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We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m 2 /day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239).Supplemental data for this article is available online at here.

In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m 2 (dose levels 1, 2, 3) or 1.3 mg/m 2 (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m 2 on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.

Background: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients., Results: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone., Conclusions: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) who are not cured by initial therapy sometimes experience disease-free survival after autologous stem cell transplantation. Chemotherapy responsiveness before transplantation is a major predictor of outcome. Patients not responding to second-line regimens may receive third-line therapy in the hopes of achieving response, but outcome data are limited., Patients and Methods: We identified patients with relapsed or refractory DLBCL at Weill Cornell Medical Center for whom data on responses to second-line chemotherapy were available., Results: A total of 74 patients with relapsed or refractory DLBCL who underwent second-line chemotherapy between 1996 and 2007 were identified. Of these patients, 27 (36%) did not respond. The median overall survival of nonresponding patients was 4 months, and only 1 patient (4%) survived for 1 year. The choice of third-line aggressive chemotherapy instead of less intensive approaches did not confer a survival benefit., Conclusion: Our data demonstrate that patients with recurrent DLBCL not responding to second-line chemotherapy demonstrate dismal outcomes. Trials of novel regimens should be prioritized as management strategies for these patients. Our data provide an important benchmark in the evaluation of the potential clinical value of such approaches.

Background: Many patients with recurrent lymphoma are unable to tolerate intensive therapies, or have disease that is refractory. Metronomic chemotherapy offers a novel, potentially less toxic yet effective treatment strategy., Methods: An analysis was performed on 75 lymphoma patients who were treated with the PEP-C regimen at a single institution. The program consisted of oral prednisone 20 mg after breakfast, cyclophosphamide 50 mg after lunch, etoposide 50 mg after dinner, and procarbazine 50 mg at bedtime with an oral antiemetic. All medications were administered daily until the white blood cell count fell to less than 3.0 x 10(9)/L, whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated weekly basis (eg, 5 of 7 days), depending on patient tolerance. Doses given per day were held constant., Results: Eighty percent of patients had previously received 2 or more treatments. Overall, 69% achieved an objective response after PEP-C treatment, with 36% complete responses and 33% partial responses. Subjects with indolent histologies had superior overall responses, complete responses, and time on therapy relative to those with aggressive histologies. The regimen was generally well tolerated., Conclusions: Metronomic therapy with low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals represents a novel, active, easily tolerated approach to management of patients with recurrent lymphoma, particularly those with indolent histologies., ((c) 2008 American Cancer Society.)

The prednisone, etoposide, procarbazine and cyclophosphamide (PEP-C) oral combination chemotherapy regimen (prednisone 20 mg, cyclophosphamide 50 mg, etoposide 50 mg, and procarbazine 50 mg with an oral anti-emetic) was employed at our center to treat 22 patients with heavily pretreated, recurrent mantle cell lymphoma (MCL). All medications were administered daily until leukocytes fell to <3.0 x 10(9)/L whereupon treatment was withheld until recovery from the nadir. Therapy was then reinstituted on a daily, alternate day, or fractionated basis (e.g. 5 of 7 days) depending on patient tolerance. Doses given per day were held constant. Eighty-two percent achieved an objective response with 46% complete responses and 36% partial responses. Median time on therapy was 17 months. The regimen was well tolerated. Our findings demonstrate that low-dose oral agents administered in combination for continuous, prolonged periods with minimal drug-free intervals (metronomic therapy) may represent a novel, effective, easily tolerated approach to MCL and that this treatment approach warrants further exploration.