnoses of these patients were included in the analysis to consider the reason to visit the ED. Charges were corrected for inflation by normalizing to the 2012 US Dollar. Results: Between 2006 and 2012, 239,956 melanoma patients presented to the ED. In this time period, melanoma patients were charged a total of $567,834,100 (95% Confidence Interval (CI): $519,399,100 - $616,269,100) in the ED. The average per-patient ED charge was $3,284 (95% CI: $3,152-$3,416). The per-patient ED charge increased from $2,309 (95% CI:$2,144-$2,476) in 2006 to $3,844 (95% CI:$3,638-$4,049) in 2012 (p < 0.001), even after correcting for inflation. In the IP setting (57.6% of melanoma patients were admitted), melanoma patients were charged a total of $5,151,730,000 (95% CI:$4,768,685,000-$5,534,776,000). The average per-patient IP charge during this time period was $38,304 (95% CI: $36,952-$39,656). Over time, the per-patient IP charge increased from $34,591 (95% CI: $32,606-$36,576) in 2006 to $41,245 (95% CI:$39,151-$43,448) in 2012 (p < 0.001), even after correcting for inflation. Table 1 shows the top 5 factors associated with higher ED and IP charges. Conclusions: The ED and IP charges associated with melanoma patients has steadily increased during this period, even after correcting for inflation. ED per-patient charges have increased by a factor of 1.7 and IP per-patient charges have increased by a factor of 1.2. Furthermore, patients that present to hospitals in the West or to a Trauma Level I center have significantly higher charges. [Table: see text]
Cost-effectiveness of novel systemic therapies for advanced breast cancer: Global representativeness and influence of funding.
Authors: Lazar Neto Felippe , Melo Marina , Hidalgo Filho Cassio Murilo Trovo , Mathias Maria Cecilia , Testa Laura , Campolina Alessandro
Published: June 2023

e18924

Background: Approval of expensive novel treatments increases costs of cancer care and undermines access, particularly in low and middle-income countries. As the most incident neoplasm, breast cancer (BC) therapies have an enormous budget impact if incorporated. Therefore, cost-effectiveness (CE) studies are essential to guide such decisions. Methods: A systematic literature search of Medline, Scopus, and Web of Science from January 1st 2012 to July 8th 2022 was conducted to identify CE studies of tumor-targeted systemic therapies for advanced BC. Articles without CE (or utility) ratio calculations were excluded. Information on the country and drug studied, authors’ conflicts of interests (COI) and funding, and authors' conclusions were manually reviewed by two independent investigators. Results: Of 1103 screened records, 74 studies comprising 212 CE comparisons were included. Most studied scenarios were from high-income countries (70%, 141/212), with only 10% from Latin America and none from Africa. The most studied drug classes were iCDK4/6 (23%), anti-HER2 directed therapy (21%), anti-PD1/PDL1 (12%) and endocrine therapy (11%). In 46% of the comparisons, a new drug combined with standard of care was compared to placebo and/or standard of care, and in 37% the compared treatment were alternative same class therapies. Nearly 46% (97/212) had pharmaceutical industry funding or author’s COI associated with industry. Overall, 56% of authors’ conclusions were unfavorable. Pharmaceutical industry related-studies were associated with high-income countries (75% vs. 64%, p = 0.006), same-class drug comparators (52% vs. 33%, p = 0.047), and favorable conclusions (60% vs. 15%, p < 0.001). A combination of drugs (addition to standard of care) was associated with unfavorable conclusions (56% vs 28%, p < 0.001). Conclusions: Industry-related studies target high-income countries' scenarios and are more likely to have favorable conclusions. As expected, the addition of drugs to standard treatments (combinations) is less likely to be cost-effective. Government funding in low and middle-income countries is needed to decrease the current literature gap and provide stakeholders with proper information to make incorporation decisions.
Multi-cancer early detection screening tools: A dream come true or a nightmare in the offing.
Authors: Fleck Leonard M , Dave Aakash
Published: June 2023

e18926

Background: US cancer deaths were at 610,000 in 2022 with 1.9 million new diagnoses of cancer, 86% of which were patients over age fifty. Roughly 150,000 advanced cancers were diagnosed with five current screening techniques. That leaves 1.75 million cancers to be diagnosed symptomatically, largely in advanced stages. The dream is to screen in a minimally invasive fashion for multiple types of cancer at earlier, treatable, life-saving stages. The Galleri test claims to fulfill that dream by identifying more than fifty different cancers, and their location, using a blood test that captures ctDNA linked to aberrant methylation. As their dream approaches reality, with a dozen US hospital systems already offering Galleri, a fiscal and ethical nightmare is likely to ensue. We will demonstrate to providers that Galleri’s analytical validity and clinical utility is marginal at best – largely due to uncertainty surrounding the nature of those fifty malignancies. Methods: Systematic review of literature was performed across multiple databases using the key terms "Cancer Early Detection" AND OR "MCED" AND OR "GALLERI." Grail’s optimistic portrayal of the test’s current efficacy is largely derived from Hubbell and colleagues’ recent work modelling a Galleri-like test that claimed an achievable 24% reduction in cancer mortality (~150,000 lives). Critics contend that their assumptions are too optimistic. The natural histories of most of those fifty cancers are poorly understood, such as tumor latency periods, which means the cancer shift detection to an earlier stage is unknowable. Moreover, we cannot know whether these cancers would have been caught earlier, symptomatically, and successfully treated - which is true of 68% of diagnosed cancers. Etzioni and colleagues concluded that 6% of cancer deaths might be reduced by Galleri, despite that number is still uncertain and optimistic. Galleri cannot take credit for those saved lives. Results: GRAIL proposes population-based screening for 110 million Americans over age fifty annually at a cost of $950 per test. That would add over $100 billion per year to the health costs to discover no cancer in 99% of the persons tested. Roughly $50 billion would be added to Medicare program costs, now at $1 trillion. To save 18,000 Medicare lives would cost $2.8 million per life saved, a significant misallocation of Medicare resources, given many less costly opportunities to save more lives. Finally, individuals with marginal or no health insurance would be informed by Galleri they had an early-stage cancer unaffordable to treat. They represent statistically salvageable lives not actually salvaged, which is a presumptive injustice. This argument holds, despite the company’s pledge to reduce cost by over 40% over four years. Conclusions: In sum, Galleri, as a population-based cancer screening test, is not economically affordable, not ethically equitable, and only marginally medically beneficial.
Effect of change in ECOG performance status at diagnosis and relapse in patients with acute myeloid leukemia.
Authors: Zhang Michelle , Shaw Carole , Russell Katie , Halpern Anna B. , Appelbaum Jacob , Hendrie Paul , Ghiuzeli Cristina Maria , Walter Roland B. , Percival Mary-Elizabeth M.
Published: June 2023

e19007

Background: ECOG performance status (PS) is often utilized in treatment decision-making for patients with acute myeloid leukemia (AML). Patients with relapsed or refractory (R/R) disease have a particularly poor prognosis and require complex treatment decisions that weight patient preference, disease risk and PS. Currently, limited data exist on changes in performance status from initial diagnosis to the time when R/R AML is found. It would be interesting to characterize whether patients with R/R AML have worse performance status due to progression of disease or stable or improved performance status after initial therapy. Given there are additional factors such as induction chemotherapy that impact performance status at R/R disease, we were also interested in characterizing the association of PS in R/R AML with short and long term survival. Methods: We utilized an institutional database from University of Washington/Fred Hutchinson Cancer Center to retrospectively identify patients with AML or other high-grade myeloid neoplasms (≥10% blasts) who received both induction and salvage chemotherapy between January 1, 2008 through December 1, 2021. Patients with missing performance status at R/R were excluded. Salvage treatment was divided into high (cytarabine greater than 1g/m2/dose), intermediate (7+3 or similar), or reduced intensity (i.e., hypomethylating agents). The McNemar test was used for matched-pair analysis of PS at two timepoints. The Kaplan-Meier method was used for overall survival (OS). Univariate and multivariable linear regression models were used to evaluate associations with 4 week survival. All statistical analyses were performed using R 4.2.1 (2022). Results: Of the patients identified (n = 614), only patients with PS documented at R/R (n = 51) were included in the analysis (baseline characteristics in Table 1). No significant change was identified in PS at diagnosis versus R/R (PS≤1 66.7% vs 70.6%, p = 0.80). Better performance status (PS≤1) at R/R was correlated with improved OS (11.4 months vs 2.33 months, p = 0.003). The 4-week unadjusted mortality rate was 8.5% for patients with PS≤1, and 33.3% for patients with PS > 1 (p = 0.04). Poor performance status (PS > 1) at R/R was associated with significantly increased 4 week mortality (OR 5.5, 95% CI 1.2-30.9), even after adjustment for age and ELN2017 risk (OR 6.2, 95% CI 1.1-41.3). When OS was further stratified by chemotherapy intensity, patients with PS≤1 (n = 36) treated with high intensity chemotherapy (n = 22) had improved OS (14.1 vs 4.3 months, p = 0.007). Conclusions: PS tends to be stable at R/R disease, and poor PS is associated with very poor survival. Further work is needed to characterize the patients with R/R AML who benefit from intensive re-induction chemotherapy.
Early death (ED) in elderly acute promyelocytic leukemia (APL) patients treated with lower induction doses of all-trans retinoic acid (ATRA).
Authors: Dalgetty Mark , Kota Vamsi , Jillella Anand P. , Bryan Locke Johnson , Shah Anvay , Dontu Sruthi , Nain Priyanshu , Pavkov Isabela
Published: June 2023

e19012

Background: With the introduction of the differentiating agent ATRA, APL has progressed from being one of the most life-threatening diseases to becoming the most curable subtype of adult AML. However, despite this advancement, death within the first 30 days of treatment amongst elderly patients remains a critical issue with ED rates reportedly as high as 20-50%. There is limited data looking at the elderly population due to often being excluded from clinical trials given age associated with being prominent negative risk factor. Pharmacokinetic studies comparing 25 mg/m2/day and 45 mg/m2/day doses in adult patients have shown similar peak concentrations and mean area under the curve. Notably, low dose ATRA has been offered in pediatric patients in order to reduce incidence of differentiation syndrome. Differentiation syndrome is a key contributor to ED in elderly APL patients causing treatment failure. We propose that lower doses of ATRA in the elderly reduces the impact differentiation syndrome has on induction mortality amongst elderly APL patients and leads to a lower rate of ED. Methods: Fifteen APL patients > 60 years of age were treated. Thirteen received low doses of ATRA (equal to or less than 25mg/m2/day) and two received standard doses of ATRA (45mg/m2/day). Arsenic trioxide was also used in addition to cytoreductive agents, such as cytarabine, hydroxyurea, and idarubicin as needed during induction. Dose reductions and regimens were based on age, comorbidities, and overall clinical judgement. During the course of treatment, further dose reductions and pauses in therapy were made based on clinical course. Results: A total of 15 elderly APL patients were treated between May 2017 and November 2020 at cancer centers within Georgia and South Carolina. The age range was 65-88 years old with a median age of 71 years old. 9/15 (60%) were female and 2/15 (13%) were classified as high risk. 13/15 were Caucasian and the remaining 2 were African American. Amongst the 13 APL patients who received lower doses of ATRA, one ED was noted. This occurred in 81-year-old Caucasian male with low risk APL who had multiple significant comorbidities and elected to halt treatment and pursue hospice. Amongst the 2 low risk APL patients who received standard doses of ATRA, one ED was noted due to differentiation syndrome. This patient also had many significant comorbidities. Conclusions: The ED rate in elderly APL patients treated with low doses of ATRA during induction was noted to be 1/13 (7.7%) which is significantly lower than what has been reported in literature. [Table: see text]
Pevonedistat plus belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome: A phase I multicenter study.
Authors: Maher Keri Renee , Schafer Danielle , Schaar Dale , Sabo Roy , Bandyopadhyay Dipankar , Grant Steven
Published: June 2023

e19015

Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy, with particularly dismal prognosis in the relapsed or refractory (R/R) setting, with a median overall survival of approximately 6 months. There has been increasing interest in novel therapeutic approaches to intelligently harness cellular pathways to improve outcomes in this difficult to treat population. Pevonedistat, a first-in-class NEDD8 inhibitor, and Belinostat a HDAC inhibitor work synergistically in AML cells and human xenograft AML models supporting the clinical rationale for this Phase I study. Methods: A Phase I dose-escalation study with a 3+3 design was performed to assess safety and tolerability of pevonedistat plus belinostat. Beliniostat (D1-5) and Pevonedistat(D1,3,5) were administered in a 21 day cycle until disease progression or unacceptable toxicity. Primary endpoint was identification of MTD/RP2D, secondary endpoints included toxicity, efficacy, pharmacokinetic interactions, and pharmacodynamic studies. Results: 18 patients (67% female; median age 67.5 (41-74)), 16 of whom had AML, were treated at 5 dose levels (belinostat 800-1000mg/m2, pevonedistat 20-50mg/m2), no dose limiting toxicities were noted. Average number of prior lines of therapy was 3. Most Grade 3 or 4 toxicities were hematologic (Table). Maximum number of cycles reached was 8. Best response was stable disease in four patients, and CR in one patient. The remainder had progressive disease or were not evaluable. Most common reason for discontinuation was disease progression (67%), 11% treatment ended per protocol criteria, 6% pursued alternative therapy, 6% due to side effects. The patient achieving CR was a 54 year old female with BRAF and TET2 mutation, primarily refractory to 7+3 and also unresponsive to second line azacitidine and venetoclax. After CR, she received an allogeneic stem cell transplant and remains in remission with 2 years of follow up. Conclusions: The combination of pevonedistat plus belinostat is safe in adult R/R AML with a manageable, primarily hematologic profile, and modest but notable activity in this heavily treated population. This regimen may be effective as a bridge to transplant in some patients. MTD was not reached in this study. Clinical trial information: NCT03772925 . [Table: see text]
A phase II study of hyper-CVAD with blinatumomab (blina) and inotuzumab ozogamicin (INO) for newly diagnosed Philadelphia chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL).
Authors: Short Nicholas James , Jabbour Elias , Jain Nitin , Haddad Fadi , Macaron Walid , Yilmaz Musa , Ferrajoli Alessandra , Kadia Tapan M. , Alvarado Valero Yesid , Maiti Abhishek , Nasr Lewis Fady , Zoghbi Marianne , Nasnas Cedric Christophe , Garris Rebecca , Zhao Min , Konopleva Marina , Ravandi Farhad , Kantarjian Hagop M.
Published: June 2023

e19017

Background: Consolidation with blina, regardless of measurable residual disease (MRD) status, improves overall survival (OS) in adults with newly diagnosed B-cell ALL. The addition of INO may deepen responses and further improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina at standard doses. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina consolidation (4 total cycles with INO). Results: To date, 69 pts have been treated (38 without INO and 31 with INO). Baseline characteristics are summarized in the table. Among 53 pts with active disease at study entry, 100% achieved CR. MRD negativity by flow was achieved in 56/59 evaluable pts (95%). Of the 3 pts who did not achieve MRD negativity, 2 were later found to have a NUP214: ABL1 fusion, and 1 had KMT2A rearrangement. The median follow-up of the entire cohort is 26 months. Overall, 8 pts (12%) relapsed while on study, 22 (32%) underwent stem cell transplant (SCT) in first remission (2 of whom relapsed post-SCT), 2 (3%) died in CR, and 37 (54%) remain in continuous remission without SCT. For the entire cohort, the estimated 3-year OS was 87% and the 3-year continuous remission duration was 83%. With a median follow-up in the INO cohort of 15 months, 3 pts (10%) have relapsed, all with CNS-only relapses, and none has died. The 15-month OS in the cohorts with and without INO were 100% and 87%, respectively (P=0.06). One pt discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of SOS/VOD have been observed. Conclusions: In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential Blina, OS may be improved with the addition of INO. Clinical trial information: NCT02877303 . [Table: see text]
Identification of a novel NPM1 mutation in acute myeloid leukemia.
Authors: Yao Yiyi , Lin Xiangjie , Wang Chen , Gu Ying , Zhu Hong-Hu , Jin Jie , Zhu Yinghui , Wang Huafeng
Published: June 2023

e19019

Background: Nucleophosmin (NPM1) is predominant nucleolar localization. NPM1-mutant acute myeloid leukemia (AML) account for 25-35% of adult AML patients, has been defined as a distinct AML entity in the 2022 WHO classification. The majority of NPM1 mutations reported affect exon 12 (classical type A mutation), account for 75-80% of adult NPM1-mutated AML cases, which generate an extra nuclear export signal (NES) in the C-terminal leading to aberrant cytoplasmic localization. Similar aberrant cytoplasmic translocation has also been reported in NPM1 mutants that identified in exons 9 and 11. Identification of novel non-type A mutants is paramount for diagnosis, risk stratification, and prognosis for targeted population. Methods: Somatic mutation analysis is performed on 566 AML patients using next-generation sequencing (NGS). Immunofluorescence and immunohistochemistry were used to identify the cytological localization of mutant NPM1. HEK-293T cells transiently transfected with plasmids for ectopic expression of the GFP-mutated NPM1 fusion proteins were treated with the specific Crm1/XPO1 inhibitor leptomycin B and to evaluate the NES dependence of their subcellular localization. Results: We identified one AML patient with NPM1 mutant located on exon 5. This patient was a 59-year-old female with de novo AML, with an 18-nucletide in-frame insertion at position 405 (c.405_406insGCCCTGGAACTGGGGAAC, named MutSong) in the middle of exon 5 [variant allele fraction (VAF), 11.9%]. It generated a new NPM1 mutant protein (p.135insALELGN), and containing a leucine-rich NES. Notably, different with all NPM1 mutant in other exons reported so far, our exon 5 mutant retained the functional c-terminal but insert one leucine-rich NES, similar finding was recently reported in NPM1 mutants that identified in exon 5 but on different position. This NPM1 mutant in exon 5 resulted in cytoplasmic localization both by confocal and immunohistochemistry in AML patient sample. HEK-293T overexpressing the new GFP-NPM1 exon 5 fusion protein indicated the aberrant localization in the cytoplasm and partially in nucleoli. Moreover, NES-dependent cytoplasmic localization was inhibited by exportin-1 inhibitor leptomycin B, indicated that the novel NES generated by exon 5 mutant is responsible for cytoplasmic localization. This patient carried WT1, IKZF1, JAK2, and NUP98 mutations, and was intravenously treated with daunorubicin plus cytarabine for induction followed by 3 cycles of intermediate-dose cytarabine as consolidation. Then the patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, the patient died of severe pulmonary infection and viral encephalitis 14 months after the initial remission, 7 months after allo-HSCT. Conclusions: Our finding of the novel NPM1 mutation in exon 5 supported that beside exon 12, exon 5 mutant is another NPM1 “born to be exported” mutant critical for leukemogenesis.
A retrospective analysis of the outcomes among hospitalized patients with myeloid leukemia undergoing leukapheresis: Insight from the National Inpatient Sample.
Authors: Arya Yajur , Syal Arshi , Casipit Bruce Adrian , Dourado Claudia
Published: June 2023

e19021

Background: Hyperleukocytosis often complicates the clinical picture in hematological malignancies. Historically, leukapheresis has been used to reduce the quantity of circulating white cells to reduce leukostasis, which can predispose to hypercoagulability and thromboembolism. Literature shows that leukapheresis does not offer any long-term survival benefits to patients, with some evidence of even worse outcomes at 6 months. Methods: We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients who have myeloid leukemia undergoing leukapheresis using appropriate ICD-10 CM codes. We stratified patients based on whether they underwent leukapheresis or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of < 0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with myeloid leukemia undergoing leukapheresis looking primarily at the in-hospital mortality, hospital length of stay (LOS) as well as total hospital charges. Results: We identified a total of 27,000 hospitalized patients with acute and chronic myeloid leukemia, of which 0.5% (135/27,000) underwent leukapheresis. The overall in-hospital mortality among those with myeloid leukemia was 9.86% (2662/27,000). Among those who underwent leukapheresis, the overall in-hospital mortality rate was significantly higher at 22.22% (30/135) (p = 0.05). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, the use of leukapheresis among hospitalized myeloid leukemia patients did not significantly decrease the risk for in-hospital mortality (adjusted OR 2.54 95% confidence interval [CI], 0.84-7.73; p = 0.10), hospital LOS (adjusted OR 2.76; 95% confidence interval [CI], -2.11-7.62; p = 0.27) or total hospital charges (p = 0.19). Conclusions: Our analysis showed that among hospitalized patients with myeloid leukemia, leukapheresis did not significantly decrease the risk for in-hospital mortality, hospital LOS as well as total hospital charges. Caution should be exercised in interpreting the higher rate of in-hospital mortality among those who underwent leukapheresis as the higher mortality rate can be due to small sample size, or the fact that patients who require leukapheresis have uncontrolled and more advanced disease. Hyperleukocytosis in these patients may indicate a worse prognosis. A prospective study with a larger sample size to test for possible confounders is warranted in order to further delineate these associations.
Gilteritinib plus azacitidine and venetoclax for FLT3-ITD mutated relapsed/refractory acute myeloid leukemia.
Authors: Chen Nianci , Zhou Yile , Tong Hongyan , Wei Juying , Lou YinJun , Zhou De , Fan Cuihua , Huang Li , Mao Liping , Li Chenying , Wang Huafeng , Jin Jie
Published: June 2023

e19024

Background: Gilteritinib is a second-generation FLT3 tyrosine kinase inhibitor that has been shown significantly increase the survival of relapsed/refractory (r/r) FLT3-mutated acute myeloid leukemia (AML) patients. We investigated the clinical benefit of gilteritinib plus azacitidine and venetoclax in the treatment of r/r FLT3-ITD mutated AML in the real word. Methods: Gilteritinib was given by oral administration at a dose of 80 or 120mg/d for each cycle. Azacitidine was intravenously administrated at a dose of 75 mg/m2/day d1-7. Venetoclax was given by oral administration at a dose of 100mg/d then ramp-up at 400mg/d, some patients were administrated at a dose of 400mg/d due to prior exposure. The composite complete response (CRc) rate (complete response [CR] and CR with incomplete blood count recovery [CRi]) were assessed, and then the overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) was evaluated. Results: We retrospectively analyzed the outcomes of gilteritinib plus azacitidine and venetoclax in 14 r/r FLT3-ITD mutated AML patients. The CRc rate of the triple therapy was 57.1% (CR, n = 5, 35.7%; CRi, n = 3, 21.4%), in which, all patients achieved minimal residual disease (MRD) negative measured by multi-color flow cytometry. At a median follow-up of 136.5 days, the median OS was 216.0 days, the median EFS was 97.0 days, and the median RFS were 184 days. The common grade 3/4 hematologic adverse events included neutropenia (n = 14, 100.0%), anemia (n = 12, 85.7%), and thrombocytopenia (n = 11, 78.6%). The common grade 3/4 non-hematologic adverse events were pulmonary infection (n = 5, 35.7%), other adverse events were relatively less and milder. Conclusions: In conclusion, the current data demonstrated promising response of the triple therapy in r/r FLT3-ITD mutated AML patients, and the regimen represented a potential option as a bridge to transplant. Prospective studies are warranted to further define the risk or benefit for more patients.
Biomarker subpanel customization for different use cases in acute myeloid leukemia research.
Authors: Li Wenjun , Liang Shaoheng , Roberts Hannah , Dao Long , Wu Yalei , Zhang David , Pinto Alessandro
Published: June 2023

e19026

Background: Treatment guidance and decision making according to modified RECIST guidelines often depends on characterization of these biomarkers in patients with cancer. Although panels with larger breadths of coverage are useful for initial detection of these biomarkers for evaluation of disease burden and prognosis, their cost-effectiveness decreases as treatment and disease progress; smaller subpanels may yield equally valuable information into disease progress and guide treatment in a more cost-effective manner, potentially leading to more datapoints in decision making in comparison to larger panels. Methods: QBDA is an NGS enrichment research technology that allows the enrichment of rare variants, reducing the sequencing cost while maximizing the sensitivity. Here we introduce a new capability of our platform that allows tailoring sequencing panel breath to the disease stage needs. We demonstrate the ability to generate a 384-plex NGS subpanel from a 2400-plex acute myeloid-leukemia (AML) measurable residual disease (MRD) targeting research panel. Both panels were tested on both wild-type and 0.1% variant allele frequency (VAF) AML MRD contrived samples. Results: Without any optimization of the subpanel itself, the subpanel exhibited similar or better performance to the main panel. The main panel had a ~80% uniformity of coverage whereas the subpanel had a uniformity of coverage exceeding 75%. The subpanel covers fewer genes of interest and requires fewer overall reads. Both panels had a bulk LoD of below 0.1% VAF. Conclusions: This data represents proof-of-concept for the design of small custom panels from large-scale multiplex panels for different use cases, potentially increasing cost-effectiveness.
Sequential salvage chemotherapy and lintuzumab-Ac225 results in deep responses and prolonged survival in adverse risk relapsed/refractory AML and in AML patients that received prior venetoclax therapy.
Authors: Abedin Sameem M. , Guru Murthy Guru Subramanian , Desai Avinash , Chen Mary , Atallah Ehab L.
Published: June 2023

e19030

Background: Lintuzumab-Ac225 is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation to CD33 expressing AML blasts. Preclinical studies indicate Lintuzumab-Ac225 also depletes the anti-apoptotic protein MCL-1, which is a known resistance factor in BCL2-inhibitor (venetoclax (Ven)) exposed patients (pts). We performed a Phase I study where Lintuzumab-Ac225 was administered after salvage chemotherapy, and this study demonstrated safety and encouraging response rates in R/R AML. Herein, we report results of high-risk patients who enrolled to this study. Methods: R/R AML pts deemed fit, and with CD33 expression on >25% of blasts were enrolled onto a Phase I study, Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgrastim + Mitoxantrone (CLAG-M). Induction consisted of G-CSF, 300mcg/d on D1-6, cladribine 5mg/m2 on D2-6, cytarabine 2g/m2 on D2-6, and mitoxantrone 10mg/m2 on D2-4. Lintuzumab-Ac225 was administered once on D8 ±1 day. The trial enrolled to 4 cohorts, with Lintuzumab-Ac225 at doses ranging from 0.25 uCi/kg to 1.0 uCi/kg. We defined high-risk pts as those who met ELN 2019 criteria for adverse risk disease, or pts who received a Ven combination prior to trial enrollment. Response is descriptively reported, and KM estimator was used to report overall survival (OS). Results: 19 pts on trial met high-risk criteria. Of these, 16 pts had ELN adverse risk disease, a TP53 mutation was detected in 75% (n=12) of pts. Median age was 65 yrs, pts received a median 2 lines of prior therapy, including prior allo-HCT in 58% (n=11), and prior Ven combination in 68% (n=13) of pts. In high-risk pts, 42% (n=8) of pts achieved CRc (CR+CRi), 16% (n=3) achieved MLFS, for an overall response rate (ORR) of 58%. Among evaluable pts achieving CRc, 71% achieved flow MRD negativity. Median OS was 7.4 months. Table reports results in select subgroups. Prior to treatment initiation, 7 pts were deemed eligible for first HCT. 4 (57%) were successfully able to bridge to HCT. Median survival among transplanted pts was 28 months. Post-HCT, one pt died due to GVHD, one due to relapse. Conclusions: CLAG-M in combination with Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in pts previously treated with Ven combinations (median OS 13.8 mo.) and in pts with TP53 mutations (median OS 7.3 mo.), for which recent studies have reported a survival of 4 months or less. The results support further advance in late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML, especially in high-risk pts. Clinical trial information: NCT03441048 . [Table: see text]
Survival outcomes of acute erythroid leukemia in the United States: A 20-year population-based study.
Authors: Gera Kriti , Martir Daniela , Xue Wei , Wingard John R.
Published: June 2023

e19031

Background: Acute Erythroid Leukemia (AEL), also known as pure erythroid leukemia, is a rare subtype of Acute Myeloid Leukemia (AML) characterized by proliferation of malignant erythroid precursors. It can occur at any age and portends aggressive course with dismal outcomes. Treatment consists of high-intensity chemotherapy and allogeneic hematopoietic stem cell transplant. Outcome data at a population level is scarce. Methods: We performed a retrospective analysis of the Surveillance Epidemiology and End Results (SEER) database, a U.S. population-based registry maintained by National Cancer Institute. All cases with histologically confirmed diagnosis of Acute erythroid leukemia during the period of 2000-2019 were included in the study. Survival analysis was performed using Kaplan-Meier method. The survival between groups was compared using log-rank test. Results: A total of 968 patients were included in the study. The median age was 68 years (range 0-95). 62% of patients were males. 11% patients were Hispanic and 89% were non-Hispanic (72% white and 7% black). 62.5% (n=605) patients were treated with chemotherapy. Median Overall Survival (OS) for patients with age <18 years (n=50) was 69 months with 1-year OS of 77%. In contrast, median OS for adults with age >18 years (n=918) was only 5 months with 1-year survival of 26.7%. Patients who received chemotherapy had significantly improved OS compared to patients who did not among both adults (Median OS 8 vs 1 months, p<0.0001) and children (Median OS 152 vs 2 months, p=0.004). There were no significant differences in OS based on sex, race, ethnicity and median household income. Median OS for adults diagnosed in 2000-04, 2005-09, 2010-14, 2015-19 was 4, 6, 6 and 3 months respectively with no significant difference in OS between these groups. Conclusions: AEL occurs in all age groups but is most common in elderly. Outcomes are poor with current chemotherapeutic agents, with no improvement in last two decades. This study stresses the urgent need for new investigational agents and treatment strategies. [Table: see text]
Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.
Authors: Rehman Mohammad Ebad Ur , Khan suheb Mahammed , Umar Haddaya , Farheen Naaz Fnu , Shah Zunairah , Khan Zarak , Cheema Huzaifa Ahmad , Basit Jawad , Fazal Faizan , Maqbool Shahzaib , Farhan Muhammed , Dhama Kuldeep , Akbar Usman Ali , Iftikhar Raheel , Iftikhar Ahmad , Anwer Faiz
Published: June 2023

e19032

Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.
Intracranial hemorrhage (ICH) in acute leukemia (AL): A single-center study from a general hospital with two cases managed with middle meningeal artery (MMA) embolization.
Authors: Yohannan Binoy , Cervoni-Curet Frances Natalia , Martinez Gutierrez Juan Carlos , Chen Peng Roc , Rios Adan
Published: June 2023

e19033

Background: ICH is a devastating and potentially fatal complication in patients with AL. Contributing factors for ICH include thrombocytopenia, hyperleukocytosis, and coagulopathy. Acute promyelocytic leukemia (APL) has a higher risk of disseminated intravascular coagulation (DIC) and fatal ICH, contributing to early deaths from the disease. At our institution, we have incorporated MMA embolization into traditional methods of observation and surgery for the management of ICH in AL patients. Methods: We performed a single-center retrospective study of adult AL patients with ICH at Memorial Hermann Hospital Texas Medical Center from January 1, 2013, to December 31, 2022. Data collected included: age at diagnosis, type of AL, white blood cell count (WBC), platelet count, coagulation profile, Glasgow Coma Scale score at presentation, response to platelet transfusion, need for surgical, minimally invasive intervention, and mortality rates at 72 hours and 30 days. Descriptive statistics were used to analyze the data. Results: Among 160 consecutive AL patients, we identified 22 (13.75%) with ICH at presentation (APL = 11, AML = 6, B-ALL = 3, Burkitt leukemia = 1, myeloid sarcoma = 1). All were newly diagnosed except for one (an intracranial relapse of AML). Median age was 54 (range, 20–82) years; 60% were women. Subject races included white (n = 10), Asian (n = 5), Hispanic (n = 2), African American (n = 2), and others (n = 3). Median WBC count at admission was 23 (range, 0.2–400) × 109/L. Thrombocytopenia (platelet levels < 50,000/μL) was present in 16 patients (72%), and 3 had platelet counts < 10,000/μL. Twelve patients (54%) had evidence of DIC. Sites of ICH included intraparenchymal (n = 8), subarachnoid (n = 3), subdural (n = 10), cerebellum (n = 1). In 3 patients, ICH extended into the ventricles. Three patients had ≥2 types of ICH. Three patients had middle cerebral artery ischemic stroke in addition to ICH. One patient with myelofibrosis and myeloid sarcoma had bilateral subdural hematomas (SDHs) on admission and developed a fatal basal ganglia ICH during induction chemotherapy. All APL patients were promptly started on all-trans retinoic acid. Two patients had refractory thrombocytopenia. Five patients required craniotomy, with 2 deaths from recurrent ICH. Two patients with SDH underwent MMA embolization with favorable outcomes. Four patients (18%) died within 72 hours of admission (APL = 3, AML = 1). The 30-day mortality rate among patients presenting with ICH was 31% (n = 7). Conclusions: ICH in AL continues to be a major cause of mortality and morbidity. Early diagnosis, transfusion support, correction of coagulopathy, and neurosurgical expertise are critical in improving outcomes in AL-associated ICH. MMA embolization is a new, minimally invasive strategy for the management of SDH in these critically ill patients.
Outcomes of different therapies in acute myeloid leukemia patients with core-binding factor.
Authors: Zhou Yile , Wang Huafeng , Jin Jie
Published: June 2023

e19036

Background: Acute myeloid leukemia (AML) with RUNX1:RUNXT1 fusion or CBFB:MYH11 fusion is defined as core-binding factor AML (CBF-AML) and has been considered to show favorable prognosis. Methods: We conducted a retrospective analysis on previously untreated CBF-AML patients who received standard-dose induction therapies between Jan 2018 and Dec 2020 in our medical center. Patients were classified into 5 groups based on the induction regimens: VA, DA, IA, HAA, and DAV. The dosage of these regimens were determined as follows: VA, venetoclax 100mg d1,200mg d2, 400mg d3-28, Azacytidine 75mg/m2 d1-7; DA, daunorubicin 60mg/m2 d1-3, cytarabine 100mg/m2 d1-7; idarubicin 8-10mg/m2 d1-3, cytarabine 100mg/m2 d1-7; HAA, homoharringtonine 2mg/m2 d1-7, cytarabine 100mg/m2 d1-7, aclarubicin 12mg/m2 d1-7; DAV, daunorubicin 60mg/m2 d1-3, cytarabine 100mg/m2 d1-7, venetoclax 100mg d4, 200mg d5, 400mg d6-11. The response rate and survival data were analysed between these groups. Results: There’s a total of 106 CBF-AML patients involved, 85(80.2%) with RUNX1:RUNXT1 fusion and 21(19.8%) with CBFB:MYH11 fusion. The most common concomitant mutation was KIT (33%), and the most frequent hotspot mutation site was D816V in exon 17. The median age was 46 years ranging from 7 to 78, and 46.2% of the patients were male.Patients were classified into 5 groups based on the induction regimens, and there were 9 in VA group, 21 in HAA group, 23 in DA group, 38 in IA group, and 15 in DAV group. The CR rate of each group was 55.6%(VA), 87.0%(DA), 65.8%(IA), 90.4%(HAA), and 100%(DAV) respectively. Among the patients who received CR, patients in DAV group showed more pronounced decreasing of fusion gene levels (median 1450 fold) than other groups, while VA group had the slightest (median 8.9 fold). As to the survival, the median follow-up time was 15.2 months, and the median overall survival (OS) were not reached in all the groups. In the RUNX1:RUNXT1 fusion subgroup, DAV group showed significantly improved OS and event-free survival (EFS) than other groups, while VA groups was the worst. The median EFS were as follows: 3.5months(VA), not reached(HAA), 10.9months(DA), 7.9months(IA), and not reached(DAV) respectively. Conclusions: Our study demonstrated a promising therapeutic results of DAV regimen, and an unsatisfactory therapeutic results of VA regimen in CBF-AML. CBF-AML patients showed significantly improved CR rate, elimination of fusion genes, OS, and EFS when received intense chemotherapy, especially DAV and HAA regimen, than VA regimen. These results indicated that intense chemotherapy may be an optimal choice for CBF-AML.
Phase II trial of mini-hyper-CVD-inotuzumab (InO) followed by blinatumomab (blina) consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Nasnas Cedric Christophe , Jabbour Elias , Haddad Fadi , Short Nicholas James , Macaron Walid , Zoghbi Marianne , Nasr Lewis Fady , Jain Nitin , Almanza Emmanuel , Sasaki Koji , Ravandi Farhad , Kebriaei Partow , Huang Xuelin , Garcia-Manero Guillermo , Kadia Tapan M. , Wang Sa A , Jacob Jovitta , Garris Rebecca , O'Brien Susan M. , Kantarjian Hagop M.
Published: June 2023

e19037

Background: Promising results were seen with low intensity chemotherapy mini-Hyper-CVD (mini-HCVD) in combination with InO in R/R ALL. Adding blina may further improve outcomes. Methods: Pts with R/R Philadelphia-negative B-ALL were treated with mini-HCVD (Cycles 1, 3, 5, 7) and methotrexate/cytarabine (Cycles 2, 4, 6, 8) for 8 cycles. Initially, InO was given on Day (D) 3 of the first 4 cycles at the dose of 1.8-1.3 mg/m2 in Cycle (C) 1, followed by 1.3-1.0 mg/m2 in subsequent cycles. POMP maintenance was for a total of 3 yrs. Protocol was amended after pt #67 to add 4 cycles of blina after 4 cycles of mini-HCVD+InO. InO was given on D2 and 8 at the dose of 0.6 and 0.3 mg/m2 in C1, and then on D2 and 8 at the dose of 0.3 mg/m2 in subsequent cycles; blina was given at standard dose in C5-8. Maintenance was reduced to 12 cycles of POMP with 1 cycle of blina after each 3 cycles of POMP for a total of 4 cycles. Rituximab was given for CD20+ disease. All pts received 8 doses of intrathecal chemotherapy. Results: Between 2/2013 and 7/2021, 110 pts were treated. Patient characteristics are shown in the table. 79 (72%) pts were treated in Salvage (S) 1, and 31 (28%) in S2+. 21 (19%) pts had received prior ASCT. 91 (83%) pts responded (complete remission, 63%). The overall response rate was 93% in S1, 59% in S2, and 57% in S3+. The rates of MRD negativity by flow were higher in S1 vs S2+ (89% vs 67%; P=0.047). 53 (48%) pts underwent ASCT. After a median follow-up of 48 months (mo) (range, 9-115), the median OS and RFS were 17 mo (4-yr, 36%) and 13 mo (4-yr, 37%), respectively. Pts in S1 had better OS compared with S2+ (4-yr OS, 43% vs 18%; P<0.001). The 4-yr RFS was 38% in S1 and 27% in S2+ ( P=0.14). In S1, 41 pts were treated before the amendment and 38 after the amendment; their 4-yr OS was 41% and 48% ( P=0.99), and their 4-yr RFS was 39% and 36%, respectively ( P=0.95). A landmark analysis of pts who achieved remission showed no survival difference between pts who did or did not undergo ASCT, with 4-yr OS of 49% and 48% ( P=0.98), and 4-yr RFS of 46% and 37% ( P=0.68), respectively. Sinusoidal obstruction syndrome (SOS) was noted in 10 (9%) pts, and its incidence decreased from 13% with single dose of InO to 2% with lower and fractionated doses of InO ( P=0.056). Conclusions: The combination of mini-HCVD and reduced-dose InO with sequential blina improved the outcomes of pts with R/R ALL. The new treatment schedule resulted in a lower rate of SOS compared to the original schedule. Clinical trial information: NCT01371630 . [Table: see text]