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Page 2 of 6 Cheson. J Cancer Metastasis Treat 2022;8:8 https://dx.doi.org/10.20517/2394-4722.2021.153

Bullet, which bore a startling likeness to the structure of an antibody, that would attack the invaders while
[2]
sparing normal cells. Nonetheless, it took more than a century for Kohler and Milstein to develop the
hybridoma technology that would enable the production of adequate quantities of monoclonal antibodies
[3]
for clinical use and a few more years for Nadler et al. to identify a suitable protein (B1, now known as
CD20) on the malignant cell to target. After initial demonstrations of its activity in patients who had been
[4,5]
[6]
previously treated , Ghielmini et al. demonstrated impressive activity for the chimeric anti-CD20
monoclonal antibody rituximab in patients with and without prior therapy for their follicular lymphoma.
Countless trials ensued, combining rituximab with various chemotherapy regimens as initial treatment of
follicular and diffuse large B-cell lymphoma (DLBCL) and demonstrating a consistent survival
advantage [7-10] . Meanwhile, in a parallel universe began the pursuit of a chemo-free approach. In 2003,
investigators from what was then the Cancer and Leukemia Group B were the first to embark on a series of
biological doublets, first with two monoclonal antibodies in previously untreated patients with follicular
[11]
lymphoma: rituximab with the anti-CD80 galiximab achieved an overall response rate (ORR) of 72%, with
48% complete remissions (CRs), with ORR and CR rates of 92% and 75%, 80% and 48%, and 55% and 27%,
respectively, for low, intermediate, and high follicular lymphoma international prognostic index (FLIPI)
scores. The progression-free survival for the low FLIPI patients was 75% at three years. Rituximab with the
anti-CD22 epratuzumab achieved an ORR of 87%, including 42% CRs. They next combined the anti-
[12]
CD20 with the immunomodulatory agent lenalidomide, creating the regimen they called R . Their first
2
[13]
study in relapsed patients showed a significant benefit compared with lenalidomide alone . When used as
front-line therapy, each of these regimens was not only well-tolerated, but achieved response rates from
85%-95% , similar to what was achieved with chemoimmunotherapy regimens. Moreover, these responses
[14]
were durable, many of which often lasting beyond a decade without recurrence. R was pursued by other
2
investigators and is now approved for relapsed and refractory follicular and other indolent non-Hodgkin
[15]
[16]
lymphomas (NHL) based on data from the Augment trial . In the front-line RELEVANCE trial, R showed
2
similar efficacy with a more favorable toxicity profile compared with chemo-immunotherapy .
[17]
Unfortunately, the study did not meet its superiority endpoint.
The next generation of chemo-free agents
Over the last few years, a new wave of targeted agents has further enhanced interest in chemo-free
approaches to lymphoid malignancies. A first-in-class oral inhibitor of activating mutation of Enhancer of
zeste homolog 2, tazemetostat, offers a new option in patients with follicular lymphoma . Impressive
[18]
results with the covalent Bruton tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib
leukemia [19-24] , and the non-covalent LOXO-305 have recreated the landscape for chronic lymphocytic
[25]
leukemia (CLL) as well as other lymphoma histologies [26-30] . In addition, the bcl-2 inhibitor venetoclax has
assumed a major role as a single agent, but more so in combinations [31,32] . Also active are the PI3k inhibitors
[37]
idelalisib [33,34] , copanlisib , duvelisib , and umbralisib . As a result of these highly active, well-tolerated
[36]
[35]
agents, CIT is now a blur in the rear view mirror for CLL and small lymphocytic lymphoma, patients with
MYD88 mutated Waldenström macroglobulinemia, relapsed and refractory mantle cell lymphoma and
marginal zone lymphomas. These therapies have rapidly moved to the front line in appropriate patients [31,32] .
Chemo-free agents for Hodgkin and aggressive lymphomas
Now that we have taken care of the indolent diseases, at least for a while, what is the possibility of eschewing
chemotherapy in the more aggressive histologies? For Hodgkin lymphoma, the universe shifted with the
availability first of the antibody-drug conjugate brentuximab vedotin, and subsequently with the checkpoint
inhibitors, nivolumab and pembrolizumab. After demonstrating single-agent activity in the relapsed
refractory setting [33-40] , these agents have been combined and sequenced with chemotherapy for
relapsed/refractory patients as well as part of initial therapy [41,42] . Recently a trial of BV-Nivo in untreated HL
patients who were older or considered unsuitable for chemotherapy, demonstrated a