Overcoming Tagraxofusp-Erzs Monotherapy Resistance in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in a Real-World Clinical Setting.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy with limited treatment options. Currently, standard treatment strategies include clinical trials; chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and tagraxofusp-erzs (TAG, previously SL-401) which is the first-in-class targeted therapy against CD123. TAG received Food and Drug Administration approval for frontline BPDCN treatment in December 2018 and has increasingly become an alternative to chemotherapy, offering potentially more effective and less toxic options. However, despite promising results, there are still patients who may be resistant to TAG monotherapy and/or who respond but eventually relapse. Herein, we discuss an important patient case of BPDCN treated with TAG and review BPDCN treatment strategies.

Survival Outcomes and Prognostic Factors in Therapy-Related Acute Myeloid Leukemia: A SEER Database Study, 2000-2020.

INTRODUCTION: With advances in therapeutics and longer survival across different cancer spectrums, the incidence of therapy-related acute myeloid leukemia (tAML) has continued to rise. This study aims to evaluate the trend of survival outcomes and their association with sociodemographic factors in tAML over the last 20 years. METHODS: We identified tAML patients between 2000 and 2020 from the Surveillance, Epidemiology, and End Results database. Patients were divided into 4 age groups: 18-39, 40-59, 60-69, and >= 70 years, and 4 diagnostic periods: 2000-2005, 2006-2010, 2011-2015, and 2016-2020. Overall survival (OS) was compared using Kaplan Meier and log-rank methods. RESULTS: The 1-year (and 5-year) OS in patients with tAML was 59.3% (33.7%), 48.2% (24.8%), 37.2% (11.1%), and 32.9% (5.5%) in age groups 18-39, 40-59, 60-69, and >=70 years, respectively. The 1-year (and 5-year) OS based on the year of diagnosis was 20.9% (13.2%), 36.8% (15.2%), 41.9% (13.88%), and 40.4% (not reached) for 2000-2005, 2006-2010, 2011-2015, and 2016-2020 respectively. Among the youngest cohort aged 18-39 years, 1-year OS was 35.7%, 57.7%, 66.7%, and 59.6%, respectively, in 4 diagnostic periods, whereas 1-year OS was 10.5%, 23.9%, 32.2%, and 36.9%, respectively, in the oldest cohort aged >=70 years. Age, year of diagnosis, and geographic location were independent prognostic markers of OS. CONCLUSION: Our study demonstrates a significant improvement in the 1-year OS of tAML patients over the last decade, but the long-term prognosis remains dismal. Older patients continue to show improved survival in recent years with the addition of newer intensive and nonintensive options.

Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Diet and Nutritional Supplementation in Patients With Cancer: Is More Necessarily Better?

This editorial and the accompanying article summarize evidence-based guidelines that can inform dietary recommendations in oncology practices.

Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.

Venous Thromboembolism Risk Assessment in Hospitalized Cancer Patients: A Single Center Study.

This study aimed to identify predictors of venous thromboembolism (VTE) in hospitalized cancer patients and develop a predictive model using demographic, clinical, and laboratory data. Our analysis showed that patient groups categorized under a very high risk, and high risk, patients with low hemoglobin levels and renal disease were at a significantly increased risk of developing VTE. We developed a VTE risk-assessment model (RAM) with moderate discriminatory performance, high specificity, and negative predictive value, indicating its potential utility in identifying patients without VTE risk. However, the model's positive predictive value and sensitivity were low due to the low prevalence of VTE within the analyzed population. Future studies are needed to analyze additional predictive factors, and to validate the effectiveness of our VTE RAM to safely rule out VTE, compare it with other VTE RAMs in hospitalized cancer patients, and address any limitations of our study.

Venetoclax-based therapy in treatment-naïve and relapsed/refractory acute myeloid leukemia.

Combining venetoclax with the hypomethylating agents azacitidine or decitabine has shown high complete response rates (60-70 %) in newly diagnosed (ND) acute myeloid leukemia (AML). However, studies addressing the efficacy of this approach in relapsed/refractory (R/R) AML remain limited. We conducted a retrospective analysis on patients treated with venetoclax-based therapy at a single institution. Objective response rates (ORR) and overall survival (OS) were assessed using logistic regression and Cox regression models, respectively. The total study population exhibited an ORR of 64 % with a complete remission at 34 %, complete remission with incomplete count recovery at 19%, and morphologic leukemia free state at 11 %. Patients with ND AML had a better ORR (71 %) compared to R/R AML (55 %), but the difference was not statistically significant. Median OS for the overall population was 14.4 months (range: 2-26 months). In the ND group, patients had a longer 6-month OS (82 % vs. 55 % in R/R AML), while both cohorts showed similar 12- and 24-month OS. Factors such as the hypomethylating agent chosen, adverse cytogenetics, TP53 mutations, prior hypomethylating agent use, and stem cell transplant status did not significantly affect ORR or OS. These findings support the effectiveness of venetoclax-based treatments in ND and R/R AML.

Intralobar pulmonary sequestration in 2 extremes of ages: A Case report.

Pulmonary sequestration is a relatively rare phenomenon characterized by nonfunctional lung tissue supplied by one or more systemic arteries without direct connection to the tracheobronchial tree. Intra-lobar pulmonary sequestration comprises 75% of the total pulmonary sequestrations. Most patients with pulmonary sequestrations are often diagnosed with a childhood chest infection, so pulmonary sequestration is considered a childhood disease. However, few cases are found in adults and the elderly, with or without symptoms, and imaging findings on computed tomography (CT) or magnetic resonance imaging (MRI) are variable due to infection and inflammation. Failure to diagnose and treat this condition may lead to recurrent pneumonia and fatal hemoptysis. In this case report, we present cases of pulmonary sequestration at extremes of ages, one at 12 and the other at 65.

Therapy-related Acute Myeloid Leukemia in Non-Hodgkin Lymphoma Survivors: Risk, Survival Outcomes and Prognostic Factor Analysis.

BACKGROUND: Therapy-related acute myeloid leukemia (tAML) is a serious complication in patients with Non-Hodgkin lymphoma (NHL) exposed to chemotherapy or radiation. This extensive database study aims to quantify the risk of tAML in NHL and determine the impact of tAML on the overall survival (OS) of patients with NHL. MATERIALS AND METHODS: Patients diagnosed with NHL and de novo AML from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results database. Multiple primary standardized incidence ratio (SIR) sessions of the SEER*Stat software were used to calculate SIR and the absolute excess risk of tAML. Overall survival (OS) was evaluated using Kaplan-Meier curves and compared using log-rank tests. Multivariate analysis was used to study the role of each covariate on OS in patients with tAML. RESULTS: The SIR of tAML was 4.89 (95% CI 4.41-5.41), with a higher incidence of tAML observed for age <60 years, NHL prior to 2013 and within 5 years of diagnosis, and those who received chemotherapy. NHL patients with tAML had lower OS than those without tAML (5-year OS 59% vs. 13%, p < 0.001). Patients with tAML showed worse OS than de novo AML in univariate analysis (5-year OS 13% vs. 25%, p = 0.001) but not in multivariate analysis (HR 0.93, 95% CI 0.82-1.04, p = 0.21). Age ≥60 years and lack of chemotherapy were associated with poor OS in tAML subcategory. CONCLUSION: Age, time since NHL diagnosis, and receipt of chemotherapy directly influence the risk of development of tAML in NHL survivors.

Utilizing digital pathology and immunohistochemistry of p53 as an adjunct to molecular testing in myeloid disorders.

TP53 mutation status guides early therapeutic decisions in the treatment of clonal myeloid disorders and serves as a simple means of monitoring response to treatment. We aim here to develop a standardized protocol for evaluating TP53 mutation status in myeloid disorders using immunohistochemistry assisted by digital image analysis and further compare this approach to manual interpretation alone. To accomplish this, we obtained 118 bone marrow biopsies from patients with hematologic malignancy and molecular testing for mutations associated with acute myeloid leukemia was performed. Clot or core biopsy slides were stained for p53 and digitally scanned. Overall mutation burden was assessed digitally using two different metrics to determine positivity, compared to the results of manual review, and correlated with molecular results. Using this approach, we found that digital analysis of immunohistochemistry stained slides performed worse than manual categorization alone in predicting TP53 mutation status in our cohort (PPV 91%, NPV 100% vs. PPV 100%, NPV 98%). While digital analysis reduced inter- and intraobserver variability when assessing mutation burden, there was poor correlation between the quantity and intensity of p53 staining and molecular analysis (R2 = 0.204). Therefore, digital image analysis of p53 immunohistochemistry accurately predicts TP53 mutation status as confirmed by molecular testing but does not offer a significant advantage over manual categorization alone. However, this approach offers a highly standardized methodology for monitoring disease status or response to treatment once a diagnosis has been made.

Comorbidity burden and outcomes of older adults with acute promyelocytic leukemia: a National Cancer Database analysis of 2221 patients.

Association between comorbidity burden and patient outcomes has not been adequately investigated in acute promyelocytic leukemia (APL). We utilized the National Cancer Database to evaluate the association of the Charlson-Deyo Comorbidity Index (CCI) with one-month mortality and overall survival (OS) in adults ≥60 years with APL. One-month mortality was 16%, 24%, and 32%, and 3-year OS was 61%, 53%, and 38% for patients with CCI 0, 1, and ≥2, respectively. One-month mortality was higher for patients with CCI 1 (OR 1.67, 95% CI 1.29-2.16, p < .001) and CCI ≥ 2 (OR 2.31, 95% CI 1.70-3.13, p < .001) compared to patients with CCI 0. Patients with CCI 1 (HR 1.27, 95% CI 1.10-1.46, p < .001) and CCI ≥ 2 (HR 1.74, 95% CI 1.48-2.06, p < .001) had worse OS compared to patients with CCI 0. In conclusion, CCI is an independent predictor of survival outcomes in patients with APL.

Acute myeloid leukemia resistant to venetoclax-based therapy: What does the future hold?

Venetoclax is a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, which, combined with a DNA hypomethylating agent or low dose cytarabine, results in high rates of initial responses in patients with acute myeloid leukemia (AML). However, the disease relapses in most patients. Mechanisms of resistance to venetoclax-based therapy include TP53 gene mutations or inactivation of p53 protein, activating kinase mutations such as FLT3 and RAS, and upregulation of other BCL-2 family apoptotic proteins. Current clinical trials are exploring strategies such as doublet or triplet regimens incorporating a p53 activator, an anti-CD47 antibody, or other novel agents that target genes and proteins responsible for resistance to venetoclax. Further studies should focus on identifying predictive biomarkers of response to venetoclax-based therapy and incorporating immunotherapeutic approaches such as checkpoint inhibitors, bispecific antibodies, antibody-drug conjugates, and CAR T-cell therapy to improve outcomes for patients with AML.

Risk of second primary malignancy in patients with primary myelofibrosis: a SEER database study.

Prior studies report a greater incidence of second primary malignancy (SPM) among patients with myeloproliferative neoplasms, although the true risk in primary myelofibrosis (PMF) has not been elucidated. We utilized the Surveillance, Epidemiology, and End Results database to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Out of 5273 patients, 385 patients (7.30%) developed SPM. SPM occurred at SIR of 1.95 (95% CI 1.76-2.15) and AER of 149.01 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.76, 95% CI 1.01-2.86), lymphoma (SIR 3.38, 95% CI 2.28-4.83), and leukemia (SIR 27.19, 95% CI 23.09-31.81) was observed. The risk was significantly higher in patients ≤60 years, males, chemotherapy recipients, within 5 years of PMF diagnosis, and for PMF diagnosed after 2009.

Pegcetacoplan in paroxysmal nocturnal hemoglobinuria: A systematic review on efficacy and safety.

Introduction: Pegcetacoplan, a pegylated penta-decapeptide, targets complement C3 to control both intravascular and extravascular hemolysis. This systematic review aims to study the efficacy and safety of pegcetacoplan in paroxysmal nocturnal hemoglobinuria (PNH). Methods: We performed a comprehensive and systematic literature search for all studies on PubMed, Google Scholar, Cochrane Library, and clinicaltrials.gov. The studies were searched using keywords "paroxysmal nocturnal hemoglobinuria" or "PNH," "Pegcetacoplan" or "Empaveli." The primary outcomes included change in hemoglobin level, transfusion independence, absolute reticulocyte count, and lactate dehydrogenase (LDH) level after pegcetacoplan therapy. The safety outcomes included the proportion of deaths and adverse effects. Results: We included a total of three studies. The total number of patients with PNH was112. 59.83% were female. In the PADDOCK study and study by Hillmen et al., the average increase in hemoglobin was 3.68 g/L and 2.37 g/L, respectively. In the study by de Castro et al., the hemoglobin level increased from below the lower limit of normal and stayed in the normal range (11.1-15.9 g/L). Absolute reticulocyte count and LDH levels decreased in all patients receiving pegcetacoplan. In the study by de Castro et al., LDH level remained stable, and within <1.5× upper limit of normal, whereas in the study by Hillman, the mean change of LDH from baseline was -15 ± 43 U/L. Two of six, seven of 23, and seven of 41 patients reported adverse events in the study by de Castro et al., PADDOCK, and Hillmen et al., respectively. Conclusion: Pegcetacoplan effectively improves hemoglobin level and transfusion requirements in patients with PNH, including those unresponsive to eculizumab.

Precision Medicine in Myeloid Malignancies: Hype or Hope?

PURPOSE OF REVIEW: We review how understanding the fitness and comorbidity burden of patients, and molecular landscape of underlying acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) at the time of diagnosis is now integral to treatment. RECENT FINDINGS: The upfront identification of patients' fitness and molecular profile facilitates selection of targeted and novel agents, enables risk stratification, allows consideration of allogeneic hematopoietic cell transplantation in high-risk patients, and provides treatment selection for older (age ≥ 75) or otherwise unfit patients who may not tolerate conventional treatment. The use of measurable residual disease (MRD) assessment improves outcome prediction and can also guide therapeutic strategies such as chemotherapy maintenance and transplant. In recent years, several novel drugs have received FDA approval for treating patients with AML with or without specific mutations. A doublet and triplet combination of molecular targeted and other novel treatments have resulted in high response rates in early trials. Following the initial success in AML, novel drugs are undergoing clinical trials in MDS. Unprecedented advances have been made in precision medicine approaches in AML and MDS. However, lack of durable responses and long-term disease control in many patients still present significant challenges, which can only be met, to some extent, with innovative combination strategies throughout the course of treatment from induction to consolidation and maintenance.

Effect of Age and Socioeconomic Factors in the Utilization of Chemotherapy in Acute Lymphoblastic Leukemia (ALL): A SEER Database Study of 16,196 Patients.

INTRODUCTION: The use of multiagent chemotherapy in acute lymphoblastic leukemia (ALL) has resulted in improvement in overall survival (OS), albeit to a different extent across various age groups. This large database study aims to assess the disparity in the utilization of chemotherapy in ALL in the real-world setting. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, patients with ALL diagnosis from 2006 to 2016 were identified. Baseline characteristics were compared between the groups who did vs. did not receive chemotherapy using χ2 test. Multivariable logistic regression was used to evaluate the association between various sociodemographic factors and the receipt of chemotherapy in the entire cohort and in different age groups. RESULTS: Out of 16,196 patients, 1258 patients (8%) did not receive chemotherapy. There was a steady increase in the number of patients who did not receive chemotherapy with advancing age: 2.5% (0-18 years), 5.2% (19-40 years), 9.3% (41-65 years), and 36.2% (>65 years). There was an upward trend in the receipt of chemotherapy in patients >65 years over the last decade. In multivariate analysis, the likelihood of receiving chemotherapy decreased with advancing age, single or widowed status, low income and educational status, and lack of insurance. Insurance status was an independent predictor of receipt of chemotherapy across each age category. CONCLUSION: A significant proportion of patients >65 years do not receive chemotherapy in the United States. Age, marital status, income, education, and insurance status contribute to the disparity in utilization of chemotherapy.

Association of insurance types and outcomes in acute promyelocytic leukemia.

Understanding the association between insurance status and survival in an evolving US healthcare system remains a challenge but is essential to address healthcare disparities. We utilized National Cancer Database to evaluate the effects of insurance type on one-month mortality and overall survival (OS) in patients with acute promyelocytic leukemia. Among patients <65 years, one-month mortality was worse for uninsured patients and patients with Medicare compared to patients with private insurance. OS was similar between patients with private insurance and uninsured patients but worse for patients with Medicare and Medicaid/other government insurance. In multivariate analysis, older age and greater comorbidity burden conferred worse OS. For patients ≥65 years, insurance type did not affect one-month mortality and OS. Older age, greater comorbidity burden, and treatment at non-academic centers conferred worse one-month mortality and OS. Our results highlight healthcare disparities based on insurance types for both younger and older patients.

Impact of Insurance on Overall Survival in Acute Lymphoblastic Leukemia: A SEER Database Study.

INTRODUCTION: Insurance status at diagnosis remains an important barrier to health care access and adherence to treatment. Here, we aim to assess the impact of insurance status, and age on overall survival (OS) in patients with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified all patients younger than 65 years of age diagnosed with ALL from 2010 to 2016. OS was estimated for each group using the Kaplan Meier curves and compared based on insurance type using a log-rank test. Multivariate analysis using Cox proportional hazard regression model was used to assess the effect of insurance status on OS. RESULTS: A total of 9057 patients were included in the analysis. Medicaid beneficiaries had worse 5-year OS than insured patients (HR 1.33, 95% CI 1.08-1.63, P = .006) in 0-18 years age group. Despite chemotherapy, patients older than 18 years showed poor OS in all insurance categories. Patients on Medicaid showed inferior OS compared to insured in 19-40 years (HR 1.46, 95% CI 1.21-1.76, P < .001) and 41-65 years age group (HR 1.27, 95% CI 1.09-1.49, P = .003). Interestingly, no significant difference was observed in the OS between the Medicaid and uninsured groups in each age category. CONCLUSION: Our large database study demonstrates that insured status is associated with better OS in ALL across all age groups. Further studies to develop effective strategies to bridge health care disparities areessential.

Determinants of ten-year overall survival of acute myeloid leukemia: a large national cancer database analysis.

Clinical trials do not routinely capture long-term overall survival (OS) in acute myeloid leukemia (AML). We utilized a large National Cancer Database (NCDB) to determine different factors affecting 10-year OS in AML. For patients, 18-59 years who were treated with chemotherapy only without upfront hematopoietic cell transplant (HCT), younger age, female, CBF AML, higher income, and private insurance conferred higher 10-year OS. Among patients, 18-59 years treated with chemotherapy and upfront HCT, younger age and private insurance conferred higher 10-year OS. In a Cox proportional hazard model, the likelihood of death decreased with younger age, fewer comorbidities, treatment at an academic center, private insurance, and use of multiagent chemotherapy. Our results demonstrate poor long-term OS even among younger patients and highlights disparities in leukemia care based on insurance type.