Table 1 Characteristics and outcomes of included CLL studies (n = 17)

Robak et al. 2010 [16]

Europe

To compare CIT with fludarabine, cyclophosphamide and rituximab (FCR) with standard chemotherapy (FC) in patients with previously treated CLL

Binet Stage

A, B and C

No

PFS; HR: 0.65,

OS; HR: 0.83

CIT with rituximab improved a 2-year PFS. Patients with poor prognostic factors such as del11q, unmutated IGHV, or positive ZAP-70 benefited from FCR

Hallek et al. 2010 [17]

Europe

To investigate whether adding rituximab to chemotherapy with FC would improve the survival outcomes of treatment-naïve, physically fit patients with CD20⁺ CLL

Binet Stage A, B and C

No

PFS; HR: 0.56,

OS; HR: 0.67

The addition of rituximab to chemotherapy improved 3-year PFS and OS and resulted in significantly higher PFS in most genetic subgroups including del(17p), del(11q), del(13q) and trisomy 12. An improvement in PFS was noted in all disease stages

Goede et al. 2014 [15]

Europe

To determine whether CIT with rituximab or obinutuzumab would be beneficial in previously untreated patients with CLL and comorbidities

Binet stage C, symptomatic disease

No

PFS; HR: 0.44,

OS; HR: 0.66 (R-Chl vs Chl)

PFS; HR: 0.18,

OS; HR: 0.41 (O-Chl vs Chl)

CIT with rituximab or obinutuzumab resulted in a better response and prolongation of a 2-year PFS as compared to treatment with chlorambucil alone

Chanan-khan et al. 2016 [46]

Europe, Americas, Asia

To assess the efficacy and safety of ibrutinib versus placebo in combination with bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma

Binet stage A, B and C or Rai stage 0-II and III/IV

No

PFS; HR: 0.203,

OS; HR: 0.577

Addition of ibrutinib to CIT resulted in significant improvement in PFS as compared to CIT alone in patients with R/R CLL and having high-risk features such as unmutated IGHV status, del(11q), and bulky disease

Hillmen et al. 2015 [47]

To investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone

Binet stage A, B and C

No

PFS; HR: 0.91,

OS; HR: 0.57

Addition of ofatumumab led to a significant benefit in progression-free survival in most subgroups of patients

Van Oers 2015 [51]

To compare ofatumumab maintenance treatment with observation for patients in remission after re- induction treatment for relapsed CLL

Binet stage A, B and C

No

PFS; HR: 0.50,

OS; HR: 0.85

Ofatumumab maintenance improved PFS in patients with relapsed CLL

Greil et al. 2016 [44]

Europe

To investigate the potential of rituximab maintenance therapy to improve survival outcomes in patients with CLL who respond to rituximab-containing induction regimen

Rai stage 0/I/II or stage III/IV

Yes

PFS; HR: 0.50

OS; HR: 0.77

Rituximab maintenance therapy prolonged a 3-year PFS. The effect of rituximab on PFS was comparable across prognostic factors analysed. OS was not reached in both the rituximab and observation group due to shorter follow-up time

Robak 2017 [42]

18 countries

To investigate the potential of adding ofatumumab to FC to improve PFS in relapsed CLL

Rai stage 0-II or stage III/IV

No

PFS; HR: 0.67

OS; HR: 0.78

Addition of ofatumumab to chemotherapy with FC improved PFS compared to FC alone in patients with relapsed CLL

Dartigeas et al. 2017 [45]

Europe

To compare maintenance treatment with rituximab vs. no further treatment to prolong PFS in treatment-naive and fit patients aged ≥ 65 years with CLL

Binet stage B or C

Yes

PFS; HR: 0.55,

OS; HR: 0.89

Maintenance therapy with rituximab improved 3-year PFS as compared to observation. OS was not reached in both groups at the time of analysis

Robak et al. 2018 [43]

Europe

To assess the effect of maintenance treatment with rituximab vs. no further treatment in previously untreated patients with progressive CLL

Rai stage I-IV

No

PFS; HR: 0.418

A 3-year PFS was significantly longer in the maintenance arm compared to the observation arm

Woyach et al. 2018 [14]

Americas

To evaluate the efficacy of ibrutinib, either alone or in combination with rituximab in older patients with untreated CLL

Intermediate to high-risk modified Rai stage disease

No

PFS/OS; HR: 1.06

There was no significant difference in 2-year PFS and OS between the two arms. Interactions between cytogenetics and effect of treatment on PFS were observed

Seymour et al. 2018 [40]

Americas, Europe

To evaluate the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory CLL

Not stated

No

PFS; HR: 0.17,

OS; HR: 0.48

Significantly higher rate of 2 year PFS with venetoclax plus rituximab than with a standard chemoimmunotherapy, with benefit observed in all subgroups analysed

Moreno et al. 2019 [48]

Americas, Europe, Asia and Australia

To compare the efficacy of the combination of ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in first-line CLL/SLL

Rai stage III/IV

No

PFS; HR: 0.23

The progression-free survival benefit in the ibrutinib plus obinutuzumab group was particularly notable in patients considered to be in the high-risk group, which consisted of patients with del17p or TP53 mutation, del11q, or unmutated IGHV

Fischer et al. 2019 [49]

Europe, Americas and Oceania

To investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions

Binet stage A, B and C

No

PFS; HR: 0.35,

OS, HR: 1.24

targeted treatment with venetoclax–obinutuzumab was effective in previously untreated patients with CLL and coexisting conditions and resulted in a significantly higher percentage of patients with PFS than standard treatment with chlorambucil–obinutuzumab.

Shanafelt et al. 2019 [39]

To evaluate the efficacy and safety of treatment with ibrutinib in combination with rituximab, as compared with FCR, in previously untreated patients with CLL

Rai stage 0-II and III/IV

No

PFS; HR: 0.35

OS; HR: 0.17

Targeted therapy with ibrutinib improved 3-year PFS and OS as compared to standard chemoimmunotherapy in patients with previously untreated CLL

Sharman et al. 2020 [50]

To compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment naive CLL

Rai stage 0/I/II and III/IV

No

Primary comparison – PFS; HR: 0.1, OS; HR: 0.47

Secondary comparison

PFS; HR: 0.2, OS: HR: 0.60

In patients with treatment-naive CLL, acalabrutinib with or without obinutuzumab improved progression-free survival over chemoimmunotherapy

Ghia et al. 2020 [41]

Americas, Europe, Middle East, Pacific Asia

To compare the efficacy and safety of acalabrutinib monotherapy versus investigator’s choice (I-R or B-R) in patients with R/R CLL

Rai stage III/IV

No

PFS; HR:0.31,

OS; HR: 0.84

Acalabrutinib monotherapy significantly improved PFS compared with I-R or B-R in patients with R/R CLL. The benefit was shown in all prespecified subgroup analyses, including patients with high-risk genomic features, such as del(17p) plus TP53 mutation, del(11q), unmutated IGHV, as well as in prespecified analyses by baseline demographic and clinical characteristics