Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia.

Importance: Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings. Objective: To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response. Design, Setting, and Participants: A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years. Exposure: Attempting to stop using a TKI. Main Outcomes and Measures: Estimated savings after attempted discontinuation of TKI use. Results: A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy. Conclusions and Relevance: The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Economic Impact of Transformation to Acute Myeloid Leukemia Among Actively Managed Patients with Higher-Risk Myelodysplastic Syndromes in the United States.

INTRODUCTION: Transformation of higher-risk myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) may be associated with increased healthcare resource utilization (HCRU) and costs. To describe this economic impact, HCRU and costs were compared between US patients who experienced transformation to AML and those who did not. METHODS: Using the Optum administrative claims data, this retrospective matched cohort study identified patients (≥ 18 years old) with higher-risk MDS who initiated first-line therapy between January 1, 2008, and June 30, 2019. Patients whose disease transformed to AML were matched 1:1 to patients whose disease did not transform, based on the duration of follow-up. The follow-up period was divided into two periods: pre- (before transformation to AML) and post-AML (after transformation to AML). For patients who did not transform to AML, pre- and post-AML periods were determined using the transformation date of their matched pair. HCRU and total adjusted costs (2019 US dollars, $) were compared between patients who transformed to AML and those who did not. RESULTS: A total of 118 matched patient pairs were included in the study. The hospitalization rate was significantly higher in patients who transformed than in those who did not during the entire follow-up (58.8% vs. 44.1%; P = 0.0295) and post-AML (47.5% vs. 28.0%; P = 0.0028) periods. Across all periods, supportive care use was significantly higher among patients who transformed to AML vs. patients who did not transform. Adjusted mean monthly costs for patients with higher-risk MDS who transformed to AML were higher than those who did not transform ($25,964 vs. $19,150; P < 0.0001). The observed total cost difference was more notable in the post-AML period ($36,424 vs. $14,860; P < 0.0001). CONCLUSIONS: Patients with higher-risk MDS whose disease transformed to AML incurred significantly higher healthcare costs compared to those whose disease did not transform, highlighting the important need for treatments that prevent or delay transformation.

Clinical and molecular assessment of an onco-immune signature with prognostic significance in patients with colorectal cancer.

Understanding the complex tumor microenvironment is key to the development of personalized therapies for the treatment of cancer including colorectal cancer (CRC). In the past decade, significant advances in the field of immunotherapy have changed the paradigm of cancer treatment. Despite significant improvements, tumor heterogeneity and lack of appropriate classification tools for CRC have prevented accurate risk stratification and identification of a wider patient population that may potentially benefit from targeted therapies. To identify novel signatures for accurate prognostication of CRC, we quantified gene expression of 12 immune-related genes using a medium-throughput NanoString quantification platform in 93 CRC patients. Multivariate prognostic analysis identified a combined four-gene prognostic signature (TGFB1, PTK2, RORC, and SOCS1) (HR: 1.76, 95% CI: 1.05-2.95, *p < 0.02). The survival trend was captured in an independent gene expression data set: GSE17536 (177 patients; HR: 3.31, 95% CI: 1.99-5.55, *p < 0.01) and GSE14333 (226 patients; HR: 2.47, 95% CI: 1.35-4.53, *p < 0.01). Further, gene set enrichment analysis of the TCGA data set associated higher prognostic scores with epithelial-mesenchymal transition (EMT) and inflammatory pathways. Comparatively, a lower prognostic score was correlated with oxidative phosphorylation and MYC and E2F targets. Analysis of immune parameters identified infiltration of T-reg cells, CD8+ T cells, M2 macrophages, and B cells in high-risk patient groups along with upregulation of immune exhaustion genes. This molecular study has identified a novel prognostic gene signature with clinical utility in CRC. Therefore, along with prognostic features, characterization of immune cell infiltrates and immunosuppression provides actionable information that should be considered while employing personalized medicine.

Patient characteristics, treatment patterns, and mortality in elderly patients newly diagnosed with acute myeloid leukemia meeting ineligibility criteria for high intensity chemotherapy.

To describe patient characteristics, treatment patterns, and survival among elderly patients (≥66 years) newly diagnosed with acute myeloid leukemia (AML) meeting ≥1 ineligibility criteria for high-intensity chemotherapy (HIC; i.e. age >75 years, cardiac disease/prior anthracycline therapy, or secondary AML), we analyzed 2007-2017 100% Medicare hematologic cancer data. Patients were stratified based on whether they received HIC or low-intensity chemotherapy (LIC) or best supportive care (BSC) within 60 days after AML diagnosis. Of 4,152 patients, 43.2% received chemotherapy, 33.8% BSC, and 23.1% no therapy. Among chemotherapy-treated patients, HIC was more common than LIC (58.8 vs 41.2%), despite targeting patients meeting ≥1 ineligibility criteria for HIC. Poor overall survival was observed for patients receiving chemotherapy and BSC (median overall survival [interquartile range]: HIC, 1.9 [0.8, 6.6] months; LIC, 3.8 [1.4, 9.3] months; BSC, 1.0 [0.4, 2.5] months). Results highlight the need for additional effective and tolerable treatments for this population.

Epidemiology, Staging, and Management of Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

IMPORTANCE: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients. OBJECTIVE: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. DESIGN, SETTING, AND PARTICIPANTS: The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. INTERVENTION: Discontinuation of TKIs. MAIN OUTCOMES AND MEASURES: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). RESULTS: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. CONCLUSIONS AND RELEVANCE: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02269267.

Mortality trends in sickle cell patients.

BACKGROUND: Sickle cell disease affects a significant portion of US patients with African descent. It continues to be one of the leading causes of frequent hospitalizations and high in-hospital morality risk. Until the approval of disease-modifying therapies in last two years, medical therapy has relied mostly on management of pain episodes and the use of hydroxyurea. We discuss the nationwide analysis of trends in in-hospital mortality in patients with Sickle Cell Disease from 2000 to 2014. METHODS: Trends of in-hospital mortality in sickle cell patients were analyzed from a database provided by the Agency of Healthcare Research and Quality. From the data hospitalization rates and in-hospital mortality in categories by region in the US, hospital size, health insurance status, comorbidities and gender were examined. Patterns of in-hospital mortality were analyzed by logistic regression. RESULTS: Ratio for hospitalization and mortality among the four regions described Northeast, Midwest, South, West with respective values of 0.63%, 0.65%, 0.76% and 0.89% with P = 0.008 and OR = 1.07. Odds ratio for sickle cell patients that died during hospitalization and health insurance status was OR = 0.08. Comorbidities considered in sickle cell patients; diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), chronic kidney disease (CKD), smoking status. The odds ratio for comorbidities show A-fib with a value of OR = 4.47, followed by hypertension OR = 1.92, diabetes mellitus OR = 1.44 and chronic kidney disease OR = 1.29, smoking status OR = 0.60. Mortality-hospitalization ratio by gender was: males 0.77% and females 0.69% with OR = 0.87. CONCLUSIONS: In-hospital mortality by US regions, as well as health insurance status are important measurable elements that show the impact of the disease from a public health perspective. Further and more specific data of regions by states, comorbidities by states and sex, as well as health insurance status by states will provide further insight in local mortality trends.

Clinical performance and utility of a comprehensive next-generation sequencing DNA panel for the simultaneous analysis of variants, TMB and MSI for myeloid neoplasms.

The extensively employed limited-gene coverage NGS panels lead to clinically inadequate molecular profiling of myeloid neoplasms. The aim of the present investigation was to assess performance and clinical utility of a comprehensive DNA panel for myeloid neoplasms. Sixty-one previously well characterized samples were sequenced using TSO500 library preparation kit on NextSeq550 platform. Variants with a VAF ≥ 5% and a total read depth of >50X were filtered for analysis. The following results were recorded-for clinical samples: clinical sensitivity (97%), specificity (100%), precision (100%) and accuracy (99%) whereas reference control results were 100% for analytical sensitivity, specificity, precision and accuracy, with high intra- and inter-run reproducibility. The panel identified 880 variants across 292 genes, of which, 749 variants were in genes not covered in the 54 gene panel. The investigation revealed 14 variants in ten genes, and at least one was present in 96.2% patient samples that were pathogenic/ likely pathogenic in myeloid neoplasms. Also, 15 variants in five genes were found to be pathogenic/ likely pathogenic in other tumor types. Further, the TMB and MSI scores ranged from 0-7 and 0-9, respectively. The high analytical performance and clinical utility of this comprehensive NGS panel makes it practical and clinically relevant for adoption in clinical laboratories for routine molecular profiling of myeloid neoplasms.

Analysis of outcomes in hospitalized pregnant patients with acute myeloid leukemia.

BACKGROUND: There have been significant advances in the management of acute myeloid leukemia (AML) in the past decade. However, management of AML in the pregnant patient has been challenging as most interventions are contraindicated in pregnancy. Medical termination of pregnancy is advocated over chemotherapy in the first trimester as delaying chemotherapy could often be fatal. Chemotherapy during second and third trimesters may be provided with close surveillance of fetal abnormalities. The outcomes in these patients have not been systematically studied and have been limited to case reports and case series in medical literature. METHODS: Patients hospitalized with a diagnosis of AML were identified using the International Classification of Disease (ICD-9) codes in the National Inpatient Sample database. This database is maintained by the Agency of Healthcare Research Quality under the United States Department of Health and Human Services. It represents 20% of all hospitalizations occurring in the United States every year. Amongst these AML patients, all patients who were pregnant were identified and their demographic information was extracted. Other details related to their hospitalization, hospital size, location, region and teaching status were also determined. The association of outcomes with common medical comorbidities was studied. Pregnancy related outcomes, mode of delivery and mortality rates were calculated for the 15 year time period. RESULTS: During the time period of 2000 to 2014, 678942 hospitalizations involved AML patients of which 5076 were noted to be from pregnant women. The hospitalization trend gradually increased over these years and was noted to be the highest in the age group of 18-34 years. The highest hospitalization rates were noted in African American and Native American patient populations. Hypertension, hyperlipidemia, chronic kidney disease and smoking were noted to be more prevalent in pregnant women with AML. A majority of these patients had a Charlson's comorbidity index of 1-3. 3.5% of patients underwent medical termination of pregnancy, 16.25% suffered from pregnancy related complications, 0.6% suffered from puerperal infection, 4% of patients had normal vaginal delivery, 2.8% of patients had caesarian section and 5.7% of patient died. The rate of mortality was the highest in Native Americans followed by Caucasians. Multiple regression showed that odds of mortality have decreased from 2000 to 2015 and that a higher Charlson's comorbidity score was an independent predictor of mortality. CONCLUSIONS: This is the first nationwide study to document the outcomes of pregnancy in hospitalized AML patients. AML in pregnancy is rare and this study shows that the mortality has been improving over the past 15 years. Notably, vaginal delivery has been more common than caesarian section in pregnant AML patients. Native Americans have high prevalence and high mortality rates, a likely result of healthcare disparity. Pregnant AML patients with high Charlson's comorbidity score may benefit from aggressive management of their comorbidities. Further studies are required to better characterize outcomes in pregnant women with AML.

Patient characteristics, treatment patterns, and mortality in elderly patients newly diagnosed with ALL.

To describe patient characteristics and treatment patterns among elderly patients (≥66 years) newly diagnosed with acute lymphoblastic leukemia (ALL), we analyzed 100% Medicare ALL data from 2007 to 2015. Only 764 out of 1428 (53.5%) elderly patients received treatment within 90 d of diagnosis with ≥30-d follow-up; 32.4% received chemotherapy without tyrosine kinase inhibitors (TKIs), 8.8% received both chemotherapy and TKIs, 9.8% received steroids only and 2.6% received TKIs only. Among 717 patients receiving chemotherapy any time during follow-up, 65.8% received only one course of treatment. Patients treated with chemotherapy or TKIs compared to untreated patients were younger (<75 years: 51.5 vs. 21.7%) and had a lower comorbidity burden (Charlson Comorbidity index ≤ 2: 90.9 vs. 71.4%). Overall, 67.5% of patients died within 3 years of diagnosis. Our findings demonstrate that many elderly ALL patients are not treated in the real-world setting and highlight the need for tolerable therapies for these patients.

Economic burden of elderly patients with acute myeloid leukemia treated in routine clinical care in the United States.

This retrospective claims database study examined healthcare utilization (HCU) and costs associated with acute myeloid leukemia (AML) in 237 elderly patients who received chemotherapy or a stem cell transplant (SCT) following AML diagnosis. Patients with secondary AML were excluded. Over the entire follow-up period, 92.0% of patients had ≥1 inpatient admission; 85.7% had ≥1 AML-related admission, and 42.6% had ≥1 non-AML-related admission. During inpatient admissions, 39.2% of patients had ≥1 intensive care unit (ICU) admission, with 20.7% having ≥1 AML-related ICU admission, and 27.8% having ≥1 non-AML-related ICU admission. Total mean per-patient per-month (PPPM) costs over the follow-up period were $25,243 (SD: $21,909), with costs from Year 1 ($27,756 [SD: $22,121]) more than double those in Year 2 ($12,953 [SD: $26,334]) following AML diagnosis. The majority of total costs were medical ($24,512 PPPM [SD: $21,704]), which included inpatient admissions ($6548 PPPM [SD: $10,777]), other outpatient visits ($5021 PPPM [SD: $7997]), supportive care ($3640 PPPM [SD: $5589], and chemotherapy administration ($2029 PPPM [SD: $2345]). Healthcare costs of treated elderly AML patients are substantial, particularly in the first year following diagnosis. Further research is needed to understand factors contributing to high costs in various settings of care for elderly AML patients.