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The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

BACKGROUND: Covalent (irreversible) Bruton’s tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell–receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)

Guidelines for previous negative biopsy (PNB) cohorts with a suspicion of prostate cancer (PCa) after positive multiparametric (mp) magnetic-resonance-imaging (MRI) often favour the fusion-guided targeted prostate-biopsy (TB) only approach for Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions. However, recommendations lack direct biopsy performance comparison within biopsy naïve (BN) vs. PNB patients and its prognostication of the whole mount pathology report (WMPR), respectively. We suppose, that the combination of TB and concomitant TRUS-systematic biopsy (SB) improves the PCa detection rate of PI-RADS 2, 3, 4 or 5 lesions and the International Society of Urological Pathology (ISUP)-grade predictability of the WMPR in BN- and PNB patients.Patients with suspicious mpMRI, elevated prostate-specific-antigen and/or abnormal digital rectal examination were included. All PI-RADS reports were intramurally reviewed for biopsy planning. We compared the PI-RADS score substratified TB, SB or combined approach (TB/SB) associated BN- and PNB-PCa detection rate. Furthermore, we assessed the ISUP-grade variability between biopsy cores and the WMPR.According to BN (Despite csPCa is more frequently found in BN patients, the TB/SB method always detected a significantly higher number of csPCa within PI-RADS 3, 4 or 5 reports of our BN and PNB group. The TB/SB strategy predicts the ISUP-grade best in the total and BN cohort and in general shows the lowest upgrading rates, emphasizing its value not only in BN but also PNB patients.

Introduction: Chimeric antigen receptor T cell (CAR-T) therapy harnesses a patient’s own immune system to target cancer. Cardiotoxicity occurs in up to 25% of patients treated with CAR-T. There are limited data characterizing the association between the development of cardiotoxicity after CAR-T and mortality among patients following CAR T cell therapy. Hypothesis: We hypothesized that cardiotoxicity following CAR-T treatment would be associated with a higher rate of mortality. Cardiotoxicity was a composite outcome defined as the development of heart failure, cardiogenic shock, or myocardial infarction. Methods: We included the first 202 adult patients entered into a multicenter registry receiving anti-CD 19 CAR-T for lymphoma or acute lymphoblastic leukemia (ALL). Of these, 108 died and 94 survived. Covariates included standard baseline cardiovascular and cancer parameters, the occurrence of cardiotoxicity and mortality. Results: Those that did and did not die after CAR-T were similar in age, sex, and pre-lymphodepletion chemotherapy regiment. Death after CAR-T was more common in patients with than without hypertension (66% vs. 47%, p=0.009) or ALL (66% vs. 48%, p=0.02), and less common with baseline coronary artery disease (25 vs. 56%, p=0.04). There was no difference in mean cytokine release syndrome (CRS) grade, rate of ≥2 CRS, or in the use of tocilizumab or steroids between those who did and did not die after CAR-T. During a mean follow-up of 372±284 days, 33 (16%) patients experienced cardiotoxicity. Patients with vs. without cardiotoxicity died more often (76% vs. 49%, OR 3.2, CI 1.4 - 7.6, p=0.005). In a Cox model adjusted for covariates identified in univariate analyses, occurrence of cardiotoxicity with CAR-T was independently associated with an increased risk of mortality (adjusted HR: 1.85, 95% CI: 1.17-2.92, p=0.009). Conclusions: CAR-T recipients who experience cardiotoxicity have higher mortality.