Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Longitudinal changes in cognitive and physical function and health-related quality of life in older adults with acute myeloid leukemia.

INTRODUCTION: Many older adults with acute myeloid leukemia (AML) do not receive chemotherapy because of physicians' and patients' concern for toxicities and functional decline. This highlights the critical and urgent need to generate knowledge of functional changes following new treatments. MATERIALS AND METHODS: As a part of a pragmatic single-center trial, 59 older adults ≥60 years with AML completed geriatric assessment and health-related quality of life measures before treatment and at one month and three months after chemotherapy initiation. Changes in scores of various geriatric assessment measures were computed by subtracting the baseline score from the one-month and three-month scores for each patient. Established cut-offs were used to determine a clinically meaningful change (improvement or worsening). This study provides results of descriptive exploratory analyses. RESULTS: Patients experienced significant comorbidity burden and a high prevalence of functional impairments before treatment, with 56% of patients having ≥2 comorbid conditions, 69% having abnormal cognitive function (using Montreal Cognitive Assessment), 69% having impaired objective physical function (using Short Physical Performance Battery), and 64% having a positive depression screen (Patient Health Questionnaire-9). Patients (n = 53) received treatment with predominantly low-intensity chemotherapy; six patients received intensive chemotherapy. Among those who completed some or all of the three-month evaluation (N = 43), from baseline before treatment to three months later, cognitive function improved (38.7%) or remained stable (38.7%), objective physical function improved (51.6%) or remained stable (22.6%), and depression scores improved (9.4%) or remained stable (53.1%). Global health status score and role functioning moderately improved by a score of >16. DISCUSSION: An exploratory analysis of our phase 2 trial demonstrated improvement or stabilization of cognitive and physical function and depression score at three months in a high proportion of older survivors of AML, despite a high prevalence of frailty and significant comorbidity burden at baseline. These results demonstrate success of treatment in improving cognitive and physical function and depression score, and, if confirmed in larger studies, should encourage oncologists to offer chemotherapy to older adults with AML. CLINICAL TRIAL REGISTRATION: The study is registered in the ClinicalTrials.gov ID: NCT03226418.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia.

INTRODUCTION: Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection. MATERIALS AND METHODS: In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418). In the present report, we demonstrate feasibility of this approach. RESULTS: Broad eligibility criteria and co-management of patients with community oncologists allowed enrollment of 45% of all patients with AML treated at our center during the study period. The median time from enrollment to therapy initiation was two days (range 0-9). Over half of the trial patients had a score of ≥3 on hematopoietic cell transplantation comorbidity index, impairment in physical function (Short Physical Performance Battery), and Montreal Cognitive Assessment. Three fit patients received intensive chemotherapy, whereas other patients received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 3.7% (95% confidence interval [CI] 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). One-year overall survival was 66% (95% CI 60-87%). DISCUSSION: Our data demonstrate the feasibility of integrating geriatric assessment in precision oncology trials to define fitness for intensive chemotherapy. Broad eligibility criteria and academic-community collaboration can expand access to clinical trials.

The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation.

Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

BACKGROUND: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. METHODS: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). RESULTS: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017). CONCLUSIONS: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Usefulness of Charlson Comorbidity Index to Predict Early Mortality and Overall Survival in Older Patients With Acute Myeloid Leukemia.

INTRODUCTION: Older adults with acute myeloid leukemia (AML) often have significant comorbidities. We hypothesized that greater comorbidity burden predicts worse 1-month mortality and overall survival (OS) in patients ≥60 years with AML. MATERIALS AND METHODS: We included 50,668 patients ≥60 years diagnosed between 2004 and 2014 from the National Cancer Database; patients were divided into 3 groups with Charlson comorbidity index (CCI) 0, 1, and ≥2. Chi-square tests were used to examine the association between CCI and different variables. We used logistic regression and Cox proportional hazard models to determine predictors of 1-month mortality and OS, respectively. RESULTS: Among the entire cohort, 65% had CCI 0, 24% had CCI 1, and 11% had CCI ≥2. Thirty-four percent did not receive chemotherapy. Patients with CCI 0 were more likely to receive chemotherapy, especially multiagent chemotherapy and undergo upfront hematopoietic cell transplantation. In multivariate analyses, 1-month mortality and OS were significantly worse with CCI 1 or ≥2, compared with CCI 0 in the entire cohort, as the subgroup of only those patients who received chemotherapy. Younger age, male gender, higher annual income, academic facility, longer travel distance, and acute promyelocytic leukemia were associated with improved OS. CONCLUSION: In one of the largest real-world studies of older adults with AML, we demonstrated that greater comorbidity, measured by higher CCI, independently predicted worse early mortality and OS in older patients with AML. Higher CCI was more common with increasing age and correlated with lower likelihood of receiving chemotherapy and hematopoietic cell transplantation. Whether optimal comorbidity management and supportive care may improve outcomes needs to be studied further.

Effects of Distance From Academic Cancer Center on Overall Survival of Acute Myeloid Leukemia: Retrospective Analysis of Treated Patients.

INTRODUCTION: Patients living farther away from academic centers may not have easy access to resources for management of acute myeloid leukemia (AML). We aimed to analyze the effect of distance traveled on overall survival (OS) of AML patients treated at an academic center. PATIENTS AND METHODS: AML patients diagnosed at the University of Nebraska Medical Center were divided into 4 groups according to the shortest distance between the cancer center and patients' residence (<25, 25-50, 50-100, and > 100 miles). Chi-square test and ANOVA were used to examine the association of distance with patient characteristics. OS, defined as the time from diagnosis of AML to death from any cause, was determined by the Kaplan-Meier method. Comparison of survival curves was done by the log-rank test. Multivariable analysis using Cox regression was performed to detect the survival effect of distance from the cancer center. RESULTS: The total number of patients was 449. Median distance was 85 miles (interquartile range, 20-180). OS at 1 year for < 25, 25-50, 50-100, and > 100 miles was 45%, 55%, 38%, and 40% respectively (P = .6). In a Cox regression analysis, distance from treatment center, as a continuous variable, was not a significant factor for death (hazard ratio, 1.001; 95% confidence interval, 1.000-1.001). Multivariable analysis showed nonsignificant trend of increased mortality for patients traveling > 100 miles to a cancer center. CONCLUSION: This study did not demonstrate an association between distance from an academic cancer center and OS in AML. This finding should provide some assurance to patients who live farther away from academic centers.

Prevalence and effects of polypharmacy on overall survival in acute myeloid leukemia.

Polypharmacy, usually defined as taking ≥5 prescribed medications, increases chances of drug-drug interactions and toxicities, and may harm cancer patients who need multiple chemotherapeutic agents and supportive medications. We analyzed the effects of polypharmacy in overall survival (OS) in acute myeloid leukemia (AML). A total of 399 patients were divided into two groups: patients with polypharmacy (≥5 medications) versus without polypharmacy (<5 medications). Polypharmacy was associated with age ≥60 years, Karnofsky Performance Status of ≤80, hematopoietic cell transplant (HCT) comorbidity index of ≥5, and adverse cytogenetics. Patients with polypharmacy were less likely to receive intensity chemotherapy or HCT. One-year OS of patients with polypharmacy versus those without polypharmacy was 29 vs. 49% (p<.001). Polypharmacy conferred worse OS in patients <60 years (37 vs. 65% at 1 year, HR 1.95, 95% CI 1.21-3.15) but not in patients ≥60 years (26 vs. 27% at 1 year, HR 1.12, 95% CI 0.81-1.57). Thus, polypharmacy has negative impact on OS in AML, particularly among patients aged <60 years.

Survival of Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Effect of Using Multiagent Versus Single-agent Chemotherapy.

BACKGROUND: Controversy exists regarding the optimal chemotherapy regimen for older adults with acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed data from the US National Cancer Data Base of 25,621 patients aged 60 to 79 years, with a diagnosis of AML from 2004 to 2014, who had received single-agent versus multiagent chemotherapy. A Cox proportional hazard model was used for overall survival (OS) analysis for the entire study cohort and separately for patients who had received single-agent (n = 6743) versus multiagent (n = 6743) chemotherapy, matched for age, Charlson comorbidity index, and AML subtype. RESULTS: The use of multiagent chemotherapy was high overall (70%) but declined with factors, such as increasing age, Charlson comorbidity index, AML subtype other than good risk, academic center, lower rate of high school graduation, and more recent year of diagnosis. Patients treated with multiagent chemotherapy had greater 1-year OS (43% vs. 28%), especially for patients aged 60 to 69 years and those with good-risk AML or Charlson comorbidity index of 0 to 1. OS (hazard ratio, 1.32; 95% confidence interval, 1.28-1.36) remained more favorable for the multiagent chemotherapy group on multivariable analysis. This was confirmed in a matched cohort analysis. CONCLUSIONS: To the best of our knowledge, this is the largest real-world study that has demonstrated an association between factors such as age, comorbidity, and AML subtype and the use of multiagent chemotherapy. The use of multiagent chemotherapy was associated with improved OS, especially for patients aged <70 years, those with good-risk AML, and those with a low Charlson comorbidity index.

Effects of Obesity on Overall Survival of Adults With Acute Myeloid Leukemia.

BACKGROUND: The role of obesity in prognosis of acute myeloid leukemia (AML) is debatable. Our retrospective study aimed to determine the effect of obesity on overall survival (OS) in AML. PATIENTS AND METHODS: AML patients diagnosed at University of Nebraska Medical Center were divided into 3 groups according to body mass index (BMI): normal (18.5-25 kg/m2) or underweight (< 18.5 kg/m2); overweight (25-30 kg/m2); and obese (≥ 30 kg/m2). Chi-square test, Kruskal-Wallis test, and ANOVA were used to examine the association of BMI with baseline characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplantation (HCT) comorbidity index. Bonferroni correction was used to adjust P values. OS, defined as time from diagnosis to death from any cause, was determined by the Kaplan-Meier method; comparisons of survival curves were done using log-rank test. Cox regression analysis was performed to detect the effect of BMI on OS. RESULTS: Of 314 patients, 38% were obese, 68% received intensive chemotherapy, and 30% underwent HCT. Patient characteristics for all BMI groups were similar except greater HCT comorbidity index in obese patients. Actual body weight was used to calculate the chemotherapy dose in 92% of obese patients. The rates of receipt of HCT in normal, overweight, and obese groups were 33%, 32%, and 25%, respectively (P = .6). One-year OS values for normal/underweight, overweight, and obese groups was 42%, 45%, and 39%, respectively (P = .31). On multivariate analysis, obesity was associated with worse OS compared to normal-weight (hazard ratio = 0.6; 95% confidence interval, 0.4-0.9; P = .03) but not overweight patients. CONCLUSION: Obesity confers worse prognosis in AML. Differences in OS were not the result of differences in chemotherapy dose or receipt of HCT.

Intensity of chemotherapy for the initial management of newly diagnosed acute myeloid leukemia in older patients.

Aim: This study evaluated the overall survival (OS) of older patients (≥60 years) with acute myeloid leukemia based on the intensity of treatment. Methods: This single center, retrospective study included 211 patients diagnosed between 2000 and 2016, who received 10-day decitabine, low-intensity therapy or high-intensity therapy. Cox regression examined the impact of therapy on OS. Results: Younger patients were more likely to receive high-intensity therapy. Patients who received low-intensity therapy had worse OS compared with high-intensity therapy (median OS: 1.2 vs 8.5 months; p < 0.01). OS was similar with 10-day decitabine (median OS of 6.3 months) compared with either low-intensity therapy or high-intensity therapy. Conclusion: Ten-day decitabine is an effective alternative in older patients with newly diagnosed acute myeloid leukemia.

Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

Comprehensive outreach, prevention education, and skin cancer screening for Utah ski resorts.

Outdoor recreation can lead to substantial sun exposure. Employees of outdoor recreation establishments with extended time outdoors have amplified cumulative exposure to ultraviolet (UV) radiation and an increased risk of skin cancer. The "Sun Safe on the Slopes" program was created by Huntsman Cancer Institute at the University of Utah and the Utah Cancer Action Network to address increased UV exposure and skin cancer risk with free skin cancer screenings, outreach, and prevention education to local ski resorts. Herein, we describe the processes and barriers to implementation of a ski resort skin screening and education program and our 5-year report of the experience and screening data. Nine free skin cancer screenings were held at Utah ski resorts between 2011 and 2016, resulting in the presumptive diagnosis of 38 skin cancers (9.6%) in 394 participants. Behavioral data collected from participants indicates suboptimal sun safety practices, including underuse of sunscreen and protective clothing. Ski resort employees who experience sun exposure during peak hours at high altitudes and UV reflection from the snow are at an increased risk of skin cancer. These data indicate a need for emphasis on sun safety education and screening and can serve as a model for future endeavors.

Initial therapy for acute myeloid leukemia in older patients: principles of care.

Older patients with acute myeloid leukemia (AML) frequently have significant comorbidities, geriatric syndromes, and high-risk leukemia that make them susceptible to high early mortality, chemotherapy-related toxicities, and poor long-term survival. The receipt of chemotherapy or hematopoietic cell transplantation is low, and the choices between intensive or low-intensity chemotherapy is often not clear. Geriatric and multidisciplinary interventions targeted to optimize functional status and improve management of comorbidities may enhance chemotherapy tolerance. Comprehensive geriatric assessment, and other integrated risk assessment models have been developed to predict the risk of chemotherapy-related toxicities and survival, and may guide therapy assignment. Development of low intensity but effective therapy is a major need. Deeper understanding of the molecular biology of AML has allowed several novel therapies to enter clinical trials in recent years. Continuation of successful collaboration between several stakeholders will be necessary to build upon the clinical and research improvements made thus far.