Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations.

BACKGROUND: Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. METHODS: In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). RESULTS: Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. CONCLUSIONS: Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Stewart-Treves Syndrome: A Case Report and Review of the Literature.

The Stewart-Treves syndrome is a rare and deadly entity, which is defined as angiosarcoma arising in the setting of chronic lymphedema. It typically presents in women who develop lymphedema in the upper extremity secondary to axillary lymph node dissection for breast cancer surgery. It is extremely uncommon in the lower extremities as a result of idiopathic chronic lymphedema. Here, we present the case of a 63-year-old female patient with idiopathic chronic lymphedema of the lower extremities having morbid obesity (BMI 82.6) and multiple comorbidities. She developed multiple confluent, hemorrhagic and necrotic elevated purple-black papules in the lower extremities, for which the initial diagnosis was cellulitis. Because there was no improvement with antibiotics, a lower extremity ultrasound and biopsy was performed which showed multiple masses in the left inner upper calf with solid and cystic components. The pathology results of the punch biopsies were consistent with angiosarcoma. Immunohistochemical studies revealed positivity for CD31, FLI-1, and a high Ki-67 proliferation rate. Because of the patient's weight and medical comorbidities, no further extensive diagnostic tests were performed to detect metastatic disease, and because of contraindications, no further medical treatment was provided. The patient subsequently died 1 month after diagnosis.

CD30: an important new target in hematologic malignancies.

CD30 is abundantly and selectively expressed on the surface of Hodgkin Reed-Sternberg cells, anaplastic large cell lymphomas (ALCLs), and other lymphoid malignancies as well as on several non-lymphoid malignancies including selected germ cell tumors. Expression of CD30 on normal cells is highly restricted, thereby allowing differential targeting of malignant cells. CD30, a member of the tumor necrosis factor (TNF)-receptor family has pleiotropic biologic functions, and antibodies targeting CD30 and other TNF family receptors can exhibit both agonistic and antagonistic signaling functions. Recently, antibody-drug conjugates targeting CD30, such as brentuximab vedotin, have shown striking activity in phase I and II trials, with manageable toxicity. This has defined an important emerging role for targeting of CD30 in the setting of Hodgkin lymphoma, ALCL, and possibly other CD30+ malignancies.