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D. Qualls and G. Salles
Figure 4. Schema for treatment choice in third-line and subsequent settings. Given the paucity of randomized data and large number of effective therapies in this setting, treatment is highly personalized, dependent on disease characteristics, prior therapies, and patients’ ability to tolerate treatment. Clinical trials should always be strongly considered. ASCT: autologous stem cell transplantation; HCT: hematopoietic cell transplantation; R2: rituximab and lenalidomide; PI3K: phospho- inositide 3-kinase; mut: mutated; WT: wild-type.
offer substantial benefits for these patients while avoid- ing significant toxicity.
Management in early progression
In cases of early progression (i.e., EFS12 or POD24 dis- ease), histological transformation should always be con- sidered. A biopsy should be systematically performed in all cases to rule out such transformation; several clinical featues, such as lack of response during chemotherapy or rapid tumor growth, elevated serum lactate dehydroge- nase levels, hypercalcemia, appearance of B symptoms, or rapid decline of the performance status are highly sugges- tive of histological transformation and might be used as surrogates when a biopsy is not feasible.3 If histological transformation is confirmed, in patients not previously exposed to anthracycline, R-CHOP often constitutes the standard of care. Alternative salvage chemotherapy regi- mens followed by ASCT are recommended for those pre- viously exposed to anthracycline, or in those unrespon- sive to R-CHOP. Cellular therapy is an important emerg- ing option for patients with histological transformation but unmet needs remain.5
If histological transformation is ruled out, several options should be considered. Standard options such as obinutuzumab-bendamustine and anti-CD20-lenalido- mide combinations are often utilized, and their efficacy in POD24 patients has been demonstrated.20,72,79,115 If an ade- quate response is achieved, some centers advocate for ASCT consolidation in eligible patients, and this remains a viable option, particularly in younger, fit patients in whom durable response is desirable. Aside from chemoimmunotherapy and R2, other strategies appear to be active in patients with POD24, including some PI3K inhibitors, bispecific antibodies (such as mosunetuzum- ab), and CAR T cells.50,83,92,116 Decisions in this situation can remain challenging, and studies such as SWOG S1608
(NCT03269669) comparing obinutuzumab-chemothera- py versus obinutuzumab-lenalidomide or obinutuzumab- umbralisib will be helpful to further elucidate the optimal management of these patients.
Third-line setting and beyond
In multiply relapsed and refractory disease, a broad array of effective options (Figure 4) remains available, although the choice of therapy is more individualized and less defined by randomized trials. Decisions depend pri- marily on patients’ prior treatment, response to therapies, disease-related symptoms and tumor burden. The choice of drug is then based on relative efficacy (limited by cross-trial comparisons), toxicity profiles, response rates, and patients’ priorities.
Repeating rituximab-based regimens with chemothera- py or lenalidomide is often feasible if a significant pro- gression-free interval of at least 2 years was achieved with the last treatment. In cases of refractory disease or early progression, changing the class of agents is generally preferred.
The choice of agent is also dictated by the anticipated depth and duration of response. Oral agents such as PI3K or EZH2 inhibitors are often considered earlier in treatment despite the low complete response rates observed and the median PFS and duration of response close to 12-14 months. These agents may be better positioned when more efficacious strategies have been exhausted, or as temporary solutions before implementing a more effective therapy.
Beside the presence of an EZH2 mutation, there are no biological criteria available to guide us toward a given treatment option. If the patient presents with significant tumor bulk or significant disease-related symptoms, it is probably preferable to use regimens allowing a more rapid and sustained response. In fit patients, if adverse features (high FLIPI, bulky disease, B symptoms, short
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haematologica | 2022; 107(1)