Page 163 - 2019_10 resto del Mondo_web

Olaptesed pegol + BR in relapsed/refractory CLL
The triple regimen of olaptesed pegol in combination with BR was generally well tolerated with neutropenia recorded as the most frequent adverse event. The inci- dences of grade 3/4 anemia and thrombocytopenia were low. Non-hematologic toxicities, mostly nausea and pyrexia followed by mild diarrhea and constipation, were generally manageable. Altogether, the reported frequency and severity of adverse events were to be expected in a population of relapsed/refractory CLL patients during standard BR therapy.14-17 Therefore, it does not appear that treatment with olaptesed pegol results in significant addi- tional toxicities on top of BR.
Treatment with olaptesed pegol in combination with BR resulted in an ORR of 86% with 11% of patients achieving a complete response. Acknowledging the limi- tations of cross-trial comparisons due to different inclu- sion criteria of patients as well as the limited sample size of 28 patients in this study, the ORR of 86% compares favorably with responses to BR alone reported earlier with ORR ranging from 45-72%.14-17 Although limited by the low numbers of patients, subgroup analyses showed that all ten high-risk patients, including four with a 17p deletion, achieved a partial response with the combina- tion of olaptesed pegol and BR, even though 17p-deleted patients have been reported to respond poorly to BR alone.15,17
Other combinations with BR in relapsed/refractory CLL patients resulted in ORR of 84% for cytarabine + BR,21 82.7% for the BTK inhibitor ibrutinib + BR,14 70% for the PI3K inhibitor idelalisib + BR,17 67% for fludarabine + BR,22 and 47% for lenalidomide + BR.23 Of note, higher toxicity rates were reported for the addition of kinase inhibitors to BR regarding neutropenia, diarrhea and pneumonia14,17 and very high incidences of grade 3/4 neutropenia and throm- bocytopenia were reported if another chemotherapeutic drug was combined with BR.21,22
The median progression-free survival of 15.4 months in the ITT population is in the range of what is expected after BR treatment alone (11.1, 13.3, 14.7, and 17 months).14-17 Seymour et al. reported a progression-free sur- vival of 16.6 months for patients treated with BR only after one prior therapy line, which is slightly longer than the progression-free survival of 15.4 months in our study;
A
however only 12.9% of the patients in the MURANO study had Rai stage III-IV CLL whereas 39% of patients in our study had Binet stage C disease.16 Comparable pro- gression-free survival values were achieved by the addi- tion of another chemotherapy to BR such as fludarabine + BR or cytarabine + BR (19 and 16 months, respectively),21,22 however much better progression-free survival results were reported for the combination of kinase inhibitors and BR (20.8 months for idelalisib17 and not reached for ibrutinib14) . Notably, kinase inhibitors strongly interfere with CXCR4 downstream signaling and the resulting CLL cell displacement from their supportive microenviron- ment, followed by leukemia cell death due to ‘death by neglect’, is a central mechanism of action of kinase inhibitors.20 In contrast to olaptesed pegol which was given once per 28-day cycle, however, the kinase inhibitors were administered daily or twice daily. Thus, the authors suggest studying whether longer progression- free survival could be achieved if olaptesed pegol were to be administered more often to fully exploit the ‘death by neglect’ mechanism indicated by the transient CXCR4- increase on peripheral CLL cells following olaptesed pegol treatment. Furthermore, kinase inhibitor treatment was sustained after completion of six BR cycles and could, therefore, further prolong the time to progression, where- as olaptesed pegol treatment was stopped after six BR- combination cycles. The median overall survival was not reached, resulting in a 3-year survival rate of >80% in the ITT population which compares favorably with other effective BR combinations (60% - 75%).17,21,22
A recent combination therapy utilizing bendamustine for initial debulking followed by obinutuzumab and vene- toclax resulted in an ORR of 90% in a subgroup of 29 relapsed/refractory CLL patients.24 A comparable ORR of 92% was achieved in 12 relapsed/refractory CLL patients when chemotherapy was omitted and obinutuzumab, ibrutinib and venetoclax were administered sequentially.25 Another chemotherapy-free combination of rituximab and venetoclax produced an ORR of 92.3% in 194 relapsed/refractory CLL patients.16 Interestingly, olaptesed pegol was reported to synergize with anti-CD20 antibod- ies such as rituximab or obinutuzumab by enhancing immune cell infiltration and antibody-dependent cellular
B
Figure 4. Progression-free survival and overall survival of patients. Kaplan-Meier analyses of (A) progression-free survival and (B) overall survival in the intent-to-treat population (n=28) are depicted. PFS: progression-free survival; OS: overall survival.
haematologica | 2019; 104(10)
2059