Frontline Management of DLBCL (April 2019)

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While discussing management of DLBCL it becomes imperative to know about how CHOP came into picture and what impact addition of Rituximab to CHOP made to the management of DLBCL.

While the general concept of immunotherapies has been around for over a century, effective antibody therapies were not feasible before the ability to generate mAbs using continuously growing cell lines on large scale. In 1975, Köhler and Milstein generated the first hybridoma cell lines capable of producing mAbs by immunizing mice against sheep red blood cells followed by isolation of B-lymphocytes from the murine spleens and subsequent fusion of those cells with a myeloma cell line to produce mAbs.

Rituximab was created by Ronald Levy for the express purpose of targeting malignant B cells. In 1982, it was made public that his first mAb cancer patient was successfully treated with the mAb, which rapidly lead to the creation of the pharmaceutical company IDEC.

At IDEC Dr Nabil Hanana and his team took rituximab to its present status and lead to its first approval in 1997.

In 2006 Rituximab was approved as first line in combination chemotherapy for DLBCLs based on some land mark trials which will be dealt further.

Point to be noted is on an average 10 % improvement in PFS as well as OS by addition of rituximab to Chemotherapy protocols.

The EFS, PFS and OS were much better as compared to CHOP only arm as shown in previous slide.

So slides presented till now clearly shows that rituximab improves OS among all age groups as well as across all stages as compared to conventional chemotherapy regimes there by consolidating the view that R-CHOP is a clear leader for frontline treatment of DLBCL

Based on the finding ESMO guidelines incorporate R-ACVBP as Choice in < 60 years Low IPI with bulk as well as Low-Intermediate IPI group along with R-CHOP.

Use of R-ACVBP in < 60 years Low IPI with bulk removes the need of Additional RT.

Reducing a 21 day cycle to 14 days cycle added no benefit in therapy as shown in survival curves.

The COO theory in DLBCL looks new however this was first reported by Alizedah et al in nature in 2002 in a small study and later the findings were substantiated by Rosenwald et al in NEJM.

They showed that ABC subtype has 30% 5 year OS rate as compared to 60% in GCB type, A marked difference.

So we will now look into fact that – Is there any advantage of change in therapy based on cell of origin of DLBCL???

BCR/NFkB pathway is significant in pathogenesis of ABC type and it was postulated that selective targeting of this pathway will lead to improved survival in DLBCL.

In Phase I and II studies lenalidomide addiction to R-CHOP backbone has shown promising results and to substantiate this a Phase III ROBUST trial is going on with oral lenalidomide (15 mg, days 1-14) plus R-CHOP-21 x 6 vs placebo–R-CHOP-21 x 6 in patients with ABC DLBCL, with PFS as the primary endpoint.

Whether the success of lenalidomide could be translated in this large Phase III trail is too be seen.

Another approach is to add maintainence therapy and it was shown that adding Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving CR to R-CHOP so was the results of adding Everolimus.

In a metanalysis of studies using Rituximab maintenance showed no difference in 3 year OS.

Schmitz N, et al in their analysis showed that risk of CNS relapse is as high as 12% in High CNS IPI group and all these recurrences were early event within 2 years.

Thereby warranting a change in approach and add something to R-CHOP backbone for CNS prophylaxis in this high CNS IPI group.

ESMO: Although widely used, IT may not be an optimal method. IV HD MTX has been shown to be associated with efficient disease control.

NCCN: IT MTX or IV MTX in cases with High CNS IPI or those with Testicular/kidney/adrenal involvement should be given.

Spanish lymphoma group (GELTAMO) has publised a guideline for CNS prophylaxis where it mandates use of CSF analysis in high risk patients by flowcytometry as well as cytology.

Based on above guidelines IV HD-MTX @3-3.5G/M2 (2-4 CYCLES) given on Day 10-15 of R-CHOP Cycle should be considered In selected fit patients with preserved renal function as a CNS prophylaxis in HIGH RISK patients.

The difference being, IV HD MTX can be given at end of treatment as its is a known fact that in testicular DLBCL, Late CNS relapses occur in contrast to early CNS relapse seen in other DLBCLs.