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Outcomes With PET-Directed Therapy for Limited-Stage DLBCL


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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

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.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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