Professor, Medicine, Hematology Oncology Division; Feinberg School of Medicine
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I have been studying biologic correlates of outcome measures in the context of the US Intergroup CHOP vs. Rituximab(R)-CHOP clinical trial for diffuse, large B-cell lymphoma (DLBCL). The addition of R to conventional CHOP chemotherapy either as induction or maintenance has now been shown to improve outcome in patients with DLBCL (both US and European trials). My findings suggest this improvement in outcome is primarily due to the beneficial effect of R added to CHOP in the bcl-6 negative subset of DLBCL. Furthermore, addition of rituximab to CHOP chemotherapy, does NOT benefit patients who are bcl-6+, the majority of cases. Differences between the clinical behavior of bcl-6 positive and negative lymphoma provide clues to the underlying biologic nature of DLBCL. Different therapeutic strategies may be designed to specifically target bcl-6-positive and negative DLBCL based upon differences in their underlying cell survival mechanisms and sensitivity to chemotherapy and rituximab. Analysis of additional biologic markers (p53, p21) is in progress. Along with Dr. John Reed of the Burnham Institute, a long-standing collaborator, we are investigating protein expression of paracaspase in lymphomas.In collaboration with Dr. E. Terry Papoutsakis of the Department of Chemical Engineering, NU, we are creating gene expression arrays on follicular lymphomas to identify patterns of gene expression reflective of the nonmalignant cells component of the biopsy specimen, and their relationship to clinical outcome.
Radioimmunotherapy using anti-CD20 reagents targets radiation to the malignant lymphocytes and their immediate neighbors by means of the cross-fire effect. To improve outcomes, we have added Y-90-ibritumomab tiuxetan to conventional BEAM chemotherapy for patients undergoing autologous stem cell transplant. This was an investigator initiated phase I trial conducted under an investigator-held IND. Colleagues at the Mayo Clinic were our co-investigators. Forty-three patients were accrued to this study; the maximal tolerated dose of Y-90-Ibritumomab tiuxetan is one that will deliver 1500 cGy to critical organs. We are recommending a phase II trial of this radioimmunotherapeutic at 1.0 mCi/kg administering higher doses of Y-90-ibritumomab tiuxetan be conducted prior to proceeding to a phase III randomized trial.
Continuing in our efforts to develop novel therapies for patients with non-Hodgkin lymphoma, I have written a phase I trial to combine bortezomib, the proteosome inhibitor, with Y-90-ibritumomab tiuxetan for patients with follicular lymphoma. This study has just opened.
Other clinical investigations include anti-idiotype vaccines, novel targeted agents such as histone deacetylase inhibitors and new monoclonal reagents such as the anti-CD40 monoclonal antibody and an anti-CD22 chemoimmunoconjugate. In the context of our recently submitted SPORE in Lymphoma application, I will lead studies of targeted 'nanobins' created by Dr. O'Halloran, and help to develop bcl-6 peptide inhibitors for clinical use with Drs. Licht and Melnick (Albert Einstein).