As reported in the Journal of Clinical Oncology by Daniel O. Persky, MD, and colleagues, the phase II Intergroup National Clinical Trials Network Study S1001 has shown good outcomes with positron-emission tomography (PET)-directed therapy in patients with limited-stage diffuse large B-cell lymphoma (DLBCL).
As stated by the investigators, “Diffuse large B-cell lymphoma presents as a limited-stage disease in 25% to 30% of patients, with better overall survival than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of PET-directed treatment approaches, we designed a National Clinical Trials Network study to improve outcomes and decrease toxicity.”
Daniel O. Persky, MD
Study Details
S1001 enrolled previously untreated patients with nonbulky (< 10 cm) stage I/II CD20-positive DLBCL. With a change in World Health Organization classification during the study period, new categories of high-grade B-cell lymphoma with or without MYC and BCL2 or BCL6 rearrangements were also eligible. The study was activated in July 2011, with accrual completed in June 2016.
A total of 132 eligible patients received three cycles of standard R-CHOP treatment given every 3 weeks, consisting of rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, vincristine at 1.4 mg/m2 (maximum 2 mg), and prednisone at 100 mg per day for 5 days. Patients underwent interim PET between day 15 and 18 of cycle 3, with findings centrally reviewed in real time.
Patients with negative results received one additional cycle of R-CHOP. Those with positive results received 36 Gy of involved-field radiation therapy (IFRT) and an additional boost to fluorodeoxyglucose (FDG)-avid areas of up to 9 Gy within 5 weeks of cycle 3 of R-CHOP. At 3 to 6 weeks after completion of IFRT, patients received ibritumomab tiuxetan radioimmunotherapy with rituximab at 250 mg/m2 on day 1 and days 7, 8, or 9 and ibritumomab tiuxetan at 0.4 mCi/kg on days 7, 8, or 9 after rituximab.
A final PET scan was performed 12 weeks after completion of treatment. Patients were followed with examination and testing, including computed tomography scans every 6 months for the first 2 years and then annually for up to 7 years or until death.
Treatment Outcomes
Of the 132 eligible patients, 128 underwent interim PET. Of these, 14 patients (11%) had positive findings—2 refused radiation and 12 received IFRT followed by ibritumomab tiuxetan. Of the 12 who received treatment, 8 converted from partial response in germinal center B-cell (GCB) disease to complete response, and 4 had partial response. Overall, compete response was achieved in 92% of patients, partial response in 4%, and stable disease in 1%, with four patients (3%) being unevaluable.
KEY POINTS
- Overall, 89% of patients had a negative interim PET and received R-CHOP x 4.
- Over a median follow-up of 4.92 years, six patients experienced disease progression and three died as a result of lymphoma.
Over a median follow-up of 4.92 years (range = 1.1–7.7 years), disease progression occurred in six patients, and three patients died from lymphoma. Of the six patients who experienced progression, four were interim PET–negative and received R-CHOP x 4, one was interim PET–positive but declined radiation, and one went off treatment after one cycle of R-CHOP. One patient had progression in the central nervous system. No cases of primary refractory disease were observed. A total of 11 patients died as a result of nonlymphoma causes; the median age of these patients was 80 years (range = 56–86 years).
Among all patients, estimated 5-year progression-free survival was 87% and 5-year overall survival was 89%, including progression-free survival rates of 86% vs 89% and overall survival rates of 85% vs 91% among interim PET–positive vs interim PET–negative patients. Histology was not associated with outcome, whereas associations were observed for stage-modified International Prognostic Index (smIPI) score, cell of origin, and double protein expression (DPE) status.
Progression-free survival at 5 years was:
- 97% for smIPI of 0
- 86% for smIPI of 1 to 2
- 30% for smIPI of 3
- 95% for GCB disease
- 72% for activated B-cell disease
- 49% for unclassifiable disease
- 89% for patients with negative DPE status
- 70% for patients with positive DPE status.
Adverse Events
The most common grade 3 or 4 adverse events among all patients were decreased neutrophil count (31%), decreased white blood cell count (27%), decreased lymphocyte count (17%), febrile neutropenia (10%), anemia (8%), and decreased platelets (8%). In addition, two patients (2%) had grade 3 lung infection, three (2%) had grade 3 urinary tract infection, and two (2%) had grade 3 peripheral neuropathy. Of the 12 patients who received IFRT and ibritumomab tiuxetan, 2 had grade 3 or 4 neutropenia, 3 had grade 3 or 4 thrombocytopenia, and 2 had radiation dermatitis. Adverse events led to death in two patients, due to sepsis in one and hypoxia in the other.
The investigators concluded, “With PET-directed therapy, 89% of the patients with a negative interim PET received R-CHOP x 4, and only 11% had a positive interim PET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP x 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.”
Dr. Persky, of the University of Arizona Cancer Center, Tucson, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Institutes of Health/National Cancer Institute grants and by Spectrum Pharmaceuticals, Inc. For full disclosures of the study authors, visit ascopubs.org.
