Can Patients With Limited-Stage Diffuse Large B-Cell Lymphoma Skip Radiation Therapy?

Results from the Intergroup National Clinical Trials Network (NCTN) study S1001 demonstrated that 89% of patients with limited-stage diffuse large B-cell lymphoma (DLBCL) maintained survival outcomes at 5 years, after PET-directed therapy with 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).1 These findings, presented at the 2019 ASH Annual Meeting, suggest that most patients can avoid receiving radiation therapy.

“Diffuse large B-cell lymphoma presents as limited-stage in about 30% of [patients],” said lead investigator Daniel O. Persky, MD, from the University of Arizona Cancer Center in Tucson. While patients with limited-stage disease have better overall survival (OS) than those with advanced-stage disease, they can experience late relapses regardless of treatment strategy.

While National Comprehensive Cancer Network guidelines recommend these patients receive abbreviated R-CHOP followed by radiation therapy, recent research has suggested that certain patients who have a negative PET scan after 3 cycles of chemotherapy may be able to skip radiation therapy. In the S1001 study, Dr. Persky and investigators evaluated this approach in patients with newly diagnosed, stage I or II, non-bulky (< 10 cm in greatest diameter) DLBCL. Patients with CNS lymphoma, testicular lymphoma, primary mediastinal B-cell lymphoma, and concurrent or preceding indolent lymphoma were excluded. All participants received standard R-CHOP therapy, then had an interim PET scan performed on days 15 through 18 of cycle 3. If the PET scan was negative (defined as a Deauville score 1-3), patients proceeded with 1 additional cycle of R-CHOP; if the PET scan was positive (Deauville score 4-5), patients received involved-field radiation therapy (IFRT) within 5 weeks, followed by ibritumomab tiuxetan.

Initially, 159 patients were enrolled, but 1 was upstaged by PET and 26 were considered ineligible due to incorrect histology (n=21), no specimen submitted (n=3), and bulky bone disease (n=2).

The 132 remaining evaluable patients (median age = 62 years; range = 18-86) proceeded with 3 cycles of R-CHOP. Of these patients, 62% (n=82) had stage I disease. The median largest diameter on imaging was 3.5 cm (range = 1.0-9.7 cm); 43% of patients (n=57) had extranodal involvement, while 66% (n=87) had involvement only with head and neck. Stage-modified international prognostic index (smIPI) was 0 in 27% of patients, I in 42%, II in 28%, and III in 4% of patients. The study population also included 4 patients (3%) with double-hit lymphoma (DHL), either MYC/BCL2 (n=2) or MYC/BCL6 (n=2).

Prior to PET scan, 4 patients went off treatment, leaving 128 patients who underwent PET scans. Upon central review, 110 patients were considered PET-negative and 18 were PET-positive. Dr. Persky noted that, of the PET-positive patients, 4 were due to infection (Deauville X) and so were treated as having a PET-negative scan. One patient in the PET-negative arm died, so 113 patients continued R-CHOP per study protocol.

In the “truly PET-positive” group, 2 patients refused radiation, and the 12 remaining patients received per-protocol IFRT plus ibritumomab tiuxetan.

During a median follow-up of 4.5 years (range = 1.1-7.5), only 5 patients had progressive disease: 3 who received 4 cycles of R-CHOP, 1 who was PET-positive but declined radiation, and 1 who went off treatment after the first cycle of R-CHOP.

Two study participants died from lymphoma, while 11 patients died from non-lymphoma causes (including 1 PET-negative patient who died from secondary acute myeloid leukemia and another who died of lung adenocarcinoma that was diagnosed via PET scan). Dr. Persky pointed out that the patients in the latter group were older, with a median age of 80 years.

Overall, survival outcomes were similar between PET-negative and PET-positive patients, confirming the authors’ hypothesis that PET-directed therapy would improve survival by guiding intensity of treatment based on risk. The 5-year progression-free survival (PFS; primary endpoint) and OS rates for PET-positive and PET-negative patients, respectively, were:

  • PFS: 86% vs. 88%
  • OS: 93% vs. 91%

This compared favorably with the historical 5-year PFS for patients with limited-stage DLBCL, which has been reported at 85%, Dr. Persky said. He added that survival outcomes appeared to differ according to disease stage at enrollment. For example, patients with smIPI stage 0 had a 5-year PFS of 97%, stage I and II had a 5-year PFS of 86%, and stage III had a 5-year PFS of 30%. At the time of data presentation, all 4 patients with “double hit” lymphoma (DHL) had disease that was still in remission.

Together with results from the FLYER trial, which suggested that younger patients with favorable-prognosis limited stage disease can achieve similarly high 5 year PFS and OS rates with 4 cycles of R-CHOP plus two cycles of rituximab monotherapy as with 6 cycles of R-CHOP, “this NCTN trial establishes four cycles of R-CHOP alone as the new standard approach to limited-stage disease for the majority of patients,” Dr. Persky said.2 He noted, however, that because of the small number of lymphoma events, the researchers were unable to draw conclusions about the prognostic ability of scoring systems like smIPI or lymphoma subtype.

The authors report no relevant conflicts of interest.

References

  1. Persky D, Li H, Stephens D, et al. PET-directed therapy for patients with limited-stage diffuse large B-cell lymphoma – results of intergroup NCTN Study S1001. Abstract #626. Presented at the 2019 American Society of Hematology Annual Meeting, December 8, 2019; Orlando, FL.
  2. Poeschel V, Held G, Ziepert M, et al. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2020;394:2271-2281.