The frontline treatment of Diffuse Large B-cell Lymphoma (DLBCL) is becoming somewhat of a graveyard for randomised phase III clinical trials. The last major breakthrough came when rituximab was added to CHOP chemotherapy (see previous post). Since then, a number of approaches have been taken to try to improve outcomes, but they have by and large failed. 3 broad approaches have been pursued, with some overlap:
1. Intensify treatment (especially for patients with high risk disease)
2. Add something to the R-CHOP backbone
3. Use biological stratification to target a new agent or approach to those likely to respond
1. Intensify treatment
This first approach hasn't yet yielded much meaningful fruit. It's easy to comment in retrospect but perhaps this isn't too surprising. My favourite clinical trial of all time was published by Richard Fisher and colleagues in 1993. This study was performed to evaluate claims from phase II studies that their new intensive regimen appeared better that CHOP. We hear similar claims today of course. The study compared 8 courses of standard CHOP chemotherapy with 3 intensive regimens: ProMACE-CytaBOM, MACOP-B and m-BACOD. The result was that all were equally effective whilst CHOP had fewer side effects, was cheaper and safer. In subsequent letters it was noted that the results for ProMACE-CytaBOM and MACOP-B were about 30% lower that in the previously reported phase II studies, providing ample reason for insisting on randomised phase III data before a more intensive and toxic regimen is introduced as standard of care.
More recently, Dose Adjusted (DA) EPOCH-R (etoposide, prednisolone, cyclophosphamide, doxorubicin and rituximab) was developed by the National Cancer Institute in the US for the treatment of aggressive non-Hodgkin lymphoma. The regimen is a model of scientific logic. Lymphoma cell lines are killed more effectively when longer drug exposure occurs, rather than short boluses hence a key part of this regimen is a 4 days continuous infusion. The addition of etoposide also increased cell kill in vitro. Perhaps the most important aspect though is that it takes seriously the observation that different patients handle drugs differently and that patients who excrete chemotherapy drugs rapidly may not have enough exposure to the components of a bolus regimen. The doses of subsequent cycles are therefore titrated according to the nadir neutrophil count of the prior cycle, providing a biomarker for drug exposure. Sufficient myelosuppression indicates that sufficient chemotherapy drug levels have been achieved leading to biological activity within the individual at a given dose of cycle. Phase II studies appeared promising. However, Bartlett and colleagues have recently published the Alliance/CALGB 50303 study which was a well performed study compared R-CHOP with DA-EPOCH-R in the front line treatment of DLBCL. There was no difference in the primary endpoint of progression free survival (PFS) and the toxicity of DA-EPOCH-R was clearly greater than for R-CHOP. This underscores the point that any new regimen must be tested in this way and I congratulate the US groups for doing just this. The point has been made that a clinically meaningful benefit maybe seen in high risk patients. This is true, but for a regimen which is more toxic and less convenient for patients and physicians, this needs to demonstrated in a comparative trial powered to answer the question.
2. Add something to the R-CHOP backbone.
A number of studies have looked at, and are looking at R-CHOP+X. One of the recent, large studies reporting on this approach was the Phoenix trial which randomised non-GCB cases (defined by immunohistochemistry which isn't ideal as only gene expression profiling can really define cell of origin) to receive either 6-8 courses of R-CHOP or 6-8 courses of R-CHOP+ibrutinib (a BTK inhibitor). No difference was seen in the primary endpoint. On further evaluation of prior defined subgroups, younger patients did seem to benefit whereas older patients seemed to suffer from more side effects of the combination leading to a reduced dose intensity of immunochemotherapy and increased relapse rate. However as the trial was not powered to look at this group alone, the combination will not receive a license. The REMODL-B trial from the UK assessed the addition of bortezomib to R-CHOP in cycles 2-6 in a randomised phase III and again no benefit was found.
On-going trials include the ROBUST study, a randomised phase III trial of R-CHOP versus R-CHOP plus lenalidomide in gene expression profile-defined ABC subtype of DLBCL. The trial was based on the observation of phase II studies which seemed to show that R-CHOP+lenalidomide overcame the worse outcomes seen in the ABC subtype when treated with R-CHOP. Results are awaited. The POLARIX study is also an ongoing randomised phase III trial but this time comparing R-CHOP with R-CHOP + polatuzumab vedotin, the antibody-drug conjugate targeting CD79b. There is much hope that this trial may lead to a positive result, in view of a randomised trial of bendamustine rituximab (BR) vs BR + polatuzumab in relapsed / refractory DLBCL showing a PFS and OS survival advantage. However we need to wait until these trials are recruited and published with appropriate follow up. Watch this space!
3. Use biological stratification to target a new agent or approach to those more likely to respond
The Phoenix trial attempted this by only randomising those with non-GCB subtype by immunohistochemistry. One flaw with this approach is that it's far from proven that ibrutinib is significantly more effective in this subtype. A small trial in relapsed / refractory disease did show an enrichment for responses in non-GCB subtype, but this is a long way off showing that the combination of R-CHOP + ibrutinib is only going to work in the non-GCB subtype in the upfront setting. The UK REMODL-B trial in my view performed a better study. Although they predicted that bortezomib would work better in the ABC subtype, all patients were randomised and interim analyses were performed during the trial to see in the randomisation into the GCB subtype could be stopped. This did not happen and indeed on subgroup analysis the only real signal of possible improved outcome with the combination was in those patients with a so-called 'molecular high grade subtype' which is largely found in GCB cell of origin patients. There is a lot of belief surrounding the power of biomarkers but they need to properly tested to determine their true potential for directing therapy.
Another approach is to identify those patients not responding well to R-CHOP and to switch to an alternative strategy. The PETAL study identified such high risk patients with an interim PET scan after 2 cycles of R-CHOP. For those with a positive PET scan, patients were randomised to continue with R-CHOP or switch to a Burkitt-lymphoma type of intensive regimen. No benefit was found with the more intensive treatment but more toxicity was certainly evident.
To conclude, R-CHOP gives very good results for many patients with DLBCL. However those who do not respond well have biologically difficult disease and it's proven difficult to improve outcomes despite numerous attempts. This does not mean we should give up trying. Not at all - randomised phase III trials of promising agents are necessary to make progress. But let's demand these trials to be performed before recommending changes in the standard of care, especially when the new therapy is more toxic than the old. Let's learn from Fisher et al, NEJM 1993.
A number of studies have looked at, and are looking at R-CHOP+X. One of the recent, large studies reporting on this approach was the Phoenix trial which randomised non-GCB cases (defined by immunohistochemistry which isn't ideal as only gene expression profiling can really define cell of origin) to receive either 6-8 courses of R-CHOP or 6-8 courses of R-CHOP+ibrutinib (a BTK inhibitor). No difference was seen in the primary endpoint. On further evaluation of prior defined subgroups, younger patients did seem to benefit whereas older patients seemed to suffer from more side effects of the combination leading to a reduced dose intensity of immunochemotherapy and increased relapse rate. However as the trial was not powered to look at this group alone, the combination will not receive a license. The REMODL-B trial from the UK assessed the addition of bortezomib to R-CHOP in cycles 2-6 in a randomised phase III and again no benefit was found.
On-going trials include the ROBUST study, a randomised phase III trial of R-CHOP versus R-CHOP plus lenalidomide in gene expression profile-defined ABC subtype of DLBCL. The trial was based on the observation of phase II studies which seemed to show that R-CHOP+lenalidomide overcame the worse outcomes seen in the ABC subtype when treated with R-CHOP. Results are awaited. The POLARIX study is also an ongoing randomised phase III trial but this time comparing R-CHOP with R-CHOP + polatuzumab vedotin, the antibody-drug conjugate targeting CD79b. There is much hope that this trial may lead to a positive result, in view of a randomised trial of bendamustine rituximab (BR) vs BR + polatuzumab in relapsed / refractory DLBCL showing a PFS and OS survival advantage. However we need to wait until these trials are recruited and published with appropriate follow up. Watch this space!
3. Use biological stratification to target a new agent or approach to those more likely to respond
The Phoenix trial attempted this by only randomising those with non-GCB subtype by immunohistochemistry. One flaw with this approach is that it's far from proven that ibrutinib is significantly more effective in this subtype. A small trial in relapsed / refractory disease did show an enrichment for responses in non-GCB subtype, but this is a long way off showing that the combination of R-CHOP + ibrutinib is only going to work in the non-GCB subtype in the upfront setting. The UK REMODL-B trial in my view performed a better study. Although they predicted that bortezomib would work better in the ABC subtype, all patients were randomised and interim analyses were performed during the trial to see in the randomisation into the GCB subtype could be stopped. This did not happen and indeed on subgroup analysis the only real signal of possible improved outcome with the combination was in those patients with a so-called 'molecular high grade subtype' which is largely found in GCB cell of origin patients. There is a lot of belief surrounding the power of biomarkers but they need to properly tested to determine their true potential for directing therapy.
Another approach is to identify those patients not responding well to R-CHOP and to switch to an alternative strategy. The PETAL study identified such high risk patients with an interim PET scan after 2 cycles of R-CHOP. For those with a positive PET scan, patients were randomised to continue with R-CHOP or switch to a Burkitt-lymphoma type of intensive regimen. No benefit was found with the more intensive treatment but more toxicity was certainly evident.
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