Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial.

Experimental Design: We report the long-term outcome [median follow-up of 47 months (range, 36–51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated.

Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2–51 months), and median number of treatment cycles was 42 (range, 2–49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p (n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached.

Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 23(9); 2154–8. ©2016 AACR.

Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor with clinical activity in several B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (1). A series of clinical trials demonstrated a major improvement in progression-free (PFS) and overall survival (OS) in patients with CLL treated with ibrutinib in the first-line (2, 3) and the relapse-refractory (4, 5) disease setting. The advent of ibrutinib is especially significant for high-risk CLL patients, such as patients with 17p deletion, who generally do not achieve durable responses with chemo-immunotherapy. Three-year follow-up of a clinical trial with single-agent ibrutinib in relapsed-refractory and in treatment-naïve patients (age ≥ 65 years) demonstrated durable responses and an acceptable safety profile with continued long-term therapy in the majority of patients (6). However, with ibrutinib single-agent use, most patients, even after long-term therapy, achieve partial remissions, and complete remissions remain the exception. Therefore, ibrutinib combination therapy has been pursued in a number of clinical trials. We previously reported the results of a phase II trial of the combination of ibrutinib with rituximab (IR) in patients with high-risk CLL (7), which was the first trial to report ibrutinib combination therapy data. In this trial, we demonstrated that the addition of rituximab attenuated the redistribution lymphocytosis observed in studies with single-agent ibrutinib in patients with CLL, which often results in partial remission (PR) with lymphocytosis, and consequently, patients achieved remissions within a shorter time. However, the long-term impact of IR on survival, response, immunologic parameters, and the toxicities in patients with high-risk CLL has not been characterized (8). In this report, we describe the long-term follow-up data of IR in patients with high-risk CLL.

This single-arm phase II study in high-risk patients with CLL (n = 40) treated with ibrutinib and rituximab (IR) was developed by the investigators in collaboration and supported by Pharmacyclics, Inc. and was approved by The University of Texas MD Anderson Cancer Center Institutional Review Board. Informed consent was obtained in accordance with institutional guidelines and the Declaration of Helsinki. Patients with high-risk CLL included patients with the presence of a 17p deletion, TP53 mutation, and/or 11q deletion and patients with short remission durations of <36 months after first-line treatment with chemo-immunotherapy. Details of the inclusion, exclusion criteria, study design, follow-up, and response assessment were reported previously (7). Treatment consisted of ibrutinib (420 mg orally daily) combined with weekly rituximab (375 mg/m2) for weeks 1 to 4 (cycle 1), then monthly rituximab until cycle 6, followed by single-agent ibrutinib continuously. Patients remained on ibrutinib treatment until disease progression or toxicities or complications precluded further therapy. The primary endpoint was to assess the activity of ibrutinib and rituximab in high-risk CLL, measured as overall response rate (ORR) and PFS. Statistical analyses were conducted using GraphPad Prism Version 6.00 for Windows (GraphPad Software). Survival or time to progression function was estimated using the Kaplan–Meier method. Toxicity was reported by the type, frequency, and severity.

Patients and treatment

Previously untreated (n = 4, all with del17p) and previously treated (n = 36) patients were included in the study. The clinical characteristics of the patients are described in Table 1. Eleven patients (27%) were over the age of 70 years. Twenty-one patients had del17p FISH cytogenetic aberration, and 12 patients had del11q. Thirty-three patients had unmutated immunoglobulin heavy chain variable region genes (IGHV), one patient had mutated IGHV, and six patients had inconclusive IGHV status. Median follow-up of the patients was 47 months (range, 36–51 months). At the time of last follow-up, 19 patients (47%) remained on treatment (6 with del17p), and 21 (52%) had discontinued treatment, 10 due to disease progression, 9 due to other complications, and 2 patients underwent stem cell transplantation in response. Causes of treatment discontinuation, death, and clinical characteristics are detailed in Table 2. Of note, among the four previously untreated patients with CLL with del17p, two patients are still continuing on study, and two discontinued treatment, one due to complicated ear infections and ear bleeding and another due to significant arthralgias, enthesitis, and bruising. Among these four patients, three were alive, and one died from disease progression approximately 2 months after discontinuation of ibrutinib. Among the 10 patients who discontinued due to disease progression, 2 patients developed Richter transformation, both with del17p. Thirteen patients (46%) had complex karyotype, and disease progression was more frequent within this subgroup (in 7/13 or 54% of these patients). Overall, the median number of cycles received by the patients was 42. The majority of patients (38/40 or 95%) received ≥6 cycles of therapy. The median dose of ibrutinib was 420 mg daily. Median duration of ibrutinib therapy was 41 months (range, 2–51 months). Among the 21 patients who came off therapy, the median survival after treatment discontinuation was 8 months. The best ORR was 95%, with 28 patients (72%) achieving a PR, 9 (23%) a complete remission (CR), 2 patients did not respond, and 1 patient was not evaluable. Of the 9 patients with CR, 2 patients achieved a minimal residual disease (MRD) negative CR. The CR rate improved from 4 patients (10%) reported initially (7) to 9 patients (23%) with the longer follow-up, which is consistent with the single-agent ibrutinib experience and longer follow-up (6). Among the 21 patients with del17p, 18 of 21 responded (86%), 5 achieved a CR (24%), and 13 a PR (62%). Among the four patients who were previously untreated and had del17p, three (75%) achieved a CR (two were MRD negative), and one patient a PR. The toxicities that were considered to be likely related to IR treatment are displayed in the Supplementary Table S1. Overall, we noted that 16 patients (40%) developed clinically significant infections, requiring therapy, involving the upper respiratory tract and/or the lungs. Overall, 14 patients died, 5 while being on study, 3 due to complicated infections, 1 had a sudden death without antecedent illness, presumed cardiac, and 1 patient from metastatic non–small cell lung cancer. Figure 1A–D shows the PFS and OS. Overall, the median PFS was 45 months, and the median OS was not reached. The number of events and deaths were higher in patients with del17p, resulting in a significantly shorter PFS and shorter OS in patients with del17p (PFS, P = 0.02; OS, P = 0.24; Fig. 1B–D). The median PFS of patients with del17p was 32.3 months. Similarly, patients with complex karyotype abnormalities, which constitutes another high-risk subset of patients, had shorter PFS or OS (Fig. 2A and B); however, these differences did not reach statistical significance. In a subset analysis, among the patients with del17p (n = 21), the PFS and OS were not significantly different according to the presence (n = 11) or absence of complex karyotype (n = 4) (Supplementary Fig. S1). This could be due to smaller number of patients in each group and require large dataset for the analysis.

Figure 1.

Survival outcomes for patients treated with IR, PFS and OS after a median follow-up of 42 months. A, Median PFS in all patients was 45 months. B, PFS according to the presence or absence of deletion 17p; median survival not reached in patients without deletion 17p and median PFS 32 months in patients with deletion 17p (P = 0.02). C, Median OS in all patients was not reached. D, OS according to the presence or absence of deletion 17p; median survival not reached in both group of patients with/without deletion 17p (P = 0.24).

Figure 1.

Survival outcomes for patients treated with IR, PFS and OS after a median follow-up of 42 months. A, Median PFS in all patients was 45 months. B, PFS according to the presence or absence of deletion 17p; median survival not reached in patients without deletion 17p and median PFS 32 months in patients with deletion 17p (P = 0.02). C, Median OS in all patients was not reached. D, OS according to the presence or absence of deletion 17p; median survival not reached in both group of patients with/without deletion 17p (P = 0.24).

Close modal
Figure 2.

Survival outcomes for patients treated with IR, complex versus noncomplex karyotype. A, Median PFS in patients with complex versus noncomplex karyotype was 31.8 months versus not reached (P = 0.76). B, OS according to the presence or absence of complex karyotype; median survival not reached in both group of patients (P = 0.67).

Figure 2.

Survival outcomes for patients treated with IR, complex versus noncomplex karyotype. A, Median PFS in patients with complex versus noncomplex karyotype was 31.8 months versus not reached (P = 0.76). B, OS according to the presence or absence of complex karyotype; median survival not reached in both group of patients (P = 0.67).

Close modal
Table 1.

Initial patient characteristics (N = 40)

Patients (N = 40)
Median age (range) 65 (35–82) 
Female 14 (35%) 
Male 26 (65%) 
Del (17p)a 21 (52%) 
Del (11q) 12 (30%) 
Del (13q) 5 (12.5%) 
FISH negative 2 (5%) 
Mutation status IGVH (immunoglobulin heavy chain variable region) Unmutated (33), not done (6), mutated (1) 
 Median (range) 
Prior treatments 2.0 (0–8) 
Cycles completed 42 (2–49) 
Median follow-up time of alive patients (months) 47 (36–51) 
Hemoglobin (g/dL) 11.7 (6.7–15.6) 
Platelets (103/μL) 91.5 (36–242) 
White blood cell count (103/μL) 22.4 (2.2–297.8) 
Absolute lymphocytes (103/μL) 19.9 (0.4–277) 
Patients (N = 40)
Median age (range) 65 (35–82) 
Female 14 (35%) 
Male 26 (65%) 
Del (17p)a 21 (52%) 
Del (11q) 12 (30%) 
Del (13q) 5 (12.5%) 
FISH negative 2 (5%) 
Mutation status IGVH (immunoglobulin heavy chain variable region) Unmutated (33), not done (6), mutated (1) 
 Median (range) 
Prior treatments 2.0 (0–8) 
Cycles completed 42 (2–49) 
Median follow-up time of alive patients (months) 47 (36–51) 
Hemoglobin (g/dL) 11.7 (6.7–15.6) 
Platelets (103/μL) 91.5 (36–242) 
White blood cell count (103/μL) 22.4 (2.2–297.8) 
Absolute lymphocytes (103/μL) 19.9 (0.4–277) 

aOverall, among the 40 patients, 21 were del17p by FISH, of which only 3 were del17p alone, and the distribution of other FISH abnormalities in the remaining 18 patients was as follows: 1 with del11q, 1 with 11q and trisomy 12, 2 with trisomy 12, 6 with del11q and del13q, and 8 with del13q. Similarly, there were 12 patients with del11q (without del17p), of which only 4 were del11q alone and 8 were del11q with del13q.

Table 2.

Summary of causes of discontinuation of ibrutinib with rituximab (IR) with patient characteristics (n = 21)

Patient characteristics
Age (y)GenderFISH#IGHV mutation statusCause of discontinuationType of complicationDuration of ibrutinib (months)Salvage treatmentSurvival statusOn study death (Y/N)Post-IR survival (months)Causes of deathDisease transformation (Y/N)
65 Male Neg. UM Stem cell transplant None 12.6 Unknown Dead 4.5 Disease progression No 
63 Female 17p UM Stem cell transplant None 14.9 None Alive 23.4 — No 
62 Male 17p UM Complications Ear infections 16.8 — Dead 0.0 Pulmonary complications No 
67 Male 11q UM Complications Unknown, found dead in his sleep 16.4 — Dead 0.0 Unknown No 
61 Male 17p UM Complications Pulmonary infections 9.5 — Dead 1.5 Pulmonary infections No 
68 Male 11q UM Complications Diarrhea, subdural hematoma 21.5 Restarted ibrutinib Alive 14.8 — No 
72 Male 11q UM Complications Progressive lung cancer 31.8 On ibrutinib Dead 0.0 Lung cancer No 
76 Male 17p UM Complications Multifocal aspergillosis 2.1 — Dead 0.2 Pneumonia, brain abscess No 
57 Female 17p Complications Mucositis 6.0 OFAR, ibrutinib restarted Dead 18.5 Sepsis No 
82 Male 17p UM Complications Comp-CHF, COPD 8.4 — Dead 3.9 CHF, COPD No 
61 Female 17p UM Complications Toxicity-arthritis 45 Planning Alive — No 
73 Female 17p UM Disease progression — 14.4 Rituximab Died 1.4 Resistant disease No 
58 Male 17p UM Disease progression — 34.3 Idelalisib + rituximab Alive 4.2 — No 
52 Male 13q UM Disease progression — 21.4 ABT-199, HCVAD, idelalisib Died 15.8 Resistant disease with TP53 acquisition No 
35 Female 11q UM Disease progression — 6.8 — Died 2.1 Pneumonia No 
76 Female 17p UM Disease progression — 45.1 Ibrutinib with BR Alive 0.0 — No 
65 Female 17p UM Disease progression — 13.1 R-MP then IPI-145 Died 2.5 Progressive disease Yes 
73 Female 17p UM Disease progression — 32.3 Expt. agents Died 8.6 Infections No 
73 Female 17p UM Disease progression — 21.9 ABT-199 Died 3.1 Progressive disease Yes 
78 Female 17p UM Disease progression — 22.5 Ofatumumab Alive 20.0 — No 
65 Male 17p ND Disease progression — 47.1 Venetoclax Alive 2.9 — No 
Patient characteristics
Age (y)GenderFISH#IGHV mutation statusCause of discontinuationType of complicationDuration of ibrutinib (months)Salvage treatmentSurvival statusOn study death (Y/N)Post-IR survival (months)Causes of deathDisease transformation (Y/N)
65 Male Neg. UM Stem cell transplant None 12.6 Unknown Dead 4.5 Disease progression No 
63 Female 17p UM Stem cell transplant None 14.9 None Alive 23.4 — No 
62 Male 17p UM Complications Ear infections 16.8 — Dead 0.0 Pulmonary complications No 
67 Male 11q UM Complications Unknown, found dead in his sleep 16.4 — Dead 0.0 Unknown No 
61 Male 17p UM Complications Pulmonary infections 9.5 — Dead 1.5 Pulmonary infections No 
68 Male 11q UM Complications Diarrhea, subdural hematoma 21.5 Restarted ibrutinib Alive 14.8 — No 
72 Male 11q UM Complications Progressive lung cancer 31.8 On ibrutinib Dead 0.0 Lung cancer No 
76 Male 17p UM Complications Multifocal aspergillosis 2.1 — Dead 0.2 Pneumonia, brain abscess No 
57 Female 17p Complications Mucositis 6.0 OFAR, ibrutinib restarted Dead 18.5 Sepsis No 
82 Male 17p UM Complications Comp-CHF, COPD 8.4 — Dead 3.9 CHF, COPD No 
61 Female 17p UM Complications Toxicity-arthritis 45 Planning Alive — No 
73 Female 17p UM Disease progression — 14.4 Rituximab Died 1.4 Resistant disease No 
58 Male 17p UM Disease progression — 34.3 Idelalisib + rituximab Alive 4.2 — No 
52 Male 13q UM Disease progression — 21.4 ABT-199, HCVAD, idelalisib Died 15.8 Resistant disease with TP53 acquisition No 
35 Female 11q UM Disease progression — 6.8 — Died 2.1 Pneumonia No 
76 Female 17p UM Disease progression — 45.1 Ibrutinib with BR Alive 0.0 — No 
65 Female 17p UM Disease progression — 13.1 R-MP then IPI-145 Died 2.5 Progressive disease Yes 
73 Female 17p UM Disease progression — 32.3 Expt. agents Died 8.6 Infections No 
73 Female 17p UM Disease progression — 21.9 ABT-199 Died 3.1 Progressive disease Yes 
78 Female 17p UM Disease progression — 22.5 Ofatumumab Alive 20.0 — No 
65 Male 17p ND Disease progression — 47.1 Venetoclax Alive 2.9 — No 

Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; HCVAD, hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone); M, mutated; ND, not detected; OFAR, oxaliplatin, fludarabine, cytarabine, and rituximab; UM, unmutated.

Only one patient developed a secondary cancer after starting treatment, a squamous cell cancer of the lungs, diagnosed 2 years after starting IR therapy. Patterns of change in other disease-associated parameters, absolute lymphocyte count (ALC), absolute neutrophil count, platelet count, and serum β2 microglobulin (β2M) levels, are shown in Supplementary Fig. S2. Serum immunoglobulin levels (IgG, IgM, IgA) and absolute T-cell subsets were analyzed and are summarized in the Supplementary Material (Supplementary Figs. S3 and S4). There was no significant change in serum immunoglobulin levels over time, consistent with the ibrutinib single-agent experience. The ALC levels decreased and stabilized, and T-cell subset numbers and β2M levels decreased after starting IR treatment and stabilized over time when followed for up to 36 months.

In the current analysis, we present the long-term follow-up data of patients with high-risk CLL treated with a combination of ibrutinib and rituximab (IR). The majority of patients (36/40) were previously treated. This study demonstrated that IR in high-risk patients with CLL is well tolerated, active, and can induce durable remissions, including CR in patients with high-risk CLL. The improvement in long-term PFS in high-risk patients with CLL with ibrutinib-based therapy is a significant advance in treatment of CLL. Recently, the 3-year follow-up of single-agent ibrutinib was reported (6) and demonstrated that responses improve over time in treatment-naïve and in relapsed-refractory patients with CLL. In our study, with an extended follow-up of over 3 years, we demonstrated that patients with high-risk CLL treated with the IR combination have high response rates, which also further improve over time when compared with the original report (7). Median PFS and OS achieved after 3 years in our study (45 months and not reached) appear similar to single-agent ibrutinib data in relapsed-refractory patients, although cross trial comparisons are problematic. Nonetheless, as our study involved only patients with CLL who had high-risk disease, the achievement of median PFS of 45 months in patients with high-risk CLL constitutes a major improvement over previously reported data in patients with high-risk CLL with more conventional treatments (9, 10). Of note, in patients with del17p, the long-term follow-up data when using first-line chemo-immunotherapy with the FCR regimen showed a median PFS of 15 months (11). The fact that 21 patients came off study (10 were due to disease progression) and 14 patients died (5 deaths due to CLL) emphasizes that, despite the major improvement in outcome with ibrutinib-based therapy in high-risk CLL, there remains an urgent need for further improvement in these patients, which may come from cellular therapy approaches (allogeneic SCT, CAR-T cell therapy) and/or BCL2 antagonist, such as venetoclax. Furthermore, this dataset reemphasizes that outcomes of patients with CLL after they progress or develop disease transformation on ibrutinib-based treatment generally are poor (median survival, 2.8 months; ref. 12). Interestingly, with longer follow-up, serum immunoglobulin and T-cell numbers remained stable with IR therapy.

In summary, our data show that the combination of ibrutinib with rituximab is a potent treatment option for patients with high-risk CLL and can induce durable remissions in a majority of patients. However, data from the ongoing randomized study of IR versus ibrutinib single agent (Clinical trial identifier, NCT02007044) are required to determine the benefit from the addition of rituximab to ibrutinib in the treatment of patients with CLL.

P.A. Thompson is a consultant/advisory board member for Pharmacyclics. Z. Estrov is a consultant/advisory board member for and reports receiving commercial research grants from Incyte. J. Burger is a consultant/advisory board member for Janssen and reports receiving commercial research grants from Gilead, GlaxoSmithKline, and Pharmacyclics. No potential conflicts of interest were disclosed by the other authors.

Conception and design: M.J. Keating, W.G. Wierda, H. Kantarjian, S. O'Brien, J.A. Burger

Development of methodology: H. Kantarjian, S. O'Brien, J.A. Burger

Acquisition and collection of data (provided and managed patients, provided facilities, etc.): P. Jain, M.J. Keating, W.G. Wierda, P.A. Thompson, A. Ferrajoli, Z. Estrov, S. O'Brien, J.A. Burger

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P. Jain, W.G. Wierda, Z. Estrov, H. Kantarjian, S. O'Brien, J.A. Burger

Writing, review, and/or revision of the manuscript: P. Jain, W.G. Wierda, M. Sivina, P.A. Thompson, A. Ferrajoli, H. Kantarjian, S. O'Brien, J.A. Burger

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P. Jain, W.G. Wierda, A. Ferrajoli, S. O'Brien

Study supervision: W.G. Wierda, M.J. Keating, S. O'Brien, J.A. Burger

Other (enlisted many patients): M.J. Keating

The authors thank the patients who participated in this trial and their families and the study investigators and coordinators at MD Anderson for sample and data collection.

This work was supported by Pharmacyclics, Inc., Leukemia & Lymphoma Society, NCI grant P30 CA016672, and MD Anderson's Moon Shot Programin CLL.

1.
Ponader
S
,
Burger
JA
. 
Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies
.
J Clin Oncol
2014
;
32
:
1830
9
.
2.
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
.
3.
O'Brien
S
,
Furman
RR
,
Coutre
SE
,
Sharman
JP
,
Burger
JA
,
Blum
KA
, et al
Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial
.
Lancet Oncol
2014
;
15
:
48
58
.
4.
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
.
5.
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
.
6.
Byrd
JC
,
Furman
RR
,
Coutre
SE
,
Flinn
IW
,
Burger
JA
,
Blum
KA
, et al
Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib
.
Blood
2015
;
125
:
2497
506
.
7.
Burger
JA
,
Keating
MJ
,
Wierda
WG
,
Hartmann
E
,
Hoellenriegel
J
,
Rosin
NY
, et al
Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study
.
Lancet Oncol
2014
;
15
:
1090
9
.
8.
Robak
T
. 
Ibrutinib in chronic lymphocytic leukaemia: alone or in combination?
Lancet Oncol
2016
;
17
:
129
31
.
9.
Dreger
P
,
Schetelig
J
,
Andersen
N
,
Corradini
P
,
van Gelder
M
,
Gribben
J
, et al
Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents?
Blood
2014
;
124
:
3841
9
.
10.
Stilgenbauer
S
. 
Prognostic markers and standard management of chronic lymphocytic leukemia
.
Hematology Am Soc Hematol Educ Program
2015
;
2015
:
368
377
.
11.
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
.
12.
Jain
P
,
Keating
M
,
Wierda
W
,
Estrov
Z
,
Ferrajoli
A
,
Jain
N
, et al
Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib
.
Blood
2015
;
125
:
2062
7
.