•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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Background: We analyzed CML mortality from 1999 to 2020 in the US in relation to FDA approval of tyrosine kinase inhibitors (TKIs). These agents were introduced in the 2000s, revolutionizing the ...treatment of CML and providing a paradigm for targeted therapy in oncology. Starting with imatinib in 2001, followed by dasatinib (2006), nilotinib (2007), and bosutinib (2012). TKIs have increased tolerability and efficacy for the treatment of CML as compared to previous treatment modalities. We investigated age-adjusted mortality rates (AAMR) and annual percent change (APC) in this population in relation to TKI approval. Methods: Using the CDC WONDER database, we examined mortality trends from 1999 to 2020 for CML in the US. AAMRs were calculated per 100,000 people and stratified by sex, race/ethnicity, and census region. AAMR groups were listed as pre-TKI era and 1 year post-FDA approval of different TKI agents. We computed the APC trends for the respective stratification with Joinpoint, a regression analysis program. Results: Between 1999 and 2020 there were 35,268 deaths from CML. In 1999, overall AAMR initially was 0.8, which improved to 0.5 by 2020 with a respective APC of -2.5%. In our subgroup analysis there was a consistent and significant decrease in AAMR since the introduction of Imatinib in 2001. With additional TKI releases, AAMR continued to decline in all subgroups. APC for mortality rates was similar between all subgroups -2.0 to -2.8% indicating a similar benefit regardless of subgroup. Male AAMR was consistently higher than female AAMR. Black and white patients (0.5, 2020) have a 2.5x higher AAMR (0.2, 2020) compared to Asian patients. Census region did not show a significant difference between each other. Conclusions: Since the FDA approval of imatinib in 2001 and the subsequent release of TKIs there has been a significant impact on reducing AAMR for patients with CML. The decline was seen in sex, race, and census region. The APCs were similar between all subgroups indicating a consistent improvement in survival. Possible etiologies of disparities in AARM for males in comparison to females and for black and white patients in comparison to Asian patients include gender and race-associated gene polymorphisms possibly inducing differences in drug metabolism. Further gender and race specific pharmacokinetic studies would be useful to further elucidate etiology of the disparity and may lead to changes in TKI dosing strategies. Table: see text
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Background: Hodgkin Lymphoma has a bimodal distribution with the first peak between ages 15-35 and the second peak being 55 years old and older. Advancements in treatment therapies have ...improved mortality such that Hodgkin Lymphoma is considered a curable disease. However, treatment outcomes in elderly patients are inferior to those of younger patients. In our study, we analyzed Hodgkin Lymphoma mortality from 1999 to 2020 in the United States. We investigated age-adjusted mortality rates and annual percent changes with a sub-group analysis. Methods: Using the CDC Wonder database, we examined mortality trends from 1999 to 2020 for Hodgkin Lymphoma in adults age 55 and older in the United States. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 people and stratified patients by sex, race/ethnicity, and census region. We computed the annual percentage change trends for the respective stratification using Joinpoint regression software. Additionally, a comparison group between ages 15 and 54 was added for the analysis. Results: In the United States, between 1999 and 2020 there were 24,898 deaths from Hodgkin Lymphoma in Adults 55 and older. The overall age adjusted mortality rate improved from 1.9 per 100,000 people to 1.4, with a respective APC of -2.06%. Our subgroup analysis by sex, race, and census region showed improvements circumferentially. Males consistently had higher rates of improvement than females. Most notably black patients had the lowest difference in AAMR from 1999 to 2020 (0.2), however, white patients and Hispanic patients respectively had higher AAMRs. The comparison group ages 15-54 had lower AAMR change from 1999 to 2020 by sex, race, and region. However, the respective AAMR for the age 15-54 group was significantly lower. Conclusions: Hodgkin Lymphoma has had significant age adjusted mortality rate improvements since 1999. Comparing adults 55 and older to patients 15-54 there is still a notable difference in AAMR. The greater magnitude of improvement in AAMR in older adults with Hodgkin Lymphoma may be related to the approval of agents such as brentuximab vedotin, which has improved tolerability as compared to bleomycin. Alleviating pulmonary toxicity with this novel agent may be more relevant in an older patient population with increased comorbidities. Further, research is needed to continue to identify more efficacious and less toxic therapies for older individuals with Hodgkin Lymphoma. Table: see text
ABSTRACTIntroduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, non-malignant hematologic disease characterized by complement-mediated hemolysis (with or without hemoglobinuria), ...fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction. The development of complement inhibitors has transformed outcomes for patients with PNH, but patients may still experience pharmacodynamic breakthrough hemolysis (BTH), which can be caused by exposure to a complement amplifying condition (CAC), such as vaccination, infection, or surgery.Materials and methods: A 13-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on how to classify pharmacodynamic BTH in patients with complement-inhibitor treated PNH. Physicians reviewed literature, rated the appropriateness of over 400 scenarios, and discussed the ratings at an in-person meeting.Results: After the meeting, the panel agreed on 77% of scenarios. Here, we present the group’s agreed-upon recommendations on how to manage BTH caused by a CAC, as well as provide a severity classification system for BTH and strategies to mitigate risk of BTH in special circumstances (e.g. vaccination, planned or unplanned surgery, and pregnancy).Discussion: In general, as severity of BTH increased, experts agreed more interventions to manage the BTH were appropriate. These recommendations are based on clinical experience and opinion. Without clear data from randomized trials to guide the management of BTH, expert opinion can be useful to support patient care.
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This open-label phase 1 study (clinicaltrials.gov, NCT03555955) assessed CPX-351 pharmacokinetics (PK) and safety in patients with hematologic malignancies with normal or impaired renal function. ...Patients were enrolled into three cohorts based on their creatinine clearance (CrCl): ≥90 mL/min (Cohort 1, normal renal function,
= 7), 30 to <59 mL/min (Cohort 2, moderate renal impairment,
= 8), or <30 mL/min (Cohort 3, severe renal impairment,
= 6). Patients received intravenous CPX-351 for initial induction; blood and urine samples were collected for PK analysis. The primary objective was to assess the PK parameters for cytarabine, daunorubicin, and their respective metabolites, arabinosyluracil (Ara-U) and daunorubicinol. Renal impairment did not significantly impact the cytarabine, daunorubicin, or daunorubicinol exposure, but it caused a slight increase in the Ara-U exposure. The CPX-351 side effect profile was similar in patients with impaired renal function compared to those with normal renal function. All the patients reported ≥1 treatment-emergent adverse event (TEAE), most commonly febrile neutropenia and nausea (57% each) and hyperglycemia (43%); no patients discontinued treatment due to TEAEs. These data suggest that CPX-351 dose adjustment is not required for patients with hematologic malignancies with moderate or severe renal impairment.
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Introduction
Cytogenetic analysis is important for stratifying patients with various neoplasms. We explored the use of targeted next generation sequencing (NGS) in detecting chromosomal structural ...abnormalities or copy number variations (CNVs) in patients with myeloid neoplasms.
Methods
Plasma cell-free DNA (cfDNA) from 2821 myeloid or lymphoid neoplasm patients were collected. cfDNA was sequenced using a 275 gene panel. CNVkit software was used for analyzing and visualizing CNVs. Cytogenetic data from corresponding bone marrow (BM) samples was available on 89 myeloid samples.
Results
Of the 2821 samples, 1539 (54.5%) showed evidence of mutations consistent with the presence of neoplastic clones in circulation. Of these 1539 samples, 906 (59%) showed abnormalities associated with myeloid neoplasms and 633 (41%) with lymphoid neoplasms. Chromosomal structural abnormalities in cfDNA were detected in 146 (16%) myeloid samples and 76 (12%) lymphoid samples. Upon comparison of the myeloid samples with 89 BM patients, NGS testing was able to reliably detect chromosomal gain or loss, except for fusion abnormalities. When cytogenetic abnormalities were classified according to prognostic classes, there was a complete (100%) concordance between cfDNA NGS data and cytogenetic data.
Conclusions
This data shows that liquid biopsy using targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms. In specific circumstances, targeted NGS may be reliable and efficient to provide adequate information without the need for BM biopsy considering broad mutation profiling can be obtained through adequate sequencing within the same test. Overall, this study supports the use of liquid biopsy for early diagnosis and monitoring of patients with myeloid neoplasms.
Introduction: Leukemia patients have abnormal immune function due to both the innate characteristics of their disease and the treatments, which are almost invariably immunosuppressive in nature. ...Treatment modalities may lead to both temporary and long term immunosuppression. For these reasons, the coronavirus disease 2019 (COVID-19) pandemic has posed challenges to the management of patients with leukemia.With the approval of several types of COVID-19 vaccines, the first of which became available in December 2020, there has been a significant decrease in morality from COVID-19 among vaccinated adults compared to unvaccinated adults. It is unclear if the same trend applies to adults with leukemia who may have an impaired immune response to vaccination. To further elucidate the efficacy of COVID-19 vaccination in this inherently immunocompromised group of patients, we performed a nationwide analysis of COVID-19 mortality trends in adults over 25 years old with leukemia. Methods: Using the CDC Wonder Database, we reviewed death certificates for COVID-19 related mortality trends from March 2020 to June 2023 for all subtypes of leukemia in the United States in adults above 25 years old. We included respective ICD codes: C91 lymphoid leukemia, C92 myeloid leukemia, C93 monocytic leukemia, C94 other leukemias of specified cell types, and C95 leukemia of unspecified cell types. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 people. Data was stratified by reported sex, race/ethnicity, and census region. Results: Deaths from COVID-19 in people with leukemia were reported as 1800 in 2020, 2813 in 2021, 2445 in 2022, and 481 as of June 2023 (Figure 1). There were fluctuations of COVID-19 AAMR per 100,000 people with all subtypes of leukemia from 2020 to 2023 (Table 1). The provisional and incomplete data in 2023 showed a sudden decrease of AAMR within all groups. In 2020 the overall AAMR in all groups was 0.7 which increased to 1.1 in 2021, decreased to 0.9 in 2022, and 0.2 as of June 2023. There is a difference in mortality rates between sex with male AAMR being greater than female in all 3 years. For example in 2021 the AAMR for males was 1.4 while for females it was 0.6. Analysis of racial and ethnic groups showed Asians with the lowest AAMR (0.3 AAMR, 2020) compared to Whites (1.5 AAMR, 2020), Blacks (0.9 AAMR, 2020), and Hispanics (0.6 AAMR, 2020). The trends between the census regions were also comparable. Conclusion: The data demonstrates variations in AAMRs from each year to the next. These variations can be affected by infection rates, public health measures, healthcare access, and socioeconomic factors. The 2023 data is still provisional and incomplete, however, they do offer a glimpse of the 2023 trends. The multiple subtypes of leukemia have different degrees of immunosuppression, thus not all leukemia patients have the same risk profile. Despite the type of Leukemia, it is widely accepted that these patients are in an immunocompromised state and at a higher risk to develop complications from COVID-19. It is recommended for all patients with leukemia to receive non-live, attenuated viral vaccines. Although considered safe and recommended, there is very limited data regarding efficacy of the COVID-19 vaccine in immunocompromised patients. One study showed patients with CLL about 36% of patients were seronegative after vaccination (Chatzikonstantinou et al., 2021) and seronegativity rates may be even higher in patients with acute leukemias. Certainly the absence of steady downward trend in mortality following the availability of vaccination suggests either that leukemia patients are not complying with vaccination recommendations or that vaccination is often ineffective in the setting of their inherent immunocompromise. Certainly a limitation of this analysis is the lack of data regarding COVID-related mortality in vaccinated versus unvaccinated individuals. Given the lack of improvement in AAMR among leukemic patients following the availability of a COVID 19 vaccination, it seems appropriate that physicians still recommend using additional preventative measures from COVID-19 including social distancing and mask wearing. It is important to continue studying the relationship between serology positivity, immunity, and overall outcomes.
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Introduction: The incidence of many types of leukemia increases with age. Intensive induction chemotherapy containing cytarabine and an anthracycline has been part of the upfront and salvage ...treatment of AML for decades. Regimens for the treatment of ALL are also often anthracycline-based. Anthracyclines are associated with a significant risk of cardiotoxicity including anthracycline-related left ventricular dysfunction. Comprehensive baseline evaluation of cardiac function and risk may lead to better risk stratification and selection of patients who are best suited to anthracycline-based therapy. With the advent of more effective, yet less chemo-intense regimens for the management of older or unfit adults with leukemia, for example hypomethylator and venetoclax-based combinations, which gained widespread use with their accelerated approval in November 2018, one would hypothesize decreased rates of cardiovascular complications associated with the treatment of adult leukemia. To further investigate this hypothesis, we performed a nationwide analysis for adults age 25 and older with leukemia of all types and their associated cardiovascular disease related mortality. Methods: We utilized the Wide-ranging Online Data for Epidemiologic Research from the CDC. Patients were identified using ICD codes: C91 (Lymphoid leukaemia, C92 (Myeloid leukaemia), C93 (Monocytic leukaemia), C94 (Other leukaemias of specified cell type), and C95 (Leukaemia of unspecified cell type) with an underlying cause of death I00-I99 (Diseases of the circulatory system). Data was reviewed between 1999 to 2020 and included patients who were aged ≥25. We analyzed the age adjusted mortality rate (AAMR) per 100,000 people and stratified the data by sex, race/ethnicity, and geographical location within the USA by census region. Results: There were a total of 19,368 cardiovascular related deaths in leukemia patients between 1999 and 2020. There has been a decreasing trend in overall mortality associated with cardiovascular diseases from 1999 to 2019, falling from 4.6 to 3.9 deaths per 100,000 people, with an annual percent change of -2.89% (Figure 1). Both sexes mirrored this trend, with female mortality rates improving from 3.4 to 2.7 (APC -3.26%) and male rates from 6.5 to 5.6 (APC -3.07%) between 1999 and 2019. In 2020, it was observed that leukemia patients had an increased cardiovascular related mortality: 4.5 AAMR overall, 3.0 AAMR in females, and 6.5 AAMR in males . There was not a statistically significant difference in mortality changes by race (Table 1). Conclusion: Our study reveals a decrease in mortality rates from cardiovascular disease in leukemia patients from 1999 to 2018 followed by a relatively sharp increase noted in 2020. The steady improvements noted from the early 2000s to the 2010s may be attributable to awareness of known toxicities that led to enhanced screening and active monitoring for cardiovascular complications. Electrocardiograms, echocardiograms, and cardiotoxic markers including troponins and natriuretic peptides have served as diagnostic and risk-stratification tools. In 2020 leukemia patients exhibited a sudden increase in mortality across all sub-groups. One may postulate that this is related to COVID-19-related complications/delays in treatment, however, another possible explanation may be incompletely recognized toxicities of novel therapeutics. Interestingly, preclinical data have demonstrated that venetoclax treatment resulted in cardiac damage as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2 has been observed (AlAsmari et al Int J Mol Sci 2022). Clearly, continued monitoring and further exploration is needed to identify the reason or reasons for the noted 2020 phenomenon. Continued data collection in the post-Covid vaccine era is likely to help to further elucidate the reasons for the unexpected uptick in cardiovascular-related morbidity and mortality in our leukemia patients.
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Introduction: Acute Lymphoblastic Leukemia (ALL) has a bimodal distribution and while it is the most common malignancy in children, it can also present in adults 55 years of age and older. Adverse ...disease biology and comorbidities that preclude delivering curative regimens are factors that underlie the markedly disparate outcomes seen between childhood and older adult ALL. Advancements in therapy have improved prognosis in children, however in adults' treatment outcomes are worse. Our study aims to compare mortality trends in older adults compared to children within the United States with ALL. Methods: Using the Center for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database, we reviewed death certificate data for ALL patients from 1999 to 2020, age 55 and older in the United States. ICD code C91.0 (Acute lymphoblastic leukemia - Malignant neoplasms) was used to identify patients with ALL. Age-adjusted mortality rates (AAMRs) were calculated per 1,000,000 people and stratified patients by sex, race/ethnicity, and census region (Northeast, Midwest, South, and West). A comparison group between ages 0 and 15 was added with an identical stratification of sub-group data. Results: In the United States from 1999 to 2020 there were 17,238 deaths in ALL patients 55 and older. For this population there was not an improvement in mortality over the last twenty years (10.8, AAMR 1999) and (10.6, AAMR 2020). Further subgroup analysis did not reveal a significant difference over the years by reported sex, race, and US census region. Men and hispanic patients had the highest AAMR consistently, 12 and 13.6 in 2020. There was a statistically significant improvement in ages 0-15 for overall AAMR, 3.5 in 1999 to 2.2 in 2020 (Table 1). Conclusion: There has not been a significant improvement in AAMR for adults 55+ with ALL despite improvements seen in the pediatric patient population. Over the last twenty years AAMR in the older adult population has unfortunately been stagnant. This is despite the approval of several new therapies for adult patients with ALL including blinatumumab, inotuzumab, and the increased recognition of the importance of targeted tyrosine kinase inhibitor-based therapy for patients with Ph+ ALL, which is certainly much more prevalent in the older adult ALL population. The lack of AAMR despite the numerous seemingly therapeutic advances made in the adult population underscores the need to specifically study new therapeutics, their outcomes, utilization, and toxicities, in the sub-population of older adults with ALL in order to understand the lack of collective benefit seen in this unique patient population. Continued monitoring of the AAMR trends in this patient population will soon begin to reflect the availability of CART therapy.
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Introduction: Amyloidosis is a collective term for conditions with an abnormal extracellular deposition of amyloid protein. Amyloidosis can be classified based on the location of deposition ...(localized vs systemic) and by the different subtypes of proteins which are created as a result of a variety of diseases (plasma cell dyscrasias, chronic inflammation, nephrotic syndrome, genetic). Depending on the affected organs, amyloidosis can present with, not limited to, hepatomegaly, renal impairment, nerve conduction impairment, cardiac conduction abnormalities, restrictive cardiomyopathy, and multiorgan failure. In the last century there has been an increase in innovations leading to a better understanding of the pathology, diagnostic tests, staging, and treatment options for amyloidosis. Our study aims to compare all cause mortality trends in adults over 25 years old diagnosed with amyloidosis in the United States. Methods: The national mortality trends from 1999 to 2020 for all subtypes of amyloid were analyzed from the CDC WONDER database. The data was extracted using ICD codes E85 (Amyloidosis) with subgroups E85.0 (Non-neuropathic heredofamilial amyloidosis), E85.3 (Secondary systemic amyloidosis), E85.4 (Organ-limited amyloidosis), E85.8 (Other amyloidosis), and E85.9 (Amyloidosis, unspecified. Data was stratified for age groups above 25 years old. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 people and death certificate data was stratified by reported sex, race/ethnicity, and US census region. Results: Between 1999 and 2020 there were 40,015 deaths from amyloid. Our analysis revealed that all-cause AAMR per 100,000 people with amyloid showed an increasing trend between 1999 to 2020 (Figure 1). Subgroup analysis on race/ethnicity revealed the AAMR for the Black population has been consistently higher to other groups (Table 1). On average, from 1999 to 2020, the Black population had the highest AAMR (1.52 AAMR) followed by the White population (0.78 AAMR), Hispanic (0.55 AAMR), and Asian (0.5 AAMR). Further subgroup analysis revealed men have a higher AAMR (1.9 AAMR, 2020) compared to women (0.8 AAMR, 2020). Overall there are similar census region trends of all mortality in Amyloid: North (1.5 AAMR, 2020), Midwest (1.5 AAMR, 2020), South (1.0, AAMR, 2020) and West (1.3 AAMR, 2020). Conclusion: Due to advancement in technology, amyloid diseases are becoming more widely recognized and increasingly diagnosed. Unfortunately, treatment of amyloidosis remains limited to early diagnosis and treatment of the underlying condition. This includes modalities such as chemotherapy and stem cell transplantation for plasma cell dysplasias and TTR stabilizers for hereditary amyloidosis. These trends in increase in AAMR likely reflect the increased awareness/diagnostics of amyloid disease and complications. The African American population may have higher AAMR due to socioeconomic and environmental factors, health disparities, and research bias. We also suspect men have a higher ATTR than women as it has been reported that ATTR and AL Amyloidosis tends to occur more frequently in men than women and is associated with more severe disease (Kroi et al., 2020, Desport et al., 2012). Further research is necessary to expand on the disparities seen with the ultimate goal of providing targeted therapies to reverse this downward trend.
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