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C.Y. Cheah et al.
The selective BTK inhibitor zanubrutinib was exam- ined in a single-arm phase II study by Opat et al.83 Eligible patients with MZL who had had one or more prior line of therapy were treated with 160 mg of zanubrutinib twice daily. Among the 68 patients, 38% had MALT lym- phoma, 38% had nodal MZL, 18% had splenic MZL and 6% had an indeterminate subtype. Patients had received a median of two prior lines of therapy and the ORR was 68% (complete responses, 26%) with similar rates between MZL subtypes. The estimated 15 month PFS rate was 82.5%. The most common TEAE were diarrhea (22%), bruising (21%), and constipation (15%) with neu- tropenia (10%) being the most common grade ≥3 TEAE. Atrial fibrillation and hypertension each occurred in 3% of patients. On the basis of these data zanubrutinib was recently approved for patients with relapsed MZL.
Phosphatidylinositol-3-kinase inhibitors
Three phosphatidylinositol-3-kinase (PI3K) inhibitors have been approved by the FDA for the treatment of relapsed/refractory MZL. The PI3Kd inhibitor idelalisib was the first-in-class agent, with significant activity in a range of indolent B-cell malignancies. In the phase II reg- istration trial, Gopal et al. treated 125 patients with indo- lent lymphoma including 15 with MZL with 150 mg of idelalisib orally twice daily.84 Efficacy was encouraging, but the infectious and immune toxicities were notewor- thy. Although results for the subset of MZL patients were not reported separately in that study; Martin et al. report- ed pooled data from 21 patients treated in the phase I and phase II trials: two of six patients (both with partial responses) in phase I and seven of 15 (one with a com- plete response) in phase II achieved a response for a cumulative ORR of 43%.85 The median PFS in phase II was 6.6 months and the toxicity profile was consistent with that observed in other histological subtypes. Although phase III trials in indolent lymphoma were commenced, the toxicity observed when combining ide- lalisib with chemo-immunotherapy and other novel agents was considerable and further clinical development was halted.86-88
Other PI3K inhibitors have been developed, including the intravenous pan-class I PI3K inhibitor copanlisib. In the phase II CHRONOS-1 study Dreyling et al. enrolled 142 patients with relapsed/refractory indolent B-cell lym- phoma, of whom 23 had MZL.89 Patients received 60 mg of copanlisib intravenously on days 1, 8 and 15 of 28-day cycles until disease progression or unacceptable toxicity. At the primary analysis after four cycles of therapy, the ORR was 70%, resulting in breakthrough therapy desig- nation for adults with MZL who had received two or more prior systemic therapies. Long-term follow-up of the 23 patients in this study with relapsed/refractory MZL was recently reported.90 These patients had a medi- an age of 69 years and had received a median of three prior lines of therapy. The most common MZL subtype was nodal MZL (n=15) with four patients each having splenic and MALT lymphoma. The eventual ORR was 78%, with the rates for nodal, splenic and MALT lym- phoma being 87%, 75% and 50%, respectively. Complete responses were observed in three (13%) patients, all with splenic MZL. The median duration of response was 17.4 months; the median PFS was 24.1 months and the median OS was not reached. The esti- mated 2-year OS rate was 83%. The most frequent TEAE
of any grade were fatigue (52%), diarrhea and hyper- glycemia (each 48%), while the most common grade ≥3 TEAE were hyperglycemia, hypertension (each 39%), fatigue, diarrhea, neutropenia and pneumonia (each 26%). The increase in infectious and immune toxicity observed with idelalisib was not apparent.
Umbralisib is a novel, oral, dual inhibitor of PI3Kd and casein kinase-1-e, with minimal PI3Kg inhibition, which is taken once daily. Fowler et al. performed a phase IIb registration trial of umbralisib 800 mg daily in 208 patients with relapsed/refractory indolent B-cell lym- phoma, including 69 patients with MZL.91 These patients had a median age of 67 years, they had received a median of two prior lines of therapy and 21% were refractory to their previous line of therapy. The ORR was 49% (com- plete responses, 16%) and consistent across the MZL sub- types. After a median follow-up of 27 months, the medi- an duration of response was not reached, with the esti- mated 2-year PFS rate being 50.5%. Among all patients, the most frequent TEAE of any grade were diarrhea (59%), nausea (39%) and fatigue (30%), with the grade ≥3 ones being neutropenia (11%) and diarrhea (10%). TEAE of interest included opportunistic infections (grade ≥3 3.4%), elevation of liver enzymes (all grades 20.2%; grade ≥3 6.7%) pneumonitis (all grades 1.4%; grade ≥3 1.0%) and non-infectious colitis (all grades 1.9%; grade ≥3 0.5%). Overall the agent was active and resulted in durable remissions with an acceptable safety profile and has received accelerated FDA approval for patients with relapsed MZL. Other PI3K inhibitors such as parsaclisib and zandelisib (NCT037685050) have also been explored in phase II studies.92
Although the focus of chimeric antigen receptor T-cell therapy (CAR-T) studies has mainly been on patients with aggressive histological subtypes such as relapsed/refractory diffuse large B-cell lymphoma, a few studies have looked at patients with indolent lym- phomas. ZUMA-5 is an ongoing phase II study of axicab- tagene ciloleucel in patients with relapsed/refractory indolent B-cell lymphoma.93 Jacobson et al. treated 146 patients, including 22 patients with MZL who had received two or more prior lines of therapy including a CD20 monoclonal antibody combined with an alkylating agent. The median age of the MZL patients was 66 years, the median number of prior lines of therapy was three and 52% had experienced a prior progression of disease within 24 months despite CD20 and alkylator-based ther- apy. The ORR for MZL patients was 85% (complete responses, 60%) and after a median follow-up of 12.1 months, the median PFS was 11.8 months and the esti- mated 12-month OS rate was 92.9%. Cytokine release syndrome occurred in all 22 patients (100%), with two (9%) experiencing grade ≥3 events and 15 (68%) requir- ing tocilizumab. Typically for axicabtagene ciloleucel, the rate of neurological toxicity was substantial: 17 (77%) patients experienced a neurological event and in nine (41%) cases these were grade ≥3 events. Steroids were required in 14 (64%) of patients. Notably the rate of grade ≥3 neurological toxicity appeared higher in MZL than in the follicular lymphoma cohort of the same study (15%) and the median increases in analytes associated with axi- cabtagene ciloleucel toxicity were higher in patients with MZL than in those with follicular lymphoma. Although these results were disappointing, the number of patients with MZL was small and results are preliminary. In the
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haematologica | 2022; 107(1)