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Cheson. J Cancer Metastasis Treat 2022;8:8 https://dx.doi.org/10.20517/2394-4722.2021.153 Page 3 of 6

[43]
cure without chemotherapy .

The last bastion appeared to be DLBCL. Aggressive diseases need aggressive treatment, right? Perhaps not!
For patients who have already been failed by chemoimmunotherapy, repeating similar programs makes
little sense. One of the newer regimens for relapsed or refractory DLBCL to even include a modest
chemotherapy drug has been the combination of polatuzumab vedotin, the anti-CD79b antibody-drug
conjugate, with bendamustine and rituximab, which has been approved in the United States as a third or
subsequent line of therapy. Indeed, the new therapies have tended to rely more on targeted approaches.
Indeed, the first regimen to be approved by the FDA for patients following a single prior line of therapy is
L-MIND, the combination of the anti-CD19 monoclonal antibody tafasitamab with the immunomodulatory
agent lenalidomide. This non-chemotherapeutic regimen achieves an overall response rate of 58% with 40%
CRs, median duration of response of 34.6 months, with a median PFS of a year, at least as good as many
multi-agent chemotherapy regimens in this setting . More recently, loncastuximab tesirine, a CD-19
[44]
directed antibody-drug conjugate, was granted accelerated FDA approval for patients with relapsed and
refractory DLBCL beyond the second line, based on the results of a multicentre phase II study LOTIS-2. The
[45]
overall response rate was 48.3% with 24.1% CR rate and a median response duration of 10.3 months .
Selinexor, an oral inhibitor of nuclear transport protein exportin 1, induces responses in 28% of patients
[46]
with 12% CR and a median duration of response of 9.3 months . Based on these data from the SADAL
trial, this drug was granted accelerated approval by the FDA for patients who have progressed following two
or more lines of therapy. Although the single-agent results with this drug are modest, the drug has a
promising future in combination with other drugs.

The potential of new cellular and immunotherapies
Presentations at the American Society of Hematology Annual Meeting in 2020 describing results with
bispecific T-cell engagers and cellular therapies also strongly support a chemo-free future [47,48] . Not only does
the CD3xCD20 bispecific mosunetuzumab exhibit activity in relapsed and refractory DLBCL and FL , but,
[49]
in previously untreated, older, frail patients, it achieved responses in 57%-75% of patients, based on dose,
[50]
including 37.5%-50% complete remissions, some of which were ongoing beyond a year . Causing at least as
much excitement were the results of ZUMA-12, a phase II study of the Chimeric antigen receptor-T (CAR-
T) product axicaptagene ciloleucel as first-line therapy in patients with high-risk DLBCL characterized by
being a high-grade B-cell NHL with MYC and BCL2 and/or Bcl-6 translocations, or an IPI score ≥ 3. The
[51]
ORR was 85% with 74% CRs. 70% of responses were ongoing beyond the median follow-up of 9.3 months .

[52]
Nonetheless, the road to a chemo-free world has not always been a smooth one . In a number of instances,
combining agents either with chemotherapy or even with others, each with a favorable safety profile led to
life-threatening or even fatal toxicities. The experience with CAR-T has certainly been a steep learning
curve. As more targeted drugs and cellular therapies become more readily available in general practice, the
temptation to arbitrarily combine them in general practice will be powerful. However, multi-agent
combinations must first be carefully monitored in clinical trials before subjecting patients to a risk of
serious, unforeseen adverse effects.

One chemo-free approach does not fit all
Before we can totally banish chemoimmunotherapy from our armamentarium, a number of challenges
must be overcome. First and foremost, biomarkers must be identified to help direct specific treatments to
individual patients. Second, rather than what is usually empiric, targeted combinations should be based on
sound scientific rationale for efficacy, with careful consideration for avoiding overlapping toxicities.
Adaptive randomized trial design incorporating multiple arms and rapidly dropping those that fail to
demonstrate sufficient efficacy or tolerability may help facilitate the completion of studies while preventing