Rituximab, Lenalidomide, and Ibrutinib With Sequential Addition of Chemotherapy in Newly Diagnosed DLBCL: Smart Start Trial

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In a single-institution phase II trial (Smart Start) reported in the Journal of Clinical Oncology, Jason Westin, MD, MS, and colleagues found that initiating treatment with rituximab, lenalidomide, and ibrutinib (RLI) followed by the sequential addition of chemotherapy resulted in high response rates in newly diagnosed patients with non–germinal center B-cell–like diffuse large B-cell lymphoma (DLBCL).

Jason Westin, MD, MS

Jason Westin, MD, MS

Study Details

The investigator-initiated trial enrolled 58 evaluable patients at The University of Texas MD Anderson Cancer Center between May 2016 and February 2019. Patients received RLI as rituximab at 375 mg/m2 on day 1, lenalidomide at 25 mg once daily on days 1 to 10, and ibrutinib at 560 mg once daily continuously in 21-day cycles. After two cycles, standard chemotherapy with EPOCH (etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide; n = 31) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; n = 25) was added to RLI for six additional cycles; two patients did not receive chemotherapy. The primary endpoints were overall response rate after two cycles of RLI and complete response rate after completion of RLI with chemotherapy.


After two cycles of RLI, objective response was observed in 50 (86.2%, 95% confidence interval [CI] = 74.6%–93.9%) of 58 evaluable patients, with complete response in 21 (36.2%). At the end of RLI/chemotherapy, complete response was observed in 52 (94.5%, 95% CI = 84.9%–98.9%) of 55 evaluable patients; objective response was observed in all 55 patients (100%).

Median follow-up was 31 months (95% CI = 30–40.9 months). Median progression-free survival was not reached, with a 2-year rate of 91.3% (95% CI = 84.3%–98.9%). Median overall survival was not reached, with a 2-year rate of 96.6% (95% CI = 92%–100%). Death occurred in two patients during treatment, due to fungal infection and Clostridium difficile infection, respectively; two additional deaths occurred at more than 24 months after enrollment, due to DLBCL progression and unrelated malignancy.


  • The objective response rate after two cycles of rituximab, lenalidomide, and ibrutinib was 86.2%.
  • The complete response rate after rituximab, lenalidomide, and ibrutinib with sequential addition of chemotherapy was 94.5%.

Adverse Events

Among the total of 60 enrolled patients who received any study treatment, the most common adverse events of any grade were nausea (85%), peripheral sensory neuropathy (83%), diarrhea (78%), and mucositis (75%). The most common grade 3 or 4 adverse events were neutropenia (53%), thrombocytopenia (47%), anemia (38%), and febrile neutropenia (38%; 52% among patients receiving EPOCH, 24% among those receiving CHOP). Grade 3 rash occurred in 16% of patients. Any-grade atrial fibrillation occurred in 12% (grade ≥ 3 in two patients, 3%).

The investigators concluded, “Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high overall response rate, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.”

Dr. Westin, of the Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Conquer Cancer, Schweitzer Family Foundation, National Cancer Institute, Celgene, and Janssen. For full disclosures of the study authors, visit

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