Citations

Anaplastic large cell lymphoma (ALCL) can be classified genetically based on rearrangements (R) of the ALK, TP63, and/or DUSP22 genes. ALK-R defines a specific entity, ALK-positive ALCL, while DUSP22-R and TP63-R define subgroups of ALK-negative ALCLs with distinct clinicopathologic features. ALK-R and TP63-R produce oncogenic fusion proteins that can be detected by immunohistochemistry. ALK immunohistochemistry is an excellent surrogate for ALK-R and screening with p63 immunohistochemistry excludes TP63-R in two third of ALCLs. In contrast, DUSP22-R does not produce a fusion protein and its identification requires fluorescence in situ hybridization. However, DUSP22-R ALCL has a characteristic phenotype including negativity for cytotoxic markers and phospho-STAT3Y705. Recently, we also identified overexpression of the LEF1 transcription factor in DUSP22-R ALCL. Here, we sought to validate this finding and examine models for predicting DUSP22-R using immunohistochemistry for LEF1 and TIA1 or phospho-STAT3Y705. We evaluated these 3 markers in our original discovery cohort (n=45) and in an independent validation cohort (n=46) of ALCLs. The correlation between DUSP22-R and LEF1 expression replicated strongly in the validation cohort (P<0.0001). In addition, we identified and validated a strategy using LEF1 and TIA1 immunohistochemistry that predicted DUSP22-R with positive and negative predictive values of 100% after exclusion of indeterminate cases and would eliminate the need for fluorescence in situ hybridization in 65% of ALK-negative ALCLs. This approach had similar results in identifying DUSP22-R in the related condition, lymphomatoid papulosis. Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL.

Abstract Objectives Patients with clonal cytopenia of undetermined significance (CCUS) are at increased risk of developing myeloid neoplasia (MN). We evaluated whether a simple flow cytometry immunophenotyping (FCIP) assay could differentiate the risk of development of MN in patients with CCUS. Methods Bone marrow aspirates were assessed by FCIP panel in a cohort of 80 patients identified as having CCUS based on next-generation sequencing or cytogenetics from March 2015 to May 2020, with available samples. Flow cytometric assay included CD13/HLA-DR expression pattern on CD34-positive myeloblasts; CD13/CD16 pattern on maturing granulocytic precursors; and aberrant expression of CD2, CD7, or CD56 on CD34-positive myeloblasts. Relevant demographic, comorbidity, and clinical and laboratory data, including the type and extent of genetic abnormalities, were extracted from the electronic health record. Results In total, 17 (21%) patients with CCUS developed MN over the follow-up period (median survival follow-up, 28 months [95% confidence interval, 19-31]). Flow cytometry immunophenotyping abnormalities, including the aberrant pattern of CD13/HLA-DR expression, as detected at the time of the diagnosis of CCUS, were significantly associated with risk of developing MN (hazard ratio, 2.97; P = .006). Additional FCIP parameters associated with the development of MN included abnormal expression of CD7 on myeloblasts and the presence vs absence of any FCIP abnormality. Conclusions A simple FCIP approach that includes assessment of CD13/HLA-DR pattern on CD34-positive myeloblasts can be useful in identifying patients with CCUS at higher risk of developing MN.

AbstractObjectivesWe provide a contemporary consideration of long‐term outcomes and trends of induction therapy use following lung transplantation in the United States. Methods: We reviewed the United Network for Organ Sharing registry from 2006 to 2018 for first‐time, adult, lung‐only transplant recipients. Long‐term survival was compared between induction classes (Interleukin‐2 inhibitors, monoclonal or polyclonal cell‐depleting agents, and no induction therapy). A 1:1 propensity score match was performed, pairing patients who received basiliximab with similar risk recipients who did not receive induction therapy. Outcomes in matched populations were compared using Cox, Kaplan‐Meier and Logistic regression modeling.Measurements and main results22 025 recipients were identified; 8003 (36.34%) were treated with no induction therapy, 11 045 (50.15%) with basiliximab, 1556 (7.06%) with alemtuzumab and 1421 (6.45%) with anti‐thymocyte globulin. Compared with those who received no induction, patients receiving basiliximab, alemtuzumab or anti‐thymocyte globulin were found on multivariable Cox‐regression analyses to have lower long‐term mortality (all p < .05). Following propensity score matching of basiliximab and no induction populations, analyses demonstrated a statistically significant association between basiliximab use and long‐ term survival (p < .001). Basiliximab was also associated with a lower risk of acute rejection (p < .001) and renal failure (p = .002).ConclusionInduction therapy for lung transplant recipients—specifically basiliximab—is associated with improved long‐term survival and a lower risk of renal failure or acute rejection.

SummaryPatients with chronic lymphocytic leukaemia (CLL) disease progression on ibrutinib or after sequential ibrutinib and venetoclax‐based treatments (double‐refractory) have poor outcomes. In this retrospective study, we analysed outcomes with combined ibrutinib and venetoclax treatment in these groups of patients. The median treatment‐free and overall survival for 22 patients with prior progression on ibrutinib (venetoclax‐naïve) were 23.7 and 47.1 months respectively. In 11 patients with double‐refractory CLL, the median treatment‐free and overall survival were 11.2 and 27.0 months respectively. The combination of ibrutinib and venetoclax may help bridge the current gap in options for patients with disease refractory to the most commonly used novel agents.

Importance National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. Objective To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. Design, Setting, and Participants This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Interventions Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m 2 ; irinotecan, 180 mg/m 2 ; leucovorin, 400 mg/m 2 ; and infusional fluorouracil, 2400 mg/m 2 ) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m 2 ; leucovorin, 400 mg/m 2 ; bolus fluorouracil, 400 mg/m 2 ; and infusional fluorouracil, 2400 mg/m 2 over 46 hours). Main Outcomes and Measures Each treatment arm’s 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Results Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. Conclusions and Relevance This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. Trial Registration ClinicalTrials.gov Identifier: NCT02839343

PURPOSE Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.

Summary Exploratory analysis of a phase III trial in esophageal cancer found that the patients who most contributed to an overall survival benefit from PD-1 blockade were not responders, but non-responders. The analysis has limitations but may have implications for investigating the optimal timing of immunotherapy relative to other treatments. See related article by Okada et al., p. 3277