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A.R. Mato et al.
Table 4. First treatment following venetoclax discontinuation and treatment outcomes.
Treatment
Ibrutinib-based
Idelalisib-based
Rituximab monotherapy
CAR-T
Anthracycline-based (R-CHOP/R-EPOCH) Allogeneic SCT
Other
Number treated
with agent (Percentage of 24 patients who received subsequent line of therapy)
5 (20.8%)
2 (8.3%) 3 (12.5%) 2 (8.3%) 3 (12.5%) 3 (12.5%) 6 (25%)
Patient level responses (n)
PR (1), SD (2), PD (2)
CR (1), No response assessment (1)
PR (2), PD (1)
No response assessment (2)
PD (2), no response assessment (1)
CR (2), no response assessment (1)
PR (1), SD (1), PD (2), no response assessment (2)
comes, including TLS risk categorization, TLS events, and response were documented per physician assessment. Although we recommended the use of iwCLL response cri- teria, Howard criteria for TLS, and tumor burden classifica- tion per package insert, central review of outcomes was outside the scope of this study and, therefore, outcomes may have been subject to misclassification bias. While the case report form captured information on TLS prophylaxis and events, it was not designed to discern the detailed infor- mation that would be required to understand rate of TLS by management strategy. This was beyond the scope of this study but future research should consider examining this important information. Additionally, AE assessment was not comprehensive and included data on select AEs such as TLS, hematologic, infection or gastrointestinal toxicities. Applying CTCAE criteria retrospectively may result in underreporting of events and caution is emphasized in interpreting these findings. Indications for treatment were based on treating physicians’ discretion and were not spec- ified. Detailed information regarding reason for discontinu- ation of line of therapy prior to venetoclax was not cap- tured. As we know from prior studies, outcomes can differ significantly in patients who discontinue a kinase inhibitor due to toxicity as compared to progression.8 Future studies of venetoclax should consider stratifying patients by these subgroups. While we did include data from community practices, the fact that most patients were treated in aca- demic centers could introduce a selection bias. Our median follow up of 7 months is short and does not capture pro- gressions on venetoclax that occur later.
Despite its inherent limitations, this series represents the largest real-world cohort of CLL patients treated with venetoclax. Neutropenia and thrombocytopenia were the most common toxicities, and progression was the leading cause of venetoclax discontinuation. Venetoclax was active in patients with mutations known to confer ibruti- nib resistance as well as in patients with other poor risk features. However, TP53 interruption was associated with an inferior PFS. While we report the largest series of post- venetoclax outcomes, we demonstrate no clear sequenc- ing pattern. Because the number of patients who discon- tinue venetoclax due to disease progression or toxicity within the first 2 years of initiating therapy is not trivial, understanding how these patients should be subsequently treated is a critical area of future research.
Acknowledgments
The authors would like to thank Joseph and Cindy Riggs for their support.
due to other reasons with no patients discontinuing due to toxicity.2 We also note these results differ from recent real world BCR inhibitor series where AEs were the most common reason for drug discontinuation, followed by CLL progression.20
Even less is known about sequencing of therapies fol- lowing venetoclax discontinuation. Anderson et al. report outcomes on 25 patients who progressed following vene- toclax, 8 with progressive CLL and 17 with RT. In this series, 6 CLL patients with progression, all of whom were ibrutinib naïve, were treated with a BTK inhibitor as the first therapy after discontinuation. Five of six (83%) ini- tially achieved a partial response.2
Our study is unique in that we report patient level treat- ment data on 24 CLL patients progression following vene- toclax, which represents the largest series reported to date. These patients are representative of the U.S. population currently treated with venetoclax in that they are treated in the R/R setting, and 89% had been exposed to a BCR inhibitor prior to venetoclax treatment, most commonly ibrutinib. We found that, following progression on vene- toclax, ibrutinib was most commonly selected agent, accounting for 20.8% of the cases. However, idelalisib- based, rituximab monotherapy, CAR-T, anthracycline based therapy, and allogeneic stem cell transplant were also selected as next therapy in other cases. Interestingly, 3 patients underwent allogeneic stem cell transplant as first therapy after venetoclax. Two achieved a CR and 1 did not have an available response assessment. One patient received an allogeneic SCT as second therapy fol- lowing venetoclax and achieved CR. Although interpreta- tion of the SCT results are subject to selection bias, they suggest that there is a potential role for effective cellular therapies and should be explored. Our data demonstrate that no clear consensus exists for therapy selection follow- ing venetoclax failure and highlights the importance addressing sequencing strategies in future clinical trials. This will become increasingly important as more patients in practice are treated with venetoclax alone or in combi- nation with antibodies and/or ibrutinib.
Our study has several limitations. Data were collected retrospectively by multiple physicians and are subject to differences in clinical experience, practice style, and incon- sistencies in chart review. Missing data varied with individ- ual data points and were infrequent. To address this, we included absolute numbers and percentages to highlight any data that was not reported for individual data points. Additional data, including performance status, could offer additional insight but was not collected. Variables and out-
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haematologica | 2018; 103(9)