An observational study of hospitalized COVID-19 patients with cancer in San Diego county.

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 with a hematologic and/or solid tumor malignancy presenting to the authors' institution between 1 March 2020 and 5 January 2021, with a laboratory confirmed diagnosis of COVID-19. Univariate and multivariate logistic regression analyses were used to determine associations between specific severity outcomes and clinical characteristics. Results: Among 2771 hospitalized patients with COVID-19, 246 (8.88%) met inclusion criteria. Patients who were actively receiving treatment had an increased rate of death following admission (odds ratio [OR]: 2.7). After adjusting for significant covariates, the odds ratio increased to 4.4. Patients with cancer involvement of the lungs had a trend toward increased odds of death after adjusting for covariates (OR: 2.3). Conclusions: Among COVID-19 positive hospitalized cancer patients, systemic anti-cancer therapy was associated with significantly increased odds of mortality.

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 greater susceptibility to COVID-19 infection and more likely to experience morbidity and mortality from COVID-19 infection than non-cancer patients. In this study, the authors reviewed the clinical characteristics of patients with a diagnosis of cancer hospitalized with COVID-19 to assess potential correlates of COVID-19 severity in this population. Notably, analysis of the hospital data revealed a statistically significant increased incidence of mortality in cancer patients who were receiving systemic anti-cancer treatment, including chemotherapy, immunotherapy or targeted therapy, than in those not on therapy. Likewise, there was a trend toward increased mortality in those with either primary or metastatic tumor involvement of the lung compared with those without lung involvement.

The role of Globo H and SSEA-4 in the development and progression of cancer, and their potential as therapeutic targets.

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 conditions including tumorigenesis. Glycosphingolipids (GSLs), consisting of glycans conjugated to a lipid (ceramide) core, are found in the lipid bilayer of eukaryotic cell membranes. GSLs, play an active role in cell processes. Several GSLs are expressed by human embryonic stem cells and have been found to be overexpressed in several types of cancer. In this review, we discuss the data, hypotheses and perspectives related to the GSLs Globo H and SSEA-4.

Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma.

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.

Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors.

CGP results from >60,000 cases were screened to identify NTRK fusion events from cases of neuroendocrine tumors. 2417 NET patients from diverse anatomic sites were identified. From this dataset, six cases harbored NTRK fusions which included intra- and inter-chromosomal translocations. A NTRK fusion frequency of approximately 0.3% was found across all subtypes of NETs. Three cases involved translocations of NTRK1 with unique fusion partners (GPATCH4, PIP5K1A, CCDC19). Co-occurring alterations occurred in five cases. NTRK alterations were identified in nearly the full spectrum of NETs, including from the small intestine, pancreas, lung, and others. With the late stage clinical development of NTRK TKIs (including entrectinib and larotrectinib), these findings may further inform targeted approaches to therapy in NET.

HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Targeting B lymphoma with nanoparticles bearing glycan ligands of CD22.

CD22 is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family expressed on B cells that recognizes glycans of glycoproteins as ligands. Because siglecs exhibit restricted expression on one or a few leukocyte cell types, they have gained attention as attractive targets for cell-directed therapies. Several antibody-based therapies targeting CD22 (Siglec-2) are currently in clinical trials for the treatment of hairy cell leukemia and other B cell lymphomas. As an alternative to antibodies we have developed liposomal nanoparticles decorated with glycan ligands of CD22 that selectively target B cells. Because CD22 is an endocytic receptor, ligand-decorated liposomes are bound by CD22 and rapidly internalized by the cell. When loaded with a toxic cargo such as doxorubicin, they are efficacious in prolonging life in a Daudi B cell lymphoma model. These B cell targeted nanoparticles have been demonstrated to bind and kill malignant B cells from patients with hairy cell leukemia, marginal zone lymphoma and chronic lymphocytic leukemia. The results demonstrate the potential of using CD22 ligand-targeted liposomal nanoparticles as an alternative approach for the treatment of B cell malignancies.

Development of cladribine at Scripps for hairy cell leukemia and current results.

Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL.

Hairy cell leukemia: current therapies and future directions.

Hairy cell leukemia is a rare disease for which there are multiple treatment options. Purine nucleoside analogs (cladribine and pentostatin) are generally used for front-line treatment. Other active agents include interferon, rituximab and, although rarely, splenectomy. In the series published by Zinzani et al. in Cancer, the authors conclude that initial treatment for hairy cell leukemia should be maximized since these patients generally enjoy the highest complete response rates and the longest remission durations, and subsequent lines of therapy have lower response rates and more frequent relapses. However, evolving immunohistochemical and molecular diagnostic techniques, as well as criteria for evaluating response to therapy and clinical trials investigating chemoimmunotherapy, may result in clinicians re-evaluating how patients are treated in the front-line and when treatment should be initiated for relapsed patients.

Beyond hairy cell: the activity of cladribine in other hematologic malignancies.

Before the contemporary development of rationally designed antineoplastic therapies, cladribine was identified as a lymphocyte-specific agent. Its profound impact on the natural history of hairy cell leukemia, with responses approaching 100% and a median duration of response of nearly a decade after only a single 7-day course, is well known and revolutionized the treatment of hairy cell leukemia. However, cladribine's impressive activity in other lymphoproliferative disorders has been generally underappreciated. Multiple single-arm phase 2 trials have demonstrated cladribine's potency across the full spectrum of lymphoid malignancies. In a limited number of phase 3 trials and cross-study analyses, cladribine compared favorably with fludarabine, another purine nucleoside analog that is more commonly used in the treatment of indolent lymphoid malignancies. Cladribine has been noted to have particular activity among lymphoid disorders with few effective therapies, specifically, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Recently approved novel agents may act in synergy with cladribine for these conditions and should be incorporated into future clinical studies.

In vivo targeting of B-cell lymphoma with glycan ligands of CD22.

Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell-specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes alpha2-6-linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition-based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine.

Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin-stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.

Cladribine in indolent non-Hodgkin's lymphoma.

Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström's macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin's lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin's lymphoma.