Prognostic Impact of Interim and Final PET in Primary Mediastinal Large B-Cell Lymphoma Treated with Intensive Etoposide-Based Therapy

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma with typical clinical, pathological and genetic features. No standard frontline protocol is widely accepted and role of adjuvant radiotherapy is not established yet. New intensive etoposide-based (DA-EPOCH; Dunleavy K, NEJM 2013) regimens with added rituximab show survival benefit but certain patients are still at risk of early treatment failure. As residual masses (CT) after therapy are frequent, assessment of tumor metabolic response is of utmost importance. Complete metabolic response (CMR) measured by positron emission tomography (PET) has high predictive value after intensive treatment (Martelli M, JCO 2014), but the role of interim scans is unclear.

Aim: To analyze the prognostic impact of interim and final whole-body PET-CT fusion scans using visual and Deauville criteria in PMBCL patients receiving intensive etoposide-based regimens with rituximab.

Patients: Thirty-four consecutive PMBCL patients were treated in a single center from 5/2005 to 6/2013. The median age at diagnosis was 32.5 (19-73) years; male-to-female ratio 0.62:1. Ann Arbor stages I through IV were observed in 1, 19, 3 and 11 patients, respectively. Large mediastinal mass (≥11cm) was present in 19 (56%) patients. Thirteen patients (38%) had concurrent extranodal disease but unaffected bone marrow. IPI and age-adjusted IPI scores were: low 16 (47%) and 8 (24%), low-intermediate 11 (32%) and 11 (32%), high-intermediate 5 (15%) and 12 (35%), and high 2 (6%) and 3 (9%) patients, respectively. All patients received rituximab; intensive etoposide-doxorubicin-based therapy was given to 30 (88%; sequential n=29, MegaCHOP-ESHAP n=1), intensified CHOP (PACEBO) to 1 and CHOP to 3 patients. Treatment was consolidated with ASCT (BEAM 200) in high-risk bulky cases with extranodal involvement (n=20, 59%). Involved-field radiotherapy was used in only 9 (26%) patients. Whole-body PET-CT scans were planned after 2nd chemotherapy cycle (interim; iPET-2) and treatment completion (final; fPET). The PET results were expressed as positive/negative (IHP; Juweid ME, JCO 2007) and 5-point Deauville scale (D1-5; Meignan M, Leuk Lymphoma 2014). Treatment response was assessed using revised criteria (Cheson BD, JCO 2007).

Results: After treatment, 28 (82%) patients achieved complete remission (CR), one partial remission, three stable disease and two progressed. Seventeen CR patients (61%) had residual mass on CT (median longest diameter 40mm). After a median follow-up of 58.7 months, 8 (24%) patients relapsed or progressed and 6 (18%) of them died. Five-year overall survival (5-y OS) reached 81.2% (95% CI 0.68-0.95), 5-year progression survival (5-y PFS) was 75.5% (95% CI 0.61-0.90). There were 27 (79%) and 33 (97%) cases assessable with iPET-2 and fPET, respectively. Using visual criteria, iPET-2 was negative in 10/27 (37%) and fPET in 28/33 (85%) cases. With Deauville criteria, iPET-2 scores were D1-2 in 6 (22%), D3 in 4 (15%) and D4-5 in 17 (63%) cases, and fPET scores D1-2 in 19 (58%), D3 in 8 (24%) and D4-5 in 6 (18%). All visually negative iPET-2 were scored as D1-3. In fPET, there was only one discordant case (visually negative scored as D4). Visually negative (D1-3) iPET-2 was associated with superior 5-y OS (34% vs 100%, p=0.08) and 5-y PFS (65% vs 100%, p=0.049). Visually negative visual fPET was linked with superior 5-y OS (20% vs 96.0%, p<0.01) and 5-y PFS (20% vs 88.6%); D1-3 with 5-y OS (33.3% vs 95.8%, p<0.01) and 5y-PFS (33.3% vs 88.2%, p<0.01). Negative (NPV) and positive (PPV) predictive values for PFS were 100% and 35.3% for iPET-2 and 89.3% (visual), 90.0% (D) and 80% (visual), 66.7% (D) for fPET, respectively. Residual PET(-) mass have no impact on OS (p=0.47) or PFS (p=0.85).

Conclusion: Early CMR resulted in excellent survival and superior NPV (100%). However, two thirds of iPET-positive patients may achieve long remission (PPV is low). Final PET brings twice higher PPV but despite relatively high NPV, more than 10% of fPET-negative patients relapse later. Visual and Deauville scales are comparable; intermediate (D3) results should be considered negative. Thus, iPET-2 identifies good responders and may serve as an indicator for tailored therapy. Further studies including tumor metabolic volume analysis are needed for better early identification of poor responders.

Acknowledgment: LF-2014-001

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