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Figure 5. Recommended therapy for patients with symptomatic chronic lymphocytic leukemia. M-CLL, mutated IGHV; U-CLL, unmutated IGHV; FCR: fludarabine + cyclophosphamide + rituximab; BR: bendamustine + rituximab; V: venetoclax; VR: venetoclax + rituximab; VO: venetoclax + obinutuzumab; I: ibrutinib; IO: ibrutinib + obinutuzumab; A: acalabrutinib; ClbO: chlorambucil + obinutuzumab; R: rituximab; D: duvelisib; AlloHCT: allogeneic hematopoietic cell transplantation; R-CHOP, rit- uximab, cyclophosphamide, doxorubicin, vincristine and prednisone; IGHV, immunoglobulin heavy-chain variable region. *Acalabrutinib (A) is approved for both treat- ment-naïve and relapsed disease by the FDA but not the EMA. #Venetoclax (V) monotherapy is approved for patients with TP53 aberrations who are refractory or intolerant to ibrutinib or patients without TP53 aberrations who are refractory or intolerant to both chemoimmunotherapy and ibrutinib. Venetoclax plus rituximab (VR) is approved for any patient with relapsed disease. †Duvelisib (D) monotherapy is approved for relapsed disease (minimum of two prior therapies) by the FDA but not the EMA. ‡AlloHCT is recommended for appropriate patients with high-risk disease, defined by TP53 aberrations and/or complex karyotype in whom ibrutinib and/or venetoclax has failed. Allogeneic HCT is also recommended for appropriate patients with transformed disease who have responded to salvage chemotherapy (e.g., R-CHOP).
randomized clinical trials comparing ibrutinib with chlo- rambucil monotherapy106 and other commonly used CIT combinations, namely FCR, bendamustine plus rituximab and chlorambucil plus obinutuzumab (ClbO).107–109 Ibrutinib was superior to chlorambucil and all CIT combi- nations in terms of response rate and progression-free sur- vival, and even conferred a longer overall survival com- pared to that provided by chlorambucil monotherapy and FCR.106,107 In these trials, ibrutinib was sometimes com- bined with a monoclonal antibody, either rituximab or obinutuzumab, and sometimes given as monotherapy, but the true added value of the monoclonal antibody in this context is unknown.108,110 In terms of toxicity, ibrutinib was less toxic than CIT combinations when severe adverse events or toxic deaths were considered.107–109
Apart from ibrutinib, patients with M-CLL, devoid of
TP53 aberrations and fit enough to tolerate FCR therapy, may still be good candidates for the latter, with the benefit being that this treatment can be completed in 6 months while ibrutinib must be taken indefinitely. This option would be particularly valuable for non-compliant patients or those in whom ibrutinib is contraindicated. If FCR is the treatment of choice, caution must be taken in patients with NOTCH1 mutations, in whom rituximab appears to have little added value.59 Other genomic subgroups, such as patients with BIRC3 mutations appear to derive little benefit from CIT,111,112 but these results should be further validated.
Unfit patients also have the alternative of venetoclax plus obinutuzumab (VO) as frontline therapy. This is based on a phase III trial that compared VO with ClbO in elderly/unfit patients.113 VO was superior in terms of
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