The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

Translational Relevance

In chronic lymphocytic leukemia (CLL), although outcomes for patients have been dramatically improved, patients treated with prior BTK and BCL2 inhibitor-based therapy represent a new population with significant unmet need. Despite improved outcomes, the two most common reasons for discontinuation of these agents include drug resistance or intolerance. To date, no agent has clearly demonstrated efficacy in patients with double refractory CLL [i.e., resistant to both BTKi (BTK inhibitor) and venetoclax]. Nearly all of the patients with CLL enrolled on prior randomized studies of BTKis, PI3K inhibitors (PI3Ki), and venetoclax were conducted in patients who were BTKi and BCL2 inhibitor naïve and therefore do not represent patients in clinical practice—defining the true unmet need in CLL. Although randomized studies have an important role in generating evidence for CLL therapies, we also recognize that to our knowledge nearly all randomized phase 3 studies conducted in CLL in the last 10 years have used chemotherapy, an anti-CD20 antibody, or the combination of these agents as the comparator arm. Here, we offer our perspective on how best to define unmet needs in a modern treatment context. We review the literature with a focus on agents such as PI3Kis and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities for key stakeholders to ensure the continued innovation our patients deserve. We believe that this perspective will help to initiate a conversation among our community and key stakeholders as to how to best and most rapidly advance innovation for our patients in need.

The management paradigm for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has undergone unprecedented changes over the last decade resulting in radically improved outcomes for patients (1, 2). The previous cornerstone of treatment, cytotoxic chemotherapy, resulted in remission for many patients but also short- and long-term treatment-related morbidities (3). For patients with poor risk disease biology these remissions were short lived (4, 5). By comparison, patients can now expect to be treated sequentially with targeted therapies that are both better tolerated, orally administered, and markedly more efficacious (6–10). Despite the dramatically improved outcomes modern targeted therapies have yielded, these agents have now been incorporated into routine clinical practice for a long enough time that patients have begun to develop resistance or intolerance to multiple classes (11–17). These patients represent a new and rapidly growing frontier of unmet medical need in CLL/SLL. Ensuring continued progress for patients with CLL/SLL will require increased focus on this emerging group of patients treated with multiple classes of targeted therapy. Here, we focus on how best to define unmet needs in a modern treatment context and suggest opportunities for key stakeholders/caregivers to ensure the continued innovation our patients deserve.

Three new classes of targeted agents have been approved for CLL/SLL globally in the last 10 years. These include the BTK inhibitors (BTKi; ibrutinib, acalabrutinib, and zanubrutinib), a BCL2 inhibitor (venetoclax), and the PI3K inhibitors (PI3Ki; idelalisib and duvelisib; refs. 6–8, 10). Of these three classes, BTKis and venetoclax-based therapy, sometimes combined with anti-CD20 antibodies, are supplanting chemoimmunotherapy (CIT), whereas PI3Kis are typically reserved for later lines of treatment (1, 18–20). Although ibrutinib and venetoclax were initially approved in CLL/SLL based on the results from single-arm studies in high-risk patients, use of these agents since then has been primarily guided by randomized Phase 3 clinical trials (7, 10, 11, 21–24). Although these studies have provided insights into the efficacy and safety of these drugs, critical evaluation of these studies also reveals important areas of ongoing uncertainty.

Ibrutinib-based therapy has demonstrated superior outcomes [either PFS (progression-free survival), overall survival or both] compared with those seen with ofatumumab, chlorambucil, fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR), and chlorambucil/obinutuzumab (CO) in five Phase 3 studies (22, 25–28). The more selective BTKi acalabrutinib has demonstrated superior outcomes over those seen with CO and investigators choice of idelalisib/rituximab or BR in two randomized Phase 3 studies (23, 29). Venetoclax-based therapy has demonstrated superior outcomes over those seen with CO and BR in 2 randomized studies (21, 30). Finally, idelalisib/rituximab and duvelisib have demonstrated improvements over those seen with rituximab and ofatumumab, respectively (31, 32). With the exception of the ASCEND study (acalabrutinib vs. idelalisib/rituximab; ref. 29), common among these 11 randomized trials is a comparison of modern targeted therapy with chemotherapy, an anti-CD20 antibody, or both, as well as inclusion of patients naïve to targeted therapies.

Although CIT (FCR, BR, or CO) are still acceptable options in certain patients, most patients in North America and Western Europe are initially managed with either a BTKi, using a treat-to-progression strategy, or the combination of venetoclax–obinutuzumab for a fixed duration of 12 months (Fig. 1, Table 1; refs. 18, 33). In the next line of therapy, patients typically are either treated with a BTKi or venetoclax (either as continuous monotherapy or as 24-month fixed duration with rituximab), typically switching to the class of agent not used in the front-line setting, depending on the efficacy and tolerability of that agent (18, 33). In contemporary practice, BTKi and venetoclax-based therapy, administered in either sequence, collectively define standard first- and second-line treatment (34). Although the clinical activity of BTKis and venetoclax was established in pivotal studies that included patients naïve to the other drug class, smaller prospective Phase 2 studies and real-world data demonstrate previously unrecognized incomplete cross-resistance and intolerance between BTKis and venetoclax, allowing them to be administered in either order with sequential benefit (35–40). In addition, emerging data suggest that some patients may benefit from re-treatment with a venetoclax-based regimen, although large prospective cohort data supporting this practice are not yet available (41). Collectively, we estimate two classes of highly effective approved targeted therapy agents that typically provide patients with 10 or more years of effective disease control. However, neither class of agent is given with curative intent and some patients will derive less profound benefit due to early progression or intolerance. Therefore, ultimately many patients treated with a BTKi and venetoclax will still require subsequent therapy. Efforts to extend clinical benefit and provide time off therapy have focused on combinations of BTKis and venetoclax, which are now currently being evaluated in multiple Phase 3 studies (NCT04608318, NCT03701282, NCT03836261, NCT03737981, and NCT03462719). Although there is optimism that patients will enjoy long remissions after combined BTKi and venetoclax therapy administered on a fixed-duration schedule, limited information exists regarding the sequencing of novel agents following such combinations or the clinical efficacy of retreatment strategies.”

Figure 1.

Chemotherapy-free sequencing algorithms for patients with CLL/SLL in modern clinical practice with current unmet needs.

Figure 1.

Chemotherapy-free sequencing algorithms for patients with CLL/SLL in modern clinical practice with current unmet needs.

Close modal
Table 1.

Randomized studies of covalent BTKis, venetoclax, and PI3Kis.

Study nameDisease settingActive armComparatorPrior BTK (%)Prior BCL2 (%)Patients (N)Hazard ratio
RESONATE (26R/R Ibrutinib CD20 391 0.22 
RESONATE (26R/R (17p) Ibrutinib CD20 127 0.25 
HELIOS (11R/R Ibrutinib + Chemo + CD20 Chemo + CD20 578 0.20 
RESONATE-2 (251L Ibrutinib Chemo 269 0.16 
iLLUMINATE (221L Ibrutinib + CD20 Chemo + CD20 229 0.23 
E1912 (281L Ibrutinib + CD20 FCR 529 0.34 
ASCEND (29R/R Acalabrutinib Chemo + CD20 OR PI3K + CD20 310 0.31 
ELEVATE-TN (231L Acalabrutinib Acalabrutinib + CD20 Chemo + CD20 535 0.20 0.10 
MURANO (30R/R Venetoclax + CD20 Chemo + CD20 <2% 389 0.17 
CLL-14 1L Venetoclax + CD20 Chemo + CD20 432 0.35 
NA R/R Idelalisib + CD20 CD20 220 0.15 
DUO (31R/R Duvelisib CD20 319 0.52 
Study nameDisease settingActive armComparatorPrior BTK (%)Prior BCL2 (%)Patients (N)Hazard ratio
RESONATE (26R/R Ibrutinib CD20 391 0.22 
RESONATE (26R/R (17p) Ibrutinib CD20 127 0.25 
HELIOS (11R/R Ibrutinib + Chemo + CD20 Chemo + CD20 578 0.20 
RESONATE-2 (251L Ibrutinib Chemo 269 0.16 
iLLUMINATE (221L Ibrutinib + CD20 Chemo + CD20 229 0.23 
E1912 (281L Ibrutinib + CD20 FCR 529 0.34 
ASCEND (29R/R Acalabrutinib Chemo + CD20 OR PI3K + CD20 310 0.31 
ELEVATE-TN (231L Acalabrutinib Acalabrutinib + CD20 Chemo + CD20 535 0.20 0.10 
MURANO (30R/R Venetoclax + CD20 Chemo + CD20 <2% 389 0.17 
CLL-14 1L Venetoclax + CD20 Chemo + CD20 432 0.35 
NA R/R Idelalisib + CD20 CD20 220 0.15 
DUO (31R/R Duvelisib CD20 319 0.52 

Despite the many randomized Phase 3 trials that have led to these current treatment paradigms, significant unanswered questions remain. Head-to-head comparisons of BTKis with venetoclax-based approaches have been launched (NCT04608318, NCT05057494), although results are not available. Similarly, comparisons among BTKis have been undertaken and are recently reported as abstracts at the ASCO and EHA 2021 meetings. Importantly, the studies evaluating head-to-head comparisons of modern targeted therapies may not address key outstanding questions in terms of efficacy due to their study designs/primary endpoints that include non-inferiority for PFS in the ELEVTAE R/R and overall response rate in the ALPINE study. In addition, in terms of safety these studies demonstrate differences in safety profiles that do not definitely favor any agent over another (acalabrutinib vs. ibrutinib, zanubrutinib vs. ibrutinib) with the notable exception of cardiovascular events (42, 43). Collectively, these data gaps mean that the optimal sequencing and selection among available BTKis and venetoclax remain undefined (44). Perhaps most importantly, we still do not understand the true efficacy of available therapies in the patient population increasingly seen in our clinics today—namely those who have been previously treated with BTKis, venetoclax, or both. Indeed, it is remarkable to note that only 9 of 921 (∼1%) patients treated on 6 recent randomized studies in relapsed/refractory CLL/SLL were previously treated with at least one targeted therapy and likely none on a truly contemporary chemotherapy-free treatment (41). In short, although the randomized datasets upon which we base our current practice have yielded an impressive armamentarium of agents among which to select for our patients, these same studies have not taught us the true efficacy of these agents in the relapsed/refractory patient population that constitute the majority of patients currently seen in everyday practice.

Available therapy for patients previously exposed to both BTKis and venetoclax generally include the PI3Kis, cytotoxic chemotherapy, alemtuzumab, single-agent anti-CD20 antibodies, and allogeneic stem cell transplantation (in highly selected patients; ref. 45). Unfortunately, studies evaluating these agents or their combinations have been exclusively conducted in patients naïve to BTKis and venetoclax and as a result their safety and especially their efficacy in patients treated on a pathway that includes a BTKi and venetoclax remain unknown. Data from limited published anecdotal and retrospective case series suggest that these available therapies have limited efficacy following treatment with BTKis, venetoclax, or both (20, 38, 46).

The two pivotal studies with the PI3Kis, idelalisib and duvelisib, illustrate the challenge of applying data generated from these studies to a treatment context now dominated by use of BTKis and venetoclax (6, 31). As mentioned, no patients in these randomized studies were previously treated with a BTKi or venetoclax. Moreover, both studies used single anti-CD20 antibody monotherapies as the comparator arm, a treatment approach known to have limited efficacy in CLL/SLL. Consequently, the results of these studies cannot be used to guide treatment decisions in patients previously treated on a chemotherapy-free paradigm (41). In addition, several real-world datasets suggest that the PI3Ki class has limited effectiveness in patients who are venetoclax naïve and previously treated with BTKis (possibly due to cross resistance) or have been treated with both a BTKi and venetoclax in earlier lines of therapy. Specifically, in 17 patients who had been exposed to a prior BTKi and venetoclax, the ORR was 47% with median PFS of only 5 months (38).

The adoption of currently approved PI3Kis into contemporary treatment has also been severely limited by significant immune-mediated toxicities and infectious complications resulting in high discontinuation rates. In the Phase 3 study that compared acalabrutinib with the PI3Ki idelalisib with rituximab, 47% of the 119 patients who received idelalisib plus rituximab discontinued treatment before disease progression due to adverse events (median time on therapy 11.5 months; ref. 29). Consistent with these clinical trial data, real-world data similarly confirm discontinuation rates with PI3Kis ranging from 40% to 95%, again predominantly due to AEs. Although real-world data are not yet available for duvelisib, the discontinuation rate from the Phase 3 DUO trial was 77%, with 27% of patients discontinuing due to adverse events (31). Given these collective data, we do not consider PI3Kis a sufficiently effective standard option for patients with disease previously treated with BTK and venetoclax. As the number of patients with CLL treated with venetoclax and BTKis will continue to increase with time, novel effective therapies for this patient population are urgently needed.

Another key data gap is the lack of any studies that have evaluated CIT following progression on either BTKis or BTKis/venetoclax; neither clinical trial data nor real-world data exist to answer this question. Again, anecdotal experience and small real-world series suggest that CIT would have an extremely limited role in non-transformed patients previously treated with multiple targeted therapies in an earlier line of therapy; CIT is used with transformed disease (Richter syndrome; ref. 47). As with patients previously treated with CIT, these patients tend to have more aggressive disease characterized by resistance mutations or TP53 aberrancy, the latter predicts for reduced efficacy of CIT (48). Furthermore, older prospective Phase 2 trials and randomized trials of CIT in the second or later treatment line setting after prior CIT have typically shown relatively modest PFS (i.e., on the order of two years or less; refs. 49, 50). In the absence of convincing data at this time, we cannot counsel or encourage the use of chemotherapy or CIT as an established standard of care (particularly if the CLL clone has acquired poor risk molecular/genetic features) for patients treated with one or more targeted therapies as earlier lines of therapy. As efficacy of CIT following BTKis or BTKis/venetoclax is not available, prospective studies will need to be conducted to assess whether CIT is a valid standard of care or as a control arm in future randomized studies in this setting.

After a decade of unprecedented innovation driven largely by the adoption of BTKis and venetoclax that have collectively transformed the treatment landscape and outcomes for patients with CLL/SLL, we are now seeing a growing population of patients who are in need of new therapeutic options following treatment with both of these novel targeted agents. These patients lack therapeutic options with proven efficacy and safety following treatment with a BTKi and venetoclax and, as such, constitute the vanguard of contemporary unmet need for this disease. Achieving the next round of breakthroughs for these patients will once again require close collaboration between all key stakeholders, including the patient community, clinical investigators, the pharmaceutical industry, and global regulatory bodies. This progress begins by simply acknowledging that after a decade of enormous progress, we once again have patients with CLL/SLL with unmet medical need. These patients can be readily identified and should be preferentially enrolled into clinical trials. Progress will certainly require biologic insight into resistance mechanisms to BTKis and venetoclax. Equally importantly, however, progress will also require consensus on key aspects of new drug development for this patient population. Importantly, as new agents are developed in this population, we must determine what absolute effect size is meaningful, as measured using objective endpoints. The urgency is real, but so is the promise. We believe that further dramatic progress in CLL therapy is not only possible but imminent—the time for collective action is now.

A.P. Kater reports grants and other support from Janssen, AbbVie, BMS, Roche, and AstraZeneca and other support from Lava outside the submitted work. J. Rhodes reports personal fees from Pharmacyclics, AstraZeneca, Beigene, SeaGen, TG Therapeutics, AbbVie, Genentech, and Verastem and other support from LOXO outside the submitted work. S.J. Schuster reports grants and personal fees from Acerta, AbbVie, Celgene, Genentech/Roche, Novartis, Incyte, and Juno Therapeutics; personal fees from AstraZeneca, BeiGene, Janssen, Morphosys, Regeneron, Legend Biotech, Mustang Biotech, Nordic Nanovector, and AlloGene; and grants from Merck and TG Therapeutics outside the submitted work. C.S. Tam reports other support from Beigene, Janssen, and AbbVie during the conduct of the study. S. O'Brien reports other support from AbbVie, Acerta, Alexion, Amgen, Aptose Biosciences Inc., Astellas, Autolus, Bristol Myers Squibb, Caribou, Celgene, DynaMed, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, Kite, MEI Pharma Inc., Merck, NOVA Research Company, Pfizer, PCYC, Regeneron, Sunesis, TG Therapeutics, Vaniam Group LLC, Verastem, and Vida Ventures during the conduct of the study. N. Lamanna reports grants and personal fees from AbbVie, AstraZeneca, BeiGene, Genentech, Juno, and Eli Lilly/Loxo; personal fees from Janssen and Pharmacyclics; and grants from Oncternal, Octapharma, MingSight, TG Therapeutics outside the submitted work. C. Sun reports grants from Genmab outside the submitted work. M. Shadman reports personal fees from AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, and Atara Biotherapeutics and grants from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, and GenMab outside the submitted work. J.M. Pagel reports other support from Gilead, AstraZeneca, Beigene, and Incyte outside the submitted work. C. Ujjani reports personal fees from Atara, Epizyme, AbbVie, Pharmacyclics, Janssen, TG Therapeutics, Beigene, Incyte, Eli Lilly, Adaptive Therapeutics, Adaptive Biotechnologies, AstraZeneca, Morphosys, Gilead, and Verastem outside the submitted work. N. Jain reports grants, personal fees, and non-financial support from Pharmacyclics, AbbVie, Genentech, AstraZeneca, Servier, ADC Therapeutics, Cellectis, Precision Biosciences, and Janssen; grants and non-financial support from BMS, Pfizer, Incyte, Fate Therapeutics, Mingsight, Takeda, Medisix, and Loxo Oncology; grants and personal fees from Adaptive Biotechnologies; grants from Aprea Therapeutics and Novalgen; and personal fees from Beigene, TG Therapeutics, MEI Pharma, and CareDx outside the submitted work. C.Y. Cheah reports grants and personal fees from Roche, BMS, and MSD; grants from AbbVie; and personal fees from Loxo at Lilly, TG Therapeutics, AstraZeneca, Novartis, Gilead, and Janssen during the conduct of the study. No disclosures were reported by the other authors.

The authors would like to thank Dr. D. Hyman for his comments and insight and LOXO Oncology for editorial support in submitting this article, which did not include writing. We also thank Camilla Pena and Dr. J. Aronson for academic and editorial support.

1.
Schiattone
L
,
Ghia
P
,
Scarfò
L
.
The evolving treatment landscape of chronic lymphocytic leukemia
.
Curr Opin Oncol
2019
;
31
:
568
73
.
2.
Sengar
M
,
Jain
H
,
Rajendra
A
,
Rengaraj
K
,
Thorat
J
.
Frontline therapy of chronic lymphocytic leukemia: changing treatment paradigm
.
Curr Hematol Malig Rep
2020
;
15
:
168
76
.
3.
Fischer
K
,
Bahlo
J
,
Fink
AM
,
Goede
V
,
Herling
CD
,
Cramer
P
, et al
.
Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial
.
Blood
2016
;
127
:
208
15
.
4.
Stilgenbauer
S
,
Schnaiter
A
,
Paschka
P
,
Zenz
T
,
Rossi
M
,
Döhner
K
, et al
.
Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial
.
Blood
2014
;
123
:
3247
54
.
5.
Zenz
T
,
Eichhorst
B
,
Busch
R
,
Denzel
T
,
Häbe
S
,
Winkler
D
, et al
.
TP53 mutation and survival in chronic lymphocytic leukemia
.
J Clin Oncol
2010
;
28
:
4473
9
.
6.
Brown
JR
,
Byrd
JC
,
Coutre
SE
,
Benson
DM
,
Flinn
IW
,
Wagner-Johnston
ND
, et al
.
Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia
.
Blood
2014
;
123
:
3390
7
.
7.
Byrd
JC
,
Furman
RR
,
Coutre
SE
,
Flinn
IW
,
Burger
JA
,
Blum
KA
, et al
.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia
.
N Engl J Med
2013
;
369
:
32
42
.
8.
Byrd
JC
,
Harrington
B
,
O'Brien
S
,
Jones
JA
,
Schuh
A
,
Devereux
S
, et al
.
Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia
.
N Engl J Med
2016
;
374
:
323
32
.
9.
Frustaci
AM
,
Tedeschi
A
,
Deodato
M
,
Zamprogna
G
,
Cairoli
R
,
Montillo
M
.
Duvelisib for the treatment of chronic lymphocytic leukemia
.
Expert Opin Pharmacother
2020
;
21
:
1299
309
.
10.
Roberts
AW
,
Davids
MS
,
Pagel
JM
,
Kahl
BS
,
Puvvada
SD
,
Gerecitano
JF
, et al
.
Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia
.
N Engl J Med
2016
;
374
:
311
22
.
11.
Fraser
GAM
,
Chanan-Khan
A
,
Demirkan
F
,
Silva
RS
,
Grosicki
S
,
Janssens
A
, et al
.
Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma
.
Leuk Lymphoma
2020
;
61
:
3188
97
.
12.
Kater
AP
,
Wu
JQ
,
Kipps
T
,
Eichhorst
B
,
Hillmen
P
,
D'Rozario
J
, et al
.
Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study
.
J Clin Oncol
2020
;
38
:
4042
54
.
13.
Lama
TG
,
Kyung
D
,
O'Brien
S
.
Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies
.
Expert Rev Hematol
2020
;
13
:
871
83
.
14.
Munir
T
,
Brown
JR
,
O'Brien
S
,
Barrientos
JC
,
Barr
PM
,
Reddy
NM
, et al
.
Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma
.
Am J Hematol
2019
;
94
:
1353
63
.
15.
Ondrisova
L
,
Mraz
M
.
Genetic and non-genetic mechanisms of resistance to BCR signaling inhibitors in B-cell malignancies
.
Front Oncol
2020
;
10
:
591577
.
16.
Sharman
JP
,
Coutre
SE
,
Furman
RR
,
Cheson
BD
,
Pagel
JM
,
Hillmen
P
, et al
.
Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia
.
J Clin Oncol
2019
;
37
:
1391
402
.
17.
Coutre
SE
,
Byrd
JC
,
Hillmen
P
,
Barrientos
JC
,
Barr
PM
,
Devereux
S
, et al
.
Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies
.
Blood Adv
2019
;
3
:
1799
807
.
18.
Eichhorst
B
,
Robak
T
,
Montserrat
E
,
Ghia
P
,
Niemann
CU
,
Kater
AP
, et al
.
Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
.
Ann Oncol
2021
;
32
:
23
33
.
19.
Eyre
TA
,
Lamanna
N
,
Roeker
LE
,
Ujjani
CS
,
Hill
BT
,
Barr
PM
, et al
.
Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia
.
Haematologica
2021
;
106
:
284
7
.
20.
Mato
AR
,
Hill
BT
,
Lamanna
N
,
Barr
PM
,
Ujjani
CS
,
Brander
DM
, et al
.
Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients
.
Ann Oncol
2017
;
28
:
1050
6
.
21.
Al-Sawaf
O
,
Zhang
C
,
Tandon
M
,
Sinha
A
,
Fink
AM
,
Robrecht
S
, et al
.
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial
.
Lancet Oncol
2020
;
21
:
1188
200
.
22.
Moreno
C
,
Greil
R
,
Demirkan
F
,
Tedeschi
A
,
Anz
B
,
Larratt
L
, et al
.
Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial
.
Lancet Oncol
2019
;
20
:
43
56
.
23.
Sharman
JP
,
Egyed
M
,
Jurczak
W
,
Skarbnik
A
,
Pagel
JM
,
Flinn
IW
, et al
.
Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial
.
Lancet
2020
;
395
:
1278
91
.
24.
Stilgenbauer
S
,
Eichhorst
B
,
Schetelig
J
,
Coutre
S
,
Seymour
JF
,
Munir
T
, et al
.
Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study
.
Lancet Oncol
2016
;
17
:
768
78
.
25.
Burger
JA
,
Tedeschi
A
,
Barr
PM
,
Robak
T
,
Owen
C
,
Ghia
P
, et al
.
Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia
.
N Engl J Med
2015
;
373
:
2425
37
.
26.
Byrd
JC
,
Brown
JR
,
O'Brien
S
,
Barrientos
JC
,
Kay
NE
,
Reddy
NM
, et al
.
Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia
.
N Engl J Med
2014
;
371
:
213
23
.
27.
Chanan-Khan
A
,
Cramer
P
,
Demirkan
F
,
Fraser
G
,
Silva
RS
,
Grosicki
S
, et al
.
Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study
.
Lancet Oncol
2016
;
17
:
200
11
.
28.
Shanafelt
TD
,
Wang
XV
,
Kay
NE
,
Hanson
CA
,
O'Brien
S
,
Barrientos
J
, et al
.
Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia
.
N Engl J Med
2019
;
381
:
432
43
.
29.
Ghia
P
,
Pluta
A
,
Wach
M
,
Lysak
D
,
Kozak
T
,
Simkovic
M
, et al
.
ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia
.
J Clin Oncol
2020
;
38
:
2849
61
.
30.
Seymour
JF
,
Kipps
TJ
,
Eichhorst
B
,
Hillmen
P
,
D'Rozario
J
,
Assouline
S
, et al
.
Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia
.
N Engl J Med
2018
;
378
:
1107
20
.
31.
Flinn
IW
,
Hillmen
P
,
Montillo
M
,
Nagy
Z
,
Illés
Á
,
Etienne
G
, et al
.
The phase 3 DUO trial: duvelisib vs. ofatumumab in relapsed and refractory CLL/SLL
.
Blood
2018
;
132
:
2446
55
.
32.
Furman
RR
,
Sharman
JP
,
Coutre
SE
,
Cheson
BD
,
Pagel
JM
,
Hillmen
P
, et al
.
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia
.
N Engl J Med
2014
;
370
:
997
1007
.
33.
Wierda
WG
,
Byrd
JC
,
Abramson
JS
,
Bilgrami
SF
,
Bociek
G
,
Brander
D
, et al
.
Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2020, NCCN clinical practice guidelines in oncology
.
J Natl Compr Canc Netw
2020
;
18
:
185
217
.
34.
Mato
AR
,
Barrientos
JC
,
Ghosh
N
,
Pagel
JM
,
Brander
DM
,
Gutierrez
M
, et al
.
Prognostic testing and treatment patterns in chronic lymphocytic leukemia in the era of novel targeted therapies: results from the inform CLL registry
.
Clin Lymphoma Myeloma Leuk
2020
;
20
:
174
83
.
35.
Hampel
PJ
,
Call
TG
,
Ding
W
,
Muchtar
E
,
Kenderian
SS
,
Wang
Y
, et al
.
Addition of venetoclax at time of progression in ibrutinib-treated patients with chronic lymphocytic leukemia: combination therapy to prevent ibrutinib flare
.
Am J Hematol
2020
;
95
:
E57
e60
.
36.
Hillmen
P
,
Rawstron
AC
,
Brock
K
,
Muñoz-Vicente
S
,
Yates
FJ
,
Bishop
R
, et al
.
Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study
.
J Clin Oncol
2019
;
37
:
2722
9
.
37.
Jones
JA
,
Mato
AR
,
Wierda
WG
,
Davids
MS
,
Choi
M
,
Cheson
BD
, et al
.
Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial
.
Lancet Oncol
2018
;
19
:
65
75
.
38.
Mato
AR
,
Roeker
LE
,
Jacobs
R
,
Hill
BT
,
Lamanna
N
,
Brander
D
, et al
.
Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy
.
Clin Cancer Res
2020
;
26
:
3589
96
.
39.
Molica
S
,
Giannarelli
D
,
Montserrat
E
.
Comparison Between Venetoclax-based and bruton tyrosine kinase
inhibitor-based therapy as upfront treatment of chronic lymphocytic leukemia (CLL): a systematic review and network meta-analysis
.
Clin Lymphoma Myeloma Leuk
2021
;
21
:
216
23
.
40.
Rogers
KA
,
Huang
Y
,
Ruppert
AS
,
Abruzzo
LV
,
Andersen
BL
,
Awan
FT
, et al
.
Phase II study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naïve and relapsed or refractory chronic lymphocytic leukemia
.
J Clin Oncol
2020
;
38
:
3626
37
.
41.
Roeker
LE
,
Mato
AR
.
Approaches for relapsed CLL after chemotherapy-free frontline regimens
.
Hematology Am Soc Hematol Educ Program
2020
;
2020
:
10
7
.
42.
Hillmen
P
,
Brown
JR
,
Eichhorst
BF
,
Lamanna
N
,
O'Brien
SM
,
Qiu
L
, et al
.
ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma
.
Future Oncol
2020
;
16
:
517
23
.
43.
Byrd
JC
,
Hillmen
P
,
Ghia
P
,
Kater
AP
,
Chanan-Khan
AAA
,
Furman
RR
, et al
.
First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia
.
J Clin Oncol
2021
;
39
:
7500
.
44.
Lin
VS
,
Lew
TE
,
Handunnetti
SM
,
Blombery
P
,
Nguyen
T
,
Westerman
DA
, et al
.
BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax
.
Blood
2020
;
135
:
2266
70
.
45.
Rai
KR
,
Freter
CE
,
Mercier
RJ
,
Cooper
MR
,
Mitchell
BS
,
Stadtmauer
EA
, et al
.
Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine
.
J Clin Oncol
2002
;
20
:
3891
7
.
46.
Mato
AR
,
Nabhan
C
,
Barr
PM
,
Ujjani
CS
,
Hill
BT
,
Lamanna
N
, et al
.
Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience
.
Blood
2016
;
128
:
2199
205
.
47.
Khan
M
,
Siddiqi
R
,
Thompson
PA
.
Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies
.
Ann Hematol
2018
;
97
:
1
15
.
48.
Rossi
D
,
Spina
V
,
Deambrogi
C
,
Rasi
S
,
Laurenti
L
,
Stamatopoulos
K
, et al
.
The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation
.
Blood
2011
;
117
:
3391
401
.
49.
Badoux
XC
,
Keating
MJ
,
Wang
X
,
O'Brien
SM
,
Ferrajoli
A
,
Faderl
S
, et al
.
Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL
.
Blood
2011
;
117
:
3016
24
.
50.
Fischer
K
,
Cramer
P
,
Busch
R
,
Stilgenbauer
S
,
Bahlo
J
,
Schweighofer
CD
, et al
.
Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group
.
J Clin Oncol
2011
;
29
:
3559
66
.