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Interim PET scan predicts survival in aggressive lymphoma
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The use of interim PET accurately predicted survival among patients with aggressive lymphomas treated with rituximab plus CHOP, or R-CHOP, according to results from the randomized phase 3 PETAL clinical trial.
However, treatment intensification based on PET did not improve outcomes.
“To predict outcome, interim PET needs to be performed under strictly defined conditions and evaluated using the deltaSUVmax method. If these requirements are met, interim PET reliably identifies a group of patients with a very high likelihood of treatment failure,” Ulrich Dührsen, MD, director of the department of hematology at University Hospital Essen in Germany, told HemOnc Today. “Patients poorly responding to standard therapy do not benefit from treatment intensification. ... Interim PET may be used to identify patients who may benefit from such approaches in clinical trials.”
Studies have shown PET using 18fluorodeoxyglucose to be more beneficial than CT for baseline and end-of-treatment evaluations of aggressive lymphomas because PET scans performed during treatment may assist in identifying patients at risk for treatment failure.
Researchers initially designed a clinical trial where patients with aggressive B-cell or T-cell lymphomas underwent interim PET scanning after two cycles of R-CHOP; rituximab (Rituxan; Genentech, Biogen) was restricted to CD20-positive lymphomas. If patients had a positive scan, researchers would then randomly assign each to continue R-CHOP or to switch to an intensive methotrexate and cytarabine-based regimen.
Over time, publications suggested the exposure to rituximab be increased to improve outcomes in B-cell lymphomas. Therefore, Dührsen and colleagues amended treatment protocol and randomly assigned patients with CD20-positive lymphomas and a negative interim scan to continue R-CHOP or to receive the same treatment with two additional doses of rituximab.
The analysis included 862 patients aged 18 to 80 years (median age, 60 years; 56.5% men) with newly diagnosed aggressive B-cell or T-cell lymphoma and an ECOG performance status of 0 to 3.
Interim PET scanning occurred a median 20 days after the second R-CHOP cycle.
Investigators randomly assigned 108 patients with positive PET scan to receive six additional cycles of R-CHOP (n = 52) or six blocks of an intensive Burkitt lymphoma protocol (n = 56). The 754 patients with negative PET scan received four additional cycles of R-CHOP or the same treatment with two additional doses of rituximab.
EFS assessed by log-rank test served as the primary endpoint.
Median follow-up was 44.1 months.
Two-year EFS was 42% (95% CI, 28.2-55.2) among patients who received R-CHOP and 31.6% (95% CI, 19.3-44.6) among patients who received the Burkitt protocol, which did not represent a significant difference (HR = 1.5; 95% CI, 0.89-2.51).
Fifty patients had end-of-treatment PET scans available. Of these, 19 had negative findings and 31 held persistent abnormalities. Thirteen patients with active disease received additional treatment.
The 2-year PFS rate was 84.2% (95% CI, 58.7-94.6) among patients with normal scans and 50.5% (95% CI, 31.8-66.6) among patients with pathologic end-of-treatment PET scans (P = .005). Two-year OS rates were 100% among those with normal scans and 65.9% among those with pathologic scans (P = .0003).
Researchers observed increased grade 3 or 4 hematotoxicity, infection and mucositis among patients who received the Burkitt protocol compared with the R-CHOP regimen.
Among patients with negative PET scan, 255 underwent random assignment to R-CHOP (n = 129) or R-CHOP with additional rituximab (n = 126).
Median follow-up was 54.1 months.
The two additional doses of rituximab failed to improve outcomes. EFS was 76.4% (95% CI, 68-82.8) among patients who received R-CHOP and 73.5% (95% CI, 64.8-80.4) among patients who received R-CHOP with additional rituximab (HR = 1.04; 95% CI, 0.68-1.6).
“Increasing the cumulative dose of the CD20 antibody rituximab does not improve outcome in aggressive B-cell lymphomas,” Dührsen said, “For patients with a good response to the first two cycles of R-CHOP, six doses of rituximab are sufficient.”
Investigators studied prognostic factors among all 862 evaluable patients.
Patients with a negative interim scan appeared to have better outcomes than patients with a positive scan, with a 38.9% difference in 2-year EFS, 33.3% difference in PFS and 28.9% difference in OS.
Multivariable regression analysis showed lymphoma subtype, International Prognostic Index and interim PET to be independent determinants of EFS and OS. Outcome prediction by PET was independent of the International Prognostic Index.
The recruitment goal in interim PET-positive patients was not reached using the deltaSUVmax method because only 12.5 % of patients had a positive interim PET scan, which created a study limitation, Dührsen noted.
“Irrespective of the International Prognostic Index, patients with aggressive non-Hodgkin lymphomas and a positive interim PET scan have a poor outcome,” Dührsen said. “They may be candidates to be included in trials investigating novel first-line approaches such as chimeric antigen receptor T cells, which have been shown to be efficient in relapsed and refractory patients.”
The results suggest the Deauville scoring system may be poorly suited to identify high-risk patients or to guide treatment changes among patients with aggressive non-Hodgkin lymphoma, Reid W. Merryman, MD, clinical fellow in medicine at Dana-Farber Cancer Institute, and Ann S. LaCasce, MD, MMSc, director of the Dana-Farber/Partners Cancer Care Hematology-Medical Oncology Fellowship Program and associate professor at Harvard Medical School, wrote in an accompanying editorial.
Further, despite failing to achieve primary endpoints, the PETAL trial offers important guidance for future trial design in aggressive non-Hodgkin lymphoma.
“A positive interim PET scan ... successfully identified a small subset of patients (12.5%) with a high risk of relapse,” Merryman and LaCasce wrote. “The size of the interim PET-positive cohort is similar to prior studies ... and has important practical implications.
“The PETAL trial demonstrates that interim PET-guided chemotherapy intensification is not an effective strategy for aggressive non-Hodgkin lymphoma; however, advances in prognostic and predictive biomarkers, as well as novel treatment options for patients with chemorefractory disease, are rapidly evolving and hold great promise for response-adapted treatment algorithms,” they added. – by Melinda Stevens
For more information:
Ulrich Dührsen MD, can be reached at department of hematology, University Hospital Essen Hufelandstrasse 55, 45147 Essen, Germany; e-mail: ulrich.duehrsen@ukessen.de.
Disclosures: Dührsen reports honoraria and research funding from Amgen and Roche. Please see the study for all other authors’ relevant financial disclosures. Merryman reports no relevant financial disclosures. LaCasce reports consultant/advisory roles with Bristol-Myers Squibb, Forty-Seven and Seattle Genetics; a speakers bureau role with Research to Practice; and research funding to her institution from Sanofi.
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