Richard Burack

Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas

PURPOSEnAurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.nnnPATIENTS AND METHODSnPatients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitts lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.nnnRESULTSnWe enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitts (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitts lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.nnnCONCLUSIONnThe novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.

A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213

BACKGROUNDnRituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.nnnPATIENTS AND METHODSnForty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35-69.8 years).nnnRESULTSnNineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤ 65 years) and the median overall survival (OS) was 6.8 years.nnnCONCLUSIONSnAlthough this regimen is toxic, it is active for patients ≤ 65 years of age and can be given both at academic centers and in experienced community centers.

Splenic lymphocyte subtypes in immune thrombocytopenia: increased presence of a subtype of B‐regulatory cells

in Japanese patients with Upshaw-Schulman syndrome. Blood, 103, 1305–1310. Park, H.W., Oh, D., Kim, N., Cho, H.Y., Moon, K.C., Chae, J.H., Ahn, H.S., Choi, Y. & Cheong, H.I. (2008) Congenital thrombotic thrombocytopenic purpura associated with unilateral moyamoya disease. Pediatric Nephrology, 23, 1555–1558. Perez-Rodriguez, A., Loures, E., Rodriguez-Trillo, A., Costa-Pinto, J., Garcia-Rivero, A., Batlle-Lopez, A., Batlle, J. & Lopez-Fernandez, M.F. (2014a) Inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): a short review. Thrombosis Research, 134, 1171–1175. Perez-Rodriguez, A., Batlle-Lopez, A., Blanco, R., Varela, I., Leon, J., Delgado, M.D., Loures, E., Rodriguez-Trillo, A., Garcia-Rivero, A., CostaPinto, J., Batlle, J. & Lopez-Fernandez, M.F. (2014b) A novel mutation in ADAMTS13 of a child with Upshaw-Schulman Syndrome. Thrombosis and Haemostasis, 112, 1065–1068. Zhang, P., Pan, W., Rux, A.H., Sachais, B.S. & Zheng, X.L. (2007) The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow. Blood, 110, 1887–1894.

Increased numbers of CD23+CD21hi Bin‐like B cells in human reactive and rheumatoid arthritis lymph nodes

A unique population of CD23+ CD21high B cells in inflamed nodes (Bin) has been shown to accumulate in lymph nodes (LNs) draining inflamed joints of TNF‐transgenic (TNF‐tg) mice. Bin cells contribute to arthritis flare in mice by distorting node architecture and hampering lymphatic flow, but their existence in human inflamed LNs has not yet been described. Here, we report the characterization of resident B‐cell populations in fresh popliteal lymph nodes (PLNs) from patients with severe lower limb diseases (non‐RA) and rheumatoid arthritis (RA) patients, and from banked, cryopreserved reactive and normal human LN single cell suspension samples. Bin‐like B cells were shown to be significantly increased in reactive LNs, and strikingly elevated (>30% of total) in RA samples. Histopathology and immunofluorescence analyses were consistent with B follicular hyperplasia and histological alterations in RA vs. non‐RA PLNs. This is the first description of Bin‐like B cells in human inflamed LNs. Consistent with published mouse data, this population appears to be associated with inflammatory arthritis and distortion of LN architecture. Further analyses are necessary to assess the role of CD23+CD21hi Bin‐like B cells in RA pathogenesis and arthritic flare.

Relevance of IgVH Gene Somatic Hypermutation and Interphase Cytogenetics in Lymphomatous Presentation of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are regarded as the same entity, with SLL restricted to tissue cases featuring no leukemic phase. In this study, the authors evaluate a group of SLL cases for cytogenetic abnormalities and IgVH gene mutational status to illicit differences between CLL and SLL. Design. IgVH gene polymerase chain reaction amplification and subsequent sequencing were preformed on formalin-fixed, paraffin-embedded archival tissue of 44 patients (SLL n = 34 or CLL n = 10). Cytogenetic data, CD38, and ZAP-70 expression were also evaluated for these cases. Results. The data indicate that 9/34 (26%) SLL cases have somatic hypermutation >2%, which is less than the CLL group where 40% were mutated (4/10). Cytogenetic abnormalities were seen in 58% of the SLL cases with many showing abnormalities associated with favorable to intermediate prognosis. Conclusion. The authors’ attempt to compare CLL with SLL with regards to cytogenetic and IgVH mutational status shows no statistically significant difference.