Key Points

Abstract

Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P = .03), deletion 17p (P = .03), and complex karyotype (P = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P < .0001), but not due to progressive CLL (P = .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P < .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; P = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.

Introduction

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton tyrosine kinase (BTK)1  approved to treat chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. Ibrutinib has rapidly changed the landscape of CLL treatment, with high response rates and prolonged remission durations in both relapsed/refractory CLL and previously untreated patients.2-5  Despite these strides, a subset of patients relapse on ibrutinib. Patients relapse primarily with progressive CLL or Richter transformation, an aggressive transformation into lymphoma, predominantly diffuse large B-cell lymphoma.6  Most patients progressing with CLL acquire mutations in either the C481 ibrutinib-binding pocket of BTK or downstream activating mutations in PLCG2 that bypass the need for signaling through BTK.7,8  However, identifiable resistance mutations are considerably less frequent in patients who progress via disease transformation.6  Identifying prognostic markers associated with Richter transformation is critical at this time as an increasing number of patients have begun to receive ibrutinib and those whose CLL transforms have very aggressive disease and poor prognosis.6,9  Complex karyotype (≥3 unrelated chromosomal abnormalities) has been associated with ibrutinib discontinuation due to progressive CLL or transformation.6,10  In addition, various biomarkers in CLL have been associated with risk of Richter transformation, including inactivation of TP53 or CDKN2A, CMYC abnormalities, NOTCH1 mutation, and CD38 expression.11-16  However, for patients receiving ibrutinib, there are currently no specific risk factors associated with developing Richter transformation.

Near-tetraploidy has been reported as a rare abnormality in various lymphomas, but to our knowledge, its incidence in CLL has not been examined.17,18  Tetraploidy in cancer cells may promote chromosome instability while buffering the cells from the deleterious effects.19  In this study, we examined the presence of near-tetraploidy and its association with discontinuation of ibrutinib for progression, including Richter transformation.

Methods

All patients provided written informed consent to participate in protocols approved by The Ohio State University Cancer Institutional Review Board in accordance with the Declaration of Helsinki. Patient population characteristics and the 4 ibrutinib clinical trials have been described previously.2,3,6,20,21  We retrospectively reviewed fluorescence in situ hybridization (FISH) results to identify near-tetraploid cases. Cytogenetic procedures were performed as previously described22  on peripheral blood or bone marrow collected prior to starting ibrutinib therapy. For each patient, 7 to 10 probes, plus controls, were analyzed (supplemental Table 1). Given our probe set, we defined near-tetraploidy as the presence of 4 or more probes with 4 signals and confirmed each positive case by the presence of at least 1 near-tetraploid cell by karyotype.

Cytogenetic results were available for 297 patients. Baseline variables were compared between patients with and without near-tetraploidy using the Fisher exact test or the Wilcoxon rank-sum test. Time to treatment discontinuation was measured from the date of first treatment until the off-study date. We censored 134 patients who remained on ibrutinib at the date of last contact, and 13 patients who went off study for transplant or went offsite. Cumulative incidence of ibrutinib discontinuation due to progression or histologic transformation was estimated, with discontinuation for other reasons treated as a competing risk. The Gray test was used to test for cumulative incidence differences between groups. Multivariable models were fit using Fine and Gray models.23  Variables considered for model inclusion were age, sex, number of prior therapies, baseline lactate dehydrogenase level, FISH abnormalities [del(17)(p13.1), del(11)(q22.3), trisomy 12, del(13)(q14), MYC gain, and BCL6 gain], complex karyotype, and IGHV mutational status. The multivariable model for transformation adjusted for monotherapy with ibrutinib vs combination therapy with ibrutinib and ofatumumab, regardless of statistical significance. Overall survival (OS) was measured from the date of first treatment with ibrutinib until the date of death, censoring those alive at last follow-up. OS estimates were calculated by the Kaplan-Meier method and differences between curves were tested with the log-rank test. All tests were 2-sided; statistical significance was declared at α = 0.05.

Results

A near-tetraploid clone (supplemental Tables 2-4) was identified in 9 of 297 patients analyzed (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Clinical and molecular characteristics for each of the 9 patients are described in Table 1. Near-tetraploidy was associated with the baseline characteristics Rai stage III/IV (P = .03), deletion 17p13 (P = .03), and complex karyotype (P = .01) (Table 2). With a median follow-up of 3.4 years, 133 patients (45%) remain on therapy, 12 (4%) received transplant or therapy elsewhere, 52 (18%) discontinued ibrutinib due to progressive CLL, 28 (9%) discontinued due to disease transformation, and 72 (24%) discontinued for other adverse events (supplemental Table 5). Among the 9 near-tetraploid patients, 6 have undergone Richter transformation, 1 had progressive CLL, and only 2 remain on treatment at 4.3 and 5.4 years. The estimated cumulative incidence of disease transformation is significantly higher in near-tetraploid patients vs those without near-tetraploidy (P < .0001; Figure 1A; supplemental Table 5), with an estimated cumulative incidence of disease transformation at 3 years of 66.7% (95% CI, 23.5-89.3) and 7.6% (95% CI, 4.8-11.1), respectively. Because all 9 near-tetraploid patients had a complex karyotype and complex karyotype has been associated with progression on ibrutinib,6  cumulative incidence curves are presented for near-tetraploidy and complex karyotype (Figure 1B). Patients with neither abnormality had a low incidence of ibrutinib discontinuation due to transformation. Patients with only complex karyotype had a significantly higher cumulative incidence compared with patients without either feature (P = .007). Patients with both features had a significantly higher cumulative incidence compared with those with only complex karyotype (P < .0001). The importance of these variables was supported by a multivariable model in which both near-tetraploidy (hazard ratio = 8.66; 95% CI, 3.83-19.59; P < .0001) and complex karyotype (hazard ratio = 4.77; 95% CI, 1.42-15.94; P = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Near-tetraploidy was not significantly associated with discontinuation due to progressive CLL (P = .41; supplemental Table 5). Near-tetraploidy showed a trend toward decreased OS (P = .08; Figure 1C; supplemental Table 5). Although the survival curve is lowest in patients who have both near-tetraploidy and complex karyotype and highest in patients with neither feature, the data were insufficient to claim that near-tetraploidy provided prognostic information for OS independent of complex karyotype (P = .40; Figure 1D). The small number of patients with near-tetraploidy and complex karyotype, as well as the presence of 18 patients whose CLL had transformed, and the majority of CLL progressions being in the complex-karyotype-alone subgroup likely contributed to this nonsignificant finding.

Table 1.

Clinical and molecular characteristics of near-tetraploid patients

CharacteristicsPatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9
Classification for discontinuation CLL Richter Richter Richter Richter Richter Richter — — 
Study p12024 p10032 p10032 p11133 p10053 p12024 p11133 p10053 p10053 
Ibrutinib monotherapy 
Age, y 60 76 60 69 73 53 52 79 64 
Sex 
Rai stage IV IV III IV IV IV IV IV IV 
LDH, U/L 214 375 142 211 765 308 198 356 227 
Elevated LDH 
No. of prior therapies 
Gain of BCL6 
Gain of MYC 
Trisomy 12 
del(13q) 
del(11q) 
del(17p) 
Complex karyotype 
IGHV UM UM UM UM Unknown Unknown UM UM UM 
Time to discontinuation or last contact, y 2.50 2.15 1.06 0.85 0.46 0.71 2.20 5.38 4.33 
Richter treatment — R + DXM OFAR R-EPOCH R-EPOCH Unknown Unknown — — 
OS, y 3.77 2.48 2.08 1.01 0.83 0.73 3.97 5.38 4.33 
Survival status 
CharacteristicsPatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9
Classification for discontinuation CLL Richter Richter Richter Richter Richter Richter — — 
Study p12024 p10032 p10032 p11133 p10053 p12024 p11133 p10053 p10053 
Ibrutinib monotherapy 
Age, y 60 76 60 69 73 53 52 79 64 
Sex 
Rai stage IV IV III IV IV IV IV IV IV 
LDH, U/L 214 375 142 211 765 308 198 356 227 
Elevated LDH 
No. of prior therapies 
Gain of BCL6 
Gain of MYC 
Trisomy 12 
del(13q) 
del(11q) 
del(17p) 
Complex karyotype 
IGHV UM UM UM UM Unknown Unknown UM UM UM 
Time to discontinuation or last contact, y 2.50 2.15 1.06 0.85 0.46 0.71 2.20 5.38 4.33 
Richter treatment — R + DXM OFAR R-EPOCH R-EPOCH Unknown Unknown — — 
OS, y 3.77 2.48 2.08 1.01 0.83 0.73 3.97 5.38 4.33 
Survival status 

—, Not applicable; A, alive; D, dead; del, deletion; F, female; LDH, lactate dehydrogenase; M, male; N, no; OFAR, oxaliplatin, fludarabine, cytarabine, and rituximab; R + DXM, rituximab and dexamethasone; R-EPOCH, rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; UM, unmutated; Y, yes.

Table 2.

Near-tetraploidy is associated with aggressive disease characteristics

CharacteristicTotal, n = 297Not tetraploid, n = 288Tetraploid, n = 9P
Study, no. (%)    .25 
 OSU-10032 48 (16) 46 (16) 2 (22) 
 OSU-10053 68 (23) 65 (23) 3 (33) 
 OSU-11133 145 (49) 143 (50) 2 (22) 
 OSU-12024 36 (12) 34 (12) 2 (22) 
Monotherapy with ibrutinib, no. (%) .43 
 No 68 (23) 66 (23) 3 (33) 
 Yes 229 (77) 223 (77) 6 (67) 
Age, y    .85 
 Median 65 65 64 
 Range 26-91 26-91 52-79 
Sex, no. (%)    .29 
 Male 211 (71) 206 (72) 5 (56) 
 Female 86 (29) 82 (28) 4 (44) 
Rai stage, no. (%)    .03 
 0/I/II 101 (34) 101 (35) 0 (0) 
 III/IV 196 (66) 187 (65) 9 (100) 
LDH, U/L    .19 
 Median 220 220 227 
 Range 96-1485 96-1485 142-765 
No. of prior therapies    .12 
 Median 
 Range 0-16 0-16 2-8 
Gain of BCL6, no. (%)    .15 
 No 274 (92) 267 (93) 7 (78) 
 Yes 23 (8) 21 (7) 2 (22) 
Gain of CMYC, no. (%)   .09 
 No 235 (79) 230 (80) 5 (56) 
 Yes 62 (21) 58 (20) 4 (44) 
Trisomy 12, no. (%)    .05 
 No 245 (82) 240 (83) 5 (56) 
 Yes 52 (18) 48 (17) 4 (44) 
Del(13q), no. (%)    .75 
 No 145 (49) 140 (49) 5 (56) 
 Yes 152 (51) 148 (51) 4 (44) 
Del(11q), no. (%)    1.00 
 No 214 (72) 207 (72) 7 (78) 
 Yes 83 (28) 81 (28) 2 (22) 
Del(17p), no. (%)    .03 
 No 177 (60) 175 (61) 2 (22) 
 Yes 120 (40) 113 (39) 7 (78) 
Complex karyotype, no. (%)    .01 
 No 119 (41) 119 (42) 0 (0) 
 Yes 172 (59) 163 (58) 9 (100) 
IGHV, no. (%)    .35 
 Mutated 53 (20) 53 (21) 0 (0) 
 Unmutated 212 (80) 205 (79) 7 (100) 
CharacteristicTotal, n = 297Not tetraploid, n = 288Tetraploid, n = 9P
Study, no. (%)    .25 
 OSU-10032 48 (16) 46 (16) 2 (22) 
 OSU-10053 68 (23) 65 (23) 3 (33) 
 OSU-11133 145 (49) 143 (50) 2 (22) 
 OSU-12024 36 (12) 34 (12) 2 (22) 
Monotherapy with ibrutinib, no. (%) .43 
 No 68 (23) 66 (23) 3 (33) 
 Yes 229 (77) 223 (77) 6 (67) 
Age, y    .85 
 Median 65 65 64 
 Range 26-91 26-91 52-79 
Sex, no. (%)    .29 
 Male 211 (71) 206 (72) 5 (56) 
 Female 86 (29) 82 (28) 4 (44) 
Rai stage, no. (%)    .03 
 0/I/II 101 (34) 101 (35) 0 (0) 
 III/IV 196 (66) 187 (65) 9 (100) 
LDH, U/L    .19 
 Median 220 220 227 
 Range 96-1485 96-1485 142-765 
No. of prior therapies    .12 
 Median 
 Range 0-16 0-16 2-8 
Gain of BCL6, no. (%)    .15 
 No 274 (92) 267 (93) 7 (78) 
 Yes 23 (8) 21 (7) 2 (22) 
Gain of CMYC, no. (%)   .09 
 No 235 (79) 230 (80) 5 (56) 
 Yes 62 (21) 58 (20) 4 (44) 
Trisomy 12, no. (%)    .05 
 No 245 (82) 240 (83) 5 (56) 
 Yes 52 (18) 48 (17) 4 (44) 
Del(13q), no. (%)    .75 
 No 145 (49) 140 (49) 5 (56) 
 Yes 152 (51) 148 (51) 4 (44) 
Del(11q), no. (%)    1.00 
 No 214 (72) 207 (72) 7 (78) 
 Yes 83 (28) 81 (28) 2 (22) 
Del(17p), no. (%)    .03 
 No 177 (60) 175 (61) 2 (22) 
 Yes 120 (40) 113 (39) 7 (78) 
Complex karyotype, no. (%)    .01 
 No 119 (41) 119 (42) 0 (0) 
 Yes 172 (59) 163 (58) 9 (100) 
IGHV, no. (%)    .35 
 Mutated 53 (20) 53 (21) 0 (0) 
 Unmutated 212 (80) 205 (79) 7 (100) 

Associations between near-tetraploidy and demographic, clinical, and molecular variables. Associations were tested using the Fisher exact for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Figure 1.

Near-tetraploidy is associated with Richter transformation on ibrutinib. (A) Cumulative incidence curves for transformation on ibrutinib with and without near-tetraploidy. (B) Cumulative incidence curves for transformation by near-tetraploidy and complex karyotype status. (C) Kaplan-Meier curves of OS for patients with or without near-tetraploidy. (D) Kaplan-Meier curves of OS by near-tetraploidy and complex karyotype status.

Figure 1.

Near-tetraploidy is associated with Richter transformation on ibrutinib. (A) Cumulative incidence curves for transformation on ibrutinib with and without near-tetraploidy. (B) Cumulative incidence curves for transformation by near-tetraploidy and complex karyotype status. (C) Kaplan-Meier curves of OS for patients with or without near-tetraploidy. (D) Kaplan-Meier curves of OS by near-tetraploidy and complex karyotype status.

Discussion

As a retrospective study, there are several limitations. The sampling time varied from days to months before beginning treatment. Because serial samples were unavailable for most patients, we were unable to determine whether the frequency of the near-tetraploid clones changed during treatment, or if gain of near-tetraploidy after starting treatment is associated with Richter transformation. We were also unable to assess whether the transformed lymphoma was clonally related to the preceding CLL. To address these questions, it would be useful to monitor patients serially for near-tetraploidy before and throughout treatment, as well as analyze lymph node tissue at the time of transformation. Interestingly, in 3 near-tetraploid patients with FISH results available near the time of transformation, the near-tetraploid clone was still present, whereas for the 2 patients who have not progressed, the near-tetraploid clone is no longer detectable.

Our study suggests that near-tetraploidy may be a prognostic marker for progression on ibrutinib through Richter transformation and provides rationale for further interrogation of this biomarker in CLL. It will be important to confirm the relationship with Richter transformation on ibrutinib in a second, independent cohort, as well as to examine the frequency and clinical associations of near-tetraploidy with transformation in other settings (eg, other therapies, at diagnosis, etc). Using FISH probes for regions prone to variation in CLL complicates the identification and quantification of near-tetraploidy, thus there is a need for further research to optimize detection. Near-tetraploid cells are typically unstable and this may serve as a mechanism for generating diverse subclones that could promote transformation in CLL. Future studies to interrogate downstream effects and identify the mechanisms driving near-tetraploidy in CLL are of considerable interest.

The full-text version of this article contains a data supplement.

Acknowledgments

This work was supported by the D. Warren Brown Foundation, Michael and Judy Thomas, the Four Winds Foundation, The Leukemia & Lymphoma Society, an American Society of Clinical Oncology Young Investigator Award, an American Society of Hematology Scholar Award, the National Institutes of Health, National Institute of General Medical Sciences (T32 GM068412), and National Cancer Institute (R01 CA197870, R01 CA183444, R01 CA177292, K23 CA178183, P50 CA140158, P01 CA095426, R35 CA197734, and R01 CA182905). Clinical trials were funded all or in part by Pharmacyclics.

Authorship

Contribution: C.R.M., A.S.R., J.A.W., and J.C.B. wrote the manuscript; C.R.M., A.S.R., N.A.H., K.J.M., J.L., H.B., G.L., J.S.B., K.A.R., F.T.A., W.Z., A.L.G., J.A.J., J.M.F., S.M.J., L.A.A., K.A.B., M.R.G., A.J.J., L.V.A., E.K.H., J.A.W., and J.C.B. collected and analyzed data, reviewed the paper, and approved the final version; and J.A.W. and J.C.B. supervised the study.

Conflict-of-interest disclosure: M.R.G. is a paid consultant for Pharmacyclics. The remaining authors declare no other competing financial interests.

Correspondence: John C. Byrd, The Ohio State University, 455B OSUCCC, 410 West 12th Ave, Columbus, OH 43210; e-mail: john.byrd@osumc.edu.

References

References
1.
Honigberg
LA
,
Smith
AM
,
Sirisawad
M
, et al
.
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy
.
Proc Natl Acad Sci USA
.
2010
;
107
(
29
):
13075
-
13080
.
2.
Byrd
JC
,
Furman
RR
,
Coutre
SE
, et al
.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia
.
N Engl J Med
.
2013
;
369
(
1
):
32
-
42
.
3.
Byrd
JC
,
Brown
JR
,
O’Brien
S
, et al
;
RESONATE Investigators
.
Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia
.
N Engl J Med
.
2014
;
371
(
3
):
213
-
223
.
4.
O’Brien
S
,
Furman
RR
,
Coutre
SE
, 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
(
1
):
48
-
58
.
5.
Byrd
JC
,
Furman
RR
,
Coutre
SE
, et al
.
Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib
.
Blood
.
2015
;
125
(
16
):
2497
-
2506
.
6.
Maddocks
KJ
,
Ruppert
AS
,
Lozanski
G
, et al
.
Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia
.
JAMA Oncol
.
2015
;
1
(
1
):
80
-
87
.
7.
Liu
TM
,
Woyach
JA
,
Zhong
Y
, et al
.
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
.
Blood
.
2015
;
126
(
1
):
61
-
68
.
8.
Woyach
JA
,
Furman
RR
,
Liu
TM
, et al
.
Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib
.
N Engl J Med
.
2014
;
370
(
24
):
2286
-
2294
.
9.
Jain
P
,
Keating
M
,
Wierda
W
, et al
.
Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib
.
Blood
.
2015
;
125
(
13
):
2062
-
2067
.
10.
Woyach
JA
,
Ruppert
AS
,
Guinn
D
, et al
.
BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia
.
J Clin Oncol
.
2017
;
35
(
13
):
1437
-
1443
.
11.
Jain
P
,
O’Brien
S
.
Richter’s transformation in chronic lymphocytic leukemia
.
Oncology (Williston Park)
.
2012
;
26
(
12
):
1146
-
1152
.
12.
Scandurra
M
,
Rossi
D
,
Deambrogi
C
, et al
.
Genomic profiling of Richter’s syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas
.
Hematol Oncol
.
2010
;
28
(
2
):
62
-
67
.
13.
Chigrinova
E
,
Rinaldi
A
,
Kwee
I
, et al
.
Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome
.
Blood
.
2013
;
122
(
15
):
2673
-
2682
.
14.
Rossi
D
,
Cerri
M
,
Capello
D
, et al
.
Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome
.
Br J Haematol
.
2008
;
142
(
2
):
202
-
215
.
15.
Rossi
D
,
Spina
V
,
Deambrogi
C
, et al
.
The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation
.
Blood
.
2011
;
117
(
12
):
3391
-
3401
.
16.
Fabbri
G
,
Khiabanian
H
,
Holmes
AB
, et al
.
Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome
.
J Exp Med
.
2013
;
210
(
11
):
2273
-
2288
.
17.
Ott
G
,
Kalla
J
,
Ott
MM
, et al
.
Blastoid variants of mantle cell lymphoma: frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones
.
Blood
.
1997
;
89
(
4
):
1421
-
1429
.
18.
Kaneko
Y
,
Rowley
JD
,
Variakojis
D
, et al
.
Prognostic implications of karyotype and morphology in patients with non-Hodgkin’s lymphoma
.
Int J Cancer
.
1983
;
32
(
6
):
683
-
692
.
19.
Storchova
Z
,
Kuffer
C
.
The consequences of tetraploidy and aneuploidy
.
J Cell Sci
.
2008
;
121
(
Pt 23
):
3859
-
3866
.
20.
Jaglowski
SM
,
Jones
JA
,
Flynn
JM
, et al
. A phase 1b/2 study evaluating activity and tolerability of the BTK inhibitor ibrutinib in combination with ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases [abstract].
J Clin Oncol
.
2014
;
32
(
suppl 15
). Abstract 7009.
21.
Maddocks
K
,
Flynn
J
,
Andritsos
L
, et al
.
A phase 2 study of the BTK inhibitor ibrutinib in genetic risk-stratified relapsed and refractory patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
[abstract].
Haematologica
.
2014
;
99
(
suppl 1
). Abstract 522.
22.
Muthusamy
N
,
Breidenbach
H
,
Andritsos
L
, et al
.
Enhanced detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide in combination with pokeweed mitogen and phorbol myristate acetate
.
Cancer Genet
.
2011
;
204
(
2
):
77
-
83
.
23.
Fine
JP
,
Gray
RJ
.
A proportional hazards model for the subdistribution of a competing risk
.
J Am Stat Assoc
.
1999
;
94
(
446
):
496
-
509
.

Author notes

*

C.R.M., A.S.R., and N.A.H. contributed equally to this work.

J.A.W. and J.C.B. contributed equally to this work.