Celeste M. Bello

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.

Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression

Several non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), variably express CD30. This phase 2, open-label study evaluated the efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30(+) NHL. This planned subset analysis of B-cell NHLs includes 49 patients with DLBCL and 19 with other B-cell NHLs. Objective response rate was 44% for DLBCL, including 8 (17%) complete remissions (CRs) with a median duration of 16.6 months thus far (range, 2.7 to 22.7+ months). There was no statistical correlation between response and level of CD30 expression; however, all responding patients had quantifiable CD30 by computer-assisted assessment of immunohistochemistry. DLBCL patients were generally refractory to first-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% CRs). Patients with other B-cell lymphomas also responded: 1 CR, 2 partial responses (PRs) of 6 with gray zone, 1 CR of 6 with primary mediastinal B-cell, and 1 CR of 3 with posttransplant lymphoproliferative disorder. Adverse events were consistent with known toxicities. The combination of brentuximab vedotin with rituximab was generally well tolerated and had activity similar to brentuximab vedotin alone. Overall, significant activity with brentuximab vedotin was observed in relapsed/refractory DLBCL, and responses occurred across a range of CD30 expression. This study was registered at www.clinicaltrials.gov as #NCT01421667.

Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: A single institutional experience and literature review

Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.

Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome

Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline‐based induction therapy.

Outcome of Diffuse Large B-Cell Lymphoma in the United States Has Improved Over Time but Racial Disparities Remain: Review of SEER Data

BACKGROUND Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) outcome in the United States has not been reported outside the context of clinical trials. PATIENTS AND METHODS We reviewed the Surveillance, Epidemiology, and End Results (SEER) registry and compared survival trends among DLBCL patients from 1973 to 2004. RESULTS We identified 59,728 patients (mean age, 63 years; 54.4% men, 86.7% white) and had staging information for 57%, including 30% early-stage (I/II) and 27% advanced-stage (III/IV). Median overall survival (OS) from 1973 to 1979, 1980 to 1989,1990 to 1999, and 2000 to 2004 was 15, 18, 20, and 47 months, respectively (P < .005). For the period from 2000 to 2004, 4-year OS was 46%. Outcome was better in white patients than in black (47 months versus 29 months) (P = .001). Median OS for patients younger than 60 years old was not reached versus 23 months for patients older than 60 years. CONCLUSION The outcome of DLBCL in the United States has improved significantly in the era of monoclonal antibodies; however, racial disparities remain.

Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome after azanucleoside failure.

For patients with acute myeloid leukemia from antecedent myelodysplastic syndrome particularly after azanucleoside treatment failure, outcome is poor. Here, we conducted a case-control study in these patients to compare the efficacy of CLAG-M induction (28 patients) versus standard 3+7 induction chemotherapy (24 patients). Response rates (P=0.014) and median overall survival (P=0.025) were 64% and 202 days (95% CI 37-367 days) versus 29% and 86 days (95% CI 36-136) in the CLAG-M and 3+7 cohorts, respectively. Median overall survival was 202 (95% CI 37-367 days) versus 86 days (95% CI 36-136) (P=0.025), respectively. CLAG-M has encouraging activity in this patient group.

Serum albumin as a stable predictor of prognosis during initial treatment in patients with diffuse large B cell lymphoma.

Dear Editor, Low serum albumin has been identified as a prognostic indicator in several hematologic malignancies including diffuse large B cell lymphoma (DLBCL) [1]. In both the preand post-rituximab era, pre-treatment of serum albumin <37 g/L has been shown to be a poor prognostic factor in patients with DLBCL [2, 1]. Since serum albumin does not change greatly over time, we hypothesized that serum albumin may be a stable biomarker during treatment in patients with DLBCL. Our study aims to determine whether serum albumin remains a stable prognostic factor when measured at different points during treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL. After obtaining Institutional Review Board approval, patients at the Moffitt Cancer Center with DLBCL who underwent chemotherapy with R-CHOP between 2007 and 2010 were identified using the institutional database. Clinical and treatment data at baseline, prior to each cycle of chemotherapy and 4 weeks after treatment, were recorded and summary statistics were calculated. Patients with missing serum albumin data were excluded from that particular analysis. The clinical outcomes, overall survival (OS), and progression free survival (PFS) were analyzed using a univariate Cox Proportional Hazard model with serum albumin <37 or ≥37 g/L. A total of 124 patients were initially identified. Thirty-six patients were excluded for not having serum albumin data or due to treatment at an outside institution. The majority of the patients were male (63.6 %), 64.8 % received 6 cycles of RCHOP, 63 (71.6 %) had complete response as best response, and 7 (19.3 %) relapsed [1]. Serum albumin remained a predictor of PFS and OS at baseline prior to cycles 1, 2, and 4 of R-CHOP. At 4 weeks after R-CHOP, serum albumin was a predictor of OS, but not of PFS (Table 1). Serum albumin values were statistically different when compared between cycles 1 vs. 2 (p = 0.004), but not between other cycles, indicating that serum albumin levels were stable throughout R-CHOP. Our analysis indicates that serum albumin levels during treatment of R-CHOP remain stable and that serum albumin <37 g/L may predict survival at the start of treatment prior to cycle 2, prior to cycle 4, and 4 weeks after during treatment of DLBCL with R-CHOP. Other biomarkers including Creactive protein, lymphocyte count, and beta2-microglobulin levels have been suggested to be predictors of survival in patients with DLBCL during treatment or at relapse [3–6]. Serum albumin is easily collected and may be a better indicator of comorbid status than age and/or a marker of worsening tumor biology [1]. We suspect that when used in conjunction with other clinical indicators, serum albumin may help to identify patients who may relapse or require additional therapy to better identify an “at-risk” group of patients. The results of this small sample size should be confirmed prior to using serum albumin as a prognostic marker over the course of treatment in DLBCL treated with R-CHOP. J. Eatrides : C. Bello Division of Hematological Malignancies, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

Primary B-cell CNS lymphoma clinicopathologic and treatment outcomes in 89 patients from a single tertiary care center

Primary central nervous system lymphoma (PCNSL) is a rare aggressive variant of diffuse large B-cell lymphoma with a poor prognosis and no defined optimal therapeutic strategies. Our aim was to compare the role of intrathecal chemotherapy with current high-dose methotrexate (HDMTX) treatments. Clinicopathologic characteristics, therapy, and outcomes of patients with PCNSL at Moffitt Cancer Center were reviewed in 89 patients identified over an 11-year period. Patients treated initially with HDMTX-based therapy showed improved overall and progression-free survival, with no improvement shown with added radiation or intrathecal therapy. Age and performance status were also important prognostic indicators. Our conclusion is that initial therapy in PCNSL should include an HDMTX backbone. The use of intrathecal chemotherapy or radiation therapy initially likely does not improve outcomes. Future multicenter phase III clinical trials are needed to better establish the superior initial treatment in PCNSL.

Ofatumumab in the treatment of low-grade non-Hodgkin’s lymphomas and chronic lymphocytic leukemia

Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved for the treatment of chronic lymphocytic leukemia refractory to alemtuzumab and fludarabine. Ofatumumab has also demonstrated activity in other low-grade non-Hodgkin’s lymphomas. However, the optimal time to use ofatumumab and in what patient population is debatable. This article will review some of the key clinical studies that led to the drug’s approval, current recommended usage of the drug and significant future directions.

Rapid infusion rituximab for maintenance therapy: is it feasible?

Rituximab is an anti-CD-20 monoclonal antibody used in the management of lymphoproliferative disorders. The use of maintenance rituximab has improved progression free survival and overall survival in follicular lymphomas. Although rapid rituximab infusions have been studied extensively, there is little data on the use of rapid infusions during maintenance therapy for low grade lymphomas. The primary objective of this retrospective analysis was to evaluate the incidence of Grade 3 and 4 toxicities with maintenance rapid infusion rituximab according to the Common Terminology Criteria for Adverse Events version 4 (CTC v. 4). Secondary objectives included evaluating all grade infusion related adverse events and correlation of adverse events with varying schedules of rituximab maintenance therapy. All patients who received rapid infusion rituximab as maintenance therapy for low grade lymphoma between December 2007 and November 2011 were included. Rapid rituximab infusions were administered over 90 minutes. Demographic, laboratory and clinical data were collected. A total of 109 patients received 647 rapid rituximab infusions. Three patients experienced an adverse reaction which resulted in one grade 1 infusion reaction and three grade 3 infusion reactions. No patients required hospitalization. All 3 patients received pharmacological and/or supportive care to relieve symptoms associated with the reaction.