ISH/BSH 2016: DLBCL: controversies and global challenges

Dr Sridhar Chaganti, University Hospital, Birmingham NHS Foundation Trust, UK.

by Christine Clark: In general the outcomes of treatment for diffuse large B-cell lymphoma (DLBCL) are good – R-CHOP chemotherapy achieves a 75% cure after two years. The challenge for clinicians is identifying the 25-30% of patients who will fail – something that needs to be done early, explained Dr Sridhar Chaganti (University Hospital, Birmingham NHS Foundation Trust, UK)

Factors associated with an unfavourable prognosis include a high IPI (International prognostic index) score, activated B-cell type, the presence of MYC and BCL translocations, and a positive interim PET scan.

The IPI is well known to most clinicians and it retains its usefulness even in the rituximab era. The revised IPI identifies three groups, namely ‘very good’, ‘good’ and ‘poor risk’. About 50% of the ‘poor risk’ patients will be cured with R-CHOP. Unfortunately the revised IPI is limited in its ability to identify those with the very poorest risk.  The enhanced IPI (NCCN IPI), based on the same factors as the revised IPI, (Zhou Z. 2014) identifies four groups and can separate out those who have only a 30% chance of survival with R-CHOP.

The next question was whether high risk patients could be offered anything better than R-CHOP. The options are to give high intensity treatment using either R-CODOXM /R-IVAC or R-CHOEP 14 or performing an early transplant at first remission.  One trial showed that R-CODOXM /R-IVAC achieved a 2-year PFS of 68% and a 3-year PFS of 65%, however there was no randomised comparison with R-CHOP.  A trial of RCHOEP14 resulted in 70% EFS at two years, but there was no direct comparison with R-CHOP.  In view of these considerations the guideline says that for high IPI patients there is no established standard of care; R-CHOP is often used and RCHOEP and R-CODOXM /R-IVAC are alternatives.

 

DLBCL cells of origin

DLBCL can arise from either activated B cells (ABC type) or germinal centre B cells (GCB type) and this can be determined by means of gene expression profiling (GEP).  About 10% DLBCLs are unclassifiable.  GCB-type tumours respond better to R-CHOP than the ABC type. AS GEP is not routinely available, immunohistochemistry (IHC) has been explored and numerous algorithms have been devised.  Most of the algorithms do not correlate well with GEP or even with each other.  The only way to determine cell-type of origin (in order to assess a patient’s risk level) is to use GEP; IHC is not a satisfactory surrogate, said Dr Chaganti.

The REMODLB trial was designed to compare R-CHOP and R-BCHOP (where B is bortezomib) in ABC-type  and GCB-type DLBCL. Overall response rates showed no differences according to the cells of origin. The two-year PFS was 71%. There are no data on RCHOP vs RBCHOP as yet. However, another trial which randomised non-GCB DLBCL patients to RCHOP or RBCHOP showed a 78% PFS at two years. Thus, even if it were possible to ABC-type DLBCL confidently, “we have no idea what to do with these patients” said Dr Chaganti. For this reason the current guidelines make no recommendations regarding cell of origin.

 

MYC translocations  

Patients who have MYC rearrangements account for 5-15% of DLBCL patients. Such individuals also commonly have a second rearrangement of BCL2 or BCL6 – the so-called ‘double hit’ or ‘triple hit’ lymphomas. A MYC rearrangement is a prognostic factor associated with a PFS of less than 12 months. Other factors also influence the prognosis including bad histology e.g. BCL-unclassifiable, bone marrow involvement, MYC rearrangement affecting an immunoglobulin gene. Patients should be tested for MYC if they have a high IPI, if they have tumours with a high proliferation index and if they have unclassifiable B cell tumours. This approach will still miss a number of patients with MYC rearrangements. Double-hit lymphoma (DHL) is exclusively seen in patients with GCB-type DLBCL (identified by GEP). If GEP is not available then all tumours should be checked for MYC rearrangements.

Between 5 and 15% of DLBCL have MYC rearrangement and these can be identified by FISH. Some 30-64% of DLBCLs express MYC protein and this can be identified by IHC.30-35% of all DLBCLs will express both MYC and BCL2 – the so-called ‘double expressors’. Double-expressors are different from DHLs, emphasised Dr Chaganti.   DHLs are identified by gene translocations and have very poor PFSs and OSs.

Patients with DHL appear to respond better to intensified regimens including R-Hyper CVAD, DA-EPOCH-R, R-CODOXM-IVAC, achieving better PFSs than those who received R-CHOP alone. However, the evidence does not lend itself to very strong recommendations so the guidelines recommend testing for MYC rearrangements, because of its prognostic value, and then list the available treatment options.

Interim PET

The PETAL trial, a large, German, phase 3, randomised trial involving patients with high grade lymphomas, showed that patients who were PET-positive after two cycles of R-CHOP had worse outcomes than those who were PET-negative. As there is no way to improve outcomes for these patients the guidelines have steered away from recommending interim PET scans.

 

Reference

Zhou z. et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014 Feb 6;123(6):837-42