Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia

Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive days plus 14 or 7 days’ rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days’ rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-daily (BID) for 7 days plus 14 days’ rest in 21-day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-013-0050-9) contains supplementary material, which is available to authorized users

Targeting CLL-1 for acute myeloid leukemia therapy

Abstract Despite major scientific discoveries and novel therapies over the past four decades, the treatment outcomes of acute myeloid leukemia (AML), especially in the adult patient population remain dismal. In the past few years, an increasing number of targets such as CD33, CD123, CLL-1, CD47, CD70, and TIM3, have been developed for immunotherapy of AML. Among them, CLL-1 has attracted the researchers’ attention due to its high expression in AML while being absent in normal hematopoietic stem cell. Accumulating evidence have demonstrated CLL-1 is an ideal target for AML. In this paper, we will review the expression of CLL-1 on normal cells and AML, the value of CLL-1 in diagnosis and follow-up, and targeting CLL-1 therapy-based antibody and chimeric antigen receptor T cell therapy as well as providing an overview of CLL-1 as a target for AML

Complete Response to R-EPOCH in Primary Cardiac Lymphoma

Primary cardiac lymphoma (PCL) is a rare extranodal lymphoma involving only the heart and/or the pericardium. Most common presenting signs and symptoms are nonspecific including dyspnea, pericardial effusion, and arrhythmia. Prognosis of PCL patients remain poor compared to non‐cardiac lymphoma patients. Since most of the information about PCL comes from case reports or case series, there is no treatment consensus. Anthracycline containing chemotherapy remains main treatment modality which is potentially cardiotoxic. We present a case of PCL that achieved complete remission using R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). We also used dexrazoxane in an effort to reduce cardiotoxicity of chemotherapy

CD70 Expression in Mature T-Cell Lymphomas

Abstract Introduction Mature T-cell lymphomas (TCLs) represent about 15% of the non-Hodgkin lymphomas in U.S. and are a heterogeneous group of neoplasms. TCLs usually have poor outcomes and are resistant to conventional chemotherapy regimens. Therefore, there is a need for identifying biomarkers that could translate into effective novel treatments. CD70 is the TNF superfamily ligand of CD27 and it is being explored as a potential target in CAR-T therapy against TCLs and other neoplasms. Although CD70 expression has been documented in TCL cell lines, thus providing a potential rationale for its use as a therapeutic target, the expression of CD70 among the most frequent TCL subtypes in patient samples has not been previously evaluated. Methods Patients with de novo and/or relapsed mature TCLs diagnosed between 01/2010 and 06/2020 and with available tissue sections were included in the study. The assessment of CD70 expression was performed by immunohistochemistry (IHC) using a novel proprietary antibody developed by CRISPR Therapeutics. CD70 expression was scored using % of expression, intensity (negative, +1, +2, and +3) and H-score {H-score = [(%positive cells intensity 1+) x 1] + [(%positive cells intensity 2+) x 2] + [(%positive cells intensity 3+) x 3]} in neoplastic cells (Figure 1). Clinicopathologic characteristics were collected retrospectively and included age, sex, staging, biopsy site, WHO pathologic classification, immunophenotype, presence of other malignancies, treatment status, disease progression/relapsed, and follow-up. These characteristics were compared with CD70 expression using ANOVA or non-parametric analysis. Overall-survival (OS) was estimated using Kaplan-Meier method and compared using log-rank. A p< 0.05 was considered statistically significant. Results One hundred thirty-six patient samples representing the major subtypes of the 4 categories of mature TCLs were included [nodal TCLs (n=64; including PTCL Th1, and Th2 subtypes and angioimmunoblastic T cell lymphoma - AITL), extranodal (n=35; including primary intestinal lymphomas), cutaneous (n=24; including mycosis fungoides (MF) with large cell transformation), and leukemic (n=13; including adult T cell leukemia/lymphoma)]. Most patients were male (58.8%), in the 6 th or 7 th decade (47.1%), with advanced stage IV (55.7%), no previous malignancies (69.9%) and previously treated (57.2%); 59 of which (88%) received two or more lines of treatment. The median expression of CD70 was 40% (ranged from 0 to 100%) and the median H-score was 110 (ranged from 0 to 300) and was significantly higher (p= 0.006) in peripheral T-cell lymphoma, NOS, primary cutaneous TCLs (non-mycosis fungoides), and AITL (180, 150, and 150, respectively) (Figure 1). The expression of CD70 was more frequent in nodal and extranodal subtypes (including skin), compared to leukemic TCLs (p= 0.005). The expression of CD70 was associated with advanced age at the diagnosis (p= 0.003), CD2 expression (p= 0.01), CD3 expression (p= 0.001), CD16 negativity (p= 0.03), and absence of ALK-1 expression (p= 0.005). After a median follow-up of 19 months (range: 1 - 300 months), 42% of the patients died of disease. The median OS was 76 months (CI95, 38.5 - 113.4 months) and it was not associated with CD70 expression. Conclusions CD70 was highly expressed in most mature TCLs and it was negative in most ALK-positive ALCL. Its expression was associated with nodal and extranodal subtypes, advanced age, expression of CD2, CD3, and negativity for CD16. Therefore, CD70 can be used as a potential biomarker and a target in clinical trials of patients with mature TCLs. Figure 1 Figure 1. Disclosures Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Sagert: CRISPR Therapeutics: Current Employment. Pham: CRISPR Therapeutics: Current Employment. Tipton: CRISPR Therapeutics: Current Employment. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding

Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy

Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics.Trial registrationwww.clinicaltrials.gov (NCT00410163)