NCCN Clinical Practice Guidelines Research Articles

Prevention and Treatment of Cancer-Related Infections, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a 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. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Current and Emerging Biomarkers: Impact on Risk Stratification for Neuroblastoma.

Neuroblastoma has heterogenous clinical presentations that are reflected by several well-defined clinical factors and biomarkers. Combinations of these clinical and biologic prognostic factors have been used for decades to generate classifiers to stratify patients into risk groups (low, intermediate, and high), which in turn are used to inform and tailor treatment as reported in the new NCCN Clinical Practice Guidelines in Oncology for Neuroblastoma. Risk classification uses clinical features, such as age and tumor stage, along with the most significant prognostic tumor biomarkers, including histologic features (differentiation and mitosis-karyorrhexis index), MYCN amplification status, chromosomal copy number alterations (segmental or numerical), and ploidy (DNA content). Recent next-generation sequencing approaches have identified additional tumor-specific genetic factors that have potential roles as prognostic and predictive biomarkers. These emerging biomarkers include telomerase maintenance mechanisms, such as telomerase reverse transcription (TERT) expression and alternative lengthening of telomeres (ALT) status. Somatic alterations of genes, including mutations in the anaplastic lymphoma kinase gene ALK, detected in >10% of patients with newly diagnosed disease, have both prognostic and predictive roles in determining eligibility for targeted therapies (eg, ALK tyrosine kinase inhibitors). In addition to diagnostic tumor-derived biomarkers, significant effort is being directed toward identification of markers to predict response to chemotherapy and immunotherapies. With the increasing use of GD2-containing immunotherapy regimens, efforts are aimed at identifying host or tumor microenvironment immune correlatives that can serve as predictive biomarkers. Understanding the potential role of liquid biopsies as biomarkers during and following treatment, including sequential circulating tumor DNA or tumor-specific mRNA transcripts, is expected to enhance the ability to predict recurrences and also inform understanding of tumor evolution and therapy resistance. These and other emerging biomarkers will lead to refinement and optimization of future neuroblastoma risk classification systems.

Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

Covalent-103: A phase 1, open-label, dose-escalation and expansion study of BMF-500, an oral covalent FLT3 inhibitor, in adults with acute leukemia (AL).

TPS6589 Background: FLT3 mutations occur in 25-35% of AML and result from an internal tandem duplication (ITD) of amino acids in the juxtamembrane domain of FLT3 kinase or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased relapse, shorter remission, and decreased disease-free and overall survival. BMF-500 is a novel oral, highly potent and selective covalent inhibitor of FLT3 including wild-type (WT), ITD, TKD, and resistance mutations (e.g., gatekeeper F691). BMF-500 has high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing despite drug washout (Law et al., ASH 2022 Abst 2756). BMF-500 shows sustained tumor regression and improved survival in subcutaneous and disseminated xenografts of FLT3-m AML. Methods: COVALENT-103 (NCT05918692) is a multicenter, first-in-human study evaluating the safety, tolerability, and antileukemic activity of escalating doses of daily BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3-m. The trial has 2 arms that dose escalate in parallel: Arm A (without) and Arm B (with) concomitant use of a CYP3A4 inhibitor. Using an accelerated titration design (ATD), doses of BMF-500 are escalated in single-subject cohorts until one subject experiences ≥Grade 2 related adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may enroll up to 33% per arm. Treatment continues in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care, including hematopoietic stem cell transplant (HSCT). FLT3-positive AML patients must have received a FLT3 inhibitor approved for R/R FLT3-m AML. Additional inclusion criteria include ECOG PS ≤2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease, clinically significant cardiovascular disease, and WBC >50,000/µL (uncontrollable with cytoreductive therapy). The primary objective is to evaluate safety and tolerability and determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 monotherapy based on available pharmacokinetic/pharmacodynamic (PK/PD), safety and efficacy data. Secondary objectives include characterization of the PK/PD of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. The study was initiated in July 2023, is currently in dose escalation, and we plan to enroll approximately 110 patients total. Clinical trial information: NCT05918692 .

Finding errors in the blink of AI: Use of an artificial intelligence tool to identify clinically important corrections to references cited by NCCN Guidelines for gynecologic malignancies.

e13658 Background: Scientific articles are being retracted at higher rates for many reasons. Retractions or corrections may be unknown to authors citing these materials as primary sources, unwittingly perpetuating incorrect information. Our goal was to assess the utility of a scholarly artificial intelligence (AI) tool to identify errata to sources cited in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for gynecologic cancers and to evaluate the clinical importance of identified errata. Methods: scite (scite Inc., Brooklyn, NY) is an AI tool that analyzes citations to generate a list of linked publications, display the context for each citation, and flag any published errata or retractions for each source. Using scite with references from NCCN Guidelines as of June 2023, we identified corrections to primary sources. Each author categorized errata as having major, minor, or no clinical relevance, with resolution of conflicts through discussion until consensus. To check whether scite missed errata, we assessed a random sample (20%) of unflagged references. Results: The guidelines cited 2,364 primary sources, and scite successfully linked to 1,984 (84%) of them . scite flagged 50 references (2.5%) as having corrections; all 50 did have errata (100% accuracy). scite identified 56 total errata, which were not always apparent on journal websites or PubMed. After review, 31 errors (55%) were classified as clinically relevant; 71% of those errors had major clinical importance and 29% were considered minor. Twenty errors (65%) had relevance to the guideline statements in which the source was cited, but only 1 (3%) error had potential to change current guideline text. Among the sample of sources scite did not flag, we identified none with published errata. Conclusions: We demonstrated use of an AI tool to accurately identify sources in clinical guidelines with published corrections. Sources with errata were uncommon, and our analysis did not reveal perpetuation of major errors in NCCN Guidelines. However, the proportion of corrections with major clinical relevance underscores the importance of awareness of errata when writing clinical guidelines or reviews. Compared to manual review of each source, AI tools can improve speed and accuracy in finding important errors. [Table: see text]

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Generative AI enhanced with NCCN clinical practice guidelines for clinical decision support: A case study on bone cancer.

e13623 Background: Bone cancer is a complex and challenging disease to diagnose and treat in clinical practice. Recently, generative AI, especially large language models (LLMs), has demonstrated potential as a decision support tool for cancer. However, most implementations have overlooked the integration of available cancer guidelines, such as the NCCN Bone Cancer Guidelines, in fine-tuning the outputs of generative AI models. Incorporating these guidelines into LLMs presents an opportunity to harness the extensive clinical knowledge they contain and improve the decision-support capabilities of the model. Methods: In this study, the aim is to enhance the LLM with cancer clinical guidelines to enable accurate medical decisions and personalized treatment recommendations. Therefore, we introduce a novel method for incorporating the NCCN Bone Cancer Guidelines into LLMs using a Binary Decision Tree (BDT) approach. The approach involves constructing a BDT based on NCCN Bone Cancer Guidelines, where internal nodes represent decision points from the Guidelines, and leaf node signify final treatment suggestions. Then the LLM makes decision at each internal node, considering a given patient's characteristics, and guides toward a treatment recommendation in the leaf node. To assess the efficacy of Guideline-enhanced LLMs, an oncologist from our team created 11 hypothetical osteosarcoma patients’ medical progress notes. Each note contains their demographics, medical history, current illness, physical exams, diagnostic tests. We tested three LLMs in the implementation (GPT-4, GPT-3.5, and PaLM 2) and compared the LLM-generated treatment recommendations with the gold standard treatment across four runs with different random seeds (random seeds is a setting to control the LLM outputs). The results are reported as the average of four runs. The original LLMs are used as baseline methods for comparison. Results: The table below provides a comparison between the performance of original LLMs and those augmented with cancer guidelines for osteosarcoma treatment recommendations. We can observe that the PaLM 2 model demonstrated superior performance compared to its counterparts, underscoring the effectiveness of integrating cancer guidelines into LLMs for decision support. Conclusions: The clinical decision support capabilities of the LLMs are promising when enhanced by NCCN Bone Cancer Guidelines using our approach. To fully exhibit the potential of our proposed method as a clinical decision support tool, further investigation into other subtypes of bone cancer should be conducted in the future study. [Table: see text]

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Sequencing considerations in the third-line treatment of metastatic colorectal cancer.

Numerous advances in the standard of care for metastatic colorectal cancer (mCRC), including the approval of several new treatments indicated for treatment in the third line or later (3L+), have been made, yet data and appropriate guidance on the optimal sequencing and treatment strategies for these lines of therapy are lacking. Four treatments-regorafenib, trifluridine/tipiracil alone or with bevacizumab, and fruquintinib-are FDA-approved and recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for the treatment of mCRC in the 3L+. When considering sequencing of treatment options for patients in the 3L+, the goal of treatment is to improve survival, but also maintain quality of life, a goal that requires consideration of relative efficacy and cumulative toxicity such as persistent myelosuppression.

Clinical Outcomes and Healthcare Resource Utilization for Patients With Lower-Risk Myelodysplastic Syndromes Treated With Erythropoiesis-Stimulating Agents

IntroductionReal-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States. Patients and MethodsThis retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©). ResultsA total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure. ConclusionOur results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Treating patients with platinum-sensitive extensive-stage small-cell lung cancer in a real-world setting.

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive disease with poor 5-year survival. The first-line standard-of-care for ES-SCLC is platinum plus etoposide, along with 1 of the immune checkpoint inhibitors atezolizumab or durvalumab. Although SCLC first-line therapy often leads to rapid responses, treatment becomes more challenging at progression, particularly for those with a chemotherapy-free interval (CTFI) of ≤6 months. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for SCLC no longer specify treatment recommendations in this setting, but options approved by the US Food and Drug Administration include topotecan and lurbinectedin. Participation in a clinical trial is recommended as an option regardless of CTFI. Other NCCN-recommended regimens are paclitaxel, irinotecan, temozolomide, and cyclophosphamide/doxorubicin/vincristine, among others. Nivolumab and pembrolizumab are options in those not previously treated with a checkpoint inhibitor. For patients with platinum-sensitive SCLC (CTFI >6 months), preferred treatment per the NCCN Guidelines® for SCLC is retreatment with platinum and etoposide, although the use of immune checkpoint inhibitors is discouraged if there is progression on a drug in this class. Further research on immunotherapies and combination regimens is ongoing, and continuing work on the subcharacterization of SCLC may lead to better precision of therapies that promote more durable responses in individual patients with ES-SCLC.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.

Impact of Ethnicity in Treatment Choice for Multiple Myeloma in the 3 First Lines of Therapy: Data from Observational Retrospective Real-World Study in the USA

Background In Multiple myeloma (MM) patient ethnic origin appears to be associated with significant disparities including access to care and treatment patterns in some western countries, including the USA (3). Aims Identify impact of ethnicity in real world setting on choice of treatment regimens and new combinations for MM in 1st line and relapsed/refractory (R/R) setting among patients (pts) treated recently in the USA. Methods A total of 1,209 anonymous patient charts were reported by onco-hematologists in the USA, in 2022 - 2023. The analysis focused on first 3 lines of therapy for MM: 397 first line (1L) pts, 89 receiving induction treatment prior to autologous stem cell transplantation (SCT), 101 receiving maintenance therapy after SCT and 207 pts non eligible for intensive treatment, + 457 second line (2L) and 355 third line (3L) pts. D= daratumumab; V=bortezomib; T=thalidomide; d= dexamethasone; R=lenalidomide; M= melphalan; p= prednisone; K=carfilzomib Results 39% of pts were female and 61% were male. 49% were white/Caucasians vs. non-white race, (9% Asians, 25% black/African Americans, 15% Hispanic/Latinos and 2% American Indians/native Hawaiians/other pacific islanders). In 1st line induction prior to SCT, the most frequently used regimens were VRd (33 pts), D-VRd (17 pts) and DRd (6 pts), in line with NCCN and IMWG clinical practice guidelines. Black/African Americans and Hispanic/Latinos were underrepresented in the D-VRd group, with these 2 groups corresponding 6% of pts as compared to 88% for white/Caucasian pts. No significant discrepancy in the VRd and DRd groups among different ethnic origins. In 1st line maintenance post SCT, treatment with R alone or Rd were the most frequently used (44 and 13 pts, respectively), with no difference between different ethnic subgroups. In 1st line non SCT eligible pts, the 3 major regimens used were VRd (73 pts), DRd (38 pts) and D-VRd (15 pts) and in accordance with international IMWG guidelines, except for D-VRd which is not yet recommended for this subset of pts. Breakdown between different ethnic groups was in line with the sample population, except in the VRd group where black/African Americans were slightly overrepresented compared to overall population (36% vs. 25%). In the R/R setting, there was more heterogeneity and the most frequently used regimens in 2nd line treatments were DRd (35 pts), DPd (38 pts), DKd (37 pts), Dd (30 pts) and KRd (21 pts). In this subset, black/African Americans were underrepresented in the DKd group (14% of all pts vs. 56% for white and 19% for Hispanic/Latinos). Conversely, black pts more commonly received Dd combination despite this not being included in international guidelines and considered suboptimal as a second line treatment. Few pts received doublets with no anti-CD38 antibody in 2nd line, mainly Rd (14 pts) and Vd (16 pts) but no discrepancy was identified among different ethnic subgroups. In the 3rd line setting, the 3 most used combinations were DPd (21 pts), Dd (21 pts) and Kd (18 pts). Black/African Americans were overrepresented in the DPd and, in particular in the Kd group where they represented 50% of all pts. Conclusion Those results show that regimens recommended in the last NCCN and IMWG clinical practice guidelines are the most frequently used regardless patient's ethnic origin in 1st, 2nd and 3rd line MM. However, racial disparities are noted in treatment choices with lower usage of next generation combinations for black/African Americans in first line SCT eligible pts (D-VRd) and 2nd line (DKd) when compared with white/Caucasian population. Conversely, some regimens, such as Dd in 2nd line and Kd in 3rd line tend to be more regularly considered in black/African Americans even if they may be suboptimal.

Germline Predisposition in Myeloid Neoplasms Aged ≥50: A Novel Approach for Allogeneic Stem Cell -Transplantation Decision-Making

Introduction Patients aged 50 or older (≥50) with myeloid neoplasms (MNs), non-affected relatives, and no previous platelet or organ disorder are routinely not tested for germline predisposition. However, approximately 70% of myelodysplastic neoplasms (MDS) patients undergoing an allogeneic hematopoietic stem cell transplantation (alloHSCT) from familial donors, in 2021, were ≥50 years old (y.o.) (EBMT). Given the significant frequency of pathogenic/likely pathogenic (P/LP) germline variants in these patients (about 8%) along with the risk of transplanting cells with the same variant, it seems reasonable to perform universal germline testing in hematological neoplasms although challenging due to labor and cost constraints. Aims To address this, we developed a pragmatic approach incorporating a specific gene list to the diagnostic myeloid somatic panel to identify patients and exclude relatives with shared germline variants. To do that we: (1) Conducted a literature review to assess the gene-disease association's validity in this specific context. (2) Designed a germline-augmented virtual somatic panel (GASP) based on our findings. (3) Tested the virtual panel's performance in 133 MNs cases, aged ≥50, with matched germline-tumor exome sequencing, and no prior organ or platelet disorders. Methods We considered those genes included in the WHO Classification and NCCN Clinical Practice Guidelines as myeloid predisposition genes. For autosomal recessive disorders, heterozygous carriers were not considered. We analyzed the relation of these genes with MNs diagnosed ≥50 y.o. without prior organ or platelet dysfunction: To establish a valid association for a gene, we required the presence of P/LP variants in at least two peer-reviewed studies in the subset of interest. GASP combined genes with recurrent somatic mutations in myeloid disorders, as proposed by Duncavage et al. (Blood 2022), and those associated with the specific cohort of interest. WES was performed on paired tumoral-germline samples on a HiSeq 2000/Novaseq6000 instrument (Illumina Inc) with a target of 100x depth coverage. Results From 2018 to 2023, we collected samples from 133 patients (121 MDS and 12 CMML cases -FAB myelodysplastic variant) diagnosed with WHO-established MDS, aged ≥50, without prior organ or platelet disorders. Among the main characteristics at baseline, we highlight a median age at diagnosis of 57 years old (range, 50-88), and the presence of a first-degree relative with a myeloid neoplasm diagnosis in 7% of the cases. The literature search revealed 11 genes associated with germline predisposition within the cohort of interest. Seven were WHO/NCCN genes: DDX41, TERT, GATA2, CEBPA, SAMD9, ERCC6L2, and TP53. Additionally, four “recently associated genes” were incorporated based on recent descriptions in germline MNs ≥50 y.o. and reported at least in two peer-reviewed articles: CHEK2, DNAH9, ATM, and SH2B3 (Table 1). Next, we tested the accuracy of both the GASP and Duncavage's recommended somatic panel in our cohort of 133 myeloid neoplasms characterized by WES. Among these cases, we identified 15 (11%) P/LP germline variants in both WHO/NCCN and recently associated genes. Duncavage's somatic panel could only detect 8 out of 15 (53%) cases, while the expanded GASP detected 13 out of 15 (87%) variants (Figure 1). The GASP showed a C-index of 0.933, outperforming Duncavage's panel, which scored 0.767. Conclusions Eleven genes have been found to harbor P/LP germline variants in patients with MNs diagnosed ≥50 y.o. and no previous organ or platelet disorder. In our cohort, 11% of patients carried a P/LP germline variant in a MNs predisposition gene. Such a finding would have gone undetected as germline predisposition testing is not typically advised for these patients. Expanding the myeloid somatic panel (GASP) allows the identification of 87% of P/LP variants during the diagnosis process, enabling clinicians to exclude carrier relatives as potential allo-SCT donors.

Real-World Applications of Guideline Based Diagnostic and Treatment Patterns for Diffuse Large B-Cell Lymphoma within the Veterans Health Administration (VHA)

CONCLUSION High grade lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (HGL) occur in less than 10% of DLBCL. While clinical trials demonstrated poor outcomes following standard rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) therapy for HGL since the early 2000s, the World Health Organization (WHO) identified this as a new category in 2016. There was a lack of consensus for FISH testing until NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) (V.1.2020) moved Karyotype/FISH testing for MYC from “USEFUL UNDER CERTAIN CIRCUMSTANCES” to “ESSENTIAL”. NCCN Guidelines ® V.1.2018 recognizes the lack of standard of care for HGL and comments about using dose-adjusted (DA) R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) DA-EPOCH-R for this category. The VHA is the largest integrated, uniform care access system in the United States. The objective of this study is to understand the real-world applications of NCCN Guidelines on testing and treatment patterns in DLBCL within VHA. 6266 patients were randomly selected for this retrospective chart review with an ICD code for DLBCL managed in the VHA from 01/01/2011 to 12/31/2021. This 11-year period is divided into three blocks: 2011-2015, 2016-2019 and 2020-2021, which represent pre-identification of HGL based on WHO classification, post-identification of HGL based on 2016 WHO classification Lymphoid neoplasm classification, and the change in MYC testing NCCN Guidelines(Version 1.2020), respectively. VHA is divided into five geographic regions, which includes the Pacific, Continental, Midwest, Southeast, and North Atlantic. Data abstractors collected baseline patient and disease characteristics, both manually and electronically, including but not limited to, testing and treatment patterns for those with a diagnosis of DLBCL in each time frame. Statistical comparisons were done using the Chi-Squared test. 3178 met our inclusion criteria for DLBCL. Of the total patients, 1471 (46.3%) had FISH testing performed. Table 1 shows baseline characteristics. Of the patients tested, 97% of the patients were male, 75% were non-Hispanic white and median age was 68 years. The median Charlson Comorbidity Index (CCI) was 2. FISH testing rates increased over time from 28% in the first study period to 76% during the last study period. There was no statistically significant racial difference in FISH testing rates. Continental VHA district patients were less likely to have FISH testing completed when compared to other districts (p<0.0001). Despite an overall increase in FISH testing, as well as a change in testing NCCN Guidelines(Version 1.2020) there was no significant increase in the real-world utilization rate of DA-EPOCH-R for HGL during the different study periods (Figure 2). This is one of the largest retrospective studies reporting FISH testing and treatment patterns based on NCCN Guidelines for HGL. Despite significant improvement in the rates of FISH testing during our study period, there are significant regional differences, and 25% of the patents did not undergo FISH testing after the recommendation change in 2020. Our data also highlights the underutilization of DA-EPOCH-R in HGL patients within VHA. This may be attributed to knowledge gaps, diagnosis at older age, higher Charlson score due to multiple comorbidities, and regimen feasibility. Limitations of this study include a predominantly older, male population with equal health care access that may limit generalizability of our findings to the non-Veteran population. Data from our study underscores a need for increased awareness of NCCN Guidelinesrecommendations both in terms of testing and treatment planning outside the clinical trial setting.

Main Treatment Choices in the 2 First Lines of Therapy for Multiple Myeloma in Patients with High Risk Cytogenetics: Lesson from the Real World in the EU5 Countries and the USA

Background Typical approach to initial therapy in multiple myeloma (MM) includes more aggressive combinations early on with triplets. To further improve response rates and survival, quadruplets are moving to frontline, in both stem cell transplant (SCT) eligible and ineligible patients (pts). Defining high risk features is crucial; current international NCCN and IMWG clinical practice guidelines stratify pts based on those criteria proposing more aggressive therapy in this setting. Definitions of high risk are: cytogenetic abnormalities incl. del(17p), some laboratory factors with ISS III and increased LDH, some clinical features including plasma cell leukaemia, extramedullary involvement or age and functional assessment with primary refractory disease and rapid progression within 18 months of diagnosis. Aims Identify in real world setting the main regimens used in first line SCT eligible and ineligible pts as well as in 2nd line high risk pts with MM in EU5 countries (France, Germany, Italy, Spain, UK) and in the USA. Methods Anonymous patient charts were analysed based on data reported by onco-haematologists treating MM pts in EU5 countries and USA. A total of 1,575 unique patient charts in 1st line (530 SCT eligible and 1,045 SCT ineligible pts) and 1,665 unique pts in 2nd line were included in the analysis, from Oct. to Dec. 2022. The analysis focused on pts with high risk cytogenetic features and regimens used in accordance with international clinical practice guidelines. D= daratumumab; V=bortezomib; T=thalidomide; d= dexamethasone; R=lenalidomide; M= melphalan; p= prednisone; K=carfilzomib; Isa=isatuximab Results Mean age in 1st line SCT eligible pts was 59.0 years (n=441) in EU5 and 60.9 years (n=89) in the USA. In 1st line SCT ineligible pts, mean age was 74.0 years (n=838) in EU5 and 65.9 years (n=207) in the USA. Among all 1st line SCT eligible pts, 34% in EU5 and 29% in US had high risk cytogenetic features, with del17p identified in 12% of EU5 cases and 16% of US cases. In 1st line SCT ineligible pts in the EU5 and in the US 14% and 17% respectively were high risk, including 9% and 13% del17p. In the 2nd line setting, 1,208 unique pts were included in the EU5 and 457 in the US with 17% and 14% classified at high risk, respectively, del17p was identified in 9% and 11% of pts. The most frequently used regimens in 1st line SCT eligible pts in EU5 are D-VRd (n=56), VRd (n=69) and D-VTd (n=136) with 41% and 39% of high-risk pts. In the US, the most frequent regimens used in this subset were D-VRd (n=17) and VRd (n=33) with 35% and 39% of pts belonging to the high-risk group. For 1st line SCT ineligible pts in EU5, 40% of patients were high risk, with the most common regimen being VRd (n=67). Pts with del17p were also overrepresented in this subgroup with 15% of total population receiving VRd. Other frequently used regimens were D-VMP (n=95), DRd (n=188), Rd (n=148) and VMP (n=80) but none was preferred in high-risk pts. In the US, the most frequently-used regimen in 1st line SCT ineligible population was VRd (n=73) with 27% of pts with high-risk features (vs. 17% in the overall population). For 2nd line treatment in the EU5, carfilzomib-based combinations are more frequently used in high-risk pts, particularly DKd (n=42) and KRd (n=118), both associated with 35% of pts with high-risk features. Kd was also regularly used in this subset (n=76) with 32% of high-risk pts. Despite a small number of pts (n=29), Isa-Kd triplet is more regularly used in pts with del17p (21% of all pts). In 2nd line setting in the USA, the most frequently used regimen was DKd (n=37) with 30% high-risk pts. In pts with del17p, Kd was regularly used (n=14) with 21% of pts presenting this abnormality. Among other regimens, such as DPd (n=38), Dd (n=30), DRd (n=35) and KRd (n=21), none was preferred in high-risk pts. Conclusion This real-world study reveals quite heterogeneous treatment choices in 1st and 2nd line pts with high-risk cytogenetic features with no large consensus, especially between EU5 and the US. Some trends can be identified between different pts subsets: quadruplets with D-VRd and D-VTd in EU5 and D-VRd in the US are preferred as induction treatment prior to SCT. VRd is regularly used in 1st line SCT ineligible pts in the EU5, particularly in case of del17p. Carfilzomib-based regimens are more common in 2nd line pts in both EU5 and US, especially DKd, KRd and Kd. Those are in line with the main international guidelines and expert recommendations for high-risk pts.

Covalent-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of Bmf-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.