Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p

Hamiltonian domain wall fermions at strong coupling

We apply strong-coupling perturbation theory to gauge theories containing domain-wall fermions in Shamir's surface version. We construct the effective Hamiltonian for the color-singlet degrees of freedom that constitute the low-lying spectrum at strong coupling. We show that the effective theory is identical to that derived from naive, doubled fermions with a mass term, and hence that domain-wall fermions at strong coupling suffer both doubling and explicit breaking of chiral symmetry. Since we employ a continuous fifth dimension whose extent tends to infinity, our result applies to overlap fermions as well.Comment: Revtex, 21 pp. Some changes in Introduction, dealing with consistency with previous wor

CD39 activity correlates with stage and inhibits platelet reactivity in chronic lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature appearing lymphocytes and is rarely complicated by thrombosis. One possible explanation for the paucity of thrombotic events in these patients may be the presence of the ecto-nucleotidase CD39/NTDPase-1 on the surface of the malignant cells in CLL. CD39 is the major promoter of platelet inhibition <it>in vivo </it>via its metabolism of ADP to AMP. We hypothesize that if CD39 is observed on CLL cells, then patients with CLL may be relatively protected against platelet aggregation and recruitment and that CD39 may have other effects on CLL, including modulation of the disease, via its metabolism of ATP.</p> <p>Methods</p> <p>Normal and malignant lymphocytes were isolated from whole blood from patients with CLL and healthy volunteers. Enzyme activity was measured via radio-TLC assay and expression via FACS. Semi-quantititative RT-PCR for CD39 splice variants and platelet function tests were performed on several samples.</p> <p>Results</p> <p>Functional assays demonstrated that ADPase and ATPase activities were much higher in CLL cells than in total lymphocytes from the normal population on a per cell basis (p-value < 0.00001). CD39 activity was elevated in stage 0–2 CLL compared to stage 3–4 (p < 0.01). FACS of lymphocytes demonstrated CD39 expression on > 90% of normal and malignant B-lymphocytes and ~8% of normal T-lymphocytes. RT-PCR showed increased full length CD39 and splice variant 1.5, but decreased variant 1.3 in CLL cells. Platelet function tests showed inhibition of platelet activation and recruitment to ADP by CLL cells.</p> <p>Conclusion</p> <p>CD39 is expressed and active on CLL cells. Enzyme activity is higher in earlier stages of CLL and decreased enzyme activity may be associated with worsening disease. These results suggest that CD39 may play a role in the pathogenesis of malignancy and protect CLL patients from thrombotic events.</p

Effective Lagrangian for strongly coupled domain wall fermions

We derive the effective Lagrangian for mesons in lattice gauge theory with domain-wall fermions in the strong-coupling and large-N_c limits. We use the formalism of supergroups to deal with the Pauli-Villars fields, needed to regulate the contributions of the heavy fermions. We calculate the spectrum of pseudo-Goldstone bosons and show that domain wall fermions are doubled and massive in this regime. Since we take the extent and lattice spacing of the fifth dimension to infinity and zero respectively, our conclusions apply also to overlap fermions.Comment: 26 pp. RevTeX and 3 figures; corrected error in symmetry breaking scheme and added comments to discussio

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors

BACKGROUND: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS: A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS: Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3–4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3–4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS: Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00435916