Taking the hatchet to R-CHOP – considerations in DLBCL
2025 is most definitely upon us, but reflecting back on my ‘take-homes’ from ASH December 2024, what will impact the year ahead? While sitting in the audience in San Diego, a speaker started their presentation not with a drug name or a tumour type, but by saying how worrying it can be when young people present with very aggressive disease. In this case the disease was aggressive diffuse large B-cell lymphoma (DLBCL), requiring intensive treatment that would undoubtedly cause the patient additional stress through toxicities. This struck a chord throughout ASH as I listened to various sessions that created something of a dichotomy – introducing new drugs to chemotherapy regimens for increased efficacy, whereas other sessions and audience questions were striving for chemotherapy-free regimens, or at the very least trying to reduce one component of these classical regimens.
These considerations of course underpin the usual benefit–risk assessment of aggressive treatment and assigning a regimen from an ever increasing list of options that is most suited to the patient. There is a drive to better define high-risk patients who will benefit from more intensive regimens versus those patients who will do equally well on a less intensive regimen like R-mini-CHOP or reduced R-CHOP cycles. I am sure we will continue to hear more on efforts to better define tailored treatment regimens, including how AI algorithms will analyse complex datasets and play a key role in helping us find the right treatment for the right patient.
Many haematologic malignancies were untreatable with extremely poor prognosis only a few decades ago, so we have certainly come a long way, and for some, chemotherapy regimens have been surpassed by diverse immunotherapy/targeted approaches. So where are we now on the journey – reaching a chemo-free reality or still seeing this as a hopeful vision for the future? The answer I feel is somewhere in the middle and may well be disease-dependent at this time.
A plethora of new compounds with novel modes of action are set to transform treatment of many haematological malignancies in the near future. In DLBCL for example, the addition of rituximab to CHOP improved survival, and then targeting CD79b provided some additional improvements. Many patients, however, still experience progression and require further treatment lines for relapsed/refractory disease. First-line treatment is expected to radically change with upcoming label expansions and new therapies for DLBCL, but many new therapies will be given in combination with chemotherapy. Compounds targeting CD19, BTK inhibitors, targeted protein degraders, and several CD20 x CD3 bispecific antibodies, often combined with chemotherapy, are expected in the coming years. CAR T-cell therapy may also move further up the DLBCL treatment line for some eligible patients.
With bispecific antibodies having varying targets it might also be possible for patients to benefit from more than one along the treatment pathway. Perhaps some learnings on treatment sequencing and overcoming resistance can also be taken from other tumour types such as chronic lymphocytic leukemia (CLL), where the shift to chemotherapy-free regimens targeting BTK and BCL2 have led to improved survival. Of course, DLBCL is a very different condition to CLL, but there may be instances of shared biology and potential overlapping therapeutic strategies, which are no doubt being investigated.
Other key challenges come from how best to assess treatment response – we know minimal residual disease has helped significantly in this regard for chemotherapy regimens, but do we need to look more widely for non-chemo regimens? We must also consider additional ways to improve outcomes with non-chemo treatments, for example to improve the success of CAR T if we are to reach a goal of reducing dependency on chemo regimens.
Targeted therapy has come a long way, yet for now, dependency on chemo-containing regimens remains the standard of care for first-line DLBCL despite the toxicities given their high efficacy. I for one will be interested to see where we are by ASH 2025 and indeed in another decade – can we reach that goal of targeting highly effective personalized therapy with as low toxicity as possible? I would think so, and it reminds me of a quote from Paulo Coelho, “When we strive to become better than we are, everything around us becomes better too.”
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Author: Michelle Utton-Mishra, Group Director, Scientific Strategy - Prime
