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To evaluate high-dose therapy and autologous or allogeneic blood or marrow transplantation (BMT) for mantle cell lymphoma, patients receiving BMT for newly diagnosed or relapsed mantle cell lymphoma were identified through the registry at Johns Hopkins. The pathologic diagnostic criteria were reviewed, and details of the presentation, transplant procedure, and survival outcomes were determined. Fifty-eight patients were identified, of whom 64% underwent transplantation in first remission and 12% had primary induction failure. Nineteen patients (one third) received an allograft. Preparative regimens consisted of cyclophosphamide in combination with either busulfan or total body irradiation. On multiple regression analysis, transplantation after 1 or more relapses (hazard ratio, 2.98; P = .02), primary induction failure (hazard ratio, 5.39; P = .002), and allogeneic transplantation (hazard ratio, 3.03; P = .007) were associated with an inferior event-free survival (EFS). However, EFS curves were not statistically different for autologous and allogeneic BMT performed in first remission, with an estimated 3-year EFS approaching or equaling 70%. Primary induction failure and residual bone marrow involvement were the only statistically significant predictors of relapse on multiple regression analysis. At 3 years, the estimated EFS for the entire cohort after BMT was 51%, the probability of relapse was 31%, and the overall survival was 59%. The benefit of autologous or allogeneic BMT for mantle cell lymphoma is thus most apparent when transplantation is performed in first remission. Whether allogeneic BMT ultimately confers an advantage because of a graft-versus-lymphoma effect remains to be determined.

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The PINC trial (NCT01023477) examined the dosage efficacy of oral chloroquine (CQ), an autophagy inhibitor, as a neoadjuvant therapy to reduce the volume, cause regression and decrease the recurrence of breast ductal carcinoma in situ (DCIS), for any grade or ER/PR/Her2 status. Study Objectives: Establish the safety of preventive doses of chloroquine in patients receiving external beam radiation. Elucidate functional molecular and cellular impacts of in vivo autophagy pathway treatment for DCIS. Study the impact of autophagy inhibitors on the MRI characteristics of DCIS lesions. Study the molecular cytogenetic profile of DCIS lesions before and after therapy. This trial implemented a general strategy to accelerate the pace of community-based translational research. Technology for providing immediate feedback on the therapeutic efficacy at the molecular level can be broadly extended to other trials. Methodology: 12 patients diagnosed with DCIS (any grade or ER/PR/Her2 status) were enrolled and randomly assigned to receive CQ at 250mg/week (n=5) or 500mg/week (n=7) for 4 weeks, followed by standard of care surgical therapy. MRI was performed before/after CQ treatment. DCIS spheroid forming cells were isolated and propagated from fresh human DCIS lesions. DCIS cells were characterized by organ culture, xenograft transplantation, molecular cytogenetics, and 59 cell signaling kinases were quantified by Reverse Phase Protein Microarrays. Results: 12 patients completed 4 weeks of CQ treatment prior to surgical excision of their DCIS lesion, with 1 yr follow-up information. CQ treatment reduced PCNA proliferation index in DCIS lesions compared to untreated controls (p=0.001) and inhibited autophagic flux (LC3B positive puncta by IHC). CQ reduced the number of mammospheres in organoid culture without altering copy number variation. Xenograft transplants in NOD/SCID mouse mammary fat pads failed to generate tumors (n=4). 7/12 patients exhibited a reduction in lesion diameter by MRI, 3/12 patients exhibited no measurable change, and 2/12 had a slight increase. Calcium export channel protein (PMCA2) co-localized with 3+ HER2 positive DCIS lesions. Tumor infiltrating macrophages migrated into DCIS ducts following CQ therapy compared to controls (p=0.006). Conclusion: Oral chloroquine, as anti-autophagy therapy, generates a measurable reduction in proliferation of DCIS lesions and enhances immune cell migration into the duct. Citation Format: Virginia A. Espina, Lance Liotta, Svetlana Rassulova, Holly Gallimore, Thalia Grant-Wisdom, Geetha Menezes, Hassan Nayer, Kirsten Edmiston. PINC trial: Preventing invasive breast neoplasia with chloroquine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT140. doi:10.1158/1538-7445.AM2017-CT140

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