David J. Hermel

Purine nucleoside analogues are highly effective in the treatment of hairy cell leukemia (HCL) but are associated with myelosuppression and immunosuppression. Targeted therapy with the BRAF inhibitor vemurafenib in combination with the anti-CD20 antibody rituximab has shown marked efficacy, but traditional dosing of vemurafenib (960 mg twice daily) requires frequent dose reductions. We conducted a prospective observational study of low-dose vemurafenib (240 mg twice daily orally for 8 weeks) plus rituximab (375 mg/m² intravenously every 2 weeks for 14 weeks, 8 total doses) in adults with treatment-naïve or relapsed/refractory HCL. Fifteen patients were enrolled. All achieved complete hematologic recovery, with normalization of thrombocytopenia (>100 ×10³/µL) and neutropenia (>1.0 ×10³/µL) by a median of 15 and 29 days, respectively. The overall response rate was 87%, including 11 complete responses (73%; 95% CI, 48-89%) and 2 partial responses, with 8 patients (53%; 95% CI: 27-79%) achieving MRD negativity at 6 months. Front-line patients (n=7) had 6 CRs (86%; 95% CI: 42-100%) and 4 were MRD-negative (57%; 95% CI: 18-90%), while relapsed/refractory patients (n=8; median of 1 prior therapy) had 5 CRs (63%; 95% CI: 24-91%) and 4 were MRD-negative (50%; 95% CI: 16-84%). At a median follow-up of 18 months, one patient progressed at 20 months; median progression-free survival was not reached. No grade 3-4 toxicities or deaths occurred. Low-dose vemurafenib combined with rituximab induced rapid hematologic recovery, and favorable tolerability in patients with both untreated and relapsed/refractory HCL. NCT05388123

Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48–1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03–1.96), representing a statistically significant increase in the risk of death (P = .03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients.

Aim: To delineate clinical correlates of COVID-19 infection severity in hospitalized patients with malignancy. Methods: The authors conducted a retrospective review of all hospitalized patients wit... Plain language summary Though cancer is a biologically heterogenous disease with a wide spectrum of clinical features and behavior, accumulating evidence suggests that cancer patients are at greate...

Glycans, chains of sugar molecules found conjugated to cell proteins and lipids, contribute to their growth, movement and differentiation. Aberrant glycosylation is a hallmark of several medical co... Tweetable abstract There is an opportunity to utilize anti-Globo H and anti-SSEA-4 agents both as monotherapy and in combination with immune checkpoint inhibitors. It is hoped that these agents wil...

Aim: This study investigates the association between ABO blood phenotype and COVID-19 severity, measured by intensive care unit admission, need for intubation, hospitalization length and death. It ... Lay abstract In patients diagnosed with COVID-19, identifying those at increased risk for morbidity and mortality is imperative given the wide spectrum of clinical disease manifestations. Emerging ...

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

Computational algorithms are often used to assess pathogenicity of Variants of Uncertain Significance (VUS) that are found in disease-associated genes. Most computational methods include analysis of protein multiple sequence alignments (PMSA), assessing interspecies variation. Careful validation of PMSA-based methods has been done for relatively few genes, partially because creation of curated PMSAs is labor-intensive. We assessed how PMSA-based computational tools predict the effects of the missense changes in the APC gene, in which pathogenic variants cause Familial Adenomatous Polyposis. Most Pathogenic or Likely Pathogenic APC variants are protein-truncating changes. However, public databases now contain thousands of variants reported as missense. We created a curated APC PMSA that contained >3 substitutions/site, which is large enough for statistically robust in silico analysis. The creation of the PMSA was not easily automated, requiring significant querying and computational analysis of protein and genome sequences. Of 1924 missense APC variants in the NCBI ClinVar database, 1800 (93.5%) are reported as VUS. All but two missense variants listed as P/LP occur at canonical splice or Exonic Splice Enhancer sites. Pathogenicity predictions by five computational tools (Align-GVGD, SIFT, PolyPhen2, MAPP, REVEL) differed widely in their predictions of Pathogenic/Likely Pathogenic (range 17.5–75.0%) and Benign/Likely Benign (range 25.0–82.5%) for APC missense variants in ClinVar. When applied to 21 missense variants reported in ClinVar and securely classified as Benign, the five methods ranged in accuracy from 76.2–100%. Computational PMSA-based methods can be an excellent classifier for variants of some hereditary cancer genes. However, there may be characteristics of the APC gene and protein that confound the results of in silico algorithms. A systematic study of these features could greatly improve the automation of alignment-based techniques and the use of predictive algorithms in hereditary cancer genes.