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M. Fürstenau et al.
were hematologic toxicities such as neutropenia (40% of all patients) and thrombocytopenia (21%), gastrointestinal disorders including diarrhea (41%) and nausea (39%) as well as upper respiratory tract infections (25%).
As previously reported for ibrutinib, continued drug exposure may result in the development of specific resist- ance mutations in the context of indefinite venetoclax treatment. A venetoclax-specific resistance mutation in the BCL2 gene was recently reported.37 Of 15 patients whose disease progressed during venetoclax treatment, seven showed a heterozygous nucleotide variant (Gly101Val) in BCL2 that impaired binding of venetoclax to the protein. The mutation was detected as early as 25 months before clinically apparent CLL progression. Another study showed various other molecular aberra- tions in patients who developed resistance upon BCL2- inhibition by venetoclax, including cancer-related genes such as TP53, BRAF and CD274.38
Sequential use of novel agents
Despite the long PFS that novel agents have produced, most patients will probably require a second-line treat- ment after the first novel agent either because of disease progression or because of toxicity-related treatment dis- continuation. As novel agents have only been approved recently, there is limited evidence on how best to sequence these agents and how to treat patients who relapse after these therapies. Available data are largely based on retrospective cohort studies and registry data.
Mato et al. systematically assessed treatment sequences in a large cohort of patients treated with ibrutinib or vene- toclax.39 Ibrutinib given as a first kinase inhibitor yielded better outcomes than idelalisib, while in the setting of ibrutinib failure, venetoclax produced superior survival compared with idelalisib and chemoimmunotherapy. Jones and colleagues confirmed this observation in their analysis of 127 patients who received venetoclax after kinase inhibtor failure with a median PFS of 24.7 months for venetoclax treatment after ibrutinib and an estimated 1-year PFS of 79% for venetoclax after idelalisib failure.40 Within another analysis, Mato and colleagues assessed outcomes in patients who had previously been treated with idelalisib or ibrutinib with regard to the reason of prior treatment discontinuation.19 The main reason for dis- continuation of treatment with a kinase inhibitor was tox- icity (51%), followed by disease progression (29%) and Richter transformation. Patients who were retreated due to intolerance of the previously used kinase inhibitor had significantly better outcomes than patients whose disease had progressed during the kinase inhibitor treatment.
Patients in whom venetoclax treatment fails have not yet been extensively analyzed. In a recently published analysis, 204 venetoclax-treated patients were evaluated of whom about 47% discontinued treatment due to pro- gressive disease, 21% due to Richter transformation and 11% because of mostly hematologic adverse events.41 Nineteen patients who were subsequently treated with a kinase inhibitor showed a good ORR of 69% and a medi- an PFS that was not reached after a median follow-up of 7 months. First data from patients progressing on the MURANO trial who were subsequently treated with ibru- tinib indicate that this kinase inhibitor can be successfully used after venetoclax.42 Of eight patients who were
included in this analysis, seven responded to ibrutinib (6 partial responses, 1 complete response).
Furthermore, alternate kinase inhibitors were investigat- ed in patients who were intolerant to either ibrutinib or idelalisib.43,44 Thirty-three patients who discontinued ibru- tinib treatment due to toxicities were treated with acal- abrutinib and showed an ORR of 76%. The median PFS had not been reached after a median follow-up of 9.5 months. During this time only 6% of the ibrutinib-intoler- ant patients discontinued treatment with acalabrutinib due to adverse events.43 In a similar study, 36 BTK inhibitor-intolerant and four PI3K inhibitor-intolerant patients were treated with umbralisib; four of these patients discontinued treatment due to an adverse event within a median follow-up of 7 months.44
Prospective clinical trials including long-term follow-ups are urgently needed to establish an optimal sequencing strategy. Nonetheless, some conclusions on the sequence of therapy can be drawn based on the limited, existing data. Venetoclax-containing regimens appear to be superi- or after ibrutinib failure while ibrutinib seems the best option after venetoclax.39-41 Patients in whom idelalisib fails can be treated equally with either ibrutinib or veneto- clax. When ibrutinib treatment is discontinued due to tox- icities, changing to an alternative BTK inhibitor, such as acalabrutinib, can be considered, where available. However, other factors must also be taken into account when deciding on a treatment sequence. These factors include the genetic risk profile, specific co-morbidities and co-medications as well as the expected compliance and personal treatment preference of the patient. Figures 2 and 3 show proposed treatment algorithms based on the avail- able evidence and current approval status of the drugs.
Limitations of monotherapy with novel agents
Optimal sequencing of single agents ideally leads to durable remissions with each new substance while other effective substances are saved for the next line of treat- ment. In reality, however, this is often not the case.
Retrospective and registry data show markedly higher discontinuation rates of monotherapy with ibrutinib or venetoclax than those documented in the pivotal clinical trials, either due to disease progression, toxicities or other long-term adherence issues.3,15,16,19,45 After several years of exposure to ibrutinib, the incidence of BTK and PLCγ2 mutations appears to increase drastically and certain toxi- cities, such as cardiac arrhythmias, seem to occur at a con- stant frequency during ibrutinib treatment.16,18-20,37,46,47 In the long-term follow-up of the RESONATE trial, atrial fibrilla- tion occurred in 11% of the ibrutinib-treated patients with a median follow-up of 44 months. While hematologic tox- icities and infections occurred mostly in the first year of ibrutinib treatment and decreased afterwards, hyperten- sion and rare major hemorrhages were seen constantly during the following years.48
Another crucial drawback of indefinite monotherapy is the financial burden, as all novel agents approved for use in CLL are extremely costly compared to established treat- ment options such as chemoimmunotherapy.49 Furthermore, kinase inhibitor monotherapy rarely leads to complete and deep molecular remissions due to various mechanisms of adaptation that have recently been described.50
For these reasons, efforts have been made to design time-limited combination treatments that, despite their
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haematologica | 2019; 104(11)