NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma.

BACKGROUND AND OBJECTIVES: Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS: We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH). RESULTS: Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC. CONCLUSIONS: PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.

Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

In the original publication, the sixth author name was published incorrectly as Matthew Stein. The correct author name should read as Matthew K Stein.

Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Ampullary adenocarcinoma: Defining predictors of survival and the impact of adjuvant therapy following surgical resection for stage I disease.

BACKGROUND AND OBJECTIVES: Outcomes and recommendations regarding adjuvant therapy (AT) for stage I ampullary adenocarcinoma (AAC) are inadequately described. We sought to determine factors associated with survival and better define the impact of AT. METHODS: The NCDB was queried for stage I AAC patients undergoing resection. We evaluated variables influencing the administration of AT and affecting survival, including the receipt of AT. RESULTS: Five hundred thirty-seven patients were identified. 1, 3, and 5-year OS were 91.3%, 78.8%, and 67.4%, respectively. 103 received AT: 101 chemotherapy, 31 radiation, and 29 a combination of both. AT was more commonly utilized in patients with poorly differentiated and T2 tumors. Comorbid disease was inversely associated with use of AT. Age ≥65 was associated with decreased survival for stage IA and IB, while positive resection margins and sampling of <12 LNs were associated with decreased OS for stage IA and IB, respectively. After propensity matching key covariates, no significant difference in OS was observed between those receiving and not receiving AT (P = 0.449). CONCLUSION: This analysis revealed a modest 5-year OS for stage I AAC. Age, positive resection margins, and evaluation of <12 LNs negatively influenced OS and AT did not convey a survival benefit.

Desmoplastic small round cell tumor: A nationwide study of a rare sarcoma.

BACKGROUND AND OBJECTIVES: Desmoplastic small round cell tumor (DSRCT) is a rare peritoneal surface malignancy. Current research is limited by the scarcity of this disease. METHODS: Patients with DSRCT were identified in the 2004-2014 NCDB. Factors affecting overall survival (OS) were assessed. Additionally, trends were examined based on the volume of cases treated at individual facilities. RESULTS: A total of 125 patients were identified with a median age of 21 (IQR 15-27). Six had extra-abdominal disease and 15 (12%) had liver involvement. Median OS was 28 months. Systemic chemotherapy (HR 0.4, P = 0.015) and surgery (HR 0.6, P = 0.047) were associated with reduced mortality. For the 74 patients undergoing surgery, absence of liver involvement and receipt of postoperative chemotherapy were associated with improved OS on univariate analysis. On multivariable analysis, two factors approached significance: adjuvant chemotherapy was associated with a reduced risk of mortality (HR 0.3, P = 0.073) and residual macroscopic disease after resection correlated with increased risk of mortality (HR 5.3, P = 0.071). High-volume facilities (≥5 cases) experienced improved OS (median 59.1 vs 28.8 months), albeit not significantly (P = 0.135), compared to low-volume centers. CONCLUSION: Despite multimodal treatment, DSRCT is associated with dismal outcomes. Facilities familiar with treating this uncommon disease may experience superior outcomes.

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.

Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia.

Clofarabine has shown activity and tolerability in older patients with acute myeloid leukemia (AML). We investigated the safety and tolerability of an oral formulation of clofarabine for consolidation therapy of patients aged 60 and older with AML. In this phase I study, twenty-two patients older than 60 years with AML in first complete remission were treated once daily with oral clofarabine for 14 or 21 days of a 28-day cycle, for up to five cycles. Dose escalation from 1 mg to 6 mg daily using a 3 + 3 design was used to determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and tolerability of oral clofarabine. No DLTs or Grade 3-4 nonhematologic toxicities were observed. The primary toxicities were hematologic, including uncomplicated grade 3-4 neutropenia (50%) and thrombocytopenia (50%). Given that myelosuppression necessitating dose delays/reductions was observed more commonly at higher doses, the recommended phase II dose is 2 mg daily for 21 of 28 days. At doses equal to or greater than 2 mg, the median relapse-free survival was 28.35 months. Oral clofarabine was well-tolerated with encouraging activity in patients older than 60 years. Further investigation of oral clofarabine as a consolidation and/or maintenance therapy in AML for older individuals is warranted. (ClinicalTrials.gov:NCT00727766).

Acute myeloid leukemia, version 2.2013.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.

Rectal cancer.

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.

Age-Related Chromosomal Aberrations in Patients with Diffuse Large B-Cell Lymphoma: An In Silico Approach.

Background: In diffuse large B-cell lymphoma (DLBCL), chromosomal aberrations are known to increase with advancing age. Our study aims to determine if there are other genetic aberrations associated with DLBCL based on age. Methods: Using the Mitelman Database of Genetic Aberrations, we were able to find 749 cases of DLBCL with genomic aberrations with a median age of 62 years. Patients with DLBCL chromosomal aberration analysis results were divided into four groups based on age (0 - 30, 31 - 50, 51 - 70, > 71 years) and examined by chi-square analysis and Mantel-Cox for survival analysis. Results: Ten aberrations were found to be significant with a particular age range: t(2;3), trisomy 19p13, trisomy 18q21, trisomy 3, trisomy 7, trisomy 14, trisomy 16, trisomy 18, monosomy 3 and monosomy 11, and survival ranged from 7 to 25 months. Conclusion: This suggests that patients with DLBCL are likely to accumulate specific translocations depending on their age at the onset of DLBCL.

Evaluation of Detection Methods and Values of Circulating Vascular Endothelial Growth Factor in Lung Cancer.

Lung cancer is the deadliest cancer in the world. Angiogenesis plays a crucial role of the incidence, progression, and metastasis in lung cancer. Angiogenesis inhibitors are used to treat non-small cell lung cancer (NSCLC) patients, and the molecular biomarkers are also being assessed to predict treatment response/therapeutic response and patients' prognosis. Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates angiogenesis. Due to its predictive values of prognosis on NSCLC, a large number of methods have been developed and evaluated to detect VEGF levels in a variety of studies. In this article, we review the detection methods designed to measure the VEGF levels in different body fluids and prognosticate the value of VEGF in treatment, diagnosis and survival in lung cancer.

Early experience with cytoreduction and hyperthermic intraperitoneal chemotherapy at a newly developed center for peritoneal malignancy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has improved outcomes for patients with peritoneal carcinomatosis (PC). We present our experience from a newly developed peritoneal surface malignancy program. METHODS: An IRB approved retrospective review was performed for the first 50 patients treated with CRS/HIPEC with clinicopathologic data described. RESULTS: Patients treated with CRS/HIPEC were Caucasian (64%), female (66%) with a median age of 53 years (range, 11-73 years). Primary pathology included: appendix (40%, n=20), ovary (20%, n=10), colon (14%, n=7), desmoplastic small round cell tumor (14%, n=7) or other (12%, n=6). The median peritoneal cancer index (PCI) score was 15.5 (range, 1-39) and 92% underwent complete cytoreduction (CCR 0/1). Median hospital length of stay was 9.0 days (range, 6-35 days). Eight patients (16%) suffered major morbidity with 2 (4%) 30-day mortalities. CONCLUSIONS: Short-term outcomes observed after CRS/HIPEC in a newly developed center for PC are consistent with published higher volume center experiences.

Navigational bronchoscopy-guided dye marking to assist resection of a small lung nodule.

Electromagnetic navigational bronchoscopy (ENB) can be used to dye mark nodules that are difficult to identify during minimally invasive lung resection thoracic surgery. This case report describes the technique of ENB to identify and resect a suspicious small pulmonary nodule in a patient undergoing resection of lung adenocarcinoma.

Role of Genomic Instability in Immunotherapy with Checkpoint Inhibitors.

AIM: We evaluated whether tumor genome sequencing to detect the number and type of alterations could be used as a valuable biomarker for judging the potential utility of immune checkpoint inhibitors in patients with advanced cancers. MATERIALS AND METHODS: We identified patients with solid tumors who were treated with checkpoint inibitors and had received commercially available next generation sequencing (NGS). Tumors profiled by Caris Life Sciences, Foundation Medicine and Guardant360 between 2013 and 2015. Patients were divided into 5 quintiles based on mutational load (pathogenic mutations plus variants of undetermined significance). RESULTS: Fifty patients with solid tumors on immunotherapy that had NGS reports available were identified. Top quintile patients had more genomic alterations (median=16.5) than the others (median=2) and had more pathogenic mutations in cell-cycle regulatory genes (100% versus 48%). The overall survival (OS) was significantly superior for patients in the top quintile (722 days) versus the others (432 days). We found no significant difference in progression-free survival (PFS) between the two groups. The objective response rate was numerically higher for the top quintile (50%) vs. others (20%). Programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PDL1) status by immunohistochemistry was not associated with outcomes. CONCLUSION: The use of immune checkpoint blockade in tumors with higher mutational load was associated with improved OS. Our results suggest that the evaluation of tumor genomes may be predictive of immunotherapy benefit.

Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine.

BACKGROUND: Daunorubicin and cytarabine has been the standard-of-care for induction therapy for acute myeloid leukemia (AML). Adding cladribine to daunorubicin (60 mg/m(2)) and cytarabine has increased complete remission (CR) rates and median overall survival (OS). However, the efficacy of adding cladribine to 7+3 with other anthracyclines is unknown. PATIENTS AND METHODS: We retrospectively evaluated patients with AML receiving induction with idarubicin, cytarabine and cladribine (ICC) between 1/1/2010 and 06/30/2015 at the Methodist University Hospital in Memphis, Tennessee. Institutional Review Board approval was obtained for the study. Patient, disease characteristics and outcomes were analyzed with GraphPad Prism, Microsoft Excel and SPSSv19.0 software. RESULTS: Twenty-four patients induced with ICC for AML were identified. Thirteen (54.2%) had at least one high-risk feature. Hypoplastic marrow was achieved in all by day 14; 19 (79.2%) achieved CR. Thirty-day mortality was 8.3%; 33-month OS and disease-free survival were 56% and 36%, respectively. CONCLUSION: Induction of AML with ICC was associated with a high CR rate and OS in our high-risk population.