C-C Chemokine Receptor 1 Expression in Human Hematolymphoid Neoplasia

Chemokine receptor 1 (CCR1) is a G protein–coupled receptor that binds to members of the C-C chemokine family. Recently, CCL3 (MIP-1α), a high-affinity CCR1 ligand, was identified as part of a model that independently predicts survival in patients with diffuse large B-cell lymphoma (DLBCL). However, the role of chemokine signaling in the pathogenesis of human lymphomas is unclear. In normal human hematopoietic tissues, we found CCR1 expression in intraepithelial B cells of human tonsil and granulocytic/monocytic cells in the bone marrow. Immunohistochemical analysis of 944 cases of hematolymphoid neoplasia identified CCR1 expression in a subset of B- and T-cell lymphomas, plasma cell myeloma, acute myeloid leukemia, and classical Hodgkin lymphoma. CCR1 expression correlated with the non–germinal center subtype of DLBCL but did not predict overall survival in follicular lymphoma. These data suggest that CCR1 may be useful for lymphoma classification and support a role for chemokine signaling in the pathogenesis of hematolymphoid neoplasia

Remission of subcutaneous panniculitis-like T-cell lymphoma in a pregnant woman after treatment with oral corticosteroids as monotherapy

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous T-cell lymphoma characterized by neoplastic α/β T cells infiltrating subcutaneous tissues in a lobular pattern. Few data support the optimal treatment regimen for patients, given the rarity of this condition, and even fewer data describe treatment when diagnosed during pregnancy. We describe a case of SPTCL in a pregnant patient who achieved clinical remission after treatment with corticosteroid monotherapy. Our case suggests that corticosteroids should be considered as first-line treatment in pregnant patients with SPTCL

Outcomes after diagnosis of mycosis fungoides and Sézary syndrome before 30 years of age: a population-based study.

ImportanceMycosis fungoides and Sézary syndrome (MF/SS) are rare in children and young adults, and thus the incidence and outcomes in this patient population are not well studied.ObjectiveTo assess the incidence and outcomes of MF/SS in patients diagnosed before 30 years of age.Design, setting, and participantsRetrospective study of 2 population-based cancer registries-the California Cancer Registry (n = 204) and 9 US cancer registries of the Surveillance, Epidemiology, and End Results program (SEER 9; n = 195)-for patients diagnosed with MF/SS before 30 years of age.Main outcomes and measuresOverall survival was calculated by the Kaplan-Meier method. The risk of a second cancer was assessed by calculating the standard incidence ratio (SIR) comparing observed cancer incidence in patients with MF/SS with the expected incidence in the age-, sex-, and race-standardized general population.ResultsThe incidence of MF/SS is rare before 30 years of age, with an incidence rate of 0.05 per 100,000 persons per year before age 20 years and 0.12 per 100,000 persons per year between ages 20 and 29 years in the California Cancer Registry. At 10 years, patients with MF/SS had an overall survival of 94.3% (95% CI, 89.6%-97.2%) in the California Cancer Registry and 88.9% (95% CI, 82.4%-93.2%) in SEER 9. In SEER 9, there was a significant excess risk of all types of second cancers combined (SIR, 3.40; 95% CI, 1.55-6.45), particularly lymphoma (SIR, 12.86; 95% CI, 2.65-37.59) and melanoma (SIR, 9.31; 95% CI, 8.75-33.62). In the California Cancer Registry, the SIR for risk of all types of second cancers was similar to that in SEER 9 (SIR, 3.45; 95% CI, 0.94-8.83), although not statistically significant.Conclusions and relevanceYoung patients with MF/SS have a favorable outcome, despite a strong suggestion of an increased risk of second primary cancers. Prolonged follow-up is warranted to definitively assess their risk of developing second cancers in a lifetime

Outcomes after diagnosis of mycosis fungoides and Sézary syndrome before 30 years of age: a population-based study.

ImportanceMycosis fungoides and Sézary syndrome (MF/SS) are rare in children and young adults, and thus the incidence and outcomes in this patient population are not well studied.ObjectiveTo assess the incidence and outcomes of MF/SS in patients diagnosed before 30 years of age.Design, setting, and participantsRetrospective study of 2 population-based cancer registries-the California Cancer Registry (n = 204) and 9 US cancer registries of the Surveillance, Epidemiology, and End Results program (SEER 9; n = 195)-for patients diagnosed with MF/SS before 30 years of age.Main outcomes and measuresOverall survival was calculated by the Kaplan-Meier method. The risk of a second cancer was assessed by calculating the standard incidence ratio (SIR) comparing observed cancer incidence in patients with MF/SS with the expected incidence in the age-, sex-, and race-standardized general population.ResultsThe incidence of MF/SS is rare before 30 years of age, with an incidence rate of 0.05 per 100,000 persons per year before age 20 years and 0.12 per 100,000 persons per year between ages 20 and 29 years in the California Cancer Registry. At 10 years, patients with MF/SS had an overall survival of 94.3% (95% CI, 89.6%-97.2%) in the California Cancer Registry and 88.9% (95% CI, 82.4%-93.2%) in SEER 9. In SEER 9, there was a significant excess risk of all types of second cancers combined (SIR, 3.40; 95% CI, 1.55-6.45), particularly lymphoma (SIR, 12.86; 95% CI, 2.65-37.59) and melanoma (SIR, 9.31; 95% CI, 8.75-33.62). In the California Cancer Registry, the SIR for risk of all types of second cancers was similar to that in SEER 9 (SIR, 3.45; 95% CI, 0.94-8.83), although not statistically significant.Conclusions and relevanceYoung patients with MF/SS have a favorable outcome, despite a strong suggestion of an increased risk of second primary cancers. Prolonged follow-up is warranted to definitively assess their risk of developing second cancers in a lifetime

Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models.

CD70 is a member of the tumor necrosis factor receptor superfamily. Emerging data indicate that CD70 may be a suitable target for various malignancies. We investigated the expression of CD70 in cutaneous and systemic T-cell lymphomas and conducted preclinical studies of SGN-CD70A, a CD70-directed antibody-drug conjugate (ADC), using patient-derived xenograft cutaneous T-cell lymphoma (CTCL PDX) models. CD70 expression was examined by immunohistochemical (IHC) stains in 49 diagnostic specimens of T-cell lymphomas. The activities of SGN-CD70A in growth inhibition and apoptosis induction were examined in CTCL cell lines and primary CTCL tumor cells. Using previously established CTCL PDXs, we conducted a dose-finding trial followed by a phase 2-like trial to evaluate the optimal dosing and the efficacy of SGN-CD70A in tumor-bearing PDX animals. The therapeutic efficacy of SGN-CD70A was measured by tumor-associated cell-free DNA (cfDNA) and survival of treated PDXs. We found that CD70 is highly expressed in T-cell lymphomas, especially in CTCL. SGN-CD70A inhibited cell growth and induced apoptosis in CD70-expressing CTCL cell lines and primary tumors cells. Additionally, SGN-CD70A at 100 μg/kg and 300 μg/kg prolonged the survival of PDXs in a dose-dependent manner. Finally, treatment with 3 doses of SGN-CD70A at 300 μg/kg was superior to a single-dose treatment in survival prolongation (median survival: 111 days vs 39 days; P = .017). Most importantly, multiple dosing of SGN-CD70A induced complete eradication of established tumors in PDXs measured by cfDNA. Our results demonstrated marked antitumor activity of SGN-CD70A in CTCL PDXs, providing compelling support for its clinical investigation

Cutaneous T-Cell Lymphoma PDX Drug Screening Platform Identifies Cooperation between Inhibitions of PI3Kα/δ and HDAC

Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome are life threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high-value targets, including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development