German High-Grade Lymphoma Study Group Research Articles

A Simplified IPI Including BCL2 Identifies IPI 3 Patients with Poor Prognosis - a GLA/ Dshnhl and Lysa Collaboration

Introduction: The original IPI remains valid to identify prognostic groups of DLBCL patients (pts) treated with R-CHOP (Ruppert et al. Blood 2020) and has been used to define eligibility for more than 20 studies randomizing pts between R-CHOP and R-CHOP + X, none of which except the Polarix study met its endpoint. One reason why some studies failed was the inclusion of IPI 2/3 pts equalizing the difference between standard and experimental arm although significant survival differences in pts with higher IPI were detected. Following the WHO-HAEM5 classification, determination of BCL2 and MYC rearrangements is mandatory to diagnose DLBCL, NOS and HGBL- MYC/ BCL2. As surrogate markers, we included immunohistochemistry (IHC) for MYC and BCL2 into the IPI model hoping for a wider spread of survival curves and better selection of pts suitable for future clinical trials. Methods: We analyzed 2765 pts treated on DSHNHL (German high-grade lymphoma study group) phase 2/3 studies, calculated the IPI, and added results for BCL2 and MYC expressionto individual IPI factors using published thresholds (50%; 70%) (Ziepert et al. Haematologica 2020). In univariate analyses, log-rank tests were used. Proportional hazard models for each of the biologic markers were separately adjusted for IPI factors. Using a variable selection algorithm the final model was built. Hazard ratios (HR) with p-values are presented. Results: 2765 DLBCL pts by reference pathology treated on 12 DSHNHL phase 2/ 3 studies were eligible. Median age at diagnosis was 57 years (range: 18-80 years), 43% of pts were female. Median observation time was 5 years. All pts had been treated with R-CHOP or variations. At diagnosis, 610 pts (22%) scored an IPI of 0, IPI was 1, 2, 3, 4, or 5 in 895 (32%), 546 (20%), 436 (16%), 212 (8%) and 64 (2%) pts with 3-year PFS- and OS-rates of 95%,87%,77%,66%,66%,47% and 98%,92%,83%,71%,73% and 54%, respectively. Multivariate analyses confirmed the significance of IPI factors (age, stage, performance status, and LDH) except the number of extranodal sites (EN) which did not significantly contribute to the model in this cohort (HR EFS,PFS,OS=1.0). Accordingly, EN>1 was deleted also resulting in better distinction of IPI groups (3-year PFS- and OS-rates: 95%,87%,74%,63%,51% and 98%,92%,80%,70%,57%%). In the final model, adjusted for all IPI factors except EN>1, BCL2 and MYC expression remained significant (HR PFS=2.3 and 2.0, p<0.001 and p=0.003). These results were validated and confirmed in 1176 DLBCL patients from 5 French (LYSA) studies. EN>1 but also MYC expression did not significantly contribute the final model in the validation set. Thus, MYC expression was deleted from the final model. Using the IPI deleting EN>1 but including BCL2 expression we observed 3-year PFS-rates of 74% vs. 83% in BCL2-positive vs. BCL2-negative patients with IPI 2 (p=0.136). In pts with IPI 3 the 3-year PFS rates were 53% vs. 80% (p=0.011) (see figure 1); in pts with IPI 4 the respective 3-year PFS rates were 49%% vs. 71%. This latter difference was not significant due to small pt numbers (p=0.381). Conclusions: Deletingthe number of extranodal sites and adding BCL2expression tothe original IPI factors as the only readily available biologic marker allows building an IPI model which effectively separates IPI 3 pts in 2 groups with significantly different prognosis. Restricting eligibility for future clinical trials to DLBCL pts with IPI 3 (and IPI 4) who are BCL2-pos. may help to avoid overtreatment of pts well treated with R-CHOP and at the same time better select pts representing a group with truly unmet medical need who are most likely to benefit from experimental therapies.

Optimization of Rituximab for Treatment of DLBCL in Young, High-Risk Patients-Results of the Dense-R-CHOEP Trial of the German High-Grade Lymphoma Study Group

Background. The German High-Grade Non-Hodgkin Lymphoma Study Group published several studies performed in order to optimize the use of Rituximab (R) in conjunction with CHOP chemotherapy in older patients (pts) with diffuse large B-cell lymphoma (DLBCL) (Pfreundschuh et al., J Clin Oncol 2014, 32, 4127; Murawski et al., Ann Oncol 2014, 25, 1800). The prospective, randomized R-MegaCHOEP study reported 3-yr-PFS and -OS rates of 74 and 85%, respectively, in young, high-risk pts (aaIPI 2, 3) treated with 6 x R and 8 x CHOEP-14 (Schmitz et al., Lancet Oncol. 2012,13,1250). We wanted to further improve treatment results in young, high-risk pts. by doubling the number of R infusions from 6 to 12.Methods. Pts. with aggressive B-NHL (90% DLBCL), age 18-60 yrs., aaIPI 2 or 3, received treatment with 8 x CHOEP-14. In contrast to the randomized study reported previously, where R (375 mg/ m2) had been administered only six times (days 0, 15, 29, 43, 71 and 99) R was administered twelve times (days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99) after an amendment. Event-free survival (EFS) (primary endpoint) and overall survival (OS) achieved with 12 x R vs. 6 x R were compared.Results. Between 10/ 2010 and 02/ 2014 seventy-nine pts (median age 47 yrs., 53% males) were registered, 78 pts were analyzed. Sixty-six pts (85 %) presented with aaIPI 2 and 11 pts. presented with aaIPI 3. Feasibility (86 % of pts. received all study treatment) and safety (TRM 0%) of this intense regimen was excellent. CR/ CRu rate was 77 %, 2-yr-EFS 69% (95% CI:59-80%), 2-yr-PFS 76% (95% CI: 66-86%) and 2-yr OS 82% (95% CI: 73-92%). After a median observation time of 24 months 12 patients have died, 8 patients from lymphoma, 2 pts. from toxicity of salvage therapy, and 2 from other causes. Comparing these results to those achieved in 130 pts. treated with 6 x R and 8 x CHOEP-14 2-yr-EFS (71% (95% CI: 63-79%), p=0.766), 2-yr-PFS (75% (95% CI: 67-83%), p=0.871) and 2-yr-OS (85% (95% CI: 78-91%), p=0.843) did not significantly differ. These results could be confirmed in multivariate analyses adjusted for factors of aaIPI, bulk and gender. Interestingly, in pts. with aaIPI 3 12 x R + 8 x CHOEP-14 resulted in 2-yr-EFS and -OS rates of 72% (95% CI: 44-99%) and 91% (95% CI: 74-100%), respectively. These remarkable results, however, were not significantly different from those achieved with 6 x R + 8 x CHOEP-14 because only 11 pts. with aaIPI 3 had received 12 x R. Conclusions. In contrast to the significant improvements of EFS and OS achieved with the SMARTE-R- CHOP-14 regimen (Pfreundschuh et al. 2014) but in agreement with the results of the DENSE-R-CHOP-14 trial (Murawski et al, 2014) in older pts. (60-80 years) with high-risk disease (IPI 3-5) increasing the number of R infusions from 6 to 12 in young, high-risk pts. did not result in a significant improvement of EFS and OS in pts. with aaIPI 2 and overall. This may reflect the necessity of longer R exposure of tumor cells in order to achieve optimal results. EFS and OS in pts. with aaIPI 3 were surprisingly good but improvement was not statistically significant because only 11 pts. with aaIPI 3 had been enrolled; more pts. with aaIPI 3 need to be investigated. Among other possible explanations for the lack of further improvement by doubling the number of R infusions, the more aggressive chemotherapy (CHOEP vs. CHOP), the different timing of R in pts. receiving 6 and 12 R infusions, and differences in pharmacokinetics between younger and older patients may be responsible. DisclosuresSchmitz:Roche, Celgene, Takeda, Riemser, Ctilifescience: Honoraria, Research Funding. Off Label Use: different rituximab schedule. Viardot:Gilead: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria; CTI: Consultancy. Borchmann:Millennium: Research Funding. Pfreundschuh:Roche, Janssen, Celgene: Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding.

Comparison Of R-CHOP14 and R-CHOEP14 As First Line Treatment In Young Patients With High-Risk (aaIPI 2-3) Diffuse Large B-Cell Lymphoma (DLBCL): A Joint Analysis Of Two Prospective Phase III Randomized Trials Conducted By The Fondazione Italiana Linfomi (FIL) and The German High-Grade Lymphoma Study Group (DSHNHL)

IntroductionThe prognosis of young DLBCL patients at high risk treated with standard R-CHOP is still rather poor. With the aim to improve outcome of these patients the Italian (Vitolo U et al, Blood, ASH annual Meeting 2012) and German (Schmitz N et al, Lancet Oncology 2012:13,1250) cooperative study groups conducted two randomized phase III studies aimed to compare conventional chemotherapy with intensified chemotherapy with stem cell support both in combination with Rituximab (R). The standard reference arms were R-CHOP14 in the Italian and R-CHOEP14 in the German study. No randomized studies comparing R-CHOP14 and R-CHOEP14 exist. Therefore, FIL and DSHNHL did a joint analysis of the two randomized trials, with the aim to compare the two conventional arms R-CHOP14 and R-CHOEP14. Patients and MethodsThe primary endpoint of this joint analysis was to compare the progression free survival (PFS) of DLBCL patients treated with R-CHOP14 or R-CHOEP14 within the two prospective trials. Inclusion criteria were superimposable for the two studies as follows: age 18-60 years; untreated CD20+ DLBCL or follicular lymphoma grade IIIb; age-adjusted IPI (aa-IPI) score 2 or 3. FIL patients were treated with R-CHOP14 for 8 courses; DSHNHL patients were treated with R-CHOEP-14 for 8 courses. Involved-field radiotherapy (IF-RT) for patients with extranodal sites or with bulky disease was based on the investigator choice in the FIL trial and was mandatory in the DSHNHL study. Central nervous system prophylaxis was done in patients at risk for CNS recurrence. Response criteria used were the same in both studies (Cheson 1999). ResultsFrom June 2005 to September 2010 100 patients were enrolled in the FIL study and treated with R-CHOP14. From March 2003 to April 2009, 130 patients were enrolled in the DSHNHL study and treated with R-CHOEP14. All 230 patients were included in the present analysis. Clinical characteristics were: median age 49 (IQR 38; 55); stage III/IV 96%; LDH > normal 93%; ECOG PS >1 38%; aa-IPI score 2/3 74/26%; extranodal sites >1 41%, bulky disease 50% and bone marrow (BM) involvement 16%. All characteristics were well balanced between patients treated with R-CHOP14 or R-CHOEP14 with the exception of significantly more patients with elevated LDH and bulky disease in the R-CHOEP14 group (98% vs 87%; 59% vs 37%) and more patients with PS >1 in the R-CHOP14 group (45% vs 32%). IF-RT consolidation was less frequently used in the R-CHOP14 group (16% vs 74%). Median follow-up times were: 47 (R-CHOP14) and 42 (R-CHOEP14) months. Patients treated with R-CHOP14 had a 3-year PFS of 63% (95% CI:52-71%) compared to 74% of those treated with RCHOEP14 (95% CI:65-81%); p = .177 (Figure 1). In a Cox model for PFS including treatment arm, age, gender, aaIPI, extranodal sites, bulky disease and BM involvement the adjusted HR was 0.68 (95% CI: 0.42-1.2) in favor of RCHOEP14, but this difference was not significant (p = .128). The analysis of the role of consolidation IF-RT is ongoing. ConclusionsThis analysis comparing R-CHOP14 and R-CHOEP14 as standard arms in two prospective trials suggests that RCHOEP14+RT has high activity in young poor-risk DLBCL. To confirm these encouraging findings, a formal joint FIL/ DSHNHL randomized study comparing R-CHOEP+RT vs R-CHOP+RT +/- novel drugs is planned by the two cooperative groups. [Display omitted] Disclosures:Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL

AbstractThe survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)–DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.

Mature T-/NK-cell lymphomas: Prognostic factors and treatment outcome of patients treated on studies of the German High-Grade Lymphoma Study Group (DSHNHL)

8564 Background: T-cell lymphomas represent a heterogeneous group of malignancies difficult to diagnose and to treat. We evaluated patients (pts) diagnosed according to WHO standards and treated on prospective studies of the DSHNHL. Chemotherapy regimens (CHOP-14 and CHOEP) had significantly improved outcomes of patients with aggressive B-NHL. Methods: Between 1993 and 2006 we treated 329 pts with ALK-positive ALCL (73 pts), ALK-negative ALCL (108 pts), PTCL, NOS (68 pts), AITL (28 pts), NK-/T-cell lymphoma (18 pts), and rare T-cell lymphomas on prospective studies. All pts received CHOP ± etoposide (E) every 2 or 3 weeks; in pts <=60 yrs C, H, and E were escalated to further improve outcomes. Results: The majority of pts with ALK-positive ALCL presented with IPI 0, 1 (62%) or IPI 2 (26%) and had an excellent overall survival (OS) of 89 % and event-free survival (EFS) of 75% at 3 yrs. E significantly improved TTTF for pts <=60 yrs (p=0.007). Pts with other histologies did significantly worse (OS 58%, EFS 44 % at 3 yrs). The IPI discriminated between pts with a favorable (IPI 0, 1: OS 73%), moderate (IPI 2: OS 55%), and poor prognosis (IPI 3: OS 35%; IPI 4, 5: OS 19%) at 3 yrs. OS, EFS were significantly better for ALK-positive ALCL but did not significantly differ for pts in other histological subgroups. Neither shortening of the treatment interval (CHOP-14) nor the addition of E (CHOEP-21 or -14) significantly improved outcome of elderly pts. In younger pts (ALK-positive ALCL were excluded) and good-risk disease (LDH <= N) there was a trend for better EFS after the addition of E to CHOP (EFS 63% vs. 48%, p = 0.065). The MegaCHOEP protocol (Schmitz et al., CANCER 2006) failed to improve treatment results for younger pts with poor-risk disease (EFS at 3 yrs: 25.9%, 95% CI: 10.4–41.4); the prospective study comparing MegaCHOEP with CHOEP-14 was stopped for pts with T-cell lymphoma. Conclusions: CHO(E)P results in excellent OS of pts with ALK-positive ALCL and selected pts with other histologies and low IPI. All other pts did poorly; CHOP-14 or the addition of E failed to significantly improve outcomes. Notably, also the MegaCHOEP protocol characterized by repetitive high-dose therapy and ASCT did not result in significant improvement. No significant financial relationships to disclose.