PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma

SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common Non-Hodgkin Lymphoma diagnosed in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 yrs or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

Approximately 25-30% of DLBCL present as limited stage. Three cycles of Rituximab (RITUXAN®) along with CHOP plus Radiation Therapy (RT) is the standard treatment approach for limited stage DLBCL based on SWOG S0014 study. Data from retrospective studies suggested that 80% of patients were PET negative after 3 cycles of R-CHOP (defined as Deauville score 1-2), on a mid-treatment interim PET/CT scan, and only 8% of them relapsed after receiving 1 additional cycle of R-CHOP without RT.

S1001 is a prospective, Phase II, Intergroup, National Clinical Trials Network, PET-directed study, designed to tailor therapy for patients with limited-stage DLBCL after 3 cycles of R-CHOP. The goal of this study was to eliminate toxicities associated with RT, for the majority of patients with a negative PET scan after 3 cycles of R-CHOP and to improve the outcome in the minority of patients with a positive interim PET scan.

This study included 132 eligible, treatment naïve, Stage I/II, CD20-positive, DLBCL patients, with nonbulky (less than 10 cm) disease. All patients received 3 cycles of standard R-CHOP treatment given every 3 weeks, with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m2 IV, Vincristine 1.4 mg/m2 (capped at 2 mg) IV, and Prednisone 100 mg orally daily for 5 days. Patients had an interim PET scan between days 15 and 18 of cycle 3, which was centrally reviewed in real time. Patients with a negative PET, defined as Deauville score 1-3, proceeded with 1 additional cycle of R-CHOP. Patients with a positive PET (Deauville score 4-5) initiated 36 Gy of involved field radiation therapy, plus an additional boost of up to 9 Gy to FDG-avid areas, within 5 weeks of cycle 3 of R-CHOP. Three to 6 weeks after completing radiation therapy, patients received ZEVALIN® (Ibritumomab tiuxetan) administered per standard protocol, with Rituximab 250 mg/m2 IV given on day 1 and day 7, 8, or 9, and ZEVALIN® 0.4 mCi/kg on day 7, 8, or 9, after Rituximab. A final PET scan was performed 12 weeks after treatment completion. Patients were followed up with clinical examination and testing, including CT scans every 6 months for the first 2 years and then annually for up to 7 years or death.

The median age was 62 years, 62% of patients had Stage I disease, 17% had B symptoms, 43% had extranodal involvement, 66% had exclusive involvement of the head and neck region, and 10% had fully resected disease at baseline. Stage-modified IPI score was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the patients. Overall, 72% of the patients 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 and/or BCL6 rearrangements (double-hit lymphoma or triple-hit lymphoma). Among 87 patients for whom Cell of Origin could be assessed, 68% had Germinal Center B-cell (GCB), 23% had Activated B-Cell (ABC), and 9% were unclassifiable.

With a median follow up of 4.92 years, only 6 of 132 eligible patients progressed, and 3 died as a result of lymphoma, for a 5-year Progression Free Survival (PFS) estimate of 87% and an Overall Survival (OS) estimate of 89%. Eighty-nine percent of the patients with a negative interim PET/CT received R-CHOP × 4, whereas only 11% had a positive interim PET/CT and required radiation-based therapy, with both groups having excellent outcomes.

The authors concluded that, this largest prospective study in the US of limited-stage DLBCL establishes R-CHOP × 4 alone as the new standard treatment for the absolute majority of patients.

Positron Emission Tomography–Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. Persky DO, Li H, Stephens DM, et al. J Clin Oncol. 2020;38:3003-3011