R-CHOP Alone Should Be New Standard in Early-Stage DLBCL, Researchers Say

Daniel O. Persky, MD

Four cycles of R-CHOP (Rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) alone should be the new standard approach to limited-stage disease for the majority of patients with diffuse large B-cell lymphoma (DLBCL). That’s the conclusion of a new Journal of Clinical Oncology study that used positron emission tomography (PET)–directed treatment approaches to assess the outcomes and toxicity associated with the current standard of care.

A total of 158 patients were enrolled in the study and of those patients, 132 were eligible and 128 underwent interim PET scans after completing 3 cycles of R-CHOP. Only 14 patients (11%) had a positive PET scan; they then received radiation therapy per protocol. With a median follow-up of 4.92 years (range, 1.1 - 7.7 years), only 6 patients experienced progressive disease and only 3 patients died of lymphoma. Eleven patients died of unrelated causes during follow-up at a median age of 80 years. The 5-year progression-free survival (PFS) estimate was 87% (95% Confidence Interval [CI], 79% - 92%) and the overall survival (OS) estimate was 89% (95% CI, 82% - 94%). Patient outcomes were similar regardless of whether their PET scan was positive or negative.

“Together with the FLYER results in younger, more favorable-risk patients, the findings of our study have established that R-CHOP x 4 is a new standard, less morbid approach in limited-stage DLBCL for the absolute majority of patients, reserving radiation for the small subset of patients with interim PET-positive disease,” wrote the authors, led by Daniel O. Persky, MD, of the University of Arizona, Tucson, AZ. “The results were also favorable in subgroups defined by age, smIPI, cell of origin, and histology and were marginally unfavorable for DPE.”

S1001 (NCT01359592) was a phase II study for previously untreated patients with non-bulky (< 10 cm) stage I/II CD20-positive DLBCL. S1001’s primary end point was the 5-year PFS rate. Secondary end points included 5-year OS. Patients needed a WHO performance status of 0-2, adequate organ function, a normal left ventricular ejection fraction, and a negative bone marrow biopsy to enroll.

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 IV, and oral prednisone 100 mg for 5 days. Patients had an interim PET between day 15 and 18 of cycle 3 for central review. Patients whose PET scans were negative, defined as Deauville 1-3, then received 1 additional cycle of R-CHOP.

Patients whose PET was positive (Deauville 4-5) then received 36 Gy of involved field radiation therapy (IFRT), plus an additional boost to fluorodeoxyglucose (FDG)-avid areas of up to 9 Gy, within 5 weeks of cycle 3. Within 6 weeks after completing IFRT, patients received ibritumomab tiuxetan (Zevalin), with rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, and ibritumomab tiuxetan 0.4 mCi/kg on day 7, 8, or 9, after rituximab.

Of 128 patients whose interim PET scan received central review, 110 were negative. Of 18 patients with positive scans, 4 had infections and were treated as negative with 1 additional cycle of R-CHOP. Of the 14 patients whose scans were truly positive, 12 received IFRT followed by ibritumomab tiuxetan. Two-thirds of these patients (n = 8) converted from partial response (PR) to complete response (CR) after this additional treatment. Overall, CR was 92%, PR was 4%, and stable disease (SD) was 1%.

Persky et al reported that 1 patient died of sepsis and 1 of hypoxia. Additionally, 13 patients (10%) had febrile neutropenia, and nearly one-third of patients (n = 57, 31%) had grade 3-4 neutropenia. Ten patients each (8%) had grade 3 anemia and grade 3-4 thrombocytopenia. Of the 12 patients who received IFRT followed by ibritumomab tiuxetan, 2 had grade 3-4 neutropenia, 3 had grade 3-4 thrombocytopenia, and 2 experienced radiation dermatitis.

The authors note that, of the 6 patients who progressed, 4 had negative interim PET and then received R-CHOP x 4. One patient with positive PET declined radiation, and 1 went off treatment after 1 cycle of R-CHOP because of treatment delay. No patients had primary refractory disease. The median time to progression was 1.1 years (range, 0.2 - 6.2 years), with a continuous pattern of relapse.

Given the relatively long follow-up, Persky et al observed several non-lymphoma deaths, particularly in older patients. “Indeed, our observed 5-year PFS rate of 87% did not meet our original goal of 93%, primarily because of the competing risk of death as a result of non-lymphoma causes (12.8% at 5 years) occurring in patients at a median age of 80 years,” they wrote. “Considering these competing risks of death in an older population over a prolonged time period, we feel that the traditional end point of PFS does not adequately reflect the observed treatment effects, which was supported by our competing risk modeling.”

_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: Results of Intergroup National Clinical Trials Network Study S1001. J Clin Oncol 38. Published online July 13, 2020.}