Frontline Management of DLBCL (April 2019)

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Slide 1
DLBCL is most common type of NHL accounting for almost 40% of all NHLs diagnosed.

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.

Slide 2
In randomized clinical trials, the CHOP protocol was introduced by the National Cancer Institute’s ‘gang of five’ in 1975
Slide 3
The slide shows results of three landmark trials submitted to FDA for its approval as frontline drug in treatment of DLBCL.

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

Slide 4
The results of MabThera International trial which shows significant improvement in EFS, PFS and OS in DLBCL patients aged 18-60 with low IPI and no bulk.

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

Slide 5
Shen et al published Results of a randomized trial of non-rituximab containing regimens as historical controls for British Columbia outcome data with R-CHOP and showed that R-CHOP as a clear leader among all chemotherapy protocols including CHOP showing 20 % OS benefit in follow up of  4-5 years.
Slide 6
Shen et al updated the results and long term follow up showed OS benefit even on long term follow up and this included advanced stage disease also.
Slide 7
The slide presents data from french registry in rituximab era and pre rituximab era and shows the OS benefit of aproxx 10 % across All age groups.

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

Slide 8 & 9 
Now slides ahead will show Is there any advantage of change in conventional chemoimmunotherapy ie can we intensify therapy to further improve outcomes.
Slide 10 
Gela group showed in a phase three randomised trial that intensifying therapy using R-ACVBP in 18-59 year age group DLBCL patients with low-intermediate IPI improves outcome significantly with manageable toxicity.

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.

Slide 11
Similarly Largest phase III study analysing efficacy of R-DA-EPOCH over R-CHOP showed that Dose-Adjusted EPOCH-R is No Better Than R-CHOP in Diffuse Large B-Cell Lymphoma with almost similar CR/OS/PFS rates that too at cost of more toxicity.
Slide 12
Frontline use of G-CHOP proved no better than R-CHOP with similar OS/PFS rate in a study published in JCO in 2017.
Slide 13
The studies reported above showed effect of increasing dose intensity. A study was conducted to know whether increasing dose density of R-CHOP would be beneficial?

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

Slide 14/15/16/17
Since the  theory of COO has arrived in DLBCL, different groups have shown that patients with ABC like gene signature has worser prognosis as compared to GCB type with R-CHOP based therapy.

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.

Slide 18-27
Results of adding bortezomib, ibrutinib didnt translate into improved survival of these patients.

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.

Slide 28
Adding maintenance to standard R-CHOP in High risk patients.

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.

Slide 29/30
Adding rituximab maintenance to standard R-CHOP therapy was not beneficial DLBCL as reported by Jaegler et al in hematologica.

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

Slide 31
In a large REMARC study of 24 months of Len maintenance in > 60 age advanced disease DLBCL, 2-year PFS improved from 75% in the placebo arm to 80% in the lenalidomide arm. There was no difference in overall survival.
No advantage in Non GCB vs ABC analysis.
Slide 32
In non-MYC rearranged DLBCL, the CNS-IPI is a useful clinical tool to predict the risk for CNS relapse in patients with DLBCL.

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.

Slide 33
It is important to note that in contrast to CNS relapses in ALL which is mostly leptomeningeal, the CNS relapse in lymphomas are mostly Parenchymal So IT MTX may not be optimal approach.

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.

Slide 34
The rationale of this use of IV HD MTX is supported by studies shown in this slide where they report significanly reduced CNS relapses when IV HD MTX in incoporated in regime.
Slide 35
IELSG30 Protocol for primary testicular DLBCL is based on fact that Patients with primary testicular involvement have a particularly high risk of CNS involvement (>15%) when achieving CR and hence it incorporates IV HDMTX in protocol.

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.

Slide 36 Onwards are case discussion and slide in itself is enough to explain the contents and no explanation is needed. 

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