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Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.
Melani, Christopher; Lakhotia, Rahul; Pittaluga, Stefania; Phelan, James D; Huang, Da Wei; Wright, George; Simard, Jillian; Muppidi, Jagan; Thomas, Craig J; Ceribelli, Michele; Tosto, Frances A; Yang, Yandan; Xu, Weihong; Davies-Hill, Theresa; Pack, Svetlana D; Peer, Cody J; Arisa, Oluwatobi; Mena, Esther; Lindenberg, Liza; Bergvall, Ethan; Portell, Craig A; Farah, Rafic J; Lee, Seung Tae; Pradhan, Amynah; Morrison, Candis; Tadese, Atekelt; Juanitez, Anna Marie; Lu, Crystal; Jacob, Allison; Simmons, Heidi; Figg, William D; Steinberg, Seth M; Jaffe, Elaine S; Roschewski, Mark; Staudt, Louis M; Wilson, Wyndham H.
Affiliation
  • Melani C; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Lakhotia R; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Pittaluga S; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Phelan JD; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Huang DW; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Wright G; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Simard J; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Muppidi J; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Thomas CJ; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Ceribelli M; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Tosto FA; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Yang Y; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Xu W; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Davies-Hill T; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Pack SD; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Peer CJ; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Arisa O; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Mena E; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Lindenberg L; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Bergvall E; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Portell CA; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Farah RJ; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Lee ST; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Pradhan A; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Morrison C; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Tadese A; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Juanitez AM; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Lu C; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Jacob A; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Simmons H; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Figg WD; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Steinberg SM; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Jaffe ES; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Roschewski M; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Staudt LM; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
  • Wilson WH; From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management
N Engl J Med ; 390(23): 2143-2155, 2024 Jun 20.
Article in En | MEDLINE | ID: mdl-38899693
ABSTRACT

BACKGROUND:

The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.

METHODS:

We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.

RESULTS:

In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.

CONCLUSIONS:

Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
Subject(s)
Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Piperidines; Prednisone; Sulfonamides; Humans; Lymphoma, Large B-Cell, Diffuse/drug therapy; Lymphoma, Large B-Cell, Diffuse/mortality; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Antineoplastic Combined Chemotherapy Protocols/adverse effects; Sulfonamides/adverse effects; Sulfonamides/administration & dosage; Sulfonamides/therapeutic use; Aged; Male; Bridged Bicyclo Compounds, Heterocyclic/adverse effects; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage; Lenalidomide/adverse effects; Lenalidomide/administration & dosage; Lenalidomide/therapeutic use; Piperidines/adverse effects; Piperidines/therapeutic use; Piperidines/administration & dosage; Adult; Antibodies, Monoclonal, Humanized/adverse effects; Antibodies, Monoclonal, Humanized/therapeutic use; Antibodies, Monoclonal, Humanized/administration & dosage; Prednisone/adverse effects; Prednisone/administration & dosage; Prednisone/therapeutic use; Adenine/analogs & derivatives; Adenine/adverse effects; Adenine/therapeutic use; Adenine/administration & dosage; Aged, 80 and over; Recurrence; Pyrazoles/adverse effects; Pyrazoles/therapeutic use; Pyrazoles/administration & dosage; Pyrimidines/adverse effects; Pyrimidines/therapeutic use; Pyrimidines/administration & dosage; Molecular Targeted Therapy; Progression-Free Survival
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Sulfonamides / Prednisone / Adenine / Antineoplastic Combined Chemotherapy Protocols / Lymphoma, Large B-Cell, Diffuse / Bridged Bicyclo Compounds, Heterocyclic / Antibodies, Monoclonal, Humanized / Lenalidomide Limits: Aged80 Language: En Journal: N Engl J Med Year: 2024 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Sulfonamides / Prednisone / Adenine / Antineoplastic Combined Chemotherapy Protocols / Lymphoma, Large B-Cell, Diffuse / Bridged Bicyclo Compounds, Heterocyclic / Antibodies, Monoclonal, Humanized / Lenalidomide Limits: Aged80 Language: En Journal: N Engl J Med Year: 2024 Document type: Article