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Letters to the Editor
patient remained on acalabrutinib at the time of data cut- off; this patient has maintained CR since December 2016 through the last follow-up assessment (August 2020).
Median duration of exposure to acalabrutinib was 2.3 months (range, 0.5–22.5), with a median relative dose intensity of 98.1% (range, 6.3–100.0%). Two patients had a dose reduction, one due to grade 2 orthostatic hypotension, and the other due to prescription of a strong CYP3A inhibitor. Three (14.3%) patients had ≥1 doses withheld for ≥7 days, including two due to AE (both grade 3 abdominal pain considered not related to the study drug).
Treatment-emergent AE occurred in 95% of patients, most commonly diarrhea (43%) and fatigue (43%); 29% experienced grade 3/4 AE (Table 1). Treatment-related AE occurred in 16 (76%) patients; five (24%) experienced grade 3/4 treatment-related AE; two patients developed grade 3 serious AE that were considered treatment-relat- ed (pyrexia in one patient, and positive influenza B virus test in the other patient).
Regarding AE of clinical interest, no atrial fibrillation, hypertension, tumor lysis syndrome, or grade ≥3 bleed- ing were reported; any-grade AE of special interest included hemorrhage in eight (38%) and infections in 11 (52%) patients, with three patients (14%) having grade ≥3 infections. Grade ≥3 infections included one patient with grade 4 pneumonia (lower respiratory culture iden- tified Staphylococcus aureus), one patient with grade 3 rhi- novirus infection, staphylococcal infection, staphylococ- cal urinary tract infection, and grade 5 septic shock, and one patient with grade 3 viral infection. Several factors may have contributed to the lack of atrial fibrillation and hypertension reported in this study, beyond the acalabru- tinib selectivity for BTK, including comorbid health con- ditions, small population sample, and short follow- up/drug exposure duration.
The ORR was 24% (n=5 of 21), with four patients achieving a CR and one experiencing a PR; one patient had stable disease (SD) (Figure 1A and 1B). Median dura- tion of response for the five responders was 7.8 months (95% Confidence Interval [CI]: 1.8-not reached). NanoString subtyping was available for 15 patients and revealed nine ABC, five GCB, and one unclassified sub- type (Figure 2). ORR in patients with ABC subtype by NanoString was 33% (three of nine), with 22% (two of nine) achieving CR. Among patients with GCB subtype by gene expression, one achieved CR; none achieved PR. Duration of response was substantially longer in two of the patients with CR than in the majority of patients (Figure 1B). One patient with ABC subtype disease expe- rienced PD after 13.7 months; the other, who remained on treatment at the time of data cutoff (15.9 months) had GCB subtype disease, in a background rich in T cells and histiocytes (Figure 2A). This latter patient had had a PR to prior R-CHOP and experienced PD on regimens of ritux- imab/gemcitabine/dexamethasone/cisplatin and of lenalidomide+rituximab.
Median PFS and overall survival based on Kaplan- Meier analysis were 1.9 months (95% CI: 1.8-2.7) and 15.5 months (95% CI: 4.0-not reached), respectively (Online Supplementary Figures S1A and B). For the 11 patients who received subsequent lines of therapy, medi- an time to next treatment was 4.0 months (95% CI: 3.0- 7.5).
The pharmacokinetics of acalabrutinib were character- ized by rapid absorption and elimination, indicating low potential for accumulation. These results were consistent with previous studies in patients with CLL and MCL.7,10
Among 14 patients for whom pharmacokinetic data were available, comparable steady-state mean maximum con- centration (Cmax) and area under the concentration time curve (AUClast) were observed between responders (n=5) and non-responders (n=9) (Online Supplementary Figure S2). BTK receptor occupancy data were available for five patients with evaluable predose and postdose samples, including three responders and two non-responders. Consistent with previous results in CLL and MCL,7,10 median steady-state BTK target occupancy was 97% to 99% throughout the dosing interval, and was >90% for all patients at all time points (irrespective of clinical responses), indicating complete target coverage by acal- abrutinib (data not shown).
Acalabrutinib monotherapy demonstrated activity in R/R DLBCL patients, some with durable responses. The ORR of 24%, with a rate of 33% in ABC subtype, was overall consistent with that reported for ibrutinib and tirabrutinib.4,5 Nevertheless, one patient of confirmed GCB subtype who had documented primary resistance to R-CHOP chemotherapy entered a durable CR, which per- sists over 4 years since commencing therapy. Comparable exceptional responders have been observed with ibrutinib, but these cases were of ABC subtype.
Overall, BTK inhibitors appear to be moderately effec- tive in ABC DLBCL,4 possibly due to the necessity for maintained BCR signaling; BTK inhibition thus results in apoptosis, as observed in vitro in some ABC cell lines.11 However, in most patients with ABC DLBCL, responses, if present, are usually short-lived4; mechanisms behind resistance or short duration of response in DLBCL are not known, precluding prospective identification of patients who would benefit most from this therapy. This problem is highlighted by two observations. Firstly, a study of tirabrutinib in primary central nervous system DLBCL found it to be effective against DLBCL with CARD11 mutations in the coiled-coil domain, suggesting that a more precise molecular understanding of the B-cell recep- tor pathway will help better guide patient selection for this treatment.12,13 Secondly, the best responder in our study was of GCB subtype (though rich in T cells and his- tiocytes; subtyping determined via NanoString Lymphoma Subtyping Test), suggesting that some patients with this subtype can have durable responses to BTK inhibition. This durable response in GCB disease perhaps reflects the fact that there are multiple genomic subtypes across ABC and GCB DLBCL, each with differ- ent risk profiles and expected responsiveness to BTK inhibitors.14-16 Given that inclusion criteria required immunohistochemically confirmed non-GCB DLBCL, the presence of patients with GCB within this cohort highlights the variable concordance between immunohis- tochemistry algorithms and gene-expression profiling and the potential benefits of genomic profiling in defining treatment subgroups.17 Furthermore, genomic profiling beyond gene expression analysis may also represent a better means of selecting patients who may respond to different treatment modalities compared with using cell- of-origin classification. The incidental inclusion of patients with GCB DLBCL may be a limitation of this study given the known sensitivity of non-GCB DLBCL to BTK-dependent B-cell receptor signaling inhibition and the reported preferential activity of BTK inhibitors in the non-GCB DLBCL subtype.4
Macrophage impairment that has been observed with ibrutinib18,19 has not been observed with acalabrutinib; in addition, the comparable efficacy in ABC DLBCL to other BTK inhibitors4,5 and the acceptable toxicity profile sug-
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