As reported in the Journal of Clinical Oncology by Daniel O. Persky, MD, of the University of Arizona Cancer Center, Tucson, 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).1
Daniel O. Persky, MD
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.”
Study Details
The S1001 study enrolled previously untreated patients with nonbulky (< 10 cm) stage 1/2 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/d for 5 days. Patients underwent interim PET between days 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 and an additional boost to fluorodeoxyglucose-avid areas of up to 9 Gy within 5 weeks of cycle 3 of R-CHOP. At 3 to 6 weeks after completion of involved-field radiation therapy, patients received ibritumomab tiuxetan radioimmunotherapy with 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 death.
Among the 132 patients, median age was 62 years, 62% had stage I disease, 17% had B symptoms, 14% had elevated lactate dehydrogenase, 43% had extranodal involvement and 66% had exclusive involvement of the head and neck region, and 10% had fully resected disease. Stage-modified International Prognostic Index (smIPI) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4%.
Overall, 72% had DLBCL–not otherwise specified, 17% had high-grade B-cell lymphoma–not otherwise specified , and 3% had high-grade B-cell lymphoma with MYC and BCL2 or/and BCL6 rearrangements. Among 87 patients for whom cell of origin could be assessed, 68% had germinal center B cell, 23% had activated B-cell germinal center B cell, and 9% were unclassifiable. Among 123 assessable patients, 17% had double protein expression.
Treatment Outcomes
Of the 132 eligible patients, 128 underwent interim PET. Of these, 14 patients (11%) had positive findings. Of these patients, 2 refused radiation and 12 received involved-field radiation therapy followed by ibritumomab tiuxetan; of these 12 patients, 8 converted from a partial response to a complete response and 4 had a partial response. Overall, a complete response was achieved in 92% of patients, a partial response in 4%, and stable disease in 1%, with four patients (3%) being unevaluable.
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 had disease progression, four were interim PET-negative and received R-CHOP × 4, one was interim PET-positive but declined radiation, and one went off treatment after one cycle of R-CHOP. One patient had disease progression in the central nervous system. No cases of primary refractory disease were observed. A total of 11 patients died from 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 smIPI, cell of origin, and double protein expression status. Progression-free survival at 5 years was 97% for smIPI of 0, 86% for smIPI of 1 to 2, and 30% for smIPI of 3; 95% for germinal center B cell, 72% for activated B cell, and 49% for unclassifiable; and 89% for patients with non–double protein expression lymphoma and 70% for those with double protein expression disease.
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 involved-field radiation therapy 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.
KEY POINTS
- Overall, 89% of patients had negative interim PET and received R-CHOP x 4.
- Over median follow-up of 4.92 years, only six patients had disease progression and three died as a result of lymphoma.
The investigators concluded: “To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best National Clinical Trials Network results in this disease subset. 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.”
DISCLOSURE: The study was supported by National Institutes of Health/National Cancer Institute grants and by Spectrum Pharmaceuticals, Inc. Dr. Persky has served in a consulting or advisory role for Bayer, Celgene, Cellectar, Debiopharm Group, Kymera, and MorphoSys; and has received institutional research funding from Merck.
REFERENCE
1. Persky DO, Li H, Stephens DM, et al: Positron emission tomography–directed therapy for patients with limited-stage diffuse large B-cell lymphoma. J Clin Oncol. July 13, 2020 (early release online).
