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Introduction Treatment of patients with high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) with intensified immune-chemotherapy DA-EPOCH-R results in a 48-month event-free survival of 71.0% [Dunleavy, Lancet Haematol 2018]. In the HOVON-152, we investigate the added value of immune checkpoint PD-1 inhibition for patients who achieve complete metabolic remission (CMR) after DA-EPOCH-R induction. Nonetheless, whether DA-EPOCH-R has an effect on the immune system, and - reversely - whether the composition of immune system influences DA-EPOCH-R therapy are not known. To gain more insight on these important issues, we performed longitudinal high-throughput immune profiling of patients during the DA-EPOCH-R induction phase of the HOVON-152.Methods In the HOVON-152 single arm, phase II trial (NCT03620578) HGBL-DH/TH patients received 1 cycle of R-CHOP followed by 5 cycles of DA-EPOCH-R induction treatment. Peripheral blood was sampled after one cycle of R-CHOP (enrollment), before start of the 3rd DA-EPOCH-R cycle (midterm) and after the last DA-EPOCH-R cycle (end-of-induction, EOI). Patients achieving CMR at EOI (Deauville score 1-3 after induction) were identified as responders and proceeded with nivolumab consolidation (480 mg iv every 4 weeks) for 1 year.For the profiling we selected 55 patients (32 responders and 23 non-responders, enriched for non-responders) who completed the whole study. T and NK cells were enumerated through quantitative, dual platform flow cytometry of unseparated full blood. The frequencies of NK and T cell subsets were determined in cryopreserved PBMC through multiparameter flow cytometry. The high-throughput flow cytometry data were analyzed by computational methods UMAP and FlowSOM. Non-parametric methods were used for statistical testing.Results DA-EPOCH-R had no apparent effects on the total number of NK cells. The frequency of cytotoxic CD56dim NK cells was, however, gradually decreased during DA-EPOCH-R (pMore interestingly, DA-EPOCH-R appeared to have significant impact on T cells: while total T cell frequencies and numbers showed only a temporary decrease at midterm, a progressive decrease in the CD4/CD8 ratio (p=0.016) and a progressive increase in the expression of T cell activation markers CD127 (pFurther analyses regarding the possible impact of immune system on DA-EPOCH-R outcome revealed that a (relative) abundance of non-cytotoxic CD56bright NK cells (p=0.006) and higher CD3 T cells (p=0.04) at enrollment was associated with achievement of CMR.Conclusion In conclusion, treatment of HGBL-DH/TH patients with DA-EPOCH-R results not only in the expected rituximab-mediated alterations in the NK cell compartment, but also influences the T cell compartment with a shift towards a lower CD4/CD8 ratio, more T cell activation and a reduction of PD-1 expression on CD8 T cells. Higher T cell frequencies at baseline and decreased frequencies of PD-1+ CD8 T cells at EOI were furthermore associated with achievement of CMR. Overall, these data contribute to a wider understanding of NK and T cell dynamics during DA-EPOCH-R and points to an considerable involvement of T cells in therapy outcome.DisclosuresNijland:Takeda: Research Funding; Roche: Research Funding; Genmab: Consultancy. Klerk:Roche: Other: speaker fee (ASH). Mutseaers:Glaxo Smith Kline: Consultancy; Astra Zeneca: Research Funding; BMS: Consultancy. Mutis:Janssen: Research Funding; Genmab: Research Funding; Takeda: Research Funding. Chamuleau:Genmab: Research Funding; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Gilead: Research Funding; BMS/Celgene: Honoraria, Research Funding.OffLabel Disclosure:Nivolumab as immune checkpoint inhibitor (inhibiting PD-1) in consolidation phase for the treatment of DH/TH-HGBL patientsAuthor notes*Asterisk with author names denotes non-ASH members.

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34–expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Clin Cancer Res; 23(17); 5292–301. ©2017 AACR.