User login
Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.3 Studies combining BTK and BCL2 inhibitors are also promising in this setting.
Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.
At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).
This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.
Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study2, demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.
Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.
Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.
Additional References
- Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
- Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281
Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.3 Studies combining BTK and BCL2 inhibitors are also promising in this setting.
Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.
At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).
This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.
Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study2, demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.
Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.
Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.
Additional References
- Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
- Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281
Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.3 Studies combining BTK and BCL2 inhibitors are also promising in this setting.
Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.
At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).
This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.
Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study2, demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.
Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.
Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.
Additional References
- Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
- Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281