First Report on a Successful Screening Program for MYC Rearrangements and a Prospective Clinical Trial Based on MYC Rearrangement in Newly Diagnosed DLBCL Patients in the Netherlands

Introduction

Patients with aggressive B-cell lymphoma that harbor a MYC rearrangement (WHO 2008: Diffuse Large B-cell Lymphoma (DLBCL) or B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma (BCL-U)) have a dismal prognosis following standard first-line treatment. Intensifying chemotherapy prolongs disease free survival when compared to R-CHOP. Despite this, relapses often occur and overall survival has not been improved, hence justifying trials with MYC targeting drugs.Lenalidomide has demonstrated to down-regulate MYC and its target genes in MYC rearranged B-cells and therefor potentially is an effective MYC targeting compound. Although lenalidomide seems mainly effective in ABC subtype DLBCL, the ability of MYC downregulation provides the rationale of lenalidomide administration in MYC rearranged lymphoma, that are usually of GCB subtype. The addition of lenalidomide to R-CHOP has already been demonstrated to be safe and well tolerable. Until now, no prospective studies for MYC rearranged DLBCL patients have been conducted. This is at least partially due to lack of adequate screening facilities for MYC rearrangements.

To this end we initiated a registration and screening program for all newly diagnosed DLBCL patients in which performing MYC FISH was advocated and financially supported (HOVON 900). Patients with a proven MYC rearrangement were subsequently included in a clinical trial (HOVON 130: A phase II study evaluating the effect of the addition of lenalidomide to R-CHOP for patients with newly diagnosed MYC positive DLBCL and BCL-U (EudraCT 2014-002654-39)). Here we present data from the screening program and demographic data of the first 64 eligible patients included in the prospective clinical trial.

Material, methods and preliminary results

During the screening period for MYC rearrangements, administration of one cycle of R-CHOP21 is allowed. After being diagnosed with a MYC rearrangement, lenalidomide 15 mg on day 1-15 of R-CHOP21 is added. In total patients receive 6 cycles of R-CHOP21 plus 6 cycles of lenalidomide plus 2 cycles of rituximab monotherapy. Moreover, as these patients have a high risk of CNS relapse, intrathecal prophylaxis is given to all patients . Primary endpoint of the study is centrally reviewed end-of-treatment complete metabolic remission rate on PET-CT scan.Screening database (HOVON 900): Between August 1^st 2015 and July 17^th 2017, 581 newly diagnosed DLBCL patients from 62 centers covering all regions of the Netherlands have been registered. Median age at diagnosis was 65 years (range 19 to 82 years). Male: female ratio 62%: 38%. MYC FISH analysis was successful in 73% of patients. Clinical trial (HOVON 130): In total 67 patients were diagnosed with a MYC rearrangement and were included. After central pathology review, 3 patients were declared ineligible (2 transformed follicular lymphoma, 1 MYC rearrangement not confirmed). Additional FISH analysis on BCL2 and BCL6 rearrangements revealed that 27% of the cases were MYC single hit, 59% were double hit (MYC and BCL2 or BCL6) and 14% were triple hit (MYC and BCL2 and BCL6) DLBCL patients (analysis of 51 patients, to be completed).Clinical baseline characteristics of the 64 eligible patients are shown in table 1. A planned interim analysis, after 27 eligible patients finished treatment, has been performed. Safety results showed toxicities grade 2 in 41%, grade 3 in 33% and grade 4 in 15% of patients. Most common toxicities were polyneuropathy grade 2 or 3 (44%), infections grade 2 or 3 (33%) and gastrointestinal disorders grade 2 or 3 (30%). 16 severe adverse events were reported (all hospitalizations, including 5 infections). Based on these results, the DSMB concluded that no safety issues prohibit continuation of the trial. Efficacy results are blinded until the inclusion will be completed (expected Q4 2017). Updated demographic results will be available in December 2017.

Conclusion

A successful screening program for MYC rearrangements for all newly diagnosed DLBCL patients is initiated in the Netherlands. This program, which allows start of treatment during the screening period, enables newly diagnosed DLBCL patients with a proven MYC rearrangement to switch to a prospective biomarker-based clinical trial that evaluates the addition of lenalidomide to standard R-CHOP.

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